SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 'highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19.

Comparison of 4 mm-sized and 3 mm-sized Stent Retrievers in Mechanical Thrombectomy for M2 Occlusion.

INTRODUCTION: A stent retriever (SR) is widely used in mechanical thrombectomy (MT) for M2 segment occlusion. However, the suitable size of SR in M2 occlusion remains unclear. Therefore, we aimed to compare 4 mm-sized SR with 3 mm-sized SR in M2 occlusion. METHODS: Patients who underwent MT with SR for M2 occlusion were dichotomized into 4×20 mm SR and 3×20 mm SR groups. Then, 1:1 propensity score matching was performed. The M2 segment was divided into proximal and distal segments according to the occlusion site. Subgroup analysis was then performed for each cohort. RESULTS: A total of 111 patients were enrolled, with 4×20 mm SR and 3×20 mm SR applied in 72 (64.9%) and 39 (35.1%) cases, respectively. In propensity score matching, mean number of stent passages for reperfusion was significantly lower in the 4×20 mm SR group than in the 3×20 mm SR group (1.5 ± 0.8 vs. 2.1 ± 1.1; p = 0.004). First-pass reperfusion (FPR) was more highly achieved in the 4×20 mm SR group than in the 3×20 mm SR group (52.6% vs. 42.1%; p = 0.007). In both proximal and distal occlusion cohorts, the 4 mm SR group showed lower mean number of SR passage (p = 0.004 and p =0.003, respectively) and higher FPR rate than the 3 mm SR group (p = 0.003 and p = 0.007, respectively). CONCLUSION: In MT for M2 occlusion, 4×20 mm SR enables an effective procedure with lesser SR passage for reperfusion and a higher rate of FPR than 3×20 mm SR.

Predictors of Emboli in Mechanical Thrombectomy for Anterior Circulation Stroke.

OBJECTIVE: Emboli commonly occurs in mechanical thrombectomy (MT). The objective of this study was to analyze predicting factors of emboli after MT. METHODS: Patients who underwent MT with successful reperfusion for anterior circulation occlusion were enrolled. Emboli included distal emboli at digital subtraction angiography (DSA) and unexpected embolic infarct on diffusion-weighted image (DWI) without distal emboli at DSA. Baseline characteristics, procedural details, angiographic outcomes, and clinical outcomes were reviewed. Multivariable analyses were performed to evaluate predictive factors for the occurrence of emboli. RESULTS: Of 601 patients, 149 (24.8%) patients had distal emboli at DSA, and 169 (28.1%) patients had unexpected embolic infarction on DWI even without distal emboli at DSA. A total of 318 (52.9%) patients were enrolled in the embolic group, and 283 (47.1%) patients were assigned to the non-embolic group. In multivariate analysis, larger microcatheter (OR 1.26, 95% CI 1.12-1.94; p = 0.047), clot passage (OR 1.33, 95% CI 1.07-1.87; p = 0.041), use of balloon guide catheter (BGC) (OR 0.70, 95% CI 0.52-0.92; p = 0.014), early ballooning of BGC (OR 0.68, 95% CI 0.50-0.90; p = 0.009), and longer stent retriever (OR 0.72, 95% CI 0.54-0.90; p = 0.029) were associated with occurrence of emboli. CONCLUSION: MT with only a stent retriever, use of a larger microcatheter, and clot passage might increase the risk of emboli. In contrast, contact aspiration thrombectomy, use of BGC, early ballooning of BGC, and use of longer stent retrievers could reduce the chance of emboli.

