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"Wang, Guozheng"
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Immune dysregulation in sepsis: experiences, lessons and perspectives
Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host responses to infection. Not only does sepsis pose a serious hazard to human health, but it also imposes a substantial economic burden on the healthcare system. The cornerstones of current treatment for sepsis remain source control, fluid resuscitation, and rapid administration of antibiotics, etc. To date, no drugs have been approved for treating sepsis, and most clinical trials of potential therapies have failed to reduce mortality. The immune response caused by the pathogen is complex, resulting in a dysregulated innate and adaptive immune response that, if not promptly controlled, can lead to excessive inflammation, immunosuppression, and failure to re-establish immune homeostasis. The impaired immune response in patients with sepsis and the potential immunotherapy to modulate the immune response causing excessive inflammation or enhancing immunity suggest the importance of demonstrating individualized therapy. Here, we review the immune dysfunction caused by sepsis, where immune cell production, effector cell function, and survival are directly affected during sepsis. In addition, we discuss potential immunotherapy in septic patients and highlight the need for precise treatment according to clinical and immune stratification.
Journal Article
Association of life’s essential 8 and inflammatory biomarkers with nutritional anemia in UK adults
Several modifiable health factors in Life’s Essential 8 (LE8) are linked to nutritional anemia and can assess overall cardiovascular health (CVH). This study explored the associations of CVH measured by LE8 score with nutritional anemia and iron deficiency anemia (IDA), including the mediating role of inflammatory biomarkers. This prospective cohort study included 181,069 participants from UK Biobank. CVH was categorized into low (0–49), medium (50–79), and high (80–100) based on the LE8 score. Weibull regression models were used to quantify the association between CVH and nutritional anemia and IDA. During a median follow-up of 8.6 years, 6749 cases of nutritional anemia occurred, including 92% (6223/6749) IDA cases. After adjusting for covariates, participants with moderate CVH and high CVH had a 44% and 54% lower risk of nutritional anemia (Moderate: hazard ratio [HR] 0.56; 95% confidence interval [CI], 0.51–0.60; High: HR 0.46; 95% CI, 0.41–0.51), and a 46% and 54% lower risk of IDA (Moderate: HR 0.54; 95% CI, 0.50–0.59; High: HR 0.46; 95% CI, 0.41–0.51), respectively, compared to those with low CVH. An L-shaped association was observed between CVH score and both types of anemia. Inflammatory biomarkers explained 22.1% and 21.6% of the associations between CVH and nutritional anemia and IDA, respectively. Higher CVH scores were associated with lower risk of nutritional anemia and IDA, and these associations may be partially mediated by inflammatory biomarkers. These findings emphasize the importance of CVH and inflammation in preventing nutritional anemia.
Journal Article
Circulating Histones Are Mediators of Trauma-associated Lung Injury
Abstract
Rationale
Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology.
Objectives
To investigate the pathological roles of circulating histones in trauma-induced lung injury.
Methods
Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause–effect relationship was studied using cells and mouse models.
Measurements and Main Results
In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality.
Conclusions
This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.
Journal Article
The Critical Roles and Mechanisms of Immune Cell Death in Sepsis
Sepsis was first described by the ancient Greek physicians over 2000 years ago. The pathophysiology of the disease, however, is still not fully understood and hence the mortality rate is still unacceptably high due to lack of specific therapies. In the last decade, great progress has been made by shifting the focus of research from systemic inflammatory response syndrome (SIRS) to multiple organ dysfunction syndrome (MODS). Sepsis has been re-defined as infection-induced MODS in 2016. How infection leads to MODS is not clear, but what mediates MODS becomes the major topic in understanding the molecular mechanisms and developing specific therapies. Recently, the mechanism of infection-induced extensive immune cell death which releases a large quantity of damage-associated molecular patterns (DAMPs) and their roles in the development of MODS as well as immunosuppression during sepsis have attracted much attention. Growing evidence supports the hypothesis that DAMPs, including high-mobility group box 1 protein (HMGB1), cell-free DNA (cfDNA) and histones as well as neutrophil extracellular traps (NETs), may directly or indirectly contribute significantly to the development of MODS. Here, we provide an overview of the mechanisms and consequences of infection-induced extensive immune cell death during the development of sepsis. We also propose a pivotal pathway from a local infection to eventual sepsis and a potential combined therapeutic strategy for targeting sepsis.
