Tetrahedral DNA loaded siCCR2 restrains M1 macrophage polarization to ameliorate pulmonary fibrosis in chemoradiation-induced murine model.

Idiopathic pulmonary fibrosis (IPF) is a chronic lethal disease in the absence of demonstrated efficacy for preventing progression. Although macrophage-mediated alveolitis is determined to participate in myofibrotic transition during disease development, the paradigm of continuous macrophage polarization is still under-explored due to lack of proper animal models. Here, by integrating 2.5 U/kg intratracheal Bleomycin administration and 10 Gy thorax irradiation at day 7, we generated a murine model with continuous alveolitis-mediated fibrosis, which mimics most of the clinical features of our involved IPF patients. In combination with data from scRNA-seq of patients and a murine IPF model, a decisive role of CCL2/CCR2 axis in driving M1 macrophage polarization was revealed, and M1 macrophage was further confirmed to boost alveolitis in leading myofibroblast activation. Multiple sticky-end tetrahedral framework nucleic acids conjunct with quadruple ccr2-siRNA (FNA-siCCR2) was synthesized in targeting M1 macrophages. FNA-siCCR2 successfully blocked macrophage accumulation in pulmonary parenchyma of the IPF murine model, thus preventing myofibroblast activation and leading to the disease remitting. Overall, our studies lay the groundwork to develop a novel IPF murine model, reveal M1 macrophages as potential therapeutic targets, and establish new treatment strategy by using FNA-siCCR2, which are highly relevant to clinical scenarios and translational research in the field of IPF.

The prognostic value of an age-adjusted BIG score in adult patients with traumatic brain injury.

Background: The base deficit, international normalized ratio, and Glasgow Coma Scale (BIG) score was previously developed to predict the outcomes of pediatric trauma patients. We designed this study to explore and improve the prognostic value of the BIG score in adult patients with traumatic brain injury (TBI). Methods: Adult patients diagnosed with TBI in a public critical care database were included in this observational study. The BIG score was calculated based on the Glasgow Coma Scale (GCS), the international normalized ratio (INR), and the base deficit. Logistic regression analysis was performed to confirm the association between the BIG score and the outcome of included patients. Receiver operating characteristic (ROC) curves were drawn to evaluate the prognostic value of the BIG score and novel constructed models. Results: In total, 1,034 TBI patients were included in this study with a mortality of 22.8%. Non-survivors had higher BIG scores than survivors (p < 0.001). The results of multivariable logistic regression analysis showed that age (p < 0.001), pulse oxygen saturation (SpO2) (p = 0.032), glucose (p = 0.015), hemoglobin (p = 0.047), BIG score (p < 0.001), subarachnoid hemorrhage (p = 0.013), and intracerebral hematoma (p = 0.001) were associated with in-hospital mortality of included patients. The AUC (area under the ROC curves) of the BIG score was 0.669, which was not as high as in previous pediatric trauma cohorts. However, combining the BIG score with age increased the AUC to 0.764. The prognostic model composed of significant factors including BIG had the highest AUC of 0.786. Conclusion: The age-adjusted BIG score is superior to the original BIG score in predicting mortality of adult TBI patients. The prognostic model incorporating the BIG score is beneficial for clinicians, aiding them in making early triage and treatment decisions in adult TBI patients.

A Propensity Score-Matched Study on the Changes of TB Status and TB-IGRA Values in Patients with Psoriasis with Latent TB Receiving Secukinumab.

