Impact of Off-Hour Admission on In-Hospital Outcomes for Patients With Stroke Receiving Reperfusion Therapy in China.

BACKGROUND: The structure and staffing of hospitals greatly impact patient outcomes, with frequent changes occurring during nights and weekends. This retrospective cohort study assessed the impact of admission timing on in-hospital management and outcomes for patients with stroke receiving reperfusion therapy in China using data from a nationwide registry. METHODS: Data from patients receiving reperfusion therapy were extracted from the Chinese Stroke Center Alliance. Hospital admission time was categorized according to day/evening versus night and weekday versus weekend. Primary outcomes were in-hospital death or discharge against medical advice, hemorrhage transformation, early neurological deterioration, and major adverse cardiovascular events. Logistic regression was performed to compare in-hospital management performance and outcomes based on admission time categories. RESULTS: Overall, 42 381 patients received recombinant tissue-type plasminogen activator (r-tPA) therapy, and 5224 underwent endovascular treatment (EVT). Patients admitted during nighttime had a higher probability of receiving r-tPA therapy within 4.5 hours from onset or undergoing EVT within 6 hours from onset compared with those admitted during day/evening hours (adjusted odds ratio, 1.04 [95% CI, 1.01-1.08]; P=0.021; adjusted odds ratio, 1.72 [95% CI, 1.59-1.86]; P<0.001, respectively). However, no significant difference was observed between weekend and weekday admissions for either treatment. No notable differences were noted between weekends and weekdays or nighttime and daytime periods in door-to-needle time for r-tPA or door-to-puncture time for EVT initiation. Furthermore, weekend or nighttime admission did not have a significant effect on the primary outcomes of r-tPA therapy or EVT. Nevertheless, in patients undergoing EVT, a higher incidence of pneumonia was observed among those admitted at night compared with those admitted during day/evening hours (adjusted odds ratio, 1.22 [95% CI, 1.05-1.42]; P=0.011). CONCLUSIONS: Patients admitted at nighttime were more likely to receive r-tPA therapy or EVT within the time window recommended in the guidelines. However, patients receiving EVT admitted at night had an increased risk of pneumonia.

Structural optimizations on the 7H-pyrrolo[2,3-d]pyrimidine scaffold to develop highly selective, safe and potent JAK3 inhibitors for the treatment of Rheumatoid arthritis.

Janus Kinase 3 (JAK3) is important for the signaling transduction of cytokines in immune cells and is identified as potential target for treatment of rheumatoid arthritis (RA). Recently, we designed and synthesized two JAK3 inhibitors J1b and J1f, which featured with high selectivity but mild bioactivity. Therefore, in present study the structure was optimized to increase the potency. As shown in the results, most of the compounds synthesized showed stronger inhibitory activities against JAK3 in contrast to the lead compounds, among which 9a was the most promising candidate because it had the most potent effect in ameliorating carrageenan-induced inflammation of mice and exhibited low acute in vivo toxicity (MTD > 2 g/kg). Further analysis revealed that 9a was highly selective to JAK3 (IC50 = 0.29 nM) with only minimal effect on other JAK members (>3300-fold) and those kinases bearing a thiol in a position analogous to that of Cys909 in JAK3 (>150-fold). Meanwhile, the selectivity of JAK3 was also confirmed by PBMC stimulation assay, in which 9a irreversibly bound to JAK3 and robustly inhibited the signaling transduction with mild suppression on other JAKs. Moreover, it was showed that 9a could remarkably inhibited the proliferation of lymphocytes in response to concanavalin A and significantly mitigate disease severity in collagen induced arthritis. Therefore, present data indicate that compound 9a is a selective JAK3 inhibitor and could be a promising candidate for clinical treatment of RA.

Baicalin nanodelivery system based on functionalized metal-organic framework for targeted therapy of osteoarthritis by modulating macrophage polarization.

Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.

MMP9 rs17576 Is Simultaneously Correlated with Symptomatic Intracranial Atherosclerotic Stenosis and White Matter Hyperintensities in Chinese Population.

