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Context: Recently, increasing studies investigated the association between inflammation parameter such as neutrophil to lymphocyte ratio (NLR) and the prognosis of cancers. However, the clinical and prognostic significance of NLR in breast cancer remains controversial.Aim: This meta-analysis was conducted to establish the overall accuracy of the NLR test in the diagnosis of breast cancer.Materials and Methods: A comprehensive search of the literature was conducted using PubMed and Web of Science. Six studies dating up to July 2014 with 2267 patients were enrolled in the present study. STATA 11.0 software (STATA Corporation, College Station, TX, USA) was selected for data analysis. In order to evaluate the association between NLR and overall survival (OS), disease-free survival (DFS), recurrence-free survival or cancer-specific survival, the hazard ratios (HRs), and their 95% confidence intervals (CIs) were extracted.Results: Subgroup analyses showed that NLR was a strong prognostic factor for OS in multivariate analysis (HR = 2.81, 95% CI = 2.13-3.71, PH = 0.992) and without metastasis (HR = 1.45, 95% CI = 0.37-5.66, PH < 0.001). Elevated NLR was associated with a high risk for DFS in subgroups of multivariate analysis (HR = 2.16, 95% CI = 1.67-2.80, PH = 0.977) and mixed metastasis (HR = 2.13, 95% CI = 1.38-3.30, PH = 0.84).Conclusion: In summary, NLR may be considered as a predictive factor for patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: Telbivudine can cause severe side effects, including myositis, neuritis, rhabdomyolysis, and lactic acidosis. However, reported cases of telbivudine leading to multiple organ failure are rare. Here, we report a case of telbivudine-induced severe polymyositis, lactic acidosis, and multiple organ failure.Case Presentation: A 30-year-old Chinese man with hepatitis B virus infection received antiviral treatment with 600 mg of telbivudine daily for more than 11 months. He developed progressive weakness and myalgia, and subsequently experienced palpitations, chest tightness, lethargy, hypotension, and hypoxemia. Blood tests showed markedly elevated levels of alanine aminotransferase (955 U/L), aspartate aminotransferase (1375 U/L), blood urea nitrogen (14.9 mmol/L), creatine kinase (peak at 8050 U/L), and blood lactate (>20.0 mmol/L). His symptoms improved after continuous renal replacement therapy and short-term methylprednisolone treatment. Hyperbaric oxygen therapy, physical therapy, and rehabilitation for more than 2 months led to recovery of muscle strength to the normal range.Conclusions: We conclude that continuous renal replacement and steroid therapies play key roles in stabilizing telbivudine-induced severe rhabdomyolysis, lactic acidosis, and multiple organ failure. Hyperbaric oxygen, physical therapy, and rehabilitation may aid in functional recovery after the acute phase of lactic acidosis and organ failure. [ABSTRACT FROM AUTHOR]

Aim Of Study: Genetic studies have shown a significant association between lung cancer risk and single nucleotide polymorphisms on chromosome 15q25.1. The potential association of three polymorphisms in the CHRNA3 (rs1051730(G > A)), CHRNA5 (rs16969968(G > A)), and AGPHD1 (rs8034191(A > G)) with the lung cancer risk has been widely investigated, but the results are inconsistent. The aim of meta-analysis was toclarify the link between three polymorphisms and susceptibility to lung cancer.Materials and Methods: All the relevant data were retrieved by Embase, PubMed, and Web of Science, and then 38 eligible studies were chosen in this meta-analysis.Results: There was no association of rs16969968 polymorphism with cancer risk in the overall pooled analysis. For the rs1051730 and rs8034191 polymorphisms, the results revealed that the five models were significantlyassociated with elevated risk of cancer. Further stratified analysis indicated that increased risk for lung cancer was foundinthe Caucasian, African American, and Asian population.Conclusion: In summary, CHRNA3 rs1051730 (G > A) and AGPHD1 rs8034191 (A > G) were more susceptible to lung cancers than noncarriers. [ABSTRACT FROM AUTHOR]

Fas and its ligand (FasL) play an important role in apoptosis and carcinogenesis. Therefore, the potential association of polymorphisms in the Fas (-670A>G, rs1800682; -1377G>A, rs2234767) and FasL (-844C>T, rs763110) with cancer risk has been widely investigated. However, all the currently available results are not always consistent. In this work, we performed a meta-analysis to further determine whether carriers of the polymorphisms in Fas and FasL of interest could confer an altered susceptibility to cancer. All relevant data were retrieved by PubMed and Web of Science, and 52 eligible studies were chosen for this meta-analysis. There was no association of the Fas -670A>G polymorphism with cancer risk in the pooled data. For the Fas -1377G>A and FasL -844C>T polymorphisms, results revealed that the homozygotes of -1377A and -844C were associated with elevated risk of cancer as a whole. Further stratified analysis indicated markedly increased risk for developing breast cancer, gastric cancer, and esophageal cancer, in particular in Asian population. We conclude that carriers of the Fas-1377A and the FasL -844C are more susceptible to the majority of cancers than non-carriers. [ABSTRACT FROM AUTHOR]

It has been reported that hepatitis B virus (HBV) core protein (HBc) can inhibit the transcription of human interferon-induced MxA gene. In this study, we investigated whether HBc protein mutations at hot spots (L60V, S87G and I97L) could still inhibit MxA transcription and the potential significance of this inhibition in virus replication in vitro. Our data indicated that the IFN-induced MxA mRNA expression level and MxA promoter activity was significantly down-regulated by mutant protein of HBc(I97L), compared to WT and the other two mutated HBc proteins( L60V or S87G). However, in Huh7 cells stably expressing WT or the mutated HBc proteins (L60V, S87G or I97L), IFN-α could inhibit the extra- and intracellular HBV DNA level and HBsAg secretion to a similar level compared to that in cells transfected with control plasmids. In conclusion, HBc protein with I97L mutation may play an especial role in suppressing the transcription of MxA gene. Moreover, the inhibitory effect on MxA gene transcription by the WT or mutated HBc proteins (L60V, S87G and I97L) has no impact on inhibition of HBV replication by IFN-α in Huh7 cells. The clinical significance of the inhibitory effect of MxA gene transcription by HBc protein requires further study. [ABSTRACT FROM AUTHOR]

Multi-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8) agonist, has potential antineoplastic properties. Here, we reported the antibacterial and antibiofilm activities of D-3263. Minimum inhibitory concentrations (MICs) against S. aureus, Enterococcus faecalis and E. faecium were ≤ 50 µM. D-3263 exhibited bactericidal effects against clinical methicillin-resistant S. aureus (MRSA) and E. faecalis strains at 4× MIC. Subinhibitory D-3263 concentrations effectively inhibited S. aureus and E. faecalis biofilms, with higher concentrations also clearing mature biofilms. Proteomic analysis revealed differential expression of 29 proteins under 1/2 × MIC D-3263, influencing amino acid biosynthesis and carbohydrate metabolism. Additionally, D-3263 enhanced membrane permeability of S. aureus and E. faecalis. Bacterial membrane phospholipids phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) dose-dependently increased D-3263 MICs. Overall, our data suggested that D-3263 exhibited potent antibacterial and antibiofilm activities against S. aureus by targeting the cell membrane. [ABSTRACT FROM AUTHOR]