INTRODUCTION: The utilization of biologics in patients with psoriasis with latent tuberculosis infection (LTBI) has garnered significant attention. Although the tuberculosis (TB) safety profile of second-generation biologics, including secukinumab, has been partially confirmed in both clinical trials and real-world studies, the necessity for prophylactic therapy in patients with LTBI prior to administering this class of biologics remains a topic of controversy. METHODS: This study enrolled 62 patients with psoriasis with LTBI who underwent secukinumab with routine TB reexamination. Patients were divided into two groups based on whether they received antituberculosis therapy (ATB; n = 48) or not (NTB; n = 16). We performed a propensity score-matched (PSM) analysis between ATB and NTB subgroups and retrospectively reviewed their interferon-gamma release assays (IGRA) and radiographic results. RESULTS: No active TB case was reported on the basis of medical records and chest radiographs in either two group. Before PSM, the mean reexamining IGRA value was significantly elevated in patients who received prophylactic therapy (P = 0.00), but no significant increase was observed in patients who were not. After PSM, there was no significant IGRA value enhancement whether or not patients received prophylactic treatment. CONCLUSION: Our data provide additional information on the safety profile of secukinumab in patients with psoriasis with LTBI. Furthermore, our presentation of the reexamined IGRA results revealed no significant elevation in the ATB or NTB group. As such, we believe further exploration is necessary to determine whether anti-TB medication is required prior to administering secukinumab.

In the past decade, biologics have revolutionized psoriasis treatment. Among patients receiving biologics, tuberculosis infection is a big concern. Secukinumab, an interleukin-17 inhibitor, belongs to the second-generation biologics. Clinical trials and real-life experience have partially reported its tuberculosis safety. In 2020, a systematic review of randomized clinical trials of secukinumab found no reactivate tuberculosis case. However, when participants tested positive for latent tuberculosis infection at screening in the clinical trials, they received antituberculosis treatment. Should patients with latent tuberculosis infection receive antituberculosis medication before receiving secukinumab? The answer is controversial and lacks evidence. This study enrolled patients with psoriasis with latent tuberculosis infection who underwent secukinumab with routine tuberculosis reexamination. Then, the patients were divided into two groups based on whether they received antituberculosis therapy and not. We observed that neither of these two groups presented tuberculosis activation cases. We also matched patients who received antituberculosis therapy and those who did not. The interferon-gamma release assay showed no significant increase after balancing the baseline. Our data indicated that secukinumab is safe among patients with latent tuberculosis infection even when they did not receive antituberculosis treatment.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Anticoagulation medication in nontraumatic intracranial hemorrhage survivors with atrial fibrillation.

BACKGROUND: The relative effectiveness of anticoagulation agents in patients with atrial fibrillation (AF) who survive an intracranial hemorrhage (ICH) is unknown. This study was performed to examine the comparative effectiveness of different oral anticoagulation (OAC) on clinical outcomes in this group of patients. METHODS: We performed a Bayesian network meta-analysis of randomized controlled trials (RCTs) and observational studies comparing different OAC (direct oral anticoagulant [DOAC] and warfarin) for the treatment of patients with AF who sustained ICH. Outcomes included repeat ICH, thromboembolic events, and all-cause mortality. The values derived from the surface under the cumulative ranking curve were obtained to rank the treatment hierarchy. RESULTS: We identified 12 studies (two RCTs and ten observational studies) involving 23,265 patients; 346 patients were treated with any OAC agents; 5,006 received DOAC; 5,271 received warfarin; 12,007 received antiplatelet or no therapy, and 635 did not received relevant therapy. Both DOAC and warfarin (RR, 0.58; 95% CI, 0.45-0.74; RR, 0.83; 95% CI, 0.69-0.98) were superior to antiplatelet or no therapy in preventing thromboembolic events. Moreover, DOAC also showed superiority in preventing thromboembolic events (RR, 0.70; 95% CI, 0.58-0.83), repeat ICH (RR, 0.52; 95% CI, 0.40-0.67), and all-cause mortality (RR, 0.51; 95% CI, 0.46-0.56) than warfarin. CONCLUSIONS: Our study suggests DOACs may be a reasonable alternative to anti-platelet therapy and warfarin for patients with AF who experienced ICH. However, given the available evidence is primarily observational, further validation by ongoing trials directly comparing these two classes of drugs are needed.

Effect of extended duration of thromboprophylaxis for medically ill patients.

