Vitamin D accelerates the subdural hematoma clearance through improving the meningeal lymphatic vessel function.

Subdural hematoma (SDH) drains into the extracranial lymphatic system through the meningeal lymphatic vessels (mLVs) but the formation of SDH impairs mLVs. Because vitamin D (Vit D) can protect the endothelial cells, we hypothesized that Vit D may enhance the SDH clearance. SDH was induced in Sprague-Dawley rats and treated with Vit D or vehicle. Hematoma volume in each group was measured by H&E staining and hemoglobin quantification. Evans blue (EB) quantification and red blood cells injection were used to evaluated the drainage of mLVs. Western blot analysis and immunofluorescence were conducted to assess the expression of lymphatic protein markers. We also examined the inflammatory factors levels in subdural space by ELISA. Vit D treatment significantly reduced SDH volume and improved the drainage of SDH to cervical lymph nodes. The structure of mLVs in SDH rats were protected by Vit D, and the expressions of LYVE1, PROX1, FOXC2, and VE-cadherin were increased after Vit D treatment. The TNF-α, IL-6, and IL-8 levels were reduced in Vit D group. In vitro, Vit D also increased the VE-cadherin expression levels under inflammation. Vit D protects the structure of mLVs and enhances the absorption of SDH, partly by the anti-inflammatory effect of Vit D.

The inflammatory cellular feature in the peripheral blood of chronic subdural hematoma patients.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurosurgical disease with an increasing incidence. The absorption route of CSDH is not clear. Whether inflammatory factors enter the peripheral blood and cause systemic reactions is unknown. METHODS: We screened 105 CSDH patients and 105 control individuals. Their clinical characteristics and blood routine results were collected and compared. The blood routine changes of CSDH patients before and after treatment were compared. Age-stratified analysis was performed due to age may affect the inflammatory markers. RESULTS: The white blood cell count, absolute neutrophil count, neutrophil percentage, neutrophil-lymphocyte count ratio (NLR), and platelet to lymphocyte count ratio (PLR) of CSDH patients before treatment were within the normal range, while were significantly higher than the control individuals (p < 0.001). The absolute lymphocyte count and lymphocyte percentage of control individuals were higher than those of patients (p < 0.001). The inflammatory cells in patients of different age groups were similar. After the patient was cured, the white blood cell count, the absolute value and percentage of neutrophils decreased (p < 0.05), while the number of monocytes increased. CONCLUSIONS: CSDH caused slight systemic inflammatory responses in the peripheral blood, implying that there is a non-hematologic route for the absorption of hematoma.

Dexamethasone enhances the efficacy of atorvastatin in inhibiting excessively inflammation-induced abnormal angiogenesis by regulating macrophages.

BACKGROUND: We have recently showed that atorvastatin (ATO) combined with low dose of dexamethasone (DEX) was more efficacious in treating patients with chronic subdural haematoma (CSDH) than ATO monotherapy. This study was designed to investigate the underlying mechanisms of the improved efficacy of this combined therapy. METHODS: Mass spectrometry was performed to quantitatively detect drugs in haematoma fluids and serum samples from CSDH patients and also in cultured macrophages after treatment with either ATO alone or in combination with DEX. The differentiation and apoptosis of macrophages were evaluated using flow cytometry. The expression of cytokines, chemokines and angiogenesis-related proteins was evaluated using proteome profile arrays, immunoblots and ELISA, respectively. RESULTS: ATO was detected in haematoma fluids and serum samples, whose levels were increased significantly in samples collected from patients treated with both ATO and DEX. ATO was also increased in cultured macrophages treated with ATO and DEX. The numbers of M1-polarized macrophages were higher than the M2 phenotype in the haematoma fluids of patients. Cultured macrophages treated with ATO and DEX had reduced numbers of M1-polarized macrophages, increased numbers of M2-polarized macrophages as compared to monotherapies, and decreased rate of apoptosis induced by high-dose DEX. DEX enhanced the anti-inflammatory and anti-angiogenic activity of ATO by suppressing VEGFA and other inflammatory angiogenic factors. Consistent with the finding, patients responded well to the drug treatments had lower serum levels of VEGFA. CONCLUSIONS: We have shown for the first time that ATO given orally was detected in CSDH haematoma fluids. DEX enhances the anti-inflammatory and anti-angiogenic effects of ATO, primarily by increasing the presence of ATO in haematoma and macrophages and by regulating the functions of macrophages.

