Transfer of miR-877-3p via extracellular vesicles derived from dental pulp stem cells attenuates neuronal apoptosis and facilitates early neurological functional recovery after cerebral ischemia-reperfusion injury through the Bclaf1/P53 signaling pathway.

Cerebral ischemia-reperfusion injury (I/RI) is one of the principal pathogenic factors in the poor prognosis of ischemic stroke, for which current therapeutic options to enhance neurological recovery are notably insufficient. Dental pulp stem cell-derived extracellular vesicles (DPSC-EVs) have promising prospects in stroke treatment and the specific underlying mechanisms have yet to be fully elucidated. The present study observed that DPSC-EVs ameliorated the degree of cerebral edema and infarct volume by reducing the apoptosis of neurons. Furthermore, the miRNA sequencing and functional enrichment analysis identified that miR-877-3p as a key component in DPSC-EVs, contributing to neuroprotection and anti-apoptotic effects. Following target prediction and dual-luciferase assay indicated that miR-877-3p interacted with Bcl-2-associated transcription factor (Bclaf1) to play a function. The miR-877-3p inhibitor or Bclaf1 overexpression reversed the neuroprotective effects of DPSC-EVs. The findings reveal a novel therapeutic pathway where miR-877-3p, transferred via DPSC-EVs, confers neuroprotection against cerebral I/RI, highlighting its potential in promoting neuronal survival and recovery post-ischemia.

Insights into treatment-specific prognostic somatic mutations in NSCLC from the AACR NSCLC GENIE BPC cohort analysis.

BACKGROUND: Treatment of non-small lung cancer (NSCLC) has evolved in recent years, benefiting from advances in immunotherapy and targeted therapy. However, limited biomarkers exist to assist clinicians and patients in selecting the most effective, personalized treatment strategies. Targeted next-generation sequencing-based genomic profiling has become routine in cancer treatment and generated crucial clinicogenomic data over the last decade. This has made the development of mutational biomarkers for drug response possible. METHODS: To investigate the association between a patient's responses to a specific somatic mutation treatment, we analyzed the NSCLC GENIE BPC cohort, which includes 2,004 tumor samples from 1,846 patients. RESULTS: We identified somatic mutation signatures associated with response to immunotherapy and chemotherapy, including carboplatin-, cisplatin-, pemetrexed- or docetaxel-based chemotherapy. The prediction power of the chemotherapy-associated signature was significantly affected by epidermal growth factor receptor (EGFR) mutation status. Therefore, we developed an EGFR wild-type-specific mutation signature for chemotherapy selection. CONCLUSION: Our treatment-specific gene signatures will assist clinicians and patients in selecting from multiple treatment options.

Blood inflammatory biomarkers predict in-hospital pneumonia after endovascular treatment of aneurysm in patients with aneurysmal subarachoid hemorrhage.

The systemic inflammatory response index (SIRI) is a well-known marker of systemic inflammation reflecting the body's inflammatory/immune state. The study aimed to evaluate the relationship between the SIRI on admission and aneurysmal subarachnoid hemorrhage (aSAH)-associated pneumonia and compare with other currently used bio-markers. We reviewed 562 successive patients with aneurysmal SAH who underwent endovascular treatment between January 2019 and September 2021. ASAH-associated pneumonia was diagnosed using the modified Centers for Disease Control and Prevention criteria. The SIRI on admission was calculated as monocyte count × neutrophil count / lymphocyte count. Multiple logistic regression models were used for data analysis. A total of 158 (28.11%) patients developed aSAH-associated pneumonia. Using the Multiple logistic regression analysis, a notable dose-response association was found between the elevated SIRI (fourth quartile) and aSAH-associated pneumonia (adjusted odds ratio = 6.759; 95% confidence interval [CI], 3.280-13.930; p < 0.001 [p for trend < 0.001]). The SIRI (0.701, 95% CI: 0.653-0.749) presented a higher area under the curve (AUC) than systemic immune- inflammation index (SII) (0.669, 95% CI: 0.620-0.718) (p = 0.089); neutrophil-to-lymphocyte ratio (NLR) (0.665, 95% CI: 0.616-0.714) (p = 0.035) and platelet-lymphocyte ratio (PLR) (0.587, 95% CI: 0.534-0.641) (p < 0.001). A higher SIRI on admission was associated with aSAH-associated pneumonia, which may guide further clinical trials of prophylactic antibiotic therapy.

Association between higher systemic immune inflammation index (SII) and deep vein thrombosis (DVT) in patients with aneurysmal subarachnoid hemorrhage (aSAH) after endovascular treatment.

