Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

Objectives:To investigate the clinical efficacy of staged percutaneous endoscopic posterior decom-pression for treating multi-segment thoracic ossification of ligamentum flavum(mTOLF).Methods:The clinical data of 16 patients with mTOLF who were treated with staged percutaneous endoscopic posterior decompres-sion at our hospital between June 2021 and June 2023 were retrospectively analyzed,including 9 males and 7 females,aged 46-67(55.4±6.8)years old.The preoperative imaging examinations of the patients indicated multi-segment ossification of ligamentum flavum,including double segments in 14 cases and triple segments in 2 cases.The responsible segments were as follows:upper thoracic spine(T1-T4)in 4 cases,middle thoracic spine(T5-T9)in 6 cases,and lower thoracic spine(T10-T12)in 24 cases.Staged percutaneous endoscopic posterior decompression was performed for mTOLF,targeting only one responsible segment in each surgery.The operative time,blood loss,hospitalization days,and complications were recorded.The Oswestry disability index(ODI)and the modified Japanese Orthopaedic Association(mJOA)11-point scale scores were recorded preoperatively,on 3d postoperatively,and at the final follow-up,and the mJOA improvement rate at the final follow-up was calculated.Statistical analysis was performed to evaluate the clinical efficacy.The spinal canal area and the anterior-posterior spinal canal diameter were measured on CT images preoperatively,on 3d post-operatively,and at the final follow-up to evaluate the improvement of imaging findings.Results:All the 16 patients successfully completed the surgery,and no cerebrospinal fluid leakage or permanent lower limb paral-ysis occurred except for one dural tear during operation.The operative time was 80-205min(150.2±36.1min),blood loss was 30-70mL(50.3±12.4mL),hospitalization days were 9-15d(10.8±1.8d)and the follow-up time ranged from 9-20(14.3±3.2)months.The mJOA scores and ODIs before surgery,on 3d after surgery,and at the final follow-up were 5.7±1.3,7.1±1.3,8.5±1.4,and(41.4±1.8)％,(17.8±1.6)％,(15.6±1.3)％,respectively,which were both significantly improved on 3d postoperatively and at final follow-up compared with those val-ues before operation(P＜0.05).The mJOA recovery rate was 28.6％-100％[(56.1±19.3)％],and according to the mJOA evaluation criteria,the outcomes were classified as excellent in 3 cases,good in 9 cases,fair in 4 cases,and poor in no case,with an excellent and good rate of 75.0％.The spinal canal area and anterior-posterior diameter before surgery,on 3d after surgery,and at the final follow-up were 76.7±12.5mm2,159.9±22.1mm2,157.7±21.6mm2,and 7.4±0.5mm,15.5±0.9mm,15.3±0.9mm,respectively.Both the spinal canal area and anterior-posterior diameter on 3d postoperatively and at the final follow-up significantly increased com-pared to preoperative values(P＜0.05).Conclusions:Staged percutaneous endoscopic posterior decompression for treating mTOLF is safe and effective,and yields satisfactory clinical outcomes.

