Acute ischemic stroke with or without asymptomatic intracranial hemorrhage after endovascular treatment: a propensity-score matching study.

BACKGROUND: The long-term follow-up of asymptomatic intracranial hemorrhage (aICH) in patients with acute ischemic stroke after endovascular treatment (EVT) remains controversial.ObjectiveTo evaluate the potential effect of aICH in a real-world practice setting using a matched prospective database. METHODS: This observational cohort study enrolled patients between January 2015 and December 2022 in a prospective database. Eligible patients with occlusions in the anterior circulation were given endovascular treatment and achieved successful reperfusion. The primary outcome was functional independence (modified Rankin Scale (mRS) score 0-2). Propensity score (PS)-weighted multivariable logistic regression analyses were adjusted and were repeated in subsequent 1:1 PS-matched cohorts. RESULTS: 732 patients, 516 without any ICH and 216 with aICH, were included. 418 and 348 patients were identified after matching in the aICH substudy and hemorrhagic infarction type aICH substudy, respectively. In the postmatched population, patients with aICH had worse functional outcomes (mRS score 0-2) at 90 days than patients without any ICH (37.8% vs 55.5%: P<0.001). Worse functional outcomes were seen in patients with aICH who were older (OR=5.59 (95% CI 2.91 to 10.74)), had higher baseline National Institutes of Health Stroke Scale score (OR=6.80 (95% CI 3.72 to 12.43)), lower baseline Alberta Stroke Program Early CT Score (OR=2.08 (95% CI 1.23 to 3.51)), and who received general anesthesia (OR=3.37 (95% CI 1.92 to 5.90)). CONCLUSIONS: This matched-control study largely confirmed that asymptomatic ICH after EVT is associated with worse functional outcomes, and the harmful effect is more significant in older patients and those with severe baseline clinical and radiological features.

Avelumab in Combination With Lorlatinib or Crizotinib in Patients With Previously Treated Advanced NSCLC: Phase 1b/2 Results From the JAVELIN Lung 101 Trial.

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced NSCLC, respectively. Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: In the avelumab plus lorlatinib group (ALK-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (ALK-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses). Conclusions: Avelumab plus lorlatinib treatment in ALK-positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group. ClinicalTrialsgov identifier: NCT02584634.

Structure-activity relationships, product species distribution and the mechanism of effect of multi-component flue gas on Hg0 adsorption and oxidation over CuO/ACs.

A series of Cu-doped activated cokes (CuO/ACs) were synthesized via an impregnation method and applied for the removal of elemental mercury (Hg0). Structure-activity relationships between Hg0 removal and CuO/AC surface characteristics were identified. Hg0 removal over CuO/AC occurs through a combination of physisorption and chemisorption and is mainly dominated by chemisorption. It was found that 1 nm micropores facilitate Hg0 physisorption. Hg0 could weakly adsorb onto an O-terminated crystal layer, whereas strongly adsorb onto Cu-terminated single highly dispersed, clustered and bulk CuO (110) crystal planes via the Mars-Maessen mechanism. Product distributions and mechanisms of Hg0 adsorption and oxidation over the CuO/AC catalyst under multi-component flue gases are also discussed. O2 enhances both physisorption and chemisorption toward Hg0 by 38%. Inhibition of Hg0 removal by SO2 originates from the competitive adsorption and deactivation of CuO cation vacancies, whereas the impact is weakened by O2 through generating 20% of physically adsorbed mercury product species. NO and O2 promote Hg0 chemisorption efficiency by 93% to form Hg(NO3)2. HOCl and/or Cl2 produced by HCl can oxidize 100% of Hg0 to HgCl2, and the catalytic oxidation efficiency is approximately 29%, but O2 slightly lowers the Hg0 catalytic oxidation efficiency by 8%. The affinity ability between various flue gases and Hg0 follows the order O2 < NO < HCl.

A combination of multiple LC-MS approaches for the comprehensive characterization of cysteine-linked ADCs.

