Abstract Background Noble gases xenon (Xe) and argon (Ar) emerge as promising therapeutic agents. Extensive studies have validated their efficacy across various models of organ injury, positioning them as novel candidates for clinical translation in critical care and perioperative medicine. Main Body Xe and Ar exert protective effects through multiple mechanisms, including activation of hypoxia-inducible factor-1 (HIF-1) pathway, inhibition of regulated cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis, and suppression of pro-inflammatory signaling. By modulating these key signaling pathways, Xe and Ar have been shown to improve outcomes in neurological, cardiac, renal, and hepatic systems across diverse models of ischemia-reperfusion injury, traumatic brain injury, and systemic inflammation. Clinically, Xe has shown efficacy in anesthesia, neonatal neuroprotection, and cardiac arrest management. Ar, with greater availability and lower costs, holds promise for broader clinical use but remains in the early stage of translational research. Conclusion Xe and Ar represent novel biologically active gases with the potential to provide promising therapies in perioperative and clinical care medicine. Overcoming current limitations, such as a lack of standardized delivery systems and optimized dosing strategies, is key to uncovering their clinical application.

Background:Fulminant myocarditis (FM) in children can progress rapidly to cardiogenic shock, with high risk of mortality. Early recognition of prognostic markers is critical to guide timely escalation of circulatory support. This multicenter study sought to characterize clinical features and identify early predictors of in-hospital mortality in pediatric FM. Methods:We conducted a retrospective cohort study of patients <18 years with FM admitted to eight ECMO-capable pediatric intensive care units between January 2018 and August 2023. Clinical, biochemical, electrocardiographic, and echocardiographic variables were analyzed. Logistic regression was used to identify predictors of mortality, and receiver operating characteristic (ROC) curves were generated to assess discriminatory performance. Results:A total of 187 children were included; 157 (84.0%) required ECMO. In-hospital mortality was 16.6% (31/187). Univariate analysis identified elevated CK-MB, higher peak lactate, and ventricular tachycardia as associated with mortality. In multivariate analysis, peak lactate (AUC 0.791) and CK-MB (AUC 0.774) remained independent predictors. A combined model of peak lactate and ventricular tachycardia demonstrated moderate discrimination (AUC 0.772), whereas a composite model incorporating CK-MB, peak lactate, and ventricular tachycardia achieved the best predictive performance (AUC 0.815). Elevated lactate measured 12 h after initiation of extracorporeal membrane oxygenation or intensive conventional therapy further increased mortality risk (OR 1.219, 95% CI 1.004-1.481). Conclusion:Peak lactate, CK-MB, and ventricular tachycardia are early independent predictors of in-hospital mortality in pediatric FM. Persistent hyperlactatemia within 12 h of advanced support provides additional prognostic value and may assist clinicians in early risk stratification.

Abstract Background Sleep, pain, affect, cognition and energy (SPACE) has been described as a latent symptom-severity construct in chronic overlapping pain conditions. Its population-level structure and associations with chronic pain interference and functional disability remain uncertain. Methods We conducted a cross-sectional analysis of UK Biobank participants aged ≥40 years. Prespecified standardised symptom domains were examined using correlation analysis, principal component analysis, exploratory factor analysis and k-means clustering. Associations with chronic pain interference, current work disability, poor self-rated health and longstanding illness or disability were assessed using covariate-adjusted logistic regression. A four-domain score excluding pain tested whether associations extended beyond the pain domain. Secondary analyses examined convergence with actigraphy, biomarkers, polygenic risk scores and brain magnetic resonance imaging phenotypes. Results Of 501,935 eligible participants, 475,134 had complete domain data. Domains were modestly intercorrelated (r=0.04–0.46). Clustering identified lower- and higher-burden phenotypes comprising 70.5% and 29.5% of participants; current work disability occurred in 1.3% and 10.3%, respectively. Adding the four non-pain domains increased the area under the curve for chronic pain interference from 0.593 to 0.672 and for work disability from 0.748 to 0.850. Inclusion of pain increased the work-disability area under the curve to 0.863. Multimodal measures added smaller increments. Conclusions A multidimensional symptom profile was identifiable at population scale and was concurrently associated with chronic pain interference and work disability, with non-pain domains contributing information beyond pain burden alone. Significance Chronic pain interference and work disability were associated with a broader multidimensional symptom burden spanning sleep, affect, cognition and energy, rather than pain alone. In a large population cohort, the non-pain domains added substantial concurrent discriminatory information. These findings support multidimensional assessment of functionally impairing pain and justify prospective evaluation of whether symptom-system profiles predict incident disability, healthcare use, recovery trajectories or treatment response.

