Benefit of endovascular treatment for primary versus secondary medium vessel occlusion: A multi-center experience.

AIMS: This study aimed to compare the clinical outcomes and safety of endovascular treatment (EVT) in patients with primary versus secondary medium vessel occlusion (MeVO). METHODS: From the endovascular treatment for acute ischemic stroke in the China registry, we collected consecutive patients with MeVO who received EVT. The primary endpoint was a good outcome, defined as a modified Rankin Scale (mRS) 0 to 2 at 90 days. RESULTS: 154 patients were enrolled in the final analysis, including 74 primary MeVO and 80 secondary MeVO. A good outcome at 90 days was achieved in 42 (56.8%) patients with primary MeVO and 33 (41.3%) patients with secondary MeVO. There was a higher probability of good outcomes in patients with the primary vs secondary MeVO (adjusted odds ratio, 2.16; 95% confidence interval, 1.04 to 4.46; p = 0.04). There were no significant differences in secondary and safety outcomes between MeVO groups. In the multivariable analysis, baseline ASPECTS (p = 0.001), final modified thrombolysis in cerebral infarction score (p = 0.01), and any ICH (p = 0.03) were significantly associated with good outcomes in primary MeVO patients, while baseline National Institutes of Health Stroke Scale (p = 0.002), groin puncture to recanalization time (p = 0.02), and early neurological improvement (p < 0.001) were factors associated with good outcome in secondary MeVO patients. CONCLUSION: In MeVO patients who received EVT, there was a higher likelihood of poor outcomes in patients with secondary versus primary MeVO.

Genetic factors associated with acquired phenotypic drug resistance and its compensatory evolution during tuberculosis treatment.

OBJECTIVES: We elucidated the factors, evolution, and compensation of antimicrobial resistance (AMR) in Mycobacterium tuberculosis (MTB) isolates under dual pressure from the intra-host environment and anti-tuberculosis (anti-TB) drugs. METHODS: This retrospective case-control study included 337 patients with pulmonary tuberculosis from 15 clinics in Tianjin, China, with phenotypic drug susceptibility testing results available for at least two time points between January 1, 2009 and December 31, 2016. Patients in the case group exhibited acquired AMR to isoniazid (INH) or rifampicin (RIF), while those in the control group lacked acquired AMR. The whole-genome sequencing (WGS) was conducted on 149 serial longitudinal MTB isolates from 46 patients who acquired or reversed phenotypic INH/RIF-resistance during treatment. The genetic basis, associated factors, and intra-host evolution of acquired phenotypic INH/RIF-resistance were elucidated using a combined analysis. RESULTS: Anti-TB interruption duration of ≥30 days showed association with acquired phenotypic INH/RIF resistance (aOR = 2·2, 95% CI, 1·0-5·1) and new rpoB mutations (p = 0·024). The MTB evolution was 1·2 (95% CI, 1·02-1·38) single nucleotide polymorphisms per genome per year under dual pressure from the intra-host environment and anti-TB drugs. AMR-associated mutations occurred before phenotypic AMR appearance in cases with acquired phenotypic INH (10 of 16) and RIF (9 of 22) resistances. DISCUSSION: Compensatory evolution may promote the fixation of INH/RIF-resistance mutations and affect phenotypic AMR. The TB treatment should be adjusted based on gene sequencing results, especially in persistent culture positivity during treatment, which highlights the clinical importance of WGS in identifying reinfection and AMR acquisition before phenotypic drug susceptibility testing.

Vav1 promotes inflammation and neuronal apoptosis in cerebral ischemia/reperfusion injury by upregulating microglial and NLRP3 inflammasome activation.

