Traumatic brain injury (TBI) triggers a robust inflammatory response that is closely linked to worsened clinical outcomes. S100A8/A9, also known as calprotectin or myeloid-related protein-8/14 (MRP8/14), is an alarmin primarily secreted by activated neutrophils with potent pro-inflammatory property. In this study, we explored the roles of S100A8/A9 in modulating neuroinflammation and influencing TBI outcomes, delving into the underlying mechanisms. S100A8/A9-enriched neutrophils were present in the injured brain tissue of TBI patients, and elevated plasma levels of S100A8/A9 were correlated with poorer neurological function. Furthermore, using a TBI mouse model, we demonstrated that treatment with the selective S100A8/A9 inhibitor Paquinimod significantly mitigated neuroinflammation and neuronal death, thereby improving the prognosis of TBI mice. Mechanistically, we found that S100A8/A9, in conjunction with neutrophil activation and infiltration into the brain, enhances reactive oxygen species (ROS) production within neutrophils, accelerating PAD4-mediated neutrophil extracellular trap (NET) formation, which in turn exacerbates neuroinflammation. These findings suggest that S100A8/A9 amplifies neuroinflammatory responses by promoting NET formation in neutrophils. Inhibition of S100A8/A9 effectively attenuated NET-mediated neuroinflammation; however, when PAD4 was overexpressed in the brain using adenovirus, leading to an increased formation of NET in the brain, the anti-inflammatory effects of S100A8/A9 inhibition were markedly diminished. Further experiments with PAD4 knockout mice confirmed that the reduction of NETs could substantially alleviate S100A8/A9-driven neuroinflammation. Finally, we established that the suppression of NET formation by S100A8/A9 inhibition is primarily mediated through the AMPK/Nrf2/HO-1 signaling pathway. These findings underscore the critical pathological role of S100A8/A9 in TBI and emphasize the need for further exploration of S100A8/A9 inhibitor Paquinimod as a potential therapeutic strategy for TBI.

The understanding of neuroimmune function has evolved from concepts of immune privilege and protection to a new stage of immune interaction. The discovery of skull meninges channels (SMCs) has opened new avenues for understanding central nervous system (CNS) immunity. Here, we characterize skull bone marrow and SMCs by detailing the anatomical structures adjacent to the skull, the differences between skull and peripheral bone marrow, mainstream animal processing methods, and the role of skull bone marrow in monitoring various CNS diseases. Additionally, we highlight several unresolved issues based on current research findings, aiming to guide future research directions.

Biocatalytic activity of artificial nanozymes is strongly correlated with the detection sensitivity of lateral flow immunoassays (LFIA). Modulating the electronic structure is a promising and effective strategy to improve the catalytic activity of nanozymes, but remains a challenge. In this study, we develop a single-atom nanozyme LFIA platform with high active and electron-rich Pt single atoms onto AuPd support (Pt1/PA). The Pt1/PA nanozymes exhibit superior peroxidase (POD)-like activity with the catalytic efficiency (Kcat/Km) of 9.29 x 106 mM- 1 & sdot;min- 1, which is 315-fold higher than natural horseradish peroxidase (HRP). Density Functional Theory calculations reveal that the remarkable activity is attributed to the formation of electron-rich site of Pt single atoms through electron transfer from support to Pt 5d orbitals, as well as d-band center modulation. Moreover, more electron transfer numbers are available for Pt single atoms at the surface in the lattice than outside the lattice. Benefiting from excellent biocatalytic activity, the limits of detection (LOD) of Pt1/PA-LFIA for carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) are 1.21 pg mL- 1 and 0.6 pg mL-1, which are 20.4 and 13.3-fold lower than commercial enzyme-linked immunosorbent assay kits (CEA: ab264604, 24.68 pg mL-1; PSA: ab264615, 8 pg mL- 1), respectively. More importantly, Pt1/PA-LFIA achieves the accurate detection of prostate cancer and lung cancer clinical patients. This work presents a paradigm for ultrasensitive biomarker diagnostics based on single-atom nanozyme immunoassays.