Impact of pelvic dimensions on anastomotic leak after anterior resection for patients with rectal cancer.

AIM: The impact of pelvis on the development of anastomotic leak (AL) in rectal cancer (RC) patients who underwent anterior resection (AR) remains unclear. The aim of this study was to evaluate the impact of pelvic dimensions on the risk of AL. METHODS: A total of 1058 RC patients undergoing AR from January 2013 to January 2016 were enrolled. Pelvimetric parameters were obtained using abdominopelvic computed tomography scans. RESULTS: Univariate analyses showed that pelvic inlet, pelvic outlet, interspinous distance, and intertuberous distance were significantly associated with the risk for AL (P < 0.05). Multivariate analysis confirmed that pelvic inlet and intertuberous distance were independent risk factors for AL (P < 0.05). Significant factors from multivariate analysis were assembled into the nomogram A (without pelvic dimensions) and nomogram B (with pelvic dimensions). The area under curve (AUC) of nomogram B was 0.72 (95% CI 0.67-0.77), which was better than the AUC of nomogram A (0.69, [95% CI 0.65-0.74]), but didn't reach a statistical significance (P = 0.199). Decision curve supported that nomogram B was better than nomogram A. CONCLUSION: Pelvic dimensions, specifically pelvic inlet and intertuberous distance, seemed to be independent predictors for postoperative AL in RC patients. Pelvic inlet and intertuberous distance incorporated with preoperative radiotherapy, preoperative albumin, conversion, and tumor diameter in the nomogram might provide a clinical tool for predicting AL.

Low-temperature laminar flow ward for the treatment of multidrug resistance Acinetobacter baumannii pneumonia.

This study was designed to investigate the effect of low-temperature laminar flow ward (LTLFW) on the Acinetobacter baumannii pneumonia (MDR-ABP) in neurosurgical intensive care unit (NICU) patients. We evaluated whether patients in a LTLFW had significantly improved clinical outcomes as compared to those in nonconstant-temperature NICU (room temperature). The association of temperature with the prevalence of ABP and A. baumannii isolates (ABI) found in NICU patients was specifically investigated. In vitro microbiological experiments were conducted to measure the proliferation, antibiotic sensitivity, and genomic profiles of A. baumannii (AB) that grew in variable temperatures. MDR-ABP patients in LTLFW had significantly improved outcomes than those in the room temperature NICU. In addition, the numbers of ABI were positively associated with mean ambient outdoor temperatures (P = 0.002), with the incidence of ABP and average numbers of ABI among NICU patients being substantially lower in the winter as compared to other seasons. However, there were no significant seasonal variations in the other strains of the top five bacteria. Consistent with these clinical observations, AB growing at 20°C and 25°C had significantly reduced viability and antibiotic resistance compared to those growing at 35°C. The expression of genes related to AB survival ability, drug resistance, and virulence also differed between AB growing at 20°C and those at 35°C. LTLFW is effective in promoting the recovery of MDR-ABP patients because low temperatures reduced the density and virulence of AB and enhanced the efficacy of antibiotics, likely at the genetic level.

Trust in AI-augmented design: Applying structural equation modeling to AI-augmented design acceptance.

With the emergence of Artificial Intelligence (AI) 2.0, computers are now equipped with new creative capabilities and are playing an increasingly significant role in design. The use of AI augmentation has the potential to enhance design performance, however, there is limited research on the acceptance of AI-augmented design. The research gap under consideration in this study is addressed by presenting an acceptance model designed for AI-augmented design. This model integrates a range of variables including perceived privacy risk, enjoyment, perceived value, perceived usefulness, perceived ease of use, perceived behavioral control, social influence, and behavioral intention. The proposed model was validated through a questionnaire survey of 249 designers in China. The results reveal that enjoyment, perceived value, perceived ease of use, perceived behavioral control, and social influence have a significant positive impact on users' intention to use AI-augmented design, while perceived privacy risk has a significant negative impact. Perceived value was found to mediate the relationship between enjoyment and behavioral intention, while perceived behavioral control play a mediation role in the relationship between social influence and behavioral intention. In conclusion, this study highlights the variables that influence the acceptance of AI-augmented design and provides valuable insights into the potential benefits and drawbacks of integrating AI technologies in design. The proposed acceptance model serves as a framework for future research in this area and can guide the development of more user-friendly and effective AI-augmented design tools and technologies.

