Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

M2a macrophages regulate fibrosis and affect the outcome after stroke via PU.1/mTOR pathway in fibroblasts.

The moderate formation of the fibrotic scar plays an important role in functional recovery after stroke. M2a macrophages have been identified as an important source of early fibrosis after cerebral ischemia. However, the underlying mechanisms by which macrophages interact with fibroblasts in this context remain largely unknown. Therefore, our study aimed to further investigate the potential mechanisms underlying the effects of macrophages on fibroblasts following ischemic stroke. In vitro and in vivo, recombinant rat interleukin 4 (IL4) was used to induce macrophages to polarize into M2a macrophages. In vitro, primary Sprague-Dawley newborn rat meningeal-derived fibroblasts were treated with PU.1 knockdown, the PU.1 inhibitor DB1976 or the mTOR inhibitor rapamycin, which were then co-cultured with M2a macrophage conditioned medium (MCM). In vivo, Sprague-Dawley adult rats were infected with negative control adenoviruses or PU.1-shRNA adenoviruses. Ten days after infection, an injury model of middle cerebral artery occlusion/reperfusion (MCAO/R) was constructed. Subsequently, IL4 was injected intracerebroventricularly to induce M2a macrophages polarization. In vitro, M2a MCM upregulated PU.1 expression and promoted the differentiation, proliferation, migration and extracellular matrix generation of fibroblasts, which could be reversed by treatment with the PU.1 inhibitor DB1976 or PU.1 knockdown. In vivo, PU.1 expression in fibroblasts was increased within ischemic core following MCAO/R, and this upregulation was further enhanced by exposure to IL4. Treatment with IL4 promoted fibrosis, increased angiogenesis, reduced apoptosis and infarct volume, as well as mitigated neurological deficits after MCAO/R, and these effects could be reversed by PU.1 knockdown. Furthermore, both in vivo and in vitro studies showed that IL4 treatment increased the levels of phosphorylated Akt and mTOR proteins, which were markedly decreased by PU.1 knockdown. Additionally, the use of an mTOR inhibitor rapamycin obviously suppressed the migration and differentiation of fibroblasts, and Col1 synthesis. In conclusion, our findings suggest for the first time that M2a macrophages, at least in part, regulate fibrosis and affect the outcome after cerebral ischemic stroke via the PU.1/mTOR signaling pathway in fibroblasts.

Efficacy and safety of tirofiban combined with endovascular therapy for basilar artery occlusion stroke due to large artery atherosclerosis.

BACKGROUND: This study aimed to evaluate the efficacy and safety of adjuvant tirofiban in patients with acute basilar artery occlusion due to large-artery atherosclerotic (LAA) receiving endovascular therapy (EVT). METHODS: This was a non-randomized, multicenter study using data from the Endovascular Treatment for Acute BASILAR Artery Occlusion (BASILAR) registry. Patients with acute basilar artery occlusion due to LAA within 24h of symptom onset who underwent EVT were included. Patients were divided into tirofiban and non-tirofiban groups according to whether tirofiban was used. The primary outcome was the ordinal modified Rankin scale score at 90 days. Safety outcomes were mortality within 90 days and symptomatic intracranial hemorrhage (sICH) within 48 h. RESULTS: A total of 417 patients were included, of whom 275 patients were in the tirofiban group and 142 patients in the non-tirofiban group. Compared with patients in the non-tirofiban group, patients in the tirofiban group were associated with a favorable shift in functional outcome at 90 days (6[4-6] vs 5 [2-6]; adjusted common OR, 2.51; 95 % CI, 1.64-3.83). The mortality was lower in the tirofiban group than the non-tirofiban group (40.7 % vs 58.5 %; adjusted OR, 0.35; 95 % CI, 0.21-0.56). The rate of sICH was 12.2 % in the non-tirofiban group and 5.2 % in the tirofiban group (adjusted OR, 0.37; 95 % CI, 0.17-0.80; P = 0.012). CONCLUSION: Tirofiban plus EVT might improve functional outcomes with a good safety for patients with acute basilar artery occlusion due to LAA. The results need to be confirmed in a randomized trial.

Correlation between Vitamin B12 and Mental Health in Children and Adolescents: A Systematic Review and Meta-analysis.