Objectives:To investigate the clinical efficacy of staged percutaneous endoscopic posterior decom-pression for treating multi-segment thoracic ossification of ligamentum flavum(mTOLF).Methods:The clinical data of 16 patients with mTOLF who were treated with staged percutaneous endoscopic posterior decompres-sion at our hospital between June 2021 and June 2023 were retrospectively analyzed,including 9 males and 7 females,aged 46-67(55.4±6.8)years old.The preoperative imaging examinations of the patients indicated multi-segment ossification of ligamentum flavum,including double segments in 14 cases and triple segments in 2 cases.The responsible segments were as follows:upper thoracic spine(T1-T4)in 4 cases,middle thoracic spine(T5-T9)in 6 cases,and lower thoracic spine(T10-T12)in 24 cases.Staged percutaneous endoscopic posterior decompression was performed for mTOLF,targeting only one responsible segment in each surgery.The operative time,blood loss,hospitalization days,and complications were recorded.The Oswestry disability index(ODI)and the modified Japanese Orthopaedic Association(mJOA)11-point scale scores were recorded preoperatively,on 3d postoperatively,and at the final follow-up,and the mJOA improvement rate at the final follow-up was calculated.Statistical analysis was performed to evaluate the clinical efficacy.The spinal canal area and the anterior-posterior spinal canal diameter were measured on CT images preoperatively,on 3d post-operatively,and at the final follow-up to evaluate the improvement of imaging findings.Results:All the 16 patients successfully completed the surgery,and no cerebrospinal fluid leakage or permanent lower limb paral-ysis occurred except for one dural tear during operation.The operative time was 80-205min(150.2±36.1min),blood loss was 30-70mL(50.3±12.4mL),hospitalization days were 9-15d(10.8±1.8d)and the follow-up time ranged from 9-20(14.3±3.2)months.The mJOA scores and ODIs before surgery,on 3d after surgery,and at the final follow-up were 5.7±1.3,7.1±1.3,8.5±1.4,and(41.4±1.8)％,(17.8±1.6)％,(15.6±1.3)％,respectively,which were both significantly improved on 3d postoperatively and at final follow-up compared with those val-ues before operation(P＜0.05).The mJOA recovery rate was 28.6％-100％[(56.1±19.3)％],and according to the mJOA evaluation criteria,the outcomes were classified as excellent in 3 cases,good in 9 cases,fair in 4 cases,and poor in no case,with an excellent and good rate of 75.0％.The spinal canal area and anterior-posterior diameter before surgery,on 3d after surgery,and at the final follow-up were 76.7±12.5mm2,159.9±22.1mm2,157.7±21.6mm2,and 7.4±0.5mm,15.5±0.9mm,15.3±0.9mm,respectively.Both the spinal canal area and anterior-posterior diameter on 3d postoperatively and at the final follow-up significantly increased com-pared to preoperative values(P＜0.05).Conclusions:Staged percutaneous endoscopic posterior decompression for treating mTOLF is safe and effective,and yields satisfactory clinical outcomes.

Objective To investigate the impact of recent rhythmic interventions on the depth of sedation during anesthesia induction in patients undergoing general anesthesia with remazolam toluene sulfonate.Methods Patients aged 18～65 years who underwent elective surgery under general anesthesia were selected and divided into a day group(7:00～19:00)and a night group(19:00～7:00 the following day)based on the start time of anesthesia induction.Each group comprised 70 patients,further subdivided into five equal dose groups of remazolam toluene sulfonate at 0.11,0.13,0.16,0.18,and 0.22 mg/kg,with 14 patients in each subgroup.The Modified Observer's Assessment of Alertness/Sedation(MOAA/S)score and Bispectral Index(BIS)value were recorded 3 minutes post-administration,and the correlation coefficient between these two parameters was calculated.The induction dose and unit body weight dose of remazolam toluene sulfonate were documented when the MOAA/S score was≤1.Addition-ally,the induction dose of remazolam for both day and night groups as well as for patients of different genders was recorded.The half effective dose(ED50),95％effective dose(ED95),and 95％confidence interval(CI)for both the day and night groups were also calculated.Results When MOAA/S≤1,the induced dose of remazolam in the night group(12.34±3.51)mg was significantly lower than that in the day group(13.98±4.21)mg.Additionally,the dose per unit body weight of remazolam in the night group(0.20±0.049)mg/kg was also significantly lower than that in the day group(0.22±0.056)mg/kg.Statistically significant differences were observed in the ED50 and ED95 values of remazolam between the day and night groups(P<0.05).The correlation coefficient between BIS and MOAA/S was 0.902(95％CI:0.876～0.925)in the day group and 0.905(95％CI:0.879～0.929)in the night group,indicating a strong correlation between MOAA/S and BIS in both groups.However,there was no significant difference in the correlation coefficients between the two groups(P>0.05).The correlation coefficients between BIS and MOAA/S were 0.763(95％CI:0.726～0.799)in the daytime group and 0.777(95％CI:0.739～0.808)in the nighttime group.In a separate analysis,the correlation coefficients were 0.768(95％CI:0.723～0.804)for the day-time group and 0.771(95％CI:0.723～0.811)for the nighttime group.A strong correlation was observed between MOAA/S and BIS in both male and female patients during both day and night,with no significant difference in corre-lation coefficients between groups(P>0.05).However,BIS values were significantly lower in the nighttime group compared to the daytime group(P<0.05).Additionally,male patients required a higher total induced dose of rem-azolam than female patients during both day and night,with this difference being statistically significant(P<0.05).Furthermore,female patients exhibited a significant decrease in BIS values at night(P<0.05).Conclusions Recent studies have shown that circadian rhythm significantly influences anesthesia-induced sedation in patients undergoing general anesthesia with remazolam toluenesulfonate.Specifically,the sedation effect is more pronounced in nighttime procedures,and there is a notable gender difference,with female patients exhibiting better sedation outcomes during nighttime surgeries.