BACKGROUND: There are knowledge gaps regarding the comparative efficacy and safety of various venous thromboprophylaxis regimens with extended timing in patients hospitalized for acute medical illnesses. This study aims to investigate the optimal regimen for the prevention of venous thromboembolism in these patients. METHODS: We conducted a Bayesian network meta-analysis of randomized controlled trials (RCTs) comparing different venous thromboprophylaxis regimens for acutely ill medical patients. Outcomes included venous thromboembolism, major bleeding, and all-cause mortality. Risk ratios (RR) and associated 95% credible interval (CrI) were estimated. In addition, we assessed the most effective interventions in a subgroup of patients with stroke. RESULTS: We identified five RCTs involving 40,124 patients. Extended thromboprophylaxis with direct oral anticoagulant (DOAC) (RR 0.78, 95% CrI 0.68 to 0.89) and low molecular weight heparin (LMWH) (RR 0.62, 95% CrI 0.45 to 0.84) were superior to standard therapy in the prevention of venous thromboembolism. However, both of them (DOAC: RR 1.99, 95% CrI 1.38 to 2.92; LMWH: RR 2.56, 95% CrI 1.26 to 5.68) lead to a significant increase in major bleeding). Moreover, both LMWH (RR 0.76, 95% CrI 0.57 to 1.00) and DOAC (RR 0.86, 95% CrI 0.76 to 0.98) with extended thromboprophylaxis showed favorable net clinical benefit compared to standard therapy. CONCLUSIONS: Extended thromboprophylaxis, especially with LMWH, showed better efficacy in venous thromboembolism reduction with increased risk of major bleeding. The beneficial effect of LMWH with extended timing has also been shown in stroke patients. Overall, extended thromboprophylaxis is associated with a positive net clinical benefit.

Secretome of human umbilical cord mesenchymal stem cell maintains skin homeostasis by regulating multiple skin physiological function.

Skin is the largest organ in the body and the first defense to resist various diseases and external stimuli that easily cause infection and inflammation. Aseptic inflammation, barrier damage, and foreign aid pressure induce the destruction and damage to the skin microenvironment. Subsequently, it destroys the skin's physiological function, leading to the maintenance and circulation of steady-state imbalance and aggravating the process of skin disorders. Our study evaluated the therapeutic potential of the secretome of human umbilical cord mesenchymal stem cells (UC-CM) for dermatological diseases in adult human skin cells, ex vivo skin tissue, and a 3D skin model. Our data suggested several advantages of UC-CM due to (1) their low cytotoxicity and sensitization properties; (2) their anti-inflammatory capacity for treating inflammatory chronic cutaneous diseases; (3) their enhanced capacity of the skin barrier for treating abnormal barrier metabolism; and (4) their positive impact on restoring skin homeostasis due to effective regulation ability of skin physiological function including cell apoptosis, detoxification, and anti-aging. We thus envisage that the possibility of harnessing the therapeutic potential of UC-CM might benefit patients suffering from inflammatory skin disorders such as atopic dermatitis, acne, and psoriasis.

Cerebral hemorrhage after thrombolysis in stroke patients with unruptured intracranial aneurysms: a systemic review and meta-analysis.

BACKGROUND: For ischemic stroke patients with concomitant unruptured aneurysm, intravenous thrombolysis therapy (IVT) remains a disputable decision. We hence performed a meta-analysis to identify the related brain hemorrhage rate of unruptured aneurysms and the risk ratio for their rupture comparing to stroke patients who do not have aneurysms. METHODS: A comprehensive search was conducted to identify the studies from the online database from 2000 to September 1st, 2022. Cohort studies were included and assessed by Newcastle-Ottawa Scale (NOS) for quality. The research procedures were subjected to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Fixed-effects model was used based on the heterogeneity tests. RESULTS: In 10 eligible studies, 7238 ischemic stroke patients were screened, a total of 302 patients with 348 aneurysms were included. 10 studies were eligible for ICH rate analysis, 8 for SAH rate analysis and 7 for risk ratio of stroke patients with unruptured aneurysms. The pooled any ICH rate was 16% (95% CI 11-21%), symptomatic ICH rate was 4% (95% CI 1-7%, I2 = 0.00%, p = 0.90), and 0% (95% CI 0-1%) for aneurysm-related ICH. Subarachnoid hemorrhage was as low as 2% (95% CI 0-5%), while 0% (95% CI 0-2%) directly related to the aneurysm rupture. The risk ratio of ICH in stroke patients with aneurysms was 1.18 (95% CI 0.79-1.77). Additionally, the hemorrhage rate difference was not evident between saccular and fusiform aneurysms due to a lack of details. CONCLUSIONS: IVT is unlikely to induce hemorrhage of pre-existing unruptured aneurysms in stroke patients. Further randomized control studies are warranted to validate these conclusions.

