Diabetic kidney disease (DKD) with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression. Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials. In this study, we integrated large-scale plasma proteomics, genetic-driven causal inference, and experimental validation to identify prioritized targets for DKD using the UK Biobank (UKB) and FinnGen cohorts. Among 2844 diabetic patients (528 with DKD), we identified 37 targets significantly associated with incident DKD, supported by both observational and causal evidence. Of these, 22% (8/37) of the potential targets are currently under investigation for DKD or other diseases. Our prospective study confirmed that higher levels of three prioritized targets-insulin-like growth factor binding protein 4 (IGFBP4), family with sequence similarity 3 member C (FAM3C), and prostaglandin D2 synthase (PTGDS)-were associated with a 4.35, 3.51, and 3.57-fold increased likelihood of developing DKD, respectively. In addition, population-level protein-altering variants (PAVs) analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD, through the classic NLR family pyrin domain containing 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) apoptotic axis. Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin’s lymphoma Berlin–Frankfurt–Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% (95% confidence interval [CI], 69.0% to 83.9%) and 92.3% (95% CI, 86.1% to 95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5% to 95.5%), and 67.9% (95% CI, 55.4% to 77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6% to 19.0%), 65.7% (95% CI, 47.6% to 78.9%), 55.7% (95% CI, 26.2% to 77.5%), and 70.7% (95% CI, 48.6% to 84.6%), respectively. At the end of follow-up, one of the five patients who received maintenance therapy with VBL relapsed, and seven patients receiving anaplastic lymphoma kinase inhibitor maintenance therapy did not experience relapse. Conclusion This study has confirmed the poor prognostic of MDD (+), high-risk site and SC/LH, but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

Femoral neck fracture (FNF) in the elderly patients is currently a major health challenge worldwide, with excessive consumption of medical resources, high incidence of complications as well as suboptimal outcome and prognosis. Hip joint arthroplasty (HJA) has been the mainstream treatment for FNF in the elderly, but the conventional surgical approaches and techniques are still confronted with a series of bottlenecks such as dislocation, limp and limb length discrepancy. In recent years, direct anterior approach (DAA) for HJA (DAA-HJA) has been a major new choice in the field of joint replacement, which achieves improved clinical effectiveness of HJA in the treatment of elderly FNF, due to the fact that DAA approach involves the neuromuscular interface and accords with the idea of soft tissue retention and enhanced recovery after surgery. However, there is still a lack of unified understanding of standard technique and procedure of DAA-HJA in the treatment of elderly FNF. Therefore, relevant experts from the Hip Joint Group of Chinese Orthopedics Association of Chinese Medical Association, Youth Arthrology Group of Orthopedic Committee of PLA, Orthopedic Committee of Chongqing Medical Association, Branch of Orthopedic Surgeons of Chongqing Medical Doctor Association and Sport Medicine Committee of Chongqing Medical Association were organized to formulate the " Chinese expert consensus on the technical standard of direct anterior hip arthroplasty for elderly femoral neck fracture ( version 2023)" based on evidence-based medicine. This consensus mainly proposed 13 recommendations covering indications, surgical plans, prosthesis selections, surgical techniques and processes, and postoperative management of DAA-HJA in elderly patients with FNF, aiming to promote standardized, systematic and patient-specific diagnosis and treatment to improve the functional prognosis of the patients.

External apical root resorption is among the most common risks of orthodontic treatment, and it cannot be completely avoided and predicted. Risk factors causing orthodontic root resorption can generally be divided into patient- and treatment-related factors. Root resorption that occurs during orthodontic treatment is usually detected by radiographical examination. Mild or moderate root absorption usually does no obvious harm, but close attention is required. When severe root resorption occurs, it is generally recommended to suspend the treatment for 3 months for the cementum to be restored. To unify the risk factors of orthodontic root resorption and its clinical suggestions, we summarized the theoretical knowledge and clinical experience of more than 20 authoritative experts in orthodontics and related fields in China. After discussion and summarization, this consensus was made to provide reference for orthodontic clinical practice.
Humans ; Tooth Movement Techniques/adverse effects* ; Root Resorption/etiology* ; Consensus ; Dental Cementum ; Risk Factors

