Hemispheric epilepsy surgery for hemimegalencephaly: The UCLA experience.

OBJECTIVES: Hemimegalencephaly (HME) is a rare congenital brain malformation presenting predominantly with drug-resistant epilepsy. Hemispheric disconnective surgery is the mainstay of treatment; however, little is known about how postoperative outcomes compare across techniques. Thus we present the largest single-center cohort of patients with HME who underwent epilepsy surgery and characterize outcomes. METHODS: This observational study included patients with HME at University of California Los Angeles (UCLA) from 1984 to 2021. Patients were stratified by surgical intervention: anatomic hemispherectomy (AH), functional hemispherectomy (FH), or less-than-hemispheric resection (LTH). Seizure freedom, functional outcomes, and operative complications were compared across surgical approaches. Regression analysis identified clinical and intraoperative variables that predict seizure outcomes. RESULTS: Of 56 patients, 43 (77%) underwent FH, 8 (14%) underwent AH, 2 (4%) underwent LTH, 1 (2%) underwent unknown hemispherectomy type, and 2 (4%) were managed non-operatively. At median last follow-up of 55 months (interquartile range [IQR] 20-92 months), 24 patients (49%) were seizure-free, 17 (30%) required cerebrospinal fluid (CSF) shunting for hydrocephalus, 9 of 43 (21%) had severe developmental delay, 8 of 38 (21%) were non-verbal, and 15 of 38 (39%) were non-ambulatory. There was one (2%) intraoperative mortality due to exsanguination earlier in this cohort. Of 12 patients (29%) requiring revision surgery, 6 (50%) were seizure-free postoperatively. AH, compared to FH, was not associated with statistically significant improved seizure freedom (hazard ratio [HR] = .48, p = .328), although initial AH trended toward greater odds of seizure freedom (75% vs 46%, p = .272). Younger age at seizure onset (HR = .29, p = .029), lack of epilepsia partialis continua (EPC) (HR = .30, p = .022), and no contralateral seizures on electroencephalography (EEG) (HR = .33, p = .039) independently predicted longer duration of seizure freedom. SIGNIFICANCE: This study helps inform physicians and parents of children who are undergoing surgery for HME by demonstrating that earlier age at seizure onset, absence of EPC, and no contralateral EEG seizures were associated with longer postoperative seizure freedom. At our center, initial AH for HME may provide greater odds of seizure freedom with complications and functional outcomes comparable to those of FH.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

An intramolecular charge transfer based fluorescent probe for imaging of OCl.

The discovery and utilization of new fluorescent chromophore is indispensable to exploit high performance probes for biological research. Stokes shift is one of the most important properties of chromophore accounting for super-resolution fluorescence imaging. Intramolecular charge transfer (ICT) is one of the fundamental mechanisms for fluorescence that accompanied by large Stokes shifts. Based on the conformational changes between ground and excited states, ICT models can be divided into two types: conformation-steady ICT, whose conformation remains unchanged, and conformation-changeable ICT, which is characterized by the rotation of the chromophore around an axis upon excitation. Herein, we report a new chromophore whose donor and acceptor parts took a butterfly geometry with a dihedral angle of 21° in ground state and a planar conformation upon photo excitation. The bent conformation might be ascribed to the extra conjugated double bond, which made the coplanarity of the chromophore in ground state get worse. The chromophore shows a remarkable Stokes shift over 150 nm and a high fluorescence quantum yieldof 0.62. The limit of detection is 41 nM, which enabled the imaging of basal as well as induced OCl- in different cells. Moreover, the pronounced spectroscopic properties ensure the in vivo monitoring of OCl- in arthritic mice. This finding would shed light on the exploitation of small molecule probes based on new fluorescence chromophore for precise biological imaging.

miRNA-mediated loss of m6A increases nascent translation in glioblastoma.