Objective To investigate the impact of recent rhythmic interventions on the depth of sedation during anesthesia induction in patients undergoing general anesthesia with remazolam toluene sulfonate.Methods Patients aged 18～65 years who underwent elective surgery under general anesthesia were selected and divided into a day group(7:00～19:00)and a night group(19:00～7:00 the following day)based on the start time of anesthesia induction.Each group comprised 70 patients,further subdivided into five equal dose groups of remazolam toluene sulfonate at 0.11,0.13,0.16,0.18,and 0.22 mg/kg,with 14 patients in each subgroup.The Modified Observer's Assessment of Alertness/Sedation(MOAA/S)score and Bispectral Index(BIS)value were recorded 3 minutes post-administration,and the correlation coefficient between these two parameters was calculated.The induction dose and unit body weight dose of remazolam toluene sulfonate were documented when the MOAA/S score was≤1.Addition-ally,the induction dose of remazolam for both day and night groups as well as for patients of different genders was recorded.The half effective dose(ED50),95％effective dose(ED95),and 95％confidence interval(CI)for both the day and night groups were also calculated.Results When MOAA/S≤1,the induced dose of remazolam in the night group(12.34±3.51)mg was significantly lower than that in the day group(13.98±4.21)mg.Additionally,the dose per unit body weight of remazolam in the night group(0.20±0.049)mg/kg was also significantly lower than that in the day group(0.22±0.056)mg/kg.Statistically significant differences were observed in the ED50 and ED95 values of remazolam between the day and night groups(P<0.05).The correlation coefficient between BIS and MOAA/S was 0.902(95％CI:0.876～0.925)in the day group and 0.905(95％CI:0.879～0.929)in the night group,indicating a strong correlation between MOAA/S and BIS in both groups.However,there was no significant difference in the correlation coefficients between the two groups(P>0.05).The correlation coefficients between BIS and MOAA/S were 0.763(95％CI:0.726～0.799)in the daytime group and 0.777(95％CI:0.739～0.808)in the nighttime group.In a separate analysis,the correlation coefficients were 0.768(95％CI:0.723～0.804)for the day-time group and 0.771(95％CI:0.723～0.811)for the nighttime group.A strong correlation was observed between MOAA/S and BIS in both male and female patients during both day and night,with no significant difference in corre-lation coefficients between groups(P>0.05).However,BIS values were significantly lower in the nighttime group compared to the daytime group(P<0.05).Additionally,male patients required a higher total induced dose of rem-azolam than female patients during both day and night,with this difference being statistically significant(P<0.05).Furthermore,female patients exhibited a significant decrease in BIS values at night(P<0.05).Conclusions Recent studies have shown that circadian rhythm significantly influences anesthesia-induced sedation in patients undergoing general anesthesia with remazolam toluenesulfonate.Specifically,the sedation effect is more pronounced in nighttime procedures,and there is a notable gender difference,with female patients exhibiting better sedation outcomes during nighttime surgeries.

【Objective】 To explore the causal association between the onset of gastroesophageal reflux disease (GERD) and migraine and to provide genetic evidence, a two-sample bidirectional Mendelian randomization (MR) method was used in this study. 【Methods】 Single nucleotide polymorphism (SNP) information for both samples was obtained from publicly available genome-wide association study (GWAS) databases, in which the appropriate SNPs were selected as instrumental variables, and then bidirectional MR analysis used five MR analysis methods including inverse variance weighting (IVW), MR-Egger regression, weighted median, weighted mode and simple mode methods, followed by sensitivity analysis. 【Results】 IVW showed positive results of forward MR analysis with GERD as exposure [OR=1.398 7, 95%CI (1.181 7-1.655 6), P=9.59×10^-5] , while no positive significance of reverse MR analysis results with migraine as exposure (P>0.05). The same results were obtained in methods other than MR-Egger method. Meanwhile, none of the instrumental variables were found to be horizontally polytomous (P=0.92, P=0.64), and the results were robust after the leave-one-out method to exclude single SNPs. 【Conclusion】 There may be a unidirectional causal association between GERD and migraine, and GERD is a risk factor for migraine development.