ObjectiveTo summarize the effect of visual electrophysiological diagnosis and treatment technology on postoperative urinary incontinence in early intervention after transurethral enucleation and resection of the prostate （TUERP）. MethodsTotally 86 patients with benign prostatic hyperplasia （BPH） who underwent TUERP in the Puji Branch Hospital of Dongguan People's Hospital from December 2020 to June 2022 were selected as the treatment group， who received electrophysiological treatment after postoperative removal of the catheter on the 6th day after surgery， while 79 cases who received no electrophysiological treatment after surgery were selected as the control group. The urinary incontinence rates of the two groups on the 6^th day， at 1 month and 3 months after surgery were observed. ResultsThere was no statistical difference between the two groups in the preoperative basic data. The rates of urinary incontinence after removal of the catheter in the two groups on the 6^th day after surgery were 13 cases （15.1%） in the treatment group and 12 cases （15.2%） in the control group. There was no significant difference between the two groups （P >0.05）， and the overall postoperative urinary incontinence rate in the two groups was 15.2% （25/165）. At one month after surgery， only 4 cases （4.65%） had slight urinary incontinence in the treatment group， while 13 cases （16.5%） in the control group still had urinary incontinence， and the difference between the two groups was statistically significant （ P=0.019）. After follow-up to three months after operation， there was no case of urinary incontinence in the treatment group， and there were still 7 cases （8.86%） of urinary incontinence in the control group. The difference between the two groups was statistically significant （P=0.005）. ConclusionThe early intervention of visual electrophysiological diagnosis and treatment technology can effectively prevent the occurrence of urinary incontinence after TUERP， and has good value in clinical application.

Aristolochic acids (AAs) are widely distributed in Aristolochiaceae, and are important toxic components in medicinal plants of Aristolochiaceae. As one of the most powerful carcinogens in the Carcinogenic Potency Database (CPDB), AAs can induce hepatotoxicity, nephrotoxicity, carcinogenicity, mutagenicity, and other adverse reaction. AAs also can produce a series of metabolites such as AA-DNA adducts in the body, and their specific metabolites can be used as biomarkers for early diagnosis and treatment of related diseases. Thus, the current discovery for technical means that can quickly and accurately detect biomarkers possesses significant research value. AAs can be attenuated by processing, compatibility, molecular breeding, and other methods to improve the clinical safety of Chinese medicine containing AAs. In this review, we report the distribution of AAs, attenuation strategies and biomarker detection. We would like to provide a reference for the quality control of AAs-containing Chinese medicines, as well as for the prevention and control of diseases caused by AAs.

Alzheimer' s disease (AD) is an age-related neurodegenerative disease which seriously damages the physical and mental health of the elderly and causes huge economic pressure to the society. However, the pathogenesis of AD is not completely elucidated. There is still no effective drug to cure AD in clinical practice. Tau protein is a soluble and non-aggregating microtubule-related protein, which can stabilize microtubule structure. The structure and function of Tau protein are abnormal in AD' s brain while under pathological conditions, and the abnormal Tau protein aggregates to insoluble neurofibrillary tangles which damages microtubules and leads to cognitive dysfunction. These changes of Tau protein are regulated by a variety of post-translational modifications, which directly change the properties and functions of proteins by attaching specific chemical moieties to Tau protein's C-terminus or N-terminus. It's confirmed that a variety of Tau post-translational modifications, like phosphorylation, glycosylation, acetylation and sumoylation is abnormal in AD's brain, which is closely related to Tau degradation and the accumulation of toxic substances. In this review, we summarized the latest progress supporting the role of exercise regulated Tau post-translational modification in the prevention and treatment of Alzheimer's disease. Firstly, exercise inhibits tau protein hyperphosphorylation by suppressing the activity of GSK-3β and MAPKs and possibly by up-regulating the activity of PP2A. Secondly, exercise increases tau protein O-GlcNAcylation by up-regulating the expression of GLUT1 and GLUT3, also possibly by regulating the balance of activity of OGT and OGA. Thirdly, exercise decreases tau protein acetylation possibly by inhibiting p300 and activating SIRT1; exercise regulates the acetylation of Tau KXGS possibly by inhibiting HDAC6. Lastly, exercise inhibits abnormal Tau sumoylation possibly by regulating the co-location sites of phosphorylation and sumoylation.