Microglia, which are the resident macrophages of the central nervous system, are an important part of the inflammatory response that occurs after cerebral ischemia. Vav guanine nucleotide exchange factor 1 (Vav1) is a guanine nucleotide exchange factor that is related to microglial activation. However, how Vav1 participates in the inflammatory response after cerebral ischemia/reperfusion injury remains unclear. In this study, we subjected rats to occlusion and reperfusion of the middle cerebral artery and subjected the BV-2 microglia cell line to oxygen-glucose deprivation/reoxygenation to mimic cerebral ischemia/reperfusion in vivo and in vitro, respectively. We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral artery and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation. Silencing Vav1 reduced the cerebral infarct volume and brain water content, inhibited neuronal loss and apoptosis in the ischemic penumbra, and improved neurological function in rats subjected to occlusion and reperfusion of the middle cerebral artery. Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3 (NLRP3) inflammasome in the ischemic penumbra, as well as the expression of inflammatory factors. In addition, Vav1 knockdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxygenation. Taken together, these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/reperfusion through inhibiting the activation of microglia and NLRP3 inflammasome.

Intra-arterial tenecteplase is safe and may improve the first-pass recanalization for acute ischemic stroke with large-artery atherosclerosis: the BRETIS-TNK trial.

Background and purpose: The first-pass recanalization of endovascular treatment (EVT) is closely correlated with clinical outcome of patients with large vessel occlusion (LVO) stroke. The aim of the study was to explore whether intra-arterial tenecteplase (TNK) during the first pass of EVT can increase first-pass successful reperfusion and improve the neurological outcome in AIS-LVO patients. Materials and methods: The BRETIS-TNK trial (ClinicalTrials.gov Identifier: NCT04202458) was a prospective, single-arm, single center study. Twenty-six eligible AIS-LVO patients with large-artery atherosclerosis etiology were consecutively enrolled from December 2019 to November 2021. Intra-arterial TNK (4 mg) after microcatheter navigation through the clot was administered, followed by TNK (0.4 mg/min) given continuously for 20 min after the first retrieval attempt of EVT without confirmation of the reperfusion status by DSA. The 50 control patients comprised of a historical cohort before the BRETIS-TNK trial (from March 2015 to November 2019). Successful reperfusion was defined as modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b. Results: The first-pass successful reperfusion rate was higher in the BRETIS-TNK vs. control group (53.8% vs. 36%, p = 0.14), and the difference became statistically significant after propensity score matching (53.8% vs. 23.1%, p = 0.03). There was no difference in symptomatic intracranial hemorrhage between the BRETIS-TNK and control groups (7.7% vs. 10.0%, p = 0.92). There was a trend toward higher proportion of functional independence at 90 days in the BRETIS-TNK comparing with the control group (50% vs. 32%, p = 0.11). Conclusion: This is the first study to report that intra-arterial TNK during the first pass of EVT seems safe and feasible in AIS-LVO patients.

Predicting symptomatic intracranial hemorrhage in anterior circulation stroke patients with contrast enhancement after thrombectomy: the CAGA score.

BACKGROUND: The aim of the study was to establish a reliable scoring tool to identify the probability of symptomatic intracranial hemorrhage (sICH) in anterior circulation stroke patients with contrast enhancement (CE) on brain non-contrast CT (NCCT) after endovascular thrombectomy (EVT). METHODS: We retrospectively reviewed consecutive patients with acute ischemic stroke (AIS) who had CE on NCCT immediately after EVT for anterior circulation large vessel occlusion (LVO). We used the Alberta stroke program early CT score (ASPECTS) scoring system to estimate the extent and location of CE. Multivariable logistic regression was performed to derive an sICH predictive score. The discrimination and calibration of this score were assessed using the area under the receiver operator characteristic curve, calibration curve, and decision curve analysis. RESULTS: In this study, 194 of 322 (60.25%) anterior circulation AIS-LVO patients had CE on NCCT. After excluding 85 patients, 109 patients were enrolled in the final analysis. In multivariate regression analysis, age ≥70 years (adjusted OR (aOR) 9.23, 95% CI 2.43 to 34.97, P＜0.05), atrial fibrillation (AF) (aOR 4.17, 95% CI 1.33 to 13.12, P＜0.05), serum glucose ≥11.1 mmol/L (aOR 9.39, 95% CI 2.74 to 32.14, P＜0.05), CE-ASPECTS ＜5 (aOR 3.95, 95% CI 1.30 to 12.04 P＜0.05), and CE at the internal capsule (aOR 3.45, 95% CI 1.03 to 11.59, P＜0.05) and M1 region (aOR 3.65, 95% CI 1.13 to 11.80, P＜0.05) were associated with sICH. These variables were incorporated as the CE-age-glucose-AF (CAGA) score. The CAGA score demonstrated good discrimination and calibration in this cohort, as well as the fivefold cross validation. CONCLUSION: The CAGA score reliably predicted sICH in patients with CE on NCCT after EVT treatment.