Development and comparison of machine-learning models for predicting prolonged postoperative length of stay in lung cancer patients following video-assisted thoracoscopic surgery.

Objective: This study aimed to develop models for predicting prolonged postoperative length of stay (PPOLOS) in lung cancer patients undergoing video-assisted thoracoscopic surgery (VATS) by utilizing machine-learning techniques. These models aim to offer valuable insights for clinical decision-making. Methods: This retrospective cohort study analyzed a dataset of lung cancer patients who underwent VATS, identifying 25 numerical features and 45 textual features. Three classification machine-learning models were developed: XGBoost, random forest, and neural network. The performance of these models was evaluated based on accuracy (ACC) and area under the receiver operating characteristic curve, whereas the importance of variables was assessed using the feature importance parameter from the random forest model. Results: Of the 6767 lung cancer patients, 1481 patients (21.9%) experienced a postoperative length of stay of > 4 days. The majority were male (4111, 60.8%), married (6246, 92.3%), and diagnosed with adenocarcinoma (4145, 61.3%). The Random Forest classifier exhibited superior prediction performance with an area under the curve (AUC) of 0.792 and ACC of 0.804. The calibration plot revealed that all three classifiers were in close alignment with the ideal calibration line, indicating high calibration reliability. The five most critical features identified were the following: surgical duration (0.116), age (0.066), creatinine (0.062), hemoglobin (0.058), and total protein (0.054). Conclusions: This study developed and evaluated three machine-learning models for predicting PPOLOS in lung cancer patients undergoing VATS. The findings revealed that the Random Forest model is most accurately predicting the PPOLOS. Findings of this study enable the identification of crucial determinants and the formulation of targeted interventions to shorten the length of stay among lung cancer patients after VATS, which contribute to optimize the allocation of healthcare resources.

Susceptibility to Hepatotoxic Drug-Induced Liver Injury Increased After Traumatic Brain Injury in Mice.

The early stages of brain injury can induce acute liver injury, which can be recovered in the short term. Continued medication treatment during hospitalization for brain injury alleviates the prognosis and contributes to a high incidence of drug-induced liver injury (DILI). We hypothesize that there is an interaction between changes in the hepatic environment after brain injury and liver injury produced by intensive drug administration, leading to an upregulation of the organism's sensitivity to DILI. In this study, mice models of TBI were established by controlled cortical impact (CCI) and models of DILI were constructed by acetaminophen (APAP). All mice were divided into four groups: Sham, TBI, APAP, and TBI+APAP, and related liver injury indicators in liver and serum were detected by Western blot, Quantitative real-time PCR (qRT-PCR), and immunohistochemical staining. The results suggested that liver injury induced in the early stages of brain injury recovered in 3 days, but this state could still significantly aggravate DILI, represented by higher liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), oxidative stress (increase in malondialdehyde [MDA] concentration and deregulation of glutathione [GSH] and superoxide dismutase [SOD] activities), inflammatory response (activation of the HMGB1/TLR4/NF-κB signaling pathway, and increased messenger RNA [mRNA] and protein levels of pro-inflammatory cytokines including tumor necrosis factor alpha [TNF-α], interleukin [IL]-6, and IL-1ß), and apoptosis (TUNEL assay, upregulation of Bax protein and deregulation of Bcl-2 protein). In summary, our results suggested that TBI is a potential susceptibility factor for DILI and exacerbates DILI.

Cognitive impairment in Chinese traumatic brain injury patients: from challenge to future perspectives.

Traumatic Brain Injury (TBI) is a prevalent form of neurological damage that may induce varying degrees of cognitive dysfunction in patients, consequently impacting their quality of life and social functioning. This article provides a mini review of the epidemiology in Chinese TBI patients and etiology of cognitive impairment. It analyzes the risk factors of cognitive impairment, discusses current management strategies for cognitive dysfunction in Chinese TBI patients, and summarizes the strengths and limitations of primary testing tools for TBI-related cognitive functions. Furthermore, the article offers a prospective analysis of future challenges and opportunities. Its objective is to contribute as a reference for the prevention and management of cognitive dysfunction in Chinese TBI patients.