Journal Article
Comprehensive Treatment of Trans-Arterial Chemoembolization Plus Lenvatinib Followed by Camrelizumab for Advanced Hepatocellular Carcinoma Patients
Aim: This study aimed to report the efficacy and safety of trans -arterial chemoembolization (TACE) plus lenvatinib and camrelizumab in patients with advanced hepatocellular carcinoma (HCC). Methods: This retrospective study enrolled 22 patients with advanced HCC from March 2018 to December 2019. All the patients received comprehensive treatment with TACE plus lenvatinib followed by camrelizumab. Overall survival (OS) and progression-free survival (PFS) were calculated and analysed using the Kaplan-Meier method and log-rank test. Treatment response and adverse events (AEs) were also evaluated. Results: The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 68.2 and 100% at the first month and 72.7 and 95.5% at the third month, respectively. The median OS was 24 months (95% CI, 20.323–27.677 months), and the median PFS was 11.4 months (95% CI, 8.846–13.954 months). The majority of treatment-related adverse reactions were mild or moderate, except for 4 that developed to grade 3–4 (3 reactions of grade 3, 1 reaction of grade 4). No deaths or other serious adverse reactions occurred. Conclusion: Trans -arterial chemoembolization plus lenvatinib and camrelizumab shows good results incontrolling tumour progression and prolonging median OS in patients with advanced HCC.
Journal Article
Neural connectivity and balance control in aging: Insights from directed cortical networks during sensory conflict
•Aging impairs adaptive sensory reweighting for balance control in conflicting environments.•Older adults exhibit reduced neural network flexibility and efficiency during balance tasks.•EEG-based directed connectivity reveals age-related differences in cortical network dynamics.•Virtual reality and EEG combined provide novel insights into balance control mechanisms.•Findings highlight neural targets for fall prevention interventions in older populations.
Balance control is crucial for stability during daily activities, relying on the integration of sensory inputs from the visual, vestibular, and somatosensory systems. Aging impairs the efficiency of these systems, leading to an increased risk of falls; however, the neural mechanisms underlying this decline, particularly under sensory conflict, are not fully understood. This study investigated the effects of aging on neural connectivity and sensory integration during balance tasks. Ninety-six participants (47 older adults and 49 young adults) were subjected to balance perturbation tasks under sensory-congruent and sensory-conflict conditions using a virtual reality headset and rotating platform. Behavioral measures, including postural sway and perceptual accuracy, were recorded. Electroencephalography (EEG) data were analyzed using generalized partial directed coherence (GPDC) to assess the directed functional connectivity and network efficiency. Older adults exhibited significantly greater postural sway, reduced perceptual accuracy, and a diminished ability to detect sensory conflicts than young adults, particularly under conflict conditions. As demonstrated by connectivity analysis, young adults showed adaptive shifts in connectivity from the visual to somatosensory regions during sensory conflict. In contrast, older adults demonstrated a less adaptable mode of connectivity. At the same time, global efficiency and clustering coefficients of young adults were higher, suggesting more effective and modular brain networks. Correlation analyses in older adults revealed that higher visual cortex efficiency was linked to lower postural sway specifically during sensory conflict, whereas higher motor cortex efficiency was associated with greater sway only under sensory-congruent conditions. In short, neural adaptability is vital in sensory integration and balance control. Due to decreased neural flexibility and network efficiency in older adults, their sensory reweighting was undermined and instability increased during the sensory conflict. These findings establish a foundation for development of targeted interventions to strengthen balance and lower the risks of falls in older adults.
Journal Article
Cortical adaptations in Tai Chi practitioners during sensory conflict: an EEG-based effective connectivity analysis of postural control
Background
Tai Chi (TC) is recognized for enhancing balance and postural control. However, studies on its effects on the central nervous system are limited and often involve static experiments despite the dynamic nature of TC. This study addressed that gap by examining cortical network activity during dynamic, multisensory conflict balance tasks. We aimed to determine whether long-term TC practice leads to neuroplastic changes in brain connectivity that improve sensory integration for postural control.
