Model based on single-nucleotide polymorphism to discriminate aspirin resistance patients.

BACKGROUND: Aspirin is widely used for preventing ischaemic events. About 20%-40% of patients have aspirin resistance (ASR), which prevents them from benefiting from aspirin medication. This study aimed to develop and validate a model based on single-nucleotide polymorphism (SNP) to distinguish ASR patients. METHODS: We included patients with spontaneous intracerebral haemorrhage and continuing antiplatelet therapy from a multicentre, prospective cohort study as the derivation cohort. Thromboelastography (inhibition of arachidonic acid channel<50%) was used to identify ASR. Genotyping was performed to identify the ASR-related SNP. Based on the result of the logistic analysis, the aspirin resistance in the Chinese population score (ASR-CN score) was established, and its accuracy was evaluated using the area under the curve (AUC). Patients receiving dual antiplatelet therapy for unruptured intracranial aneurysm embolism were prospectively included in the validation cohort. After embolism, 30-day ischaemic events, including ischaemic stroke, new or more frequent transient ischaemic attack, stent thrombosis and cerebrovascular death, were recorded. RESULTS: The derivation cohort included 212 patients (155 male patients and the median age as 59). 87 (41.0%) individuals were identified with ASR. The multivariate logistic analysis demonstrated six SNPs of GP1BA, TBXA2R, PTGS2 and NOS3 as risk factors related to ASR. The ASR-CN score integrating these SNPs performed well to discriminate ASR patients from non-ASR patients (AUC as 0.77). Based on the validation cohort of 372 patients receiving antiplatelet therapy after embolism (including 130 ASR patients), the ASR-CN score continued to distinguish ASR patients with good accuracy (AUC as 0.80). Patients with high a ASR-CN score were more likely to suffer from 30-day ischaemic events after embolism (OR, 1.28; 95% CI, 1.10 to 1.50; p=0.002). CONCLUSION: GP1BA, TBXA2R, PTGS2 and NOS3 were SNPs related to ASR. The ASR-CN score is an effective tool to discriminate ASR patients, which may guide antiplatelet therapy. CLINICAL TRIAL REGISTRATION: Surgical Treatments of Antiplatelet Intracerebral Hemorrhage cohort (unique identifier: ChiCTR1900024406, http://www.chictr.org.cn/edit.aspx?pid=40640&htm=4).

Early-start antiplatelet therapy after operation in patients with spontaneous intracerebral hemorrhage and high risk of ischemic events (E-start): Protocol for a multi-centered, prospective, open-label, blinded endpoint randomized controlled trial.

Background: For severe spontaneous intracerebral hemorrhage (sSICH) patients with high risk of ischemic events, the incidence of postoperative major cardiovascular/cerebrovascular and peripheral vascular events (MACCPE) is notable. Although antiplatelet therapy is a potential way to benefit these patients, the severe hemorrhagic complications, e.g., intracranial re-hemorrhage, is a barrier for early starting antiplatelet therapy. Objectives: This randomized controlled trial aims to identify the benefit and safety of early starting antiplatelet therapy after operation for sSICH patients with high risk of ischemic events. Methods: This study is a multicenter, prospective, randomized, open-label, blinded-endpoint trial. We will enroll 250 sSICH patients with a high risk of ischemic events (including cerebral infarcts, transient ischemic attack, myocardial infarction, pulmonary embolism, and deep venous thrombosis). The participants will be randomized in a 1:1 manner to early-start group (start antiplatelet therapy at 3 days after operation) and normal-start group (start antiplatelet therapy at 30 days after operation). The early-start group will receive aspirin 100 mg daily. The control group will not receive antithrombotic therapy until 30 days after operation. The efficacy endpoint is the incidence of MACCPE, and the safety endpoint is the incidence of intracranial re-hemorrhage. Discussion: The Early-Start antiplatelet therapy after operation in patients with spontaneous intracerebral hemorrhage trial (E-start) is the first randomized trial about early start antiplatelet therapy for operated sSICH patients with a high risk of ischemic events. This study will provide a new strategy and evidence for postoperative management in the future. Clinical trial registration: ClinicalTrials.gov, identifier NCT04820972; Available at: https://clinicaltrials.gov/ct2/show/NCT04820972?term=NCT04820972&draw=2&rank=1.Chinese Clinical Trial Registry, identifier ChiCTR2100044560; Available at: http://www.chictr.org.cn/showproj.aspx?proj=123277.