Background:Postoperative delirium (POD) is an acute neuropsychiatric syndrome that occurs following surgery, characterized by inattention and broader cognitive deficits. This study aimed to synthesize randomized evidence on perioperative strategies that prevent POD in elderly patients undergoing orthopaedic surgery. Methods:We conducted a Bayesian network meta-analysis of randomised controlled trials (RCTs) retrieved from PubMed, Embase, Web of Science, and Cochrane Library from inception to March 2026. Eligible trials enrolled adults aged 60 years or older undergoing orthopaedic surgery and reported POD incidence with validated assay assessments. Risk ratios (RR) and mean differences with 95% Credible Interval (CrI) were estimated. The risk of bias was assessed using the Cochrane tool, and the certainty of the evidence was evaluated with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Results:79 RCTs comprising 16,012 patients were included. Compared with placebo, dexmedetomidine (RR 0.49, 95% CrI 0.39-0.61) has the most consistent evidence for reducing the risk of POD incidence, while ketamine (RR 0.39, 95% CrI 0.23-0.64), rivastigmine (RR 0.33, 95% CrI 0.16-0.65), olanzapine (RR 0.35, 95% CrI 0.17-0.71), and lidocaine (RR 0.41, 95% CrI 0.21-0.77) showed promising but heterogeneous benefits across current literature. Evidence for analgesic and anaesthetic interventions was limited. Conclusion:Dexmedetomidine offers the most substantial evidence for lowering POD incidence after orthopaedic surgery in elderly; ketamine, rivastigmine, olanzapine, and lidocaine warrant further evaluation. High-quality, low-bias RCTs are needed to verify the effects of specific analgesic or anaesthetic regimens on POD occurrence. Translational potential statement:This network meta-analysis highlights the promising translational potential of dexmedetomidine in preventing POD for elderly orthopaedic patients. Dexmedetomidine emerges as the most reliable option for immediate clinical adoption, while ketamine, rivastigmine, olanzapine, and lidocaine show promise but require confirmatory trials before routine use. The findings set the stage for personalized anaesthetic protocols that minimize POD and its associated morbidity and healthcare costs.

MYOM1, a major component of the vertebrate myofibrillar M band, binds myosin, titin, and light meromyosin, has been linked to cardiomyopathy and unexpected sudden death, yet the pathogenic mechanisms remain unclear. Leveraging the UK Biobank, we identified a significant association between dilated cardiomyopathy (DCM) and loss-of-function (LoF) MYOM1 variants. Functional studies showed that MYOM1 deficiency precipitates DCM with overt heart failure, accompanied by sarcomeric disorganization, pathological structural remodeling, and mitochondrial abnormalities. Optical mapping of cardiac electrophysiology revealed slowed ventricular conduction with increased heterogeneity, alongside marked prolongation of action potential duration and depolarization. At the molecular level, transcriptomic and immunoblot analyses demonstrated downregulation of key sarcoplasmic reticulum regulators, including RYR2 and SERCA2. Consistent with these findings, calcium imaging documented impaired calcium conduction velocity and blunted intracellular calcium transients, indicating sarcoplasmic reticulum dysfunction. Our study provided significant insights into the role of MYOM1 variants in DCM. LoF of MYOM1 contributes to DCM and heart failure by disrupting sarcomere integrity and destabilizing sarcoplasmic reticulum calcium homeostasis, with secondary mitochondrial abnormalities. These data establish MYOM1 as a disease-relevant determinant of myocardial remodeling and excitation-contraction coupling, and support MYOM1 as a potential target for risk stratification and therapy in DCM.