PURPOSE: The aim of this study was screening for single nucleotide polymorphisms (SNPs) associated with white matter hyperintensities (WMHs) in symptomatic intracranial atherosclerotic stenosis (sICAS) patients and exploring a possible connection in the genetic background between macrovascular disease and small vessel disease. METHODS: There were 400 sICAS patients enrolled in the study. Fazekas scores were applied to WMH classification. Healthy controls were referred to 1,000 Genome Project and GeneSky company who provided 1,007 Chinese healthy controls. Fast target sequencing technology was used to select the SNPs of 102 genes related to the pathogenesis of sICAS in the sICAS patients. RESULTS: The allele frequencies of 88 SNPs were significantly different between the sICAS group and the healthy controls (p < 0.05). The allele frequencies of 53 SNPs were significantly different between the sICAS patients with and without WMHs (p < 0.05). Further analysis found that matrix metalloproteinase 9 (MMP9) rs17576 was simultaneously related to sICAS and WMHs. The frequency of the rs17576 A allele was significantly lower in sICAS patients when compared to the normal controls (p = 0.03, OR [95% CI] = 0.75 [0.625-0.91]). Also, the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.009), dominant (p = 0.014), and recessive (p= 0.023) models. The frequency of the rs17576 A allele was significantly higher in sICAS with WMH patients, compared to those without WMHs (p = 0.022, OR [95% CI] = 1.54 [1.06-2.22]); the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.019) and recessive (p = 0.032) models. Logistic regression analysis showed that age, hypertension, and MMP9 rs17576 AA genotype were independent risk factors for sICAS with WMHs. CONCLUSION: MMP9 rs17576 may be simultaneously associated with the risk of sICAS and WMHs.

Low-normal free triiodothyronine and high leukocyte levels in relation to stroke severity and poor outcome in acute ischemic stroke with intracranial atherosclerotic stenosis.

BACKGROUND: It is uncertain that the effect of free triiodothyronine (FT3) within normal ranges on initial severity and early functional outcomes in acute ischemic stroke (AIS) patients with Intracranial Atherosclerotic Stenosis (ICAS). The predictive values of white blood cell (WBC) and FT3 are also unclear in symptomatic ICAS (sICAS) patients. METHODS: We consecutively reviewed 848 ischemic stroke patients admitted into Xiangya Hospital within 72 h after symptom onset. sICAS was defined as AIS patient with degree of ICAS ≥50% proved by magnetic resonance angiography, computed tomography angiography or digital subtraction angiography. WBC and FT3 were assessed within 24 h after admission. Neurological severity was evaluated on admission using the National Institutes of Health Stroke Scale (NIHSS). Stroke outcomes were defined by the modified Rankin Scale (mRS) on the 14th day after admission. RESULTS: Logistic regression analysis showed that hypertension, lower FT3 and higher WBC concentrations independently associated with severe stroke [FT3 (odds ratio(OR) = 0.543, 95% confidence interval(95% CI): 0.383-0.769); hypertension (OR = 0.436, 95% CI: 0.238-0.800); WBC (OR = 1.17; 95% CI:1.041-1.316]. Besides, lower FT3, higher FT4, higher WBC and higher plasma glucose concentrations independently associated with unfavorable outcomes [FT3 (OR = 0.460; 95% CI: 0.306-0.690); FT4 (OR = 1.151; 95% CI: 1.055-1.255); WBC (OR = 1.178; 95% CI: 1.039-1.334); Plasma glucose (OR = 1.160; 95% CI: 1.002-1.342)]. CONCLUSIONS: Lower FT3 levels within normal ranges and higher WBC count are independently associated with the severity and early poor prognosis of sICAS simultaneously, FT3 and WBC count might be important biomarkers for sICAS patients.

Immunity and inflammation predictors for short-term outcome of stroke in young adults.

BACKGROUND: The current study was conducted to identify independent predictors of severity and short-term outcome of first-ever ischemic stroke in young adults. METHODS: We retrospectively enrolled 325 consecutive patients aged 18-49 years with first-ever ischemic stroke admitted to our center between April 2013 and June 2015. Variables were systematically registered and compared between patients with different neurological severity (mild stroke: National Institutes of Health Stroke Scale [NIHSS] ≤ 8 and severe stroke: >8) and different stroke outcome (favorable: modified Rankin scale score 0-2 and unfavorable: 3-5 or death) at 14 days after stroke onset. RESULTS: A total of 325 patients fulfilled the inclusion criteria. There were 242 patients with mild stroke. They exhibited lower white blood cell (WBC), globulin, plasma glucose, fibrinogen (Fib) levels and higher albumin, albumin/globulin (A/G), free triiodothyronine (FT3) levels. Logistic regression analysis showed that FT3 (≧3.18) and WBC (≧7.1) were independent predictors. There were 122 patients demonstrating an unfavorable outcome. Higher WBC, globulin, plasma glucose and Fib levels, lower albumin, FT3, A/G levels, higher NIHSS score and longer hospital stay were significantly associated with unfavorable outcome. In the logistic regression model, we found that A/G (≧1.56), FT3 (≧4.09) and WBC (≧7.1) were independent predictors for short-term outcome. CONCLUSIONS: Our data suggested that higher A/G, FT3 levels served as independent predictors of favorable outcome, and a higher FT3 value may also predict mild stroke, while higher WBC may predict a poor functional outcome and severe stroke in patients with acute ischemia.

