Unraveling the mechanisms of NK cell dysfunction in aging and Alzheimer's disease: insights from GWAS and single-cell transcriptomics.

Background: Aging is an important factor in the development of Alzheimer's disease (AD). The senescent cells can be recognized and removed by NK cells. However, NK cell function is gradually inactivated with age. Therefore, this study used senescence as an entry point to investigate how NK cells affect AD. Methods: The study validated the correlation between cognition and aging through a prospective cohort of the National Health and Nutrition Examination Survey database. A cellular trajectory analysis of the aging population was performed using single-cell nuclear transcriptome sequencing data from patients with AD and different ages. The genome-wide association study (GWAS) cohort of AD patients was used as the outcome event, and the expression quantitative trait locus was used as an instrumental variable. Causal associations between genes and AD were analyzed by bidirectional Mendelian randomization (MR) and co-localization. Finally, clinical cohorts were constructed to validate the expression of key genes. Results: A correlation between cognition and aging was demonstrated using 2,171 older adults over 60 years of age. Gene regulation analysis revealed that most of the highly active transcription factors were concentrated in the NK cell subpopulation of AD. NK cell trajectories were constructed for different age populations. MR and co-localization analyses revealed that CHD6 may be one of the factors influencing AD. Conclusion: We explored different levels of AD and aging from population cohorts, single-cell data, and GWAS cohorts and found that there may be some correlations of NK cells between aging and AD. It also provides some basis for potential causation.

Total Cerebral Small Vessel Disease Burden Predicts the Outcome of Acute Stroke Patients after Intra-Arterial Thrombectomy.

INTRODUCTION: Various types of cerebral small vessel diseases (cSVD) markers commonly coexist. The neurological function outcome is affected by their combined effect. To investigate the effect of cSVD on intra-arterial thrombectomy (IAT), our study aimed at developing and testing a model with fusing a combination of multiple cSVD markers as total cSVD burden to predict the outcome of acute ischemic stroke (AIS) patients after IAT treatment. METHODS: From October 2018 to March 2021, continuous AIS patients with IAT treatment were enrolled. We calculated the cSVD markers identified by magnetic resonance imaging. The outcomes of all patients were assessed according to the modified Rankin Scale (mRS) score at 90 days after stroke. The relationship between total cSVD burden and outcomes was analyzed by logistics regression analysis. RESULTS: A total of 271 AIS patients were included in this study. The proportions of score 0∼4 in the total cSVD burden group (i.e., score 0, 1, 2, 3, and 4 groups) were 9.6%, 19.9%, 23.6%, 32.8%, and 14.0%, respectively. The higher the cSVD score, the more patients with a poor outcome. Heavier total cSVD burden (1.6 [1.01∼2.27]), diabetes mellitus (1.27 [0.28∼2.23]), and higher national institute of health stroke scale (NIHSS) on admission (0.15 [0.07∼0.23]) were associated with poor outcome. In the two Least Absolute Shrinkage and Selection Operator regression models, model 1 using age, duration from onset to reperfusion, Alberta stroke program early CT score (ASPECTS), NIHSS on admission, modified thrombolysis in cerebral infarction (mTICI) and total cSVD burden as variables perform well on predicting short-term outcome in area under curve (AUC) of 0.90. Model 2, including all of the variables above except cSVD, showed less predictive capability than model 1 (AUC 0.90 vs. 0.82, p = 0.045). CONCLUSIONS: The total cSVD burden score was independently associated with the clinical outcomes of AIS patients after IAT treatment and it may be a reliable predictor for poor outcomes of AIS patients after IAT treatment.

Clinical Characteristics and Follow-up of Cases of Streptococcus suis Meningitis in Patients of Liuzhou, China.

We analyzed the clinical characteristics and outcomes of patients with Streptococcus suis meningitis in Liuzhou, China, to improve diagnostic accuracy and lower the chances of misdiagnosis. The major clinical manifestations, auxiliary examination results, treatment strategies, treatment efficacy, and follow-up results of 17 consecutively admitted patients with S. suis meningitis were evaluated. The most common clinical manifestations were fever (15/17), sensorineural hearing loss (13/17), headache (11/17), and altered mental status (8/17). In addition, 64.71% of the patients had residual symptoms of sensorineural hearing loss at discharge, and moderate disabilities occurred in 68.75% of the patients in the form of sensorineural deafness (11/17) and hemiparesis (1/17). The cerebrospinal fluid (CSF) of nine patients was used for metagenomic analysis with next-generation sequencing. The metagenomic analysis of CSF of four patients was positive, whereas blood and CSF cultures were negative. The average modified Rankin Scale (mRS) and Activities of Daily Living (ADL) scores improved significantly at the 6-month follow-up compared with those at admission (P < 0.05). There was no correlation between altered mRS and ADL scores and the CSF findings (P > 0.05). Early administration of antibiotics can prevent sensorineural hearing loss. Early CSF metagenomic analysis may be superior to blood and CSF culture.