To conduct the association between vitamin B12 and mental health in children and adolescents. Five databases were searched for observational studies in any language reporting on mental health and vitamin B12 levels or intake in children and adolescents from inception to March 18, 2022. Two authors independently extracted data and assessed study quality. Qualitative and quantitative analysis of data were performed. The review was registered in the PROSPERO database (CRD42022345476). Fifty six studies containing 37,932 participants were identified in the review. Vitamin B12 levels were lower in participants with autism spectrum disorders (ASD) (standardized mean difference [SMD], -1.61; 95% confidence interval [95% CI], -2.44 to -0.79; p ＜ 0.001), attention deficit hyperactivity disorders (SMD, -0.39; 95% CI, -0.78 to -0.00; p = 0.049) compared with control group. Vitamin B12 intake were lower in participants with ASDs (SMD, -0.86; 95% CI, -1.48 to -0.24; p = 0.006) compared with control group, but showed no difference between depression group (SMD, -0.06; 95% CI, -0.15 to 0.03; p = 0.17) and the control group. Higher vitamin B12 intake were associated with lower risk of depression (odds ratio [OR], 0.79; 95% CI, 0.63-0.98; p = 0.034) and behavioral problems (OR, 0.83; 95% CI, 0.69-0.99; p = 0.04). The vast majority of included studies supported potential positive influence of vitamin B12 on mental health, and vitamin B12 deficiency may be a reversible cause for some mental health disorders in children and adolescents.

Low vitamin B12 levels may predict the risk of ischemic stroke: A cross-sectional study.

BACKGROUND: To examine serum vitamin B12 concentrations in relation to the risk of ischemic stroke among hospitalized patients in the Department of Neurology. METHODS: We performed a cross-sectional study involving 2,212 inpatients discharged from the Department of Neurology of the First Affiliated Hospital of Chongqing Medical University, from January 2020 to January 2022. The results of laboratory assays such as serum vitamin B12, homocysteine, and folate levels were measured. Logistic regression analysis was used to investigate the association between serum vitamin B12 concentrations and ischemic stroke, with adjustment for a number of relevant demographic and lifestyle factors and comorbidities. RESULTS: A total of 961 (43.4%) patients had an ischemic stroke. In the fully adjusted model, logistic regression analysis suggested a positive association between serum vitamin B12 levels<150 pg/mL (aOR: 1.42; 95% CI 1.02-1.97; p = 0.035), serum vitamin B12 150-300 pg/mL (aOR: 1.37; 95% CI 1.11-1.68; p = 0.003) and the prevalence of ischemic stroke. Furthermore, an inverse association was observed between serum vitamin B12 levels ≥ 900 pg/mL (aOR: 0.38; 95% CI: 0.19-0.77; p =0.007) and the prevalence of ischemic stroke. Moreover, the cut-off value of vitamin B12 concentration was 316.4 pg/mL and the discrimination power of the score evaluated by AUC-ROC was 0.71 (95%CI 0.68-0.73, p<0.001) in the vitamin B12 and ischemic stroke. CONCLUSION: Findings suggest that low vitamin B12 levels may predict the risk of ischemic stroke, early and timely supplementation of vitamin B12 can improve the short-term prognosis of ischemic stroke patients.

Rational Design and Construction of Graphdiyne (CnH2n-2) Based NiMoO4/GDY/CuO in Situ XPS Proved Double S-Scheme Heterojunctions for Photocatalytic Hydrogen Production.

As a new two-dimensional (2D) carbon hybrid material, graphdiyne has attracted much attention due to its good conductivity, adjustable electronic structure, and special electron transfer enhancement properties. In this work, graphdiyne/CuO and NiMoO4/GDY/CuO composite catalysts were prepared by cross coupling method and high temperature annealing method. The CuI introduced by clever design not only acts as a catalytic coupling but also as a precursor of CuO. The CuO produced by the postprocessing improves the inefficient charge separation of graphdiyne and provides a good acceptor for the consumption of unwanted holes. The good conductivity and strong reduction ability of graphdiyne play key roles in the performance improvement of the composite catalyst. Under the dual evidence of XPS and in situ XPS, the charge transfer mode of double S-scheme heterojunction with graphdiyne as the active site of hydrogen evolution is constructed reasonably, which not only gives full play to the performance advantages of graphdiyne but also effectively improves the separation efficiency of photogenerated carriers. In this study, a clean and efficient multicomponent system was constructed by graphdiyne, which opened up a broad application prospect in the field of photocatalytic hydrogen production.

Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion.

BACKGROUND: The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. METHODS: In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. RESULTS: A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. CONCLUSIONS: In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban. (Funded by the National Natural Science Foundation of China; RESCUE BT2 Chinese Clinical Trial Registry number, ChiCTR2000029502.).

Vitamin B12, Folate, Homocysteine, Inflammatory Mediators (Interleukin-6, Tumor Necrosis Factor-α and C-Reactive Protein) Levels in Adolescents with Anxiety or Depressive Symptoms.

Purpose: To evaluate the prevalence of abnormal vitamin B12, folate, total homocysteine (tHcy), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) levels, to analyze the relationship between these parameters and the severity of anxiety or depressive symptoms, and to explore the possible factors associated with abnormal levels of these parameters in adolescents with anxiety or depressive symptoms. Methods: Adolescent (aged 12-18 years) outpatients with anxiety or depressive symptoms were recruited. The patient health questionnaire-9 and generalized anxiety disorder scale-7 were used to measure the severity of depression and anxiety. Serum vitamin B12, folate, tHcy, IL-6, TNF-α, and CRP levels were determined. Results: 128 subjects were recruited. The prevalence of vitamin B12 and folate deficiency, tHcy, TNF-α, IL-6, and CRP elevation was 8.6%, 10.2%, 25.8%, 14.8%, 21.9%, and 10.2%, respectively, in adolescents with anxiety or depressive symptoms. Lower vitamin B12 levels were correlated with a higher risk of severe anxiety and depressive symptoms. The severity of some symptoms of anxiety or depression were weakly correlated with vitamin B12, folate, tHcy, IL-6, and CRP levels. Vitamin B12, folate, and tHcy levels were not associated with inflammatory mediators. Vitamin B12 deficiency was associated with older age and higher tHcy levels. Folate deficiency was associated with elevated tHcy. Elevated tHcy was associated with lower vitamin B12 and folate levels. IL-6 elevation was associated with elevated CRP and TNF-α. CRP elevation was associated with older age, higher BMI, and current drinking. Conclusion: Lower vitamin B12 levels were correlated with a higher risk of severe anxiety or depressive symptoms. Weak correlations were observed between the severity of some symptoms of anxiety or depression and vitamin B12, folate, tHcy, IL-6, and CRP levels. Vitamin B12, folate, and tHcy levels were related to each other. IL-6 elevation was associated with elevated CRP and TNF-α. CRP elevation was associated with older age, higher BMI, and current drinking.

M2 macrophages mediate fibrotic scar formation in the early stages after cerebral ischemia in rats.

In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury (within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4 (IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.

Effect of endovascular treatment within 6 hours for acute basilar artery occlusion.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of endovascular treatment (EVT) plus standard medical treatment (SMT) in patients with acute basilar artery occlusion (BAO) within 6 hours of the estimated occlusion time, based on a Chinese population. METHODS: The authors selected patients from the Endovascular Treatment of Acute Basilar Artery Occlusion Study (BASILAR) registry, which was a nationwide prospective registry, within 6 hours after the estimated time of onset of a stroke in acute BAO. Patients were divided into the SMT-alone group or the EVT+SMT group according to treatment modalities. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale score between 0 and 3 at 90 days. Safety outcomes included death at 90 days and symptomatic intracerebral hemorrhage. RESULTS: The authors assessed 590 patients for eligibility. Of these patients, 127 received SMT alone and 463 were treated with EVT plus SMT. EVT was associated with a higher rate of a favorable functional outcome (adjusted OR 3.804, 95% CI 1.890-7.658; p < 0.001) and a lower proportion of deaths at 90 days (adjusted OR 0.364, 95% CI 0.223-0.594; p < 0.001). Lower age (adjusted OR 0.978, 95% CI 0.960-0.997; p = 0.022); lower baseline National Institutes of Health Stroke Scale score (adjusted OR 0.926, 95% CI 0.902-0.950; p < 0.001); higher baseline posterior circulation Alberta Stroke Program Early CT Score (adjusted OR 1.681, 95% CI 1.424-1.984; p < 0.001); absence of diabetes mellitus (adjusted OR 0.482, 95% CI 0.267-0.871; p = 0.016); and modified Thrombolysis in Cerebral Infarction scores 2b-3 (adjusted OR 5.117, 95% CI 2.304-11.367; p < 0.001) were independent factors for a favorable outcome in the EVT+SMT group. CONCLUSIONS: Based on the study design, patients with acute BAO who received EVT within 6 hours were associated with improved favorable outcome and decreased deaths compared with patients who received SMT. Predictors of desirable outcome in patients undergoing EVT included lower age, lower baseline National Institutes of Health Stroke Scale score, higher baseline posterior circulation Alberta Stroke Program Early CT Score, absence of diabetes mellitus, and modified Thrombolysis in Cerebral Infarction scores 2b-3.

