The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.

BACKGROUND:Cervical spondylotic myelopathy is a progressive disease leading to dysfunction in the middle-aged and elderly,and early diagnosis is difficult.In recent years,some clinical scholars have found that dynamic magnetic resonance imaging technology can detect spinal cord compression in a dynamic position earlier,but its specific biomechanical mechanism needs to be clarified. OBJECTIVE:To investigate the biomechanical compression characteristics of early cervical spondylotic myelopathy in hyperextension and flexion position,and to verify the effectiveness of dynamic magnetic resonance imaging in the diagnosis of early cervical spondylotic myelopathy. METHODS:A retrospective analysis was made on the patients who underwent cervical dynamic magnetic resonance imaging in the Department of Orthopedics of First Affiliated Hospital of Guangxi University of Chinese Medicine from January to June 2022.16 subjects were selected and divided into two groups.The pathological group included 8 patients with early cervical spondylotic myelopathy with hypertrophy of ligamentum flavum as the main sign,with 5 male patients and 3 female patients.The normal group included 8 normal degenerative people,with 4 male patients and 4 female patients.All patients were photographed with cervical CT plain scan,magnetic resonance imaging plain scan,and dynamic magnetic resonance imaging plain scan.This study was divided into the following three parts:(1)collect the dynamic magnetic resonance imaging image DCOM data of two groups of subjects,and collect the cervical vertebra CT and neutral magnetic resonance imaging image DCOM data to understand the bone and soft tissue of the two groups of subjects in the neutral position.(2)Based on the DCOM data of magnetic resonance imaging and CT plain scan,the three-dimensional finite element models of lower cervical vertebra(C3-7)of normal degenerative population and early cervical spondylotic myelopathy patients were established by reverse engineering software.The equivalent stress and equivalent elastic strain of the spinal cord and posterior dura were analyzed,and the distribution of stress and strain was observed.(3)After obtaining the stress and strain data,the data between groups were compared to analyze the mechanical characteristics of spinal cord compression caused by early cervical spondylotic myelopathy in a dynamic position and to verify the effectiveness of dynamic magnetic resonance imaging in the diagnosis of early cervical spondylotic myelopathy. RESULTS AND CONCLUSION:(1)When simulating the posterior extension,flexion and neutral position of the lower cervical vertebrae(C3-7)in the two groups,the values of stress and strain in the posterior part of the spinal cord were in the following order:extension>flexion>neutral(P<0.05).The strain values from large to small were as follows:extension>flexion>neutral(P<0.05).(2)Compared with the normal degenerative population model,the equivalent stress and strain of the spinal cord in the pathological group were higher than those in the normal group under two degrees of freedom of flexion and extension(P<0.05).The distribution area of stress and strain in the posterior part of the spinal cord was irregular.(3)In the neutral position,there was no significant difference in the strain value of the spinal cord between the two groups(P>0.05),and the strain distribution was uniform and regular.(4)It is indicated that in the cervical extension position,the dural sac and the posterior part of the spinal cord were compressed and deformed in the early cervical spondylotic myelopathy patients with the hypertrophy of ligamentum flavum as the main sign,and the degree of compression deformation of the spinal cord was significantly higher than that in the anterior flexion position and neutral position.In the neutral position,there were no obvious signs of spinal cord deformation in patients with early cervical spondylotic myelopathy.This study verified the role of dynamic magnetic resonance imaging in the diagnosis of early cervical spondylotic myelopathy from the point of view of biomechanics.