The Untargeted Metabolomics Reveals Differences in Energy Metabolism in Patients with Different Subtypes of Ischemic Stroke.

AIMS: Ischemic stroke (IS) is the most common subtype of stroke. The risk factors and pathogenesis of IS are complex and varied due to different subtypes. Therefore, we used metabolomics technology to investigate the biomarkers and potential pathophysiological mechanisms of different subtypes of IS. METHODS: We included 126 IS patients and divided them into two groups based on the TOAST classification: large-artery atherosclerosis (LAA) group (n = 87) and small-vessel occlusion (SVO) group (n = 39). Plasma metabolomics analysis was performed using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to identify metabolic profiles in LAA and SVO subtype IS patients and to determine metabolic differences between patients with the two subtypes of IS. RESULTS: We identified 26 differential metabolites between LAA and SVO subtype IS. A multiple prediction model based on the plasm metabolites had good predictive ability for IS subtyping (AUC = 0.822, accuracy = 77.8%), with 12,13-DHOME being the most important differential metabolite in the model. The differential metabolic pathways between the two subtypes of IS patients included tricarboxylic acid (TCA) cycle, alanine, aspartate and glutamate metabolism, and pyruvate metabolism, mainly focused on energy metabolism. CONCLUSION: 12,13-DHOME emerged as the primary discriminatory metabolite between LAA and SVO subtypes of IS. In LAA subtype IS patients, energy metabolism, encompassing pyruvate metabolism and the TCA cycle, exhibited lower activity levels when compared to patients with the SVO subtype IS. The utilization of targeted metabolomics holds the potential to improve diagnostic accuracy for distinguishing stroke subtypes.

3D Bioprinted Xanthan Hydrogels with Dual Antioxidant and Chondrogenic Functions for Post-traumatic Cartilage Regeneration.

Intra-articular trauma typically initiates the overgeneration of reactive oxidative species (ROS), leading to post-traumatic osteoarthritis and cartilage degeneration. Xanthan gum (XG), a branched polysaccharide, has shown its potential in many biomedical fields, but some of its inherent properties, including undesirable viscosity and poor mechanical stability, limit its application in 3D printed scaffolds for cartilage regeneration. In this project, we developed 3D bioprinted XG hydrogels by modifying XG with methacrylic (MA) groups for post-traumatic cartilage therapy. Our results demonstrated that the chemical modification optimized the viscoelasticity of the bioink, improved printability, and enhanced the mechanical properties of the resulting scaffolds. The XG hydrogels also exhibit decent ROS scavenging capacities to protect stem cells from oxidative stress. Furthermore, XGMA(H) (5% MA substitution) exhibited superior chondrogenic potential in vitro and promoted cartilage regeneration in vivo. These dual-functional XGMA hydrogels may provide a new opportunity for cartilage tissue engineering.

Intracranial hemorrhage management in the multi-omics era.

Intracranial hemorrhage (ICH) is a devastating disorder. Neuroprotective strategies that prevent tissue injury and improve functional outcomes have been identified in multiple animal models of ICH. However, these potential interventions in clinical trials produced generally disappointing results. With progress in omics, studies of omics data, including genomics, transcriptomics, epigenetics, proteomics, metabolomics, and the gut microbiome, may help promote precision medicine. In this review, we focused on introducing the applications of all omics in ICH and shed light on all of the considerable advantages to systematically analyze the necessity and importance of multiple omics technology in ICH.

The association between neutrophil counts and neutrophil-to-lymphocyte ratio and stress hyperglycemia in patients with acute ischemic stroke according to stroke etiology.

