Tranexamic Acid Inhibits Hematoma Expansion in Intracerebral Hemorrhage and Traumatic Brain Injury. Does Blood Pressure Play a Potential Role? A Meta-Analysis from Randmized Controlled Trials.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent, which has shown an effect on reducing blood loss in many diseases. Many studies focus on the effect of TXA on cerebral hemorrhage, however, whether TXA can inhibit hematoma expansion is still controversial. Our meta-analysis performed a quantitative analysis to evaluate the efficacy of TXA for the hematoma expansion in spontaneous and traumatic intracranial hematoma. METHOD: Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to May 2020 for randomized controlled trials (RCTs). RESULT: We pooled 3102 patients from 7 RCTs to evaluate the efficacy of TXA for hematoma expansion. Hematoma expansion (HE) rate and hematoma volume (HV) change from baseline were used to analyze. We found that TXA led to a significant reduction in HE rate (P = 0.002) and HV change (P = 0.03) compared with the placebo. Patients with moderate or serious hypertension benefit more from TXA. (HE rate: P = 0.02, HV change: P = 0.04) TXA tends to have a better efficacy on HV change in intracerebral hemorrhage (ICH). (P = 0.06) CONCLUSIONS: TXA showed good efficacy for hematoma expansion in spontaneous and traumatic intracranial hemorrhage. Patients with moderate/severe hypertension and ICH may be more suitable for TXA administration in inhibiting hematoma expansion .

Different doses of galcanezumab versus placebo in patients with migraine and cluster headache: a meta-analysis of randomized controlled trials.

BACKGROUND: Galcanezumab is a novel monoclonal antibody that target to calcitonin gene-related peptide (CGRP). It has been tested for the preventive treatment of migraine and episodic cluster headache by multiple randomized clinical trials (RCTs) and have been found to reduce headache frequency. METHODS: We systematically searched PubMed and Embase on Cochrane Central Register of Controlled Trials (CENTRAL) from the earliest date to August 1, 2019. Relative risk (RR) and weighted mean difference (WMD) were used to evaluate clinical outcomes. RESULTS: Seven studies were pooled with 3889 patients. Subcutaneous injection of Galcanezumab at 120 mg, 240 mg leads to a statistically significant response rate for the treatment of migraine compared with placebo (120 mg: RR = 1.51; 95% CI, 1.33 to 1.70; P < 0.001; 240 mg: RR = 1.58; 95% CI, 1.43 to 1.76; P < 0.001). Among them, 120 mg group has the same treatment efficacy with 240 mg group (50% response: RR = 1.06; 95% CI, 0.92 to 1.22; P = 0.425; 75% response: RR = 1.07; 95% CI, 0.94 to 1.23; P = 0.301; 100% response; RR = 1.06; 95% CI, 0.81 to 1.37; P = 0.682; MHD: RR = - 0.08; 95% CI, - 0.55 to - 0.40; P = 0.748) while related to a lower risk for adverse events for the treatment of migraine (120 mg RR = 1.06; 95% CI, 0.99 to 1.14; P = 0.084; 240 mg: RR = 1.17; 95% CI, 1.09 to 1.25; P < 0.001). 300 mg per month galcanezumab is effective for the prevention of episodic cluster headache measured by at least 50% reduction of cluster headache frequency at week 3 (RR = 1.36; 95% CI, 1.00-1.84; P = 0.048). CONCLUSIONS: Use of galcanezumab is related to a significantly reduced monthly headache frequency compared with placebo for the treatment of migraine and episodic cluster headache, 120 mg has the same treatment efficacy with 240 mg group while related to a lower risk for adverse effects for the treatment of migraine. 300 mg per month galcanezumab is effective for the prevention of episodic cluster headache with no significantly increased adverse events.

SP140 inhibitor suppressing TRIM22 expression regulates glioma progress through PI3K/AKT signaling pathway.