Dynamic changes of systemic inflammation response index and systemic immune-inflammation index are associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Delayed cerebral ischemia (DCI) is a factor contributing to poor outcome of aneurysmal subarachnoid hemorrhage (aSAH). Serial inflammatory response is known to affect the occurrence of DCI. The aim of this study was to evaluate associations of dynamic changes of various inflammatory markers with occurrence of DCI after aSAH. METHODS: A total of 279 patients with interventional treatment for aSAH were enrolled, and dichotomized according to the occurrence of DCI. Various inflammatory markers, including systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and their dynamic changes were analyzed at four different time points. Receiver operating characteristic (ROC) curve analysis with area under the curve (AUC) and univariate, multivariate Cox regression analyses with hazard ratio (HR) and 95 % confidence interval (CI) were performed to identify predictors for DCI. RESULTS: Differences of SII and SIRI values between DCI (+) and DCI (-) group were significantly higher at 5-7 days than at other time points (P < 0.001 and P < 0.001, respectively). SII and SIRI had higher predicting values for DCI occurrence than other inflammatory markers (AUC: 0.862, 95 % CI: 0.786-0.928; P < 0.001 and AUC: 0.851, 95 % CI: 0.769-0.913; P < 0.001, respectively). SII at 5-7 days (HR: 1.74, 95 % CI: 1.38-3.22, P = 0.020) and SIRI at 5-7 days (HR: 1.62, 95 % CI: 1.28-2.84, P = 0.035) were associated with occurrence of DCI. CONCLUSIONS: Dynamic changes of SII and SII might be predictors of DCI occurrence in patients with aSAH.

Pan-immune-inflammation value predict delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage.

Inflammatory reaction and immune dysregulation are known as components contributing to delayed cerebral ischemia (DCI) in patients with following aneurysmal subarachnoid hemorrhage (aSAH). The objective of this study was to investigate the role of pan-immune-inflammation value (PIV) as a novel comprehensive inflammatory marker in predicting the DCI development following aSAH. A total of 1028 participants with aSAH were enrolled. There were 296 patients with DCI and 732 patients without DCI. Various inflammatory markers were analyzed using peripheral blood sample obtained at admission. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff value of PIV for distinguishing DCI. Multivariate analysis was used to determine independent predictors for DCI. Mean PIV was significantly higher in the DCI (+) group than in the DCI (-) group (437.6 ± 214.7 vs 242.1 ± 154.7, P = 0.007). In ROC analysis, the optimal cutoff value of PIV was 356.7 for predicting DCI (area under the curve [AUC] 0.772, 95 % confidence interval [CI] 0.718-0.816; P < 0.001). Multivariate analysis showed that high Hunt-Hess grade (odds ratio [OR] 1.70, 95 % CI 1.38-2.22; P = 0.007), thick SAH (OR 1.82, 95 % CI 1.44-2.32; P = 0.005), and elevated PIV (≥356.7) (OR 1.42, 95 % CI 1.10-1.74; P = 0.013) were independent predictors of DCI after aSAH. PIV is a potent predictor of DCI in patients with aSAH. Elevated PIV is associated with more DCI development. Thus, PIV has predictive value for DCI development.

Effect of Early Balloon Inflation of Balloon Guide Catheter in Mechanical Thrombectomy for Large Vessel Occlusion.

OBJECTIVE: A balloon guide catheter (BGC) is widely used in mechanical thrombectomy (MT). However, the balloon inflation timing of BGC has not been clearly established. We evaluated whether balloon inflation timing of BGC affects the results of MT. METHODS: Patients who underwent MT with BGC for anterior circulation occlusion were enrolled. Patients were dichotomized into early and late balloon inflation groups, according to the timing of BGC inflation. Angiographic and clinical outcomes were compared between the two groups. Multivariable analyses were performed to evaluate the predictive factors for first-pass reperfusion (FPR) and successful reperfusion (SR). RESULTS: Of 436 patients, the early balloon inflation group showed a shorter procedure time (21 min (11-37) vs. 29 min (14-46), p = 0.014), a higher rate of SR with aspiration only (64.0% vs. 55.4%, p = 0.016), a lower aspiration catheter delivery failure rate (11.1% vs. 19.4%, p = 0.005), less frequent technique conversion (36.0% vs. 44.5%, p = 0.009), higher rate of FPR (58.2% vs. 50.2%, p = 0.011), and a lower rate of distal embolization (7.9% vs. 11.7%, P = 0.006), compared to the late balloon inflation group. In multivariate analysis, early balloon inflation was an independent predictor for FPR (odds ratio, OR 1.53, 95% confidence interval, CI 1.37-2.57; p = 0.011) and SR (OR 1.26, 95% CI 1.18-1.64; p = 0.018). CONCLUSION: Early balloon inflation of BGC enables an effective procedure than late balloon inflation. Early balloon inflation was associated with higher rates of FPR and SR.