Objective:To establish a qualitative and quantitative method for the determination of aristolochic acids in Aristolochia cinnabarina dried root tubers. Method:The dried root tubers of A. cinnabarina was qualitative and quantitative analysis by ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry （UPLC-QTOF-MS/MS）. The analysis was performed on Waters ACQUITY UPLC-BEH C₁₈ column （ 2.1 mm×100 mm， 1.7 μm） with the mobile phase of 0.1% formic acid aqueous solution （A）-acetonitrile （B） for gradient elution （0-1 min， 10%B； 1-9 min， 10%-30%B； 9-11 min， 30%-50%B； 11-15 min， 50%-90%B）. The flow rate was 0.45 mL·min^-1， column temperature was 35 ℃， and the detection wavelength was 250 nm. Mass spectral data was acquired in positive mode of electrospray ionization （ESI）. At the same time， the UPLC fingerprints of aristolochic acids in 21 batches of A. cinnabarina dried root tubers were established， and the contents of 5 aristolochic acids in A. cinnabarina dried root tubers from different producing areas and different harvesting periods were determined. Result:A total of 17 compounds， including 8 aristolochic acids， 7 aristololactams and 2 4，5-dioxoaporphine alkaloids， were identified from A. cinnabarina dried root tubers by mass spectrometry data and bibliographic information. Ten common peaks were identified in the UPLC fingerprint， and they were tuberosinone-N-β-D-glucoside， aristolactam Ⅰa-N-β-D-glucoside， aristolochic acid Ⅳa-O-β-D-glucoside， aristolactam Ⅲa-N-β-D-glucoside， aristolactam Ⅰ-N-β-D-glucoside， aristolochic acid Ⅲa， aristolochic acid Ⅳa， aristolochic acid Ⅱ， aristolactam Ⅰ and aristolochic acid Ⅰ. According to the quantitative analysis， the results exhibited that aristolochic acid Ⅲa， aristolochic acid Ⅳa， aristolochic acid Ⅱ， aristolactam Ⅰ and aristolochic acid Ⅰ had good linear relationships in the linear range. The relative standard deviations （RSDs） of precision， stability and reproducibility tests were all less than 3.0%， the recovery was 97.06%-101.84% （RSD<3.0%）. The contents of aristolochic acid Ⅰ， aristolochic acid Ⅱ， aristolochic acid Ⅲa， aristolochic acid Ⅳa， and aristolactam Ⅰ in 21 batches of A. cinnabarina dried root tubers were 0.938 6-3.567 5， 1.377 6-3.688 1， 0.056 3-0.527 7， 0.108 8-0.305 5， 0.021 0-0.081 7 mg·g^-1， respectively. Conclusion:The content of aristolochic acids in A. cinnabarina dried root tubers has a certain difference， the contents of aristolochic acid Ⅰ and Ⅱ are higher than other aristolochic acids. The established method is rapid， simple， accurate and reliable， which can provide reference for the quality control and evaluation of A. cinnabarina dried root tubers.

The incidence and prevalence of asthma have increased remarkably in recent years. There are lots of factors contributing to the occurrence and development of asthma. With the improvement of sequencing technology, it has been found that the microbiome plays an important role in the formation of asthma in early life. The roles of the microbial environment and human microbiome in the occurrence and development of asthma have attracted more and more attention. The environmental microbiome influences the occurrence of asthma by shaping the human microbiome. The specific mechanism may be related to the immune regulation of Toll-like receptors and T cells (special Tregs). Intestinal microbiome is formed and changed by regulating diet and lifestyle in early life, which may affect the development and maturation of the pulmonary immune system through the intestinal-pulmonary axis. It is well-recognized that both environmental microbiomes and human microbiomes can influence the onset of asthma. This review aims to summarize the recent advances in the research of microbiome, its relationship with asthma, and the possible mechanism of the microbiome in the occurrence and development of asthma. The research of the microbial environment and human microbiome may provide a new target for the prevention of asthma in children who have high-risk factors to allergy. However, further study of "when and how" to regulate microbiome is still needed.
Asthma/prevention & control* ; Child ; Gastrointestinal Microbiome ; Humans ; Hypersensitivity ; Intestines ; Microbiota