Background: Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the impact of edaravone dexborneol on functional outcomes and systematic inflammatory response in AIS patient. Methods: All participants were recruited from the AISRNA study (registered 21/11/2019, NCT04175691 [ClinicalTrials.gov]) between January 2022 and December 2022. The AIS patients were divided into two groups based on whether they received the treatment of edaravone dexborneol (37.5 mg/12 hours, IV) within 48 h after stroke onset. Inflammatory response was determined by detecting levels of cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-8, IL-6, IL-10, IL-12p70, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], IFN-α, and IL-1β) within 14 days after stroke onset. Results: Eighty-five AIS patients were included from the AISRNA study. Patients treated with edaravone dexborneol showed a significantly higher proportion of modified Rankin Scale score < 2 compared to those who did not receive this treatment (70.7% versus 47.8%; P = 0.031). Furthermore, individuals receiving edaravone dexborneol injection exhibited lower expression levels of interleukin (IL)-1β, IL-6, and IL-17, along with higher levels of IL-4 and IL-10 expression during the acute phase of ischemic stroke (P < 0.05). These trends were not observed for IL-2, IL-5, IL-8, IL-12p70, tumor necrosis factor-α, interferon-γ [IFN-γ], and IFN-α (P > 0.05). Conclusions: Treatment with edaravone dexborneol resulted in a favorable functional outcome at 90 days post-stroke onset when compared to patients without this intervention; it also suppressed proinflammatory factors expression while increasing anti-inflammatory factors levels. Trial registration: ClinicalTrials.gov NCT04175691. Registered November 21, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691. [ABSTRACT FROM AUTHOR]

Background: Solithromycin, the fourth generation of ketolides, has been demonstrated potent antibacterial effect against commonly-isolated gram-positive strains. However, Staphylococcus aureus (S. aureus) strains with a higher solithromycin MIC have already been emerged, the mechanism of which is unknown.Methods: Antimicrobial susceptibility test was performed on 266 strains of S. aureus. The antibiotic resistance phenotype of erm-positive strain was determined by D-zone test. Spontaneous mutation frequency analysis was performed to compare the risk levels for solithromycin resistance among different strains. Efflux pumps and mutational analysis of ribosomal fragments as well as erm(B) gene domains were detected. Quantitative reverse transcription polymerase chain reaction was conducted to compare the transcriptional expression of the erm gene between the constitutive macrolide-lincosamide-streptogramin B (cMLSB)- and inducible MLSB (iMLSB)-phenotypes.Results: In the erm-positive S. aureus strains, the minimum inhibitory concentration (MIC)50/90 of solithromycin (2/> 16 mg/L) was significantly higher than that in the erm-negative strains (0.125/0.25 mg/L). Of note, the MIC50 value of the strains with iMLSB (0.25 mg/L) was significantly lower than that of the strains with cMLSB (4 mg/L). A comparison among strains demonstrated that the median mutational frequency in isolates with cMLSB (> 1.2 × 10- 4) was approximately > 57-fold and > 3333-fold higher than that in iMLSB strains (2.1 × 10- 6) and in erythromycin-sensitive strains (3.6 × 10- 8), respectively. The differential antibiotic in vitro activity against strains between cMLSB and iMLSB could not be explained by efflux pump carriers or genetic mutations in the test genes. The expression of the erm genes in strains with cMLSB did not differ from that in strains with iMLSB.Conclusions: The reduced susceptibility to solithromycin by S. aureus was associated with the cMLSB resistance phenotype mediated by erm. [ABSTRACT FROM AUTHOR]

De-identification, identifying and removing all protected health information (PHI) present in clinical data including electronic medical records (EMRs), is a critical step in making clinical data publicly available. The 2014 i2b2 (Center of Informatics for Integrating Biology and Bedside) clinical natural language processing (NLP) challenge sets up a track for de-identification (track 1). In this study, we propose a hybrid system based on both machine learning and rule approaches for the de-identification track. In our system, PHI instances are first identified by two (token-level and character-level) conditional random fields (CRFs) and a rule-based classifier, and then are merged by some rules. Experiments conducted on the i2b2 corpus show that our system submitted for the challenge achieves the highest micro F-scores of 94.64%, 91.24% and 91.63% under the "token", "strict" and "relaxed" criteria respectively, which is among top-ranked systems of the 2014 i2b2 challenge. After integrating some refined localization dictionaries, our system is further improved with F-scores of 94.83%, 91.57% and 91.95% under the "token", "strict" and "relaxed" criteria respectively. [ABSTRACT FROM AUTHOR]

Despite recent progress in prediction and prevention, heart disease remains a leading cause of death. One preliminary step in heart disease prediction and prevention is risk factor identification. Many studies have been proposed to identify risk factors associated with heart disease; however, none have attempted to identify all risk factors. In 2014, the National Center of Informatics for Integrating Biology and Beside (i2b2) issued a clinical natural language processing (NLP) challenge that involved a track (track 2) for identifying heart disease risk factors in clinical texts over time. This track aimed to identify medically relevant information related to heart disease risk and track the progression over sets of longitudinal patient medical records. Identification of tags and attributes associated with disease presence and progression, risk factors, and medications in patient medical history were required. Our participation led to development of a hybrid pipeline system based on both machine learning-based and rule-based approaches. Evaluation using the challenge corpus revealed that our system achieved an F1-score of 92.68%, making it the top-ranked system (without additional annotations) of the 2014 i2b2 clinical NLP challenge. [ABSTRACT FROM AUTHOR]

High-resolution magnetic resonance imaging (HRMRI) is the most important and popular vessel wall imaging technique for the direct assessment of vessel wall and cerebral arterial disease. It can identify the cause of stroke in high-risk plaques and differentiate the diagnosis of head and carotid artery dissection, including inflammation, Moya Moya disease, cerebral aneurysm, vasospasm after subarachnoid hemorrhage, reversible cerebral vasoconstriction syndrome, blunt cerebrovascular injury, cerebral arteriovenous malformations, and other stenosis or occlusion conditions. Through noninvasive visualization of the vessel wall in vitro, quantified assessment of luminal stenosis and pathological features of the vessel wall can provide clinicians with further disease information. In this report, technical considerations of HRMRI are discussed, and current clinical applications of HRMRI are reviewed. [ABSTRACT FROM AUTHOR]