Validation of the predictive accuracy of "clinical + morphology nomogram" for the rebleeding risk of ruptured intracranial aneurysms after admission.

BACKGROUND: Rebleeding can cause a catastrophic outcome after aneurysmal subarachnoid hemorrhage. A clinical + morphology nomogram was promoted in our previous study to assist in discriminating the rupture intracranial aneurysms (RIAs) with a high risk of rebleeding. The aim of this study was to validate the predictive accuracy of this nomogram model. METHOD: The patients with RIAs in two medical centers from December 2020 to September 2021 were retrospectively reviewed, whose clinical and morphological parameters were collected. The Cox regression model was employed to identify the risk factors related to rebleeding after their admission. The predicting accuracy of clinical + morphological nomogram, ELAPSS score and PHASES score was compared based on the area under the curves (AUCs). RESULTS: One hundred thirty-eight patients with RIAs were finally included in this study, 20 of whom suffering from rebleeding after admission. Hypertension (hazard ratio (HR), 2.54; a confidence interval of 95% (CI), 1.01-6.40; P = 0.047), bifurcation (HR, 3.88; 95% CI, 1.29-11.66; P = 0.016), and AR (HR, 2.68; 95% CI, 1.63-4.41; P < 0.001) were demonstrated through Cox regression analysis as the independent risk factors for rebleeding after admission. The clinical + morphological nomogram had the highest predicting accuracy (AUC, 0.939, P < 0.01), followed by the bifurcation (AUC, 0.735, P = 0.001), AR (AUC, 0.666, P = 0.018), and ELAPSS score (AUC, 0.682, P = 0.009). Hypertension (AUC, 0.693, P = 0.080) or PHASES score (AUC, 0.577, P = 0.244) could not be used to predict the risk of rebleeding after admission. The calibration curve for the probability of rebleeding showed a good agreement between the prediction through clinical + morphological nomogram and actual observation. CONCLUSION: Hypertension, bifurcation site, and AR were independent risk factors related to the rebleeding of RIAs after admission. The clinical + morphological nomogram could help doctors to identify the high-risk RIAs with a high predictive accuracy.

A Novel Coagulation Classification and Postoperative Bleeding in Severe Spontaneous Intracerebral Hemorrhage Patients on Antiplatelet Therapy.

BACKGROUND AND PURPOSE: For patients with severe spontaneous intracerebral hemorrhage on antiplatelet therapy (patients with APT-SICH), postoperative rebleeding (PR) is an important cause of poor outcomes after surgery. As impacted by coagulation disorder caused by APT, patients with APT-SICH are likely to suffer from PR. This study aimed to assess the risk of PR in patients with APT-SICH receiving emergency surgery using a novel coagulation classification. METHODS: This prospective, multicenter cohort study consecutively selected patients with APT-SICH between September 2019 and March 2021. The preoperative coagulation factor function was recorded, and the platelet function was assessed using thrombelastography. Based on platelet and coagulation factor function, a novel four-type coagulation classification, i.e., Type I (severe coagulation disorder), Type IIa (low platelet reserve capacity), Type IIb (normal coagulation), and Type III (hypercoagulation), was presented. The primary outcome was PR, defined as the rebleeding in the operative region or new intracerebral hemorrhage correlated with the operation. RESULTS: Of the included 197 patients with APT-SICH, PR occurred in 40 patients (20.3%). The novel coagulation classification categorized 28, 32, 122, and 15 patients into Type I, Type IIa, Type IIb, and Type III, respectively. The Type I patients had the highest incident rate of PR (39.3 per 100 persons), followed by the Type IIa patients (31.3 per 100 persons). In the PR-related analysis, the large hematoma volume (hazard ratio (HR): 1.02; 95% CI: 1.02-1.03; p < 0.001), Type I (HR: 9.72; 95% CI: 1.19-79.67; p = 0.034), and Type IIa (HR: 8.70; 95% CI: 1.09-69.61; p = 0.041) were correlated with the highest risk of PR. The coagulation classification could discriminate the PR patients from no PR (NPR) patients (p < 0.001), and it outperformed the conventional coagulation assessment (only considering platelet count and coagulation factor function) (c-statistic, 0.72 vs. 0.55). CONCLUSION: The novel coagulation classification could discriminate the patients with APT-SICH with the highest risk of PR preoperatively. For the Type I and Type IIa patients, emergency surgery should be performed carefully.

