ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease (AD), but the neurobiological mechanisms linking synaptic pathology, neural oscillatory dynamics, and brain network reorganization remain unclear. This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments, molecular profiling, and neurophysiological monitoring. MethodsIn this prospective double-blind trial, 12 AD patients underwent a 14-day protocol of 20 Hz rTMS, with comprehensive multimodal assessments performed pre- and post-intervention. Cognitive functioning was quantified using the mini-mental state examination (MMSE) and Montreal cognitive assessment (MOCA), while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living (ADL) scale and combined neuropsychiatric inventory (NPI)-Hamilton depression rating scale (HAMD). Peripheral blood biomarkers, specifically Aβ1-40 and phosphorylated tau (p-tau181), were analyzed to investigate the effects of rTMS on molecular metabolism. Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients, while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization. Furthermore, systematic assessment of correlations between cognitive scale scores, blood biomarkers, and network characteristics was performed to elucidate cross-modal therapeutic associations. ResultsClinically, MMSE and MOCA scores improved significantly (P<0.05). Biomarker showed that Aβ1-40 level increased (P<0.05), contrasting with p-tau181 reduction. Moreover, the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores. Post-intervention analyses revealed significant modulations in oscillatory power, characterized by pronounced reductions in delta (P<0.05) and theta bands (P<0.05), while concurrent enhancements were observed in alpha, beta, and gamma band activities (all P<0.05). Network analysis revealed frequency-specific reorganization: clustering coefficients were significantly decreased in delta, theta, and alpha bands (P<0.05), while global efficiency improvement was exclusively detected in the delta band (P<0.05). The alpha band demonstrated concurrent increases in average nodal degree (P<0.05) and characteristic path length reduction (P<0.05). Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181. Additionally, the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band. However, the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands. Conclusion20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) significantly improves cognitive function and enhances the metabolic clearance of β-amyloid and tau proteins in AD patients. This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation, which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks. These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales, blood biomarkers, and EEG——in understanding and monitoring the progression of AD. This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as ¹⁷⁷Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of ¹⁷⁷Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, ¹⁷⁷Lu-LNC1010, for PRRT. In preclinical studies, ¹⁷⁷Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of ¹⁷⁷Lu-LNC1010 in patients with advanced/metastatic NETs. ¹⁷⁷Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of ¹⁷⁷Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two ¹⁷⁷Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.

Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + d-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP₃)-Ca²⁺ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGKζ as a novel therapeutic target.

Tumor cells use glycolysis to provide material and energy under hypoxic conditions to meet the energy requirements for rapid growth and proliferation， namely the Warburg effect. Even under aerobic conditions， tumor cells mainly rely on glycolysis to provide energy. Therefore， glucose transporter protein 1（GLUT1）， which is involved in the process of glucose metabolism， plays an important role in tumorigenesis， development and drug resistance， and is considered to be one of the important targets in the treatment of malignant tumors. In recent years， research on tumor glucose metabolism has gradually become a hot spot. It has been shown that various factors are involved in the regulation of tumor energy metabolism， among which the role of GLUT1 is the most critical. In this paper， the authors reviewed the latest research progress of GLUT1-targeted traditional Chinese medicine（TCM） active ingredient nano-delivery system in tumor therapy， aiming to reveal the feasibility and effectiveness of this system in the delivery of chemotherapeutic drugs. The GLUT1-targeted TCM active ingredient nano-delivery system can overcome the bottleneck of the traditional targeting strategy as well as the high-permeability long retention（EPR） effect. In summary， the authors believe that the GLUT1-targeted TCM active ingredient nano-delivery system provides a new strategy for targeted treatment of tumors and has a broad application prospect in tumor prevention and treatment.