BACKGROUND:The specific molecular mechanism of the transformation from normal healthy people to acute cervical spondylotic radiculopathy has not been clear,which needs to be further studied. OBJECTIVE:To investigate the differential expression of serum proteomics between normal healthy people and patients with acute cervical spondylotic radiculopathy,and to find and identify potential specific serum markers between them. METHODS:The serum samples of eight patients with acute cervical spondylotic radiculopathy and eight normal healthy people were collected,and the proteomic screening and analysis were performed by tandem mass tag combined with liquid chromatography-tandem mass spectrometry technology,in order to explore and identify serum proteins differentially expressed in patients with acute cervical spondylotic radiculopathy. RESULTS AND CONCLUSION:A total of 183 significantly differential proteins were screened by tandem mass tag technology,and 11 significantly differential proteins were identified(P＜0.05).Compared with normal healthy people,three differential proteins were significantly up-regulated,including human leukocyte antigen-A,secretoglobin family 1a member 1,and protein 4-hydroxyphenylpyruvate dioxygenase,and seven differential proteins were significantly down-regulated,such as immunoglobulin heavy constant gamma 3,skin factor,and myosin light chain 3,in patients with acute cervical spondylotic radiculopathy.Gene ontology enrichment analysis showed that these differential proteins participated in antigen binding,immunoglobulin receptor binding and other molecular functions.Protein-protein interaction analysis showed that among the common differential proteins between normal healthy people and patients with acute cervical spondylotic radiculopathy,HLA-A,HPD,PSMA3,DMKN,SCGB1A1,and MYL3 were located at the nodes of the functional network,and were closely related to the systems of body immunity,cellular inflammatory response,energy metabolism,and mechanical pressure.The significantly differential proteins HLA-A,HPD and MYL3 were verified by western blot,and the results were consistent with those of proteomics.To conclude,tandem mass tag combined with liquid chromatography-tandem mass spectrometry technology can be used to find the differentially expressed proteins in serum between normal healthy people and patients with acute cervical spondylotic radiculopathy.It is preliminarily believed that HLA-A,HPD and MYL3 may be specific serum markers of acute cervical spondylotic radiculopathy,providing a new direction for further research on its pathogenesis.

BACKGROUND:Anterior subtotal corpectomy,decompression and fusion is a conventional method to treat cervical degenerative diseases.A titanium cage is an important implant to maintain the stability of the cervical spine after subtotal corpectomy.In recent years,many patients have complications such as titanium cage sinking,which are highly controversial. OBJECTIVE:To investigate the internal biomechanical relationship between the tilt angle of the titanium cage and postoperative titanium cage subsidence after anterior subtotal cervical corpectomy,decompression and fusion. METHODS:A three-dimensional finite element model of the C4-C6 segment was established by CT images of a normal human cervical spine,in which the anterior subtotal resection,decompression and fusion of the C5 vertebral body were simulated,and titanium cages with different tilt angles(-6° to-1° negative angle,that is,the front edge of titanium cage is shorter than the rear edge of titanium cage;1° to 6° positive angle,that is,the front edge of titanium cage is longer than the rear edge of titanium cage)were placed.After setting the boundary conditions,preloads of 50,100 and 150 N were applied respectively on the C4 vertebral body.The stress value of each contact point between the titanium cage and C4 lower-end plate and C6 lower-end plate(seven stress contact points on the contact surface of titanium mesh)was recorded and statistical analysis was conducted. RESULTS AND CONCLUSION:(1)The tilt angles of the titanium cage of the positive angle group and negative angle group under 50,100 and 150 N stress respectively were found by Mann Whitn test,with P<0.05,which was statistically significant.The dispersion coefficients of the positive angle group were smaller than those of the negative angle group under 50,100 and 150 N stress conditions.(2)Under 50,100 and 150 N stress conditions,the Wilcoxon sign rank test in the positive angle group of titanium cage tilt angle found that when the angle was set to 1° to 5°,the difference was not statistically significant(P>0.05).However,when the tilt angle of the titanium cage was set to 6°,the difference was statistically significant(P<0.05).(3)Under 50,100 and 150 N stress conditions,the Wilcoxon sign rank test in the negative angle group of titanium cage tilt angle found that when the tilt angle was set to-1° to-6°,the difference was not statistically significant(P>0.05).(4)It is concluded that in the sagittal position,the titanium cage with a positive tilt angle is more stable than with a negative tilt angle,which is more suitable for clinical use.The tilt angle of the titanium cage is relatively stable in the range of 1° to 5°.When the tilt angle is 6°,the stability starts to decline,which is easy to cause complications of titanium cage sinking after surgery.It is more suitable to select the titanium cage with a tilt angle of 1° to 5° according to the clinical situation during surgery to improve the efficacy.

