Telomerase RNA (TERC) is subject to various modifications, yet the implications of these modifications for telomerase biology remain largely unexplored. In this study, we conducted a comprehensive mapping of N6-Methyladenosine (m6A) modifications within TERC RNA and elucidated their regulatory role in telomerase function. Our findings demonstrate that TERC undergoes methylation at adenosine residues A111 and A435 by METTL3. A deficiency in TERC m6A, which is also linked to various human telomerase disease-related mutations and deletions, significantly reduces telomerase activity and telomere length by disrupting the association between TERC and TERT. Mechanistically, YTHDC1 was identified as a scaffold facilitating the interaction between TERT and TERC, binding to TERT while recognizing m6A sites on TERC. Knockdown of YTHDC1 significantly diminished the interaction between TERT and TERC, thereby reducing telomerase activity and phenocopying the deficiency of METTL3. Furthermore, reconstituting wild-type YTHDC1 rescued telomere attrition, proliferation defects, and senescence in YTHDC1-knockdown alveolar epithelial cells, whereas truncated YTHDC1 (which retains m6A recognition but lacks TERT-binding capacity) failed to restore these phenotypes. Collectively, our work establishes m6A modification of TERC as a central regulator of telomerase function and reveals YTHDC1's scaffolding role in TERT-TERC assembly, shedding new light on the regulation of telomerase and related diseases.

BACKGROUND:The clinical importance of transient intraoperative hypotension (IOH) remains debated, and existing models often rely on high-resolution waveform data that are not routinely available. METHODS AND FINDINGS:We developed a Transformer-based deep learning model to predict IOH in real time using continuous vital sign time-series data. The model was trained on 319,699 surgical cases from a tertiary hospital in China (2013-2023) and externally validated using an independent dataset from South Korea. Model interpretability was explored through a real-time alert simulation using 10 representative surgical cases from the internal validation cohort, comparing predicted IOH risk trajectories with measured mean arterial pressure (MAP). To assess clinical relevance, a nested cohort study evaluated the association between IOH burden (cumulative MAP ≤65/60/55 mmHg in mmHg·min) and postoperative acute kidney injury (AKI) and acute kidney disease (AKD). The Transformer model achieved strong prediction performance at 5-, 10-, and 15-min horizons (AUCs 0.904, 0.892, 0.882; recall ≥88.3%). Compared with XGBoost, the Transformer had higher recall (internal 5-min recall 0.891 versus 0.737) and substantially better probability calibration (expected calibration error 0.0083 versus 0.0373). XGBoost showed higher overall accuracy and specificity (internal 5-min specificity 0.913 versus 0.723). External validation confirmed comparable discrimination across models and generalizability, with attenuated calibration differences. In alert simulations, predicted IOH risk closely corresponded to MAP fluctuations. IOH burden was significantly associated with postoperative AKI and AKD (MAP ≤65 mmHg: OR per 60 mmHg·min 1.10 (95% CI, [1.02, 1.19]; p = 0.012) for AKI; 1.26 (95% CI, [1.19, 1.33]; p < 0.001) for AKD). The study is limited by its retrospective design, and prospective, multicenter validation is needed to confirm real-time applicability and generalizability of the model. CONCLUSIONS:IOH burden is associated with increased risk of postoperative AKI and AKD. The Transformer model prioritizes sensitivity and calibration for short-term IOH prediction, whereas XGBoost emphasizes accuracy and specificity, reflecting different operating characteristics. Prospective, real-time evaluation is needed before clinical implementation.

Aging involves morphological and functional changes across different organs, but how these changes are linked among the different organs remains to be elucidated. Here, we uncover a central role of platelets in systemic aging. In aged mice, the levels of platelet-secreted pro-inflammatory factors (PSPF) increased greatly in the serum and platelets, leading to a diffuse increase of platelet infiltration in the brain, liver, lung, kidney, and aortic root. The RNA-binding protein HuR/ELAVL1, a major regulator of RNA metabolism, promoted the production of PSPF in platelets. Platelet-specific deletion of HuR reduced the expression of PSPF in platelets, alleviated platelet infiltration in the brain, liver, lung, kidney, and aortic root, and delayed systemic aging. By using single-nucleus sequencing, platelet-specific HuR ablation was found to alleviate p53 and pro-inflammatory signaling pathways in liver, lung, and brain tissues in aged mice. Our findings highlight a role of platelets in coordinating aging traits across organs.