Early tirofiban administration for patients with acute ischemic stroke treated with intravenous thrombolysis or bridging therapy: Systematic review and meta-analysis.

OBJECTIVE: In the present systematic review and meta-analysis, we sought to compare the efficacy and safety of tirofiban administered in patients with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT) with or without mechanical thrombectomy (MT). METHODS: We searched PubMed, Web of Science, Embase and the Cochrane Library for randomized clinical trials and observational studies published between 2001 and 2021 that provided outcomes of AIS patients who underwent IVT alone or IVT bridging with or without tirofiban. The primary outcome was the proportion of patients achieving a modified Rankin Scale (mRS) score of 0-2 at 90 days. The secondary outcomes included the rates of (1) an excellent outcome defined as a mRS score of 0 or 1 at 90 days, (2) any type of intracranial hemorrhage (ICH), (3) symptomatic intracranial hemorrhage (sICH), (4) mortality, and (5) successful recanalization. RESULTS: We included 722 patients with IVT bridging therapy in 3 trials; there were 171 patients in the tirofiban group and 551 patients in the nontirofiban group. We included 846 patients with IVT alone in 7 studies; there were 471 patients in the tirofiban group and 375 patients in the nontirofiban group. The patients treated with tirofiban had a reduced risk of mortality compared to the patients treated without tirofiban during IVT bridging (OR, 0.46; 95 % CI, 0.24-0.89; p = 0.02), but no significant differences were found in safety outcomes on sICH, ICH, recanalization or efficacy outcomes on modified Rankin scale 0-2 (p > 0.05). Pooled results showed that tirofiban combined with IVT alone did not increase the risks of sICH, ICH or mortality but was significantly associated with excellent (OR, 2.68; 95 % CI, 1.58-4.55; P = 0.0003) and favorable (OR, 2.36; 95 % CI, 1.58-3.52; p < 0.0001) functional outcomes at 90 days. CONCLUSION: In AIS patients who underwent IVT or bridging therapy, early administration of tirofiban may be effective and safe, but further studies are needed to confirm the efficacy.

Association Between Blood Pressure Variability and Short-Term Outcome After Intra-arterial Thrombectomy in Acute Stroke Patients With Large-Vessel Occlusion.

The optimal range of blood pressure variability (BPV) for acute stroke patients with large-vessel occlusion (LVO) remains unclear. This study investigated the association between BPV from admission through the first 24 h after intra-arterial thrombectomy (IAT) and short-term outcome in LVO patients. We retrospectively analyzed 257 consecutive patients with LVO stroke who were treated with IAT. BP values were recorded at 2-h intervals from admission through the first 24 h after IAT. BPV, as reflected by pulse pressure variability (PPV), was determined based on standard deviation (SD), coefficient of variation (CV), successive variation (SV), and the difference between maximum and minimum blood pressure (ΔBP; systolic BP minus diastolic BP). The association between BPV and clinical outcome (Modified Rankin Scale score at 90 days) was analyzed by multivariate logistic regression analysis. Of the 257 included patients, 70 had a good outcome at 3 months. PPV from admission through the first 24 h after IAT was independently associated in a graded manner with poor outcome [multivariable-adjusted odds ratios (95% confidence interval) for the highest of PPV were 43.0 (8.7-212.8) for SD, 40.3 (9.8-165.0) for CV, 55.0 (11.2-271.2) for SV, and 40.1 (8.0-201.9) for ΔBP]. The area under the receiver operating characteristic curve (95% confidence interval) of the PPV parameters were 0.924 (0.882-0.965) for SD, 0.886 (0.835-0.938) for CV, 0.932 (0.891-0.973) for SV, and 0.892 (0.845-0.939) for ΔBP, and the Youden index values were 0.740, 0.633, 0.759, and 0.756, respectively. In summary, BPV from admission through the first 24 h after IAT was independently associated with poor outcome at 3 months in patients with LVO, with greater variability corresponding to a stronger association. Thus, PPV may be a clinically useful predictor of functional prognosis in LVO patients treated with IAT.