Background: The L-oxiracetam Outcomes in Clinical Assessment of Traumatic Brain Injury Effects (LOCATE) trial is a national, multicenter, randomized, parallel-group, phase III trial including 74 centers across 51 hospitals from 2019 to 2024. The objective is to evaluate the efficacy and safety of L-oxiracetam in improving memory and cognitive impairment in patients with acute traumatic brain injury (TBI). Methods: A total of 591 patients aged 18-75 years will be enrolled with mild acute TBI. The primary outcome is the change in scores on the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) at 90 days post-treatment compared to baseline. Secondary outcomes included change from baseline in LOTCA, Glasgow Coma Scale (GCS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Glasgow Outcome Scale-Extended (GOS-E), and Barthel Index of Activities of Daily Living (ADL-BI) assessed at the end of treatment, 30 days, 60 days, and/or 90 days. A sample size of 591 allows 80% power (a=0.05) for the efficacy test in the primary outcome of LOTCA assessed at 90 days. Results: A detailed statistical analysis plan was developed for the LOCATE trial following international guidelines. The plan determined the statistical models for the primary and secondary outcomes and defined the covariates to be controlled and the content of the exploratory analyses. Conclusion: The application of this statistical analysis plan in the upcoming LOCATE trial will support an unbiased analysis of these important clinical data.

AbstractObjectivesPatients with traumatic brain injury (TBI) often suffer memory and cognitive impairments, and oxiracetam‐like drugs are considered to have a positive impact on these symptoms potentially. However, the efficacy and safety of L‐oxiracetam and oxiracetam in TBI patients have not been sufficiently investigated.MethodsThe study adopts a multicenter, randomized, double‐blind, parallel‐group, phase 3 clinical trial design in 74 centers across 51 hospitals in China. A total of 590 TBI patients meeting criteria will be randomly allocated into three groups in a 2:2:1 ratio: L‐oxiracetam group, oxiracetam group, and placebo group. The treatment period is 14 days, with a follow‐up period of 90 days. The primary outcome measure is the change in the Loewenstein Occupational Therapy Cognitive Assessment score at 90 days after treatment. Secondary outcomes include changes in other cognitive assessments, neurological function, activities of daily living, and safety assessments.DiscussionThere is no robust evidence to suggest that L‐oxiracetam and oxiracetam can enhance memory and cognitive function in patients with mild to moderate TBI. This study has the potential to answer this crucial clinical question.Trial registrationchinadrugtrials.org.cn, identifier CTR20192539; ClinicalTrials.gov, identifier NCT04205565.

Gliomas are highly heterogeneous brain tumours that are resistant to therapies. The molecular signatures of gliomas play a high-ranking role in tumour prognosis and treatment. In addition, patients with gliomas with a mesenchymal phenotype manifest overpowering immunosuppression and sophisticated resistance to treatment. Thus, studies on gene/protein coexpression networks and hub genes in gliomas holds promise in determining effective treatment strategies. Therefore, in this study, we aimed to. Using average linkage hierarchical clustering, 13 modules and 224 hub genes were described. Top ten hub genes (CLIC1, EMP3, TIMP1, CCDC109B, CASP4, MSN, ANXA2P2, CHI3L1, TAGLN2, S100A11), selected from the most meaningful module, were associated with poor prognosis. String analysis, co-immunoprecipitation and immunofluorescence revealed a significant correlation between TIMP1 and CHI3L1. Furthermore, we found, both in vivo and in vitro, that TIMP1 promoted gliomagenesis via CHI3L1 overexpression as well as NF-κB activation. TIMP1 expression correlated with tumour immune infiltration and immune checkpoint-related gene expression. In addition, TIMP1 resulted in immunosuppressive macrophage polarization. In summary, TIMP1/CHI3L1 might be perceived as a diagnostic marker and an immunotherapy target for gliomas.