Tailored antiplatelet therapy in stent assisted coiling for unruptured aneurysms: a nationwide registry study.

BACKGROUND: Antiplatelet therapy, where regimens are tailored based on platelet function testing, has been introduced into neurointerventional surgery. This nationwide registry study evaluated the effect and safety of tailored antiplatelet therapy in stent assisted coiling for unruptured aneurysms compared with conventional therapy using a standard regimen. METHODS: This study enrolled 1686 patients in 44 participating centers who received stent assisted coiling for unruptured aneurysms between January 1, 2019 and December 31, 2019. The standard regimen (aspirin and clopidogrel) was used for all patients in the conventional group (924, 19 centers). The regimen was selected based on platelet function testing (standard regimen for clopidogrel responders; adding cilostazol or replacing clopidogrel with other thienopyridines (ticlopidine, prasugrel, or ticagrelor) for clopidogrel non-responders) in the tailored group (762, 25 centers). The primary outcome was thromboembolic events. Secondary outcomes were bleeding and poor outcomes (increase in modified Rankin Scale score). Outcomes within 30 days after coiling were compared using logistic regression analysis. RESULTS: The thromboembolic event rate was lower in the tailored group than in the conventional group (30/762 (3.9%) vs 63/924 (6.8%), adjusted OR 0.560, 95% CI 0.359 to 0.875, P=0.001). The bleeding event rate was not different between the study groups (62/762 (8.1%) vs 73/924 (7.9%), adjusted OR 0.790, 95% CI 0.469 to 1.331, P=0.376). Poor outcomes were less frequent in the tailored group (12/762 (1.6%) vs 34 (3.7%), adjusted OR 0.252, 95% CI 0.112 to 0.568, P=0.001). CONCLUSION: Tailored antiplatelet therapy in stent assisted coiling for unruptured aneurysms reduced thromboembolic events and poor outcomes without increasing bleeding.

Comparison of Neuroform Atlas Stent-Assisted Coiling and Coiling Alone in Ruptured Intracranial Aneurysms: A Propensity Score Matching Analysis.

BACKGROUND: Although Neuroform Atlas stent is commonly used in stent-assisted coiling (SAC) to treat ruptured intracranial aneurysms (RIA), its safety and efficacy remain controversial. OBJECTIVE: To assess the safety and efficacy of SAC using Neuroform Atlas for treating RIA compared with coiling alone by performing a propensity score matching analysis. METHODS: RIA treated with coiling alone and SAC between January 2017 and May 2021 were retrospectively reviewed. Demographics, periprocedural complication rates, angiographic outcomes, and clinical outcomes of the SAC using Neuroform Atlas group and the coiling-alone group were analyzed with 1:1 propensity score matching. RESULTS: A total of 375 aneurysms were enrolled, and 274 (63.1%) aneurysms were treated with coiling alone. In total, 101 (26.9%) aneurysms were treated with SAC, and Neuroform Atlas stent was used in 71 aneurysms. In propensity score matching, the SAC using Neuroform Atlas group showed higher incidence of complete occlusion (69.0% vs 56.3%, P = .029), lower rate of recanalization (11.3% vs 25.4%, P = .011), and lesser need for retreatment (7.0% vs 16.9%, P = .016) compared with the coiling-alone group. However, there were no significant differences in periprocedural complications such as intraprocedural thrombosis or postprocedural cerebral infarct between the 2 groups. CONCLUSION: The use of Neuroform Atlas is safe and effective for SAC in RIA with comparable procedure-related complication rates but better angiographic outcome in comparison with coiling alone.