Purpose:Currently, there are limited effective treatment strategies available for refractory chemotherapy-induced peripheral neuropathy (CIPN). Lumbar sympathicolysis is a minimally invasive therapy and may offer an option for CIPN. This single-center, prospective, observational study aimed to evaluate the efficacy and safety of CT-guided lumbar sympathicolysis in alleviating multiple symptoms of refractory CIPN in the lower extremities. Methods:This single-arm study conducted at Henan Cancer Hospital from September 2022 to July 2024,twenty-five patients with refractory CIPN in both lower extremities received CT-guided lumbar sympathicolysis. The effectiveness of the treatment for pain, numbness, cold sensation, and dyskinesia was evaluated using a Numerical Rating Scale (NRS) at day 3, one month, and three months following treatment. Treatment response was defined as an NRS score reduction of ≥30%. Changes in NRS scores over time were analyzed using generalized estimating equations. Any adverse effects related to the treatment were recorded. Results:Postoperative NRS scores for pain, numbness, cold sensation, and dyskinesia at 3 days, 1 month, and 3 months were significantly lower than these assessed before the treatment. The pain improvement assessed with NRS scores was reported to be 61.1% at 3 days, 55.5% at 1 month, and 55.5% at 3 months by patients (n=18). The numbness improvement was 24.0% at day 3, 16.0% at 1 month, and 16.0% at 3 months (n=25). Cold sensation improvement (n=21) was 71.4%, 57.1%, and 52.4% at day 3, 1 month, and 3 months (n=21), respectively. The decreased dyskinesia sensation was reported by 50.0% at day 3 and 1 month, and 57.1% at 3 months (n=14). Overall, all symptoms were decreased by 68% at day 3, 64% at 1 month, and 60% at 3 months. Conclusion:The CT-guided lumbar sympathicolysis may offer substantial symptom relief for CIPN in the lower extremities without clinically significant adverse effects. These preliminary findings warrant further validation in larger, controlled studies.

OBJECTIVES:To determine whether early total bilirubin (T-Bil) trajectories during the first 72 hours after intubation identify trajectory-defined groups with distinct prognostic profiles associated with short-term mortality in mechanically ventilated ICU patients. DESIGN:Multicenter retrospective cohort study with a prespecified day 3 landmark design to mitigate immortal-time bias. SETTING:Mixed medical-surgical ICUs at four tertiary centers. PATIENTS:Adults receiving invasive mechanical ventilation who survived to the day 3 landmark and had serial T-Bil measurements on day 0 and day 3 (± 24 hr). INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Patients were classified according to baseline T-Bil (≤ 1.2 vs. > 1.2 mg/dL) and the direction of change between day 0 and day 3 (change in T-Bil [ΔT-Bil]), yielding four trajectory-defined groups. The primary outcome was 30-day all-cause mortality after the day 3 landmark; 90-day mortality was secondary. Conditional survival was assessed using Kaplan-Meier methods with log-rank tests. Multivariable Cox models adjusted for prespecified covariates available by day 3 (age, sex, body mass index, intubating department, baseline mean arterial pressure, log-transformed aspartate aminotransferase/alanine aminotransferase ratio and platelet count, creatinine, renal replacement therapy, and vasoactive support). Rising T-Bil trajectories were independently associated with higher 30-day mortality, with the strongest association among patients with normal baseline T-Bil who exhibited early increases. In contrast, elevated baseline T-Bil followed by early decline was not associated with excess risk. Findings were consistent in complete-case analyses, in models incorporating day 3 partial Sequential Organ Failure Assessment for severity adjustment, and in analyses of 90-day mortality. Restricted cubic spline analyses demonstrated a nonlinear dose-response relationship between ΔT-Bil and mortality. CONCLUSIONS:Early T-Bil dynamics within 72 hours after intubation were associated with distinct prognostic profiles beyond baseline bilirubin levels and may provide a pragmatic marker for early risk stratification in mechanically ventilated ICU patients.