Comprehensive analysis of immune cell infiltration and role of MSR1 expression in aneurysmal subarachnoid haemorrhage.

Aneurysmal subarachnoid haemorrhage (aSAH), resulting from the rupture of intracranial aneurysms, can yield high mortality and disability. This study aimed to explore the immune infiltration of aneurysmal tissues and investigate a novel mechanism underlying aSAH. We downloaded datasets containing expression profiles of aneurysmal and normal arterial tissues from the online database. Then a comprehensive bioinformatic strategy was conducted to select the biomarkers of aneurysmal tissues. Two calculation algorithms were performed to identify the unique immune characteristics between aneurysmal tissues and normal arteries. Double immunofluorescence staining was used to investigate the role of pathway-related proteins in the inflammatory process after aSAH. Six microarray datasets were integrated, and another RNA-sequencing dataset was used as the validation dataset. Functional enrichment analysis of the differentially expressed genes indicated that immune-related processes were closely related to the progression of aSAH. We then performed immune microenvironment infiltration analysis, and the results suggested macrophages were abnormally enriched in aneurysmal tissues. Core gene MSR1 was filtered through a comprehensive bioinformatic strategy. Our analysis suggested that MSR1 might be associated with macrophage activation and migration. Our study elucidated the impact of macrophage and MSR1 on aSAH progression. These findings were helpful in gaining insight into the immune heterogeneity of aneurysmal tissues and normal arteries, and in identifying patients who might benefit from immunotherapy.

The prognostic value of the Charlson comorbidity index in aged patients with intracerebral hemorrhage.

BACKGROUND: Comorbidities are common in aged intracerebral hemorrhage patients. The purpose of this study was to assess whether the Charlson Comorbidity Index (CCI) was associated with in-hospital death and short-term functional outcome in elderly patients (age ≥ 70) with intracerebral hemorrhage (ICH). METHODS: This was a retrospective cohort of aged ICH patients (≥70 years old) admitted within 24 hours of ICH onset. The CCI was derived using hospital discharge ICD-9 CM codes and patient history obtained from standardized case report forms. Multivariable logistic regression was used to determine the independent effect of the CCI score on clinical outcomes. RESULTS: In this cohort of 248 aged ICH patients, comorbid conditions were common, with CCI scores ranging from 2 to 12. Logistic regression showed that the CCI score was independently predictive of 1-month functional outcome (OR = 1.642, P < 0.001) and in-hospital death (OR = 1.480, P = 0.003). Neither ICH volume nor the presence of IVH was an independent predictive factor for 1-month functional outcome or in-hospital mortality (P < 0.05). CONCLUSION: Comorbid medical conditions as assessed by the CCI independently influence short-term outcomes in aged ICH patients. The characteristics of the hematoma itself, such as ICH volume and the presence of IVH, seem to have a reduced effect on it.

A propensity score-matched study on the short-term outcome of ruptured blood blister-like aneurysm treated by microsurgery or endovascular surgery: a single-center study of 155 cases.

Treating blood blister-like aneurysms (BBA) is a major neurosurgical challenge. Whether endovascular repair serves as a better strategy than microsurgery remains controversial. We aim to perform a propensity score-matched (PSM) retrospective study to analyze the short-term outcome in BBA patients who received microsurgery and endovascular treatment. One hundred fifty-five eligible patients with internal carotid artery BBA were retrospectively collected with demographic and angiographic baseline in a single center. Three-month outcome and adverse events were set as outcome endpoints. PSM was used to match the microsurgery and endovascular group. Matching effect was evaluated by distribution variation analysis and love plot. The outcome of neurosurgery and endovascular treatment was then compared before and after PSM. Better WFNS levels (p = .017) and modified Fisher grade (p = .027) were noted in endovascular group before matching. Other baseline including angiographic features were comparable between two groups. Before matching, the 3-month outcome of endovascular repair surgery was more favorable than microsurgery (p < .0001). The occurrence of adverse events was also higher in the microsurgery group (p = .0079). In PSM-adjusted groups, the superior outcome effect of endovascular treatment still existed but with a reduced significance (p = .004). Similar trend was also observed in the adverse event rate (p = .038). Fatality rate was comparable between two adjusted groups regardless of PSM adjustment. Endovascular surgery of BBAs exhibits overall more favorable short-term outcome regardless of PSM matching. Microsurgery does not cause a higher fatality rate, hence it could be considered a salvage plan for those high-grade BBA patients.

