Genetically predicted high serum sex hormone-binding globulin levels are associated with lower ischemic stroke risk: A sex-stratified Mendelian randomization study.

OBJECTIVE: Cross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke. METHODS: Single-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders. RESULTS: Inverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003). CONCLUSION: Our findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.

Incidence of post-stroke cognitive impairment in patients with first-ever ischemic stroke: a multicenter cross-sectional study in China.

Background: Post-stroke cognitive impairment (PSCI) is a common sequela after stroke. China has a large population of stroke survivors, but a large-scale survey on the incidence and risk factors for PSCI has not been undertaken. We aimed to calculate the incidence and risk factors for vascular cognitive symptoms among first-ever stroke survivors in China through a multicenter cross-sectional study. Methods: From May 1, 2019 to November 30, 2019, patients with a clinical diagnosis of first-ever ischemic stroke were recruited from 563 hospitalized-based stroke center networks in 30 provinces of China. Cognitive impairment was measured by 5-min National Institute of Neurological Disease and Stroke-Canadian Stroke Network (NINDS-CSN) at 3-6 months after the indexed stroke. Stepwise multivariate regression and stratified analysis were performed to assess the association between PSCI and demographic variables. Findings: A total of 24,055 first-ever ischemic stroke patients were enrolled, with an average age of 70.25 ± 9.88 years. The incidence of PSCI as per the 5-min NINDS-CSN was 78.7%. Age ≥75 years old (OR: 1.887, 95%CI: 1.391-2.559), western regional residence (OR: 1.620, 95%CI: 1.411-1.860) and lower education level were associated with increased PSCI risk. Hypertension might be related to non-PSCI (OR: 0.832, 95%CI: 0.779-0.888). For patients under 45 years old, unemployment was an independent risk factor for PSCI (OR: 6.097, 95%CI: 1.385-26.830). For patients who were residents of the southern region (OR: 1.490, 95%CI: 1.185-1.873) and non-manual workers (OR: 2.122, 95%CI: 1.188-3.792), diabetes was related to PSCI. Interpretation: PSCI is common in Chinese patients with first-ever stroke, and many risk factors are related to the occurrence of PSCI. Funding: The Beijing Hospitals Authority Youth Program (No. QMS20200801); Youth Program of the National Natural Science Foundation of China (No. 81801142); the Key Project of Science and Technology Development of China Railway Corporation (No. K2019Z005); The Capital Health Research and Development of Special (No. 2020-2-2014); Science and Technology Innovation 2030-Major Project (No. 2021ZD0201806).

Recurrent ischemic stroke from reversible extracranial internal carotid artery and middle cerebral artery vasospasm: A case report.

Idiopathic internal carotid artery (ICA) vasospasm is a rare cause of ischemic stroke. Its pathophysiology remains unclear and diagnostic and treatment protocols are yet to be defined. A 45-year-old male, presenting with recurrent transient dizziness, blurred vision, and speech disturbances, was diagnosed with recurrent ischemic stroke caused by bilateral ICA and middle cerebral artery (MCA) vasospasm, and the vascular ultrasound and imaging techniques have grabbed the reversible changes in a short time. This case underscores the importance of considering idiopathic ICA vasospasm as a potential cause of recurrent ischemic stroke, even in the absence of common diagnostic markers. The case also indicates the possible, albeit rare, involvement of the MCA in this condition. Therefore, it is crucial to maintain a high index of suspicion for idiopathic ICA vasospasm in similar clinical presentations and to explore more inclusive diagnostic criteria.

Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees.