Methods
Fifty-two young adult participants (long-term TC practitioners = 22; non-practitioners = 30) performed balance tasks under sensory congruent and conflict conditions using a virtual reality headset with a rotating supporting surface. EEG was performed, and generalized partial directed coherence was used to assess directed functional connectivity in the mu rhythm (8–13 Hz) between predefined regions of interest (ROIs) in the cortex implicated in sensory and motor integration. Graph-theoretic measures (in-strength and out-strength) indexed the total incoming and outgoing connection strengths for each region. Statistical analysis used mixed-design ANOVAs (Group × Condition) to compare balance and connectivity measures.
Results
TC practitioners demonstrated significantly better postural stability under both sensory conditions, with a reduced sway area. EEG analysis revealed that increased sensory conflict decreased the global efficiency of the visual integration network but increased that of the somatosensory integration network. Furthermore, TC practitioners demonstrated enhanced out-strength of the somatosensory cortex and lower out-strength of the right posterior parietal cortex (PPC) compared to non-practitioners.
Conclusions
Long-term TC practice is associated with quantifiable neuroplastic changes in mu-band cortical effective connectivity, specifically enhanced information outflow from somatosensory reduce parietal influence regions. Our findings demonstrate central mechanisms by which TC practice may improve balance, providing neuroengineering evidence for TC as a neuroplasticity-driven balance intervention.
Journal Article
Nonlinear dynamics of postural control system under visual-vestibular habituation balance practice: evidence from EEG, EMG and center of pressure signals
Human postural control system is inherently complex with nonlinear interaction among multiple subsystems. Accordingly, such postural control system has the flexibility in adaptation to complex environments. Previous studies applied complexity-based methods to analyze center of pressure (COP) to explore nonlinear dynamics of postural sway under changing environments, but direct evidence from central nervous system or muscular system is limited in the existing literature. Therefore, we assessed the fractal dimension of COP, surface electromyographic (sEMG) and electroencephalogram (EEG) signals under visual-vestibular habituation balance practice. We combined a rotating platform and a virtual reality headset to present visual-vestibular congruent or incongruent conditions. We asked participants to undergo repeated exposure to either congruent ( n = 14) or incongruent condition ( n = 13) five times while maintaining balance. We found repeated practice under both congruent and incongruent conditions increased the complexity of high-frequency (0.5–20 Hz) component of COP data and the complexity of sEMG data from tibialis anterior muscle. In contrast, repeated practice under conflicts decreased the complexity of low-frequency (<0.5 Hz) component of COP data and the complexity of EEG data of parietal and occipital lobes, while repeated practice under congruent environment decreased the complexity of EEG data of parietal and temporal lobes. These results suggested nonlinear dynamics of cortical activity differed after balance practice under congruent and incongruent environments. Also, we found a positive correlation (1) between the complexity of high-frequency component of COP and the complexity of sEMG signals from calf muscles, and (2) between the complexity of low-frequency component of COP and the complexity of EEG signals. These results suggested the low- or high-component of COP might be related to central or muscular adjustment of postural control, respectively.
Journal Article
Rapid reconfiguration of cortical networks after repeated exposure to visual-vestibular conflicts
Visual-vestibular conflicts can induce motion sickness and further postural instability. Visual-vestibular habituation is recommended to reduce the symptoms of motion sickness and improve postural stability with an altered multisensory reweighting progress. However, it is unclear how the human brain reweights multisensory information after repeated exposure to visual-vestibular conflicts. Therefore, we synchronized a rotating platform and a virtual scene to present visual-vestibular congruent (natural visual stimulation) and incongruent (conflicted visual stimulation) conditions and collected EEG and center of pressure (COP) data. We constructed the effective brain connectivity of region of interest (ROI) derived from source-space EEG in theta-band activity, and quantified the postural stability and the inflow and outflow of each ROI. We found repeated exposure to congruent and incongruent conditions both decreased COP path length and increased COP complexity. Besides, we found that repeated exposure to the incongruent environment decreased the inflow into visual cortex, suggesting the brain down-weighted the less reliable visual information for postural stability. In contrast, repeated exposure to the congruent environment increased the inflow into posterior parietal cortex and the outflow from visual cortex and S1, suggesting an increase in efficiency of multisensory integration. We concluded that repeated exposure to congruent and incongruent conditions both improved postural stability with different multisensory reweighting patterns as revealed by different dynamic changes of brain networks.
Journal Article