Strain engineering plays an important role in tuning electronic structure and improving catalytic capability of biocatalyst, but it is still challenging to modify the atomic-scale strain for specific enzyme-like reactions. Here, we systematically design Pt single atom (Pt1), several Pt atoms (Ptn) and atomically-resolved Pt clusters (Ptc) on PdAu biocatalysts to investigate the correlation between atomic strain and enzyme-like catalytic activity by experimental technology and in-depth Density Functional Theory calculations. It is found that Ptc on PdAu (Ptc-PA) with reasonable atomic strain upshifts the d-band center and exposes high potential surface, indicating the sufficient active sites to achieve superior biocatalytic performances. Besides, the Pd shell and Au core serve as storage layers providing abundant energetic charge carriers. The Ptc-PA exhibits a prominent peroxidase (POD)-like activity with the catalytic efficiency (Kcat/Km) of 1.50 × 109 mM-1 min-1, about four orders of magnitude higher than natural horseradish peroxidase (HRP), while catalase (CAT)-like and superoxide dismutase (SOD)-like activities of Ptc-PA are also comparable to those of natural enzymes. Biological experiments demonstrate that the detection limit of the Ptc-PA-based catalytic detection system exceeds that of visual inspection by 132-fold in clinical cancer diagnosis. Besides, Ptc-PA can reduce multi-organ acute inflammatory damage and mitigate oxidative stress disorder.

Recent advances in neuroscience have transformed our understanding of the meninges, the layers surrounding the central nervous system (CNS). Two key findings have advanced our understanding: researchers identified cranial bone marrow as a reservoir for meningeal immune cells, and rediscovered a brain lymphatic system. Once viewed merely as a protective barrier, the meninges are now recognized as a dynamic interface crucial for neuroimmune interactions. This shift in perspective highlights their unique role in maintaining CNS balance, shaping brain development, and regulating responses to injury and disease. This review synthesizes the latest insights into meningeal anatomy and function, with a focus on newly identified structures such as dural-associated lymphoid tissues (DALT) and arachnoid cuff exit (ACE) points. We also examine the diverse immune cell populations within the meninges and their interactions with the CNS, underscoring the emerging view of the meninges as active participants in brain immunity. Finally, we outline critical unanswered questions about meningeal immunity, proposing directions for future research. By addressing these knowledge gaps, we aim to deepen our understanding of the meninges’ role in brain health and disease, potentially paving the way for novel therapeutic approaches.

Background Several studies have suggested a potential link between immune cells and epilepsy. Nonetheless, the precise causal relationship between immune cells and epilepsy, and the role of metabolites as potential mediators, remain ambiguous. Methods We extracted information on immune cells, metabolites and epilepsy from pooled data from a large-scale genome-wide association study (GWAS). We used Mendelian randomization (MR) analyses to elucidate causal links between immune cells, metabolites and epilepsy. The main statistical method used was inverse variance weighting (IVW). In addition, we investigated the potential mediating role of metabolites in the pathway from immune cells to epilepsy. Finally, we applied bioinformatics methods for validation. Results In assessing the genetic susceptibility of immune cells to epilepsy, we observed 12 positive associations. However, when analyzed in reverse, we found two of these associations to be negative. Similarly, we found 60 positive and 8 negative associations between metabolites and epilepsy. Subsequently, mediation analysis revealed that Naive CD8br T cells affect epilepsy through Partial Sphingomyelin as a mediator. Finally, the bioinformatics analysis revealed alterations in the immune microenvironment between healthy individuals and patients with epilepsy, with notable changes in the differentiation of Naive CD8 T cells. Conclusion There exists a causal association between immune cells, and metabolites with epilepsy, wherein metabolites serve as mediators in the pathway from immune cells to epilepsy.