Objective:Global aging has led to a steady rise in the number of older adults suffering from the first-episode depression with cognitive impairment (FEDCI), which imposes a huge medical and financial burden on patients and their families. The aim of this study was to explore the influence of the NOS3 rs1799983 polymorphism on the FEDCI. Methods:A total of 224 first-episode depression (FED) and 295 FEDCI patients were included in the study, whose serum levels of NOS3 and inflammatory factors were detected by RT-qPCR. The TaqMan probe method was used to detect the rs1799983 genotype distribution. GDS-15 and HAMD-17 were used to detect the level of depression, and MMSE was used to detect cognitive impairment. Chi-square analysis was used to detect the correlation between clinical characteristics and NOS3 expression. Risk factors for FEDCI were analyzed by logistic regression. Results:The NOS3 expression decreased, and TNF-α, IL-1β, and IL-6 expression increased in the FEDCI group, and these two factors' expression was negatively correlated. The MMSE score was positively correlated with the NOS3 expression. The TT genotype and T gene frequency in the distribution of FEDCI patients accounted for a high percentage, with the TT genotype being the causative genotype. Education, GDS-15, HAMD-17, and MMSE are correlated with the NOS3 expression. MMSE, NOS3 expression, and the rs1799983 TT genotype were risk factors of FEDCI. Conclusion:The NOS3 expression was decreased in FEDCI, and the rs1799983 TT genotype was pathogenic. The NOS3 rs1799983 polymorphism in FEDCI provided a potential diagnostic and therapeutic target.

Triple-negative breast cancer is getting more attention due to its unfavorable prognosis. Although the surgical resection is the first-line option in the treatment of breast cancer. But due to the poor efficacy and prognosis, now Cisplatin (DDP) based preoperative Neo-adjuvant therapy becomes the mainstay of triple-negative breast cancer. Immune cells in the tumor environment have significant impacts on the effectiveness of treatment. In this study, we observed an anti-tumor effect of combining Parecoxib with DDP in a 4T1 mouse model. Then we designed a co-delivery system based on a thermo-sensitive injectable hydrogel for preoperative Neo-adjuvant combination chemotherapy of the triple-negative breast cancer. The hydrogel system co-loaded with Parecoxib and DDP characterized by a special sol-gel transition in response to temperature and presented a sustained release in vitro and in vivo. In the tumor microenvironment (TME), we observed a synergistic anti-tumor effect and inhibition of cell proliferation, as well as a significant increase in mature Dendritic cells (mDCs) and IFN-gamma+CD8+ T cells. Hydrogel loaded with Parecoxib and DDP also reduced the need for frequent administration. These findings demonstrate that the co-delivery hydrogel system DDP-Pa@Gel has great potential in the preoperative Neoadjuvant chemotherapy of triple-negative breast cancer, that will promote the efficacy and reduce the frequency of administration as a valuable option.

Delayed extubation after anesthesia can lead to adverse clinical outcomes. We aimed to identify the risk factors for delayed extubation in patients undergoing robot-assisted radical prostatectomy and to develop a visualized nomogram prediction model for clinical use. A total of 624 patients were enrolled and divided into training group, validation group, and temporal validation group. The training group was utilized to develop a nomogram, whereas the validation group and temporal validation group were used to assess its performance. LASSO regression was employed to refine variables and select predictors, and a nomogram was constructed using multivariate logistic regression. The performance of the model was internally validated using calibration and receiver operating characteristic curves. Additionally, decision curve analysis and clinical impact curves were used to assess the clinical utility of the model. Patients who underwent robot-assisted radical prostatectomy between January 2022 and April 2024 were included and divided into a training group (n = 389), a validation group (n = 98), and a temporal validation group (n = 137). Logistic regression identified cerebral infarction, pulmonary disease, coronary heart disease, age, and intraoperative hypotension as independent predictors of delayed extubation. A nomogram constructed based on these factors demonstrated excellent predictive performance, with area under the curve values of 0.763 (95

