Dynamic evolution of frontal-temporal network connectivity in temporal lobe epilepsy: A magnetoencephalography study.

Temporal lobe epilepsy (TLE) frequently involves an intricate, extensive epileptic frontal-temporal network. This study aimed to investigate the interactions between temporal and frontal regions and the dynamic patterns of the frontal-temporal network in TLE patients with different disease durations. The magnetoencephalography data of 36 postoperative seizure-free patients with long-term follow-up of at least 1 year, and 21 age- and sex-matched healthy subjects were included in this study. Patients were initially divided into LONG-TERM (n = 18, DURATION >10 years) and SHORT-TERM (n = 18, DURATION ≤10 years) groups based on 10-year disease duration. For reliability, supplementary analyses were conducted with alternative cutoffs, creating three groups: 0 < DURATION ≤7 years (n = 11), 7 < DURATION ≤14 years (n = 11), and DURATION >14 years (n = 14). This study examined the intraregional phase-amplitude coupling (PAC) between theta phase and alpha amplitude across the whole brain. The interregional directed phase transfer entropy (dPTE) between frontal and temporal regions in the alpha and theta bands, and the interregional cross-frequency directionality (CFD) between temporal and frontal regions from the theta phase to the alpha amplitude were further computed and compared among groups. Partial correlation analysis was conducted to investigate correlations between intraregional PAC, interregional dPTE connectivity, interregional CFD, and disease duration. Whole-brain intraregional PAC analyses revealed enhanced theta phase-alpha amplitude coupling within the ipsilateral temporal and frontal regions in TLE patients, and the ipsilateral temporal PAC was positively correlated with disease duration (r = 0.38, p <.05). Interregional dPTE analyses demonstrated a gradual increase in frontal-to-temporal connectivity within the alpha band, while the direction of theta-band connectivity reversed from frontal-to-temporal to temporal-to-frontal as the disease duration increased. Interregional CFD analyses revealed that the inhibitory effect of frontal regions on temporal regions gradually increased with prolonged disease duration (r = -0.36, p <.05). This study clarified the intrinsic reciprocal connectivity between temporal and frontal regions with TLE duration. We propose a dynamically reorganized triple-stage network that transitions from balanced networks to constrained networks and further develops into imbalanced networks as the disease duration increases.

The Effect of Mindfulness on Death Escape Acceptance in Young People: Emotion Regulation as a Mediator.

Few studies have examined young people's attitudes toward death escape acceptance and its relationship to mindfulness. This study addressed this issue and examined the mediating role of emotion regulation. In Study 1, 61 undergraduate students aged 19-22 years participated in a mindfulness intervention program, and the results showed that increasing young people's levels of mindfulness could improve their attitudes toward death escape acceptance. The Study 2, which recruited 440 young people aged 18-26 years to complete a cross-sectional survey, replicated the main effect and showed that young people's difficulty in emotion regulation fully mediated the coping effect of mindfulness. These findings suggest that individuals with high levels of mindfulness may have low levels of difficulty in emotion regulation and in turn promote healthy attitudes toward death escape acceptance.

Hartnup disease presenting as hereditary spastic paraplegia and severe peripheral neuropathy.

Hartnup disease cases were rare, and the genotype-phenotype correlation was not fully understood. Here we reported two unrelated young men diagnosed as Hartnup disease, who carried novel compound heterozygote mutations in the SLC6A19 gene and presented with new phenotypes. Other than intermittent encephalopathy and photosensitive rashes, they displayed symptoms and signs of spastic paraplegia and severe peripheral nerve damages. Magnetic resonance imaging showed mild bilateral cerebellar atrophy and thinning of the thoracic spinal cord. Electromyogram detected mixed sensorimotor polyneuropathy in lower limbs. Sural nerve biopsy and pathological study indicated the moderately reduced neural fibers in the periphery nerves. Urinary amino acid analysis showed increased levels of multiple neutral amino acids. Moreover, muscle strengths in the lower limbs and the walking ability have been improved in both cases (MRC 3/5 to 4/5 in Patient 1; walking distance elongated from 50 to 100 m in Patient 2) after the treatment with oral nicotinic acid and intravenous injection of multiple amino acids. Exome sequencing revealed and confirmed the existence of the novel compound heterozygous SLC6A19 mutations: c.533G>A (p.Arg178Gln) and c.1379-1G>C mutations in patient1, and c.1433delG (p.Gly478AlafsTer44) and c.811G>A (p.Ala271Thr) in patient 2. Taken together, these findings expanded the clinical, neuroimaging, pathology, and genetic spectrum of Hartnup disease. However, the co-existence of HSP and peripheral neuropathy was only inferred based on clinical observations, and pathological and molecular studies are needed to further dissect the underlying mechanisms.