177Lu-prostate specific membrane antigen(PSMA)radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China.Based on domestic clinical practice and experimental data and referred to international experience and viewpoints,the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Objective To explore the presence and potential interactions of microbes and bacteriophages in the blood of healthy individuals by employing in-depth bioinformatics mining to analyze the structure and function of the blood microbi-ome ecosystem.Methods Blood plasma samples from 1 600 voluntary blood donors collected at Mianyang Central Blood Station from 2012 to 2018 were subjected to DNA extraction and library construction.High-throughput sequencing was con-ducted using the Illumina HiSeq 4500 platform,followed by extensive bioinformatics analysis.Microbial abundance in blood samples was analyzed using metagenomic analysis software such as Bowtie2,Trimmomatic and Kraken.Subsequent phage-ome analysis included sequence quality control,assembly,identification,clustering and functional annotation using software such as Megahit,geNomad,CheckV and eggNOG-mapper.Phylogenetic trees,species annotation and host analysis and pre-diction for the identified blood bacteriophages were constructed using iTOL,BLAST and PhaBOX software.Results Met-agenomic sequencing identified microbes across 36 phyla,151 orders,338 families,338 genera and 3 757 species in the plasma samples.At the species level,the most abundant species included Bacillus cereus,Lactobacillus murinus,L.johnso-nii,Faecalibacterium prausnitzii,B.thuringiensis,L.reuteri,Cutibacterium acnes,Dietzia sp.JS16-p6b,Mycoplasma hyo-rhinis,M.hyopneumoniae and Staphylococcus aureus.Through phageome analysis,202 viral Operational Taxonomic Units(vOTUs)were identified,revealing 24 types of bacteriophages.Host analysis using the viral host database completed mat-ches for 15 potential bacteriophage hosts,including Stenotrophomonas maltophilia,Rhodoferax lacus,Pseudoalteromonas marina,Thalassotalea loyana,Vibrio alginolyticus,V.tasmaniensis,V.vulnificus,Pseudomonas sp.,Agrobacterium sp.ST15.13/040,Enterococcus gallinarum,Flavobacterium sp.,Thermotoga naphthophila,Chryseobacterium sp.RU33C,L.acidipiscis and Neisseria mucosa.Conclusion The study of the healthy human blood microbiome and phageome reveals the presence of microbes and phages in the blood,which may have profound impacts on human health.

AIM:To explore the therapeutic effect of teprenone(geranylgeranylacetone,GGA)on lipopolysac-charide(LPS)-induced cardiac dysfunction and its mechanism.METHODS:(1)Eight-week-old male C57BL/6 wild-type mice and carboxyl terminus of heat shock protein 70(HSP70)-interacting protein(CHIP)gene knockout mice were randomly divided into control group,LPS group,LPS+GGA group and GGA group,with 8 mice in each group.The model was established by intraperitoneal injection of LPS(25 mg/kg),and 1 h after LPS stimulation,mice were given intraperito-neal injection of GGA(100 mg/kg).The technique of high-resolution ultrasonography system was used to evaluate the car-diac function of mice.The serum of mice from each group were collected to detect the levels of creatine kinase-MB(CK-MB)and lactate dehydrogenase(LDH).HE staining was performed to observe histological changes of cardiac tissues.ELISA was used to detect the levels of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in cardiac tissues.West-ern blot was used to detect the protein levels of HSP70,CHIP,karyopherin-α 2(KPNA2),myeloperoxidase(MPO),vas-cular cell adhesion molecule(VCAM),intercellular cell adhesion molecule(ICAM),and nuclear factor-κB(NF-κB)in cardiac tissues.(2)In vitro cell inflammation model was established using mouse myocardial cells HL-1 stimulated with LPS.ELISA was used to detect the levels of TNF-α and IL-6 in cell supernatants.Western blot was used to detect the pro-tein expression levels of HSP70,CHIP,and KPNA2 in myocardial cells.Immunofluorescence staining was performed to observe the content of nuclear NF-κB.RESULTS:(1)GGA effectively improved cardiac function of LPS-stimulated mice,significantly increased ejection fraction and left ventricular fractional shortening(P<0.01),reduced serum levels of CK-MB and LDH(P<0.01),and alleviated myocardial injury.