Sepsis is an immune dysregulation syndrome triggered by infection, characterized by host self-damage due to immune imbalances. This study focuses on dynamic changes of mitochondrial symbiotic function in host cells during sepsis and systematically investigates dysregulation of mitochondrial communication modes and the intrinsic link between mitochondrial DNA (mtDNA) release and immune dysregulation. We demonstrate that during early-stage LPS treatment, mitochondria actively remodel by extruding flagella-like extensions (termed mitoFLARE). These structures, nanotubes mediating long-distance transport, form through glycosylated TRAK1 binding FHL2 to drive actin network formation, thereby shifting mitochondrial communication from direct fusion to nanotube-mediated transport. This helps maintain dynamic exchange within the inner mitochondrial membrane under LPS treatment. However, as inflammation progresses, deteriorated mitochondrial quality control disrupts the MICOS-SAM complex, abrogates inner-outer membrane anchoring, and suppresses mitoFLARE functions. All these ultimately enhance endoplasmic reticulum-mitochondrial contacts to promote outer membrane rupture and result in mtDNA release into the cytoplasm to activate cGAS-STING signaling, further triggering immune dysregulation and inflammatory storm, culminating in programmed cell death and organ dysfunction. This study elucidates the pivotal role of dysregulated mitochondrial-host symbiosis in sepsis progression and provides important insights into the underlying mechanisms of sepsis-associated immune imbalances, laying a theoretical foundation for targeted therapy development.

Delirium is a serious acute neurocognitive condition that is common and debilitating in older people who undergo major surgery or are acutely ill. The nature of delirium, baseline comorbidity of older adults and related contextual factors present unique ethical challenges in delirium prevention and treatment trials; yet there is limited literature on how these challenges should be best addressed. The objective of this rapid review was to examine the reporting of key ethical processes for older adults (approval, recruitment, consent, retention) in delirium intervention trials. A rapid search in December 2023 with restricted key terms (“Delirium,” “Randomized Controlled Trial”), databases (PubMed, CINAHL), older adult participants and English language, and a final publication date range of 2020 to 2023, resulted in 411 articles screened, 153 full-text reviews, and 51 randomized controlled trial (RCTs) reports (with 11 published protocols) included. Data extraction and synthesis aligned with general guidance for ethical approval, processes and reporting of clinical studies, including for people with key vulnerabilities for research participation. Trials were categorized by degree of ethical reporting and statistical tests explored associated trial characteristics. The 51 RCTs were conducted in diverse countries, with the most sizeable proportion in China (51%). Most trials evaluated a delirium prevention (96%) and/or pharmacological intervention (69%) and were individually randomized (88%), phase 3 (84%), and perioperative (75%). No trial fully reported all ethical processes. Most of the 51 trials fully reported who provided consent (88%), the consent approach (88%), and ethical approval details (63%); around half fully reported safety assessments (59%) and how, where and when participants were recruited (49%). However, few trials fully reported who recruited participants (31%), who obtained consent (22%); how trial information was provided (27%), whether capacity was assessed prior to consent (10%), how participants were supported though the trial design or processes (18%) or in-trial communications (8%). Compared to the 19 trials (37%) with little to no reporting of ethical processes, the 16 (31%) trials with fuller reporting more often had a separately published protocol (56% vs 0%, P < .001), were conducted outside of China (87.5% vs 11%, P < .001) and had lower median consent (56% vs 96%, P < .01) and retention rates (89% vs 96%, P < .05). These results will help inform future efforts focused on improving the conduct and reporting of ethical processes in delirium trials.

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia‐enriched surface receptor that plays a central role in sensing lipid ligands and damage‐associated molecular patterns within the central nervous system. Growing evidence has expanded our understanding of TREM2 in both physiological homeostasis and a broad range of neurological disorders, and has further identified TREM2 as a promising therapeutic target. Objective This review aims to provide an updated overview of TREM2 signaling in microglial physiology and pathology, and to summarize the therapeutic potential of TREM2‐targeted interventions across neurological diseases. Methods A narrative synthesis of recent literature was performed to examine TREM2 signaling, its context‐dependent functions in both physiological and pathological states, and emerging advances in TREM2‐targeted therapeutic strategies for neurological disorders. Key Findings Under physiological conditions, TREM2 maintains microglial survival, homeostatic surveillance, and synaptic pruning. In pathological contexts, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, and glioblastoma, TREM2 signaling regulates microglial activation, promotes the clearance of pathological substrates, and shapes neuroinflammatory responses. Conclusions TREM2‐mediated microglial responses are highly context dependent and may exert distinct or even opposing functions across different disease types. A major challenge for future research is to tailor TREM2‐based interventions to the specific disease context, timing, and microenvironment in order to maximize their neuroprotective and immunomodulatory effects.