BACKGROUND: SP gene family, consisting of SP100, SP110, SP140, and SP140L, has been implicated in the initiation and advancement of numerous malignancies. Nevertheless, their clinical significance in glioma remains incompletely understood. METHOD: Expression levels and prognostic significance of SP family members were evaluated in the TCGA and CGGA datasets. Multifactorial analysis was used to identify SP gene family members that can independently impact the prognosis of glioma patients. A SP140-based predictive risk model/nomogram was developed in TCGA dataset and validated in CGGA dataset. The model's performance was evaluated through receiver operating characteristic (ROC) curves, calibration plots, and decision curve analyses. Phenotypic associations of SP140 and TRIM22 were examined through CancerSEA and TIMER. The effect of SP140 inhibitor in glioma progress and TRIM22/PI3K/AKT signaling pathway was confirmed in U251/U87 glioma cells. RESULTS: The SP family members exhibited elevated expression in gliomas and were negatively correlated with prognosis. SP140 emerged as an independent prognostic factor, and a SP140-based nomogram/predictive risk model demonstrated high accuracy. SP140 inhibitor, GSK761, lead to the suppression of TRIM22 expression and the PI3K/AKT signaling pathway. GSK761 also restrain glioma proliferation, migration, and invasion. Furthermore, SP140 and TRIM22 coexpressed in glioma cells with high level of vascular proliferation, TRIM22 is closely associated with the immune cell infiltration. CONCLUSION: SP140-based nomogram proved to be a practical tool for predicting the survival of glioma patients. SP140 inhibitor could suppress glioma progress via TRIM22/PI3K/AKT signaling pathway.

Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment. We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt. METHODS: Western blot analysis, aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression. RESULTS: The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo. CONCLUSIONS: We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.

Prognostic prediction and immune checkpoint profiling in glioma patients through neddylation-associated features.

BACKGROUND: Gliomas are the most common primary malignant tumours of the central nervous system, and neddylation may be a potential target for the treatment of gliomas. Our study analysed neddylation's potential role in gliomas of different pathological types and its correlation with immunotherapy. METHODS: Genes required for model construction were sourced from existing literature, and their expression data were extracted from the TCGA and CGGA databases. LASSO regression was employed to identify genes associated with the prognosis of glioma patients in TCGA and to establish a clinical prognostic model. Biological changes in glioma cell lines following intervention with hub genes were evaluated using the CCK-8 assay and transwell assay. The genes implicated in the model construction were validated across various cell lines using Western blot. We conducted analyses to examine correlations between model scores and clinical data, tumor microenvironments, and immune checkpoints. Furthermore, we investigated potential differences in molecular functions and mechanisms among different groups. RESULTS: We identified 249 genes from the Reactome database and analysed their expression profiles in the TCGA and CGGA databases. After using LASSO-Cox, four genes (BRCA1, BIRC5, FBXL16 and KLHL25, p < 0.05) with significant correlations were identified. We selected FBXL16 for validation in in vitro experiments. Following FBXL16 overexpression, the proliferation, migration, and invasion abilities of glioma cell lines all showed a decrease. Then, we constructed the NEDD Index for gliomas. The nomogram indicated that this model could serve as an independent prognostic marker. Analysis of the tumour microenvironment and immune checkpoints revealed that the NEDD index was also correlated with immune cell infiltration and the expression levels of various immune checkpoints. CONCLUSION: The NEDD index can serve as a practical tool for predicting the prognosis of glioma patients, and it is correlated with immune cell infiltration and the expression levels of immune checkpoints.

Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression.

BACKGROUND: Glioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies. METHODS: We conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment. RESULTS: Our research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models. CONCLUSION: This study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.

ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.

Protein homeostasis is fundamental to the development of tumors. Ribosome-associated quality-control (RQC) is able to add alanine and threonine to the stagnant polypeptide chain C-terminal (CAT-tail) when protein translation is hindered, while Ankyrin repeat and zinc-finger domain-containing-protein 1 (ANKZF1) can counteract the formation of the CAT-tail, preventing the aggregation of polypeptide chains. In particular, ANKZF1 plays an important role in maintaining mitochondrial protein homeostasis by mitochondrial RQC (mitoRQC) after translation stagnation of precursor proteins targeting mitochondria. However, the role of ANKZF1 in glioblastoma is unclear. Therefore, the current study was aimed to investigate the effects of ANKZF1 in glioblastoma cells and a nude mouse glioblastoma xenograft model. Here, we reported that knockdown of ANKZF1 in glioblastoma cells resulted in the accumulation of CAT-tail in mitochondria, leading to the activated mitochondrial unfolded protein response (UPRmt) and inhibits glioblastoma malignant progression. Excessive CAT-tail sequestered mitochondrial chaperones HSP60, mtHSP70 and proteases LONP1 as well as mitochondrial respiratory chain subunits ND1, Cytb, mtCO2 and ATP6, leading to mitochondrial oxidative phosphorylation dysfunction, membrane potential impairment, and mitochondrial apoptotic pathway activation. Our study highlights ANKZF1 as a valuable target for glioblastoma intervention and provides an innovative insight for the treatment of glioblastoma through the regulating of mitochondrial protein homeostasis.