(2)GGA significantly reduced the release of TNF-α and IL-6 caused by LPS(P<0.01),as well as nuclear translocation of NF-κB,decreased the levels of KPNA2,MPO,VCAM and ICAM in cardiac tissues,and increased the levels of HSP70 in cardiac tissues and cells(P<0.01).(3)In CHIP knockout myocardial cells and mice,GGA failed to inhibit LPS-induced inflammatory response and lost its effect on im-proving cardiac function.CONCLUSION:The protective effect of GGA against LPS-caused cardiac dysfunction of mice is related to increasing expression of HSP70 and promoting CHIP activation,which inhibits the translocation of NF-κB into nucleus and suppresses inflammatory factor release.CHIP knockout abolishes the effects of GGA on reducing LPS-induced inflammatory response and myocardial injury.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Objective To investigate the correlation between traditional Chinese medicine(TCM)syndrome elements and risk factors in children with IgA vasculitis(IgAV,also known as Henoch-Sch?nlein purpura).Methods The medical records of 131 children with IgAV were retrospectively analyzed.And then the distribution of their TCM syndrome elements was investigated,and the correlation of TCM syndrome elements with the gender,age,clinical symptoms,as well as risk factors such as mosquito bite,pathogen infection,and allergic rhinitis was analyzed.Results(1)Among the 131 children with IgAV,the diseases-location syndrome elements of IgAV involved lung in 97 cases(74.05%),spleen in 61 cases(46.56%),kidney in 54 cases(41.22%),liver in 17 cases(12.98%),and heart in 11 cases(8.40%);the disease-nature syndrome elements of IgAV involved blood stasis in 131 cases(100.00%),wind-damp in 125 cases(95.42%),wind-heat in 90 cases(68.70%),damp-heat in 72 cases(54.96%),blood heat in 49 cases(37.40%),qi deficiency in 19 cases(14.50%),and yin deficiency in three cases(2.29%).(2)There were 69 cases(52.67%)of females and 62 cases(47.33%)of males among the IgAV children,with females outnumbering males.The age group of IgAV children was predominated by five to six years old,and 10 cases(7.63%)were younger than four years old,18 cases(13.74%)were four years old,39 cases(29.77%)were five years old,34 cases(25.95%)were six years old,17 cases(12.98%)were seven years old,and 13 cases(9.92%)were older than seven years old.The disease-nature syndrome elements such as blood stasis,wind-damp,wind-heat,and damp-heat were frequently seen in the age group of five to seven years old,yin deficiency was frequently seen in the age group older than seven years,and blood stasis was seen in all age groups.(3)The results of logistic regression analysis of the correlation between TCM syndrome elements and risk factors in IgAV patients showed that allergic rhinitis was positively correlated with blood stasis[OR=2.236,95%CI(1.049-4.007)],damp-heat[OR=2.183,95%CI(1.554-3.671)]and wind-damp[OR=1.202,95%CI(1.050-2.409)];pathogen infection was positively correlated with blood stasis[OR=3.199,95%CI(1.457-4.101)]and damp-heat[OR=1.119,95%CI(1.072-2.009)];mosquito bite was positively correlated with blood stasis[OR=4.533,95%CI(1.029-9.022)]and damp-heat[OR=2.257,95%CI(1.081-13.207)];the gender was positively correlated with blood stasis[OR=1.352,95%CI(1.271-3.018)]and wind-damp[OR=1.149,95%CI(1.071-3.102)].The differences were all statistically significant(P＜0.05 or P＜0.01).Conclusion IgAV usually involves the lungs and is also related to the five zang organs.Its pathogenesis is characterized by excess in superficiality such as blood stasis and wind-damp-heat in the early stage,and is predominated by deficiency in origin such as qi deficiency and yin deficiency in the later stage.For the children with IgAV,mosquito bite,pathogen infection and allergic rhinitis are more likely to induce blood stasis and wind-damp-heat;TCM syndrome elements such as wind-heat,damp-heat,blood heat,and qi deficiency are frequently seen in the males,while TCM syndrome elements such as blood stasis,wind-damp,and yin deficiency are frequently seen in the females.