Serum IL-1, Pyroptosis and Intracranial Aneurysm Wall Enhancement: Analysis Integrating Radiology, Serum Cytokines and Histology.

BACKGROUND AND PURPOSE: Aneurysm wall enhancement (AWE) is correlated with the rupture and growth risk of unruptured intracranial aneurysms (UIAs). Pyroptosis is a proinflammation mode of lytic cell death, mediated by pyroptosis-related proteins, i.e., gasdermin D and interleukin 1 ß (IL-1ß). Integrating serum cytokines and histology, this study aimed to investigate the correlation between AWE and pyroptosis in UIAs. METHODS: UIA patients receiving microsurgical clipping were prospectively enrolled from January 2017 and June 2020. UIA samples were collected, as well as the corresponding blood samples. In this study, high-resolution magnetic resonance was employed to identify the AWE. The serum 46-cytokines examination and the histological analysis were conducted to determine pyroptosis, CD68 and MMP2. The IL-1 ra/beta ratio was determined by complying with the serum IL-1ß and IL-1.ra. A comparison was drawn in the differences between UIAs with and without AWE. Lastly, the correlation between inflammation in UIA samples and serums was investigated. RESULTS: This study included 34 UIA patients. The serum proinflammatory cytokines [IL-1ß (P < 0.001) and TNF-α (P < 0.001)] were up-regulated, and serum anti-inflammatory cytokine (IL-1.ra, P = 0.042) were down-regulated in patients with AWE UIAs. The patients with AWE UIAs achieved a higher IL-1.ra/beta ratio (P < 0.001). The multivariate logistic analysis demonstrated IL-1ß [odds ratio (OR), 1.15; 95% confidence interval (CI), 1.02-1.30; P = 0.028] and IL-1.ra (OR, 0.998; 95% CI, 0.997-1.000; P = 0.017) as the risk factors correlated with the AWE. IL-1.ra/beta ratio achieved the highest predictive accuracy [area under the curve (AUC), 0.96] for AWE, followed by IL-1.ra (AUC, 0.90), IL-1ß (AUC, 0.88) and TNF-α (AUC, 0.85). As compared with the UIAs without AWE, the AWE UIAs were manifested as a severer wall remodeling, with higher relative levels of pyroptosis-related proteins, CD68 and MMP2. The serum IL-1ß, IL-1.ra and IL-1.ra/beta ratio had a positive correlation with the relative levels of pyroptosis-related proteins, CD68 and MMP2 in UIA tissues. CONCLUSION: The serum IL-1ß and IL-1.ra were correlated with the AWE. More pyroptosis-related proteins were identified in UIAs with AWE. The serum IL-1ß and IL-1.ra were correlated with the pyroptosis-related proteins in aneurysm tissues.

The Relationship of Morphological-Hemodynamic Characteristics, Inflammation, and Remodeling of Aneurysm Wall in Unruptured Intracranial Aneurysms.

Aneurysm wall remodeling (AWR) is an important pathological characteristic in aneurysm wall, which was characterized by abnormal histological structure and inflammation infiltration. In the present study, the aim is to determine the relationships of morphological-hemodynamic characteristics, inflammation, and AWR in intracranial aneurysms (IAs), as well as the pathological basis of morphological-hemodynamic predictors to achieve IA development. For this end, 113 unruptured IAs were prospectively collected from 110 cases. In addition, patient-specific computational fluid dynamics and geometry were adopted to determine hemodynamic and morphological parameters. Moreover, Hematoxylin-Eosin staining was performed to identify the AWR. By performing immunofluorescence, the inflammatory markers were detected. Masson staining was conducted to characterize the characteristics of atherosclerosis in aneurysm wall. To demonstrate the parameters regarding the AWR, a multivariate logistic analysis was conducted. Besides, correlation analyses were conducted to verify the relationship between morphological-hemodynamic and pathological characteristics. For 113 unruptured IAs, no difference was identified in baseline information. AWR was demonstrated in 92 (81.4%) IAs. To be specific, the aneurysm size (odds ratio (OR), 2.63; confidence interval (CI), 1.04-6.67; P = 0.041), size ratio (SR; OR, 1.95; CI, 1.38-2.76; P < 0.001), normalized wall shear stress average (NWSSA; OR, 0.05; CI, 0.01-0.15; P = 0.007), and relative resident time (RRT; OR, 1.28; CI, 1.07-1.53; P = 0.007) were proved as the factors of AWR. As revealed from the results of immunofluorescence, aneurysm size, SR, NWSSA, and RRT were significantly correlated with the level of inflammation in IA tissues. Furthermore, Masson staining revealed that atherosclerosis area in IA tissues and NWSSA was correlated with RRT. In this study, SR, NWSSA, and RRT were demonstrated as the risk factors of AWR. The mentioned parameters could also reflect the characteristics of inflammation and atherosclerosis in aneurysm wall as well. This study revealed that biomechanical stress and inflammation in aneurysm wall are correlated, which might suggest the pathological evidence of morphological-hemodynamic predictors for IA development.