Background and purpose: Stress hyperglycemia ratio (SHR), which is used to assess stress hyperglycemia, is associated with the functional outcome of ischemic stroke (IS). IS can induce the inflammatory response. Neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) as good and easily available inflammatory biomarkers, the relationship between neutrophil counts and NLR and SHR were poorly explored in IS. We aimed to systemically and comprehensively explore the correlation between various blood inflammation markers (mainly neutrophil counts and NLR) and SHR. Methods: Data from 487 patients with acute IS(AIS) in Xiangya Hospital were retrospectively reviewed. High/low SHR groups according to the median of SHR (≤1.02 versus >1.02). Binary logistic regression analysis was used to evaluate the correlation between neutrophil counts and NLR and high SHR group. Subgroup analyses were performed in the TOAST classification and functional prognosis. Results: The neutrophil counts and NLR were all clearly associated with SHR levels in different logistic analysis models. In the subgroup analysis of TOAST classification, the higher neutrophil counts and NLR were the independent risk factors for high SHR patients with large-artery atherosclerosis (LAA) (neutrophil: adjusted OR:2.047, 95% CI: 1.355-3.093, P=0.001; NLR: adjusted OR:1.315, 95% CI: 1.129-1.530, P<0.001). The higher neutrophil counts were the independent risk factor for high SHR patients with cardioembolism (CE) (adjusted OR:2.413, 95% CI: 1.081-5.383, P=0.031). ROC analysis showed that neutrophil counts was helpful for differentiating high SHR group with CE and low SHR group with CE (neutrophil: AUC =0.776, P=0.002). However, there were no difference in levels of neutrophil counts and NLR between patients with SVO and without SVO. The higher neutrophil counts and NLR independently associated with high SHR patients with mRS ≤2 at 90 days from symptom onset, (neutrophil: adjusted OR:2.284, 95% CI: 1.525-3.420, P<0.001; NLR: adjusted OR:1.377, 95% CI: 1.164-1.629, P<0.001), but not in patients with mRS >2. Conclusions: This study found that the neutrophil counts and NLR are positively associated with SHR levels in AIS patients. In addition, the correlation between neutrophil counts and NLR and different SHR levels are diverse according to TOAST classification and functional prognosis.

Elevated Chinese visceral adiposity index increases the risk of stroke in Chinese patients with metabolic syndrome.

Introduction: Patients with Metabolic Syndrome (MetS) are considered at high-risk for incident stroke. An indicator of visceral adiposity dysfunction, the Chinese Visceral Adiposity Index (CVAI) is used to evaluate the dysfunction of visceral fat. Given the impact of visceral adiposity dysfunction on elevating cardiovascular hazards, this study aimed to examine the association between CVAI and stroke risk in MetS patients. Method: Between November 2017 and December 2018, a total of 18,974 individuals aged ≥40 underwent standardized in-person clinical interviews in Hunan Province, with 6,732 meeting the criteria for MetS. After the baseline survey was completed, subsequent surveys were conducted biennially. The study was split into two stages performed at baseline and after two years. During the former, receiver-operating characteristic curves were used to assess the accuracy of using baseline CVAI in diagnosing MetS. After two years, we examined the association between CVAI and incident stroke in MetS patients using logistic regression, subgroup analysis, and restricted cubic spline (RCS) analysis. Result: As evidenced by a higher AUC (AUC:0.741), CVAI demonstrated superior diagnostic performance relative to body mass index (AUC:0.631) and waist circumference (AUC:0.627) in diagnosing MetS. After a 2-year follow-up, 72 MetS patients had a stroke event. There was a robust positive correlation between incident stroke and CVAI in patients with MetS. Each 1 SD increase in CVAI was associated with a 1.52-fold higher risk of stroke after adjustment for confounding factors (aOR=1.52, 95%CI: 1.18-1.95). The RCS demonstrated a reduced risk of stroke for MetS patients when the CVAI was below 110.91. However, no significant correlation was detected between CVAI and stroke in non-MetS patients. Conclusion: Our findings recommend CVAI as a superior screening tool for detecting MetS and suggest that reducing CVAI can mitigate the risk of stroke in patients with MetS.

Comparison between healthcare quality in primary stroke centers and comprehensive stroke centers for acute stroke patients: evidence from the Chinese Stroke Center Alliance.