Within the glioblastoma cellular niche, glioma stem cells (GSCs) can give rise to differentiated glioma cells (DGCs) and, when necessary, DGCs can reciprocally give rise to GSCs to maintain the cellular equilibrium necessary for optimal tumor growth. Here, using ribosome profiling, transcriptome and m6A RNA sequencing, we show that GSCs from patients with different subtypes of glioblastoma share a set of transcripts, which exhibit a pattern of m6A loss and increased protein translation during differentiation. The target sequences of a group of miRNAs overlap the canonical RRACH m6A motifs of these transcripts, many of which confer a survival advantage in glioblastoma. Ectopic expression of the RRACH-binding miR-145 induces loss of m6A, formation of FTO/AGO1/ILF3/miR-145 complexes on a clinically relevant tumor suppressor gene (CLIP3) and significant increase in its nascent translation. Inhibition of miR-145 maintains RRACH m6A levels of CLIP3 and inhibits its nascent translation. This study highlights a critical role of miRNAs in assembling complexes for m6A demethylation and induction of protein translation during GSC state transition.

Concussions in ice hockey: mixed methods study including assessment of concussions on games missed and cap hit among National Hockey League players, systematic review, and concussion protocol analysis.

OBJECTIVE: Concussions can occur at any level of ice hockey. Incidence estimates of concussions in ice hockey vary, and optimal prevention strategies and return-to-play (RTP) considerations have remained in evolution. The authors performed a mixed-methods study with the aim of elucidating the landscape of concussion in ice hockey and catalyzing initiatives to standardize preventative mechanisms and RTP considerations. METHODS: The authors performed a five-part mixed-methods study that includes: 1) an analysis of the impact of concussions on games missed and income for National Hockey League (NHL) players using a publicly available database, 2) a systematic review of the incidence of concussion in ice hockey, 3) a systematic review of preventative strategies, 4) a systematic review of RTP, and 5) a policy review of documents from major governing bodies related to concussions in sports with a focus on ice hockey. The PubMed, Embase, and Scopus databases were used for the systematic reviews and focused on any level of hockey. RESULTS: In the NHL, 689 players had 1054 concussions from the 2000-2001 to 2022-2023 seasons. A concussion led to a mean of 13.77 ± 19.23 (range 1-82) games missed during the same season. After cap hit per game data became available in 2008-2009, players missed 10,024 games due to 668 concussions (mean 15.13 ± 3.81 per concussion, range 8.81-22.60 per concussion), with a cap hit per game missed of $35,880.85 ± $25,010.48 (range $5792.68-$134,146.30). The total cap hit of all missed games was $385,960,790.00, equating to $577,635.91 per concussion and $25,724,052.70 per NHL season. On systematic review, the incidence of concussions was 0.54-1.18 per 1000 athlete-exposures. Prevention mechanisms involved education, behavioral and cognitive interventions, protective equipment, biomechanical studies, and policy/rule changes. Rules prohibiting body checking in youth players were most effective. Determination of RTP was variable. Concussion protocols from both North American governing bodies and two leagues mandated that a player suspected of having a concussion be removed from play and undergo a six-step RTP strategy. The 6th International Conference on Concussion in Sport recommended the use of mouthguards for children and adolescents and disallowing body checking for all children and most levels of adolescents. CONCLUSIONS: Concussions in ice hockey lead to substantial missed time from play. The authors strongly encourage all hockey leagues to adopt and adhere to age-appropriate rules to limit hits to the head, increase compliance in wearing protective equipment, and utilize high-quality concussion protocols.

Presurgical MRI-Based Radiomics Models for Predicting Cerebellar Mutism Syndrome in Children With Posterior Fossa Tumors.

BACKGROUND: Current studies have indicated that tumoral morphologic features are associated with cerebellar mutism syndrome (CMS), but the radiomics application in CMS is scarce. PURPOSE: To develop a model for CMS discrimination based on multiparametric MRI radiomics in patients with posterior fossa tumors. STUDY TYPE: Retrospective. POPULATION: A total of 218 patients (males 132, females 86) with posterior fossa tumors, 169 of which were included in the MRI radiomics analysis. The MRI radiomics study cohort (169) was split into training (119) and testing (50) sets with a ratio of 7:3. FIELD/SEQUENCE: All the MRI were acquired under 1.5/3.0 T scanners. T2-weighted image (T2W), T1-weighted (T1W), fluid attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI). ASSESSMENT: Apparent diffusion coefficient (ADC) maps were generated from DWI. Each MRI dataset generated 1561 radiomics characteristics. Feature selection was performed with univariable logistic analysis, correlation analysis, and least absolute shrinkage and selection operator (LASSO) penalized logistic regression. Significant clinical features were selected with multivariable logistic analysis and used to constructed the clinical model. Radiomics models (based on T1W, T2W, FLAIR, DWI, ADC) were constructed with selected radiomics features. The mix model was based on the multiparametric MRI radiomics features. STATISTICAL TEST: Multivariable logistic analysis was utilized during clinical features selection. Models' performance was evaluated using the area under the receiver operating characteristic (AUC) curve. Interobserver variability was assessed using Cohen's kappa. Significant threshold was set as P < 0.05. RESULTS: Sex (aOR = 3.72), tumor location (aOR = 2.81), hydrocephalus (aOR = 2.14), and tumor texture (aOR = 5.08) were significant features in the multivariable analysis and were used to construct the clinical model (AUC = 0.79); totally, 33 radiomics features were selected to construct radiomics models (AUC = 0.63-0.93). Seven of the 33 radiomics features were selected for the mix model (AUC = 0.93). DATA CONCLUSION: Multiparametric MRI radiomics may be better at predicting CMS than single-parameter MRI models and clinical model. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: 2.