Early neurologic deterioration (END) is a common and feared complication for acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). This study aimed to develop an interpretable machine learning (ML) model for individualized prediction to predict END in AIS patients treated with MT. The retrospective cohort of AIS patients who underwent MT was from two hospitals. ML methods applied include logistic regression (LR), random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver operating characteristic curve (AUC) was the main evaluation metric used. We also used Shapley Additive Explanation (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) to interpret the result of the prediction model. A total of 985 patients were enrolled in this study, and the development of END was noted in 157 patients (15.9%). Among the used models, XGBoost had the highest prediction power (AUC = 0.826, 95% CI 0.781–0.871). The Delong test and calibration curve indicated that XGBoost significantly surpassed those of the other models in prediction. In addition, the AUC in the validating set was 0.846, which showed a good performance of the XGBoost. The SHAP method revealed that blood glucose was the most important predictor variable. The constructed interpretable ML model can be used to predict the risk probability of END after MT in AIS patients. It may help clinical decision making in the perioperative period of AIS patients treated with MT. [ABSTRACT FROM AUTHOR]

Background: Microglia assume opposite phenotypes in response to ischemic brain injury, exerting neurotoxic and neuroprotective effects under different ischemic stages. Modulating M1/M2 polarization is a potential therapy for treating ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) held the capacity to regulate neuroinflammation and astrocytic polarization, but little is known about rTMS effects on microglia. Therefore, the present study aimed to examine the rTMS influence on microglia polarization and the underlying possible molecular mechanisms in ischemic stroke models.Methods: Previously reported 10 Hz rTMS protocol that regulated astrocytic polarization was used to stimulate transient middle cerebral artery occlusion (MCAO) rats and oxygen and glucose deprivation/reoxygenation (OGD/R) injured BV2 cells. Specific expression levels of M1 marker iNOS and M2 marker CD206 were measured by western blotting and immunofluorescence. MicroRNA expression changes detected by high-throughput second-generation sequencing were validated by RT-PCR and fluorescence in situ hybridization (FISH) analysis. Dual-luciferase report assay and miRNA knock-down were applied to verify the possible mechanisms regulated by rTMS. Microglia culture medium (MCM) from different groups were collected to measure the TNF-α and IL-10 concentrations, and detect the influence on neuronal survival. Finally, TTC staining and modified Neurological Severity Score (mNSS) were used to determine the effects of MCM on ischemic stroke volume and neurological functions.Results: The 10 Hz rTMS inhibited ischemia/reperfusion induced M1 microglia and significantly increased let-7b-5p level in microglia. HMGA2 was predicted and proved to be the target protein of let-7b-5p. HMGA2 and its downstream NF-κB signaling pathway were inhibited by rTMS. Microglia culture medium (MCM) collected from rTMS treated microglia contained lower TNF-α concentration but higher IL-10 concentration than no rTMS treated MCM, reducing ischemic volumes and neurological deficits of MCAO mice. However, knockdown of let-7b-5p by antagomir reversed rTMS effects on microglia phenotype and associated HMGA/NF-κB activation and neurological recovery.Conclusion: High-frequency rTMS could alleviate ischemic stroke injury through inhibiting M1 microglia polarization via regulating let-7b-5p/HMGA2/NF-κB signaling pathway in MCAO models. [ABSTRACT FROM AUTHOR]

Background: The increasing emergence of multidrug-resistant Gram-positive bacterial infections necessitates new antibacterial agents with novel mechanisms of action that can be used to treat these infections. Lomitapide has been approved by FDA for years in reducing levels of low-density lipoprotein (LDL) in cases of familial hypercholesterolemia, whereas the antibacterial effect of lomitapide remains elusive. In this study, the inhibitory activities of lomitapide against Gram-positive bacteria were the first time explored. Quantitative proteomics analysis was then applied to investigate the mechanisms of action of lomitapide. Results: The minimum inhibitory concentration (MIC) values of lomitapide against Gram-positive bacteria including both methicillin sensitive and resistant Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Streptococcus agalactiae were range 12.5–50 μM. Moreover, lomitapide also inhibited anti-biofilm activity against clinical S. aureus isolates. A total of 106 proteins with > 1.5-fold changes in expression were identified upon 1/2 × MIC lomitapide exposure, including 83 up-regulated proteins and 23 down-regulated proteins. Based on bioinformatics analysis, the expression of cell wall damage response proteins including two-component system VraS/VraR, lipoteichoic acid (LPA) D-alanylnation related proteins D-alanyl carrier protein (dltC) and carrier protein ligase (dltA), methionine sulfoxide reductases (mrsA1 and mrsB) were up-regulated. Moreover, the expression of SaeS and multiple fibrinogen-binding proteins (SAOUHSC_01110, FnBPB, SAOUHSC_02802, SdrC, SdrD) which were involved in the bacterial adhesion and biofilm formation, was inhibited by lomitapide. Furthermore, VraS/VraR deletion mutant (ΔvraSR) showed an enhanced lomitapide sensitivity phenotype. Conclusion: Lomitapide displayed broad antimicrobial activities against Gram-positive bacteria. The antibacterial effect of lomitapide may be caused by cell wall destruction, while the anti-biofilm activity may be related to the inhibition of surface proteins. [ABSTRACT FROM AUTHOR]

Background: Previous reports have demonstrated two thiazolidione derivatives (H2-60 and H2-81) can robustly inhibit the planktonic growth and biofilm formation of S. epidermidis and S. aureus by targeting the histidine kinase YycG. Whereas the antibacterial and anti-biofilm activity of these two thiazolidione derivatives (H2-60 and H2-81) against Enterococcus faecium remains elusive. Here, the pET28a-YycG recombinant plasmid were in vitro expressed in E. coli competent cell BL21 (DE3) and induced to express YycG' protein (conding HisKA and HATPase_c domain) by 0.5 mM IPTG and was purified by Ni – NTA agarose and then for the autophosphorylation test. Antimicrobial testing and time-killing assay were also be determined. Anti-biofilm activity of two derivatives with sub-MIC concentration towards positive biofilm producers of clinical E. faecium were detected using polystyrene microtiter plate and CLSM. Results: The MICs of H2-60 and H2-81 in the clinical isolates of E. faecium were in the range from 3.125 mg/L to 25 mg/L. Moreover, either H2-60 or H2-81 showed the excellent bactericidal activity against E. faecium with monotherapy or its combination with daptomycin by time-killing assay. E. faecium planktonic cells can be decreased by H2-60 or H2-81 for more than 3 × log10 CFU/mL after 24 h treatment when combined with daptomycin. Furthermore, over 90% of E. faecium biofilm formation could markedly be inhibited by H2-60 and H2-81 at 1/4 × MIC value. In addition, the frequency of the eradicated viable cells embedded in mature biofilm were evaluated by the confocal laser microscopy, suggesting that of H2-60 combined with ampicillin or daptomycin was significantly high when compared with single treatment (78.17 and 74.48% vs. 41.59%, respectively, P < 0.01). Conclusion: These two thiazolidione derivatives (H2-60 and H2-81) could directly impact the kinase phosphoration activity of YycG of E. faecium. H2-60 combined with daptomycin exhibit the excellent antibacterial and anti-biofilm activity against E. faecium by targeting YycG. [ABSTRACT FROM AUTHOR]