Frontoparietal paired associative stimulation versus single-site stimulation for generalized anxiety disorder: a pilot rTMS study.

BACKGROUND: At present, the use of repetitive transcranial magnetic stimulation (rTMS) for generalized anxiety disorder (GAD) is limited to single-site interventions. We investigated whether dual-site frontoparietal stimulation delivered using cortical-cortical paired associative stimulation (ccPAS) had stronger clinical efficacy than single-site stimulation in patients with GAD. METHODS: We randomized 50 patients with GAD to 1 Hz rTMS (10 sessions) using 1 of the following protocols: single-site stimulation over the right dorsolateral prefrontal cortex (dlPFC; 1500 pulses per session); single-site stimulation over the right posterior parietal cortex (PPC; 1500 pulses per session); repetitive dual-site ccPAS (rds-ccPAS) over the right dlPFC and right PPC with 1500 pulses per session (rd-ccPAS-1500); or rds-ccPAS over the right dlPFC and right PPC with 750 pulses per session (rd-ccPAS-750). Both rds-ccPAS treatments used a between-site interval of 100 ms. RESULTS: Clinical scores for anxiety, depression and insomnia were reduced in all 4 groups after treatment. We found greater improvements in anxiety symptoms in the rds-ccPAS-1500 group compared to the rds-ccPAS-750 and single-site groups. We found greater improvements in depression symptoms and insomnia in the rds-PAS-1500 group compared to the single-site groups. The rds-ccPAS-1500 group also showed significant or trend-level improvements in anxiety symptoms and insomnia at 10-day and 1-month followup. More patients responded to treatment with rds-ccPAS-1500 than with single-site stimulation. The between-group differences in response rates persisted to the 3-month follow-up. Treatment using rds-ccPAS with a between-site interval of 100 ms induced a more significant improvement than the between-site interval of 50 ms we evaluated in a previous study. LIMITATIONS: These results need to be replicated in a larger sample using sham control and equal-pulse single-site stimulation. CONCLUSION: Frontoparietal rds-ccPAS may be a better treatment option for GAD.

Epilepsy centers in China: Current status and ways forward.

OBJECTIVE: China has the largest population of patients with epilepsy worldwide, which imposes a heavy burden on the public and health care systems. Several epidemiological surveys on epilepsy have been performed in China. Although these surveys grossly describe the prevalence and gap in treatment of epilepsy, the status of epilepsy centers is unclear. The number of epilepsy centers has increased substantially in recent decades. Therefore, a nationwide investigation of the scale and distribution, personnel, equipment, and epilepsy care capacity of each epilepsy center is of great value. METHODS: In 2017-2018, a multicenter cross-sectional survey was performed by the Commission on Standardized Development of Epilepsy Centers, China Association Against Epilepsy in 31 provinces, autonomous regions, and municipalities. The survey consisted of 74 questions divided into four sections: (1) overview, (2) personnel, (3) essential equipment and facilities, and (4) epilepsy care service capacity. The questions ranged from January 1, 2016 to December 31, 2016. The data were analyzed using descriptive statistics. RESULTS: There were 358 epilepsy centers for the 1.38 billion national population in 2016. Three quarters were in the eastern and western regions, and >90% were in tertiary hospitals. There were 9688 doctors engaged in epilepsy care, and 4.8% of doctors and electrophysiological physicians/technicians passed the national test for electroencephalography technical accreditation. A total of 9667 patients underwent resective surgeries in 2016. There were 888 vagus nerve stimulation procedures and 275 deep brain stimulation procedures. SIGNIFICANCE: This study is the first unique survey of epilepsy centers in China. Despite their rapid development, epilepsy centers cannot meet patients' needs at this stage. The results provide data-based evidence for the formulation of policies related to epilepsy service planning.

Neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 encephalitis.

OBJECTIVE: To evaluate the cognitive and neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. METHODS: A cohort follow-up study was performed after a median of 33 months (range 6-78) from disease onset to the last follow-up in patients diagnosed with anti-LGI1 encephalitis, to assess the neurofunctional outcomes using modified Rankin Scale (mRS), activities of daily living (ADL), neuropsychiatric inventory (NPI) and modified telephone interview for cognitive status (TICS-M). Remote symptomatic seizure and clinical relapses were also recorded. The clinical, laboratory features, and treatment responses that characterize the disability were analyzed. RESULTS: The results showed that 81 of 86 (94.2%) patients with anti-LGI1 encephalitis were successfully followed up, while eight (9.9%) died after discharge. Among the 73 survivors, clinical relapses occurred in 18 (24.7%) patients, and those with relapses were at a higher risk of developing remote symptomatic seizure (p = .019). Although 85.2% of the patients became functionally independent (mRS ≤2), the sequelae of symptomatic seizure, neuropsychiatric symptoms, and cognitive deficits were found in 11.0%, 21.9%, and 39.7% of the patients, respectively. Residual cognitive deficits primarily occurred in the elderly subjects as well as those with symptoms of memory deficit, psychiatric disorders, sleep disturbance, disturbance of consciousness at diagnosis, and higher CSF protein levels. CONCLUSIONS: Although most patients survived and became functionally independent, a subset of patients could not return to all premorbid activities. They may have clinical relapses or suffer from remote symptomatic seizure, neuropsychiatric symptoms, and cognitive impairment.

Value of 7T MRI and post-processing in patients with nonlesional 3T MRI undergoing epilepsy presurgical evaluation.

OBJECTIVE: Ultra-high-field 7-Tesla (7T) magnetic resonance imaging (MRI) offers increased signal-to-noise and contrast-to-noise ratios, which may improve visualization of cortical malformations. We aim to assess the clinical value of in vivo structural 7T MRI and its post-processing for the noninvasive identification of epileptic brain lesions in patients with pharmacoresistant epilepsy and nonlesional 3T MRI who are undergoing presurgical evaluation. METHODS: Sixty-seven patients were included who had nonlesional 3T MRI by official radiology report. Epilepsy protocols were used for the 3T and 7T acquisitions. Post-processing of the 7T T1-weighted magnetization-prepared two rapid acquisition gradient echoes sequence was performed using the morphometric analysis program (MAP) with comparison to a normal database consisting of 50 healthy controls. Review of 7T was performed by an experienced board-certified neuroradiologist and at the multimodal patient management conference. The clinical significance of 7T findings was assessed based on intracranial electroencephalography (ICEEG) ictal onset, surgery, postoperative seizure outcomes, and histopathology. RESULTS: Unaided visual review of 7T detected previously unappreciated subtle lesions in 22% (15/67). When aided by 7T MAP, the total yield increased to 43% (29/67). The location of the 7T-identified lesion was identical to or contained within the ICEEG ictal onset in 13 of 16 (81%). Complete resection of the 7T-identified lesion was associated with seizure freedom (P = .03). Histopathology of the 7T-identified lesions encountered mainly focal cortical dysplasia (FCD). 7T MAP yielded 25% more lesions (6/24) than 3T MAP, and showed improved conspicuity in 46% (11/24). SIGNIFICANCE: Our data suggest a major benefit of 7T with post-processing for detecting subtle FCD lesions for patients with pharmacoresistant epilepsy and nonlesional 3T MRI.

Quantitative positron emission tomography-guided magnetic resonance imaging postprocessing in magnetic resonance imaging-negative epilepsies.