Male Predisposition in Cerebellar Mutism Syndrome: a Cohort Study.

The aim of this study was to explore the association between sex and cerebellar mutism syndrome and to examine other potential risk factors. This ambispective cohort study examined 218 pediatric patients (132 boys) with a posterior fossa tumor who underwent tumor resection from July 2013 to March 2021. The patients' demographics and tumor characteristics were examined and statistically analyzed to explore the associations among the variables. Multivariable and subgroup analyses were conducted to validate the independent risk factors for cerebellar mutism syndrome (CMS). The male and female patients did not differ significantly in terms of age, tumor size, tumor location, tumor consistency, VP shunt placement before resection, extent of resection, or surgeon, as well as with respect to the presence of hydrocephalus or paraventricular edema. The overall incidence of CMS was 32.6%. The incidence of CMS was significantly higher in male patients than that in female patients (41.7% vs. 18.6%; P = 0.001). In the multivariable analysis, male sex (adjusted odds ratio [OR], 3.27; P = 0.001), solid tumor consistency (adjusted OR, 5.61; P = 0.001), midline location (adjusted OR, 3.78; P = 0.004), and hydrocephalus (adjusted OR, 2.56; P = 0.047) were independent risk factors for the CMS. Chi-square analysis revealed that solid tumor consistency and midline location were associated with medulloblastoma (P < 0.001). Male patients had a higher risk of developing CMS after a posterior fossa tumor resection. Midline location, solid tumor consistency, and hydrocephalus were independent risk factors for CMS.

Clinical utility of intraoperative electrocorticography for epilepsy surgery: A systematic review and meta-analysis.

Despite the widespread use of intraoperative electrocorticography (iECoG) during resective epilepsy surgery, there are conflicting data on its overall efficacy and inability to predict benefit per pathology. Given the heterogeneity of iECoG use in resective epilepsy surgery, it is important to assess the utility of interictal-based iECoG. This individual patient data (IPD) meta-analysis seeks to identify the benefit of iECoG during resective epilepsy surgery in achieving seizure freedom for various pathologies. Embase, Scopus, and PubMed were searched from inception to January 31, 2021 using the following terms: "ecog", "electrocorticography", and "epilepsy". Articles were included if they reported seizure freedom at ≥12-month follow-up in cohorts with and without iECoG for epilepsy surgery. Non-English articles, noncomparative iECoG cohorts, and studies with <10% iECoG use were excluded. This meta-analysis followed the PRISMA 2020 guidelines. The primary outcome was seizure freedom at last follow-up and time to seizure recurrence, if applicable. Forest plots with random effects modeling assessed the relationship between iECoG use and seizure freedom. Cox regression of IPD was performed to identify predictors of longer duration of seizure freedom. Kaplan-Meier curves with log-rank test were created to visualize differences in time to seizure recurrence. Of 7504 articles identified, 18 were included for study-level analysis. iECoG was not associated with higher seizure freedom at the study level (relative risk = 1.09, 95% confidence interval [CI] = 0.96-1.23, p = .19, I2  = 64%), but on IPD (n = 7 studies, 231 patients) iECoG use was independently associated with more favorable seizure outcomes (hazard ratio = 0.47, 95% CI = .23-.95, p = .037). In Kaplan-Meier analysis of specific pathologies, iECoG use was significantly associated with longer seizure freedom only for focal cortical dysplasia (FCD; p < .001) etiology. Number needed to treat for iECoG was 8.8, and for iECoG in FCD it was 4.7. We show iECoG seizure freedom is not achieved uniformly across centers. iECoG is particularly beneficial for FCD etiology in improving seizure freedom.