Background Postoperative sleep disturbance (PSD) is a common complication following laparoscopic cholecystectomy (LC). It is associated with delirium, cognitive decline and delayed recovery. Effective preventive strategies are currently lacking. Dexmedetomidine, a highly selective α₂-adrenergic receptor agonist, offered in a nasal spray formulation with high bioavailability and convenient administration, may present a novel approach for PSD prevention.Objectives The primary objective is to evaluate the effect of evening dexmedetomidine nasal spray on the incidence of PSD on the first postoperative day in LC patients. Secondary objectives include assessing its impact on the quality of recovery, anxiety and depression and pain scores.Methods and analysis This is a multicentre, prospective, randomised, double-blind, controlled trial. At least 260 patients will be enrolled and randomly allocated in a 1:1 ratio to receive either dexmedetomidine (50 µg nasal spray) or saline placebo the night before and the night of surgery (between 20:00 and 22:00). The primary outcome is the incidence of PSD on postoperative day 1 defined as an Numerical Rating Scale (NRS) >6 or Athens Insomnia Scale >6 score, which will be compared between groups using the χ2 or Fisher’s exact test on the full analysis set. Secondary outcomes include quality of recovery (Quality of Recovery-15 scale, QoR-15), anxiety and depression (Hospital Anxiety and Depression Scale, HADS), pain (NRS), postoperative nausea and vomiting and adverse events, analysed using t-tests, rank-sum tests or repeated-measures mixed-effects models as appropriate.Ethics and dissemination The study protocol has been approved by the Ethics Committee of the Affiliated Drum Tower Hospital of Nanjing University Medical School (Approval No.: 2025–0064-02) and registered with the Chinese Clinical Trial Registry. The findings of this study will be disseminated through various channels. Academic dissemination will include publication in peer-reviewed journals and presentations at national and international conferences.Trial registration number ChiCTR2500101205.

Dexmedetomidine (Dex), an α2-adrenergic receptor (α2-AR) agonist, is widely used for its antihyperalgesic effects in perioperative pain management, yet its underlying mechanisms remain largely undefined. Here, we identify a rapid, circuit-specific mechanism by which Dex reverses stress-induced hyperalgesia (SIH) in mice. Stress exposure strengthens excitatory drive from the orbitofrontal cortex (OFC) to the anterior insula cortex (AIC), shifting the excitatory/inhibitory balance toward excitation and increasing the intrinsic excitability of AIC glutamatergic neurons. Viral tracing and optogenetics reveal a direct OFC-AIC glutamatergic projection. Optogenetic or chemogenetic activation of this pathway in otherwise naïve mice potentiates glutamatergic synaptic transmission and is sufficient to induce hyperalgesia, phenotyping SIH. Dex rapidly suppresses these effects by engaging presynaptic α2-ARs on OFC terminals, thereby reducing transmitter release at OFC-AIC synapses. Consistently, chemogenetic silencing of AIC neurons or of the OFC-AIC projection alleviates hyperalgesia in SIH mice. These findings define the OFC-AIC glutamatergic circuit as a key substrate for stress-related pain amplification and uncover a rapid presynaptic α2-AR "brake" as the mechanism underlying Dex's antihyperalgesic action, highlighting a tractable therapeutic entry point for stress-exacerbated pain states.

BackgroundDespite recent advancements in blood conservation strategies, perioperative allogeneic red blood cell (RBC) transfusion remains common in pediatric patients undergoing scoliosis surgery. This study aimed to develop a simplified preoperative risk score to predict allogeneic RBC transfusion requirements in this population.MethodsWe conducted a retrospective cohort study of 1,992 pediatric patients (<18 years) who underwent scoliosis surgery at two tertiary care centers between January 2018 and May 2023. The primary outcome was perioperative allogeneic RBC transfusion. Missing data were addressed via multiple imputation, generating 10 imputed datasets. Predictor variables were screened through univariate and least absolute shrinkage and selection operator (LASSO) regression. Multivariable logistic regression was used to develop the prediction model, followed by stepwise variable selection to identify a parsimonious set of predictors without compromising model performance. A simplified risk score and corresponding risk stratification system were derived from the final model coefficients.ResultsThe overall perioperative RBC transfusion rate was 32.9% (655/1,992). After variable selection and model optimization, the final prediction model included four preoperative variables: American Society of Anesthesiologists (ASA) physical status grade, Cobb angle, diagnosis, and weight. The resulting risk score ranged from 0 to 20 points and exhibited strong discriminative ability, with an area under the receiver operating characteristic curve (AUC) of 0.818 [95% confidence interval (CI): 0.793–0.843] in the training set and 0.814 (95% CI: 0.764–0.864) in the validation set. Three risk categories were established: low risk (0–4 points), medium risk (5–10 points), and high risk (≥11 points). Transfusion rates exhibited a progressive increase across risk categories in both training (9.6, 37.3, 76.3%) and validation (7.3, 32.1, 74.1%) sets.ConclusionWe developed a simplified risk score based on four readily available preoperative variables (diagnosis, weight, Cobb angle, and ASA grade) to predict perioperative allogeneic RBC transfusion in pediatric scoliosis surgery. This tool facilitates preoperative transfusion risk assessment and stratification, serving as a practical clinical aid that may contribute to optimized perioperative blood management strategies.