OBJECTIVE: Detection of focal cortical dysplasia (FCD) is of paramount importance in epilepsy presurgical evaluation. Our study aims at utilizing quantitative positron emission tomography (QPET) analysis to complement magnetic resonance imaging (MRI) postprocessing by a morphometric analysis program (MAP) to facilitate automated identification of subtle FCD. METHODS: We retrospectively included a consecutive cohort of surgical patients who had a negative preoperative MRI by radiology report. MAP was performed on T1-weighted volumetric sequence and QPET was performed on PET/computed tomographic data, both with comparison to scanner-specific normal databases. Concordance between MAP and QPET was assessed at a lobar level, and the significance of concordant QPET-MAP+ abnormalities was confirmed by postresective seizure outcome and histopathology. QPET thresholds of standard deviations (SDs) of -1, -2, -3, and -4 were evaluated to identify the optimal threshold for QPET-MAP analysis. RESULTS: A total of 104 patients were included. When QPET thresholds of SD = -1, -2, and -3 were used, complete resection of the QPET-MAP+ region was significantly associated with seizure-free outcome when compared with the partial resection group (P = 0.023, P < 0.001, P = 0.006) or the no resection group (P = 0.002, P < 0.001, P = 0.001). The SD threshold of -2 showed the best combination of positive rate (55%), sensitivity (0.68), specificity (0.88), positive predictive value (0.88), and negative predictive value (0.69). Surgical pathology of the resected QPET-MAP+ areas revealed mainly FCD type I. Multiple QPET-MAP+ regions were present in 12% of the patients at SD = -2. SIGNIFICANCE: Our study demonstrates a practical and effective approach to combine quantitative analyses of functional (QPET) and structural (MAP) imaging data to improve identification of subtle epileptic abnormalities. This approach can be readily adopted by epilepsy centers to improve postresective seizure outcomes for patients without apparent lesions on MRI.

Deep Source Localization with Magnetoencephalography Based on Sensor Array Decomposition and Beamforming.

In recent years, the source localization technique of magnetoencephalography (MEG) has played a prominent role in cognitive neuroscience and in the diagnosis and treatment of neurological and psychological disorders. However, locating deep brain activities such as in the mesial temporal structures, especially in preoperative evaluation of epilepsy patients, may be more challenging. In this work we have proposed a modified beamforming approach for finding deep sources. First, an iterative spatiotemporal signal decomposition was employed for reconstructing the sensor arrays, which could characterize the intrinsic discriminant features for interpreting sensor signals. Next, a sensor covariance matrix was estimated under the new reconstructed space. Then, a well-known vector beamforming approach, which was a linearly constraint minimum variance (LCMV) approach, was applied to compute the solution for the inverse problem. It can be shown that the proposed source localization approach can give better localization accuracy than two other commonly-used beamforming methods (LCMV, MUSIC) in simulated MEG measurements generated with deep sources. Further, we applied the proposed approach to real MEG data recorded from ten patients with medically-refractory mesial temporal lobe epilepsy (mTLE) for finding epileptogenic zone(s), and there was a good agreement between those findings by the proposed approach and the clinical comprehensive results.

Comparative Analysis of Lennox-Gastaut Syndrome With Different Subtypes of Tonic Seizures: A Single-Center Retrospective Cohort Study.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is one of the most severe childhood-onset epileptic encephalopathies, primarily characterized by tonic seizures. In clinical practice, we have identified various subtypes of tonic seizures in LGS. This study aimed to analyze the clinical characteristics, electrographic features, treatment responses, and prognosis across different subtypes of LGS. METHODS: This retrospective cohort study included 46 patients diagnosed with LGS at our center between January 2017 and January 2020. Patients were classified into four groups based on tonic seizure subtypes: Group A (tonic), Group B (spasm-tonic), Group C (myoclonic-tonic), and Group D (combination of spasm-tonic and myoclonic-tonic). Comprehensive clinical data were collected and analyzed. RESULTS: Of the 46 patients, 33 were male. The mean age of onset for Group B (12.38 ± 7.85 months) was significantly less than those of the other three groups (P = 0.02). No significant differences in etiology were found among the groups. Genetic analysis identified mutations in SCN8A, MCCC2, STXBP1, GABRB3, and CACNA1H. After a minimum follow-up of 24 months, the treatment outcomes were more favorable in Groups A and C, whereas psychomotor development was notably poorer in Groups B and D. CONCLUSIONS: The findings of this study suggest that LGS may present with distinct subtypes of tonic seizures, with spasm-tonic seizures presenting at an earlier age. Patients with LGS experiencing spasm-tonic seizures, with or without myoclonic-tonic seizures, exhibited poorer treatment responses and psychomotor development than those with other subtypes.