Magnetic resonance-guided laser interstitial thermal therapy for drug-resistant epilepsy: A systematic review and individual participant data meta-analysis.

Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has emerged as a popular minimally invasive alternative to open resective surgery for drug-resistant epilepsy (DRE). We sought to perform a systematic review and individual participant data meta-analysis to identify independent predictors of seizure outcome and complications following MRgLITT for DRE. Eleven databases were searched from January 1, 2010 to February 6, 2021 using the terms "MR-guided ablation therapy" and "epilepsy". Multivariable mixed-effects Cox and logistic regression identified predictors of time to seizure recurrence, seizure freedom, operative complications, and postoperative neurological deficits. From 8705 citations, 46 studies reporting on 450 MRgLITT DRE patients (mean age = 29.5 ± 18.1 years, 49.6% female) were included. Median postoperative seizure freedom and follow-up duration were 15.5 and 19.0 months, respectively. Overall, 240 (57.8%) of 415 patients (excluding palliative corpus callosotomy) were seizure-free at last follow-up. Generalized seizure semiology (hazard ratio [HR] = 1.78, p = .020) and nonlesional magnetic resonance imaging (MRI) findings (HR = 1.50, p = .032) independently predicted shorter time to seizure recurrence. Cerebral cavernous malformation (CCM; odds ratio [OR] = 7.97, p < .001) and mesial temporal sclerosis/atrophy (MTS/A; OR = 2.21, p = .011) were independently associated with greater odds of seizure freedom at last follow-up. Operative complications occurred in 28 (8.5%) of 330 patients and were independently associated with extratemporal ablations (OR = 5.40, p = .012) and nonlesional MRI studies (OR = 3.25, p = .017). Postoperative neurological deficits were observed in 53 (15.1%) of 352 patients and were independently predicted by hypothalamic hamartoma etiology (OR = 5.93, p = .006) and invasive electroencephalographic monitoring (OR = 4.83, p = .003). Overall, MRgLITT is particularly effective in treating patients with well-circumscribed lesional DRE, such as CCM and MTS/A, but less effective in nonlesional cases or lesional cases with a more diffuse epileptogenic network associated with generalized seizures. This study identifies independent predictors of seizure freedom and complications following MRgLITT that may help further guide patient selection.

Fangchinoline derivatives inhibits PI3K signaling in vitro and in vivo in non-small cell lung cancer.

Fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S., which is a bis-benzyl isoquinoline alkaloids with anti-tumor activity. Therefore, 25 novel Fan derivatives have been synthesized and evaluated for their anti-cancer activity. In CCK-8 assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on six tumor cell lines than the parental compound. Compared to the parent Fan, compound 2h presented the anticancer activity against most cancer cells, especially A549 cells, with an IC50 value of 0.26 µM, which was 36.38-fold, and 10.61-fold more active than Fan and HCPT, respectively. Encouragingly, compound 2h showed low biotoxicity to the human normal epithelial cell BEAS-2b with an IC50 value of 27.05 µM. The results indicated compound 2h remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 2h could also induce A549 cell apoptosis by promoting endogenous pathways of mitochondrial regulation. In nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 2h in a dose-dependent manner, and it was found that compound 2h could inhibit the mTOR/PI3K/AKT pathway in vivo. In docking analysis, high affinity interaction between 2h and PI3K was responsible for drastic kinase inhibition by the compound. To conclude, this derivative compound may be useful as a potent anti-cancer agent for treatment of NSCLC.

Health disparities attributed to Medicare-Medicaid dual-eligible status in patients with peripheral arterial disease.

