Clopidogrel Plus Aspirin vs Aspirin Alone in Patients With Acute Mild to Moderate Stroke: The ATAMIS Randomized Clinical Trial.

Importance: Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking. Objective: To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke. Design, Setting, and Participants: This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome. Interventions: Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio. Main Outcomes and Measures: The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points. Results: Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference -1.9%; 95% CI, -3.6 to -0.2; P = .03). Similar bleeding events were found between 2 groups. Conclusions and Relevance: Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT02869009.

Correction to: Gamma-band-based dynamic functional connectivity in pigeon entopallium during sample presentation in a delayed color matching task.

[This corrects the article DOI: 10.1007/s11571-022-09916-w.].

Gamma-band-based dynamic functional connectivity in pigeon entopallium during sample presentation in a delayed color matching task.

Birds have developed visual cognitions, especially in discriminating colors due to their four types of cones in the retina. The entopallium of birds is thought to be involved in the processing of color information during visual cognition. However, there is a lack of understanding about how functional connectivity in the entopallium region of birds changes during color cognition, which is related to various input colors. We therefore trained pigeons to perform a delayed color matching task, in which two colors were randomly presented in sample stimuli phrases, and the neural activity at individual recording site and the gamma band functional connectivity among local population in entopallium during sample presentation were analyzed. Both gamma band energy and gamma band functional connectivity presented dynamics as the stimulus was presented and persisted. The response features in the early-stimulus phase were significantly different from those of baseline and the late-stimulus phase. Furthermore, gamma band energy showed significant differences between different colors during the early-stimulus phase, but the global feature of the gamma band functional network did not. Further decoding results showed that decoding accuracy was significantly enhanced by adding functional connectivity features, suggesting the global feature of the gamma band functional network did not directly contain color information, but was related to it. These results provided insight into information processing rules among local neuronal populations in the entopallium of birds during color cognition, which is important for their daily life.

Detection of a temporal salient object benefits from visual stimulus-specific adaptation in avian midbrain inhibitory nucleus.

Food and predators are the most noteworthy objects for the basic survival of wild animals, and both are often deviant in both spatial and temporal domains and quickly attract an animal's attention. Although stimulus-specific adaptation (SSA) is considered a potential neural basis of salient sound detection in the temporal domain, related research on visual SSA is limited and its relationship with temporal saliency is uncertain. The avian nucleus isthmi pars magnocellularis (Imc), which is central to midbrain selective attention network, is an ideal site to investigate the neural correlate of visual SSA and detection of a salient object in the time domain. Here, the constant order paradigm was applied to explore the visual SSA in the Imc of pigeons. The results showed that the firing rates of Imc neurons gradually decrease with repetitions of motion in the same direction, but recover when a motion in a deviant direction is presented, implying visual SSA to the direction of a moving object. Furthermore, enhanced response for an object moving in other directions that were not presented ever in the paradigm is also observed. To verify the neural mechanism underlying these phenomena, we introduced a neural computation model involving a recoverable synaptic change with a "center-surround" pattern to reproduce the visual SSA and temporal saliency for the moving object. These results suggest that the Imc produces visual SSA to motion direction, allowing temporal salient object detection, which may facilitate the detection of the sudden appearance of a predator.

Corrigendum: Corynebacterium accolens inhibits Staphylococcus aureus induced mucosal barrier disruption.

[This corrects the article DOI: 10.3389/fmicb.2022.984741.].

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial.

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.

Correlation between Pneumatization Variants of Paranasal Sinuses and Skull Base and Spontaneous Cerebrospinal Fluid Rhinorrhea: A Case-Control Study.