Cancer-related pain and anxiety significantly negate the quality of life in patients. Oligodendrocyte precursor cells (OPCs) were reported to involve in engulf synapses and remodel neural circuits. This study aimed to elucidate the role of OPCs-mediated phagocytosis of GABAergic synapses in a mouse model of bone cancer pain. Male C3H mice were utilized to establish a model of bone cancer pain. In vivo fiber photometry was used to monitor the activity of GABAergic neurons, and chemogenetic techniques were applied to modulate neuronal excitation. The phagocytosis of GABAergic synapses by OPCs was visualized via immunofluorescence-based 3D reconstruction and immunoelectron microscopy. Interventions targeting lipocalin-2 (LCN2) and its receptor SLC22A17 were carried out with adeno-associated virus (AAV), siRNA, and pharmacological tools. On the 21st postoperative day, mice with bone cancer displayed significant pain and anxiety-like behaviors. Tumor-bearing mice exhibited a compensatory increase in calcium activity among GABAergic neurons within the anterior cingulate cortex (ACC). Compared with sham-operated mice, OPC phagocytosis of GABAergic synapses was higher in the tumor-bearing mice than controls. Concurrently, a pronounced upregulation of LCN2 expression was observed in the tumor group. Administration of LCN2-neutralizing antibodies or AAV-mediated intervention markedly alleviated pain and anxiety-related behaviors in mice with bone cancer. Moreover, the LCN2 receptor SLC22A17 expression was significantly increased. Targeted inhibition of SLC22A17 induced cytoskeletal remodeling and decreased their phagocytic capacity of OPCs. Collectively, LCN2/SLC22A17 signal was involved in OPCs-mediated phagocytosis of GABAergic synapses and contributed to cancer pain and anxiety development.

BACKGROUND:Multiple scales are available to evaluate the health status of older surgical patients; however, their relative ability to predict postoperative major adverse cardiac and cerebrovascular events (MACCE) remains unclear. OBJECTIVE:To examine the association between preoperative health status, as measured by four commonly used scales, and 30-day postoperative MACCE in older surgical patients, and to compare their predictive performance and incremental value against the Revised Cardiac Risk Index (RCRI). DESIGN:A retrospective study of a large multicentre cohort. SETTING:Nineteen tertiary hospitals across China participating in a perioperative database. PATIENTS:Patients aged ≥65 years who underwent noncardiac, non-neurosurgical surgery between April 2020 and April 2022 were included in the analysis. The Activities of Daily Living (ADL), EuroQol Five-Dimension Five-Level (EQ-5D-5L), Metabolic Equivalent of Task (MET), FRAIL, and RCRI were evaluated preoperatively. MAIN OUTCOME MEASURE:The primary outcome was the occurrence of MACCE within 30 days after surgery, defined as any of the following: stroke, myocardial infarction, angina pectoris, congestive heart failure, cardiac arrest, or all-cause mortality. RESULTS:Among the 7996 patients, 126 (1.6%) experienced MACCE. Similar to the RCRI, the four health assessments were significantly associated with MACCE risk. The RCRI alone yielded an area under the curve (AUC) of 0.610 [95% confidence interval (CI): 0.563 to 0.658]. Incorporating each scale improved the predictive performance of the RCRI. The RCRI-Plus model, comprising RCRI, age, severity of anaemia, and surgical duration, achieved an AUC of 0.692 (95% CI: 0.643 to 0.741). Further addition of the four scales to the RCRI-Plus increased discrimination, with the highest AUC observed for the RCRI-Plus model incorporating FRAIL (AUC 0.724; 95% CI: 0.679 to 0.770). However, DeLong's test showed no significant differences between this model and the RCRI-Plus models incorporating ADL, EQ-5D-5L, or MET. CONCLUSIONS:Preoperative health status assessed by four geriatric scales was significantly correlated with postoperative MACCE and provided improved risk discrimination beyond the RCRI. Adding any of these assessments to the RCRI enhanced predictive performance, with FRAIL showing the greatest incremental benefit. These findings underscore the value of multidimensional health status evaluation for preoperative cardiac and cerebrovascular risk stratification, with frailty assessment warranting particular attention. TRIAL REGISTRY:ClinicalTrials.gov, NCT04911530.