GPRC5A is a potential prognostic biomarker and correlates with immune cell infiltration in non-small cell lung cancer.

Background: The tumor microenvironment (TME) plays an important role in tumor progression and immunotherapy responses in non-small cell lung cancer (NSCLC). The programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint is a central mediator of immunosuppression in the TME. However, there is still a need to identify additional biomarkers that could reflect the difference in TME and PD-L1 expression in NSCLC patients. To this end, we focused on the expression of G-protein-coupled receptor family C group 5 type A (GPRC5A) in NSCLC. GPRC5A, is a retinoic acid-inducible gene that plays multiple roles in NSCLC. However, little is known about the role of GPRC5A in regulating the TME and PD-L1. Our objective was to describe the critical role of GPRC5A expression in NSCLC in the setting of immune cell infiltration. Methods: We identified the relationship between GPRC5A expression and the clinicopathologic characteristics of NSCLC patients in the Fudan University Shanghai Cancer Center (FUSCC) cohort. Furthermore, we validated GPRC5A as a predictive biomarker by using public databases to reveal the relationship between GPRC5A expression and immune cell infiltration. To correlate the expression of GPRC5A with the spatial distribution of PD-L1 in NSCLC samples, we performed multiplex immunohistochemistry (mIHC). Results: Low GPRC5A expression is associated with earlier pathological stage (pStage). Analysis of immune cell infiltration indicates there is a relationship between low GPRC5A expression and increased infiltration of CD8+ T cells, activated CD4+ T cells, and M1 macrophages within the TME. Furthermore, low GPRC5A expression is associated with an increased immunophenotype score (IPS) in NSCLC. Additionally, analysis of mIHC reveals there is a correlation between low GPRC5A expression and spatial distribution of tumoral PD-L1 expression. Conclusions: Our study revealed the relationship between low expression of GPRC5A and earlier pStage in NSCLC. Furthermore, we observed that low expression of GPRC5A is associated with increased infiltration of immune cells, higher IPS, and spatial distribution of PD-L1-positive tumor cells. Therefore, we speculate that low expression of GPRC5A is associated with immunotherapy, but further validation is still required.

Multimodal non-invasive evaluation in MRI-negative epilepsy patients.

Presurgical evaluation is still challenging for MRI-negative epilepsy patients. As non-invasive modalities are the easiest acceptable and economic methods in determining the epileptogenic zone, we analyzed the localization value of common non-invasive methods in MRI-negative epilepsy patients. In this study, we included epilepsy patients undergoing presurgical evaluation with presurgical negative MRI. MRI post-processing was performed using a Morphometric Analysis Program (MAP) on T1-weighted volumetric MRI. The relationship between MAP, magnetoencephalography (MEG), scalp electroencephalogram (EEG), and seizure outcomes was analyzed to figure out the localization value of different non-invasive methods. Eighty-six patients were included in this study. Complete resection of the MAP-positive regions or the MEG-positive regions was positively associated with seizure freedom (p = 0.028 and 0.007, respectively). When an area is co-localized by MAP and MEG, the resection of the area was significantly associated with seizure freedom (p = 0.006). However, neither the EEG lateralization nor the EEG localization showed statistical association with the surgical outcome (p = 0.683 and 0.505, respectively). In conclusion, scalp EEG had a limited role in presurgical localization and predicting seizure outcome, combining MAP and MEG results can significantly improve the localization of epileptogenic lesions and have a positive association with seizure-free outcome. PLAIN LANGUAGE SUMMARY: Due to the lack of obvious structure abnormalities on neuroimaging examinations, the identification of epilepsy lesions in MRI-negative epilepsy patients can be difficult. In this study, we intended to use non-invasive examinations to explore the potential epileptic lesions in MRI-negative epilepsy patients and to determine the results accuracy by comparing the neuroimaging results with the epilepsy surgery outcomes. A total of 86 epilepsy patients without obvious structure lesions on MRI were included, and we found that the combinations of different non-invasive examinations and neuroimaging post-processing methods are significantly associated with the seizure freedom results of epilepsy surgery.