OBJECTIVE: Peripheral arterial disease (PAD) is a prevalent and debilitating disease that can be effectively treated by surgical revascularization. However, Medicare-Medicaid dual-eligible patients have experienced worse long-term outcomes, notably higher rates of amputation and mortality, relative to other insurance groups. In the present study, we investigated how insurance status can perpetuate health disparities in PAD outcomes. METHODS: The National Inpatient Sample was queried from 2000 to 2011 for patients aged ≥18 years with PAD who had undergone surgical revascularization with hospitalization. Patients were stratified by insurance status, and dual-eligible patients were compared with Medicare-only, Medicaid-only, private insurance, and self-pay patients. Multivariable regression analysis was performed to assess the effect of dual-eligible status on postoperative outcomes such as inpatient mortality, complications, and favorable discharge (home or home with services). RESULTS: A total of 771,790 hospitalizations were included in the present analysis and stratified by insurance type. Dual-eligible patients had the highest rates of major (32%) and extreme (11%) severity of illness and the highest rates of major (19%) and extreme (6%) risk of mortality among all insurance groups (P < .001). Dual-eligibility status was independently associated with reduced odds of favorable discharge relative to all patients (P < .001) and increased length of stay relative to Medicare-only (P = .002) and private-payor groups (P < .001). Although dual-eligible patients had increased mortality odds relative to the Medicaid-only and self-pay groups, they did not have significantly different odds of perioperative complications relative to all other insurance groups. CONCLUSIONS: Medicare-Medicaid dual-eligible patients with PAD had had more severe clinical presentations, a greater risk of extended hospitalizations, and a lower likelihood of discharge to home, relative to patients without dual eligibility. Further studies are needed to examine the link between discharge disposition and disparities in healthcare outcomes and to investigate the interventions that effectively address the increased severity of PAD in dual-eligible patients.

The effect of levetiracetam treatment on survival in patients with glioblastoma: a systematic review and meta-analysis.

BACKGROUND: Levetiracetam (LEV) is an anti-epileptic drug (AED) that sensitizes glioblastoma (GBM) to temozolomide (TMZ) chemotherapy by inhibiting O6-methylguanine-DNA methyltransferase (MGMT) expression. Adding LEV to the standard of care (SOC) for GBM may improve TMZ efficacy. This study aimed to pool the existing evidence in the literature to quantify LEV's effect on GBM survival and characterize its safety profile to determine whether incorporating LEV into the SOC is warranted. METHOD: A search of CINAHL, Embase, PubMed, and Web of Science from inception to May 2021 was performed to identify relevant articles. Hazard ratios (HR), median overall survival, and adverse events were pooled using random-effect models. Meta-regression, funnel plots, and the Newcastle-Ottawa Scale were utilized to identify sources of heterogeneity, bias, and statistical influence. RESULTS: From 20 included studies, 5804 GBM patients underwent meta-analysis, of which 1923 (33%) were treated with LEV. Administration of LEV did not significantly improve survival in the entire patient population (HR 0.89, p = 0.094). Significant heterogeneity was observed during pooling of HRs (I2 = 75%, p < 0.01). Meta-regression determined that LEV treatment effect decreased with greater rates of MGMT methylation (RC = 0.03, p = 0.02) and increased with greater proportions of female patients (RC = - 0.05, p = 0.002). Concurrent LEV with the SOC for GBM did not increase odds of adverse events relative to other AEDs. CONCLUSIONS: Levetiracetam treatment may not be effective for all GBM patients. Instead, LEV may be better suited for treating specific molecular profiles of GBM. Further studies are necessary to identify optimal GBM candidates for LEV.

Synthesis and bioactivity evaluation of novel nuciferine derivatives with antihyperuricemia and nephroprotective effects.

Hyperuricemia is a common metabolic disease with a series of complications. Nuciferine, a typical aporphine alkaloid natural compound extracted from the leaves of Nelumbo nucifera Gaertn., was confirmed to have an antihyperuricemia effect. In the present study, 30 novel nuciferine derivatives were designed and synthesized. The effects of all derivatives on the regulation of URAT1 were studied in a uric acid-induced HK-2 cell model with benzbromarone as a positive control. The results indicated that Compound 1j showed the optimal URAT1 inhibitory activity through repressing PI3K/Akt pathway in HK-2 cells and the inhibitory effect was similar to that of benzbromarone. In addition, in vivo experiments demonstrated that Compound 1j could reduce uric acid levels and ameliorate kidney damage in hyperuricemic mice. On the one hand, Compound 1j could inhibit the expression of URAT1 and GLUT9 to increase the uric acid excretion index. On the other hand, Compound 1j could regulate the TLR4/IκBα/NF-κB signaling pathway to reduce the levels of inflammatory cytokines, thereby alleviating kidney damage. Meanwhile, a molecular docking assay revealed the potential molecular binding power (-9.79 kcal/mol) between Compound 1j and URAT1, which was more tightly bound than the lead compound nuciferine (-7.44 kcal/mol). Based on these results, Compound 1j may be a future drug for the development of new potential antihyperuricemia and nephroprotective drug candidates.