Effect of the anastomosis between the posterior inferior cerebellar artery and the superior cerebellar artery on outcomes of acute basilar artery occlusion after endovascular treatment.

BACKGROUND: The effects of secondary collateral compensation on outcomes remain unclear in patients with acute basilar artery occlusion (BAO) after endovascular treatment (EVT). This study aimed to evaluate the benefits of the anastomosis between the posterior inferior cerebellar artery (PICA) and the superior cerebellar artery (SCA) in BAO after EVT. METHODS: This cohort study was conducted using data from the Endovascular Treatment for Acute Basilar Artery Occlusion Study Registry. Patients with acute BAO and treated with EVT were included. The primary outcome was a modified Rankin Scale score of 0-2 at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage (SICH) and 90-day mortality. RESULTS: Of the 646 patients included in the study, 196 (30.3%) patients had a PICA-SCA anastomosis. The PICA-SCA anastomosis was significantly associated with independent functional outcome at 90 days (67/196 (34.2%) vs 109/450 (24.2%), adjusted OR (aOR) 1.80 (95% CI 1.13 to 2.86), p=0.01) and was significantly associated with a decreased rate of SICH (40/442 (9.0%) vs 5/193 (2.6%), aOR 0.29 (95% CI 0.11 to 0.76), p=0.01). No significant difference was found between PICA-SCA anastomosis and 90-day mortality (219/450 (48.7%) vs 80/196 (40.8%), aOR 0.72 (95% CI 0.48 to 1.08), p=0.11). Subgroup analysis showed that the association between independent functional outcome and PICA-SCA anastomosis was strongest in patients with middle BAO (27/77 (35.1%) vs 22/118 (18.6%), aOR 2.64 (95% CI 1.13 to 6.15), p=0.03). CONCLUSIONS: The PICA-SCA anastomosis is significantly associated with better functional outcomes in patients with acute BAO after EVT, especially in those with middle BAO.

4-PBA Attenuates Fat Accumulation in Cultured Spotted Seabass Fed High-Fat-Diet via Regulating Endoplasmic Reticulum Stress.

Excessive fat accumulation is a common phenomenon in cultured fish, which can cause metabolic disease such as fatty liver. However, the relative regulatory approach remains to be explored. Based on this, two feeding trials were conducted. Firstly, fish were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for eight weeks and sampled at the 2nd, 4th, 6th, and 8th week after feeding (Experiment I). In the first four weeks, fish fed an HFD grew faster than those fed an NFD. Conversely, the body weight and weight gain were higher in the NFD group at the 6th and 8th weeks. Under light and transmission electron microscopes, fat accumulation of the liver was accompanied by an obvious endoplasmic reticulum (ER) swell. Accordingly, the expressions of atf-6, ire-1, perk, eif-2α, atf-4, grp78, and chop showed that ER stress was activated at the 6th and 8th weeks. In Experiment II, 50 mg/kg 4-PBA (an ERs inhibitor) was supplemented to an HFD; this was named the 4-PBA group. Then, fish was fed with an NFD, an HFD, and a 4-PBA diet for eight weeks. As the result, the excessive fat deposition caused by an HFD was reversed by 4-PBA. The expression of ER stress-related proteins CHOP and GRP78 was down-regulated by 4-PBA, and the transmission electron microscope images also showed that 4-PBA alleviated ER stress induced by the feeding of an HFD. Furthermore, 4-PBA administration down-regulated SREBP-1C/ACC/FAS, the critical pathways of fat synthesis. In conclusion, the results confirmed that ER stress plays a contributor role in the fat deposition by activating the SREBP-1C/ACC/FAS pathway. 4-PBA as an ER stress inhibitor could reduce fat deposition caused by an HFD via regulating ER stress.