Accurate cisAB typing is essential to ensure the safety of a transfusion: A case of a cisAB01 neurosurgery pediatric patient and family study.

The rare cisAB subgroups inherited from a single parent are characterized by the activities of dual A and B glycosyltransferases encoded by a gene on one chromosome. The serological complexity of cisAB challenges clinical blood transfusion practice because of misclassification in ABO grouping.

Rebleeding of Ruptured Intracranial Aneurysm After Admission: A Multidimensional Nomogram Model to Risk Assessment.

OBJECTIVE: Rebleeding is recognized as the main cause of mortality after intracranial aneurysm rupture. Though timely intervention can prevent poor prognosis, there is no agreement on the surgical priority and choosing medical treatment for a short period after rupture. The aim of this study was to investigate the risk factors related to the rebleeding after admission and establish predicting models for better clinical decision-making. METHODS: The patients with ruptured intracranial aneurysms (RIAs) between January 2018 and September 2020 were reviewed. All patients fell to the primary and the validation cohort by January 2020. The hemodynamic parameters were determined through the computational fluid dynamics simulation. Cox regression analysis was conducted to identify the risk factors of rebleeding. Based on the independent risk factors, nomogram models were built, and their predicting accuracy was assessed by using the area under the curves (AUCs). RESULT: A total of 577 patients with RIAs were enrolled in this present study, 86 patients of them were identified as undergoing rebleeding after admission. Thirteen parameters were identified as significantly different between stable and rebleeding aneurysms in the primary cohort. Cox regression analysis demonstrated that six parameters, including hypertension [hazard ratio (HR), 2.54; P = 0.044], bifurcation site (HR, 1.95; P = 0.013), irregular shape (HR, 4.22; P = 0.002), aspect ratio (HR, 12.91; P < 0.001), normalized wall shear stress average (HR, 0.16; P = 0.002), and oscillatory stress index (HR, 1.14; P < 0.001) were independent risk factors related to the rebleeding after admission. Two nomograms were established, the nomogram including clinical, morphological, and hemodynamic features (CMH nomogram) had the highest predicting accuracy (AUC, 0.92), followed by the nomogram including clinical and morphological features (CM nomogram; AUC, 0.83), ELAPSS score (AUC, 0.61), and PHASES score (AUC, 0.54). The calibration curve for the probability of rebleeding showed good agreement between prediction by nomograms and actual observation. In the validation cohort, the discrimination of the CMH nomogram was superior to the other models (AUC, 0.93 vs. 0.86, 0.71 and 0.48). CONCLUSION: We presented two nomogram models, named CMH nomogram and CM nomogram, which could assist in identifying the RIAs with high risk of rebleeding.

A scoring system to discriminate blood blister-like aneurysms: a multidimensional study using patient-specific model.

Presurgical discrimination of blood blister-like aneurysms (BBAs) can assist neurosurgeons in clinical decision-making. The aim of this study was to investigate the characteristics of BBAs and construct a useful tool to distinguish BBAs. This study reviewed patients with small/median, hemispherical, and wide-necked aneurysms of the internal carotid artery in our institution. BBAs were identified via their intraoperative findings. A hemodynamic analysis was performed using a patient-specific model. The independent risk factors of BBAs were investigated using a logistic analysis. A scoring system was then established to discriminate BBAs, in which its predicting value was analyzed using receiver operating characteristic (ROC) analysis. A total of 67 aneurysms comprising 21 BBAs were enrolled. Comparing features between BBAs and non-BBAs, statistical significances were found in the aspect ratio (AR), height-to-width ratio, aneurysm angle (AA), wall shear stress gradient (WSSG), and normalized wall shear stress average. A multivariate logistic analysis identified AR (OR = 0.29, p = 0.021), WSSG (OR = 1.54, p = 0.017) and AA (OR = 2.49, p = 0.039) as independent risk factors for BBAs. A scoring system was constructed using these parameters, effectively distinguishing BBAs (AUC = 0.931, p < 0.01). Our multidimensional scoring system may effectively assist in the discrimination of BBAs from wide-necked non-BBAs.