Safety and Efficacy of Flow Diverter Therapy for Unruptured Intracranial Aneurysm Compared to Traditional Endovascular Strategy : A Multi-Center, Randomized, Open-Label Trial.

OBJECTIVE: Endovascular treatment of large, wide-necked intracranial aneurysms by coil embolization is often complicated by low rates of complete occlusion and high rates of recurrence. A flow diverter device has been shown to be safe and effective for the treatment of not only large and giant unruptured aneurysms, but small and medium aneurysms. However, in Korea, its use has only recently been approved for aneurysms <10 mm. This study aims to compare the safety and efficacy of flow diversion and coil embolization for the treatment of unruptured aneurysms ≥7 mm. METHODS: The participants will include patients aged between 19 and 75 years to be treated for unruptured cerebral aneurysms ≥7 mm for the first time or for recurrent aneurysms after initial endovascular coil embolization. Participants assigned to a flow diversion cohort will be treated using any of the following devices : Pipeline Flex Embolization Device with Shield Technology (Medtronic, Minneapolis, MN, USA), Surpass Evolve (Stryker Neurovascular, Fremont, CA, USA), and FRED or FRED Jr. (MicroVention, Tustin, CA, USA). Participants assigned to a coil embolization cohort will undergo traditional endovascular coiling. The primary endpoint will be complete occlusion confirmed by cerebral angiography at 12 months after treatment. Secondary safety outcomes will evaluate periprocedural and post-procedural complications for up to 12 months. RESULTS: The trial will begin enrollment in 2022, and clinical data will be available after enrollment and follow-up. CONCLUSION: This article describes the aim and design of a multi-center, randomized, open-label trial to compare the safety and efficacy of flow diversion versus traditional endovascular treatment for unruptured cerebral aneurysms ≥7 mm.

Factors Related to Mechanical Thrombectomy Failure in Large Vessel Occlusion: A Propensity Score Matching Analysis.

OBJECTIVE: Mechanical thrombectomy (MT) is an effective treatment for large vessel occlusion (LVO) with a high successful recanalization (SR) rate. However, MT fails in a proportion of patients, leading to poor clinical outcomes. We analyzed the factors associated with the failure of MT. METHODS: A total of 648 consecutive patients with MT were enrolled. MT failure was defined as 0,1, or 2a of modified Thrombolysis in Cerebral Infarction (mTICI) grade. Failed MTs were divided into 3 categories, reaching failure, passage failure, and recanalization failure (RF). Various factors in RF and SR groups were analyzed with 1: 1 propensity score matching. RESULTS: Failed MT was observed in 97 patients (14.3%). Among them, 69 patients (10.2% of the entire cohort, 71.1% of the failed MT group) were included in the RF group. Propensity matching analysis with 69 patients in each group showed that the RF group had a higher rate of residual intracranial atherosclerotic stenosis (ICAS) than the SR group (30.4% vs. 14.5% P = 0.003). The rates of 4 or more passages and no change of method were significantly higher in the RF group than in the SR group (34.8% vs. 13.0%; P = 0.001 and 28.9% vs. 8.7%; P = 0.001). CONCLUSION: The failure rate for all of the MT was approximately 15%, and RF accounted for more than 70% of the failed MT. RF was associated with residual ICAS. In cases with RF, even in repeated attempts for recanalization, an alteration of the thrombectomy method should be considered.