INTRODUCTION: Spontaneous cerebrospinal fluid rhinorrhea (SCSFR) is the most common type of cerebrospinal fluid leakage and may cause serious cerebral complications. The aim of this research was to investigate the relationship between the degree of pneumatization variants of the paranasal sinus and skull base and the incidence of SCSFR. METHODS: In total, 131 patients with SCSFR were analyzed, and 50 patients suffering from the nasal septal deviation were selected as controls. The pneumatization of the paranasal sinus and skull base was observed by CT scan. RESULTS: Among the 137 fistulas, 55 (40.15%) were found in the ethmoid sinus. The incidences of Onodi cells (27.27 vs. 8%) and type 3 lateral recess of the sphenoid sinus (LRSS, 70.37 vs. 22%) in the SCSFR subgroups were significantly higher than those in the control group (p < 0.05). Moreover, the occurrence of SCSFR was linearly correlated with the classification of Onodi cells and LRSS (p < 0.05). There was no significant difference in the incidence of frontal cells, anterior clinoid process pneumatization, and posterior clinoid process pneumatization between the SCSFR patients and the controls. CONCLUSION: The most common site of SCSFR is the ethmoid sinus. The excessive pneumatization of the Onodi cell and LRSS increases the risk for the occurrence of SCSFR in the ethmoid sinus and sphenoid sinus, respectively. The possible association between the paranasal sinus ontogeny and SCSFR pathophysiology needs further studies.

Corynebacterium accolens inhibits Staphylococcus aureus induced mucosal barrier disruption.

Background: Corynebacterium accolens (C. accolens) is a common nasal colonizer, whereas Staphylococcus aureus (S. aureus) is typically regarded a pathogenic organism in patients with chronic rhinosinusitis (CRS). This study aims to evaluate the interaction of the two bacteria in vitro. Methods: Clinical isolates of C. accolens and S. aureus from sinonasal swabs, as well as primary human nasal epithelial cells (HNECs) cultured from cellular brushings of both healthy and CRS patients were used for this study. The cell-free culture supernatants of all isolates grown alone and in co-cultures were tested for their effects on transepithelial electrical resistance (TER), FITC-Dextran permeability, lactate dehydrogenase (LDH), and IL-6 and IL-8 secretion of HNECs. Confocal scanning laser microscopy and immunofluorescence were also used to visualize the apical junctional complexes. C. accolens cell-free culture supernatants were also tested for antimicrobial activity and growth on planktonic and biofilm S. aureus growth. Results: The cell-free culture supernatants of 3\C. accolens strains (at 60% for S. aureus reference strain and 30% concentration for S. aureus clinical strains) inhibited the growth of both the planktonic S. aureus reference and clinical strains significantly. The C. accolens cell-free culture supernatants caused no change in the TER or FITC-Dextran permeability of the HNEC-ALI cultures, while the cell-free culture supernatants of S. aureus strains had a detrimental effect. Cell-free culture supernatants of C. accolens co-cultured with both the clinical and reference strains of S. aureus delayed the S. aureus-dependent mucosal barrier damage in a dose-dependent manner. Conclusion: Corynebacterium accolens cell-free culture supernatants appear to inhibit the growth of the S. aureus planktonic bacteria, and may reduce the mucosal barrier damage caused by S. aureus.

Visual Responses to Moving and Flashed Stimuli of Neurons in Domestic Pigeon (Columba livia domestica) Optic Tectum.

Birds can rapidly and accurately detect moving objects for better survival in complex environments. This visual ability may be attributed to the response properties of neurons in the optic tectum. However, it is unknown how neurons in the optic tectum respond differently to moving objects compared to static ones. To address this question, neuronal activities were recorded from domestic pigeon (Columba livia domestica) optic tectum, responsible for orienting to moving objects, and the responses to moving and flashed stimuli were compared. An encoding model based on the Generalized Linear Model (GLM) framework was established to explain the difference in neuronal responses. The experimental results showed that the first spike latency to moving stimuli was smaller than that to flashed ones and firing rate was higher. The model further implied the faster and stronger response to a moving target result from spatiotemporal integration process, corresponding to the spatially sequential activation of tectal neurons and the accumulation of information in time. This study provides direct electrophysiological evidence about the different tectal neuron responses to moving objects and flashed ones. The findings of this investigation increase our understanding of the motion detection mechanism of tectal neurons.