Application of HFO and scaling analysis of neuronal oscillations in the presurgical evaluation of focal epilepsy.

PURPOSE: To explore the utility of high frequency oscillations (HFO) and long-range temporal correlations (LRTCs) in preoperative assessment of epilepsy. METHODS: MEG ripples were detected in 59 drug-resistant epilepsy patients, comprising 5 with parietal lobe epilepsy (PLE), 21 with frontal lobe epilepsy (FLE), 14 with lateral temporal lobe epilepsy (LTLE), and 19 with mesial temporal lobe epilepsy (MTLE) to identify the epileptogenic zone (EZ). The results were compared with clinical MEG reports and resection area. Subsequently, LRTCs were quantified at the source-level by detrended fluctuation analysis (DFA) and life/waiting -time at 5 bands for 90 cerebral cortex regions. The brain regions with larger DFA exponents and standardized life-waiting biomarkers were compared with the resection results. RESULTS: Compared to MEG sensor-level data, ripple sources were more frequently localized within the resection area. Moreover, source-level analysis revealed a higher proportion of DFA exponents and life-waiting biomarkers with relatively higher rankings, primarily distributed within the resection area (p<0.01). Moreover, these two LRCT indices across five distinct frequency bands correlated with EZ. CONCLUSION: HFO and source-level LRTCs are correlated with EZ. Integrating HFO and LRTCs may be an effective approach for presurgical evaluation of epilepsy.

Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages.

Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Burden of epilepsy in China and its provinces, 1990 to 2019: findings from the Global Burden of Disease Study 2019.

BACKGROUND: Epilepsy accounts for a significant portion of the global disease burden. However, little is known about the disease burden of epilepsy in China and its provinces. METHODS: We assessed the burden of epilepsy in China and its provinces, municipalities, and autonomous regions from 1990 to 2019. Burden was measured as incidence, prevalence, deaths, years lived with disability, years of life lost, and disability-adjusted life years (DALYs), by age, sex, year, and province. We used the Socio-Demographic Index (SDI) to determine the association between the provincial development level and age-standardized DALY rates of epilepsy from 1990 to 2019. RESULTS: In 2019, epilepsy caused 1367.51 thousand (95% uncertainty interval [UI]: 979.92-1837.61 thousand) DALYs, and the age-standardized DALY rate was 99.77 (95% UI: 71.33-133.52)/100,000. The age-standardized incidence and prevalence rates for epilepsy in China were 24.65/100,000 and 219.69/100,000, increased by 45.00% (95% UI: 8.03-98.74%) and 35.72% (95% UI: 0.47-86.19%) compared with that in 1990, respectively. From 1990 to 2019, the proportion of DALY caused by epilepsy in the age group under 25 years steadily decreased. The proportion of DALYs caused by epilepsy in people aged 50 years and over increased from 9.45% and 10.22% in 1990 to 29.01% and 32.72% for male and female individuals in 2019, respectively. The highest age-standardized mortality rates were seen in Tibet (4.26 [95% UI: 1.43-5.66]/100,000), Qinghai (1.80 [95% UI: 1.15-2.36]/100,000), and Yunnan (1.30 [95% UI: 0.88-1.62]/100,000), and the lowest mortality rates were in Guangdong (0.48 [95% UI: 0.39-0.64]/100,000), Zhejiang (0.56 [95% UI: 0.44-0.70]/100,000), and Shanghai (0.57 [95% UI: 0.41-0.73]/100,000). The age-standardized DALY rates across the country and in provinces, municipalities, and autonomous regions generally decreased as their SDI increased. CONCLUSIONS: The disease burden of epilepsy is still heavy in China, especially in the western provinces. The incidence and prevalence of epilepsy increased between 1990 and 2019, and the burden of epilepsy in the elderly increases gradually. This study provides evidence on epilepsy prevention and care of different regions in China.

Prognostic value of tumor immune microenvironment factors in patients with stage I lung adenocarcinoma.