Sex differences in the developing brain impact stress-induced epileptogenicity following hyperthermia-induced seizures.

Febrile seizures (FS) are common, affecting 2-5% of children between the ages of 3 months and 6 years. Complex FS occur in 10% of patients with FS and are strongly associated with mesial temporal lobe epilepsy. Current research suggests that predisposing factors, such as genetic and anatomic abnormalities, may be necessary for complex FS to translate to mesial temporal lobe epilepsy. Sex hormones are known to influence seizure susceptibility and epileptogenesis, but whether sex-specific effects of early life stress play a role in epileptogenesis is unclear. Here, we investigate sex differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis following chronic stress and the underlying contributions of gonadal hormones to the susceptibility of hyperthermia-induced seizures (HS) in rat pups. Chronic stress consisted of daily injections of 40 mg/kg of corticosterone (CORT) subcutaneously from postnatal day (P) 1 to P9 in male and female rat pups followed by HS at P10. Body mass, plasma CORT levels, temperature threshold to HS, seizure characteristics, and electroencephalographic in vivo recordings were compared between CORT- and vehicle (VEH)-injected littermates during and after HS at P10. In juvenile rats (P18-P22), in vitro CA1 pyramidal cell recordings were recorded in males to investigate excitatory and inhibitory neuronal circuits. Results show that daily CORT injections increased basal plasma CORT levels before HS and significantly reduced weight gain and body temperature threshold of HS in both males and females. CORT also significantly lowered the generalized convulsions (GC) latency while increasing recovery time and the number of electrographic seizures (>10s), which had longer duration. Furthermore, sex-specific differences were found in response to chronic CORT injections. Compared to females, male pups had increased basal plasma CORT levels after HS, longer recovery time and a higher number of electrographic seizures (>10s), which also had longer duration. Sex-specific differences were also found at baseline conditions with lower latency to generalized convulsions and longer duration of electrographic seizures in males but not in females. In juvenile male rats, the amplitude of evoked excitatory postsynaptic potentials, as well as the amplitude of inhibitory postsynaptic currents, were significantly greater in CORT rats when compared to VEH littermates. These findings not only validate CORT injections as a stress model, but also show a sex difference in baseline conditions as well as a response to chronic CORT and an impact on seizure susceptibility, supporting a potential link between sustained early-life stress and complex FS. Overall, these effects also indicate a putatively less severe phenotype in female than male pups. Ultimately, studies investigating the biological underpinnings of sex differences as a determining factor in mental and neurologic problems are necessary to develop better diagnostic, preventative, and therapeutic approaches for all patients regardless of their sex.

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

OBJECTIVE: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.

Design, synthesis and bioactive evaluation of geniposide derivatives for antihyperuricemic and nephroprotective effects.

Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC50 value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage.

Design, synthesis and in vitro anticancer research of novel tetrandrine and fangchinoline derivatives.

Cancer treatment is one of the major public health issues in the world. Tetrandrine (Tet) and fangchinoline (d-Tet) are two bis-benzyl isoquinoline alkaloids extracted from Stephania tetrandra S. Moore, and their antitumor activities have been confirmed. However, the effective dose of Tet and d-Tet were much higher than that of the positive control and failed to meet clinical standards. Therefore, in this study, as a continuation of our previous work to study and develop high-efficiency and low-toxic anti-tumor lead compounds, twenty new Tet and d-Tet derivatives were designed, synthesized and evaluated as antitumor agents against six cancer cell lines (H460, H520, HeLa, HepG-2, MCF-7, SW480 cell lines) and BEAS-2B normal cells by CCK-8 analysis. Ten derivatives showed better cytotoxic effects than the parent fangchinoline, of which 4g showed the strongest cell growth inhibitory activity with an IC50 value of 0.59 µM against A549 cells. Subsequently, the antitumor mechanism of 4g was studied by flow cytometry, Hoechst 33258, JC-1 staining, cell scratch, transwell migration, and Western blotting assays. These results showed that compound 4g could inhibit A549 cell proliferation by arresting the G2/M cell cycle and inhibiting cell migration and invasion by reducing MMP-2 and MMP-9 expression. Meanwhile, 4g could induce apoptosis of A549 cells through the intrinsic pathway regulated by mitochondria. In addition, compound 4g inhibited the phosphorylation of PI3K, Akt and mTOR, suggesting a correlation between blocking the PI3K/Akt/mTOR pathway and the above antitumor activities. These results suggest that compound 4g may be a future drug for the development of new potential drug candidates against lung cancer.

