2025年 · 第138卷第09期

Alzheimer’s disease (AD) is the leading cause of dementia and its incidence continues to increase, thereby placing a heavy burden on caregivers as well as society in general. The primary pathological features of AD include extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), as well as synaptic and neuronal loss, activated microglia, and reactive astrocytes.^[1]These pathological changes generally progress from an asymptomatic phase to clinically detectable cognitive impairment, and this process typically occurs over several years. Treatment with monoclonal antibodies that lower the amyloid plaque burden has recently been approved for the treatment of patients with early-stage AD, thus underscoring the importance of biomarkers that accurately reflect AD pathology in clinical practice.^[2]Biomarkers can indicate early signs of AD and enable early intervention in the disease process. Supplementary Figure 1, http://links.lww.com/CM9/C404 illustrates the neuropathological features of the AD brain that can be detected using fluid or imaging biomarkers.

The world is witnessing seismic shifts in the landscape of liver disease aetiologies encountered in clinical practice. In part, this is due to effective antiviral therapeutics complimented by sound public health policy, the combination of which has been highly successful in controlling hepatitis B and in reducing the burden of chronic hepatitis C. Unfortunately, economic prosperity, rising living standards and changes in dietary patterns and physical activity have heralded a new era of liver diseases defined by rising rates of metabolic syndrome and consequent metabolic dysfunction associated fatty liver disease (MAFLD). The latter is associated with liver-related complications, but also with adverse extra-hepatic outcomes. On recent estimates, at least a third of the global population is afflicted by MAFLD with 16% of these patients having the progressive subtype of metabolic dysfunction associated steatohepatitis (MASH).^[1]Alcohol related liver disease continues to overlay significantly in patient phenotypes, demanding a holistic and multidisciplinary approach to case detection and evidence-based treatment. Growing recognition of the fatty liver diseases as a major public health concern have led to updated iterations of both the European and more recently, Chinese guidelines, with the expressed goals of positively influencing the natural history of disease and preventing its adverse clinical outcomes.^[2,3]

Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation technique that regulates brain function by applying sinusoidal alternating currents of specific frequencies to targeted brain regions through the scalp electrodes.^[1]This guideline aims to evaluate and summarize the efficacy and safety of tACS in clinical applications. We conducted a structured literature search across major databases using the terms "tACS" or "transcranial alternating current stimulation" to identify all relevant literature up to June 2022. After rigorous screening, a total of 35 articles were included in this guideline (the detailed search and screening process is illustrated in Supplementary Figure 1, http://links. lww.com/CM9/C402). The guideline uses the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) evidence quality evaluation and recommendation strength grading standards established by the World Health Organization (WHO) for these 35 clinical trials.^[2]Following the Delphi method, electronic questionnaires were distributed to multiple specialized groups. After collection, summarization, and feedback, the application opinions and recommendation grades of tACS in various diseases were finalized (detailed procedures are provided in Supplementary Material 1, http://links.lww.com/CM9/C402).

Noncoding RNAs (ncRNAs) are a class of RNA molecules with little or no protein-coding potential. Emerging evidence indicates that ncRNAs are frequently dysregulated and play pivotal roles in the pathogenesis of pancreatic cancer. Their aberrant expression can arise from chromosomal abnormalities, dysregulated transcriptional control, and epigenetic modifications. ncRNAs function as protein scaffolds or molecular decoys to modulate interactions between proteins and other biomolecules, thereby regulating gene expression and contributing to pancreatic cancer progression. In this review, we summarize the mechanisms underlying ncRNA dysregulation in pancreatic cancer, emphasize the biological significance of ncRNA–protein interactions, and highlight their clinical relevance. A deeper understanding of ncRNA–protein interactions is essential to elucidate molecular mechanisms and advance translational research in pancreatic cancer.

Nanozymes are a distinct category of nanomaterials that exhibit catalytic properties resembling those of enzymes such as peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Nanozymes derived from Chinese herbal medicines exhibit the catalytic functions of their enzyme mimics, while retaining the specific medicinal properties of the herb (termed "herbzymes" ). These nanozymes can be categorized into three main groups based on their method of synthesis: herb carbon dot nanozymes, polyphenol–metal nanozymes, and herb extract nanozymes. The reported catalytic activities of herbzymes include POD, SOD, CAT, and GPx. This review presents an overview of the catalytic activities and potential applications of nanozymes, introduces the novel concept of herbzymes, provides a comprehensive review of their classification and synthesis, and discusses recent advances in their biomedical applications. Furthermore, we also discuss the significance of research into herbzymes, including the primary challenges faced and future development directions.