Elevated blood viscosity is associated with delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Delayed cerebral ischemia (DCI) is a contributing factor for poor clinical outcome in aneurysmal subarachnoid hemorrhage (aSAH). Blood viscosity can reflect flow resistance and dehydration status. Our study aimed to analyze the association between blood viscosity and DCI in patients with aSAH. METHODS: In this retrospective cohort, systolic blood viscosity (SBV) and diastolic blood viscosity (DBV) were measured at admission in patients with aSAH. Receiver operating characteristic curve analysis was used to assess the predictive values of SBV and DBV for DCI after aSAH. Univariate and multivariate logistic regression was performed to analyze the association between blood viscosity and the development of DCI. RESULTS: A total of 470 patients with aSAH were included in this study, and 184 (39.1%) patients had DCI. Optimal cut-off values of DBV and SBV were presented as 12.05 (cP) and 3.75 (cP), respectively. In addition, DBV has higher predictable value of DCI than SBV (DBV: area under the curve [AUC] 0.793; standard error [SE] 0.026; 95% CI 0.722-0.864; P < 0.001, and SBV: AUC 0.702; SE 0.040; 95% CI 0.624-0.781; P < 0.001). In multivariate logistic regression analysis, elevated DBV was a predicting factor for development of DCI (odds ratio: 1.60; 95% confidence interval: 1.32-2.58; P = 0.037). CONCLUSIONS: Blood viscosity is associated with development of DCI in patients with aSAH. Especially, DBV has a higher predictive value for the occurrence of DCI than SBV. Elevated DBV is a potential predicting factor for the occurrence of DCI.

Clinical relevance of serum procalcitonin in patients with aneurysmal subarachnoid hemorrhage.

Cerebral vasospasm (CV), which is closely related to the prognosis of aneurysmal subarachnoid hemorrhage (aSAH), is known to be related to an inflammatory reaction. The aim of the present study was to investigate predictable values of procalcitonin (PCT) for systemic infection and the development of CV in patients with aSAH. Patients who underwent endovascular treatment for aSAH were retrospectively enrolled. Receiver operating characteristic curve analysis was performed to evaluate the predicable value of PCT for systemic infection and CV in patients with aSAH. To clarify the association of PCT and CV, additional subgroup analysis was performed for patients without systemic infection. Multivariate logistic regression was used to explore the associations of PCT and the development of CV. A total of 374 patients with aSAH were enrolled. Of them, 164 (43.9%) had systemic infection. Optimal cutoff value of PCT for systemic infection was 0.21 ng/ml (P<0.001). In subgroup analysis of 210 patients without infection, 0.09 ng/ml of PCT level was defined as the optimal cutoff value for predicting CV after aSAH (P<0.001). In multivariate logistic regression analysis, PCT was a significant predicting factor for CV (odds ratio, 1.82; 95% confidence interval, 1.42-2.96; P=0.015). Overall, PCT had predictable value for systemic infection and the development of CV in patients who underwent endovascular treatment for aSAH. Further studies are needed to validate our results and establish its clinical applicability.

Effectiveness of Anchoring with Balloon Guide Catheter and Stent Retriever in Difficult Mechanical Thrombectomy for Large Vessel Occlusion.

OBJECTIVE: A distal navigation of a large bore aspiration catheter during mechanical thrombectomy (MT) is important. However, delivering a large bore aspiration catheter is difficult to a tortuous or atherosclerotic artery. We report the experience of anchoring with balloon guide catheter (BGC) and stent retriever to facilitate the passage of an aspiration catheter in MT. METHODS: When navigating an aspiration catheter failed with a conventional co-axial microcatheter delivery, an anchoring technique was used. Two types of anchoring technique were applied to facilitate distal navigation of a large bore aspiration catheter during MT. First, a passage of aspiration catheter was attempted with a proximal BGC anchoring technique. If this technique also failed, another anchoring technique with distal stent retriever was tried. Consecutive patients who underwent MT with an anchoring technique were identified. Details of procedure, radiologic outcomes, and safety variables were evaluated. RESULTS: A total of 67 patients underwent MT with an anchoring technique. Initial trial of aspiration catheter passage with proximal BGC anchoring technique was successful for 35 patients (52.2%) and the second trial with distal stent retriever anchoring was successful for 32 patients (47.8%). Overall, navigation of a large bore aspiration catheter was successful for all patients (100%) without any procedure related complications. CONCLUSION: Our study showed the usefulness of anchoring technique with proximal BGC and distal stent retriever during MT, especially in those with an unfavorable anatomical structure. This technique could be an alternative option for delivering an of aspiration catheter to a distal location.