Background: To improve stroke care quality, the guidelines for stroke center construction in China recommended establishing primary stroke centers (PSCs) and comprehensive stroke centers (CSCs). We aimed to compare stroke care quality between the two types of centers. Methods: Data were collected from acute stroke patients admitted to PSCs or CSCs in the China Stroke Center Alliance program. Twenty-one individual guideline-recommended performance measures and two summary measures were compared between the two groups. Multivariable logistic regression models were used to examine the association between stroke center status (CSC vs. PSC) and healthcare quality. Findings: Data from 750,594 stroke patients from 1474 stroke centers (252 CSCs and 1222 PSCs) were analyzed. For many components of healthcare performance in stroke patients, comparable levels of performance were observed between CSCs and PCSs. Nonetheless, CSCs outperformed PSCs in the areas of administering intravenous recombinant tissue plasminogen activator within 4.5 h (aOR = 1.31 [95% CI: 1.07-1.60]), rehabilitation for acute ischaemic stroke (AIS) (aOR = 1.19 [95% CI: 1.01-1.40]), and the provision of hypoglycemic medication and statin therapy upon discharge for AIS (aOR = 1.26 [95% CI: 1.00-1.59] and aOR = 1.28 [95% CI: 1.04-1.59], respectively). More patients with intracerebral haemorrhage and subarachnoid haemorrhage received neurosurgery in CSCs (14.4% vs. 10.6% and 51.0% vs. 33.9%, respectively). Additionally, CSCs had higher in-hospital mortality than PSCs (aOR = 1.33 [95% CI: 1.01-1.73]). Interpretation: Overall PSCs provided equivalent care for many quality measures to CSCs in China with the exception of thrombolysis, rehabilitation access, and medication at discharge for AIS, whereby improvements should be directed. Nevertheless, PSCs have demonstrated lower risk-adjusted in-hospital mortality rates. Funding: The National Key Research and Development Projects of China.

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis.

Drug delivery via intra-articular (IA) injection has proved to be effective in osteoarthritis (OA) therapy, limited by the drug efficiency and short retention time of the drug delivery systems (DDSs). Herein, a series of modified cross-linked dextran (Sephadex, S0) was fabricated by respectively grafting with linear alkyl chains, branched alkyl chains or aromatic chain, and acted as DDSs after ibuprofen (Ibu) loading for OA therapy. This DDSs expressed sustained drug release, excellent anti-inflammatory and chondroprotective effects both in IL-1ß induced chondrocytes and OA joints. Specifically, the introduction of a longer hydrophobic chain, particularly an aromatic chain, distinctly improved the hydrophobicity of S0, increased Ibu loading efficiency, and further led to significantly improving OA therapeutic effects. Therefore, hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.

Correction: Carbazate-modified cross-linked dextran microparticles suppress the progression of osteoarthritis by ROS scavenging.

Correction for 'Carbazate-modified cross-linked dextran microparticles suppress the progression of osteoarthritis by ROS scavenging' by Yanfeng Ding, et al., Biomater. Sci., 2021, 9, 6236-6250. https://doi.org/10.1039/D1BM00743B.

Association of PI3K-Akt Pathway-Related Gene Polymorphisms with Symptomatic Intracranial Atherosclerotic Stenosis with Hypertension in a Chinese Han Population.

BACKGROUND: PI3K-Akt signaling has been proved to be closely related to atherosclerosis, and hypertension has been shown to be an important risk factor for atherosclerosis. Studies have shown that genetic susceptibility is important in the etiology of symptomatic intracranial atherosclerotic stenosis (sICAS). However, few candidate genes have been identified. In the present study, we explored latent connections between single nucleotide polymorphisms (SNPs) of PI3K-Akt-related genes and sICAS with hypertension in Han Chinese subjects. METHODS: Eight genes related to the PI3K-Akt pathway in 400 patients with sICAS and 1007 healthy controls of Han nationality were sequenced, and further subgroup analysis stratified by the presence of hypertension was performed. The χ2 test and multiple logistic regression in dominant, recessive, and additive models were used to evaluate the association between the SNPs and the risk of sICAS with hypertension. When linkage disequilibrium was found in different loci of the same gene, tagSNP represents the SNP in the haplotype block. RESULTS: We found 4 common variants of 1 candidate gene differently distributed between those with sICAS with and without hypertension. Among these 4 common variations, INSR (insulin receptor) rs3745551 was significantly related to the risk of sICAS with hypertension after multiple regression analysis, with the T allele more prevalent in sICAS with hypertension. CONCLUSIONS: The variant of the INSR rs3745551 loci might be crucial to the pathogenesis of sICAS with hypertension in Chinese Han populations. Furthermore, the C allele at this locus might be a potentially harmful variant in sICAS with hypertension.