Effect of corticosteroids in patients with COVID-19: a Bayesian network meta-analysis.

OBJECTIVES: We sought to perform a network meta-analysis to compare the safety and efficacy of the systemic administration of corticosteroids for the treatment of COVID-19. METHODS: A Bayesian network meta-analysis was performed to combine the direct and indirect evidence. The surface under the cumulative ranking curve was obtained to estimate the ranking probability of the treatment agents for each outcome. The efficacy outcome was 28-day all-cause mortality. The safety outcome was serious adverse events. RESULTS: A total of 16 trials with 2992 patients comparing four treatments (dexamethasone, hydrocortisone, methylprednisolone, and placebo) were identified. Direct analysis showed that corticosteroids were associated with a reduced risk of 28-day mortality compared with usual care (risk ratio [RR] 0.83; 95% confidence interval [CrI] 0.70-0.99). Network analysis showed that the pooled RR was 0.63 (95% CrI 0.39-0.93) for all-cause mortality at 28 days comparing methylprednisolone with usual care or placebo (surface under the cumulative ranking curve: 91%). Our analysis demonstrated that patients who received a low dose of corticosteroids (RR 0.80; 95% CrI 0.70-0.91) and a long course of treatment (RR 0.81; 95% CrI 0.71-0.91) had higher survival rates than patients in the placebo group. CONCLUSION: Administration of corticosteroids was associated with a reduced all-cause mortality at 28 days compared with placebo or usual care. Our analysis also confirmed the mortality benefit associated with low-dose and long-term treatment with corticosteroids.

Identification of the key immune-related genes in aneurysmal subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a major cause of death and morbidity worldwide, often due to rupture of intracranial aneurysms (IAs). Immune infiltration and inflammatory activation play key roles in the process of aneurysmal SAH (aSAH). This study aimed to elaborate the immune infiltration and identify related biomarkers both in blood and tissue samples from patients with aSAH. Expression data of aSAH and healthy control samples were obtained from gene expression omnibus (GEO) database. Overall, a blood sample dataset GSE36791 and a tissue sample dataset GSE122897 were included. Differentially expressed genes (DEGs) between aSAH and healthy samples were explored. We applied GO biological and Gene Set Enrichment Analyses (GSEA) processes to access the functional enrichment. Then feature elimination algorithms based on random forest were used to screen and verify the biomarkers of aSAH. We performed three computational algorithms including Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), Microenvironment Cell Populations-counter (MCPcounter), and xcell to evaluate the immune cell infiltration landscape to identify the unique infiltration characteristics associated with rupturing. We found 2,220 DEGs (856 upregulated and 1,364 downregulated) in the original dataset. Functional analysis revealed most of these genes are enriched in immunological process, especially related with neutrophil response. Similar signaling pathway enrichment patterns were observed in tissue sample dataset and ClueGo. Analysis of immune microenvironment infiltration suggested neutrophils were abnormally upregulated in aSAH compared with those in the control group. Key gene SRPK1 was then filtered based on feature elimination algorithms, and transcription factor (TF) ZNF281 is assumed to participate in immunomodulation by regulating expression of SRPK1. Several immunomodulators such as CXCR1 and CXCR2 also appear to be involved in the progression of aSAH. In the present study, we performed a comprehensive stratification and quantification of the immune infiltration status of aSAH. By exploring the potential mechanism for aSAH based on several computational algorithms, key genes including SRPK1 and ZNF281 were filtered. This study may be of benefit to patients who are at high risk of suffering aSAH which allows for early diagnosis and potential therapy.

