Pathogenesis, diagnosis, and treatment of epilepsy: electromagnetic stimulation-mediated neuromodulation therapy and new technologies

Epilepsy is a severe,relapsing,and multifactorial neurological disorder.Studies regarding the accurate diagnosis,prognosis,and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy.The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression,protein expression,ion channel activity,energy metabolites,and gut microbiota composition.Satisfactory results are lacking for conventional treatments for epilepsy.Surgical resection of lesions,drug therapy,and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy.Non-pharmacological treatments,such as a ketogenic diet,gene therapy for nerve regeneration,and neural regulation,are currently areas of research focus.This review provides a comprehensive overview of the pathogenesis,diagnostic methods,and treatments of epilepsy.It also elaborates on the theoretical basis,treatment modes,and effects of invasive nerve stimulation in neurotherapy,including percutaneous vagus nerve stimulation,deep brain electrical stimulation,repetitive nerve electrical stimulation,in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation.Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures.Additionally,many new technologies for the diagnosis and treatment of epilepsy are being explored.However,current research is mainly focused on analyzing patients’clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level,which has led to a lack of consensus regarding the mechanisms related to the disease.

The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Effects of Ground Mulching Treatments on Soil Moisture Content in Second-generation Seed Garden of Pinus elliottii

Different ground mulching treatments were designed to observe the effects on soil moisture content in a second-generation seed orchard of Pinus elliottii. The results showed that： （1） there were extreme differences in soil moisture content Ⅰ and soil moisture content Ⅲ, but no obvious difference in soil moisture content II was observed; and （2） the high-to-low order of soil moisture content Ⅰ under different ground mulching treatments was white film〉sawdust〉black film〉the control, and the highest value was higher than the lowest one by 26.69%; the high-to-low order of soil moisture content Ⅱ under different ground mulching treatments was white film〉black film〉sawdust〉the control, and the highest value was higher than the lowest one by 20.64%; and the high-to-low order of soil moisture content Ⅲ under different ground mulching treatments was black film〉white film〉sawdust〉the control, and the highest value was higher than the lowest one by 26.61%.

Comparison of Histological, Microbiological, and Molecular Methods in Diagnosis of Patients with TBLN Having Different Anti-TB Treatment Background

Objective The influence of anti-tuberculosis （TB） treatment history on tuberculous lymphadenitis （TBLN） diagnosis is unclear. Therefore, this study aims to evaluate the diagnostic methods, including histology, microbiology, and molecular tests, used for TBLN. Methods In this study, suspected patients with TBLN and having different anti-T8 treatment background were enrolled. All the samples were tested simultaneously by histology, ZiehI-Neelsen （ZN） staining, mycobacterial culture （culture）, Xpert MTB/RIF （xpert）, real-time PCR, and high-resolution melting curve PCR （HRM）. Thereafter, the performance of these methods on samples with different anti-TB treatment background was assessed. Results In our study, 89 patients were prospectively included 82 patients with TBLN and 7 with other diseases. The overall sensitivities of Xpert, real-time PCR, histology, ZN staining, and culture were 86.6%, 69.5%, 58.5%, 43.9%, and 22.0%, respectively. The anti-TB treatment history revealed dramatic influences on the sensitivity of culture （P 〈 0.0001）. In fact, the treatment that lasted over 3 months also influenced the sensitivity of Xpert （P 〈 0.05）. However, the treatment history did not affect the performance of remaining tests （P 〉 0.05）. For rifampicin drug susceptibility test （DST）, the anti-T8 treatment showed only significant influence on the success rate of culture DST （P = 0.001）, but not on those of Xpert and HRM tests （P 〉 0.05）. Conclusion Other tests as welt as culture should be considered for patients with TBLN having retreatment history or over 1-month treatment to avoid false negative results.

A field study of advanced municipal wastewater treatment technology for artificial groundwater recharge

Field studies were conducted to investigate the advanced treatment of the municipal secondary effluent and a subsequent artificial groundwater recharge at Gaobeidian Wastewater Treatment Plant, Beijing. To improve the secondary effluent quality, the combined process of powdered activated carbon adsorption, flocculation and rapid sand filtration was applied, which could remove about 400 dissolved organic carbon （DOC） and 70% adsorbable organic halogens. The results of liquid size exclusion chromatography indicate that in the adsorption unit the removed organic fraction was mainly low molecular weight compounds. The fractions removed by the flocculation unit were polysaccharides and high molecular weight compounds. The retention of water in summer in the open recharge basins resulted in a growth of algae. Consequently, DOC increased in the polysaccharide and high molecular weight humic substances fraction. The majority of the DOC removal during soil passage took place in the unsaturated area. A limited reduction of DOC was observed in the aquifer zone.