Association between collaterals, cerebral circulation time and outcome after thrombectomy of stroke.

OBJECTIVE: Cerebral circulation time (CCT) and collateral score (CS) are associated with functional outcomes in acute ischemic stroke (AIS) patients after endovascular treatment (EVT), and may be related to each other. We aim to determine the relationship between CS and CCT on functional outcomes. METHODS: We retrospectively enrolled consecutive patients with anterior circulation large vessel occlusion (LVO) AIS who received EVT. CS and CCT were measured based on digital subtraction angiography (DSA). We defined CS 0-2 and 3-4 as poor and good collateral status, respectively, and used change of CCT (cCCT), which was defined as the change of stroke side CCT (sCCT) versus healthy side CCT (hCCT). Mediating analysis was used to evaluate the influence of cCCT on the association between CS and functional outcomes, and ROC curves were further used to explore the predictive ability of the interaction between cCCT and CS for functional outcomes. RESULTS: A total of 100 patients were enrolled in the final analysis. A higher cCCT (r = -0.239; p = 0.017) was associated with lower CS, and cCCT mediated the association of CS with functional outcome. Logistic regression analysis found that CS, cCCT and cCCT-CS interactions were independently associated with functional outcome, and cCCT-CS interaction has better predictive performance, with a higher area under curve value than CS or cCCT alone (0.79 vs. 0.75 or 0.75). INTERPRETATION: To our knowledge, this study provides the first report of the association of collateral status with cCCT, and their interaction effect on functional outcome in AIS-LVO patients receiving EVT.

Changes in blood gas values and electrolytes in the occluded artery predict outcomes after endovascular treatment in ischemic stroke.

BACKGROUND AND PURPOSE: Endovascular treatment (EVT) is the best treatment for acute ischemic stroke with large vessel occlusion (LVO) and makes it possible to analyze the blood contents from the occluded vascular compartments. In this study, we attempted to evaluate regional changes in blood gas values and electrolytes in the occluded vessels, aiming to determine whether these changes can predict outcomes in LVO patients receiving EVT. MATERIALS AND METHODS: We prospectively observed 45 consecutive ischemic stroke patients with LVO of the anterior circulation who underwent EVT. We collected the arterial blood proximal to the occlusion site before and after EVT, and the blood within the core of the occluded vascular compartment (distal to the thrombus) and evaluated the labs for blood gas values and electrolytes. Femoral samples were obtained under physiological flow conditions to represent systemic arterial blood. RESULTS: Compared with the femoral arterial blood samples, significant decreases in K+, Ca2+, HCO3-, BE, HCT, tHbc, and TCO2 levels were observed in the proximal luminal blood before EVT. Decreases in K+ and Ca2+ levels were also observed in the proximal luminal blood after EVT. Proximal/femoral ratio of pH and Na+ was associated with short-term clinical outcomes at 72 hours after EVT. A higher proximal/femoral Na+ ratio was associated with successful recanalization. Further analysis after propensity score matching showed significant changes in blood gas and electrolyte among different arterial locations in ICA and MCA LVO participants. Linear regression analyses indicated that the proximal/femoral ratio of pH, Na+, pCO2, HCO3, and TCO2 before EVT were associated with decrease in NIHSS score at 72 hours in ICA-LVO group. CONCLUSIONS: Obvious changes in several parameters of arterial blood gas and electrolyte from the ischemic vasculature occur during hyperacute stroke. Proximal/femoral pH and Na+ ratio before EVT may be associated with short-term clinical outcome, which deserve to be further investigated.