Background: Abnormal expression of long noncoding RNAs (lncRNAs) has been reported in the acute stage of acute ischemic stroke (AIS). This study aimed to explore differential lncRNA expression in the subpopulations of peripheral blood mononuclear cells (PBMCs) from AIS patients and further evaluate its underlying mechanisms in stroke-induced immunosuppression.Methods: We reanalyzed lncRNA microarray data and investigated abnormally expressed lncRNAs in the subpopulations of PBMCs by magnetic cell sorting and real-time quantitative PCR. The potential mechanism of small nucleolar RNA host gene 15 (SNHG15) was explored through in vitro and in vivo approaches.Results: The stroke-induced SNHG15 acted as a checkpoint to inhibit peripheral inflammatory responses. Functional studies showed that SNHG15 promoted M2 macrophage polarization. Mechanistically, SNHG15 expression was dysregulated through the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) signaling pathway. SNHG15, localized in the cytoplasm, interfered with K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 2 and thereby repressed the activation of mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and prevented the production of proinflammatory cytokines. Administration of an adenovirus targeting SNHG15 improved stroke-induced immunosuppression in mice.Conclusions: This study identified SNHG15 as a negative regulator of inflammation in stroke-induced immunosuppression, suggesting it as a novel biomarker and therapeutic target in stroke-associated infection. Trial registration ClinicalTrials.gov NCT04175691. Registered November 25, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691 . [ABSTRACT FROM AUTHOR]

Background and purpose: To investigate the association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) with post-thrombolysis early neurological outcomes including early neurological improvement (ENI) and early neurological deterioration (END) in patients with acute ischemic stroke (AIS). Methods: AIS patients undergoing intravenous thrombolysis were enrolled from April 2016 to September 2019. Blood cell counts were sampled before thrombolysis. Post-thrombolysis END was defined as the National Institutes of Health Stroke Scale (NIHSS) score increase of ≥ 4 within 24 h after thrombolysis. Post-thrombolysis ENI was defined as NIHSS score decrease of ≥ 4 or complete recovery within 24 h. Multinomial logistic regression analysis was performed to explore the relationship of NLR, PLR, and LMR to post-thrombolysis END and ENI. We also used receiver operating characteristic curve analysis to assess the discriminative ability of three ratios in predicting END and ENI. Results: Among 1060 recruited patients, a total of 193 (18.2%) were diagnosed with END and 398 (37.5%) were diagnosed with ENI. Multinomial logistic model indicated that NLR (odds ratio [OR], 1.385; 95% confidence interval [CI] 1.238–1.551, P = 0.001), PLR (OR, 1.013; 95% CI 1.009–1.016, P = 0.001), and LMR (OR, 0.680; 95% CI 0.560–0.825, P = 0.001) were independent factors for post-thrombolysis END. Moreover, NLR (OR, 0.713; 95% CI 0.643–0.791, P = 0.001) served as an independent factor for post-thrombolysis ENI. Area under curve (AUC) of NLR, PLR, and LMR to discriminate END were 0.763, 0.703, and 0.551, respectively. AUC of NLR, PLR, and LMR to discriminate ENI were 0.695, 0.530, and 0.547, respectively. Conclusions: NLR, PLR, and LMR were associated with post-thrombolysis END. NLR and PLR may predict post-thrombolysis END. NLR was related to post-thrombolysis ENI. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 outbreak has brought tremendous psychological pressure to the general population, which may lead to depression. Therefore, this study aim to evaluate the prevalence and clinical correlates of depressive symptoms in the general population quarantined during the COVID-19 outbreak in Shenzhen.Methods: 2237 quarantined general individuals participated in this cross-sectional study from February 14 to March 4, 2020, during their 14 days quarantine. They completed the Zung's Self-Rating Depression Scale (SDS) for depression, Zung's self-rating anxiety scale (SAS) for anxiety, the Pittsburgh Sleep Quality Index (PSQI) for sleep quality, and the Impact of Events Scale-Revised (IES-R) for post-traumatic stress symptoms (PTSS).Results: The prevalence of depressive symptom was 6.21% in quarantined individuals. The depressed group were younger, less married and educated, and had higher SAS, PSQI, IES-R total scores (all p<0.05), as well as more avoidance, intrusion and hyperarousal symptoms than the non-depressed group. Correlation analysis showed significant correlations between SDS score and the following parameters: age, marriage, education, SAS, PSQI, IES-R total and its three subscale scores (Bonferroni corrected all p<0.05). Further multiple regression indicated that age, marriage, education, SAS, PSQI, IES-R total score, Avoidance and Hyperarousal factor were independent predictors of depressive symptom.Limitations: This study adopted a cross-sectional design and used self-report questionnaires.Conclusions: Our results suggest an elevated prevalence of depressive symptom in quarantined general individuals in Shenzhen. Some demographic and clinical variables were associated with depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: Our previous research indicated the excellent in vitro antibacterial activity of Eravacycline (Erava) and its heteroresistance frequency against clinical Staphylococcus aureus isolates. In this study, we further aimed to investigate the mechanisms of Erava resistance and heteroresistance in S. aureus. Eight parental S. aureus isolates were induced under Erava pressure in vitro and the Erava-resistant isolates were selected and identified. Then, the genetic mutations of 30S ribosomal subunits were analyzed by PCR and sequence alignment. RT-qPCR analysis were performed to compare the relative expression of eight candidate genes impacting the susceptibility of tetracycline (Tet) between the resistant or heteroresistant and parental isolates. Furthermore, the in vitro overexpression vectors of three selected candidate genes were constructed to test their impact on the heteroresistance and resistance of Erava in S. aureus. Results: The MICs elevation in Erava-induced resistant S. aureus isolates were identified and the increasing MICs values of another two Tet class antibiotics, including both omadacycline (Omada) and tigecycline (Tige) were also tested. Genetic mutations in 30S ribosomal protein S10 were found frequently in Erava-derived resistant isolates. RT-qPCR analysis and the in vitro overexpression experiments indicated that USA300HOU_RS00550 (an Na/Pi cotransporter family protein) and USA300HOU_RS01625 (a branched-chain amino acid transport system II carrier protein) contributed to Erava heteroresistance in S. aureus. Conclusion: Genetic mutation of 30S ribosome subunits contributed to Erava resistance, and the transcriptional overexpression of USA300HOU_RS01625 and USA300HOU_RS00550 also participated in the occurrence of Erava heteroresistance in S. aureus. [ABSTRACT FROM AUTHOR]