Surgical treatment for antiplatelet intracerebral hemorrhage (SAP-ICH): protocol for a prospective cohort study of emergency surgery for severe spontaneous intracerebral hemorrhage patients on long-term oral antiplatelet treatment.

BACKGROUND: Despite the capability of emergency surgery to reduce the mortality of severe spontaneous intracranial hemorrhage (SSICH) patients, the effect and safety of surgical treatment for severe spontaneous intracranial hemorrhage (SSICH) patients receiving long-term oral antiplatelet treatment (LOAPT) remains unclear. In consideration of this, the cohort study is aimed at figuring out the effect and safety of emergency surgery for SSICH patients on LOAPT. METHODS: As a multicenter and prospective cohort study, it will be conducted across 7 representative clinical centers. Starting in September 2019, the observation is scheduled to be completed by December 2022, with a total of 450 SSICH patients recruited. The information on clinical, radiological, and laboratory practices will be recorded objectively. All of the patients will be monitored until death or 6 months after the occurrence of primary hemorrhage. RESULTS: In this study, two comparative cohorts and an observational cohort will be set up. The primary outcome is the effect of emergency surgery, which is subject to assessment using the total mortality and comparison in the survival rate of SSICH patients on LOAPT between surgical treatment and conservative treatment. The second outcome is the safety of surgery, with the postoperative hemorrhagic complication which is compared between the operated SSICH patients on and not on LOAPT. Based on the observation of the characteristics and outcome of SSICH patients on LOAPT, the ischemic events after discontinuing LOAPT will be further addressed, and the coagulation function assessment system for operated SSICH patients on LOAPT will be established. CONCLUSIONS: In this study, we will investigate the effect and safety of emergency surgery for SSICH patients on LOAPT, which will provide an evidence for management in the future. ETHICS AND DISSEMINATION: The research protocol and informed consent in this study were approved by the Institutional Review Board of Beijing Tiantan Hospital (KY2019-096-02). The results of this study are expected to be disseminated in peer-reviewed journals in 2023. TRIAL REGISTRATION: Name: Effect and safety of surgical intervention for severe spontaneous intracerebral hemorrhage patients on long-term oral antiplatelet treatment. ChiCTR1900024406 . Date of registration is July 10, 2019.

Emergency surgery is an effective way to improve the outcome of severe spontaneous intracerebral hemorrhage patients on long-term oral antiplatelet therapy.

The necessity of emergency surgery for severe spontaneous intracerebral hemorrhage (SSICH) patients on long-term oral antiplatelet therapy (LOAPT) remains unclear. The aim of this study was to investigate the effect and safety of emergency surgery for SSICH patients on LOAPT (SSICH-LOAPT patients). In this study, a retrospective review of patients admitted to our institution for SSICH from January 2012 to December 2018 was conducted. The collected data included demographic, clinical, and surgical information. The outcome was recorded at 3 months after primary hemorrhage. The outcome of SSICH-LOAPT patients receiving emergency surgery and conservative treatment were compared. The risk of postoperative intracranial bleeding (PIB) in operated SSICH-LOAPT patients was further investigated. A total of 522 SSICH patients were retrospectively reviewed, including 181 SSICH-LOAPT patients and 269 operated patients. The total mortality and in-hospital mortality were 40.6% and 19.3%, respectively. As compared with SSICH-LOAPT patients receiving conservative treatment, the operated SSICH-LOAPT patients showed a lower total (p = 0.043) and in-hospital mortality (p = 0.024). When compared with operated patients not on LOAPT, the operated patients on LOAPT exhibited a higher rate of PIB (OR, 2.34; 95% CI 1.14-4.79; p = 0.018). As demonstrated by the multivariate logistic analysis, dual antiplatelet therapy were independent risk factors associated with PIB in operated SSICH-LOAPT patients (OR, 3.42; CI, 1.01-11.51; p = 0.047). Despite of increasing risk of PIB, emergency surgery could improve the outcome of SSICH-LOAPT patients as it could be effective in reducing mortality. Dual antiplatelet therapy was the independent risk factor related to the PIB in operated SSICH-LOAPT patients.