The effect of tamsulosin in postoperative urinary retention: a meta-analysis of randomized controlled trials.

Tamsulosin is a therapeutic drug of alpha-adrenergic antagonists. Previous randomized controlled trials and retrospective analyses have proved the efficacy of tamsulosin on many urinary system diseases. However, there is still a conflict about whether tamsulosin could prevent postoperative urinary retention (POUR). This meta-analysis aims to probe into the efficacy of tamsulosin for preventing POUR versus placebo. We searched MEDLINE, EMBASE, and Cochrane Library from December 31, 1999 to April 30, 2022, for randomized controlled trials (RCTs). Studies that were not RCTs or without negative controls were excluded. Cochrane Collaboration harmonized criteria were used to assess the risk of bias in included studies. Revman (version 5.3) software was invited to synthesize the results. We performed subgroup analyses to explore the factors that could influence tamsulosin's efficacy in POUR prevention. Our meta-analysis pooled 13 RCTs with 2163 patients. We concluded that tamsulosin brought about a significant reduction in the risk of POUR versus placebo (13.54% vs 20.88% for tamsulosin vs placebo, RR = 0.63, 95% CI 0.47 to 0.84, P = 0.002). Tamsulosin could significantly reduce the risk of POUR in abdominal (11.52% vs 20.25% for tamsulosin vs placebo, RR = 0.52, 95% CI 0.31 to 0.88, P = 0.02) and female pelvic surgery (15.57% vs 31.50% for tamsulosin vs placebo, RR = 0.51, 95% CI 0.31 to 0.82, P = 0.006) but not in spinal surgery (13.45% vs 12.75% for tamsulosin vs placebo, RR = 1.07, 95% CI 0.72 to 1.60, P = 0.73) and lower limb surgery (21.43% vs 33.33% for tamsulosin vs placebo, RR = 0.64, 95% CI 0.35 to 1.14, P = 0.13). The preventive effect of postoperative (17.70% vs 33.93% for tamsulosin vs placebo, RR = 0.53, 95% CI 0.33 to 0.85, P = 0.008) and postoperative with preoperative tamsulosin (13.96% vs 23.44% for tamsulosin vs placebo, RR = 0.64, 95% CI 0.43 to 0.93, P = 0.02) on POUR were significantly better than preoperative management (11.95% vs 14.63% for tamsulosin vs placebo, RR = 0.62, 95% CI 0.23 to 1.65, P = 0.34). Postoperative catheter placement appears to have a negative impact on the POUR-preventive effect of tamsulosin. (9.37% vs 16.46% for tamsulosin vs placebo, RR = 0.51, 95% CI 0.31 to 0.83, P = 0.007) Tamsulosin showed significantly effect on POUR prevention in patients during spinal (15.07% vs 26.51% for tamsulosin vs placebo, RR = 0.52, 95% CI 0.31 to 0.90, P = 0.02) and epidural anesthesia (12.50% vs 29.79% for tamsulosin vs placebo, RR = 0.42, 95% CI 0.18 to 1.00, P = 0.05) but not in general anesthesia (12.40% vs 18.52% for tamsulosin vs placebo, RR = 0.68, 95% CI 0.45 to 1.03, P = 0.07). Tamsulosin shows better outcomes for preventing POUR than placebo. Besides, tamsulosin showed a different effect on POUR prevention in the various surgical sites, anesthesia, medication management, and catheter use. However, our conclusions still have some limitations due to the lack of evidence.