Contrast enhancement by location and volume is associated with long-term outcome after thrombectomy in acute ischemic stroke.

Contrast enhancement (CE) on brain non-contrast computed tomography (NCCT) is common after endovascular thrombectomy (EVT) in patients with acute ischemic stroke (AIS), but its association with clinical outcomes is not well established. The current study aimed to investigate this relationship. We retrospectively reviewed consecutive patients with acute ischemic stroke who had hyperdensity on NCCT immediately after EVT for anterior circulation large vessel occlusion (LVO) from January 2016 to December 2019. We used ASPECTS combined with volume measurement by 3D reconstruction to estimate the extent and location of CE. Multivariable regression analysis was conducted to explore the risk factors associated with clinical outcome. In this study, 113 of 158 (71.52%) anterior circulation AIS-LVO patients had hyperdensity on brain NCCT. After strict inclusion and exclusion criteria, a total of 64 patients were enrolled in the final analysis. In logistic regression analysis, CE-ASPECTS, CE volume, CE at the caudate nucleus, M4 and M6 region were associated with 3-month poor functional outcome after adjusting for confounding factors. The conventional variable model was used for reference, including age, initial NIHSS, the procedure time, stent retriever passes, recanalization status and baseline ASPECTS, with AUC of 0.73. When combined with the above-named variables (conventional variables + CE-ASPECTS + CE volume + CE at caudate nucleus + CE at M4 region + CE at M6 region), the predictive power was significantly improved, with AUC of 0.87 (95% CI 0.78-0.95). The spatial location and volume of CE on NCCT obtained immediately after EVT were independent and strong predictors for poor outcome at 3-months in patients with AIS after excluding definite hemorrhage by 24-h follow up CT.

Cerebral Circulation Time After Thrombectomy: A Potential Predictor of Outcome After Recanalization in Acute Stroke.

Background Despite successful recanalization, up to half of patients with acute ischemic stroke caused by large-vessel occlusion treated with endovascular treatment (EVT) do not recover to functional independence. We aim to evaluate the role of cerebral circulation time (CCT) as outcome predictor after EVT. Methods and Results We retrospectively enrolled consecutive patients with acute ischemic stroke-large-vessel occlusion undergoing EVT. Three categories of CCT based on digital subtraction angiography were studied: CCT of the stroke side, CCT of the healthy side), and change of CCT of the stroke side versus CCT of the healthy side. Dramatic clinical recovery was defined as a 24-hour National Institutes of Health Stroke Scale score ≤2 or ≥8 points drop. A modified Rankin Scale score ≤2 at 3 months was considered a favorable outcome. Logistic regression analysis was performed to evaluate the prediction of CCT on prognosis. One hundred patients were enrolled, of which 38 (38.0%) experienced a dramatic clinical recovery and 43 (43.0%) achieved a favorable outcome. Logistic regression analysis found that shorter change of CCT of the stroke side versus CCT of the healthy side and CCT of the stroke side were independent positive prognostic factors for dramatic clinical recovery (odds ratio [OR], 0.189; P=0.033; OR, 0.581; P=0.035) and favorable outcomes (OR, 0.142; P=0.020; OR, 0.581; P=0.046) after adjustment for potential confounders. A model including the change of CCT of the stroke side versus CCT of the healthy side also had significantly higher area under the curve values compared with the baseline model in patients with dramatic clinical recovery (0.780 versus 0.742) or favorable outcome (0.759 versus 0.713). Conclusions To our knowledge, this is the first report that CCT based on digital subtraction angiography data exhibits an independent predictive performance for clinical outcome in patients with acute ischemic stroke-large-vessel occlusion after EVT. Given that this readily available CCT can provide alternative perfusion information during EVT, a prospective, multicenter trial is warranted.