Inflammation contributes to deep vein thrombosis (DVT) formation in patients with aSAH after endovascular treatment. The relationship between systemic immune-inflammatory index (SII) as an inflammatory marker and DVT formation remains unclear. Thus, this study aims to evaluate the association between SII and aSAH-associated DVT following endovascular treatment. We enrolled 562 consecutive patients with aSAH after endovascular treatment at three centers from January 2019 to September 2021. The endovascular treatments included simple coil embolization and stent-assisted coil embolization. Deep venous thrombosis (DVT) was assessed by Color Doppler ultrasonography (CDUS). Multivariate logistic regression analysis was used to establish the model. We assessed the association of the SII, neutrophil-to-lymphocyte ratio (NLR), the systemic inflammatory response index (SIRI), platelet-lymphocyte ratio (PLR), and DVT by using restricted cubic spline (RCS). ASAH-associated DVT was found in 136 (24.20%) patients. Based on the multiple logistic regression analysis, the correlation was found between aSAH-associated DVT and elevated SII (fourth quartile) (adjusted odds ratio = 8.20 [95% confidence interval, 3.76-17.92]; p < 0.001 [p for trend < 0.001]), elevated NLR (fourth quartile) (adjusted odds ratio = 6.94 [95% confidence interval, 3.24-14.89]; p < 0.001 [p for trend < 0.001]), elevated SIRI (fourth quartile) (adjusted odds ratio = 4.82 [95% confidence interval, 2.36-9.84]; p < 0.001 [p for trend < 0.001]), and elevated PLR (fourth quartile) (adjusted odds ratio = 5.49 [95% confidence interval, 2.61-11.57]; p < 0.001 [p for trend < 0.001]). The increased SII was correlated with the formation of aSAH-associated DVT after endovascular treatment.

Association of elevated neutrophil-to-lymphocyte ratio with increased intracranial aneurysm stability scores and aneurysm growth.

BACKGROUND AND PURPOSE: Inflammation involves in the progression of intracranial aneurysms (IAs). However, whether the neutrophil-to-lymphocyte ratio (NLR) as an inflammatory marker links to IAs stability is unidentified. This study was performed to assess the association of the NLR with IAs stability. METHODS: We retrospectively reviewed the medical records of patients diagnosed with unruptured IAs from January 2014 to June 2018. According to the quartiles of the NLR, patients with unruptured IAs were categorized into four groups. We evaluated the association between the NLR and IAs stability scores and IAs growth. Multiple logistic regression models were used in the analysis. RESULTS: A significant dose-response association was found between the NLR with IAs stability scores and IAs growth. After adjustment for potential confounders, an elevated NLR (fourth quartile) was associated with increased PHASES score (>5) (adjusted odds ratio [OR], 2.007; 95% confidence interval [CI], 1.361-2.960; p<0.001 [p for trend <0.001]), increased ELAPSS score (>15) (adjusted OR, 1.581; 95% CI, 1.074-2.328; p=0.020 [p for trend =0.001]), increased JAPAN 3-year rupture risk score (>5) (adjusted OR, 1.512; 95% CI, 1.033-2.215; p=0.034 [p for trend <0.001]), and IAs growth (adjusted OR, 16.759; 95% CI, 3.022-92.928; p=0.001 [p for trend <0.001]). CONCLUSION: An elevated NLR was associated with increased IAs stability scores and IAs growth. The association between NLR and IAs stability need further investigate.

Effects of blood lipids and lipid-modifying drugs on intracranial aneurysms.

BACKGROUND AND PURPOSE: We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-modifying drugs on intracranial aneurysm (IA). METHODS: Genetic variants for the effects of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides and targets for lipid-modifying drugs were selected from the genome-wide discovery analyses of the UK Biobank. Summary-level data on IAs were obtained from the International Stroke Genetics Consortium. Univariate and multivariate MR analyses were performed. RESULTS: Univariate MR analyses showed that the HDL-C was negatively correlated with IA (odds ratio [OR] = 0.816, 95% confidence interval [CI] = 0.715-0.932, p = 0.003) and ruptured IA (rIA; OR = 0.775, 95% CI = 0.663-0.906, p = 0.001). The multivariate MR-inverse variance weighted analysis showed that the HDL-C was negatively correlated with IA (OR = 0.655, 95% CI = 0.434-0.988, p = 0.043) and rIA (OR = 0.563, 95% CI = 0.347-0.913, p = 0.02), and the LDL-C was negatively correlated with IA (OR = 0.402, 95% CI = 0.191-0.848, p = 0.017) and rIA (OR = 0.376, 95% CI = 0.160-0.883, p = 0.025). Using genetic proxies of known lipid-modifying drugs, we found that the increased HDL-C with cholesterol ester transfer protein proxies was associated with a decreased risk of rIA (OR = 0.852, 95% CI = 0.747-0.973, p = 0.018), and the decreased LDL-C with 3-hydroxy-3-methylglutaryl-coenzyme A reductase proxies was associated with increased risk of IA (OR = 1.772, 95% CI = 1.080-2.908, p = 0.024) and rIA (OR = 1.856, 95% CI = 1.022-3.371, p = 0.042). CONCLUSIONS: Genetically determined HDL-C and LDL-C reduce the risk of IA and rIA. The effects of different lipid-modifying drugs on IA need to be further investigated.