The production of high-quality oocytes requires precisely orchestrated intercellular communication. Extracellular vesicles (EVs) are cell-derived nanoparticles that play a vital role in the transfer of bioactive molecules, which has gained much attention in the field of diagnosis and treatment. Over the past ten years, the participation of EVs in the reproductive processes of oocytes has been broadly studied and has shown great potential for elucidating the intricacies of female reproductive health. This review provides an extensive discussion of the influence of EVs on oocytes, emphasizing their involvement in normal physiology and altered cargo under pathological conditions. In addition, the positive impact of therapeutic EVs on oocyte quality and their role in alleviating ovarian pathological conditions are summarized.

Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) is a cytosolic pattern recognition receptor that recognizes multiple pathogen-associated molecular patterns and damage-associated molecular patterns. It is a cytoplasmic immune factor that responds to cellular stress signals, and it is usually activated after infection or inflammation, forming an NLRP3 inflammasome to protect the body. Aberrant NLRP3 inflammasome activation is reportedly associated with some inflammatory diseases and metabolic diseases. Recently, there have been mounting indications that NLRP3 inflammasomes play an important role in liver injuries caused by a variety of diseases, specifically hepatic ischemia/reperfusion injury, hepatitis, and liver failure. Herein, we summarize new research pertaining to NLRP3 inflammasomes in hepatic injury, hepatitis, and liver failure. The review addresses the potential mechanisms of action of the NLRP3 inflammasome, and its regulation in these liver diseases.

Delayed platelet engraftment is a common complication after umbilical cord blood transplantation (UCBT), and there is no standard therapy. Avatrombopag (AVA) is a second-generation thrombopoietin (TPO) receptor agonist (TPO-RA) that has shown efficacy in immune thrombocytopenia (ITP). However, few reports have focused on its efficacy in patients diagnosed with thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

We conducted a retrospective study at the First Affiliated Hospital of the University of Science and Technology of China to evaluate the efficacy of AVA as a first-line TPO-RA in 65 patients after UCBT; these patients were compared with 118 historical controls. Response rates, platelet counts, megakaryocyte counts in bone marrow, bleeding events, adverse events and survival rates were evaluated in this study. Platelet reconstitution differences were compared between different medication groups. Multivariable analysis was used to explore the independent beneficial factors for platelet implantation.

Fifty-two patients were given AVA within 30 days post-UCBT, and the treatment was continued for more than 7 days to promote platelet engraftment (AVA group); the other 13 patients were given AVA for secondary failure of platelet recovery (SFPR group). The median time to platelet engraftment was shorter in the AVA group than in the historical control group (32.5 days vs. 38.0 days, Z = 2.095, P = 0.036). Among the 52 patients in the AVA group, 46 achieved an overall response (OR) (88.5%), and the cumulative incidence of OR was 91.9%. Patients treated with AVA only had a greater 60-day cumulative incidence of platelet engraftment than patients treated with recombinant human thrombopoietin (rhTPO) only or rhTPO combined with AVA (95.2% vs. 84.5% vs. 80.6%, P <0.001). Patients suffering from SFPR had a slightly better cumulative incidence of OR (100%, P = 0.104). Patients who initiated AVA treatment within 14 days post-UCBT had a better 60-day cumulative incidence of platelet engraftment than did those who received AVA after 14 days post-UCBT (96.6% vs. 73.9%, P = 0.003).

Compared with those in the historical control group, our results indicate that AVA could effectively promote platelet engraftment and recovery after UCBT, especially when used in the early period (≤14 days post-UCBT).

The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT).

A total of 1683 ALL patients from Peking University People’s Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariable analysis was performed to determine independent influencing factors from the univariable analysis.

Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity (P <0.001 for all). Disease status (complete remission 1 [CR1] vs. ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups (P = 0.027; P = 0.003; P = 0.035; P = 0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2–3, respectively (P <0.001). Multivariable analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival.

Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.