Efficacy and safety of monoclonal antibody against calcitonin gene-related peptide or its receptor for migraine patients with prior preventive treatment failure: a network meta-analysis.

OBJECTIVE: The relative effects of monoclonal antibody against calcitonin gene-related peptide (CGRP) or its receptor for adult migraine patients with prior treatment failure remains uncertain. Therefore, this study systematically assessed the comparative effectiveness of different CGRP binding monoclonal antibodies (mAbs) for these patients. METHODS: Several online databases including Ovid MEDILNE, Ovid EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to June 15, 2022. We included randomized clinical trials (RCT) of adult migraine patients with previous treatment failure that assessed any CGRP monoclonal antibody. The primary efficacy outcome was change in monthly migraine days (MMDs), and the primary safety outcome was treatment-emergent adverse events (TEAEs). RESULTS: Overall, seven studies totaling 3, 052 patients were included. Three-node analysis showed that CGRP mAbs was superior to CGRP receptor mAbs in reducing MMDs (MD: -1.55, 95% CrI: - 2.43 to - 0.44) and improving at least 50% response rates (RR: 1.52, 95% CrI: 1.04 to 2.21). Nine-node analysis showed galcanezumab 240 mg ranked first in reducing MMDs (MD -4.40, 95% CrI - 7.60 to - 1.19) and improving 50% response rates (RR: 4.18, 95% CrI: 2.63 to 6.67). Moreover, treatment with fremanezumab or eptinezumab 300 mg provides a significant advantage over erenumab 140 mg regarding an improved response rate of at least 50%. The analysis did not show difference in incidences of TEAEs and serious adverse events in any of the comparisons. CONCLUSIONS: It appears that CGRP mAbs, especially galcanezumab 240 mg, monthly fremanezumab, and eptinezumab 300 mg, seem to be the best choice for the treatment of migraine patients with previous treatment failures. This finding also calls for future research that examine the associations between these medications in migraine therapy among the same patient group to testify the present findings.

Single-Cell RNA Sequencing Reveals the Pathogenic Relevance of Intracranial Atherosclerosis in Blood Blister-Like Aneurysms.

Background: Intracranial non-branching site blood blister-like aneurysms (BBA) are extremely rare and vicious. Their etiology remains elusive, and no molecular study has been carried out to reveal its pathogenic relevance to intracranial atherosclerosis. To investigate its transcriptomic landscape and underlying potential pathogenesis, we performed single-cell RNA sequencing with extensive pathological validation. Methods: In total, 12,245 cells were recovered for single-cell RNA sequencing analysis from 1 BBA and 2 saccular intracranial aneurysms (IAs). Unbiased clustering using Seurat-based pipeline was used for cellular landscape profiling. Cellchat was used to understand intracellular communications. Furthermore, 10 BBAs and 30 IAs were retrospectively collected for pathological validations like scanning electron microscopy, H&E stain, Masson stain, Verhoeff Van Gielson stain, and immunofluorescence. Results: Single-cell transcriptome profiled 14 total subclusters in 6 major groups, namely, 6 monocyte/macrophage clusters, 2 T&NK clusters, 3 vascular smooth muscle cell (VSMC) clusters, 1 dendritic cell, 1 B cell, and 1 endothelial cell cluster. The only mural cell identified in BBAs was VSMC-2 cluster, while mural cells in IAs comprise most clusters of VSMCs and endothelial cells. Upregulated genes in BBA-derived VSMCs are related to arterial mineralization and atherosclerosis, such as PTX3, SPP1, LOX, etc., whereas vasodilation and physiological regulatory genes such as MGP, ACTA2, and MYL9 were conversely enriched in conventional IA-derived VSMCs. Immune cells in the BBA were predominantly macrophages, with a low fraction of T&NK cells, while conventional IAs had a higher percentage of T&NK. Gene enrichment analysis suggested that macrophages in BBA were highly enriched in lipid metabolism as well as atherosclerosis. Ligand-receptor interaction suggested that secretory phosphoprotein 1 (also known as osteopontin) played a major role in mediating the intracellular communication between VSMC and macrophages, especially in BBA. Pathological experiments corroborate with the bioinformatic findings and further characterized BBAs as a thin-walled thrombotic aneurysm with severe atherosclerotic lesions, where ApoE+ macrophages and OPN+ mural cells are intimately involved in the inflammation process. Conclusions: The preexisting intracranial atherosclerosis might predispose the parent artery to the pathogenic occurrence of BBAs. These data shed light on the pathophysiology of intracranial aneurysms and might assist in the further resolution of the complexity in aneurysm pathogenesis.