APE1 regulates mitochondrial DNA damage repair after experimental subarachnoid haemorrhage in vivo and in vitro.

BACKGROUND: Subarachnoid haemorrhage (SAH) can result in a highly unfavourable prognosis. In recent years, the study of SAH has focused on early brain injury (EBI), which is a crucial progress that contributes to adverse prognosis. SAH can lead to various complications, including mitochondrial dysfunction and DNA damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein with multifaceted functionality integral to DNA repair and redox signalling. However, the role of APE1 in mitochondrial DNA damage repair after SAH is still unclear. METHODS: Our study involved an in vivo endovascular perforation model in rats and an in vitro neuron oxyhaemoglobin intervention. Then, the effects of APE1 on mitochondrial DNA damage repair were analysed by western blot, immunofluorescence, quantitative real-time PCR, mitochondrial bioenergetics measurement and neurobehavioural experiments. RESULTS: We found that the level of APE1 decreased while the mitochondria DNA damage and neuronal death increased in a rat model of SAH. Overexpression of APE1 improved short-term and long-term behavioural impairment in rats after SAH. In vitro, after primary neurons exposed to oxyhaemoglobin, APE1 expression significantly decreased along with increased mitochondrial DNA damage, a reduction in the subunit of respiratory chain complex levels and subsequent respiratory chain dysfunction. Overexpression of APE1 relieved energy metabolism disorders in the mitochondrial of neurons and reduced neuronal apoptosis. CONCLUSION: In conclusion, APE1 is involved in EBI after SAH by affecting mitochondrial apoptosis via the mitochondrial respiratory chain. APE1 may potentially play a vital role in the EBI stage after SAH, making it a critical target for treatment.

Intermittent theta-burst stimulation with physical exercise improves poststroke motor function: A systemic review and meta-analysis.

Background: Intermittent theta-burst stimulation (iTBS) is an optimized rTMS modality that could modulate the excitability of neural structures. Several studies have been conducted to investigate the efficacy of iTBS in improving the motor function of stroke patients. However, the specific role of iTBS in motor function recovery after stroke is unclear. Hence, in our study, we performed a meta-analysis to investigate the efficacy of iTBS for the motor function improvement of stroke patients. Methods: MEDLINE, Embase, and Cochrane Library were searched until May 2022 for randomized controlled trials (RCTs). Results: Thirteen RCTs with 334 patients were finally included in our study. The primary endpoints were the Fugl-Meyer assessment scale (FMA) and Motor Assessment Scale (MAS) change from baseline. We found that iTBS led to a significant reduction in FMA score (P = 0.002) but not in MAS score (P = 0.24) compared with the sham group. Moreover, standard 600-pulse stimulation showed a better effect on motor function improvement than the sham group (P = 0.004), however, 1200-pulse iTBS showed no effect on motor function improvement after stroke (P = 0.23). The effect of iTBS for improving motor function only exists in chronic stroke patients (P = 0.02) but not in subacute patients (P = 0.27). Conclusion: This study supports that iTBS has good efficacy for improving motor function in stroke patients. Therefore, standard 600-pulse stimulation iTBS therapy is proper management and treatment for chronic stroke.

GrpEL1 regulates mitochondrial unfolded protein response after experimental subarachnoid hemorrhage in vivo and in vitro.

Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke disease with high mortality and disability rates. Neurological recovery in early brain injury (EBI) after SAH is a crucial stage to reduce complications and improve the prognosis of patients. The mitochondrial unfolded protein response (UPRmt) is an essential mitochondrial damage repair process, that degrades aggresomes formed by misfolded proteins. UPRmt is a response to cellular stress and enhances mitochondrial homeostasis. GrpEL1 is a nucleotide exchange factor that assists mtHSP70 in nonnative folding proteins in mitochondria. However, the role of UPRmt and GrpEL1 after SAH is unclear. Western blot, Immunofluorescence, Aggresome staining, JC-1 staining were conducted to detect UPRmt after SAH in vivo and in vitro. The results showed that the UPRmt-related proteins HSP60 and mtHSP70 did not change in the EBI after SAH in vivo and in vitro but increased in the isolated mitochondria. In vitro primary neurons treated with oxyhemoglobin (OxyHb) achieved the same result as MG132 induction, increasing neuron protein aggresomes. The expression of GRPEL1 was unchanged in total protein and mitochondrial protein by Western blot. Co-immunoprecipitation (Co-IP) experiments showed that the GRPEL1-mtHSP70 complex decreased after OxyHb treatment. After GRPEL1 overexpression, the GRPEL1-mtHSP70 complex increased, while aggresome in neurons decreased. JC-1 showed an increased mitochondrial membrane potential, ATP content increased, and Western blot analysis revealed decreased cleaved-Caspase 9, suggesting improved mitochondrial function. In conclusion, the reduced GrpEL1-mtHSP70 complex is an essential factor affecting UPRmt in EBI after SAH. Increasing GrpEL1 promotes GrpEL1 and mtHSP70 binding, promoting the neuronal mitochondrial homeostasis, and might be an essential clinical intervention target for EBI after SAH.

Therapeutic Effect of Aerobic Exercise for Adolescents After Mild Traumatic Brain Injury and Sport-Related Concussion: A Meta-Analysis from Randomized Controlled Trials.

BACKGROUND: We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials from January 1980 to April 2018 for adolescents with mild traumatic brain injury (mTBI) to explore the value of aerobic exercise in sport-related concussion (SRC) and mTBI treatment. METHODS: A meta-analysis for the postconcussion symptom scale (PCSS) score and time to recovery was performed with STATA software. RESULTS: We found that aerobic exercise versus usual treatment significantly decreased the PCSS score (weighted mean difference = 6.51, 95% confidence interval: 0.29, 12.72; P = 0.040), as well as the time to recovery (weighted mean difference = -3.87; 95% confidence interval: -6.50, -1.23; P = 0.004). However, aerobic exercise showed no significant improvement in immediate postconcussion assessment and cognitive testing (P = 0.471/0.129/0.648/0.800, respectively, in verbal memory, visual memory, visual motor speed, and reaction time). CONCLUSIONS: Compared with usual treatment, aerobic exercise promoted mTBI adolescents' recovery, assessed by PCSS and time to recovery. However, aerobic exercise may not help with neurocognitive function recovery.

Monthly versus quarterly fremanezumab for the prevention of migraine: a systemic review and meta-analysis from randomized controlled trials.

Fremanezumab (TEV-48125) is a novel therapeutic drug for migraine prevention. Previous randomized controlled trials have proved the efficacy of fremanezumab; however, no systematic review has been performed to compare the differences between monthly and quarterly administration of fremanezumab. This meta-analysis aims to probe into the safety and efficacy of monthly fremanezumab for the prevention of migraine versus quarterly fremanezumab. We searched Pubmed, Embased, and Cochrane Library from December 1999 to December 2019 for randomized controlled trials (RCTs). Our meta-analysis finally pooled three RCTs with 1884 patients. We combined 1884 patients from three randomized controlled trials; the primary endpoint was mean monthly migraine days, from baseline to week 12. We concluded that the monthly administration of fremanezumab brought about a significant reduction in migraine days versus quarterly fremanezumab (P = 0.0008). Besides, monthly and quarterly fremanezumab have the same risk with mild and severe adverse events (P = 0.50; P = 0.39). Monthly administration of fremanezumab shows better outcomes for preventing migraines than quarterly fremanezumab and will not let to more adverse events. Patients with episodic migraine (EM) benefit more from monthly fremanezumab than patients with chronic migraine (CM).

Intraoperative indocyanine green video angiography (ICG-VA) with FLOW 800 software in complex intracranial aneurysm surgery.