Abstract Background Glioma is a highly malignant primary nervous system tumor. Temozolomide（TMZ） is a commonly used chemotherapy drug, but drug resistance is increasing. Therefore, finding effective biomarkers can help us to better stratify and individualize treatment. Sirt7 is the latest member of sirtuins, which mainly plays the role of NAD+-dependent histone deacetylase. In recent years, Sirt7 has been reported to be related to the proliferation and oncogenic activity of malignant tumors such as melanoma and colon cancer, but it has been less reported in glioma. This study aimed to explore the role of Sirt7 in glioma by determining its effects on glioma cell proliferation, apoptosis, and cell cycle progression; whether Sirt7 knockdown increases the cytotoxicity of TMZ; and the regulatory microRNAs (miRNAs) upstream of Sirt7. Methods We found that Sirt7 expression was significantly upregulated in glioma tissues and cells and was correlated with tumor grade and patient Survival. We constructed Sirt7 overexpression and knockdown lentivirus for the infection of U87, U251, and LN229 cells, Expression levels of Sirt7 and miR-148a-3p were evaluated by RT-qPCR and western blotting. Cell proliferation was measured using the CCK-8 assay. Cell cycle progression and apoptosis were assessed using flow cytometry. We verified the effect of changes in Sirt7 expression on the cytotoxic effects of TMZ on glioma. Dual luciferase gene reporter assays were used to investigate the targeted regulation of Sirt7 by miR-148a-3p. The effect of SIRT7 on TMZ toxicity in glioma tumorigenesis were assessed using mouse xenotransplantation. Results Sirt7 expression was positively correlated with the pathological grade of glioma patients and negatively correlated with patient survival. Both knockdown and overexpression of Sirt7 affected the proliferation, apoptosis, and cell cycle progression in glioma cells and enhanced TMZ-induced cytotoxicity. Sirt7 is a target of miR-148a-3p, and miR-148a-3p expression in glioma tissues and cells was significantly decreased. In xenograft models, knockdown of Sirt7 inhibited tumor growth and enhanced TMZ-mediated antitumor effects. Conclusion This study deepens our understanding of the molecular functions of Sirt7, provides evidence that Sirt7 enhances TMZ-induced cytotoxicity in glioma, and demonstrates the potential of Sirt7 as a therapeutic target.

Background Neuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI. Methods Controlled cortical impact model was performed to establish TBI. Cl-amidine, 2′3′-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study. Results Neutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2′3′-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI. Conclusion Altogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI. Graphical Abstract

BACKGROUND:Contact sports athletes and military personnel who suffered a repetitive mild traumatic brain injury (rmTBI) are at high risk of neurodegenerative diseases such as advanced dementia and chronic traumatic encephalopathy (CTE). However, due to the lack of specific biological indicators in clinical practice, the diagnosis and treatment of rmTBI are quite limited.METHODS:We used 2-methacryloyloxyethyl phosphorylcholine (MPC)-nanocapsules to deliver immunoglobulins (IgG), which can increase the delivery efficiency and specific target of IgG while reducing the effective therapeutic dose of the drug.RESULTS:Our results demonstrated that MPC-capsuled immunoglobulins (MPC-n (IgG)) significantly alleviated cognitive impairment, hippocampal atrophy, p-Tau deposition, and myelin injury in rmTBI mice compared with free IgG. Furthermore, MPC-n (IgG) can also effectively inhibit the activation of microglia and the release of inflammatory factors.CONCLUSIONS:In the present study, we put forward an efficient strategy for the treatment of rmTBI-related cognitive impairment and provide evidence for the administration of low-dose IgG.

2022年美国血管外科学会(SVS)发布了《颅外段颈动脉狭窄临床治疗指南》，该指南依据相关领域的循证医学证据，对临床中存在争议的5个热点问题做了详尽分析，并给出了综合性治疗建议，具有很强的实践性。本文结合相关文献对该指南进行解读，以供参考。

We analyzed 12 cases of Chinese PCNSL using whole-exome sequencing to detect genetic alterations. We identified 448 potentially somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples. MYD88 with the most mutant frequency affected the activity of NF -KB pathway. PCNSL samples with LRP1B mutations had higher mutation rate than samples with LRP1B wildtype. In conclusion, whole-exome sequencing revealed significantly mutated genes underlying the potential molecular mechanisms of PCNSL, which could serve as therapeutic targets.Background: Primary central nervous system lymphoma (PCNSL) is a highly aggressive type of extranodal non -Hodgkin lymphoma, of which approximately 90% of the cases are diffuse large B-cell lymphoma (DLBCL). In recent years, the incidence of PCNSL has significantly increased in women and older men. Although advanced treatments such as high-dose methotrexate (HD-MTX) and targeted agents have been introduced, the prognosis of these patients remains poorer than those with other forms of non-Hodgkin's lymphoma.Methods: Twelve cases of Chinese PCNSL were analyzed to detect their genetic alterations using whole-exome sequencing (WES). We identified 448 potential somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples.Results: We found that myeloid differentiation factor 88 (MYD88) had the highest mutation frequency, which affected the activity of the nuclear factor -KB (NF -KB) pathway. PCNSL samples with low-density lipoprotein receptor-related protein 1B (LRP1B) mutations had a higher mutation rate than samples with wild-type LRP1B. Polycystic kidney and hepatic disease 1 (PKHD1), the causal gene of autosomal recessive polycystic kidney disease (ARPKD), was identified in 2 PCNSL cases and exhibited missense mutations. Pathway analysis revealed enrichment in pathways associated with central carbon metabolism in cancer, renal cell carcinoma, nicotine addiction, bladder cancer, and long-term depression.Conclusions: WES revealed significantly mutated genes associated with the molecular mechanisms of PCNSL, which could serve as therapeutic targets to improve patient outcomes.