Survival is difficult to predict in patients with resected stage I lung adenocarcinoma (LUAD), but tumor microenvironment (TME) factors appear useful in predicting survival in advanced non-small cell lung cancer. We aimed to identify the TME factors linked to recurrence/metastasis and survival in stage I LUAD patients. We evaluated TME factors in stage I LUAD patients in The Cancer Genome Atlas (TCGA) using the "ESTIMATE" and "MCP-counter" R packages. We characterized infiltrating immune cells in the tumor and stromal regions in 44 stage I LUAD patients at our hospital using immunohistochemical methods combined with the HALO® Image Analysis Platform. In TCGA LUAD patients, the number of neutrophils was higher in patients without recurrence/metastasis than in patients with recurrence/metastasis. For patients with recurrence/metastasis, higher CD8+ T lymphocyte and B lymphocyte infiltration levels were associated with better overall survival (OS), and myeloid dendritic cell (DC) infiltration was associated with better disease-free survival (DFS). In stage I LUAD patients at our hospital, CD4+ T cells, CD8+ T cells, CD14+ monocytic lineage cells, CD16+ NK cells, and CD19+ B lymphocytes were more highly expressed in stromal regions than in tumor regions. Moreover, high intratumoral CD11c+ myeloid DC and CD68+ macrophage levels were associated with recurrence/metastasis. Within tumor regions, higher CD11c+ myeloid DC and CD68+ macrophage levels were associated with shorter DFS; within stromal regions, higher CD68+ macrophage levels were associated with shorter DFS. Multivariate analysis revealed that the presence of intravascular carcinoma embolus, higher intratumoral CD11c+ myeloid DC levels, and high stromal CD68+ macrophage and CD4+ T-cell levels were independently linked to recurrence/metastasis in stage I LUAD patients. This study using 2 datasets shows that key players in the TME are associated with recurrence/metastasis in stage I LUAD patients. Higher intratumoral CD11c+ myeloid DC, stromal CD68+ macrophage and stromal CD4+ T-cell levels are independent prognostic factors for DFS in these patients.

POU2F3: A Sensitive and Specific Diagnostic Marker for Neuroendocrine-low/negative Small Cell Lung Cancer.

POU2F3 (POU class 2 homeobox 3) is a novel transcription factor used to define the special molecular subtype of small cell lung cancer (SCLC) known as SCLC-P. Nevertheless, the sensitivity and specificity of POU2F3 immunohistochemical (IHC) staining have not been fully investigated. In this study, we explored the expression of POU2F3 by IHC in a large cohort of SCLC clinical samples (n=246), other common lung cancer types (n=2207), and various other cancer types (n=194). The results showed that POU2F3 was strongly nuclear stained in 13.41% (33/246) of SCLC cases, with negative or minimal labeling for thyroid transcription factor-1 and neuroendocrine (NE) markers. Compared with POU2F3-negative SCLC, SCLC-P harbored fewer TP53 and RB1 mutations. POU2F3 was also expressed in 3.13% (8/256) of squamous cell carcinomas (SCCs) and 20% (2/10) of large cell NE carcinomas (LCNECs), whereas other lung cancer types were negative. In addition to lung cancer, POU2F3 was positive in 22.2% (4/18) of thymic tumors. All other tumors were POU2F3-negative except for thymic carcinoma, although sparsely distributed weak nuclear staining was observed in lung adenocarcinoma, cervical SCC, and colorectal carcinoma. The sensitivity and specificity of POU2F3 in NE-low/negative SCLC were 82.1% and 99.4%, respectively. Notably, some rare unique patterns of POU2F3 expression were observed. One case of thymic SCC was characterized by diffuse and uniform cytomembrane staining. One case of esophageal NE tumor was nuclear-positive, while the normal proliferating squamous epithelium was strongly membrane-stained. This is the largest cohort of clinical samples to confirm that POU2F3 is a highly sensitive and specific diagnostic marker for NE-low/negative SCLC.

The association of magnetoencephalography high-frequency oscillations with epilepsy types and a ripple-based method with source-level connectivity for mapping epilepsy sources.