The role of mesenchymal stem cell transplantation for ischemic stroke and recent research developments.

Ischemic stroke is a common cerebrovascular disease that seriously affects human health. However, most patients do not practice self-care and cannot rely on the current clinical treatment for guaranteed functional recovery. Stem cell transplantation is an emerging treatment studied in various central nervous system diseases. More importantly, animal studies show that transplantation of mesenchymal stem cells (MSCs) can alleviate neurological deficits and bring hope to patients suffering from ischemic stroke. This paper reviews the biological characteristics of MSCs and discusses the mechanism and progression of MSC transplantation to provide new therapeutic directions for ischemic stroke.

Non-radical synthesis of amide chitosan with p-coumaric acid and caffeic acid and its application in pork preservation.

p-Coumaric acid and caffeic acid were grafted onto chitosan through a non-radical synthesis method to improve the properties of chitosan and expand its application in food industry. Structural characterization demonstrated that the -COOH of the two phenolic acids were bonded to the -NH2 of the chitosan and formed an acylamino. The grafting ratios of p-coumaric acid-modified chitosan (Cm-CTS) and caffeic acid-modified chitosan (Cf-CTS) reached 10.30 % and 9.78 %, respectively. After modification, the water solubility of the chitosan greatly improved from 9.33 % (native chitosan, Nt-CTS) to 77.33 % (Cm-CTS) and 100 % (Cf-CTS). Besides, the involvement of phenolic acid and caffeic acid endowed the chitosan with strengthened antioxidation and antibacterial activities against Escherichia coli and Staphylococcus aureus. Nt-CTS and the modified chitosans were coated on the pork surface. The results indicated that Nt-CTS effectively inhibited pork spoilage and the modified chitosans could further prolong the shelf life of pork.

IOFS-SA: An interactive online feature selection tool for survival analysis.

BACKGROUND: Survival analysis is a primary problem before clinical treatments to cancer patients after their operations. In order to make this kind of analysis simple, many corresponding tools have been proposed. Though these tools are easy to use, there exist still two fatal flaws. One is that sample grouping is commonly empirical and wrongly based on original gene expressions or survival time. The other is that their feature selection methods mostly depend univariate semi-supervised regression or the multivariate one without considering the small sample size compared with the high dimension. OBJECTIVE: In order to solve the two problems, we design an automatic feature selection web tool which can also satisfy interactive sample grouping. METHODS: An automatic feature selection is performed on user-defined data or TCGA data. users can also perform manual feature selection. Then, hierarchical clustering is used and an automatic re-clustering strategy is proposed after interactive risk score split. Kaplan-Meier survival curve and log-rank test are utilized as the measurement. RESULTS: Experimental results on 53 datasets from TCGA demonstrate the effectiveness of our method. The tree view, heat map and scatter map can intuitively display the result of the selected genes to the doctors for further research. CONCLUSIONS: This method is suitable for survival analysis of high-dimensional small sample data sets. At the same time, it also provides a platform for researchers to analyze custom data. It solves the problems of the existing web tools and provides an effective feature selection method for survival analysis. AVAILABILITY: The full code package is freely available and can be downloaded at https://github.com/Yuan-23/IOFS-SA-ecp-data-main, and the online version at https://bioinfor.nefu.edu.cn/IOFS-SA/ is ready for use freely.

Effect of vertebrobasilar dolichoectasia on endovascular therapy in acute posterior circulation infarction.

Background and purpose: This study aimed to analyze the feasibility and safety of endovascular therapy (EVT) in patients with acute posterior circulation stroke and vertebrobasilar dolichoectasia (VBD). Materials and methods: BASILAR was a national prospective registry of consecutive patients with symptomatic and imaging-confirmed acute stroke in the posterior circulation within 24 h of symptom onset. We evaluated EVT feasibility and safety in patients with VBD. Primary outcomes included improvement in modified Rankin Scale scores (mRS) at 90 days and mortality within 90 days. The secondary outcome was the rate of favorable functional outcome, defined as mRS ≤ 3 (indicating independent ambulation) at 90 days. Safety outcomes included surgery-related complications and other serious adverse events. Results: A total of 534 cases were included: 159 with VBD and 375 controls. No significant difference in mRS at 90 days was found between groups, but patients with VBD had a higher baseline National Institutes of Health Stroke Scale (NIHSS) score [30 (19-33) vs. 25 (15-32)] and were older [65 (59-74) vs. 63 (55-72) year]. After propensity score matching, there were no significant differences in baseline NIHSS score between the two groups, and the efficacy and safety of EVT were similar between patients with or without VBD. Furthermore, the prognostic effect of puncture-to-recanalization time on the probability of mortality within 90 days in EVT-treated patients with VBD was significant {adjusted odds ratio, 1.008 [95% confidence interval (1.001-1.015)]}. Conclusion: Endovascular therapy is safe and feasible in patients with acute posterior circulation stroke and VBD. The puncture-to-recanalization time is important for predicting the prognosis of EVT-treated patients with VBD.