Clinical tools predicting brain edema after reperfusion therapy in acute ischemic stroke are scarce. We aim to develop a nomogram model to predict brain edema within the first 24 h after endovascular treatment (EVT) in the anterior cerebral circulation. A total of 199 patients were retrospectively identified in a single-center stroke registry. Brain edema was measured by midline shift (MLS). The associations between MLS and early neurologic outcomes were described. A nomogram predicting MLS was developed and internally validated. The nomogram was also compared with an available model using the area under the receiver operating characteristic curve (AUC) and decision curve analyses. Overall, 87 patients (43.7%) had MLS. The patients with MLS ≥ 6 mm showed progressive neurological deterioration according to repeated measures analysis of variance. Each millimeter increase in MLS was strongly correlated with the presence of in-hospital death or forgoing treatment (Spearman's rho = 0.429, P <.001). Patients with brain edema were less likely to have functional independence at 3 months (19.5% vs. 46.8%, P <.001). A nomogram model including 24-h CT ASPECT scores and cisternal effacement, hypertension and complete recanalization showed a C-index of 0.874. This tool exhibited a higher AUC and higher net benefit than the available model. This study showed a profound association between MLS and early neurologic outcomes. A nomogram model was developed to predict patients at risk of brain edema after EVT in the anterior cerebral circulation. • Patients with an MLS ≥ 6 mm showed progressive neurological deterioration. • Brain edema was correlated to in-hospital death or forgo treatment. • Patients with brain edema were less likely to have functional independence. • A nomogram model was built to predict brain edema after EVT in acute anterior stroke. [ABSTRACT FROM AUTHOR]

Background: A fraction of patients with penetrating artery infarction (PAI) experience progressive motor deficit deterioration (PMD). We sought to investigate the role of high-sensitivity C-reactive protein (hs-CRP) at admission in predicting PMD.Methods: From January 2015 to September 2018, consecutive patients with PAI from three centers were prospectively enrolled in this study. PMD was defined as worsening of motor function score by ≥1 point on the National Institutes of Health Stroke Scale during the first 5 days after admission. Multivariable logistic regression analyses were performed to explore the relationship between hs-CRP and PMD in patients with PAI. We also performed receiver operating characteristic curve analysis and constructed a nomogram to assess the overall discriminative ability of hs-CRP in predicting PMD.Results: We ultimately included 544 patients (mean age, 65.4 ± 11.8 years). A total of 85 (15.6%) patients were identified to have PMD. Multivariate logistic regression analysis showed that hs-CRP was independently associated with PMD (P = 0.001). The optimal cutoff value for hs-CRP as a predictor for PMD was 3.48 mg/L, with a sensitivity of 73.64% and a specificity of 82.35% (area under curve, 0.792). Moreover, the nomogram we constructed indicated that higher level of hs-CRP was an indicator of PMD (c-index = 0.780, P < 0.001).Conclusions: Our study suggested that hs-CRP might be a useful biomarker for predicting the risk of PMD in patients with PAI. [ABSTRACT FROM AUTHOR]

Abstract The functionality of photovoltaic devices (such as, solar cells) is converting photons to electricity. Characterization of photovoltaic devices is essential at production level and during use. Here we put forward a new concept of functional imaging for photovoltaic devices. Based on the concept, we also propose an optical technique that can simultaneously acquire functionality and structure images of a single or multiple photovoltaic devices. The technique is simple, low-cost, effective, and efficient. It requires no mechanic motion and instead structured illumination is adopted for image acquisition. The complementary information provided by the functionality and structure images acquired allows one to better identify any existing and developing faults of photovoltaic devices. What's more, the technique is able to give reliable results with much fewer measurements than image pixels by exploiting the sparsity of functionality and structure images in the Fourier domain. The technique allows not only users to monitor the 'health condition' of the utilized devices, but also manufacturers to improve their fabrication conditions. The proposed technique may be applicable for rapid characterization for other semiconductor-based devices. Highlights • A new concept of functional imaging for photovoltaic devices characterization proposed. • Current response mapping and reflectance distribution acquisition for photovoltaic devices at the same time. • Accurate and rapid characterization for photovoltaic devices and other semi-conductor devices. [ABSTRACT FROM AUTHOR]

Abstract Although combination antiretroviral therapy (cART) is highly effective in suppressing human immunodeficiency virus type 1 (HIV-1) replication, it fails to eradicate the virus from HIV-1-infected individuals because HIV-1 integrates into the resting CD4+ T cells, establishing latently infected reservoirs. Histone deacetylation is a key element in regulating HIV-1 latent infection. Chidamide, a new anticancer drug, is a novel type of selective histone deacetylase inhibitor. Here we showed that chidamide effectively reactivated HIV-1 latent provirus in different latently infected cell lines in a dose- and time-dependent manner. Chidamide had relatively low cytotoxicity to peripheral blood mononuclear cells (PBMCs) and other latent cell lines. We have demonstrated that chidamide reactivated HIV-1 latent provirus through the NF-κB signaling pathway. The replication of the newly reactivated HIV-1 could then be effectively inhibited by the anti-HIV-1 drugs Zidovudine, Nevirapine, and Indinavir. Therefore, chidamide might be used in combination with cART for functional HIV-1 cure. [ABSTRACT FROM AUTHOR]

In early 2014, a novel subclade (2.3.4.4) of the highly pathogenic avian influenza (HPAI) A(H5N8) virus caused the first outbreak in domestic ducks and migratory birds in South Korea. Since then, it has spread to 44 countries and regions. To date, no human infections with A(H5N8) virus have been reported, but the possibility cannot be excluded. By analyzing the genomic signatures of A(H5N8) strains, we found that among the 47 species-associated signature positions, three positions exhibited human-like signatures (HLS), including PA-404S, PB2-613I and PB2-702R and that mutation trend of host signatures of avian A(H5N8) is different before and after 2014. About 82% of A(H5N8) isolates collected after January of 2014 carried the 3 HLS (PA-404S/PB2-613I/PB2-702R) in combination, while none of isolates collected before 2014 had this combination. Furthermore, the HA protein had S137A and S227R substitutions in the receptor-binding site and A160T in the glycosylation site, potentially increasing viral ability to bind human-type receptors. Based on these findings, the newly emerged HPAI A(H5N8) isolates show an evolutionary trend toward gaining more HLS and, along with it, the potential for bird-to-human transmissibility. Therefore, more extensive surveillance of this rapidly spreading HPAI A(H5N8) and preparedness against its potential pandemic are urgently needed. [ABSTRACT FROM AUTHOR]

• Imges features of recurrent retropharyngeal lymph node were identified. • Analysis radiologic-histopathologic data from nasopharyngeal carcer patients. • Developed models to predict recurrent retropharyngeal lymph node. • Endonasopharyngeal ultrasonography improved the diagnosis of recurrent lymph node. The imaging criteria of malignant retropharyngeal lymph node (RLN) in nasopharyngeal cancer (NPC) have yet to be fully elucidated. This study aimed to establish predictive models based on ultrasound (US) and magnetic resonance (MR) characteristics for identifying malignant RLN in NPC patients after radiotherapy. 81 post-radiotherapy NPC patients with abnormal enlargement of RLN underwent endonasopharyngeal ultrasound-guided fine-needle aspirations (EPUS-FNA) to access the nature of RLN. The following features were assessed on US and MR: size, margin, vascular signal, echogenicity, enhancement signal and accompany with suspicious cervical nodes or not. A multivariate analysis was performed to screen out high-risk imaging features for recurrent RLN (RRLN), and models for the diagnosis of RRLN was constructed and tested with internal verification. We evaluated the clinical usefulness of the models through comparison of C-index and decision curve analysis. High-risk features of RRLN were heterogeneous echo (p < 0.01), vascular signal (p < 0.01) on EPUS, heterogeneous enhancement (p < 0.01) and minimum axis diameter > 10 mm (p < 0.01) on MR. The models based on the US and MR features showed good discrimination (AUC of 0.76 in the US model, 0.74 in the MR model and 0.77 in the US + MR model) and good net benefit in the validation group. Prediction models based on the US and MR features show good diagnostic performance for RRLN after radiotherapy in NPC patients. The combination of EPUS and MR may be constructed to provide prompt and reliable guidance to manage RLN. [ABSTRACT FROM AUTHOR]