OBJECTIVE: To explore the association between high-frequency oscillations (HFOs) and epilepsy types and to improve the accuracy of source localization. METHODS: Magnetoencephalography (MEG) ripples of 63 drug-resistant epilepsy patients were detected. Ripple rates, distribution, spatial complexity, and the clustering coefficient of ripple channels were used for the preliminary classification of lateral temporal lobe epilepsy (LTLE), mesial temporal lobe epilepsy (MTLE), and nontemporal lobe epilepsy (NTLE), mainly frontal lobe epilepsy (FLE). Furthermore, the seizure site identification was improved using the Tucker LCMV method and source-level betweenness centrality. RESULTS: Ripple rates were significantly higher in MTLE than in LTLE and NTLE (p < 0.05). The LTLE and MTLE were mainly distributed in the temporal lobe, followed by the parietal lobe, occipital lobe, and frontal lobe, whereas MTLE ripples were mainly distributed in the frontal lobe, then parietal lobe and occipital lobe. Nevertheless, the NTLE ripples were primarily in the frontal lobe and partially in the occipital lobe (p < 0.05). Meanwhile, the spatial complexity of NTLE was significantly higher than that of LTLE and MTLE and was lowest in MTLE (p < 0.01). However, an opposite trend was observed for the standardized clustering coefficient compared with spatial complexity (p < 0.01). Finally, the tucker algorithm showed a higher percentage of ripples at the surgical site when the betweenness centrality was added (p < 0.01). CONCLUSION: This study demonstrated that HFO rates, distribution, spatial complexity, and clustering coefficient of ripple channels varied considerably among the three epilepsy types. Additionally, tucker MEG estimation combined with ripple rates based on the source-level functional connectivity is a promising approach for presurgical epilepsy evaluation.

Establishing chromosomal design-build-test-learn through a synthetic chromosome and its combinatorial reconfiguration.

Chromosome-level design-build-test-learn cycles (chrDBTLs) allow systematic combinatorial reconfiguration of chromosomes with ease. Here, we established chrDBTL with a redesigned synthetic Saccharomyces cerevisiae chromosome XV, synXV. We designed and built synXV to harbor strategically inserted features, modified elements, and synonymously recoded genes throughout the chromosome. Based on the recoded chromosome, we developed a method to enable chrDBTL: CRISPR-Cas9-mediated mitotic recombination with endoreduplication (CRIMiRE). CRIMiRE allowed the creation of customized wild-type/synthetic combinations, accelerating genotype-phenotype mapping and synthetic chromosome redesign. We also leveraged synXV as a "build-to-learn" model organism for translation studies by ribosome profiling. We conducted a locus-to-locus comparison of ribosome occupancy between synXV and the wild-type chromosome, providing insight into the effects of codon changes and redesigned features on translation dynamics in vivo. Overall, we established synXV as a versatile reconfigurable system that advances chrDBTL for understanding biological mechanisms and engineering strains.

A Prognostic Analysis of the Outcomes in Patients With Anti-γ-Aminobutyric Acid B Receptor Encephalitis.

Objective: To evaluate neurological function and its influencing factors in patients with anti-γ -aminobutyric acid B receptor (GABABR) encephalitis. Methods: This was a clinical cohort study of patients diagnosed with anti-GABABR encephalitis; long-term follow-up was performed by telephone. Clinical factors associated with prognosis were analyzed, including clinical manifestations, laboratory examinations, imaging features, tumor comorbidities and therapeutic responses. Results: Twenty-two patients with anti-GABABR encephalitis were evaluated (median age: 55 years). Lung cancer was detected in eight patients. All were with serum tumor markers (mainly NSE), and three of them had additional onconeuronal antibodies. The patients with tumors were older than the patients without tumors and more likely to develop status epilepticus (62.5% vs. 14.3%; p = 0.052), central hypoventilation (50% vs. 7.1%; p = 0.039), and hyponatremia (87.5% vs. 14.3%; p = 0.001). The patients with tumors had higher mortality (87.5% vs. 0%; p < 0.05). Although 92.9% of the patients without tumors became functionally independent (mRS ≤2), sequelae of symptomatic seizures, neuropsychiatric symptoms, and cognitive impairment were still observed in 14.3%, 21.4%, and 21.4% of patients, respectively. Conclusions: (1) Elderly patients with anti-GABABR antibodies, especially those with severe symptoms, serum tumor markers, and additional onconeuronal antibodies, should be screened for lung cancer. (2) Anti-GABABR encephalitis with tumors has a poor prognosis. (3) Most patients without tumors achieve self-care, but some still experience remaining neurological deficits.