Effect of Intravenous Tirofiban vs Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke: The RESCUE BT Randomized Clinical Trial.

Importance: Tirofiban is a highly selective nonpeptide antagonist of glycoprotein IIb/IIIa receptor, which reversibly inhibits platelet aggregation. It remains uncertain whether intravenous tirofiban is effective to improve functional outcomes for patients with large vessel occlusion ischemic stroke undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke secondary to large vessel occlusion. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 55 hospitals in China, enrolling 948 patients with stroke and proximal intracranial large vessel occlusion presenting within 24 hours of time last known well. Recruitment took place between October 10, 2018, and October 31, 2021, with final follow-up on January 15, 2022. Interventions: Participants received intravenous tirofiban (n = 463) or placebo (n = 485) prior to endovascular thrombectomy. Main Outcomes and Measures: The primary outcome was disability level at 90 days as measured by overall distribution of the modified Rankin Scale scores from 0 (no symptoms) to 6 (death). The primary safety outcome was the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 948 patients randomized (mean age, 67 years; 391 [41.2%] women), 948 (100%) completed the trial. The median (IQR) 90-day modified Rankin Scale score in the tirofiban group vs placebo group was 3 (1-4) vs 3 (1-4). The adjusted common odds ratio for a lower level of disability with tirofiban vs placebo was 1.08 (95% CI, 0.86-1.36). Incidence of symptomatic intracranial hemorrhage was 9.7% in the tirofiban group vs 6.4% in the placebo group (difference, 3.3% [95% CI, -0.2% to 6.8%]). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke undergoing endovascular thrombectomy, treatment with intravenous tirofiban, compared with placebo, before endovascular therapy resulted in no significant difference in disability severity at 90 days. The findings do not support use of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR-IOR-17014167.

Oxidative Stress Can Be Attenuated by 4-PBA Caused by High-Fat or Ammonia Nitrogen in Cultured Spotted Seabass: The Mechanism Is Related to Endoplasmic Reticulum Stress.

Oxidative stress is a common phenomenon in aquaculture, which can be induced by nutritional or environmental factors. Generally, oxidative stress causes poor growth performance, metabolic dysregulation, and even the death of aquatic animals. To identify a nutritional intervention strategy, high-fat diet (HFD) feeding (Experiment I) and acute ammonia nitrogen challenge (Experiment II) tests were carried out. In Experiment I, HFD feeding significantly decreased the growth performance concomitantly with excessive fat deposition in the liver and abdomen. The addition of 4-PBA in the diet improved the excessive fat accumulation. The activities of antioxidative enzymes were suppressed, and the levels of lipid and protein peroxidation were increased, indicating that HFD feeding induced oxidative stress. The endoplasmic reticulum stress (ERs) related genes were downregulated in the HFD group. Under a transmission electron microscope (TEM), more swollen and dilated ER lumen could be observed. These results indicated that the HFD induced ERs activation. Although 4-PBA acted as a potent ERs inhibitor, as evidenced by the alleviated alterations of ERs molecules and the ER ultrastructure, the oxidative stress was also attenuated by 4-PBA. In Experiment II, dietary 4-PBA improved the tolerance to the acute ammonia nitrogen challenge, as lower mortality and serum aminotransferase activity was found. Further results showed that 4-PBA decreased the peroxidation content and attenuated ERs, thus confirming the correlation between oxidative stress and ERs. Our findings showed that dietary 4-PBA supplementation can attenuate oxidative stress induced by a HFD or acute ammonia challenge; the mechanism is related to its potent inhibition effect for ERs.