Extracranial Artery Stenosis Is Associated With Total MRI Burden of Cerebral Small Vessel Disease in Ischemic Stroke Patients of Suspected Small or Large Artery Origins.

Background and Purpose: Extracranial artery stenosis (ECAS) is related to individual imaging markers of cerebral small vessel disease (cSVD). However, little has been reported on the association between ECAS and the total burden of cSVD as assessed by magnetic resonance imaging (MRI). The purpose of this study was to investigate the relationship between ECAS and cSVD burden in patients with ischemic stroke of suspected small or large artery origin. Methods: We reviewed consecutive patients with ischemic stroke of suspected small or large artery origin who underwent color Doppler ultrasonography and brain MRI. Bilateral extracranial cerebral arteries including common carotid artery, internal carotid artery (ICA), and proximal vertebral artery (VA, ostium, V2-3 segments) were assessed using color Doppler ultrasonography. ECAS severity was classified as no/mild stenosis, moderate stenosis, severe stenosis, or occlusion. The total cSVD score was assessed by awarding one point according to the load of each of these cSVD markers as determined using MRI; lacunar infarction, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces. The relationship between ECAS severity and cSVD burden according to MRI was examined. Results: Two hundred and twenty one patients were included in this study (mean age 61 ± 12 years, 75.6% male). Hypertension, current smoking, hyperlipidaemia, and diabetic mellitus were frequent among the patients (67.4, 45.7, 43.9, and 36.7%, respectively), while the other vascular risk factors including previous stroke or TIA and alcohol excess were less frequent (19.0 and 15.4%, respectively). Patients with higher total cSVD burden was significantly older and had severer ECAS. The frequency of hypertension was significantly higher in patients with higher total cSVD burden. This analysis indicated that that increasing ECAS severity (from no stenosis through to 100%) was independently associated with increasing total cSVD score after adjusting for other vascular risk factors (odds ratio 1.76, 95% CI [1.16-2.69]). Conclusions: In this study, high levels of ECAS from ultrasound evidence were associated with coexisting advanced cerebral cSVD in ischemic stroke patients of suspected small or large artery origin. Further studies are required to determine if and how extracranial arterial imaging helps reduce cSVD burden or improves cognitive function.

Early changes in fibrinogen after administration of alteplase are associated with the short-term efficacy of thrombolysis.

The authors aimed to determine whether early changes in fibrinogen were associated with the efficacy of intravenous thrombolysis at 24 hours after alteplase infusion. The authors retrospectively reviewed a consecutive series of 56 patients with acute ischemic stroke treated with alteplase in the clinical database. The fibrinogen levels were monitored at the first and fourth hours after alteplase infusion. Additionally, the National Institutes of Health Stroke Scale (NIHSS) scores were recorded to define the short-term efficacy of intravenous thrombolysis before and 24 hours after alteplase infusion. The patients were distributed into amelioration, deterioration, and inefficiency groups according the short-term efficacy of intravenous thrombolysis. One-way ANOVA and post hoc analysis were used to compare the differences in the clinical characteristics among these groups. The relationships among changes in the fibrinogen levels, other potential risk factors, and NIHSS scores were examined using logistic regression analysis. Fifty-two patients (mean age, 65.71 ±â€Š11.04 years; male, 57.7%) were finally enrolled in the study. The median NIHSS of these patients was 11 (range, 2-23), and the mean time from symptom onset to thrombolysis was 187.17 ±â€Š67.53 minutes. The frequency of hypertension in the deterioration group was significantly higher than that in the inefficiency group (P = .01). Changes in the fibrinogen level were more significant in the amelioration group than in the other groups (P < .05). Logistic regression analysis revealed that changes in the fibrinogen levels between the first and fourth hours were positively associated with the short-term efficacy of alteplase infusion (odds ratio, 3.98; 95% confidence interval, 1.56-10.16; P = .004). Early changes in fibrinogen levels may be a potential predictor for the short-term efficacy of alteplase treatment in acute ischemic stroke. Additionally, these changes may be helpful for determining the short-term efficacy of alteplase treatment and early therapeutic strategies in clinical practice.