Antibody-drug conjugates (ADCs) represent the forefront of the next generation of biopharmaceuticals. An ADC typically comprises an antibody covalently linked to a cytotoxic drug via a linker, resulting in a highly heterogeneous product. This study focuses on the analysis of a custom-made cysteine-linked ADC. Initially, we developed a LC-MS-based characterization workflow using brentuximab vedotin (Adcetris®), encompassing native intact MS, analysis of reduced chains and subunits under denaturing condition, peptide mapping and online strong cation exchange chromatography coupled with UV and mass spectrometry detection (SCX-UV-MS) applied for brentuximab vedotin first time reported. Subsequently, we applied this in-depth characterization workflow to a custom-made cysteine-linked ADC. The measured drug-to-antibody ratio(DAR) of this ADC is 6.9, further analysis shown that there is a small amount of unexpected over-conjugation. Over-conjugation sites were successfully identified using multiple UHPLC-MS based characterization techniques. Also, one competitively cysteine-conjugated impurity was observed in native intact MS results, by combing native intact MS, reduced chains, subunit analysis and peptide mapping results, the impurity conjugation sites were also identified. Since this molecule is at early development stage, this provides important information for conjugation process improvement and link-drug material purification. SCX-UV-MS approach can separate the custom-made cysteine-linked ADC carrying different payloads and reduce the complexity of the spectra. The integrated approach underscores the significance of combining the SCX-UV-MS online coupling technique with other characterization methods to elucidate the heterogeneity of cysteine-linked ADCs.

Comparing two hazard curves when there is a treatment time-lag effect.

In cancer and other medical studies, time-to-event (eg, death) data are common. One major task to analyze time-to-event (or survival) data is usually to compare two medical interventions (eg, a treatment and a control) regarding their effect on patients' hazard to have the event in concern. In such cases, we need to compare two hazard curves of the two related patient groups. In practice, a medical treatment often has a time-lag effect, that is, the treatment effect can only be observed after a time period since the treatment is applied. In such cases, the two hazard curves would be similar in an initial time period, and the traditional testing procedures, such as the log-rank test, would be ineffective in detecting the treatment effect because the similarity between the two hazard curves in the initial time period would attenuate the difference between the two hazard curves that is reflected in the related testing statistics. In this paper, we suggest a new method for comparing two hazard curves when there is a potential treatment time-lag effect based on a weighted log-rank test with a flexible weighting scheme. The new method is shown to be more effective than some representative existing methods in various cases when a treatment time-lag effect is present.

Analysis of factors influencing hospitalization cost of patients with distal radius fractures: an empirical study based on public traditional Chinese medicine hospitals in two cities, China.

BACKGROUND: Distal radius fractures (DRFs) have become a public health problem for all countries, bringing a heavier economic burden of disease globally, with China's disease economic burden being even more acute due to the trend of an aging population. This study aimed to explore the influencing factors of hospitalization cost of patients with DRFs in traditional Chinese medicine (TCMa) hospitals to provide a scientific basis for controlling hospitalization cost. METHODS: With 1306 cases of DRFs patients hospitalized in 15 public TCMa hospitals in two cities of Gansu Province in China from January 2017 to 2022 as the study object, the influencing factors of hospitalization cost were studied in depth gradually through univariate analysis, multiple linear regression, and path model. RESULTS: Hospitalization cost of patients with DRFs is mainly affected by the length of stay, surgery and operation, hospital levels, payment methods of medical insurance, use of TCMa preparations, complications and comorbidities, and clinical pathways. The length of stay is the most critical factor influencing the hospitalization cost, and the longer the length of stay, the higher the hospitalization cost. CONCLUSIONS: TCMa hospitals should actively take advantage of TCMb diagnostic modalities and therapeutic methods to ensure the efficacy of treatment and effectively reduce the length of stay at the same time, to lower hospitalization cost. It is also necessary to further deepen the reform of the medical insurance payment methods and strengthen the construction of the hierarchical diagnosis and treatment system, to make the patients receive reasonable reimbursement for medical expenses, thus effectively alleviating the economic burden of the disease in the patients with DRFs.

Ferroptosis mediated by TNFSF9 interferes in acute ischaemic stroke reperfusion injury with the progression of acute ischaemic stroke.