Gait impairment is closely related to quality of life in patients with Parkinson’s disease (PD). This study aimed to explore alterations in brain microstructure in PD patients and healthy controls (HCs) and to identify the correlation of gait impairment in the ON and OFF states of patients with PD, respectively.

We enrolled 24 PD patients and 29 HCs from the Movement Disorders Program at Beijing Friendship Hospital Capital Medical University between 2019 and 2020. We acquired magnetic resonance imaging (MRI) scans and processed the diffusion kurtosis imaging (DKI) images. Preprocessing of diffusion-weighted data was performed with Mrtrix3 software, using a directional distribution function to track participants’ main white matter fiber bundles. Demographic and clinical characteristics were recorded. Quantitative gait and clinical scales were used to assess the status of medication ON and OFF in PD patients.

The axial kurtosis (AK), mean kurtosis (MK), and radial kurtosis (RK) of five specific white matter fiber tracts, the bilateral corticospinal tract, left superior longitudinal fasciculus, left anterior thalamic radiation, forceps minor, and forceps major were significantly higher in PD patients compared to HCs. Additionally, the MK values were negatively correlated with Timed Up and Go Test (TUG) scores in both the ON and OFF in PD patients. Within the PD group, higher AK, MK, and RK values, whether the patients were ON or OFF, were associated with better gait performance (i.e., higher velocity and stride length).

PD exhibits characteristic regional patterns of white matter microstructural degradation. Correlations between objective gait parameters and DKI values suggest that dopamine-responsive gait function depends on preserved white matter microstructure. DKI-based Tract-Based Spatial Statistics (TBSS) analysis may serve as a tool for evaluating PD-related motor impairments (e.g., gait impairment) and could yield potential neuroimaging biomarkers.

Hepatic inflammatory cell accumulation and the subsequent systematic inflammation drive acute-on-chronic liver failure (ACLF) development. Previous studies showed that the vagus nerve exerts anti-inflammatory activity in many inflammatory diseases. Here, we aimed to identify the key molecule mediating the inflammatory process in ACLF and reveal the neuroimmune communication arising from the vagus nerve and immunological disorders of ACLF.

Proteomic analysis was performed and validated in ACLF model mice or patients, and intervention animal experiments were conducted using neutralizing antibodies. PNU-282987 (acetylcholine receptor agonist) and vagotomy were applied for perturbing vagus nerve activity. Single-cell RNA sequencing (scRNA-seq), flow cytometry, immunohistochemical and immunofluorescence staining, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) technology were used for in vivo or in vitro mechanistic studies.

The unbiased proteomics identified C-X-C motif chemokine ligand 9 (CXCL9) as the greatest differential protein in the livers of mice with ACLF and its relation to the systematic inflammation and mortality were confirmed in patients with ACLF. Interventions on CXCL9 and its receptor C-X-C chemokine receptor 3 (CXCR3) improved liver injury and decreased mortality of ACLF mice, which were related to the suppressing of hepatic immune cells’ accumulation and activation. Vagus nerve stimulation attenuated while vagotomy aggravated the expression of CXCL9 and the severity of ACLF. Blocking CXCL9 and CXCR3 ameliorated liver inflammation and increased ACLF-associated mortality in ACLF mice with vagotomy. scRNA-seq revealed that hepatic macrophages served as the major source of CXCL9 in ACLF and were validated by immunofluorescence staining and flow cytometry analysis. Notably, the expression of CXCL9 in macrophages was modulated by vagus nerve-mediated cholinergic signaling.

Our novel findings highlighted that the neuroimmune communication of the vagus nerve–macrophage–CXCL9 axis contributed to ACLF development. These results provided evidence for neuromodulation as a promising approach for preventing and treating ACLF.

Alpha-glucosidase inhibitors or dipeptidyl peptidase-4 inhibitors are both hypoglycemia agents that specifically impact on postprandial hyperglycemia. We compared the effects of acarbose and sitagliptin add on to metformin on time in range (TIR) and glycemic variability (GV) in Chinese patients with type 2 diabetes mellitus through continuous glucose monitoring (CGM).