Delayed Administration of an Angiotensin II Type 2 Receptor Agonist Promotes Functional Recovery of the Brain and Heart After Traumatic Brain Injury.

Cardiac injury is a common complication following traumatic brain injury (TBI) that can lead to poor clinical outcomes. Angiotensin II type 2 receptor (AT2R) activation exerts protective roles in the brain and heart, yet its potential impact on TBI or TBI-induced cardiac deficits remains elusive. The goal of this study was to investigate the influence of AT2R activation on recovery after TBI-induced cognitive and cardiac injury using the selective nonpeptide AT2R agonist compound 21 (C21). TBI was induced by cortical impact injury in male adult C57BL/6J mice, and the mice received C21 (0.03 mg/kg, intraperitoneally) starting from 24 h after TBI and continuing once daily. C21 facilitated cognitive function recovery until 1 month after TBI. C21 alleviated blood-brain barrier leakage and brain edema and inhibited the expression of proinflammatory cytokines in the brain after 3 consecutive days of treatment. C21 improved cerebral blood flow after 1 month, although the lesion volume was not affected. C21 also reduced the expression of proinflammatory cytokines in the heart after a 3-day consecutive treatment. Meanwhile, C21 benefited cardiac function, as identified by increased left ventricular ejection fraction 1 month after TBI. In addition, C21 alleviated TBI-induced cardiac hypertrophy and fibrosis; however, blood pressure was not affected. Our results demonstrate that AT2R activation ameliorates TBI-induced neurological and cardiac deficits.

Glycolytic Activation of CD14+ Intestinal Macrophages Contributes to the Inflammatory Responses via Exosomal Membrane Tumor Necrosis Factor in Crohn's Disease.

BACKGROUND: Macrophage (Mφ) activation plays a critical role in the inflammatory response. Activated Mφ go through profound reprogramming of cellular metabolism. However, changes in their intracellular energy metabolism and its effect on inflammatory responses in Crohn's disease (CD) remain currently unclear. The aim of this study is to explore metabolic signatures of CD14+ Mφ and their potential role in CD pathogenesis as well as the underlying mechanisms. METHODS: CD14+ Mφ were isolated from peripheral blood or intestinal tissues of CD patients and control subjects. Real-time flux measurements and enzyme-linked immunosorbent assay were used to determine the inflammatory states of Mφ and metabolic signatures. Multiple metabolic routes were suppressed to determine their relevance to cytokine production. RESULTS: Intestinal CD14+ Mφ in CD patients exhibited activated glycolysis compared with those in control patients. Specifically, macrophagic glycolysis in CD largely induced inflammatory cytokine release. The intestinal inflammatory microenvironment in CD elicited abnormal glycolysis in Mφ. Mechanistically, CD14+ Mφ derived exosomes expressed membrane tumor necrosis factor (TNF), which engaged TNFR2 and triggered glycolytic activation via TNF/nuclear factor κB autocrine and paracrine signaling. Importantly, clinically applicable anti-TNF antibodies effectively prevented exosomal membrane TNF-induced glycolytic activation in CD14+ Mφ. CONCLUSIONS: CD14+ Mφ take part in CD pathogenesis by inducing glycolytic activation via membrane TNF-mediated exosomal autocrine and paracrine signaling. These results provide novel insights into pathogenesis of CD and enhance understanding of the mechanisms of anti-TNF agents.

Spinal Lymphatic Dysfunction Aggravates the Recovery Process After Spinal Cord Injury.

We aimed to evaluate the role of the spinal lymphatic system in spinal cord injury and whether it has an impact on recovery after spinal cord injury. Flow cytometry was used to evaluate the changes in the number of microvesicles after spinal cord injury. Evans blue extravasation was used to evaluate the function of the lymphatic system. Evans blue extravasation and immunofluorescence were used to evaluate the permeability of blood spinal cord barrier. The spinal cord edema was evaluated by dry and wet weight.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was used to evaluate apoptosis after spinal cord injury. Nuclear factor-kappa B pathway was detected by Western blot. Behavioral tests were used to evaluate limb function. Microvesicles released after spinal cord injury can enter the thoracic duct and then enter the blood through the lymph around the spine. After ligation of the thoracic duct, it can aggravate the neuropathological manifestations and limb function after spinal cord injury. The potential mechanism may involve nuclear factor-kappa B pathway.