In this study, we investigated the potential involvement of TNFSF9 in reperfusion injury associated with ferroptosis in acute ischaemic stroke patients, mouse models and BV2 microglia. We first examined TNFSF9 changes in peripheral blood from stroke patients with successful reperfusion, and constructed oxygen-glucose deprivation-reperfusion (OGD-R) on BV2 microglia, oxygen-glucose deprivation for 6 h followed by reoxygenation and re-glucose for 24 h, and appropriate over-expression or knockdown of TNFSF9 manipulation on BV2 cells and found that in the case of BV2 cells encountering OGD-R over-expression of TNFSF9 resulted in increased BV2 apoptosis. Still, the knockdown of TNFSF9 ameliorated apoptosis and ferroptosis. In an in vivo experiment, we constructed TNFSF9 over-expression or knockout mice by intracerebral injection of TNFSF9-OE or sh-TNFSF9 adenovirus. We performed the middle cerebral artery occlusion (MCAO) model on day four, 24 h after ligation of the proximal artery, for half an hour to recanalize. As luck would have it, over-expression of TNFSF9 resulted in increased brain infarct volumes, neurological function scores and abnormalities in TNFSF9-related TRAF1 and ferroptosis-related pathways, but knockdown of TNFSF9 improved brain infarcts in mice as well as reversing TNFSF9-related signalling pathways. In conclusion, our data provide the first evidence that TNFSF9 triggers microglia activation by activating the ferroptosis signalling pathway following ischaemic stroke, leading to brain injury and neurological deficits.

Structure and function analyses of the SRC gene in Pacific white shrimp Litopenaeus vannamei.

SRC gene encodes scavenger receptor class C, a member of the scavenger receptor family, and has only been identified and investigated in invertebrates. Our previous studies have revealed that SRC is a novel candidate gene associated with body weight in Pacific white shrimp (Litopenaeus vannamei). In order to comprehend the underlying mechanism by which LvSRC affects shrimp growth, we analyzed the structure, phylogeny, expression profiles and RNA interference (RNAi) of this gene in L. vannamei. We found that LvSRC contains two CCP domains and one MAM domain, with the highest expression level in the heart and relatively low expression level in other tissues. Notably, LvSRC exhibited significantly higher expression levels in the fast-growing group among groups with different growth rates, suggesting its potential involvement as a gene contributing to the growth of L. vannamei. RNAi of LvSRC inhibited body length and body weight gain compared to the control groups. Moreover, through RNA-seq analysis, we identified 598 differentially expressed genes (DEGs), including genes associated with growth, immunity, protein processing and modification, signal transduction, lipid synthesis and metabolism. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed significant changes in the signaling pathways related to growth, lipid metabolism and immune response, suggesting that LvSRC exhibits the potential to participate in diverse physiological processes and immune regulation. These findings deepen our understanding of the structure and function of the SRC in shrimp and lay the foundation for further research into the regulatory mechanism of LvSRC. Additionally, they provide potential applications in shrimp genetics and breeding.

Analysis and prediction of 5-year survival in patients with cutaneous melanoma: a model-based period analysis.

Background: The survival and prognosis of patients are significantly threatened by cutaneous melanoma (CM), which is a highly aggressive disease. It is therefore crucial to determine the most recent survival rate of CM. This study used population-based cancer registry data to examine the 5-year relative survival rate of CM in the US. Methods: Period analysis was used to assess the relative survival rate and trends of patients with CM in the Surveillance, Epidemiology, and End Results (SEER) database during 2004-2018. And based on the data stratified by age, gender, race and subtype in the SEER database, a generalized linear model was 12established to predict the 5-year relative survival rate of CM patients from 2019 to 2023. Results: The 5-year relative survival increased to various degrees for both total CM and CM subtypes during the observation period. The improvement was greatest for amelanotic melanoma, increasing from 69.0% to 81.5%. The 5-year overall relative survival rates of CM were 92.9%, 93.5%, and 95.6% for 2004-2008, 2009-2013, and 2014-2018, respectively. Females had a marginally higher survival rate than males for almost all subtypes, older people had lower survival rates than younger people, white patients had higher survival rates than nonwhite ones, and urban locations had higher rates of survival from CM than rural locations did. The survival rate of CM was significantly lower for distant metastasis. Conclusion: The survival rate of patients with CM gradually improved overall during 2004-2018. With the predicted survival rate of 96.7% for 2019-2023, this trend will still be present. Assessing the changes experienced by patients with CM over the previous 15 years can help in predicting the future course of CM. It also provides a scientific foundation that associated departments can use to develop efficient tumor prevention and control strategies.