Green Synthesis of Magnetic Adsorbent Using Groundwater Treatment Sludge for Tetracycline Adsorption

Groundwater treatment sludge is an industrial waste that is massively produced from groundwater treatment plants.Conventional methods for treatment of this sludge,such as discharge into deep wells or the sea,or disposal at landfills,are not environmentally sustainable.Here,we demonstrate an alternative strategy to recycle the sludge by preparing a magnetic maghemite adsorbent via a one-step hydrothermal method with NaOH solution as the only solvent.With this method,the weakly magnetized sludge,which contained 33.2%iron(Fe)and other impurities(e.g.,silicon(Si),aluminum(Al),and manganese(Mn)),was converted to magnetic adsorbent(MA)with the dissolution of Si/Al oxides(e.g.,quartz and albite)into the liquid fraction.At a NaOH concentration of 2 mol L^-1,approximately 18.1%of the ferrihydrite in the Fe oxides of the sludge was converted into 11.2%maghemite and 6.9%hematite after the hydrothermal treatment.MA2(i.e.,MA produced by a 2 mol L^-1 NaOH concentration)exhibited a good magnetic response of 8.2 emu g^-1(1 emu=10^-3 A m^2),and a desirable surface site concentration of 0.75 mmol g^-1.The synthesized MA2 was used to adsorb the cationic pollutant tetracycline(TC).The adsorption kinetics of TC onto MA2 fitted well with a pseudo-second-order model,and the adsorption isotherms complied well with the Langmuir model.The maximum adsorption capacity of MA2 for TC was 362.3 mg g^-1,and the main mechanism for TC adsorption was cationic exchange.This study is the first to demonstrate the preparation of an MA from recycled sludge without a reductant and/or exogenous Fe source.The prepared adsorbent can be used as a low-cost adsorbent with high capacity for TC sorption in the treatment of TC-containing wastewater.

Treatment options for pulmonary multifocal ground glass opacity type adenocarcinoma: Surgery combine thermal ablation?

Objectives:To retrospectively analyze the clinical results of the treatment of pulmonary multifocal adenocarcinoma presenting as ground glass opacity(GGO)by surgery and thermal ablation.Methods:87 GGO-type pulmonary adenocarcinomas of 48 patients(14 males and 34 females;mean age:59.7 years old±9.9,range:33-79 years old)had been treated from March 2015 to March 2019.Treatment means included 43 wedge resections,7 segmentectomy,17 lobectomies,and 20 thermal ablations.The indication selected for treatment means,safety,and local tumor progression rate were evaluated.Results:No operation-related death occurred in all patients.42 times of surgery were performed and 67 carcinomas were resected in 42 patients.23 times of single-port Video-assisted thoracoscopic surgery(VATS),8 times of two-port VATS and 11 times of three-port VATS were performed in total.There were 2 cases of air leak(exceeding 1 week),1 case of chylothorax and 1 case of massive pleural effusion.Time duration of surgery was between 60 and 300 mins(mean:167 mins).Intraoperative blood loss was between 5 and 300 mL(mean:44 mL).Time of chest drainage was between 2 and 23 d(mean 4.9 d).Chest drainage volume was between 14 and 4633 mL(mean:872 mL).Post-operation LOS(length of stay)was between 3 and 25 d(mean:6.2 d).15 times of thermal ablation were performed(1 case of air leak)and 20 carcinomas were ablated in 14 patients.The ablation time was between 30 and 120 min(mean:43 min);post-operation LOS was between 1 and 10 d(mean:3.5 d).During the mean follow-up period(16 months±13)(range:5-60 months),no local tumor progression occurred.Conclusions:Surgery and thermal ablation are safe and effective options for the treatment of pulmonary multifocal GGO-type adenocarcinoma.

Solar Photochemical Pre-Treatment for Sulphurous Ground Water Purification Process

The sulfurous water deposit exploitation in volcanic, swamp, or wetland regions, represents an alternative option for potable water supply in cities and communities around the world. However, before its consumption, it must be treated by the application of physicochemical or biological methods with the ability to separate high contents in sulfates, hydrogen sulphite and sulphides which have laxative, allergic and toxic properties in humans. Conventional methods require the supply of chemical compounds or the adequate control of different parameters such as pH, temperature, etc., and the constant maintenance within their reactors. For these reasons, the systems could have elevated operating costs and require additional steps to enable the treatment of its separated products and the final disposal of its residual waste generated. In this research, compound parabolic collectors are implemented for the use of solar energy radiation, UV-B type, in Solar Advanced Oxidation Processes in H2O2/O3/UVsolar homogeneous phase. Its application during the pre-treatment of four sulfur water wells from the region of Puebla, Mexico, demonstrated its ability to transform their sulfur compounds in sulfates of easy removal by a later stage of reverse osmosis, in an approximately 15 min treatment time process.

Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Working toward an integrated plasticity/network framework for repetitive transcranial magnetic stimulation to inform tailored treatments

Non-invasive brain stimulation techniques(NIBS),including repetitive transcranial magnetic stimulation(rTMS) and transcranial electric stim ulation(tES),are increasingly being adopted clinically for treatment of neuropsychiatric and neurological disorders,albeit with varying success.The rationale behind the use of NIBS has historically been that stim ulation techniques modulate neuronal activity in the targeted region and consequently induce plasticity which can lead to therapeutic outcomes.

Study of prediction for groundwater contamination in wastewater land treatment system

This paper uses a prediction model of groundwater pollution based on the experiments in the laboratory and in field .The model, which was tested and calibrated by the field observated data ,satisfactorily simulated the field conditions in land treatment system of wastewater . Particularly , the model can provide the reliable pollution prediction of heavy metals , organisms and nitrogen . The model was used to predict the groundwater pollution caused by the land treatment system in the region of North China . The calibration of the model showed that correlation coefficients between the tested and predictive data of Cr6+. As3+, organism and NH4+ could reach 0.990, which proved that the model possessed the realistic instructive significance for design and use of wastewater land treatment systems .

Pulses in ground motions identified through surface partial matching and their impact on seismic rocking consequence

In seismology and earthquake engineering,it is fundamental to identify and characterize the pulse-like features in pulse-type ground motions.To capture the pulses that dominate structural responses,this study establishes congruence and shift relationships between response spectrum surfaces.A similarity search between spectrum surfaces,supplemented with a similarity search in time series,has been applied to characterize the pulse-like features in pulse-type ground motions.The identified pulses are tested in predicting the rocking consequences of slender rectangular blocks under the original ground motions.Generally,the prediction is promising for the majority of the ground motions where the dominant pulse is correctly identified.

Influence of heat treatment on microstructure,mechanical and corrosion behavior of WE43 alloy fabricated by laser-beam powder bed fusion

Magnesium(Mg)alloys are considered to be a new generation of revolutionary medical metals.Laser-beam powder bed fusion(PBF-LB)is suitable for fabricating metal implants withpersonalized and complicated structures.However,the as-built part usually exhibits undesirable microstructure and unsatisfactory performance.In this work,WE43 parts were firstly fabricated by PBF-LB and then subjected to heat treatment.Although a high densification rate of 99.91%was achieved using suitable processes,the as-built parts exhibited anisotropic and layeredmicrostructure with heterogeneously precipitated Nd-rich intermetallic.After heat treatment,fine and nano-scaled Mg24Y5particles were precipitated.Meanwhile,theα-Mg grainsunderwent recrystallization and turned coarsened slightly,which effectively weakened thetexture intensity and reduced the anisotropy.As a consequence,the yield strength and ultimate tensile strength were significantly improved to(250.2±3.5)MPa and(312±3.7)MPa,respectively,while the elongation was still maintained at a high level of 15.2%.Furthermore,the homogenized microstructure reduced the tendency of localized corrosion and favoredthe development of uniform passivation film.Thus,the degradation rate of WE43 parts was decreased by an order of magnitude.Besides,in-vitro cell experiments proved their favorable biocompatibility.

Gut flora in multiple sclerosis:implications for pathogenesis and treatment

Multiple sclerosis is an inflammatory disorder chara cterized by inflammation,demyelination,and neurodegeneration in the central nervous system.Although current first-line therapies can help manage symptoms and slow down disease progression,there is no cure for multiple sclerosis.The gut-brain axis refers to complex communications between the gut flo ra and the immune,nervous,and endocrine systems,which bridges the functions of the gut and the brain.Disruptions in the gut flora,termed dys biosis,can lead to systemic inflammation,leaky gut syndrome,and increased susceptibility to infections.The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors,and gut flora may play a pivotal role in regulating immune responses related to multiple scle rosis.To develop more effective therapies for multiple scle rosis,we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis.This review provides an overview of the role of the gut flora in multiple scle rosis.

Prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections

Osteomyelitis is a devastating disease caused by microbial infection in deep bone tissue.Its high recurrence rate and impaired restoration of bone deficiencies are major challenges in treatment.Microbes have evolved numerous mechanisms to effectively evade host intrinsic and adaptive immune attacks to persistently localize in the host,such as drug-resistant bacteria,biofilms,persister cells,intracellular bacteria,and small colony variants(SCVs).Moreover,microbial-mediated dysregulation of the bone immune microenvironment impedes the bone regeneration process,leading to impaired bone defect repair.Despite advances in surgical strategies and drug applications for the treatment of bone infections within the last decade,challenges remain in clinical management.The development and application of tissue engineering materials have provided new strategies for the treatment of bone infections,but a comprehensive review of their research progress is lacking.This review discusses the critical pathogenic mechanisms of microbes in the skeletal system and their immunomodulatory effects on bone regeneration,and highlights the prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections.It will inform the development and translation of antimicrobial and bone repair tissue engineering materials for the management of bone infections.

Epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China:a hospital-based retrospective study

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death.China has the largest population of patients with traumatic spinal cord injury.Previous studies of traumatic spinal cord injury in China have mostly been regional in scope;national-level studies have been rare.To the best of our knowledge,no national-level study of treatment status and economic burden has been performed.This retrospective study aimed to examine the epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China at the national level.We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China.Patient epidemiological and clinical features,treatment status,and total and daily costs were recorded.Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program.The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall(annual percentage change,-0.5%and 2.1%,respectively).A total of 10,053(74.7%)patients underwent surgery.Only 2.8%of patients who underwent surgery did so within 24 hours of injury.A total of 2005(14.9%)patients were treated with high-dose(≥500 mg)methylprednisolone sodium succinate/methylprednisolone(MPSS/MP);615(4.6%)received it within 8 hours.The total cost for acute traumatic spinal cord injury decreased over the study period(-4.7%),while daily cost did not significantly change(1.0%increase).Our findings indicate that public health initiatives should aim at improving hospitals’ability to complete early surgery within 24 hours,which is associated with improved sensorimotor recovery,increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Circular RNAs in breast cancer diagnosis,treatment and prognosis

Breast cancer has surpassed lung cancer to become the most common malignancy worldwide.The incidence rate and mortality rate of breast cancer continue to rise,which leads to a great burden on public health.Circular RNAs(circRNAs),a new class of noncoding RNAs(ncRNAs),have been recognized as important oncogenes or suppressors in regulating cancer initiation and progression.In breast cancer,circRNAs have significant roles in tumorigenesis,recurrence and multidrug resistance that are mediated by various mechanisms.Therefore,circRNAs may serve as promising targets of therapeutic strategies for breast cancer management.This study reviews the most recent studies about the biosynthesis and characteristics of circRNAs in diagnosis,treatment and prognosis evaluation,as well as the value of circRNAs in clinical applications as biomarkers or therapeutic targets in breast cancer.Understanding the mechanisms by which circRNAs function could help transform basic research into clinical applications and facilitate the development of novel circRNA-based therapeutic strategies for breast cancer treatment.

Physico-Chemical and Bacterial Characteristics of Groundwater and Surface Water Quality in the Lagbe Town: Treatment Essays with <i>Moringa oleifera</i>Seeds

The river water and groundwater from Lagbe town in Benin Republic were collected and analyzed for physical, chemical and microbiological parameters. The surface water samples were treated with alum, Moringa oleifera seeds powder and the combination of alum and Moringa oleifera seeds. The jar-test essays were carried out with two water samples at initial turbidities 7.2 NTU and 14.4 NTU. The water samples analyzed are fairly mineralized (conductivity varies between 166 and 687 μS/cm), enough soft and contain the nitrate (104 mg/L for W4 sample). They are greatly polluted by pathogenic microorganisms such as Escherichia coli, Klebsiella, Enterococcus, Vibrio, Serratia. The optimal dosages of Moringa are 96 mg/L and 80 mg/L respectively. We have observed a reduction of 60% of turbidity and a substantial remove of all pathogenic microorganisms after water treatment with Moringa oleifera seeds. For the combination treatment, 93% of initial turbidity and 92% of initial concentration of organic matter in the sample E2 were eliminated. The pH remained almost constant during the treatment.

Esophageal cancer screening,early detection and treatment:Current insights and future directions

Esophageal cancer ranks among the most prevalent malignant tumors globally,primarily due to its highly aggressive nature and poor survival rates.According to the 2020 global cancer statistics,there were approximately 604000 new cases of esophageal cancer,resulting in 544000 deaths.The 5-year survival rate hovers around a mere 15%-25%.Notably,distinct variations exist in the risk factors associated with the two primary histological types,influencing their worldwide incidence and distribution.Squamous cell carcinoma displays a high incidence in specific regions,such as certain areas in China,where it meets the cost-effect-iveness criteria for widespread endoscopy-based early diagnosis within the local population.Conversely,adenocarcinoma(EAC)represents the most common histological subtype of esophageal cancer in Europe and the United States.The role of early diagnosis in cases of EAC originating from Barrett's esophagus(BE)remains a subject of controversy.The effectiveness of early detection for EAC,particularly those arising from BE,continues to be a debated topic.The variations in how early-stage esophageal carcinoma is treated in different regions are largely due to the differing rates of early-stage cancer diagnoses.In areas with higher incidences,such as China and Japan,early diagnosis is more common,which has led to the advancement of endoscopic methods as definitive treatments.These techniques have demonstrated remarkable efficacy with minimal complications while preserving esophageal functionality.Early screening,prompt diagnosis,and timely treatment are key strategies that can significantly lower both the occurrence and death rates associated with esophageal cancer.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).