Organ transplantation is a definitive therapeutic option for patients with end-stage organ dysfunction and failure.Ischaemia–reperfusion(IR)injury is one of the leading causes of low graft utilization as it significantly increases the risk of primary graft dysfunction and acute rejection following transplantation.This risk is particularly high for organs obtained from donation after circulatory death(DCD)when compared with the organs from donation after brain death(DBD).IR injury exacerbates tissue damage via various mechanisms including the induction of regulated cell death.Regulated cell death and its consequences play critical roles in determining graft survival and function,thereby influencing the overall success of the transplant.Understanding the mechanisms underlying regulated cell death in IR injury is essential for developing therapeutic strategies to minimize tissue damage and improve clinical outcomes in organ transplantation.This review mainly discusses different types of regulated cell death and underlying mechanisms towards preventive cell death strategies in DBD and DCD organ transplantation in preclinical settings.

Dear Editor, Preclinical studies have elegantly demonstrated that dis tinct populations of cavity-resident macrophages in the peritoneal and pleural spaces are ontogenically, transcrip tionally, and functionally related (Buechler et al., 2019). Notably, these cavities are recognized as immunosuppres sive environments that commonly facilitate cancer progres sion (Donnenberg et al., 2019; Morano et al., 2016; Porcel et al., 2015). Cavity-resident macrophages mediate a phys iological checkpoint that limited anti-tumor activity at these cancer sites (Chow et al., 2021). Previous genetic lin eage tracing has shown that, post-injury, cavity macro phages tend to accumulate on the surfaces of visceral organs, including the lungs (Jin et al., 2021, 2022), rather than deeply infiltrating the parenchyma (Deniset et al., 2019; Wang and Kubes, 2016). However, it remains unclear whether, in the context of tumors, these cavity macro phages penetrate into the lung parenchyma and promote tumor growth. Utilizing dual recombinase-mediated genetic lineage tracing, we observed the infiltration of cavity mac rophages into lung tumor metastases. Furthermore, genetic ablation or sequestration of these cavity macrophages sig nificantly reduced tumor growth in the lungs. This obser vation underscores the crucial role that cavity macrophages play in supporting tumorigenic processes, suggesting that targeting these cells may represent a viable therapeutic strategy for mitigating lung tumor progression.

Neuroinflammation is one of crucial pathogenic mechanisms underlying Alzheimer's disease, sepsis-associated encephalopathy, and postoperative cognitive dysfunction. These diseases or conditions are often accompanied by typical clinical manifestations of cognitive impairments, including impaired learning and memory but underlying mechanisms are unknown. Hence, effective treatments are not available. In the current study, mice received intraperitoneal administrations of LPS (0.5 mg/kg, daily, Escherichia coliO55:B5) for seven consecutive days and after which, different cohorts were used for behavioral assessments with open field, Y maze, and novel object recognition test or for electrophysiology recordings of mEPSC, mIPSC or LTP in ex vivo preparations. Their hippocampi were harvested for immunostaining or Western blotting of PSD95, vGLUT1, vGAT, gephyrin, PV, and SST. In vivo optical fiber calcium recording was used to evaluate the neuronal excitability. During the early stage of neuroinflammation induced by LPS, there was a decrease of excitatory afferent synapses and transmission in the CA1. During the later stage of neuroinflammation, there was an increase of inhibitory afferent synapses and transmission in the CA1, resulting in excessive inhibition on excitatory neurons. Both of them contributed to the decreased hippocampal neuronal excitability and impaired LTP, ultimately leading to cognitive impairments. Overexpression of CREB in the early stage or inactivation of PV-positive interneurons in the later stage in the CA1 both improved cognitive impairments. Our work suggests that negating decreased excitatory and increased inhibitory afferent in the hippocampus may improve cognitive impairments relate to neuroinflammation associated with neurological diseases.