Objective To analyze the chemical components of Xiaoshi Lidan pills by using UPLC-MS/MS and explore the mechanism of Xiaoshi Lidan pills in the treatment of cholelithiasis through network pharmacology and molecular docking techniques.Methods The pharmacologically active components of Xiaoshi Lidan pills were analyzed through UPLC-MS/MS and compared with standard references.Potential targets of these components were obtained by searching the TCMSP and ETCM databases,and disease-related targets for cholelithiasis were identified using the DisGeNET database.The overlapping targets were used to construct a protein-protein interaction(PPI)network in the String database,and a"drug-component-target"network was built using Cytoscape 3.9.1.GO and KEGG enrichment analyses were performed for the core targets.Finally,the top 5 compounds with strong activity were selected as ligands for molecular docking with the screened disease target genes.The anti-inflammatory activity was verified by RAW264.7 cells,and the mRNA expression of TNF-a and other inflammatory factors was detected by RT-PCR.Results UPLC-MS/MS identified 30 compounds in Xiaoshi Lidan pills,among which baicalin,quercetin,wogonin,baicalein-7-O-glucuronide,and emodin were identified as key components of Xiaoshi Lidan pills.Network pharmacology identified 107 targets associated with cholelithiasis,with Alb,TP53,ESR1,TNF,and INS identified as core targets.GO analysis indicated the involvement in inflammation response and steroid binding,while KEGG pathways were primarily related to lipid metabolism,atherosclerosis,and the TNF signaling pathway.Molecular docking analysis and anti-inflammatory screening in vitro showed that Xiaoshi Lidan pills exhibited certain anti-inflammatory activity by regulating inflammatory factors such as TNF and inhibiting NO production through baicalein,quercetin,emodin and other components.Conclusion Xiaoshi Lidan pills exerts its therapeutic effect on cholelithiasis by regulating TNF-related pathways through components such as baicalin,thereby inhibiting the inflammatory response.

Human herpesvirus-6 (HHV-6) is a ubiquitous virus. The incidence of HHV-6 after liver transplantation is estimated to be 22% ? 54%; it may present with fever, hepatitis, pneumonia, encephalitis, and myelosuppression and has a poor prognosis. HHV-6(+) recipients had a mortality rate of 29%, significantly higher than that of HHV-6(?) recipients (6%). Since most infections are asymptomatic, HHV-6 monitoring is not routinely performed in clinical practice, which means clinicians often ignore the diagnosis of HHV-6 and eventually delay diagnosis and treatment. In this paper, a case of human herpesvirus 6B encephalitis after liver transplantation was retrospectively analyzed, and the literature related to this disease was reviewed to improve the understanding of this disease.

Objective To explore the clinical value of neurography and nerve root sealing in treatment of multilevel lumbar spinal stenosis with lumbar instability using Endo-P/TLIF.Methods A total of 60 patients with multi-segment lumbar spinal stenosis and lumbar instability hospitalized in our hospital were included in this study From January 1,2022 to June 21,2022.All patients underwent nerve root closure angiography before surgery to confirm the responsible segments,and then the responsible segments were treated with Endo-P/TLIF.The patients were followed up for 6 months.The basic information on the age,gender,course of disease,surgical time,intraop-erative bleeding,hospitalization time,and off-bed ambulation time was collected.Then the data on VAS score,ODI score,JOA score,lumbar lordosis angle,intervertebral height,dural cross-sectional area,sacral inclination angle,pelvic projection angle,and pelvic inclination angle before,right after,3 months and 6 months after the operation were calculated.The number of responsible segments indicated by MRI and confirmed by nerve root closure angiography and the number of the single segment,double segments,3 segments,and above finally decompressed were statisti-cally analyzed.Results All patients went through the surgery safely.During the 6-month follow-up,one patient did not return to the hospital for consultation on time,and one patient was out of contact.Finally,the follow-up data of 58 patients were completely collected for statistical analysis.Fifty-five cases were remarkably improved,2 better,and 1 moderately,6 months after the operation,with a total effectiveness rate of 100%.The number of unilateral and bilateral single responsible segments confirmed by nerve root angiography and sealing was significantly larger than by MRI(P<0.05),but the number of unilateral and unilateral double,or multiple responsible segments was signifi-cantly smaller(P<0.05).There were statistically significant differences in terms of postoperative VAS score,ODI score,JOA score,VAS score,ODI score,JOA score,lumbar lordosis angle,intervertebral height,dural cross-sectional area,sacral inclination angle,pelvic inclination angle as compared to the preoperative data(P＜0.05).The pelvic projection angle was insignificantly improved as compared to the preoperative condition(P ? 0.05).Conclusion The accurate diagnosis with selective neurography and nerve root sealing improves the confirmation of responsible nerve segments before operation.Base on the accurate diagnosis,multi-segment lumbar spinal canal stenosis with lumbar instability can be effectively treated with Endo-P/TLIF,the responsible segment decompressed,trauma and bleeding reduced,hospital stay shortened,spinal physiological curvature well recovered,and clinical efficacy improved.Therefore,the method is worthy of extensive application in clinical practice.