Optimal Duration of Dual Antiplatelet Therapy after Stent- Assisted Coil Embolization of Unruptured Intracranial Aneurysms : A Prospective Randomized Multicenter Trial.

OBJECTIVE: Stent-assisted coil embolization (SAC) has been increasingly used to treat various types of intracranial aneurysms. Delayed thromboembolic complications are major concerns regarding this procedure, so dual antiplatelet therapy with aspirin and clopidogrel is needed. However, clinicians vary the duration of dual antiplatelet therapy after SAC, and no randomized study has been performed. This study aims to compare the safety and efficacy of long-term (12 months) dual antiplatelet therapy and shortterm dual antiplatelet therapy (6 months) after SAC for patients with unruptured intracranial aneurysms (UIAs). METHODS: This is a prospective, randomized and multicenter trial to investigate the optimal duration of dual antiplatelet therapy after SAC in patients with UIAs. Subjects will receive dual antiplatelet therapy for 6 months (short-term group) or 12 months (longterm group) after SAC. The primary endpoint is the assessment of thromboembolic complications between 1 and 18 months after SAC. We will enroll 528 subjects (264 subjects in each group) and perform 1 : 1 randomization. This study will involve 14 topperforming, high-volume Korean institutions specializing in coil embolization. RESULTS: The trial will begin enrollment in 2022, and clinical data will be available after enrollment and follow-up. CONCLUSION: This article describes that the aim of this prospective randomized multicenter trial is to compare the effect of short-term (6 months) and long-term (12 months) dual antiplatelet therapy on UIAs in patients undergoing SAC, and to find the optimal duration.

Prognostic significance of platelet-to-lymphocyte and platelet-to-neutrophil ratios in patients with mechanical thrombectomy for acute ischemic stroke.

OBJECTIVE: The present study aimed to analyze the correlation between platelet-to-lymphocyte ratio (PLR) and platelet-to-neutrophil ratio (PNR) with prognosis of patients who underwent mechanical thrombectomy (MT). METHODS: A total of 432 patients was included, PLR and PNR were calculated from laboratory data on admission. Prognosis was evaluated with a modified Rankin Scale at 3 months after MT. Using receiver operating characteristic (ROC) analysis, optimal cutoff values of PLR and PNR were identified to predict the prognosis after MT. Multivariate analyses were performed to identify the relationship of PLR and PLR with prognosis of MT. RESULTS: Patients with favorable outcomes had a lower mean PLR (135.0, standard deviation [SD] 120.3) with a higher mean PNR (47.1 [SD] 24.6) compared with patients with unfavorable outcomes (167.6 [SD] 139.3 and 35.4 [SD] 22.4) (p<0.001 and <0.001, respectively). In ROC analyses, the optimal cutoff value of PLR and PNR to predict the 3 months prognosis were 145 and 41, respectively (p=<0.001 and p=0.006). In multivariate analysis, PLR less than 145 (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.06-2.06; p=0.016) and PNR greater than 41 (OR 1.22, 95% CI 1.10-1.62; p=0.022) were predictors of favorable outcome at 3 months. CONCLUSIONS: In patients with MT, PLR and PNR on admission could be predictive factors of prognosis and mortality at 3 months. Decreased PLR and increased PNR were associated with favorable clinical outcome 3 months after MT.

Clinical Outcomes after Spinal Cord Stimulation According to Pain Characteristics.