Prognosis evaluation is crucial for the effective management of patients with acute traumatic brain injury (TBI). However, there is still a lack of routinely available blood indicators for mortality risk in clinical practice. To investigate whether blood red cell distribution width to platelet count ratio (RPR) correlates with hospital mortality of TBI, clinical data of 2220 patients with TBI were extracted from two large intensive care unit cohorts (MIMIC-III and eICU Database), and were integratively analyzed using our developed method named MeDICS. We found that higher RPR can be observed among non-survivors than survivors of TBI (p < 0.001). It had a moderately good prognostic performance for mortality with an area under receiver-operating characteristic curve (AUC) of 0.7367, which was greater than that of Glasgow Coma Scale (GCS; AUC = 0.6022). Besides, the nomogram consisting of RPR, GCS, and other risk factors was developed, where 10-fold cross-validation was performed to protect it against overfitting. A Harrell's C-index of 0.8523 was determined, suggesting an improved prognostic value based on RPR. The in vivo experiments further confirmed the association between RPR and neuro-outcome after TBI. It indicated that the continuous change in RPR post-injury is attributed to the development of inflammation, which emphasized the importance of controlling inflammatory response in clinical treatment. Taken together, RPR is a promising routinely available predictor of mortality for acute TBI. The nomogram generated from it can be used in resource-limited settings, thus be proposed as a prognosis evaluation aid for patients with TBI in all levels of medical system.

Regenerable nanozymes with high catalytic stability and sustainability are promising substitutes for naturally-occurring enzymes but are limited by insufficient and non-selective catalytic activities. Herein, we developed single-atom nanozymes of RhN4, VN4, and Fe-Cu-N-6 with catalytic activities surpassing natural enzymes. Notably, Rh/VN4 preferably forms an Rh/V-O-N-4 active center to decrease reaction energy barriers and mediates a "two-sided oxygen-linked" reaction path, showing 4 and 5-fold higher affinities in peroxidase-like activity than the FeN4 and natural horseradish peroxidase. Furthermore, RhN4 presents a 20-fold improved affinity in the catalase-like activity compared to the natural catalase; Fe-Cu-N-6 displays selectivity towards the superoxide dismutase-like activity; VN4 favors a 7-fold higher glutathione peroxidase-like activity than the natural glutathione peroxidase. Bioactive sutures with Rh/VN4 show recyclable catalytic features without apparent decay in 1 month and accelerate the scalp healing from brain trauma by promoting the vascular endothelial growth factor, regulating the immune cells like macrophages, and diminishing inflammation. The catalytic activity of regenerable nanozymes is currently the bottle neck for their wider employment. Here, the authors report on single-atom nanozymes of RhN4, VN4, and Fe-Cu-N-6 with higher catalytic activities than natural enzymes, and demonstrate the Rh/VN4 recyclability and scalp healing properties in bioactive sutures.

Background and Purpose: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. Methods: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib’s effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. Results: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. Conclusions: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway.