Surround Modulation Properties of Tectal Neurons in Pigeons Characterized by Moving and Flashed Stimuli.

Surround modulation has been abundantly studied in several mammalian brain areas, including the primary visual cortex, lateral geniculate nucleus, and superior colliculus (SC), but systematic analysis is lacking in the avian optic tectum (OT, homologous to mammal SC). Here, multi-units were recorded from pigeon (Columba livia) OT, and responses to different sizes of moving, flashed squares, and bars were compared. The statistical results showed that most tectal neurons presented suppressed responses to larger stimuli in both moving and flashed paradigms, and suppression induced by flashed squares was comparable with moving ones when the stimuli center crossed the near classical receptive field (CRF) center, which corresponded to the full surrounding condition. Correspondingly, the suppression grew weaker when the stimuli center moved across the CRF border, equivalent to partially surrounding conditions. Similarly, suppression induced by full surrounding flashed squares was more intense than by partially surrounding flashed bars. These results suggest that inhibitions performed on tectal neurons appear to be full surrounding rather than locally lateral. This study enriches the understanding of surround modulation properties of avian tectum neurons and provides possible hypotheses about the arrangement of inhibitions from other nuclei, both of which are important for clarifying the mechanism of target detection against clutter background performed by avians.

ISMN-loaded PLGA-PEG nanoparticles conjugated with anti-Staphylococcus aureus α-toxin inhibit Staphylococcus aureus biofilms in chronic rhinosinusitis.

Background:Staphylococcus aureus biofilms were linked to negative postsurgical outcomes of chronic rhinosinusitis (CRS). This study aims to develop a targeted nanoparticle and characterize its bactericidal effects. Methods: The authors prepared ISMN-loaded poly-lactide-co-glycolide acid (PLGA) and polyethylene glycol (PEG) nanoparticles conjugated with anti-S. aureus α-toxin (AA; ISMN-PLGA-PEG-AA), and determined its bactericidal and toxic effects. The antibiofilm propriety of ISMN-PLGA-PEG-AA was further investigated in a sheep CRS model. Results: ISMN-PLGA-PEG-AA had no toxic effect, while ISMN, ISMN-PLGA-PEG and ISMN-PLGA-PEG-AA had significantly anti-S. aureus effects. The blood concentrations and mRNA levels in sinus tissues of IL-4, IL-8 and IFN-γ in the sheep CRS model were significantly low. Conclusion: ISMN-PLGA-PEG-AA can effectively inhibit S. aureus biofilm, and is a promising drug for CRS treatment.

Long non-coding RNA nuclear paraspeckle assembly transcript 1 promotes activation of T helper 2 cells via inhibiting STAT6 ubiquitination.

T helper (Th) 2 cell-medicated immune response participates in various immune diseases, including systemic lupus erythematosus (SLE). Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be associated with T helper 2 (Th2) cell activation. Here, we demonstrated the molecular mechanism of NEAT1 in regulating Th2 cell activation. We found that NEAT1 was located in nucleus. NEAT1 overexpression promoted the levels of Th2-related cytokines IL-4, IL-5 and IL-13 in CD4+ T cells. Moreover, NEAT1 up-regulation reduced Th1-related cytokine INF-γ production and enhanced the levels of Th17-related cytokines IL-17 in CD4+ T cells. STAT6 deficiency reduced the levels of IL-4, IL-5, IL-13 and IL-17 enhanced the levels of INF-γ in CD4+ T cells, which was rescued by NEAT1 overexpression. Moreover, NEAT1 promoted STAT6 protein expression, whereas NEAT1 had no effect on the expression of STAT6 mRNA. Furthermore, NEAT1 interacted with STAT6, inhibited the ubiquitination of STAT6 in CD4+ T cells. In conclusion, our work has confirmed that NEAT1 promotes STAT6 expression by inhibiting STAT6 ubiquitination, thereby promoting Th2 cell activation. Thus, our work may highlight novel insights into the molecular mechanism of NEAT1 in regulating Th2 cell activation.