Perioperative neurocognitive disorder (PND) is a significant neurological complication in aging perioperative patients that impacts post-operative cognition. PND is currently diagnosed through cognitive function testing, which is limited by its subjectivity and time requirements. Thus, the identification of biomarkers to assess PND onset is a priority to identify at-risk individuals and enable interventions and treatments to patient outcomes. This article synthesizes expert perspectives on brain aging and PND, presents the latest clinical evidence on PND biomarkers (imaging, electroencephalography, and molecular biomarkers), and delves into the relationship between PND and other age-related cognitive disorders. Thorough review of PND research identified several biomarkers with high sensitivity and specificity, offering a solid scientific foundation to predict and diagnose PND. These biomarkers not only enhance diagnostic accuracy for clinicians but also provide opportunities for earlier intervention and more effective treatment, potentially enhancing patient outcomes and quality of life.

High-intensity work environments and high psychological stress place anaesthesiologists in a state of chronic stress. T lymphocyte subsets are an essential component of the peripheral immune cells and are important in the pathophysiology of chronic stress. The aim of this study was to investigate the levels of psychological stress, the expression levels of circulating T lymphocyte subsets, and the correlation between them. This study included 61 participants from two tertiary hospitals in Nanjing, China. The Chinese Perceived Stress Scale (CPSS), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7) scales were used to assess psychological stress levels. The percentage of circulating T lymphocyte subsets was determined using flow cytometry. The proportion of anaesthesiologists with high stress levels was 45.90 https://www.chictr.org.cn/showproj.html?proj=29630 .

Postoperative cognitive dysfunction (POCD) is a common complication following surgeries involving general anesthesia. Although the CCL5-CCR5 axis is implicated in various neurological conditions, its role in POCD remains unclear. In our POCD model, we observed an increase in CCL5 and CCR5 levels concurrent with microglial activation and significant upregulation of inflammatory cytokines IL-6 and IL-1 beta. Administration of MVC, a CCR5 antagonist, alleviated neuroinflammation, prevented dendritic spine loss, and improved cognitive deficits by inhibiting the CCR5/CREB/NLRP1 pathway. However, the cognitive benefits of MVC were reversed by the CREB inhibitor 666-15. Our findings highlight the potential of targeting the CCL5-CCR5 axis as a therapeutic strategy for preventing and treating POCD.

A single-center retrospective study was designed to investigate the risk factors associated with delayed discharge from the Anesthesia Intensive Care Unit (AICU). This retrospective study involved patients admitted in the AICU from January 2017 to December 2022. Risk factors for the delayed discharge from the AICU were analyzed by the binary multivariate logistic regression analysis. Nomogram was constructed to predict the risk of delayed discharge from AICU. The performance of the nomogram was assessed using the receiver operating characteristic curve and calibration curve. A decision curve analysis was also performed to determine the net benefit threshold of prediction. A total of 14,338 patients admitted in the AICU were retrospectively recruited, involving 9,271 males and 5,067 females. The incidence of delayed discharge from the AICU in the cohort was 1.54