The improvement of survival of osteosarcoma patients by the standard treatment strategy of osteosarcoma(neoadjuvant chemotherapy+surgical treatment+adjuvant chemotherapy)has been stabilized in the past 20 years,and the emergence of the slow(controlled)-release drug delivery system has provided a new strategy for the treatment of osteosarcoma.At present,thanks to the development of nanotechnology,great progress had been made to the technology of slow-release chemotherapy for osteosarcoma in China,but the clinical translation of the slow-release chemotherapy system has become the key to constrain its development.Based on this,this review summarizes the preclinical research progress of the main chemotherapeutic agents for osteosarcoma,including methotrexate,doxorubicin,cisplatin,and isocyclophosphamide,in the recent years,with the expectation of clarifying the safety and efficacy of the slow-release chemotherapy system for osteosarcoma,and facilitating the clinical translation of the slow-release chemotherapy system for osteosarcoma.

Objective: To compare the efficacy and safety of combining diosmin with Jiuhua hemorrhoid suppository versus diosmin alone for the treatment of hemorrhoid hemorrhage. Methods: The Jiuhua hemorrhoid suppository study was conducted in 10 medical centers across China from April 1, 2019 to June 30, 2020. Patients with hemorrhoid bleeding were randomized in a ratio of 1 : 1 to either receive Jiuhua hemorrhoid suppository and diosmin tablets (the study group) or diosmin tablets alone (the control group). The suppository was used once a day after defecation or at bedtime after rinsing the anus with warm water. Diosmin tablets were administered only once a day (0.9 g). The primary endpoint of the study was the assessment of hemorrhoid bleeding relief 7 ± 2 days after treatment, classified as “very effective” “effective” and “ineffective”. The secondary endpoint included the evaluation of pain alleviation using the visual analogue scale (VAS, with scores ranging from 0 to 10) and edema (with scores ranging from 0 to 3). The safety of the two treatment regimens was evaluated 14 ± 2 days after drug administration. Results: The full analysis set (FAS) comprised 107 participants in the study group and 111 in the control group, while the per-protocol set (PPS) included 106 participants in the study group and 111 in the control group. In terms of hemorrhoid bleeding, the proportion of very effective and effective cases in the study group were significantly higher than that in the control group [106 (99.06%) vs. 91 (81.98%), P < 0.0001] in the FAS, and the PPS results [105 (99.06%) vs. 91 (81.98%), P < 0.0001] were comparable to the FAS results. The pain VAS scores at day 7 after treatment were comparable between the two groups (0.80 ± 1.17 vs. 0.80 ± 1.20, P = 0.2177). The majority of the participants in both groups had an edema score of 0 at day 7 after treatment [96 (89.72%) vs. 99 (91.67%), P = 0.370 5]. Adverse events (AEs) occurred in 9 patients (8.4%) in the study group and 3 patients (2.7%) in the control group. In addition, 5 AEs in the study group and 1 AE in the control group were possibly in association with the study drug. Conclusion Compared with the administration of diosmin oral tablets alone, the addition of Jiuhua hemorrhoid suppository to the tablets demonstrates enhanced efficacy in addressing hemorrhoid bleeding, with satisfactory patient adherence and acceptable safety.

OBJECTIVE: To explore the clinical and genetic characteristics of a fetus with Melnick-Needles syndrome (MNS). METHODS: A fetus with MNS diagnosed at Ningbo Women and Children's Hospital in November 2020 was selected as the study subject. Clinical data was collected. Pathogenic variant was screened by using trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing. RESULTS: Prenatal ultrasonography of the fetus had shown multiple anomalies including intrauterine growth retardation, bilateral femur curvature, omphalocele, single umbilical artery, and oligohydramnios. Trio-WES revealed that the fetus has harbored hemizygous c.3562G>A (p.A1188T) missense variant of the FLNA gene. Sanger sequencing confirmed that the variant was maternally derived, whilst its father was of a wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). CONCLUSION The hemizygous c.3562G>A (p.A1188T) variant of the FLNA gene probably underlay the structural abnormalities in this fetus. Genetic testing can facilitate accurate diagnosis of MNS and provide a basis for genetic counseling for this family.
Child ; Female ; Humans ; Pregnancy ; Abnormalities, Multiple/genetics* ; Fetal Growth Retardation ; Fetus ; Filamins/genetics* ; Genetic Counseling ; Mutation ; Osteochondrodysplasias