Comparison of pop-out responses to luminance and motion contrasting stimuli of tectal neurons in pigeons.

The emergence of visual saliency has been widely studied in the primary visual cortex and the superior colliculus (SC) in mammals. There are fewer studies on the pop-out response to motion direction contrasting stimuli taken in the optic tectum (OT, homologous to mammalian SC), and these are mainly of owls and fish. To our knowledge the influence of spatial luminance has not been reported. In this study, we have recorded multi-units in pigeon OT and analyzed the tectal response to spatial luminance contrasting, motion direction contrasting, and contrasting stimuli from both feature dimensions. The comparison results showed that 1) the tectal response would pop-out in either motion direction or spatial luminance contrasting conditions. 2) The modulation from motion direction contrasting was independent of the temporal luminance variation of the visual stimuli. 3) When both spatial luminance and motion direction were salient, the response of tectal neurons was modulated more intensely by motion direction than by spatial luminance. The phenomenon was consistent with the innate instinct of avians in their natural environment. This study will help to deepen the understanding of mechanisms involved in bottom-up visual information processing and selective attention in the avian.

Assessment of three types of intranasal nebulization devices in three-dimensional printed models and volunteers: a pilot study.

BACKGROUND: Intranasal nebulization is an effective treatment for chronic rhinosinusitis and allergic rhinitis; however, terminal inhalation devices have not been fully studied. We compared the sinonasal aerosol distributions and adverse effects of different inhalation units. METHODS: A mask, double-head nozzle, and single-head nozzle were applied to atomize the methylene blue solution to 3-dimensional printed models of the pediatric nasal cavity, adult nasal cavity with septal deviation, and postsurgical paranasal sinuses, and staining of the different sites was scored. Volunteers received nebulization of normal saline via different devices; thereafter, the adverse effects were assessed using the visual analogue scale (VAS). RESULTS: After nebulization, the staining scores for the middle turbinate and middle meatus of the pediatric and adult nasal cavity models and the score for the anterior ethmoid sinus of the sinus model with the single-head nozzle were significantly higher than those with the mask and double-head nozzle (all p < 0.05; η2 for effect size estimates were above 0.68). Among the 31 volunteers, the adverse effects, including nasal irritation, facial pressure/pain, ear fullness/pain, postnasal drip, and throat irritation/cough, were mild. The variations in the incidence and VAS scores of the adverse effects among the devices were not significant (all p > 0.05). CONCLUSION: The single-head nozzle was the most effective device in aerosol delivery to the lateral wall of the nasal cavity and sinuses; conversely, the mask yielded limited sinonasal deposition. Intranasal nebulization was well tolerated, and the adverse effects among the devices were comparable. These findings are meaningful for selecting and developing inhalation units.

NEAT1 regulates Th2 cell development by targeting STAT6 for degradation.

The aim of this study was to investigate the role of lncRNA NEAT1 (nuclear enriched abundant transcript 1) in regulating Th2 cell differentiation. The overexpression vectors of NEAT1 and ITCH, and siRNA targeting NEAT1, EZH2 (enhancer of zeste homolog 2) and STAT6 (signal transducer and activator of transcription 6) were transfected into CD4+T cells. The mRNA expressions of ITCH and STAT6 were analyzed by qRT-PCR and western blotting. The levels of Th2 cytokines were detected by ELISA assay. RIP and ChIP assays were performed to analyze the association between NEAT1 and EZH2 as well as EZH2 and STAT6, respectively. Results showed that NEAT1 significantly repressed ITCH expression and increased STAT6 expression as well as the levels of IL-4, IL-5 and IL-13 in CD4+T cells. RIP and ChIP assays revealed that NEAT1 bound to EZH2 and EZH2 was recruited to the promoter region of ITCH in CD4+T cells. Silencing EZH2 significantly promoted STAT6 for ubiquitination. Furthermore, NEAT targeted STAT6 for ubiquitination and elevated levels of Th2 cytokines by regulating EZH2/ITCH axis. In conclusion, our data indicated that NEAT1 promotes Th2 cell differentiation through the EZH2/ITCH/STAT6 axis.

Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits.

AIM: To investigate the pharmacokinetics and distributions of bevacizumab by intravitreal injection of prepared bevacizumab-poly (L-lactic-co-glycolic acid) (PLGA) microspheres in rabbits, to provide evidence for clinical application of this kind of bevacizumab sustained release dosage form. METHODS: Bevacizumab was encapsulated into PLGA microsphere via the solid-in-oil-in-hydrophilic oil (S/O/hO) method. Fifteen healthy New Zealand albino-rabbits were used in experiments. The eyes of each rabbit received an intravitreal injection. The left eyes were injected with prepared bevacizumab-PLGA microspheres and the right eyes were injected with bevacizumab solution. After intravitreal injection, rabbits were randomly selected at days 3, 7, 14, 28 and 42 respectively, three animals each day. Then we used immunofluorescence staining to observe the distribution and duration of bevacizumab in rabbit eye tissues, and used the sandwich ELISA to quantify the concentration of free bevacizumab from the rabbit aqueous humor and vitreous after intravitreal injection. RESULTS: The results show that the concentration of bevacizumab in vitreous and aqueous humor after administration of PLGA formulation was higher than that of bevacizumab solution. The T1/2 of intravitreal injection of bevacizumab-PLGA microspheres is 9.6d in vitreous and 10.2d in aqueous humor, and the T1/2 of intravitreal injection of soluble bevacizumab is 3.91d in vitreous and 4.1d in aqueous humor. There were statistical significant difference for comparison the results of the bevacizumab in vitreous and aqueous humor between the left and right eyes (P<0.05). The AUC0-t of the sustained release dosage form was 1-fold higher than that of the soluble form. The relative bioavailability was raised significantly. The immunofluorescence staining of PLGA-encapsulated bevacizumab (b-PLGA) in rabbit eye tissues was still observed up to 42d. It was longer than that of the soluble form. CONCLUSION: The result of this study shows the beneficial effects of PLGA in prolonging the residency of bevacizumab in the vitreous. And the drug delivery system may have potential as a treatment modality for related disease.

Lack of association between vitamin D receptor gene FokI and BsmI polymorphisms and prostate cancer risk: an updated meta-analysis involving 21,756 subjects.

The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of vitamin D. The polymorphisms in the VDR gene have been hypothesized to alter the risk of prostate cancer. However, studies investigating the association between VDR polymorphisms (BsmI and FokI) and prostate cancer (PCa) risk report conflicting results , therefore, we conducted a meta-analysis to re-examine the controversy. Published literatures from PubMed, Embase, Google Scholar, and China National Knowledge Infrastructure (CNKI) were searched (updated to March 9, 2013). According to our inclusion criteria, studies that observed the association between VDR BsmI and FokI polymorphisms and PCa risk were included. The principal outcome measure was the odds ratio (OR) with 95 % confidence interval (CI) for PCa risk associated with VDR BsmI and FokI polymorphisms. Thirty-four studies involving 10,267 cases and 11,489 controls were recruited. Overall, we did not find evidence to support an association between any of the VDR polymorphisms and PCa risk. For BsmI, the pooled OR was 0.894 (95 % CI 0.773 to 1.034) for the Bb vs. bb genotypes, 1.002 (95 % CI 0.869 to 1.157) for the BB vs. bb genotypes, 0.922 (95 % CI 0.798 to 1.065) for the dominant model (BB/Bb vs. bb), and 1.018 (95 % CI 0.936 to 1.107) for the recessive model (BB vs. Bb/bb). ORs for the FokI polymorphisms were similar. The results suggest that the VDR BsmI and FokI polymorphisms are not related to PCa risk. Further large and well-designed studies are required to confirm this conclusion.