BACKGROUND: Indocyanine green video angiography (ICG-VA) is a safe and effective instrument to assess changes in cerebral blood flow during cerebrovascular surgery. After ICG-VA, FLOW 800 provides a color-coded map to directly observe the dynamic distribution of blood flow and to calculate semiquantitative blood flow parameters later. The purpose of our study is to assess whether FLOW 800 is useful for surgery of complex intracranial aneurysms and to provide reliable evidence for intraoperative decision-making. METHODS: We retrospectively reviewed patients with complex aneurysms that underwent microsurgical and intraoperative evaluation of ICG-VA and FLOW 800 color-coded maps from February 2019 to May 2020. FLOW 800 data were correlated with patient characteristics, clinical outcomes, and intraoperative decision-making. RESULTS: The study included 32 patients with 42 complex aneurysms. All patients underwent ICG-VA FLOW 800 data provided semiquantitative data regarding localization, flow status in major feeding arteries; color maps confirmed relative adequate flow in parent, branching, and bypass vessels. CONCLUSIONS: FLOW 800 is a useful supplement to ICG-VA for intraoperative cerebral blood flow assessment. ICG-VA and FLOW 800 can help to determine the blood flow status of the parent artery after aneurysm clipping and the bypass vessels after aneurysm bypass surgery.

Lasmiditan for Acute Treatment of Migraine in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The US Food and Drug Administration has approved orally administered 100-mg and 200-mg doses of lasmiditan for the acute treatment of migraine, with or without aura. Having a unique mechanism of action, lasmiditan is the first and only Food and Drug Administration-approved serotonin 5-HT1F receptor agonist. OBJECTIVE: The objective of this study was to systematically evaluate the efficacy and safety of lasmiditan for the acute treatment of migraine in adult patients. METHODS: We systematically searched PUBMED, EMBASE, and Cochrane Library databases. Any relevant articles published before 3 March, 2020 were collected. Inclusion criteria were: (1) randomized clinical trials; (2) enrolled adult participants diagnosed with migraine; (3) compared lasmiditan at 100 mg or 200 mg with placebo; (4) enrolled more than 100 participants; and (5) provided any available data for predefined primary or secondary outcomes. RESULTS: Three high-quality, multi-centered randomized clinical trials with 4506 patients in total were included. We found that the use of lasmiditan was related to a significantly increased rate of pain freedom at 2 h post-dose with 31.60% patients achieving freedom of pain in the lasmiditan group compared with 17.55% patients in the placebo group (relative risk [RR] 1.80 [95% confidence interval (CI) 1.34-2.42]), with no significant heterogeneity. In addition, lasmiditan is reported to significantly increase the rate of absence of the most bothersome symptoms at 2 h compared with the placebo group with no significant heterogeneity (lasmiditan, 42.82%; placebo, 30.38%; RR 1.44 [95% CI 1.03-2.01], I2 = 0%). With regard to the safety endpoints, compared with the placebo group, participants in the lasmiditan group had a higher rate of fatigue, paresthesia, and somnolence (fatigue: lasmiditan, 1.94%; placebo, 0.24%; RR 7.96 [95% CI 0.4-158.86]; paresthesia: lasmiditan, 6.91%; placebo, 1.56%; RR 4.46 [95% CI 1.54-12.93], somnolence: lasmiditan, 5.9%; placebo, 2.15%; RR 2.76 [95% CI, 1.49-5.11]) with low heterogeneity. A subgroup analysis demonstrated that without safety differences, participants who received the 200-mg dose had a higher percentage of freedom of pain at 2 h and sustained pain relief at 2-24 h compared with the 100-mg dose (freedom of pain at 2 h: lasmiditan, 34.53%; placebo, 28.67%; RR 1.2 [95% CI 1.04-1.38]; lasmiditan, 20.62%; placebo, 16.33%; RR 1.26 [95% CI 1.19-1.34]), with low heterogeneity for both outcomes (I2 = 0%). CONCLUSIONS: In this meta-analysis, the use of lasmiditan as an acute treatment for episodic migraine in adults led to a greater percentage of freedom of pain and the absence of the most bothersome symptoms at 2 h post-dose. Lasmiditan 200 mg had superior efficacy to 100-mg dose without a significantly increased risk for adverse events.