Kaempferol regulates the thermogenic function of adipocytes in high-fat-diet-induced obesity via the CDK6/RUNX1/UCP1 signaling pathway.

Activation of adipose tissue thermogenesis is a promising strategy in the treatment of obesity and obesity-related metabolic disorders. Kaempferol (KPF) is a predominant dietary flavonoid with multiple pharmacological properties, such as anti-inflammatory and antioxidant activities. In this study, we sought to characterize the role of KPF in adipocyte thermogenesis. We demonstrated that KPF-treated mice were protected from diet-induced obesity, glucose tolerance, and insulin resistance, accompanied by markedly increased energy expenditure, ex vivo oxygen consumption of white fat, and increased expression of proteins related to adaptive thermogenesis. KPF-promoted beige cell formation is a cell-autonomous effect, since the overexpression of cyclin-dependent kinase 6 (CDK6) in preadipocytes partially reversed browning phenotypes observed in KPF-treated cells. Overall, these data implicate that KPF is involved in promoting beige cell formation by suppressing CDK6 protein expression. This study provides evidence that KPF is a promising natural product for obesity treatment by boosting energy expenditure.

Allergic bronchopulmonary aspergillosis with marked peripheral blood eosinophilia and pulmonary eosinophilia: A case report.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an immune-related pulmonary disease caused by sensitization of airway by Aspergillus fumigatus. The disease manifests as bronchial asthma and recurring pulmonary shadows, which may be associated with bronchiectasis. The diagnosis of ABPA mainly depends on serological, immunological, and imaging findings. Pathological examination is not necessary but may be required in atypical cases to exclude pulmonary tuberculosis, tumor, and other diseases through lung biopsy. CASE SUMMARY: An 18-year-old man presented with recurrent wheezing, cough, and peripheral blood eosinophilia. Chest computed tomography showed pulmonary infiltration. There was a significant increase in eosinophils in bronchoalveolar lavage fluid. There was no history of residing in a parasite-endemic area or any evidence of parasitic infection. Pathologic examination of bronchoalveolar lavage fluid excluded fungal and mycobacterial infections. The patient was receiving medication for comorbid diseases, but there was no temporal correlation between medication use and clinical manifestations, which excluded drug-induced etiology. Histopathological examination of lung biopsy specimen showed no signs of eosinophilic granulomatosis with polyangiitis, IgG4-related diseases, or tumors. The diagnosis of ABPA was considered based on the history of asthma and the significant increase in serum Aspergillus fumigatus-specific immunoglobulin (Ig)E. Eosinophil-related diseases were excluded through pathological biopsy, which showed typical pathological manifestations of ABPA. CONCLUSION: The possibility of ABPA should be considered in patients with poorly controlled asthma, especially those with eosinophilia, lung infiltration shadows, or bronchiectasis. Screening for serum IgE, Aspergillus fumigatus-specific IgE and IgG, and alveolar lavage can help avoid misdiagnosis.

Association of volatile anesthesia exposure and depth with emergence agitation and delirium in children: Prospective observational cohort study.