Risk Factors for In-Hospital Seizures of Aneurysmal Subarachnoid Hemorrhage After Endovascular Treatment: A Real-World Study.

BACKGROUND AND PURPOSE: The occurrence of in-hospital seizures for aneurysmal subarachnoid hemorrhage (aSAH) ranges from 3.7% to 15.2%, and seizures remain an important factor affecting patient prognosis. Therefore, the timely identification of patients at a higher risk for aSAH-associated seizures after endovascular treatment is of paramount importance. This study aims to analyze the risk factors for in-hospital seizures after endovascular treatment for aSAH. METHODS: The study comprised 547 patients at 3 centers from January 2019 to September 2021. In the context of this study, 2 models were utilized: the first model involved no variable adjustment, while the second model included all potential confounders in the multivariate logistic regression analysis. Additionally, the dose-response relationship between biomarkers and seizure occurrence was assessed using restricted cubic spline. RESULTS: Among these patients, 28 (5.1%) developed seizures during hospitalization. In Model 2, the modified Fisher score (adjusted odds ratio [OR]: 3.138, 95% confidence interval [CI]: 1.226-8.036), body mass index (adjusted OR: 0.852, 95% CI: 0.749-0.970), aspect ratio (adjusted OR: 0.264, 95% CI: 0.115-0.604), and aspartate transaminase (adjusted OR: 1.017, 95% CI: 1.001-1.035) were showed as factors contributing to an increased risk of aSAH-associated seizures. CONCLUSIONS: Body mass index, aspartate transaminase, aspect ratio, modified Fisher scores, and Hunt-Hess scores were correlated with the formation of aSAH-associated seizures after endovascular treatment.

Combined exposure to multiple metals on hypertension in NHANES under four statistical models.

Metals exposure has gained increasing attention in the hypertension prevention. However, previous studies have focused on the impacts of single or separated metals on hypertension, and the critical metals contributing to the prevalence of hypertension are still under discussion. We collected data from 5092 participants across three consecutive National Health and Nutrition Examination Survey (NHANES) circles (2011-2016). Weighted logistic regression, weighted quantile sum (WQS) regression, quantile-based g-computation (QGC), and Bayesian kernel machine regression (BKMR) analyses were conducted to evaluate the combined and individual effects of 15 urinary metals, as well as to identify the critical metals on the development of hypertension. In our study, the weighted prevalence of hypertension was 37.9%, and the average age was 47.42 years. Manganese, uranium and tin were found as the independent risk factors for hypertension, while barium, lead, and thallium were found to have protective effects against hypertension. Lead, barium, tungsten, uranium, and tin were determined as critical elements for the prediction of hypertension. No significant interaction relationship was detected between multiple metals. There might be potential positive combined effects of urinary metal mixture on hypertension. Tungsten, uranium, and tin were positively associated with hypertension while lead and barium were negatively associated with hypertension. The underlying mechanisms of urinary metal exposure on the risk of hypertension deserve further investigations.

Inflammation index SIRI is associated with increased all-cause and cardiovascular mortality among patients with hypertension.

Background: Inflammation plays an essential role in the pathogenesis of hypertension. A novel inflammatory biomarker systemic inflammatory response index (SIRI) is related with all-cause and cardiovascular (CVD) mortality, while the role of SIRI in hypertension patients is unclear. Methods: A total of 21,506 participants with hypertension were recruited in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. SIRI was calculated as the neutrophil count * monocyte count/lymphocyte count. Hypertension was defined according to the examination of blood pressure, prescription, and self-reported physician diagnosis. Survival status was followed through 31 December 2019. The non-linear relationship was assessed using restricted cubic spline analysis. The association of all-cause mortality with SIRI was evaluated using the Kaplan-Meier curve and the weighted Cox regression analysis. The predictive abilities were assessed with Receiver operating curve. Results: During 189,063 person-years of follow-up, 5,680 (26.41%) death events were documented, including 1,967 (9.15%) CVD related deaths. A J-shaped association was observed between SIRI and all-cause and CVD mortality. The Kaplan-Meier curve indicated the all-cause and CVD mortality risks were higher in high SIRI quartiles compared with lower SIRI quartiles. After adjusting for all covariates, the SIRI was positively associated with the all-mortality risk with HR = 1.19 (1.15, 1.22), and CVD mortality with HR = 1.19 (1.15, 1.24). The result was robust in subgroup analysis and sensitivity analysis. Conclusion: Elevated SIRI level is associated with increased all-cause and CVD mortality among patients with hypertension. SIRI is considered as a potential inflammatory biomarker in the clinical practice. Further large-scale cohort studies are required to confirm our findings.