Effect of l-oxiracetam and oxiracetam on memory and cognitive impairment in mild-to-moderate traumatic brain injury patients: Study protocol for a randomized controlled trial.

Objectives: Patients 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. Methods: The 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. Discussion: There 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 registration: chinadrugtrials.org.cn, identifier CTR20192539; ClinicalTrials.gov, identifier NCT04205565.

CD4+ CD11b+ T cells infiltrate and aggravate the traumatic brain injury depending on brain-to-cervical lymph node signaling.

AIM: We aim to identify the specific CD4+ T-cell subtype influenced by brain-to-CLN signaling and explore their role during the acute phase of traumatic brain injury (TBI). METHOD: Cervical lymphadenectomy or cervical afferent lymphatic ligation was performed before TBI. Cytokine array and western blot were used to detect cytokines, while the motor function was assessed using mNss and rotarod test. CD4+ T-cell subtypes in blood, brain, and CLNs were analyzed with Cytometry by time-of-flight analysis (CyTOF) or fluorescence-activated cell sorting (FACS). Brain edema and volume changes were measured by 9.4T MRI. Neuronal apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. RESULTS: Cervical lymphadenectomy and ligation of cervical lymphatic vessels resulted in a decreased infiltration of CD4+ T cells, specifically CD11b-positive CD4+ T cells, within the affected region. The population of CD4+ CD11b+ T cells increased in ligated CLNs, accompanied by a decrease in the average fluorescence intensity of sphingosine-1-phosphate receptor-1 (S1PR1) on these cells. Administration of CD4+ CD11b+ T cells sorted from CLNs into the lateral ventricle reversed the attenuated neurologic deficits, brain edema, and lesion volume following cervical lymphadenectomy. CONCLUSION: The infiltration of CD4+ CD11b+ T cells exacerbates secondary brain damage in TBI, and this process is modulated by brain-to-CLN signaling.

Inactivation of ERK1/2 signaling mediates dysfunction of basal meningeal lymphatic vessels in experimental subdural hematoma.

Rationale: Meningeal lymphatic vessels (MLVs) are essential for the clearance of subdural hematoma (SDH). However, SDH impairs their drainage function, and the pathogenesis remains unclear. Herein, we aimed to understand the pathological mechanisms of MLV dysfunction following SDH and to test whether atorvastatin, an effective drug for SDH clearance, improves meningeal lymphatic drainage (MLD). Methods: We induced SDH models in rats by injecting autologous blood into the subdural space and evaluated MLD using Gadopentetate D, Evans blue, and CFSE-labeled erythrocytes. Whole-mount immunofluorescence and transmission electron microscopy were utilized to detect the morphology of MLVs. Phosphoproteomics, western blot, flow cytometry, and in vitro experiments were performed to investigate the molecular mechanisms underlying dysfunctional MLVs. Results: The basal MLVs were detected to have abundant valves and play an important role in draining subdural substances. Following SDH, these basal MLVs exhibited disrupted endothelial junctions and dilated lumen, leading to impaired MLD. Subsequent proteomics analysis of the meninges detected numerous dephosphorylated proteins, primarily enriched in the adherens junction, including significant dephosphorylation of ERK1/2 within the meningeal lymphatic endothelial cells (LECs). Subdural injection of the ERK1/2 kinase inhibitor PD98059 resulted in dilated basal MLVs and impaired MLD, resembling the dysfunctional MLVs observed in SDH. Moreover, inhibiting ERK1/2 signaling severely disrupted intercellular junctions between cultured LECs. Finally, atorvastatin was revealed to protect the structure of basal MLVs and accelerate MLD following SDH. However, these beneficial effects of atorvastatin were abolished when combined with PD98059. Conclusion: Our findings demonstrate that SDH induces ERK1/2 dephosphorylation in meningeal LECs, leading to disrupted basal MLVs and impaired MLD. Additionally, we reveal a beneficial effect of atorvastatin in improving MLD.

Multimodality management for chronic subdural hematoma in China: protocol and characteristics of an ambidirectional, nationwide, multicenter registry study.