Background: Sevoflurane anesthesia is widely used in pediatric ambulatory surgery. However, emergency agitation (EA) and emergency delirium (ED), as major complications following sevoflurane anesthesia in children, pose risks to surgery and prognosis. Identifying the high risk of EA/ED, especially anesthesia exposure and the depth of anesthesia, may allow preemptive treatment. Methods: A total of 137 patients were prospectively enrolled in this single-center observational cohort study to assess the incidence of EA or ED. Multivariable logistic regression analyses were used to test the association between volatile anesthesia exposure and depth with EA or ED. The Richmond Agitation and Sedation Scale (RASS), Pediatric Anesthesia Emergence Delirium Scale (PAED) and Face, Legs, Activity, Cry, and Consolability (FLACC) behavioural pain scale was used to assess the severity of EA or ED severity and pain. Bispectral index (BIS) to monitor the depth of anesthesia, as well as TimeLOW-BIS/TimeANES %, EtSevo (%) and EtSevo-time AUC were included in the multivariate logistic regression model as independent variables to analyze their association with EA or ED. Results: The overall prevalence of EA and ED was 73/137 (53.3%) and 75/137 (54.7%) respectively, where 48/137 (35.0%), 19/137 (13.9%), and 6/137 (4.4%) had mild, moderate, and severe EA. When the recovery period was lengthened, the prevalence of ED and extent of FLACC decreased and finally normalized within 30 min in recovered period. Multivariable logistic regression demonstrated that intraoperative agitation [2.84 (1.08, 7.47) p = 0.034], peak FLACC [2.56 (1.70, 3.85) p < 0.001] and adverse event (respiratory complications) [0.03 (0.00, 0.29) p = 0.003] were independently associated with higher odds of EA. Taking EtSevo-time AUC ≤ 2,000 as a reference, the incidence of EA were [15.84 (2.15, 116.98) p = 0.002] times and 16.59 (2.42, 113.83) p = 0.009] times for EtSevo-time AUC 2,500-3,000 and EtSevo-time AUC > 3,000, respectively. Peak FLACC [3.46 (2.13, 5.62) p < 0.001] and intraoperative agitation [5.61 (1.99, 15.86) p = 0.001] were independently associated with higher odds of developing ED. EtSevo (%), intraoperative BIS value and the percentage of the duration of anesthesia at different depths of anesthesia (BIS ≤ 40, BIS ≤ 30, BIS ≤ 20) were not associated with EA and ED. Conclusions: For pediatrics undergoing ambulatory surgery where sevoflurane anesthesia was administered, EA was associated with surgical time, peak FLACC, respiratory complications, and "EtSevo-time AUC" with a dose-response relationship; ED was associated with peak FLACC and intraoperative agitation.

Crafting a prognostic nomogram for the overall survival rate of cutaneous verrucous carcinoma using the surveillance, epidemiology, and end results database.

Background: The aim of this study was to establish and verify a predictive nomogram for patients with cutaneous verrucous carcinoma (CVC) who will eventually survive and to determine the accuracy of the nomogram relative to the conventional American Joint Committee on Cancer (AJCC) staging system. Methods: Assessments were performed on 1125 patients with CVC between 2004 and 2015, and the results of those examinations were recorded in the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly divided at a ratio of 7:3 into the training (n = 787) and validation (n = 338) cohorts. Predictors were identified using stepwise regression analysis in the COX regression model for create a nomogram to predict overall survival of CVC patients at 3-, 5-, and 8-years post-diagnosis. We compared the performance of our model with that of the AJCC prognosis model using several evaluation metrics, including C-index, NRI, IDI, AUC, calibration plots, and DCAs. Results: Multivariate risk factors including sex, age at diagnosis, marital status, AJCC stage, radiation status, and surgery status were employed to determine the overall survival (OS) rate (P<0.05). The C-index nomogram performed better than the AJCC staging system variable for both the training (0.737 versus 0.582) and validation cohorts (0.735 versus 0.573), which AUC (> 0.7) revealed that the nomogram exhibited significant discriminative ability. The statistically significant NRI and IDI values at 3-, 5-, and 8-year predictions for overall survival (OS) in the validation cohort (55.72%, 63.71%, and 78.23%, respectively and 13.65%, 20.52%, and 23.73%, respectively) demonstrate that the established nomogram outperforms the AJCC staging system (P < 0.01) in predicting OS for patients with cutaneous verrucous carcinoma (CVC). The calibration plots indicate good performance of the nomogram, while decision curve analyses (DCAs) show that the predictive model could have a favorable clinical impact. Conclusion: This study constructed and validated a nomogram for predicting the prognosis of patients with CVC in the SEER database and assessed it using several variables. This nomogram model can assist clinical staff in making more-accurate predictions than the AJCC staging method about the 3-, 5-, and 8-year OS probabilities of patients with CVC.