Clinical characteristics of intracranial aneurysms in elderly patents over 70 years old: a retrospective observational study.

BACKGROUND: Although the characteristics of intracranial aneurysms (IAs) in different age groups have been well documented, they remain relatively unclear in elderly patients due to a lack of large sample studies. METHODS: Data from IA patients aged more than 70 years who were treated in our centre from January 2016 to January 2020 were retrospectively collected. RESULTS: A total of 290 elderly patients (75.9% female) with a mean age of 74.0 ± 4.7 years were analysed. Rupture occurred in 60.7% of patients, 38.6% of whom presented with meningeal irritation, and seizures were noted in 2.3%. A total of 48.9% of the patients with ruptured IAs had initial symptoms presenting with slow development, and the mean delay from ictus was prolonged to 264.2 ± 914.0 hours. In addition, 61.9% of the patients with ruptured IAs had lesions with a maximum diameter of less than 5 mm. A total of 30.3% of the patients had multiple aneurysms, 35.5% had aneurysms with irregular shapes and 54.8% had cerebrovascular atherosclerotic stenosis (CAS). Pulmonary infection (n = 138, 47.6%), hydrocephalus (n = 72, 24.8%), and thrombosis (n = 35, 12.1%) were common complications during hospitalization. By the end of the 1-year follow-up, 22.1% of the patients had unfavourable clinical outcomes, and the mortality rate was 23.4%. CONCLUSIONS: Several characteristics regarding IAs in elderly patients were reported, including an obvious female predominance; mild, slow initial symptom development causing prolonged admission delay; a low incidence of meningeal irritation and seizures due to decreased electrophysiological activity of the neurons; increased percentages of CAS, multiple aneurysms, and aneurysms with daughter sacs causing a high risk of rupture even for small lesions; a high risk of complications during hospitalization; and relatively poor clinical outcomes.

"Atypical" Mild Clinical Presentation in Elderly Patients With Ruptured Intracranial Aneurysm: Causes and Clinical Characteristics.

Objective: Thunderclap-like severe headache or consciousness disturbance is the common "typical" clinical presentation after aneurysmal subarachnoid hemorrhage (aSAH); however, a slowly developing "atypical" clinical pattern, with mild headache, vomiting, or dizziness, is frequently noted in elderly patients. The aim of this study was to evaluate the clinical characteristics of this "atypical" subgroup, as well as related factors associated with the presence of these mild symptoms. Methods: The data of 176 elderly patients (≥70 years old) with ruptured intracranial aneurysms (IAs) treated at our center from January 2016 to January 2020 were retrospectively collected and analyzed. The patients were divided into "typical" and "atypical" groups based on their initial and development of clinical symptoms after the diagnosis of aSAH. Intergroup differences were analyzed, and factors related to the presence of these two clinical patterns were explored through multiple logistic regression analyses. Results: Despite significant admission delay (P < 0.001) caused by mild initial symptoms with slow development, patients in the "atypical" group achieved better clinical prognosis, as indicated by a significantly higher favourable outcome ratio and lower death rate upon discharge and at different time points during the 1-year follow-up, than the "typical" group (P < 0.05). Multiple logistic regression analysis revealed that modified Fisher grade III-IV (OR = 11.182, P = 0.003), brain atrophy (OR = 10.010, P = 0.001), a larger lesion diameter (OR = 1.287, P < 0.001) and current smoking (OR = 5.728, P < 0.001) were independently associated with the presence of "typical" symptoms. Aneurysms with wide necks (OR = 0.013, P < 0.001) were independently associated with the presence of "atypical" symptoms. Conclusions: "Atypical" presentations, with mild clinical symptoms and slow development, were commonly recorded in elderly patients after the onset of aSAH. Despite the prolonged admission delay, these "atypical" patients achieved better clinical outcomes than those with "typical" symptoms. Modified Fisher grade (III-IV), current smoking, brain atrophy and larger lesion diameter were factors predictive of "typical" symptoms, while aneurysms with wide necks were independently associated with "atypical" symptoms.

PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis.

BACKGROUND: The Food and Drug Administration has approved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors for the treatment of dyslipidemia. However, evidence of the optimal PCSK9 agents targeting PCSK9 for secondary prevention in patients with high-risk of cardiovascular events is lacking. Therefore, this study was conducted to evaluate the benefit and safety of different types of PCSK9 inhibitors. METHODS: Several databases including Cochrane Central, Ovid Medline, and Ovid Embase were searched from inception until March 30, 2022 without language restriction. Randomized controlled trials (RCTs) comparing administration of PCSK9 inhibitors with placebo or ezetimibe for secondary prevention of cardiovascular events in patients with statin-background therapy were identified. The primary efficacy outcome was all-cause mortality. The primary safety outcome was serious adverse events. RESULTS: Overall, nine trials totaling 54,311 patients were identified. Three types of PCSK9 inhibitors were evaluated. The use of alirocumab was associated with reductions in all-cause mortality compared with control (RR 0.83, 95% CrI 0.72-0.95). Moreover, evolocumab was associated with increased all-cause mortality compared with alirocumab (RR 1.26, 95% CrI 1.04-1.52). We also found alirocumab was associated with decreased risk of serious adverse events (RR 0.94, 95% CrI 0.90-0.99). CONCLUSIONS: In consideration of the fact that both PCSK9 monoclonal antibody and inclisiran enable patients to achieve recommended LDL-C target, the findings in this meta-analysis suggest that alirocumab might provide the optimal benefits regarding all-cause mortality with relatively lower SAE risks, and evolocumab might provide the optimal benefits regarding myocardial infarction for secondary prevention in patients with high-risk of cardiovascular events. Further head-to-head trials with longer follow-up and high methodologic quality are warranted to help inform subsequent guidelines for the management of these patients.

Treatment effect of DNA framework nucleic acids on diffuse microvascular endothelial cell injury after subarachnoid hemorrhage.

OBJECTIVES: The purpose of this study was to investigate the treatment effect and molecular mechanism of tetrahedral framework nucleic acids (tFNAs), novel self-assembled nucleic acid nanomaterials, in diffuse BMEC injury after SAH. MATERIALS AND METHODS: tFNAs were synthesized from four ssDNAs. The effects of tFNAs on SAH-induced diffuse BMEC injury were explored by a cytotoxicity model induced by hemin, a breakdown product of hemoglobin, in vitro and a mouse model of SAH via internal carotid artery puncture in vivo. Cell viability assays, wound healing assays, transwell assays, and tube formation assays were performed to explore cellular function like angiogenesis. RESULTS: In vitro cellular function assays demonstrated that tFNAs could alleviate hemin-induced injury, promote angiogenesis, and inhibit apoptosis in hemin cytotoxicity model. In vivo study using H&E and TEM results jointly indicated that the tFNAs attenuate the damage caused by SAH in situ, showing restored number of BMECs in the endothelium layer and more tight intercellular connectivity. Histological examination of SAH model animals confirmed the results of the in vitro study, as tFNAs exhibited treatment effects against diffuse BMEC injury in the cerebral microvascular bed. CONCLUSIONS: Our study suggests the potential of tFNAs in ameliorating diffuse injury to BMECs after SAH, which laid theoretical foundation for the further study and use of these nucleic acid nanomaterials for tissue engineering vascularization.

MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes.

BACKGROUND: Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest. METHODS: Laser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse. RESULTS: Here, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses. A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 (C3) and semaphorin 5b (Sema5b). CONCLUSIONS: We conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.