BACKGROUND: Despite its prevalence, there is ongoing debate regarding the optimal management strategy for chronic subdural hematoma (CSDH), reflecting the variability in clinical presentation and treatment outcomes. This ambidirectional, nationwide, multicenter registry study aims to assess the efficacy and safety of multimodality treatment approaches for CSDH in the Chinese population. METHODS/DESIGN: A multicenter cohort of CSDH patients from 59 participating hospitals in mainland China was enrolled in this study. The treatment modalities encompassed a range of options and baseline demographics, clinical characteristics, radiographic findings, and surgical techniques were documented. Clinical outcomes, including hematoma resolution, recurrence rates, neurological status, and complications, were assessed at regular intervals during treatment, 3 months, 6 months, 1 year, and 2 years follow-up. RESULT: Between March 2022 and August 2023, a comprehensive cohort comprising 2173 individuals who met the criterion was assembled across 59 participating clinical sites. Of those patients, 81.1% were male, exhibiting an average age of 70.12 ± 14.53 years. A historical record of trauma was documented in 48.0% of cases, while headache constituted the predominant clinical presentation in 58.1% of patients. The foremost surgical modality employed was the burr hole (61.3%), with conservative management accounting for 25.6% of cases. Notably, a favorable clinical prognosis was observed in 88.9% of CSDH patients at 3 months, and the recurrence rate was found to be 2.4%. CONCLUSION: This registry study provides critical insights into the multimodality treatment of CSDH in China, offering a foundation for advancing clinical practices, optimizing patient management, and ultimately, improving the quality of life for individuals suffering from this challenging neurosurgical condition. TRIAL REGISTRATION: ChiCTR2200057179.

rTMS treatment for abrogating intracerebral hemorrhage-induced brain parenchymal metabolite clearance dysfunction in male mice by regulating intracranial lymphatic drainage.

BACKGROUND: The discovery of the glymphatic system and meningeal lymphatic vessels challenged the traditional view regarding the lack of a lymphatic system in the central nervous system. It is now known that the intracranial lymphatic system plays an important role in fluid transport, macromolecule uptake, and immune cell trafficking. Studies have also shown that the function of the intracranial lymphatic system is significantly associated with neurological diseases; for example, an impaired intracranial lymphatic system can lead to Tau deposition and an increased lymphocyte count in the brain tissue of mice with subarachnoid hemorrhage. METHODS: In this study, we assessed the changes in the intracranial lymphatic system after intracerebral hemorrhage and the regulatory effects of repeated transcranial magnetic stimulation on the glymphatic system and meningeal lymphatic vessels in an intracerebral hemorrhage (ICH) model of male mice. Experimental mice were divided into three groups: Sham, ICH, and ICH + repeated transcranial magnetic stimulation (rTMS). Three days after ICH, mice in the ICH+rTMS group were subjected to rTMS daily for 7 days. Thereafter, the function of the intracranial lymphatic system, clearance of RITC-dextran and FITC-dextran, and neurological functions were evaluated. RESULTS: Compared with the Sham group, the ICH group had an impaired glymphatic system. Importantly, rTMS treatment could improve intracranial lymphatic system function as well as behavioral functions and enhance the clearance of parenchymal RITC-dextran and FITC-dextran after ICH. CONCLUSION: Our results indicate that rTMS can abrogate ICH-induced brain parenchymal metabolite clearance dysfunction by regulating intracranial lymphatic drainage.

Age-adjusted D-Dimer Thresholds Combined with the Modified Wells Score as a Predictor of Lower Extremity Deep Venous Thrombosis.

BACKGROUND: Neurosurgical patients are at an increased risk of deep venous thrombosis (DVT), which, if not properly managed, can lead to pulmonary embolism. This study aimed to investigate the accuracy of age-adjusted D-dimer thresholds combined with the modified Wells score as a predictor for lower extremity DVT diagnosis. METHODS: We conducted a study among patients aged >50 years with suspected lower extremity DVT in the neurosurgery intensive care unit between December 2019 and December 2020. Receiver operating characteristic curve analysis was performed to examine the diagnostic capacity of age-adjusted D-dimer combined with the modified Wells score. RESULTS: A total of 233 participants, with an average age of 71.81 ± 12.59 years, were enrolled in the study. The mean D-dimer levels were 0.73 ± 0.39 mg/L. Among the participants, 57 (57.9%, 33 males) were diagnosed with DVT. The age-adjusted D-dimer combined with the modified Wells score had the highest area under the curve for diagnosing lower extremity DVT compared to D-dimer and age-adjusted D-dimer alone, with an AUC of 0.858. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the age-adjusted D-dimer combined with the modified Wells score for DVT diagnosis were 78.95%, 80.68%, 57%, 92.2%, and 80.26%, respectively. When analyzing subgroups, the accuracy was 79.55% for participants with cerebral hemorrhage, 81.69% for those with craniocerebral injury, 74.99% for participants with intracranial infection, and 88.89% for those with craniocerebral tumor. CONCLUSION: The combination of the age-adjusted D-dimer thresholds with the modified Wells score might effectively predict lower extremity DVT.