Background Acute lymphoblastic leukaemia (ALL) is a common type of cancer in children. General anaesthetics are often used on patients undergoing painful procedures during ALL treatments but their effects on ALL malignancy remain unknown. Herein, we aim to study the effect of propofol and sevoflurane on the migration, homing and chemoresistance of ALL cells. Methods NALM-6 and Reh cells were treated with propofol (5 and 10 μg/ml) or sevoflurane (3.6%) in vitro for six hours. Then, cells were harvested for adhesion assay and migration assay in vitro. In in vivo experiments, GFP-NALM-6 cells were pre-treated with propofol (10 μg/ml) or sevoflurane (3.6%) for six hours. Then, cells were injected intravenously to C57BL/6 female mice followed by intravital microscopy. For chemoresistance study, cells were treated with rising concentrations of Ara-c (0.05-50 nM) plus 10μg/ml of propofol or Ara-C plus 3.6% of sevoflurane for 4 hours, followed by the assessment of cell viability via CCK-8 assay and detection of autophagy via flow cytometry. Results Both anaesthetics reduced in vivo migration and in vivo homing as exemplified by 1) the reduction in the number of cells entering the bone marrow and 2) the disturbance in homing location in relation to endosteal surface. Our results indicated that general anaesthetics reduced the surface CXCR4 expression and the adhesion of leukaemia cells to thrombin cleaved osteopontin (OPN) was reduced. Those changes might result in the alterations in migration and homing. In addition, both anaesthetics sensitised ALL cells to Ara-c possibly through CXCR4 mediated mechanisms. Propofol but not sevoflurane enhanced chemo-related cell death via inducing cytotoxic autophagy. Conclusion Together, our data suggest that both propofol and sevoflurane could reduce ALL migration, and homing in vivo and in vitro via CXCR4 and OPN mediated mechanisms. Both anaesthetics could sensitise ALL cells to chemotherapy possibly via CXCR4 mediated mechanisms.

Epitranscriptomics modifications play an important role in sex-dependent biological phenomena. N6-adenosine methylation (m6A), the most prevalent epitranscriptomics modification in eukaryotic mRNA, participates in regulating various sex-specific physiological processes. Here, we generated METTL4 knockout mice lacking methyltransferase-like 4, which mediates m6A. Behavioral analyses revealed that only female METTL4-/- mice exhibited pain hypersensitivity, with subsequent experiments showing the involvement of METTL4-mediated m6A in this sex-differentiated biological phenotype. Further exploration demonstrated that this sex-specific pain hypersensitivity is closely associated with sex-dependent expression of uncoupling protein 2 (UCP2) in synapses. Specifically, elevated UCP2 expression in METTL4-/- female mice enhances the efficiency of synaptic transmission by modulating mitochondrial energy metabolism at synapses. Collectively, this study identifies a distinct pathway mediated by METTL4-driven m6A modification, providing critical insights into the molecular basis of sex-specific differences in pain transmission. These findings also highlight the potential of targeting METTL4 for sex-differentiated pain management strategies in clinical settings.

With the continuous advancement of medical technologies, perioperative anesthesia management decisions are confronted with challenges of complexity and dynamicity, rendering traditional machine learning models insufficient for clinical needs. As one of the breakthrough applications in artificial intelligence, large language models (LLMs) may offer better help for intelligent anesthesia management. LLMs are capable of processing multidimensional and multi-source data, enabling more comprehensive prediction and intervention suggestions, thereby optimizing anesthesia management processes. This review summarizes the current applications of LLMs in anesthesiology and proposes methods for building specialized LLMs to tackle challenges in application. This work albeit mainly in the proposed stage aims to provide references for future development in this field and to promote in-depth research of LLMs in anesthesiology. Graphical Abstract