Objective To investigate the liver disease phenotypes and clinical features of patients with different genotypes of Wilson's disease(WD).Methods A retrospective analysis was performed for 163 patients with WD who were diagnosed and underwent genetic testing in The Fifth Medical Center of Chinese PLA General Hospital from August 2008 to June 2023,and clinical manifestations,laboratory examination,pathological examination,imaging examination,and ATP7B genetic testing results were collected.According to ATP7B gene mutation,the patients were divided into groups as follows:R778L mutation group and non-R778L mutation group;P992L mutation group and non-P992L mutation group;truncation mutation group and non-truncation mutation group.Liver disease phenotypes and clinical features were analyzed for the patients with c.2333G>T/p.R778L mutation(R778L mutation),c.2975C>T/p.P992L mutation(P992L mutation),and truncation mutation of the ATP7B gene.The Mann-Whitney U test or the Kruskal-Wallis H test was used for comparison of continuous data between groups,and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups.Results The 163 patients with WD had varying severities of liver disease phenotypes,among whom 121(74.23%)were diagnosed with chronic liver disease,36(22.09%)were diagnosed with decompensated cirrhosis,and 6(3.68%)were diagnosed with fulminant WD,and in addition,there were 5 patients(2 with chronic liver disease and 3 with decompensated cirrhosis)with neurological abnormalities.For the 163 patients with WD,R778L mutation(with an allele frequency of 28.2%)was the most common mutation in the ATP7B gene,followed by P992L mutation(with an allele frequency of 12.6%),and truncation mutation showed an allele frequency of 11.0%.There was no significant difference in the distribution of the three mutations across different liver disease phenotypes(P>0.05).The R778L mutation group had a significantly lower level of ceruloplasmin(CP)than the non-R778L mutation group[0.04(0.02-0.08)g/L vs 0.08(0.03-0.13)g/L,Z=-2.889,P=0.004].Compared with the non-P992L mutation group,the P992L mutation group had significantly higher levels of alanine aminotransferase[135.0(80.5-237.0)U/L vs 80.5(36.0-173.3)U/L,Z=2.684,P=0.007]and aspartate aminotransferase[121.4(77.0-195.0)U/L vs 84.0(39.0-123.3)U/L,Z=3.388,P<0.001].Compared with the non-truncation mutation group,the truncation mutation group had significantly lower levels of CP[0.03(0.02-0.08)g/L vs 0.06(0.03-0.11)g/L,Z=-3.136,P=0.002]and serum copper[3.20(2.15-5.00)mg/L vs 4.20(2.60-7.50)mg/L,Z=-2.296,P=0.025].Conclusion R778L mutation,P992L mutation and truncation mutation are not associated with liver disease phenotype in WD patients;however,R778L mutation is associated with a lower level of CP,P992L mutation is associated with higher levels of ALT and AST,and truncation mutation is associated with lower levels of CP and serum copper.

Objective To create a novel chitosan antibacterial hemostatic sponge(NCAHS)and to evaluate its material and biological properties.Methods Chitosan,a polysaccharide,was used as the sponge substrate and different proportions of sodium tripolyphosphate(STPP),glycerol,and phenol sulfonyl ethylamine were added to prepare the sponges through the freeze-drying method.The whole-blood coagulation index(BCI)was used as the screening criterion to determine the optimal concentrations of chitosan and the other additives and the hemostatic sponges were prepared accordingly.Zein/calcium carbonate(Zein/CaCO3)composite microspheres loaded with ciprofloxacin hydrochloride were prepared and added to the hemostatic sponges to obtain NCAHS.Scanning electron microscope was used to observe the microscopic morphology and porosity of the NCAHS.The water absorption rate,in vitro antibacterial susceptibility rate against Staphylococcus aureus(S.aureus)and Escherichia coli(E.coli),in vitro coagulation performance,and hemocompatibility of NCAHS were examined.The coagulation performance of NCAHS was evaluated by using rabbit liver injury and rabbit auricular artery hemorrhageear models and commercial hemostatic sponge(CHS)was used as a control.The in vivo biocompatibility,including such aspects as cytotoxicity,skin irritation in animals,and acute in vivo toxicity,of the NCAHS extracts was examined by using as a reference the national standards for biological evaluation of medical devices.Results The NCAHS prepared with 1.5%chitosan(W/V),0.01%STPP(W/V),0%glycerol(V/V),0.15%phenol-sulfonyl-ethylamine(V/V),Zein and CaCO3 at the mixing ratio of 5∶1(W/W),Zein at the final mass concentration of 2.5 g/L,and ethanol at the final concentration of 17.5%(V/V)were fine and homogeneous,possessing a honeycomb-like porous structure with a pore size of about 200 μm.The NCAHS thus prepared had the lowest BCI value.The water absorption([2362.16±201.15]%vs.[1102.56±91.79]%)and in vitro coagulation performance(31.338%vs.1.591%)of NCAHS were significantly better than those of CHS(P<0.01).Tests with the in vivo auricular artery hemorrhage model([36.00±13.42]s vs.[80.00±17.32]s)and rabbit liver bleeding model([30.00±0]s vs.[70.00±17.32]s)showed that the hemostasis time of NCAHS was significantly shorter than that of CHS(P<0.01).NCAHS had significant inhibitory ability against S.aureus and E.coli.In addition,NCAHS showed good in vitro and in vivo biocompatibility.Conclusion NCAHS is a composite sponge that shows excellent antimicrobial properties,hemostatic effect,and biocompatibility.Therefore,its extensive application in clinical settings is warranted.