The aims of this study were to compare the antimicrobial efficacy of Eravacycline (Erava) versus tigecycline (Tig) in vitro against clinical isolates of S. agalactiae from China and further to evaluate the heteroresistance risk and resistance mechanisms of Erava. 162 clinical isolates of S. agalactiae were collected retrospectively and the minimal inhibitory concentrations (MICs) of Erava and Tig were determined by agar dilution. Moreover, Tetracycline (Tet) specific resistance genes, genetic mutations in Tet target sites, and sequence types (ST) profiles of clinical isolates of S. agalactiae were investigated with polymerase chain reaction (PCR) experiments. The heteroresistance frequency of Erava and Tig in S. agalactiae was analyzed by population analysis profiling. Furthermore, the resistance mechanisms of both Erava and Tig were investigated in antibiotic-induced resistant S. agalactiae isolates in vitro. The MIC values of Erava and Tig were shown with ≤0.25 mg/L and ≤0.5 mg/L, respectively, against clinical S. agalactiae isolates, including that harboring the Tet-specific resistance genes tet (K), tet (M), or tet (O). The heteroresistance frequency of Tig among the clinical isolates of S. agalactiae was 1.84% (3/162), whereas no positive Erava heteroresistance was found. The enhanced MIC values of both Erava and Tig in the heteroresistance-derivative S. agalactiae clones could be reversed by the efflux pump inhibition experiments. Genetic mutations affecting 30S ribosome units (16SrRNA copies or 30S ribosome protein S10) could result in the cross resistance toward Erava and Tig in the antibiotic-induced resistant S. agalactiae isolates in vitro. Erava MIC values were nearly half of that of Tig against the clinical isolates of S. agalactiae from China and genetic mutations in the 30S ribosome units of Tet target sites (16SrRNA copies or 30S ribosome protein S10) participated in the resistance evolution of both Erava and Tig under the antibiotic pressure. • Erava exhibited robust in vitro antibacterial activity with MIC value ≤ 0.25mg/L against clinical isolates of S. agalactiae. • The heteroresistance frequency of tigecycline was 1.84% (3/162), whereas no Erava heteroresistance was found. • The MICs of Erava and Tig in the heteroresistance-derivative S. agalactiae clones were reversed by efflux pump inhibition. • The Lys57Arg mutation in the 30S ribosomal protein S10 was commonly found in the antibiotic-induced resistant S. agalactiae. [ABSTRACT FROM AUTHOR]

Intestinal ischemia/reperfusion (I/R) injury is a severe medical condition associated with high mortality rates due to its disruption of intestinal homeostasis and impairment of mucosal defenses. The intestinal epithelium, particularly goblet and Paneth cells, plays a critical role in maintaining gut barrier integrity. Protein disulfide isomerase A3 (PDIA3) is involved in protein folding within intestinal epithelial cells (IECs) and has been linked to the stress response during I/R injury. This study aims to explore the role of PDIA3 in preserving intestinal integrity and immune function during I/R injury. Our study employed both human and mouse models to investigate PDIA3's expression and function. The correlation between PDIA3 expression and disease severity was analyzed using statistical tests, including Pearson's correlation coefficient. An intestinal I/R model was established in intestinal epithelium-specific conditional knockout mice lacking the Pdia3 gene. Single-cell RNA sequencing, immunohistochemistry, and transcriptomic analysis were used to assess PDIA3 expression in various intestinal cell types and to evaluate its role in epithelial differentiation and immune responses. PDIA3 was found to be highly expressed in healthy IECs, especially in goblet and Paneth cells. Its expression was reduced in patients with mesenteric artery ischemia and Pdia3-deficient mice, leading to severe intestinal damage, including impaired goblet and Paneth cell function, reduced antimicrobial peptide production, and altered gut microbiota. Treatment with recombinant defensin α1, an antimicrobial peptide secreted by Paneth cells, significantly alleviated the adverse effects of Pdia3 deficiency, restoring gut microbiota balance and reducing inflammation in the intestinal I/R injury mice. Taken together, our findings suggest that Pdia3 plays a vital role in maintaining intestinal barrier function and immune defense. Its deficiency exacerbates I/R-induced intestinal damage by impairing epithelial differentiation, mucus production, and antimicrobial peptide secretion. Targeting Pdia3 and associated pathways offers promising therapeutic strategies for mitigating I/R injury and restoring intestinal homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Acute ischemic stroke is a clinical emergency and a condition with high morbidity, mortality, and disability. Accurate predictive, diagnostic, and prognostic biomarkers and effective therapeutic targets for acute ischemic stroke remain undetermined. With innovations in high-throughput gene sequencing analysis, many aberrantly expressed non-coding RNAs (ncRNAs) in the brain and peripheral blood after acute ischemic stroke have been found in clinical samples and experimental models. Differentially expressed ncRNAs in the post-stroke brain were demonstrated to play vital roles in pathological processes, leading to neuroprotection or deterioration, thus ncRNAs can serve as therapeutic targets in acute ischemic stroke. Moreover, distinctly expressed ncRNAs in the peripheral blood can be used as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. In particular, ncRNAs in peripheral immune cells were recently shown to be involved in the peripheral and brain immune response after acute ischemic stroke. In this review, we consolidate the latest progress of research into the roles of ncRNAs (microRNAs, long ncRNAs, and circular RNAs) in the pathological processes of acute ischemic stroke-induced brain damage, as well as the potential of these ncRNAs to act as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. Findings from this review will provide novel ideas for the clinical application of ncRNAs in acute ischemic stroke., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