Cost-effective analysis of mechanical thrombectomy alone in the treatment of acute ischaemic stroke: a Markov modelling study.

OBJECTIVE: Recently, a randomised controlled trial (DIRECT-MT) demonstrated that mechanical thrombectomy (MT) was non-inferior to MT with intravenous alteplase as to the functional outcomes. This study aims to investigate whether MT alone is cost-effective compared with MT with alteplase in China. METHODS: A Markov decision analytic model was built from the Chinese healthcare perspective using a lifetime horizon. Probabilities, costs and outcomes data were obtained from the DIRECT-MT trial and other most recent/comprehensive literature. Base case calculation was conducted to compare the costs and effectiveness between MT alone and MT with alteplase. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the results. RESULTS: MT alone had a lower cost and higher effectiveness compared with MT with alteplase. The probabilistic sensitivity analysis demonstrated that, over a lifetime horizon, MT alone had a 99.5% probability of being cost-effective under the willingness-to-pay threshold of 1× gross domestic product per capita in China based on data obtained from the DIRECT-MT trial. These results remained robust under one-way sensitivity analysis. CONCLUSIONS: MT alone was cost-effective compared with MT with alteplase in China. However, cautions are needed to extend this conclusion to regions outside of China.

Economic Evaluation of Ticagrelor Plus Aspirin Versus Aspirin Alone for Acute Ischemic Stroke and Transient Ischemic Attack.

Background: Although ticagrelor plus aspirin is more effective than aspirin alone in preventing the 30-day risk of a composite of stroke or death in patients with an acute mild-to-moderate ischemic stroke (IS) or transient ischemic attack (TIA), the cost-effectiveness of this combination therapy remains unknown. This study aims to determine the cost-effectiveness of ticagrelor plus aspirin compared with aspirin alone. Methods: A combination of decision tree and Markov model was built to estimate the expected costs and quality-adjusted life-years (QALYs) associated with ticagrelor plus aspirin and aspirin alone in the treatment of patients with an acute mild-to-moderate IS or TIA. Model inputs were extracted from published sources. One-way sensitivity, probabilistic sensitivity, and subgroup analyses were performed to test the robustness of the findings. Results: Compared with aspirin alone, ticagrelor plus aspirin gained an additional lifetime QALY of 0.018 at an additional cost of the Chinese Yuan Renminbi (¥) of 269, yielding an incremental cost-effectiveness ratio of ¥15,006 (US$2,207)/QALY. Probabilistic sensitivity analysis showed that ticagrelor plus aspirin had a probability of 99.99% being highly cost-effective versus aspirin alone at the current willingness-to-pay threshold of ¥72,447 (US$10,500)/QALY in China. These findings remain robust under one-way sensitivity and subgroup analyses. Conclusions: The results indicated that early treatment with a 30-days ticagrelor plus aspirin for an acute mild-to-moderate IS or TIA is highly cost-effective in a Chinese setting.

Cost-Effectiveness of Short-Course Radiation Plus Temozolomide for the Treatment of Newly Diagnosed Glioblastoma Among Elderly Patients in China and the United States.

Background: Glioblastoma multiforme (GBM) is a fatal type of brain tumor with a high incidence among elderly people. Temozolomide (TMZ) has proven to be an effective chemotherapeutic agent with significant survival benefits. This study aimed to evaluate the economic outcomes of radiotherapy (RT) and TMZ for the treatment of newly diagnosed GBM in elderly people in the United States (US) and China. Methods: A partitioned survival model was constructed for RT plus TMZ and RT alone among patients with methylated and unmethylated tumor status. Base case calculations and one-way and probabilistic sensitivity analyses were performed. Life-years, quality-adjusted life-years (QALYs), costs (in 2021 US dollars [$] and Chinese Yuan Renminbi [¥]), and incremental cost-effectiveness ratios (ICERs) were calculated. Results: RT plus TMZ was found to be associated with significantly higher costs and QALYs in all groups. Only US patients with methylated status receiving RT plus TMZ had an ICER ($89358.51) less than the willingness-to-pay (WTP) threshold of $100000 per QALY gained when compared with receiving RT alone. When the WTP threshold ranged from $100000 to $150000 from the US perspective, the probability of RT plus TMZ being cost-effective increased from 80.5 to 99.8%. The cost of TMZ must be lower than ¥120 per 20 mg for RT plus TMZ to be cost-effective among patients with methylated tumor status in China. Conclusion: RT plus TMZ was not cost-effective in China, and a reduction in the TMZ price was justified. However, it is highly likely to be cost-effective for patients with methylated tumor status in the US.