Efficacy and Safety of Monoclonal Antibody Therapy in Neuromyelitis Optica Spectrum Disorders: Evidence from Randomized Controlled Trials.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory disorders in central nervous system (CNS) characterized by symptoms of optic nerve, spinal cord, brainstem and cerebrum injuries. Recent studies have shown that monoclonal antibodies (Rituximab, Eculizumab, Inebilizumab, Satralizumab, etc.) were effective for the treatment of NMOSD. We performed a meta-analysis to evaluate the efficacy and safety of these monoclonal antibodies in NMOSD. METHODS: The MEDLINE, EMBASE, Central Register of Controlled Trials (CENTRAL) and clinicaltrials.gov database were searched for randomized controlled trials (RCTs) which had assessed the therapy of monoclonal antibody in NMOSD patients. RESULTS: We pooled 524 (monoclonal antibody group, n = 344 and placebo group, n = 180) from 4 RCTs and 444 patients (84.7%) were AQP4-IgG seropositive. Monoclonal antibody therapy reduced annualized relapse rate (mean -0.27, 95% CI, -0.36 to -0.18, P <0.0001), on-trial relapse risk (RR 0.25, 95% CI 0.12 to 0.52, P = 0.0003), EDSS (Expanded disability status scale) score (mean -0.51, 95% CI, -0.92 to -0.11, P = 0.01) and serious adverse events (RR 0.59, 95% CI 0.37 to 0.96, P = 0.03) but didn't show any significant differences in total adverse events or mortality. In the subgroup analysis, we found that comparing with other monoclonal antibodies, Eculizumab might be more effective in decreasing on-trial relapse risk (Chi2 =9.84, P =0.002) for AQP-4 positive patients. CONCLUSIONS: Monoclonal antibody therapy was effective and safe in NMOSD treatment. More RCTs were expected to assess monoclonal antibodies in NMOSD.

Safety and Efficacy of Fremanezumab for the Prevention of Migraine: A Meta-Analysis From Randomized Controlled Trials.

Background: Fremanezumab (TEV-48125) is a fully-humanized immunoglobulin G isotype 2a selective monoclonal antibody that potently binds to calcitonin gene-related peptide (CGRP). It is one of the novel therapeutic drugs for the prevention of migraine, which is one of the most common neurological diseases worldwide. Several controlled trials have been conducted to investigate the safety and efficacy of fremanezumab, however, there is no systematic review of the existing literature has been performed. Hence, in our study, we performed a meta-analysis to investigate the safety and efficacy of fremanezumab for the prevention of migraine. Method: Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to August 2019 for randomized controlled trials (RCTs). Five RCTs with 3,379 patients were finally included in our study. Result: We pooled 3,379 patients from 5 RCTs; the primary endpoints were mean monthly migraine and headache days, baseline to week 12. We found that fremanezumab led to a significant reduction in migraine days (P < 0.0001) and headache days (P < 0.0001) during 12 weeks compared with placebo. Moreover, after using fremanezumab, the risk of at least one adverse event (AE) (P = 0.001) and AE related to the trial regimen (P = 0.0005) significantly increased compared with the placebo. Conclusions: Fremanezumab showed good efficacy for the prevention of migraine. The administration of fremanezumab can cause some mild adverse events but no serious adverse events.

Safety and Efficacy of Ubrogepant for the Acute Treatment of Episodic Migraine: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Ubrogepant is a small molecular calcitonin gene-related peptide receptor antagonist that is used for the acute treatment of migraine. OBJECTIVE: The aim was to conduct a meta-analysis to systematically evaluate the efficacy and safety of ubrogepant for the treatment of episodic migraine compared with placebo in the adult population. METHODS: We systematically searched PubMed, EMBASE, and the Cochrane Library Central Register of Controlled Trials for relevant randomized clinical trials, from the earliest available date to November 10, 2019, to evaluate the efficacy and safety of short-term ubrogepant use. Inclusion criteria were (1) randomized clinical trial; (2) enrolled adult participants diagnosed with episodic migraine; (3) compared ubrogepant with placebo at doses that were evaluated in phase III clinical trials; (4) enrolled more than 100 patients in each group; and (5) provided any information on primary or secondary outcomes. Trials were excluded if their participants were diagnosed with chronic migraine. RESULTS: A total of three multicenter, randomized clinical trials with 3326 patients were included. Ubrogepant use was associated with a significantly higher percentage of patients with pain freedom (ubrogepant 20.8%; placebo 12.6%; relative risk [RR] 1.65, 95% confidence interval [CI] 1.38-1.98) and absence of the most bothersome migraine-associated symptoms (ubrogepant 37.3%; placebo 27.6%; RR 1.35, 95% CI 1.20-1.53) at 2 h post-dose compared with placebo. Ubrogepant increased the rate of absence of migraine-associated symptoms at 2 h post-dose compared with placebo (photophobia: RR 1.30 [95% CI 1.18-1.44], I2 = 49%; phonophobia: RR 1.20 [95% CI 1.11-1.29]; nausea: RR 1.07 [95% CI 1.02-1.13]), and patients were more likely to function normally at 2 h post-dose compared with placebo (RR 1.30 [95% CI 1.16-1.45]). No significant difference was found for treatment-related adverse events within 48 h or 30 days for ubrogepant compared with placebo (48 h: RR 1.07 [95% CI 0.85-1.35]; 30 days: RR 1.03 [95% CI 0.79-1.34]). Subgroup analysis demonstrated that compared to placebo, ubrogepant led to greater rates of freedom from pain at 2 h with 25-mg, 50-mg, and 100-mg doses and absence of the most bothersome symptoms with 50-mg and 100-mg doses. CONCLUSIONS: The use of ubrogepant as an acute treatment of episodic migraine in adults led to a greater percentage of freedom from pain and absence of the most bothersome symptoms at 2 h post-dose. Short-term use of ubrogepant was not related to an increased risk for adverse events. Further studies are needed to evaluate efficacy and safety for long-term use and in specific subgroups of patients.