An immune, stroma, and epithelial-mesenchymal transition-related signature for predicting recurrence and chemotherapy benefit in stage II-III colorectal cancer.

BACKGROUND: Debates exist on the treatment decision of the stage II/III colorectal cancer (CRC) due to the insufficiency of the current TNM stage-based risk stratification system. Epithelial-mesenchymal transition (EMT) and tumor microenvironment (TME) have both been linked to CRC progression in recent studies. We propose to improve the prognosis prediction of CRC by integrating TME and EMT. METHODS: In total, 2382 CRC patients from seven datasets and one in-house cohort were collected, and 1640 stage II/III CRC patients with complete survival information and gene expression profiles were retained and divided into a training cohort and three independent validation cohorts. Integrated analysis of 398 immune, stroma, and epithelial-mesenchymal transition (ISE)-related genes identified an ISE signature independently associated with the recurrence of CRC. The underlying biological mechanism of the ISE signature and its influence on adjuvant chemotherapy was further explored. RESULTS: We constructed a 26-gene signature which was significantly associated with poor outcome in Training cohort (p < 0.001, HR [95%CI] = 4.42 [3.25-6.01]) and three independent validation cohorts (Validation cohort-1: p < 0.01, HR [95%CI] = 1.70 [1.15-2.51]; Validation cohort-2: p < 0.001, HR [95% CI] = 2.30 [1.67-3.16]; Validation cohort-3: p < 0.01, HR [95% CI] = 2.42 [1.25-4.70]). After adjusting for known clinicopathological factors, multivariate cox analysis confirmed the ISE signature's independent prognostic value. Subgroup analysis found that stage III patients with low ISE score might benefit from adjuvant chemotherapy (p < 0.001, HR [95%CI] = 0.15 [0.04-0.55]). Hypergeometric test and enrichment analysis revealed that low-risk group was enriched in thr immune pathway while high-risk group was associated with the EMT pathway and CMS4 subtype. CONCLUSION: We proposed an ISE signature for robustly predicting the recurrence of stage II/III CRC and help treatment decision by identifying patients who will not benefit from current standard treatment.

Exogenous interleukin 33 enhances the brain's lymphatic drainage and toxic protein clearance in acute traumatic brain injury mice.

The persistent dysregulation and accumulation of poisonous proteins from destructive neural tissues and cells activate pathological mechanisms after traumatic brain injury (TBI). The lymphatic drainage system of the brain, composed of the glymphatic system and meningeal lymphatic vessels (MLVs), plays an essential role in the clearance of toxic waste after brain injury. The neuroprotective effect of interleukin 33 (IL-33) in TBI mice has been demonstrated; however, its impact on brain lymphatic drainage is unclear. Here, we established a fluid percussion injury model to examine the IL-33 administration effects on neurological function and lymphatic drainage in the acute brain of TBI mice. We verified that exogenous IL-33 could improve the motor and memory skills of TBI mice and demonstrated that in the acute phase, it increased the exchange of cerebrospinal and interstitial fluid, reversed the dysregulation and depolarization of aquaporin-4 in the cortex and hippocampus, improved the drainage of MLVs to deep cervical lymph nodes, and reduced tau accumulation and glial activation. We speculate that the protective effect of exogenous IL-33 on TBI mice's motor and cognitive functions is related to the enhancement of brain lymphatic drainage and toxic metabolite clearance from the cortex and hippocampus in the acute stage. These data further support the notion that IL-33 therapy may be an effective treatment strategy for alleviating acute brain injury after TBI.