Dynamic Color Assignment for Hierarchical Data.

Assigning discriminable and harmonic colors to samples according to their class labels and spatial distribution can generate attractive visualizations and facilitate data exploration. However, as the number of classes increases, it is challenging to generate a high-quality color assignment result that accommodates all classes simultaneously. A practical solution is to organize classes into a hierarchy and then dynamically assign colors during exploration. However, existing color assignment methods fall short in generating high-quality color assignment results and dynamically aligning them with hierarchical structures. To address this issue, we develop a dynamic color assignment method for hierarchical data, which is formulated as a multi-objective optimization problem. This method simultaneously considers color discriminability, color harmony, and spatial distribution at each hierarchical level. By using the colors of parent classes to guide the color assignment of their child classes, our method further promotes both consistency and clarity across hierarchical levels. We demonstrate the effectiveness of our method in generating dynamic color assignment results with quantitative experiments and a user study.

Cluster-Aware Grid Layout.

Grid visualizations are widely used in many applications to visually explain a set of data and their proximity relationships. However, existing layout methods face difficulties when dealing with the inherent cluster structures within the data. To address this issue, we propose a cluster-aware grid layout method that aims to better preserve cluster structures by simultaneously considering proximity, compactness, and convexity in the optimization process. Our method utilizes a hybrid optimization strategy that consists of two phases. The global phase aims to balance proximity and compactness within each cluster, while the local phase ensures the convexity of cluster shapes. We evaluate the proposed grid layout method through a series of quantitative experiments and two use cases, demonstrating its effectiveness in preserving cluster structures and facilitating analysis tasks.

Comparison of Surgical Modalities for Giant Pituitary Adenoma: A Systematic Review and Meta-Analysis of 1413 Patients.

BACKGROUND AND OBJECTIVES: Giant pituitary adenomas (GPAs) are a challenging clinical entity, composing 5% to 15% of all pituitary adenomas. While the endoscopic endonasal transsphenoidal (EET) approach has surpassed the microsurgical transsphenoidal (MT) and transcranial (TC) approaches as the first-line surgical modality in most institutions, a systematic review comparing the 3 approaches has not been undertaken since 2012. Given growing adoption of EET and development of novel operative techniques over the past decade, an updated comparison of GPA surgical modalities is warranted. METHODS: We identified all studies related to the surgical management of GPAs in PubMed, Embase, and Web of Science from inception to December 31, 2021. End points assessed included gross total resection (GTR) rates, postoperative visual improvement, mortality, and perioperative complications. RESULTS: After screening of 1701 studies, we identified 45 studies on the surgical management of GPAs for meta-analysis. Thirty-one used the EET approach (n = 1413), 11 studies used the MT approach (n = 601), and 10 used the TC approach (n = 416). The cumulative number of patients treated by EET did not exceed that of patients treated by the TC or MT approaches until 2014 and 2015, respectively. Despite patients undergoing EET having the highest average tumor diameter, pooled rates for GTR were significantly higher for EET (42%) than MT (33%, P < .001) and TC (8%, P < .001) and EET similarly exhibited superior rates of visual improvement (85%) than MT (73%, P < .001) and TC (56%, P < .001). Mortality rates were comparable between EET (0.6%) and MT (1.6%), but EET had significantly lower mortality than TC (2.7%, P < .001). Compared with MT, EET had lower rates of hypopituitarism (8.5% vs 14.9%, P = .012) but higher rates of diabetes insipidus (3.1% vs 0.5%, P = .001). CONCLUSION: In an updated meta-analysis of 1413 patients with GPA, EET resection conferred significantly higher rates of visual improvement and GTR, when compared with the MT and TC approaches.