OBJECTIVE: Spinal cord stimulation (SCS) is an effective treatment for chronic neuropathic pain. However, its clinical efficacy in regard to specific types of pain has not been well studied. The primary objective of this study was to retrospectively analyze the clinical outcomes of paddle-type SCS according to the type of neuropathic pain. METHODS: Seventeen patients who underwent paddle-lead SCS at our hospital were examined. Clinical outcomes were evaluated pre- and postoperatively (3 months, 1 year, and last follow-up) using the Neuropathic Pain Symptom Inventory (NPSI). The NPSI categorizes pain as superficial, deep, paroxysmal, evoked, or dysesthesia and assess the duration of the pain (pain time score). Changes in NPSI scores were compared with change in Visual analogue scale (VAS) scores. RESULTS: After SCS, the pain time score improved by 45% (independent t-test, p=0.0002) and the deep pain score improved by 58% (independent t-test, p=0.001). Improvements in the pain time score significantly correlated with improvements in the VAS score (r=0.667, p=0.003, Spearman correlation). Additionally, the morphine milligram equivalent value was markedly lower after vs. before surgery (~49 mg, pared t-test, p=0.002). No preoperative value was associated with clinical outcome. CONCLUSION: The NPSI is a useful tool for evaluating the therapeutic effects of SCS. Chronic use of a paddle-type spinal cord stimulation improved the deep pain and the pain time scores.

Receptor-binding domain of SARS-CoV-2 spike protein efficiently inhibits SARS-CoV-2 infection and attachment to mouse lung.

COVID-19, caused by a novel coronavirus, SARS-CoV-2, poses a serious global threat. It was first reported in 2019 in China and has now dramatically spread across the world. It is crucial to develop therapeutics to mitigate severe disease and viral spread. The receptor-binding domains (RBDs) in the spike protein of SARS-CoV and MERS-CoV have shown anti-viral activity in previous reports suggesting that this domain has high potential for development as therapeutics. To evaluate the potential antiviral activity of recombinant SARS-CoV-2 RBD proteins, we determined the RBD residues of SARS-CoV-2 using a homology search with RBD of SARS-CoV. For efficient expression and purification, the signal peptide of spike protein was identified and used to generate constructs expressing recombinant RBD proteins. Highly purified RBD protein fused with the Fc domain of human IgG showed potent anti-viral efficacy, which was better than that of a protein fused with a histidine tag. Intranasally pre-administrated RBD protein also inhibited the attachment of SARS-COV-2 to mouse lungs. These findings indicate that RBD protein could be used for the prevention and treatment of SARS-CoV-2 infection.

A Novel Frameshifting Inhibitor Having Antiviral Activity against Zoonotic Coronaviruses.

Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic agents targeting coronaviruses have not yet been developed. During coronavirus replication, a replicase gene cluster, including RNA-dependent RNA polymerase (RdRp), is alternatively translated via a process called -1 programmed ribosomal frameshift (-1 PRF) by an RNA pseudoknot structure encoded in viral RNAs. The coronavirus frameshifting has been identified previously as a target for antiviral therapy. In this study, the frameshifting efficiencies of MERS-CoV, SARS-CoV and SARS-CoV-2 were determined using an in vitro -1 PRF assay system. Our group has searched approximately 9689 small molecules to identify potential -1 PRF inhibitors. Herein, we found that a novel compound, 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline (KCB261770), inhibits the frameshifting of MERS-CoV and effectively suppresses viral propagation in MERS-CoV-infected cells. The inhibitory effects of 87 derivatives of furo[2,3-b]quinolines were also examined showing less prominent inhibitory effect when compared to compound KCB261770. We demonstrated that KCB261770 inhibits the frameshifting without suppressing cap-dependent translation. Furthermore, this compound was able to inhibit the frameshifting, to some extent, of SARS-CoV and SARS-CoV-2. Therefore, the novel compound 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline may serve as a promising drug candidate to interfere with pan-coronavirus frameshifting.