Background: The treatment of acute ischemic stroke (AIS) aims to achieve early vascular recanalization and reperfusion of the penumbra. However, the effect of early penumbral imaging within 6 h on clinical outcomes remains unclear. The objective of this study was to determine the effect of magnetic resonance-guided (MR-guided) perfusion imaging within 6 h after symptom onset on endovascular thrombectomy outcomes in AIS patients., Methods: We prospectively collected the clinical information of consecutive AIS patients undergoing endovascular thrombectomy based on MR-guided perfusion imaging within 6 h after symptom onset from AISRNA and EVTRNA studies. The primary outcome was defined as the poor outcome (mRS > 2 within 90 days). The perfusion-weighted imaging/diffusion-weighted imaging (PWI/DWI) mismatch was assessed by an automated software., Results: We enrolled 84 patients (25 in the mismatch ≤ 1.8 group and 59 in the mismatch > 1.8 group). Significant difference was found between the mismatch > 1.8 group and the mismatch ≤ 1.8 group for the incidence of disabling stroke (mRS > 2) within 90 days (40.7% vs. 68.0%, OR: 3.099, 95% CI: 1.154-8.323, P = 0.025). Intracranial hemorrhage occurred in 8 patients (13.6%) in the mismatch > 1.8 group and 10 patients in the mismatch ≤ 1.8 group (40.0%) (P = 0.010). The risk of severe cerebral edema was 2/59 (3.4%) vs. 7/25 (28.0%) (P = 0.004). These findings remained stable after adjustment., Conclusions: MR-guided perfusion imaging mismatch profiles within 6 h after symptom onset may be feasible to predictclinical outcomes and reduce clinically ineffective reperfusion after endovascular thrombectomy., Competing Interests: Declarations. Ethical approval and Informed consent: Study protocol was reviewed and approved by the Ethics Committee of Nanjing First Hospital, Nanjing Medical University (NO. 2019–695). The patients/participants provided written informed consent to participate in this study. Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. Fondazione Società Italiana di Neurologia.)

The rapid proliferation of multidrug-resistant (MDR) bacterial pathogens poses a serious threat to healthcare worldwide. Carbapenem-resistant (CR) Enterobacteriaceae, which have near-universal resistance to available antimicrobials, represent a particularly concerning issue. Herein, we report the identification of AMXT-1501, a polyamine transport system inhibitor with antibacterial activity against Gram-positive and -negative MDR bacteria. We observed minimum inhibitory concentration (MIC) 50 /MIC 90 values for AMXT-1501 in the range of 3.13-12.5 μM (2.24-8.93 μg /mL), including for methicillin-resistant Staphylococcus aureus (MRSA), CR Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa . AMXT-1501 was more effective against MRSA and CR E. coli than vancomycin and tigecycline, respectively. Subinhibitory concentrations of AMXT-1501 reduced the biofilm formation of S. aureus and Enterococcus faecalis . Mechanistically, AMXT-1501 exposure damaged microbial membranes and increased membrane permeability and membrane potential by binding to cardiolipin (CL) and phosphatidylglycerol (PG). Importantly, AMXT-1501 pressure did not induce resistance readily in the tested pathogens.

Cardiovascular disease (CVD) and ischemic stroke (IS) are the primary causes of mortality worldwide. Hypercholesterolemia has been recognized as an independent risk factor for CVD and IS. Numerous clinical trials have unequivocally demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly mitigates the risk of both cardiac and cerebral vascular events, thereby enhancing patient prognosis. Consequently, LDL-C reduction remains a pivotal therapeutic strategy for CVD and IS. However, despite intensive statin therapy, a significant proportion of high-risk hypercholesterolemic patients fail to achieve sufficient reductions in LDL-C levels. In response to this challenge, an inhibitor targeting proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed as a therapeutic intervention for hyperlipidemia. Numerous randomized controlled trials (RCTs) have conclusively demonstrated that the combination of PCSK9 inhibitors and statins significantly enhances prognosis not only in patients with CVD, but also in those afflicted with symptomatic intracranial artery stenosis (sICAS). PCSK9 inhibitors significantly reduce LDL-C levels by binding to the PCSK9 molecule and preventing its interaction with LDLRs. This prevents degradation of the receptor and increases uptake of LDL-C, thereby decreasing its concentration in blood. Besides significantly reducing LDL-C levels, PCSK9 inhibitors also demonstrate anti-inflammatory and anti-atherosclerotic properties while promoting plaque stabilization and inhibiting platelet aggregation and thrombosis. This article aims to provide a comprehensive review based on the relevant literature regarding the evolving understanding of pleiotropic effects associated with PCSK9 inhibitors, particularly focusing on their impact on the cardiovascular system and central nervous system.