BACKGROUND: Studies have confirmed active and abnormal inflammation in the hematoma cavity of chronic subdural hematoma (CSDH). However, a relationship between the peripheral blood status and the prognosis of CSDH patients has not been demonstrated. METHODS: We retrospectively analyzed 245 CSDH patients who received conservative therapy (67 under close follow-up observation, 103 treated with atorvastatin, and 75 treated with atorvastatin combined with dexamethasone) from 2014 to 2021 to evaluate the role of major inflammation-associated cells in the prognostic assessment of patients. Univariate and multivariate analyses were performed to assess the potential factors that could indicate the prognosis among the 103 patients who underwent observation only or atorvastatin therapy. Changes in peripheral blood inflammation-associated cells at different time points were compared between patients with good and poor outcomes. Furthermore, the changes in inflammatory cells in 75 patients who received atorvastatin combined with dexamethasone were analyzed. RESULTS: The monocyte percentage was the only independent influencing factor in subsequent follow-up assessments. Patients with good outcomes had obviously lower circulating monocyte percentages in their peripheral blood counts throughout the treatment period. The monocyte percentage was also significantly decreased in the patients who responded well to atorvastatin combined with dexamethasone. The peripheral monocyte percentage was significantly higher in patients who transitioned to surgery because of a poor response to pharmacotherapy. CONCLUSIONS: The peripheral monocyte percentage may be a convenient and effective indicator for predicting the outcome of CSDH for patients receiving conservative treatment. A higher percentage of monocytes could be a risk factor for a poor response.

Mild traumatic brain injury (mTBI) has a relatively higher incidence in aging people due to walking problems. Cranial computed tomography and magnetic resonance imaging provide the standard diagnostic tool to identify intracranial complications in patients with mTBI. However, it is still necessary to further explore blood biomarkers for evaluating the deterioration risk at the early stage of mTBI to improve medical decision-making in the emergency department. The activation of the inflammatory response is one of the main pathological mechanisms leading to unfavorable outcomes of mTBI. As complete blood count (CBC) analysis is the most extensively used laboratory test in practice, we extracted clinical data of 994 patients with mTBI from two large clinical cohorts (MIMIC-IV and eICU-CRD) and selected inflammation-related indicators from CBC analysis to investigate their relationship with the deterioration after mTBI. The combinatorial indices neutrophil-to-lymphocyte ratio (NLR), red cell distribution width-to-platelet ratio (RPR), and NLR times RPR (NLTRP) were supposed to be potential risk predictors, and the data from the above cohorts were integratively analyzed using our previously reported method named MeDICS. We found that NLR, RPR, and NLTRP levels were higher among deteriorated patients than non-deteriorated patients with mTBI. Besides, high NLTRP was associated with increased deterioration risk, with the odds ratio increasing from NLTRP of 1–2 (2.69, 1.48–4.89) to > 2 (4.44, 1.51–13.08), using NLTRP of 0–1 as the reference. NLTRP had a moderately good prognostic performance with an area under the ROC curve of 0.7554 and a higher prediction value than both NLR and RPR, indicated by the integrated discrimination improvement index. The decision curve analysis also showed greater clinical benefits of NLTRP than NLR and RPR in a large range of threshold probabilities. Subgroup analysis further suggested that NLTRP is an independent risk factor for the deterioration after mTBI. In addition, in vivo experiments confirmed the association between NLTRP and neural/systemic inflammatory response after mTBI, which emphasized the importance of controlling inflammation in clinical treatment. Consequently, NLTRP is a promising biomarker for the deterioration risk of mTBI. It can be used in resource-limited settings, thus being proposed as a routinely available tool at all levels of the medical system.

Neuronal death and inflammatory response are two common pathological hallmarks of acute central nervous system injury and chronic degenerative disorders, both of which are closely related to cognitive and motor dysfunction associated with various neurological diseases. Neurological diseases are highly heterogeneous; however, they share a common pathogenesis, that is, the aberrant accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER). Fortunately, the cell has intrinsic quality control mechanisms to maintain the proteostasis network, such as chaperone-mediated folding and ER-associated degradation. However, when these control mechanisms fail, misfolded/unfolded proteins accumulate in the ER lumen and contribute to ER stress. ER stress has been implicated in nearly all neurological diseases. ER stress initiates the unfolded protein response to restore proteostasis, and if the damage is irreversible, it elicits intracellular cascades of death and inflammation. With the growing appreciation of a functional association between ER stress and neurological diseases and with the improved understanding of the multiple underlying molecular mechanisms, pharmacological and genetic targeting of ER stress are beginning to emerge as therapeutic approaches for neurological diseases.