Objective To investigate ecological isolation between Oncomelania hupensis snail populations in hilly regions and marshland and lake regions in Yuanjiang valley, Changde City, Hunan Province, and to unravel its underlying mechanisms. Methods Taoyuan County, Shimen County, Linli County and Lixian County in Changde City were selected as snail sampling sites in hilly regions, and Lixian County, Jinshi City, West Lake Administration District, Hanshou County and Dingcheng District were selected as snail sampling sites in marshland and lake areas. Cytochrome C oxidase 1 (cox 1) gene was amplified in snail samples and sequenced. The genetic sequences of O. hupensis snails were aligned using the software MEGA 11, and the haplotypes of O. hupensis snails were determined using the software DNASP 5.10.01. The phylogenetic tree was generated using Bayesian inference with the software MrBayes 3.2, and analysis of molecular variance (AMOVA) was performed to analyze the source of genetic divergence and estimate the genetic divergence index (F_ST) among snail populations with the software Arlequin 3.5.2.2. The genetic barrier among 11 O. hupensis snail populations was estimated using the Monmonier algorithm of adegenet toolkit in R package. The settings with “land in winter and water in summer” in the Yuanjian River section were divided into two categories according to the upstream and downstream, and the areas with “land in winter and water in summer” in the upstream and downstream were transformed into raster data, and then loaded into the software Fragstats 4 for analysis of landscape indicators. The trends in changes of digital elevation were extracted from the Yuanjiang River section based on the digital elevation model, and made three-dimensional visualization using the R package. Results The mitochondrial cox 1 gene were amplified in 165 O. hupensis snais from 11 sampling sites and sequenced, and a total of 152 valid gene sequences were obtained, with 46 haplotypes or 9 populations determined. No haplotype was shared in snails between Taoyuan County and Dingcheng District and Hanshou County along the downstream of the Yuanjiang River. The total area of settings with “land in winter and water in summer” was 617.66 hm² in the upsteram of the Yuanjiang River, which consisted of 473 patches, with each patch measuring 1.31 hm², the largest area index of 0.735 2, the landscape division index of 0.999 9, and the landscape shape index of 45.293 7. The total area of settings with “land in winter and water in summer” was 9 956.92 hm² in the downstream of the Yuanjiang River, which consisted of 771 patches, with each patch measuring 12.91 hm², the largest area index of 97.839 9, the landscape division index of 0.042 7, and the landscape shape index of 7.249 6. The area of settings with “land in winter and water in summer” was much larger in the downstream than that in the upstream of the Yuanjiang River, and the stronger landscape connectivity and non-remarkable alteration of riverbed elevation provided suitable habitats for snail breeding. Conclusion The hydrological and environmental characteristics of the upstream of the Yuanjiang River restrain the breeding and spread of O. hupensis, resulting in ecological isolation between Oncomelania hupensis in Taoyuan County and those in the downstream of Yuanjiang River.

As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44-CXCR2- neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.
Humans ; Animals ; Mice ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Stomach Neoplasms/pathology* ; Neutrophils/pathology* ; Signal Transduction/genetics* ; YAP-Signaling Proteins ; Tumor Microenvironment ; Hyaluronan Receptors/genetics*