Infections and antimicrobial resistance are becoming serious global public health crises. Multidrug-resistant Staphylococcus aureus (S. aureus) infections necessitate novel antimicrobial development. In this study, we demonstrated TAK-285, a novel dual HER2/EGFR inhibitor, exerted antibacterial activity against 17 clinical methicillin-resistant S. aureus (MRSA) and 15 methicillin sensitive S. aureus (MSSA) isolates in vitro, with a minimum inhibitory concentration (MIC) of 13.7 μg/mL. At 1 × MIC, TAK-285 completely inhibited the growth of S. aureus bacterial planktonic cells, and at 2 × MIC, it exhibited a superior inhibitory effect on intracellular S. aureus SA113-GFP compared to linezolid. Moreover, TAK-285 effectively inhibited biofilm formation at sub-MIC, eradicated mature biofilm and eliminated bacteria within biofilms, as confirmed by CLSM. Furthermore, the disruption of cell membrane permeability and potential was found by TAK-285 on S. aureus, suggesting its targeting of cell membrane integrity. Global proteomic analysis demonstrated that TAK-285 disturbed the metabolic processes of S. aureus, interfered with biofilm-related gene expression, and disrupted membrane-associated proteins. Conclusively, we repurposed TAK-285 as an antimicrobial with anti-biofilm properties against S. aureus by targeting cell membrane. This study provided strong evidence for the potential of TAK-285 as a promising antimicrobial agent against S. aureus., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethics Approval: The strain isolates used in this study were obtained from the hospital clinical laboratory, with no direct contact with any animals or humans. According to Chinese guidelines, the isolates were collected as part of routine clinical management, therefore ethical review or patient consent was not required. Consent to Participate: Not applicable. Consent to Publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors enable an additional 54-75% reduction in low-density lipoprotein cholesterol (LDL-C) in statin-treated patients, demonstrating plaque regression in coronary artery disease. However, the impact of achieving an extremely low level of LDL-C with PCSK9 inhibitors (e.g. Evolocumab) on symptomatic intracranial atherosclerosis remains unexplored., Aim and Hypothesis: To determine whether combining Evolocumab and statins achieves a more significant symptomatic intracranial plaque regression than statin therapy alone., Sample Size Estimates: With a sample size of 1000 subjects, a two-sided α of 0.05, and 20% lost to follow-up, the study will have 83.3% power to detect the difference in intracranial plaque burden., Methods and Design: This is an investigator-initiated multicenter, randomized, open-label, outcome assessor-blinded trial, evaluating the impact of combining Evolocumab and statins on intracranial plaque burden assessed by high-resolution magnetic resonance imaging at baseline in patients undergoing a clinically indicated acute stroke or transient ischemic attack due to intracranial artery stenosis, and after 24 weeks of treatment. Subjects (n = 1000) were randomized 1:1 into two groups to receive either Evolocumab 140 mg every 2 weeks with statin therapy or statin therapy alone., Study Outcomes: The primary endpoint is the change in intracranial plaque burden assessed by high-resolution magnetic resonance imaging, performed at baseline and at the end of the 24-week treatment period., Discussion: This trial will explore whether more significant intracranial plaque regression is achievable with the treatment of combining Evolocumab and statins, providing information about efficacy and safety data., Trial Registration Number: ChiCTR2300068868; https://www.chictr.org.cn/., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Idiopathic pulmonary fibrosis (IPF) represents a severe and progressive manifestation of idiopathic interstitial pneumonia marked by an uncertain etiology along with an unfavorable prognosis. Osteoglycin (OGN), belonging to the small leucine-rich proteoglycans family, assumes pivotal functions in both tissue formation and damage response. However, the roles and potential mechanisms of OGN in the context of lung fibrosis remain unexplored., Methods: The assessment of OGN expression levels in fibrotic lungs was conducted across various experimental lung fibrosis mouse models. To elucidate the effects of OGN on the differentiation of lung myofibroblasts, both OGN knockdown and OGN overexpression were employed in vitro. The expression of integrin αv, along with its colocalization with lysosomes and latency-associated peptide (LAP), was monitored in OGN-knockdown lung myofibroblasts. Furthermore, the role of OGN in lung fibrosis was investigated through OGN knockdown utilizing adeno-related virus serotype 6 (AAV6)-mediated delivery., Results: OGN exhibited upregulation in both lungs and myofibroblasts across diverse lung fibrosis mouse models. And laboratory experiments in vitro demonstrated that OGN knockdown inhibited the TGF-β/Smad signaling pathway in lung myofibroblasts. Conversely, OGN overexpression promoted TGF-β/Smad pathway in these cells. Mechanistic insights revealed that OGN knockdown facilitated lysosome-mediated degradation of integrin αv while inhibiting its binding to latency-associated peptide (LAP). Remarkably, AAV6-targeted OGN knockdown ameliorated the extent of lung fibrosis in experimental mouse models., Conclusion: Our results indicate that inhibiting OGN signaling could serve as a promising therapeutic way for lung fibrosis., Competing Interests: Declaration of competing interest No conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Staphylococcus aureus is a versatile pathogen that can cause a wide range of infections in humans. Biofilms play a crucial role in the pathogenicity of S. aureus and contribute to its ability to cause persistent and chronic infections. Baohuoside I has garnered increasing recognition as a natural flavonol glycoside with a wide spectrum of health-related activities., Purpose: The antibacterial and anti-biofilm properties of Baohuoside I have not been extensively investigated. Our study aimed to assess its inhibitory effects and the underlying mechanisms on biofilm formation and hemolytic capacity in S. aureus., Study Design/methods: The impact of Baohuoside I on the biofilm and virulence of S. aureus was evaluated through in vitro experiments and Galleria mellonella as an in vivo infection model. The mechanisms were explored by Drug affinity responsive target stability (DARTS) and validated in genetic knockout strain and through molecular biological experiments using DARTS, molecular docking, electrophoretic mobility shift assay (EMSA), and bio-layer interferometry (BLI)., Results: Baohuoside I significantly inhibits the formation of S. aureus biofilms and hemolytic activity at 6.25 µM. Proteomics analysis revealed that treatment with Baohuoside I led to a reduction in the expression of quorum-sensing system agr-regulated genes. DARTS analysis identified Staphylococcus accessory regulator factor (SarZ), a key regulator involved in the expression of virulence factors in S. aureus by acting as activator of the agr quorum-sensing system, was the direct target of Baohuoside I. Molecular docking, DARTS, BLI and EMSA assays collectively confirmed the direct binding of Baohuoside I to SarZ, inhibiting its binding to downstream promoters. Furthermore, it is found through site-directed protein mutagenesis that the Tyr27 and Phe117 residues are key for Baohuoside I binding to SarZ. Additionally, the knockout of SarZ significantly diminished the hemolytic ability of S. aureus, underscoring its crucial role as a pivotal regulator of virulence. Lastly, in vivo tests utilizing the G. mellonella infection model demonstrated the efficacy of Baohuoside I., Conclusion: This study provides valuable insights into the mechanism by which Baohuoside I inhibits the virulence of S. aureus through its interaction with SarZ. These findings highlight the significance of SarZ as an effective target against the virulence of S. aureus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Introduction: Whether time window affects the intravenous thrombolysis (IVT) effect before endovascular thrombectomy (EVT) is uncertain. We aimed to investigate the effect of different time windows (0-3 h and &gt;3-4.5 h from stroke onset to randomization) on clinical outcomes of EVT with or without IVT in a subgroup analysis of DIRECT-MT., Methods: The primary outcome was the 90-day modified Rankin Scale (mRS) according to time window. Logistic regression models were used to analyze the effect of different treatments (EVT with or without IVT) on outcomes within 0-3 h or &gt;3-4.5 h., Results: Among 656 patients who were included in the analysis, 282 (43.0%) were randomized within &gt;3-4.5 h after stroke onset (125 without IVT and 157 with IVT), and 374 (57.0%) were randomized within 0-3 h (202 without IVT and 172 with IVT). We noted no significant difference in the thrombectomy-alone effect between the time window subgroups according to 90-day ordinal mRS (adjusted common odds ratio [acOR] in patients within 0-3 h: 1.06 [95% CI: 0.73-1.52], acOR in patients within &gt;3-4.5 h: 1.19 [95% CI: 0.78-1.82]) and 90-day functional independence. Thrombectomy alone resulted in an increased proportion of patients with 90-day mRS 0-3 treated within &gt;3-4.5 h (62.90 vs. 48.72%) but not within 0-3 h (65.84 vs. 63.95%). However, there was no interaction effect regarding all outcomes after the Bonferroni correction., Conclusions: Our results did not support thrombectomy-alone administration within 3-4.5 h in patients with acute ischemic stroke from large-vessel occlusion in the subgroup analysis of DIRECT-MT., (© 2023 S. Karger AG, Basel.)

In December 2022, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became dominant in China due to its high infectivity and lower mortality rate. The risk of critical illness and mortality among patients with hematologic malignancies who contracted SARS-CoV-2 was particularly high. The aim of this study was to draft a consensus to facilitate effective treatments for these patients based on the type and severity of the disease. Following the outbreak of the novel coronavirus in China, a steering committee consisting of experienced hematologists was formed by the Specialized Committee of Oncology and Microecology of the Chinese Anti-Cancer Association. The expert group drafted a consensus on the management and intervention measures for different types of hematologic malignancies based on the clinical characteristics of the Omicron variant of the SARS-CoV-2 infection, along with relevant guidelines and literature. The expert group drafted independent recommendations on several important aspects based on the epidemiology of the Omicron variant in China and the unique vulnerability of patients with hematologic malignancies. These included prophylactic vaccinations for those with hematologic malignancies, the use of plasma from blood donors who recovered from the novel coronavirus infection, the establishment of negative pressure wards, the use of steady-state mobilization of peripheral blood hematopoietic stem cells, the provision of psychological support for patients and medical staff, and a focus on maintaining a healthy intestinal microecology., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)