Background and Objectives: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebrovascular disease caused by homozygous or compound heterozygous variations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. However, several studies in recent years have found that some heterozygous HTRA1 mutations also cause cerebral small vessel disease (CSVD). The current study aims to report the novel genotypes, phenotypes, and histopathologic results of 3 pedigrees of CSVD with heterozygous HTRA1 mutation. Methods: Three pedigrees of familiar CSVD, including 11 symptomatic patients and 3 asymptomatic carriers, were enrolled. Whole-exome sequencing was conducted in the probands for identifying rare variants, which were then evaluated for pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Sanger sequencing was performed for validation of mutations in the probands and other family members. The protease activity was assayed for the novel mutations. All the participants received detailed clinical and imaging examinations and the corresponding results were concluded. Hematoma evacuation was performed for an intracerebral hemorrhage patient with the p.Q318H mutation, and the postoperative pathology including hematoma and cerebral small vessels were examined. Results: Three novel heterozygous HTRA1 mutations (p.Q318H, p.V279M, and p.R274W) were detected in the 3 pedigrees. The protease activity was largely lost for all the mutations, confirming that they were loss-of-function mutations. The patients in each pedigree presented with typical clinical and imaging features of CVSD, and some of them displayed several new phenotypes including color blindness, hydrocephalus, and multiple arachnoid cysts. In addition, family 1 is the largest pedigree with heterozygous HTRA1 mutation so far and includes homozygous twins, displaying some variation in clinical phenotypes. More importantly, pathologic study of a patient with p.Q318H mutation showed hyalinization, luminal stenosis, loss of smooth muscle cells, splitting of the internal elastic lamina, and intramural hemorrhage/dissection-like structures. Discussion: These findings broaden the mutational and clinical spectrum of heterozygous HTRA1-related CSVD. Pathologic features were similar with the previous heterozygous and homozygous cases. Moreover, clinical heterogeneity was revealed within the largest single family, and the mechanisms of the phenotypic heterogenetic remain unclear. Overall, heterozygous HTRA1-related CSVD should not be simply taken as a mild type of CARASIL as previously considered.

Novel Double Endobutton Technique Combined with Three-Dimensional Printing: A Biomechanical Study of Reconstruction in Acromioclavicular Joint Dislocation.

OBJECTIVE: To reconstruct the acromioclavicular (AC) joint using an adjusted closed-loop double Endobutton technique via a guiding locator that was applied using three-dimensional (3D) printing technology. At the same time, the reliability and safety of the novel double Endobutton (NDE) were tested by comparing the biomechanics of this technique with the TightRope (TR) approach. METHODS: This retrospective study was conducted between January 2017 and January 2019. The Department of Anatomy at Southern Medical University obtained 18 fresh-frozen specimens (8 left and 10 right; 12 men and 6 women). First, the guiding locators were applied using 3D printing technology. After preparation of materials, specimens were divided into an NDE group, a TR group, and a normal group. In the NDE and TR groups, the navigation module was used to locate and establish the bone tunnels; after that, the NDE or TR was implanted. However, the Endobuttons were fixed while pressing the distal clavicle downwards and the length of the loop could be adjusted by changing the upper Endobutton in the NDE group while the suture button construct was tensioned and knotted after pressing down the distal clavicle in the TR. Finally, load testing in anterior-posterior (AP), superior-inferior (SI), and medial-lateral (ML) directions as well as load-to-failure testing in the SI direction were undertaken to verify whether the NDE or TR had better biomechanics. RESULTS: In the load testing, the displacements of the NDE and TR groups in the AP, SI, and ML direction were significantly shorter than those of the normal group (P < 0.05). In the load-to-failure testing, the ultimate load of the NDE and TR groups had significantly higher increases than the normal group (722.16 ± 92.04 vs 564.63 ± 63.05, P < 0.05; 680.20 ± 110.29 vs 564.63 ± 63.05, P < 0.05). However, there was no statistically significant difference between the two techniques for these two tests (P > 0.05). In the NDE group, four of six failures were a result of tunnel fractures of the coracoid, while two of six were due to suture breakage. In the TR, three failures were due to coracoid tunnel fractures, one was a result of a clavicle tunnel fracture, and the rest were due to suture breakage. In the normal group, half of the failures were a result of avulsion fractures of the conical ligament at the point of the coracoid process, and the other three were due to rupture of the conical ligament, fracture of the distal clavicle, and fracture of the scapular body. CONCLUSION: As for the TR technique, the stability and strength of the AC joint were better in patients who underwent reconstruction using the NDE technique than in the intact state.