Hydroxytyrosol Promotes the Mitochondrial Function through Activating Mitophagy.

Emerging evidence suggests that mitochondrial dysfunction mediates the pathogenesis for non-alcoholic fatty liver disease (NAFLD). Hydroxytyrosol (HT) is a key component of extra virgin olive oil which can exert beneficial effects on NAFLD through modulating mitochondria. However, the mechanism of the impacts of HT still remains elusive. Thus, an in vivo and a series of in vitro experiments were carried out to examine the impacts of hydroxytyrosol (HT) on lipid metabolism and mitochondrial function in fish. For the in vivo experiment, two diets were produced to contain 10% and 16% fat as normal-fat and high-fat diets (NFD and HFD) and two additional diets were prepared by supplementing 200 mg/kg of HT to the NFD and HFD. The test diets were fed to triplicate groups of spotted seabass (Lateolabrax maculatus) juveniles for 8 weeks. The results showed that feeding HFD leads to increased fat deposition in the liver and induces oxidative stress, both of which were ameliorated by HT application. Furthermore, transmission electron microscopy revealed that HFD destroyed mitochondrial cristae and matrix and induced severe hydropic phenotype, while HT administration relieved these alterations. The results of in vitro studies using zebrafish liver cell line (ZFL) showed that HT promotes mitochondrial function and activates PINK1-mediated mitophagy. These beneficial effects of HT disappeared when the cells were treated with cyclosporin A (Csa) as a mitophagy inhibitor. Moreover, the PINK1-mediated mitophagy activation by HT was blocked when compound C (CC) was used as an AMPK inhibitor. In conclusion, our findings demonstrated that HT alleviates fat accumulation, oxidative stress and mitochondrial dysfunction, and its effects are deemed to be mediated via activating mitophagy through the AMPK/PINK1 pathway.

Biochemical composition and function of subalpine shrubland and meadow soil microbiomes in the Qilian Mountains, Qinghai-Tibetan plateau, China.

Microorganisms participate in the soil biogeochemical cycle. Therefore, investigating variations in microbial biomass, composition, and functions can provide a reference for improving soil ecological quality due to the sensitivity of microorganisms to vegetation coverage changes. However, the differences in soil microorganisms between shrubland and meadow have not been investigated in ecologically vulnerable subalpine areas. This study aimed to investigate the biochemical composition and functions of the soil microbial community under two shrublands and a meadow at high altitudes (3,400-3,550 m). Three sites under two shrublands, Rhododendron thymifolium (RHO) and Potentilla fruticosa (POT), and one meadow dominated by Kobresia myosuroides (MEA), were selected on the southern slope of the Qilian Mountains on the northeastern edge of the Qinghai-Tibetan Plateau, China. Soil physicochemical properties, the microbial community composition expressed by the phospholipid fatty acid (PLFA) biomarker, and enzyme activities were analyzed as well as their relationships. The results showed that water holding capacity and the soil carbon, nitrogen, and potassium content in RHO and POT were higher than those in the MEA. Moreover, the soil active carbon, dissolved organic carbon, total nitrogen, and dissolved total nitrogen content in RHO were higher than those in POT. The abundance of total PLFAs, bacteria, and fungi beneath the shrublands was considerably higher than that in the MEA. The PLFA abundance in RHO was significantly higher than that in POT. The fungal-to-bacterial ratio of RHO and POT was significantly higher than that in the MEA. The activities of ß-glucosidase, cellobiohydrolase, and leucine aminopeptidase were the highest in RHO among the three vegetation types, followed by POT and MEA. The redundancy analysis indicated that the biochemical composition of the soil microorganisms and enzyme activities were driven by total nitrogen, dissolved organic carbon, water holding capacity, and soil organic carbon. Therefore, shrublands, which have higher biomass, can improve soil moisture status, increase soil carbon and nitrogen content (especially active carbon and active nitrogen), and further increase the abundance of total PLFAs, bacteria, and fungi. The increase of microbial biomass indirectly enhances the activity of relevant soil enzymes. The variations in PLFA abundance and enzyme activities can be attributed to shrub species, especially evergreen shrubs, which create more favorable conditions for soil microorganisms. This study provides a theoretical basis for investigating the soil biogeochemical cycle and a scientific basis for soil management and vegetation restoration in the subalpine regions.