In Situ Reduced Graphene Oxide and Polyvinyl Alcohol Nanocomposites With Enhanced Multiple Properties.

The nanocomposites formed by graphene oxide (GO) and carbazate-modified polyvinyl alcohol (PVA-N) were developed to investigate their multiple properties for wide applications. Their physicochemical characterizations confirmed that the in situ reduced GO (rGO) not only decreased the crystallization but also induced the porous structures inside the nanocomposites. Significantly, it revealed that the comprehensive performance of PVA-N2-2%GO consisted of PVA-N2 with the carbazate degree of substitution (DS) of 7% and the weight ratio (wt%) of 2% GO displayed 79% of tensile elongation and tensile strength of 5.96 N/mm2 (MPa) by tensile testing, glass transition temperature (Tg) of 60.8°C and decomposition temperature (Td) of 303.5°C by TGA and DSC, surface contact angle at 89.4 ± 2.1°, and electrical conductivity of 9.95 × 10-11 S/cm. The abovementioned comprehensive performance was enhanced with the increased amount of in situ rGO, contributed by the high DS of the carbazate group in PVA-N and high amount of GO. The rGO by in situ reduction was the main driving force for enhancing the multiple properties inside the nanocomposites.

A novel multifunctional anti-PD-L1-CD16a-IL15 induces potent cancer cell killing in PD-L1-positive tumour cells.

Cancer is the most acute disease and the leading cause of patient death worldwide. Both chemotherapy and molecular-based therapies play an important role in curing cancer. However, the median and overall survival of patients is poor. To date, immune therapies have changed the treatment methods for cancer patients. Programmed death ligand 1 (PD-L1, also known as B-H1, CD274) is a well-studied tumor antigen. PD-L1 is overexpressed in colon cancer, lung cancer, and so on and plays a vital role in cancer development. In this study, anti-PD-L1 single-domain antibodies were identified from recombinant human PD-L1 (rhPD-L1)-immunized llamas. Then, we generated a novel multifunctional anti-PD-L1-CD16a-IL15 antibody targeting PD-L1-positive tumor cells. Anti-PD-L1-CD16a-IL15 was constructed by linking the Interleukin-2 (IL-2) signal peptide, anti-PD-L1 single domain antibody (anti-PD-L1-VHH) and anti-cluster of differentiation 16a single domain antibody (anti-CD16a-VHH), and Interleukin-15/Interleukin-15 receptor alpha (IL15/IL-15Rα). This anti-PD-L1-CD16a-IL15 fusion protein can be expressed and purified from HEK-293F cells. In vitro, our data showed that the anti-PD-L1-CD16a-IL15 fusion protein can recruit T cells and drive natural killer cells (NK) with specific killing of PD-L1-overexpressing tumor cells. Furthermore, in the xenograft model, the anti-PD-L1-CD16a-IL15 fusion protein inhibited tumor growth with human peripheral blood mononuclear cells (PBMCs). These data suggested that the anti-PD-L1-CD16a-IL15 fusion protein has a latent function in antitumour activity, with better guidance for future cancer immunotherapy.

Alterations in the gut microbiome with hemorrhagic transformation in experimental stroke.

OBJECTIVE: Hemorrhagic transformation (HT) is a life-threatening complication of stroke. Whether changes in gut microbial composition underlie the development of HT remains unknown. This study aimed to investigate whether the gut microbiota is altered in HT rats and examine the association between these changes and inflammatory responses. METHODS: HT was successfully established in rats injected with 50% glucose (6 ml/Kg, i.p.) 15 min before middle cerebral artery occlusion (MCAO, 90 min occlusion) with reperfusion. After 5 days, rats were euthanized, and their brains used to estimate infarct volume. The inflammatory factors, the analysis of gut microbiota, and short-chain fatty acids (SCFA) were assessed. RESULTS: In contrast with non-HT rats, gut microbiota sequencing showed an elevation in the relative abundance of Proteobacteria and Actinobacteria in HT rats. Total SCFAs, especially butyrate and valeric acid, were significantly lower in the cecal contents of HT rats than in those of non-HT rats. Hyperglycemia-induced HT exacerbation was not observed when rats were treated with antibiotics, suggesting that altered microbiota play a critical role in hyperglycemic HT pathogenesis. Furthermore, rats whose gut was colonized with HT rat microbiota showed increased susceptibility to HT. CONCLUSION: This study provides important information about the gut microbiota profiles and SCFA levels of MCAO rats with HT or non-HT. The susceptibility to HT in MCAO rats is associated with inflammation and gut microbiota modulation.