BACKGROUND:The choice of anaesthetic agents may influence specific aspects of postoperative recovery, such as haemodynamic stability, recovery times and the incidence of adverse events, in patients undergoing day-case laparoscopic cholecystectomy. Propofol is widely used in total intravenous anaesthesia (TIVA) for its favourable recovery profile, while etomidate, valued for its haemodynamic stability, is less commonly used due to concerns about adrenal suppression. This study aims to compare etomidate-based and propofol-based TIVA on postoperative quality of recovery in patients undergoing day-case laparoscopic cholecystectomy, hypothesising that etomidate is non-inferior to propofol. METHODS AND ANALYSIS:A multicentre, double-blind, randomised controlled non-inferiority trial was conducted to compare the effects of etomidate vs propofol for TIVA on postoperative quality of recovery in patients undergoing day-case laparoscopic cholecystectomy. A total of at least 336 participants were enrolled and randomly assigned to either the etomidate or propofol group in a 1:1 ratio, stratified by site. The primary outcome was quality of recovery on postoperative day 1, quantified by the Quality of Recovery-15 questionnaire. Non-inferiority between the groups was determined using a margin of -6 points and a 95% CI. Secondary outcomes included perioperative haemodynamic stability, recovery times (eg, response to verbal commands, time to extubation and duration of postanaesthesia care unit stay), postoperative complications (eg, hypoxaemia, nausea/vomiting, delirium) and patient-reported outcomes such as pain, satisfaction and quality of sleep. Long-term outcomes included quality of life at 6 and 12 months, assessed using the 36-Item Short Form Health Survey. ETHICS AND DISSEMINATION:This study was approved by the Ethics Committee of Nanjing University Medical School, Drum Tower Hospital (No. 2024-371-04) and registered in the Chinese Clinical Trial Registry. TRIAL REGISTRATION NUMBER:ChiCTR2400087413.

Smoking represents the largest preventable risk factor for human health, yet previous studies have failed to establish conclusive evidence regarding the causal relationship between smoking and neurodegenerative diseases. This study employs genetic correlation and Mendelian randomization analyses to investigate the potential association between smoking and neurodegenerative disorders. This study analyzed summary data from genome-wide association studies (GWAS) on smoking and neurodegenerative diseases. Genetic correlations were evaluated using linkage disequilibrium score regression (LDSC), and causal relationships were assessed through multiple Mendelian randomization methods including inverse-variance weighted (IVW), MR-Egger regression, weighted median (WME), weighted mode (WM), and simple mode (SM). sensitivity analyses were performed to examine heterogeneity, horizontal pleiotropy, and conduct leave-one-out analysis. whether an individual had ever smoked regularly (SmkInit) is positively correlated with an increased risk of Alzheimer’s disease (AD) (rg = 0.134, P = 2.74 × 10⁻⁸) and negatively correlated with the risk of Parkinson’s disease (PD) (rg = − 0.100, P = 1.8 × 10⁻4). cigarettes per day (CigDay) are associated with a higher risk of AD (rg = 0.162, P = 4.26 × 10⁻⁵). Smoking cessation (SmkCes) is linked to an elevated risk of AD (rg = 0.1466, P = 1.5 × 10⁻4), whereas age of initiation of regular smoking (AgeSmk) is negatively correlated with AD risk (rg = − 0.181, P = 8.63 × 10⁻⁶) but positively correlated with PD risk (rg = 0.170, P = 2.0 × 10⁻4). Results suggest that both SmkInit and CigDay significantly increase AD risk (OR = 1.030, P = 1.74 × 10⁻⁴; OR = 1.022, P = 5.04 × 10⁻⁴), while SmkCes is associated with a reduced risk of PD (OR = 0.638, P = 1.91 × 10⁻⁶) and amyotrophic lateral sclerosis (ALS) (OR = 0.830, P = 5.29 × 10⁻⁶). This study identified significant genetic associations between smoking behaviors and neurodegenerative diseases. CigDay and SmkInit increased AD risk, while SmkCes was linked to reduced risks of PD and ALS. First genome-wide study to map smoking’s direct effects across five major neurodegenerative diseases. Genetic correlation analysis revealed a genetic link between smoking phenotypes and AD and PD. We have identified a causal relationship between smoking phenotypes and AD, PD, and ALS.