COVID-19 Associated Ischemic Stroke and Hemorrhagic Stroke: Incidence, Potential Pathological Mechanism, and Management.

The outbreak of the novel coronavirus infectious disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has rapidly spread around the world. Increasing evidence has suggested that patients with COVID-19 may present neurological symptoms, and cerebrovascular diseases are one of the most frequent comorbidities. The markedly elevated D-dimer levels in patients with acute ischemic stroke suggests that SARS-CoV-2 infection may induce an inflammatory response and trigger a hypercoagulation state, thus leading to acute ischemic stroke. Cardioembolism and atherosclerosis in patients with COVID-19 infection may also increase the risk of ischemic stroke. The reduction of the angiotensin-converting enzyme II (ACE2) caused by SARS-CoV-2 binding to the ACE2 receptor can lead to abnormally elevated blood pressure and increase the risk of hemorrhagic stroke. Additionally, the cytokine storm induced by the immune response against the viral infection increases the risk of acute stroke. The management for COVID-19 patients with stroke is not only based on the traditional guidelines, but also based on the experience and new instructions from healthcare workers worldwide who are combatting COVID-19.

A new scoring system for predicting extent of resection in medial sphenoid wing meningiomas based on three-dimensional multimodality fusion imaging.

BACKGROUND: Three-dimensional (3D) fusion imaging has been proved to be a promising neurosurgical tool for presurgical evaluation of tumor removal. We aim to develop a scoring system based on this new tool to predict the resection grade of medial sphenoid wing meningiomas (mSWM) intuitively. METHODS: We included 46 patients treated for mSWM from 2014 to 2019 to evaluate their tumors' location, volume, cavernous sinus involvement, vascular encasement, and bone invasion by 3D multimodality fusion imaging. A scoring system based on the significant parameters detected by statistical analysis was created and evaluated. RESULTS: The tumor volumes ranged from 0.8 cm3 to 171.9 cm3. A total of 39 (84.8%) patients had arterial involvement. Cavernous sinus (CS) involvement was observed in 23 patients (50.0%) and bone invasion was noted in 10 patients (21.7%). Simpson I resection was achieved in 10 patients (21.7%) and Simpson II resection was achieved in 17 patients (37.0%). Fifteen patients (32.6%) underwent Simpson III resection and 4 patients (8.7%) underwent Simpson IV resections. A scoring system was created. The score ranged from 1 to 10 and the mean score of our patients was 5.3 ± 2.8. Strong positive monotonic correlation existed between the score and resection grade (Rs = 0.772, P < 0.001). The scoring system had good predictive capacity with an accuracy of 69.60%. CONCLUSIONS: We described a scoring system that enabled neurosurgeons to predict extent of resection and outcomes for mSWM preoperatively with 3D multimodality fusion imaging. TRIAL REGISTRATION: Retrospectively registered.