Stroke-associated infection in patients with co-morbid diabetes mellitus is associated with in-hospital mortality.

Background and objective: The association between infection and acute ischemic stroke (AIS) with diabetes mellitus (DM) remains unknown. Therefore, this study aimed to explore the effect of infection on AIS with DM. Materials and methods: The data of patients with AIS and DM were extracted from the Chinese Stroke Center Alliance (CSCA) database from August 2015 to July 2019. The association between infections [pneumonia or urinary tract infection (UTI)] and in-hospital mortality was analyzed. Logistic regression models were used to identify the risk factors for in-hospital mortality of patients with infection. Results: In total, 1,77,923 AIS patients with DM were included in the study. The infection rate during hospitalization was 10.5%, and the mortality rate of infected patients was 3.4%. Stroke-associated infection was an independent risk factor for an early poor functional outcome [odds ratio (OR) = 2.26, 95% confidence interval (CI): 1.97-2.34, P < 0.0001] and in-hospital mortality in AIS patients with DM. The in-hospital mortality after infection was associated with age (OR = 1.02, 95% CI: 1.01-1.03, P < 0.0001), male (OR = 1.39, 95% CI: 1.13-1.71, P = 0.0018), reperfusion therapy (OR = 2.00, 95% CI: 1.56-2.56, P < 0.0001), and fasting plasma glucose at admission (OR = 1.05, 95% CI: 1.03-1.08, P < 0.0001). In contrast, antiplatelet drug therapy (OR = 0.63, 95% CI: 0.50-0.78, P < 0.0001) and hospital stay (OR = 0.96, 95% CI: 0.94-0.97, P < 0.0001) were independent protecting factors against in-hospital mortality of patients with infection. Conclusion: Infection is an independent risk factor of in-hospital mortality for patients with AIS and DM, and those patients require strengthening nursing management to prevent infection.

Serum Bilirubin Levels and Extent of Symptomatic Intracranial Atherosclerotic Stenosis in Acute Ischemic Stroke: A Cross-Sectional Study.

Background: Bilirubin plays a paradoxical role in the pathological mechanism of stroke. To date, few clinical studies have investigated the effect of serum bilirubin on symptomatic intracranial atherosclerotic stenosis (sICAS). This study aims to evaluate the connection between serum bilirubin and sICAS. Methods: From September 2015 to May 2020, 1,156 sICAS patients without hepatobiliary diseases admitted to our hospital were included. Patients were distributed into none-mild (0-49%), moderate (50-69%) and severe-occlusion sICAS groups (70-100%) by the degree of artery stenosis. Moderate and severe-occlusion sICAS patients were classified into three groups by the number of stenotic arteries (single-, two- and multiple-vessel stenosis). The relationship between serum bilirubin levels and sICAS was analyzed by logistic regression analysis. Results: In univariable analyses, sICAS patients with severe and multiple atherosclerotic stenoses had lower levels of total bilirubin (Tbil), direct bilirubin (Dbil), and indirect bilirubin (Ibil). In multinomial logistic regression analyses, when compared with the highest tertile of bilirubin, lower levels of Tbil, Dbil, and Ibil showed higher risks of severe-occlusion sICAS (95% CI: 2.018-6.075 in tertile 1 for Tbil; 2.380-7.410 in tertile 1 for Dbil; 1.758-5.641 in tertile 1 for Ibil). Moreover, the logistic regression analyses showed that lower levels of Tbil, Dbil, and Ibil were related to multiple (≥3) atherosclerotic stenoses (95% CI: 2.365-5.298 in tertile 1 and 2.312-5.208 in tertile 2 for Tbil; 1.743-3.835 in tertile 1 and 1.416-3.144 in tertile 2 for Dbil; 2.361-5.345 in tertile 1 and 1.604-3.545 in tertile 2 for Ibil) when compared with tertile 3. Conclusions: Our findings suggest that lower bilirubin levels may indicate severe and multiple intracranial atherosclerotic stenoses.