This study was a randomized, open-label, active-controlled, parallel-group trial conducted at 15 centers in China from January 2020 to August 2022. We recruited patients with type 2 diabetes aged 18–65 years with body mass index (BMI) within 19–40 kg/m² and hemoglobin A1c (HbA1c) between 6.5% and 9.0%. Eligible patients were randomized to receive either metformin combined with acarbose 100 mg three times daily or metformin combined with sitagliptin 100 mg once daily for 28 days. After the first 14-day treatment period, patients wore CGM and entered another 14-day treatment period. The primary outcome was the level of TIR after treatment between groups. We also performed time series decomposition, dimensionality reduction, and clustering using the CGM data.

A total of 701 participants received either acarbose or sitagliptin treatment in combination with metformin. There was no statistically significant difference in TIR between the two groups. Time below range (TBR) and coefficient of variation (CV) levels in acarbose users were significantly lower than those in sitagliptin users. Median (25th percentile, 75th percentile) of TBR below target level <3.9 mmol/L (TBR_3.9): Acarbose: 0.45% (0, 2.13%) vs. Sitagliptin: 0.78% (0, 3.12%), P = 0.042; Median (25th percentile, 75th percentile) of TBR below target level <3.0 mmol/L (TBR_3.0): Acarbose: 0 (0, 0.22%) vs. Sitagliptin: 0 (0, 0.63%), P = 0.033; CV: Acarbose: 22.44 ± 5.08% vs. Sitagliptin: 23.96 ± 5.19%, P <0.001. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV (group with small wave, moderate wave and big wave). No significant difference was found in the complexity of glucose time series index (CGI) between acarbose users and sitagliptin users. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV.

Acarbose had slight advantages over sitagliptin in improving GV and reducing the risk of hypoglycemia. Time series analysis of CGM data may predict GV and the risk of hypoglycemia.

Chinese Clinical Trial Registry: ChiCTR2000039424.

During the coronavirus disease 2019 (COVID-19) pandemic, the disease severity of COVID-19 varied widely depending on the underlying conditions of infected patients.^[1]Interstitial lung disease (ILD) comprises a group of diffuse parenchymal lung disorders associated with substantial morbidity and mortality.^[2]Currently, multi-center data evaluating outcomes in patients with pre-existing ILD and COVID-19 are limited in China. Our study was based on a national multi-center prospective ILD registry study conducted by our group in China from 2017. We followed up patients in this cohort for the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and described their characteristics, disease severity and outcomes. We also explored the risk factors for COVID-19 severity and outcomes.

To the Editor: Maturity-onset diabetes of the young (MODY) is characterized as a non-autoimmune form of diabetes with an autosomal dominant inheritance pattern. Due to the overlapping clinical phenotypes among MODY, such as type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), over 80% of MODY patients are initially misdiagnosed.^[1]In recent decades, the advent and development of next-generation sequencing technology have facilitated a deeper understanding of MODY. High-throughput sequencing has remarkably expanded our knowledge of the pathogenic patterns of MODY across diverse populations.^[2,3]Given that the prevalence of MODY varies by ethnicity, clinical or research setting, selection criteria for identifying cases, and sequencing methods, the detection rate of causative genes differs among various study populations.^[4]Since the majority of previous studies on monogenic diabetes have primarily focused on populations of European descent, particularly in pediatric groups, a lack of comprehensive understanding of the clinical and genetic architecture of MODY in Chinese patients constrains the development of relevant genetic services within the health care system. Therefore, in this multi-center study, we aimed to identify novel pathogenic variants in MODY genes in three cohorts from three centers, and thereby obtain essential information for effective implementation of risk assessment, genetic counseling, and personalized therapies for those with MODY in China.

To the Editor: Charcot–Marie–Tooth disease type 2A (CMT2A), caused by mutations in Mitofusin-2 (MFN2), is the most common form of axonal CMT, accounting for 20–30% of CMT2.^[1,2]CMT2A exhibits clinical and genetic heterogeneity, with most disease-causing mutations located within the conserved guanosine triphosphatase (GTPase) domains.^[3]Intra-familial variability within the family has been observed. Consequently, comprehensive genotype–phenotype studies of CMT2A, particularly in large cohorts, are essential for advancing the understanding of CMT. Additionally, qualitative muscle magnetic resonance imaging (MRI) has been used to assess disease severity in CMT.^[4]However, studies on intramuscular fat fraction (FF), a potential sensitive marker, in CMT2A patients remain scarce in the literature.