Neoisoastilbin Ameliorates Acute Gouty Arthritis via Suppression of the NF-κB/NLRP3 Pathway.

Acute gouty arthritis (AGA) is an acute inflammatory disease, whose occurrence and development mechanism are associated with inflammatory reaction of joint tissue. This study investigated the role of neoisoastilbin (NIA) in the treatment of AGA and explored the underlying mechanisms. C57BL/6 mice underwent intraarticular injection of monosodium urate (MSU) to establish an AGA model in vivo. Enzyme-linked immunosorbent assay, histopathological hematoxylin-eosin staining, western blotting, and other methods were used to observe the therapeutic effects of NIA on AGA and investigate the role of the NF-κB/NLRP3 pathway in the treatment. We found that NIA effectively reduced MSU-induced joint swelling and inflammatory cell infiltration in a concentration-dependent manner. NIA also significantly reduced interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels as compared with the respective values in the model mice group. In addition, administration of NIA significantly mitigated the phosphorylation of NF-κB-related proteins (IKKα, NF-κB, and IκBα) and the expression of NLRP3-related proteins (NLRP3, caspase-1, and ASC) in MSU-induced joint tissues. In conclusion, our research indicated that NIA significantly improved AGA, and its underlying mechanism was achieved by simultaneously inhibiting the NF-κB/NLRP3 pathway and the expression of inflammatory factors. This research preliminarily suggested the potential role of NIA in the treatment of AGA.

Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats.

AIMS/INTRODUCTION: As a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats. METHOD: Before the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze. RESULTS: We found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1ß and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury. CONCLUSIONS: The activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats.

Early diagnosis of intracranial atherosclerotic large vascular occlusion: A prediction model based on DIRECT-MT data.

Aims: This study aimed to build a prediction model to early diagnose intracranial atherosclerosis (ICAS)-related large vascular occlusion (LVO) in acute ischemic stroke patients before digital subtractive angiography. Methods: Patients enrolled in the DIRECT-MT trial (NCT03469206) were included in our secondary analysis and distributed into ICAS-LVO and non-ICAS-LVO groups. We also retrieved demographic data, medical histories, clinical characteristics, and pre-operative imaging data. Hypothesis testing was used to compare data of the two groups, and univariate logistic regression was used to identify the predictors of ICAS-LVO primarily. Then, we used multivariate logistic regression to determine the independent predictors and formulate the prediction model. Model efficacy was estimated by the area under the receiver operating characteristic (ROC) curve (AUC) and diagnostic parameters generated from internal and external validations. Results: The subgroup analysis included 45 cases in the ICAS-LVO group and 611 cases in the non-ICAS-LVO group. Variates with p < 0.1 in the comparative analysis were used as inputs in the univariate logistic regression. Next, variates with p < 0.1 in the univariate logistic regression were used as inputs in the multivariate logistic regression. The multivariate logistic regression indicated that the atrial fibrillation history, hypertension and smoking, occlusion located at the proximal M1 and M2, hyperdense artery sign, and clot burden score were related to the diagnosis of ICAS-LVO. Then, we constructed a prediction model based on multivariate logistics regression. The sensitivity and specificity of the model were 84.09 and 74.54% in internal validation and 73.11 and 71.53% in external validation. Conclusion: Our current prediction model based on clinical data of patients from the DIRECT-MT trial might be a promising tool for predicting ICAS-LVO.

A simple and robust model for enrollment projection in clinical trials.

Enrollment projection in clinical trials is a topic gaining attention in the statistics literature in recent years. A number of methods have been proposed in this area. Some approaches are sophisticated but complicated to implement. We aim to implement a simple and robust empiric Bayes Poisson Gamma model (PGM) that is suitable for practical use. We assume a constant and site-specific underlying enrollment rate over time, which comes from a common Gamma distribution. Choice of prior parameters is data driven. We tested the proposed PGM in a simulation study as well as a number of oncology trials with various enrollment patterns, which yield satisfactory results. Compared to a flexible nonparametric model (Zhang and Long, 2010), the PGM is associated with a narrower credible interval as a result of parametric assumptions. However, the model prediction may be off when the assumptions are substantially violated.