LncRNA HAND2-AS1 promotes liver cancer stem cell self-renewal via BMP signaling.

Hepatocellular carcinoma (HCC) is the most prevalent liver cancer, characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanism underlying their self-renewal maintenance is poorly understood. Here, we identified a long noncoding RNA (lncRNA) termed HAND2-AS1 that is highly expressed in liver CSCs. Human HAND2-AS1 and its mouse ortholog lncHand2 display a high level of conservation. HAND2-AS1 is required for the self-renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, HAND2-AS1 recruits the INO80 chromatin-remodeling complex to the promoter of BMPR1A, thereby inducing its expression and leading to the activation of BMP signaling. Importantly, interfering with expression of HAND2-AS1 by antisense oligonucleotides (ASOs) and BMPR1A by siRNAs has synergistic anti-tumorigenic effects on humanized HCC models. Moreover, knockout of lncHand2 or Bmpr1a in mouse hepatocytes impairs BMP signaling and suppresses the initiation of liver cancer. Our findings reveal that HAND2-AS1 promotes the self-renewal of liver CSCs and drives liver oncogenesis, offering a potential new target for HCC therapy.

NONCODEV5: a comprehensive annotation database for long non-coding RNAs.

NONCODE (http://www.bioinfo.org/noncode/) is a systematic database that is dedicated to presenting the most complete collection and annotation of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs). Since NONCODE 2016 was released two years ago, the amount of novel identified ncRNAs has been enlarged by the reduced cost of next-generation sequencing, which has produced an explosion of newly identified data. The third-generation sequencing revolution has also offered longer and more accurate annotations. Moreover, accumulating evidence confirmed by biological experiments has provided more comprehensive knowledge of lncRNA functions. The ncRNA data set was expanded by collecting newly identified ncRNAs from literature published over the past two years and integration of the latest versions of RefSeq and Ensembl. Additionally, pig was included in the database for the first time, bringing the total number of species to 17. The number of lncRNAs in NONCODEv5 increased from 527 336 to 548 640. NONCODEv5 also introduced three important new features: (i) human lncRNA-disease relationships and single nucleotide polymorphism-lncRNA-disease relationships were constructed; (ii) human exosome lncRNA expression profiles were displayed; (iii) the RNA secondary structures of NONCODE human transcripts were predicted. NONCODEv5 is also accessible through http://www.noncode.org/.

Benchmark study on methanol C-H and O-H bond activation by bare [Fe(IV)O](2+).

We present a high-level computational study on methanol C-H and O-H bond cleavages by bare [Fe(IV)O](2+), as well as benchmarks of various density functional theory (DFT) methods. We considered direct and concerted hydrogen transfer (DHT and CHT) pathways, respectively. The potential energy surfaces were constructed at the CCSD(T)/def2-TZVPP//B3LYP/def2-TZVP level of theory. Mechanistically, (1) the C-H bond cleavage is dominant and the O-H activation only plays minor role on the PESs; (2) the DHT from methyl should be the most practical channel; and (3) electronic structure analysis demonstrates the proton and electron transfer coupling behavior along the reaction coordinates. The solvent effect is evident and plays distinct roles in regulating the two bond activations in different mechanisms during the catalysis. The effect of optimizing the geometries using different density functionals was also studied, showing that it is not meaningful to discuss which DFT method could give the accurate prediction of the geometries, especially for transition structures. Furthermore, the gold-standard CCSD(T) method was used to benchmark 19 different density functionals with different Hartree-Fock exchange fractions. The results revealed that (i) the structural factor plays a minor role in the single point energy (SPE) calculations; (ii) reaction energy prediction is quite challenging for DFT methods; (iii) the mean absolute deviations (MADs) reflect the problematic description of the DFs when dealing with metal oxidation state change, giving a strong correlation on the HF exchange in the DFs. Knowledge from this study should be of great value for computational chemistry, especially for the de novo design of transition metal catalysts.