Cancer pain, a frequent complication in patients with cancer, adversely affects quality of life and survival rates. Microglia promote nociceptive information transmission by modulating myelin integrity during pain perception. However, the specific mechanisms by which microglia regulate myelin in the context of cancer pain remain poorly understood. In this study, we developed a bone cancer pain model to examine the interactions among microglia, myelin, and oligodendrocyte precursor cells and their roles in cancer pain. Our study found that mice with bone cancer pain had oligodendrocyte differentiation defects and myelin loss, and that promoting myelination did not relieve pain. In addition, we observed that reactive microglia and inflammatory cytokines increased and microglia phagocytosed myelin in mice with bone cancer pain. Inhibition of microglia not only alleviated pain behaviors in mice with bone cancer but also mitigated myelin phagocytosis and the proliferation of oligodendrocyte precursor cells. Our study suggests that microglia-mediated myelin loss and oligodendrocyte precursor cell proliferation may be one of the pathological mechanisms underlying pain in mice with bone cancer.

Perineurial network (PNN) is a special extracellular matrix structure in the central nervous system, and its alterations are associated with the pain hypersensitivity. Recent studies have suggested a potential interaction between abnormal activation of spinal microglia and PNN. This study investigates whether S-ketamine mitigates neuropathic pain via inhibiting degradation of PNNs by spinal microglia. C57BL/6 mice were utilized for CCI modeling to induce neuropathic pain. Subsequent to modeling, we assessed the expression changes of spinal microglia, PNN and inflammatory factors. Microglia colocalization with PNN was evaluated via 3D reconstruction to quantify spatial overlap. Minocycline was administered to target microglia. S-ketamine was subsequently administered to CCI mice, and its effects on pain behavior, microglial activation, and PNN were investigated. Microglia-PNN colocalization was evaluated via 3D reconstruction to quantify spatial overlap. CCI mice exhibited significant neuropathic pain, accompanied by increased microglia-mediated phagocytosis of PNN. Minocycline and S-ketamine treatment of CCI mice led to improved pain thresholds, suppression of neuroinflammation, and reduction in microglia-mediated phagocytosis of PNN. Increased microglial phagocytosis leading to PNNs degradation in the spinal dorsal horn plays a critical role in neuropathic pain pathogenesis. The analgesic effects of S-ketamine may be attributed to its modulation of this mechanism.

Individuals with prevalent hypertension are at an increased risk of developing dementia and tend to exhibit lower cognitive function. However, the magnitude of cognitive change following the onset of new hypertension remains uncertain. A cohort of 7949 adults aged 45 and older without hypertension at baseline was followed prospectively for 7 years. Cognitive assessments were conducted initially (wave 1) and at least once between wave 2 (2013) and wave 4 (2018). Cognitive function was evaluated using a global cognition score, derived as a composite measure from four distinct cognitive tests. Linear mixed-effects models were employed to estimate the changes in cognitive function at the onset of hypertension (intercept change) and the subsequent rate of cognitive decline (slope change) over the follow-up period. The models accounted for pre-hypertension cognitive trajectories and participant-specific factors, with interaction terms included for antihypertensive medication, age and educational level. Of the 7949 participants, 1993 (25.07%, mean age 58.8 ± 8.84 years, 48.0% male) developed new-onset hypertension. Both groups-those without hypertension and those with new-onset hypertension-experienced annual cognitive decline during the follow-up period. The onset of hypertension was not associated with an acute decrease in global cognition or performance on the four cognitive tests. However, after the onset of hypertension, participants exhibited a statistically significant accelerated decline in global cognition (- 0.029 SD/year; 95% CI - 0.043 to - 0.015; p < 0.001), attention and calculation (- 0.022 SD/year; 95% CI - 0.040 to - 0.004; p = 0.017), and orientation (- 0.022 SD/year; 95% CI - 0.038 to - 0.005; p = 0.010). No significant changes were observed in episodic memory (- 0.009 SD/year; 95% CI - 0.028 to 0.010; p = 0.346) or visuospatial abilities (- 0.013 SD/year; 95% CI - 0.032 to 0.006; p = 0.185). Interaction analyses indicated that the use of antihypertensive medication, age, and educational level moderated the extent of global cognitive decline post-hypertension onset. The onset of new hypertension was not associated with an immediate decline in cognitive function compared to individuals without hypertension. However, it was linked to more rapid declines in global cognition, orientation, and attention and calculation abilities over time. These findings underscore the potential importance of hypertension prevention for maintaining long-term brain health.