Cerebrovascular disorders associated with agenesis of the internal carotid artery: Findings on digital subtraction angiography.

Objective: Agenesis of the internal carotid artery (ICA) is a rare vascular condition that is complicated by intracranial aneurysms and rete mirabile. The altered hemodynamics caused by this distinctive cerebrovascular angioarchitecture can cause ischemic or hemorrhagic accidents. Data on clinical and radiographic features have been limited to describing this vascular pattern. We present five cases of agenesis of the internal carotid artery confirmed by digital subtraction angiography (DSA) and further investigate the influence of altered angioarchitecture on the integrity of intracranial morphology. Methods: Cases of ICA anomalies were screened from the patients who underwent DSA in two hospitals. Clinical manifestation, radiographic features, management, and outcomes were retrospectively reviewed. Results: Five patients [mean age 44 years (range, 30-65 years)] were included. Two patients presented with subarachnoid hemorrhage, one with cognitive impairment, one with dizziness, and one with intermittent headache. DSA demonstrated that three cases were complicated by intracranial aneurysms, one by dural arteriovenous fistula, and one by rete aneurysm. Three patients underwent endovascular treatment and one underwent bypass surgery. No patient died or experienced cerebrovascular accident during short-term follow-up. Conclusions: ICA agenesis can be complicated by disorders such as intracranial aneurysm, rete aneurysm, and dural arteriovenous fistula. This suggests that ICA agenesis is associated with a tendency towards disrupted cerebrovascular homeostasis resulting from altered hemodynamics.

Case Report: Fenestration embedded in large vessel occlusion at non-branching site: A catastrophic trap for mechanical thrombectomy.

Fenestrations are rare anatomical variants characterized by division of an artery into two channels which join distally to form a single lumen. We here present two acute ischemic stroke patients with occlusion in an arterial segment with fenestration. Both occlusion sites were located at the non-branching site: one in the mid-basilar trunk and one middle cerebral artery trunk. Successful reperfusion was achieved in both patients, but angioplasty was avoided during thrombectomy procedure. The two cases establish that fenestration may be embedded in non-branching site occlusion. Surgeons should take this abnormality into account to prevent angioplasty from causing vessel rupture in the setting of fenestration.

The Protective Effects of Neoastilbin on Monosodium Urate Stimulated THP-1-Derived Macrophages and Gouty Arthritis in Mice through NF-κB and NLRP3 Inflammasome Pathways.

Gouty arthritis (GA) is a frequent inflammatory disease characterized by pain, swelling, and stiffness of joints. Neoastilbin is a flavonoid isolated from the rhizome of Smilax glabra, which possesses various anti-inflammatory effects. However, the mechanism of neoastilbin in treating GA has not yet been clarified. Thus, this study was to investigate the protective effects of neoastilbin in both monosodium urate (MSU) stimulated THP-1-derived macrophages and the animal model of GA by injecting MSU into the ankle joints of mice. The levels of key inflammatory cytokines in MSU stimulated THP-1-derived macrophages were detected by enzyme-linked immunosorbent assay (ELISA) kits. Protein expressions of nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome pathways were further detected by Western blotting. In addition, swelling degree of ankle joints, the levels of inflammatory factors, infiltration of inflammatory cells and the expressions of related proteins were determined. Swelling degree and histopathological injury in ankle joints of MSU-injected mice were significantly decreased after being treated with neoastilbin. Moreover, neoastilbin significantly diminished the secretion of interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), suppressing the activation of NF-κB and NLRP3 inflammasome pathways in both MSU stimulated THP-1-derived macrophages and the mouse model of GA. In summary, neoastilbin could alleviate GA by inhibiting the NF-κB and NLRP3 inflammasome pathways, which provided some evidence for neoastilbin as a promising therapeutic agent for GA treatment.