Effect of Time Window on Endovascular Thrombectomy with or without Intravenous Thrombolysis in Acute Ischemic Stroke: Results from DIRECT-MT.

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 >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 >3-4.5 h. RESULTS: Among 656 patients who were included in the analysis, 282 (43.0%) were randomized within >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 >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 >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.

Robust global arrangement by coherent enhancement in Huygens-Fresnel traveling surface acoustic wave interference field.

The application of standing surface acoustic wave (SSAW) tweezers based on backpropagation superposition to achieve precise behavior manipulation of microscale cells and even nanoscale bacteria has been widely studied and industrialized. However, the structure requires multiple transducer components or full channel resonance. It is very challenging to design a simple structure for nano-control by complex acoustic field. In this study, a reflector-interdigital transducer (R-IDT) acoustofluidic device based on unilateral coherence enhancement is proposed to achieve SSAW definition features of periodic particle capture positions. The SAW device based on a unilateral transducer can not only generate leaky-SAW in water-filled microchannel, but also have a contribution of spherical waves in the vibration area of the substrate-liquid interface due to the Huygens-Fresnel diffractive principle. Both of them form a robust time-averaged spatial periodicity in the pressure potential gradient, accurately predicting the lateral spacing of these positions through acoustic patterning methods. Furthermore, a reflector based on Bragg-reflection is used to suppress backward transmitted SAW and enhance forward conducted SAW beams. By using a finite element model, R-IDT structure's amplitude enhances 60.78% compared to single IDT structure. The particle manipulation range of the diffractive acoustic field greatly improves, verified by experimental polystyrene microspheres. Besides, biocompatibility is conformed through red blood cells and Bacillus subtilis. We investigate the overall shift of periodic pressure field that can still occur when the phase changes. This work provides a simpler and low-cost solution for the application of acoustic tweezer in biological cell culture and filtering.

Cost-Effectiveness of Low-Dose Compared to Standard-Dose Alteplase for Acute Ischemic Stroke in China: A Within-Trial Economic Evaluation of the ENCHANTED Study.

INTRODUCTION: The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) showed that a low-dose alteplase was safe but not clearly non-inferior to standard-dose alteplase in acute ischemic stroke (AIS). Given the significant cost of this medicine, we undertook a cost-effectiveness analysis to determine the probability that low-dose is cost-effective relative to standard-dose alteplase in China. METHODS: For ENCHANTED participants in China with available health cost data, cost-effectiveness and cost-utility analyses were undertaken in which death or disability (modified Rankin scale scores 2-6) at 90 days and quality-adjusted life-years (QALYs) were used as outcome measures, respectively. There was adherence to standard guidelines for health economic evaluations alongside non-inferiority trials and according to a health-care payer's perspective. The equivalence margin for cost and effectiveness was set at USD 691 and -0.025 QALYs, respectively, for the base-case analysis. Probabilistic sensitivity analyses were used to evaluate the probability of low-dose alteplase being non-inferior. RESULTS: While the mean cost of alteplase was lower in the low-dose group (USD 1,569 vs. USD 2,154 in the standard-dose group), the total cost was USD 56 (95% confidence interval [CI]: -1,000-1,113) higher compared to the standard-dose group due to higher hospitalization costs in the low-dose group. There were 462 (95% CI: 415-509) and 410 (95% CI: 363-457) patients with death or disability per 1,000 patients in the low-dose and standard-dose groups, respectively. The low-dose group had marginally lower (0.008, 95% CI: -0.016-0.001) QALYs compared to their standard-dose counterparts. The low-dose group was found to have an 88% probability of being non-inferior based on cost-effectiveness versus the standard-dose group. CONCLUSIONS: This health economic evaluation alongside the ENCHANTED indicates that the use of low-dose alteplase does not save overall healthcare costs nor lead to a gain in QALYs in the management of Chinese patients with AIS compared to the use of standard dose. There is little justification on economic grounds to shift from standard-of-care thrombolysis in AIS.

An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages.

During embryo implantation, apoptosis is inevitable. These apoptotic cells (ACs) are removed by efferocytosis, in which macrophages are filled with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the relationship between efferocytosis-related metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here, we report positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum levels of IL-33 and sST2, along with IL-33 and ST2, efferocytosis and metabolism of dMΦs, from patients with normal pregnancies and unexplained recurrent pregnancy loss (RPL). We revealed disruption of the IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from patients with RPL. The dMΦs that engulfed many apoptotic cells secreted more sST2 and less TGF-ß, which polarized dMΦs toward the M1 phenotype. Moreover, the elevated sST2 biased the efferocytosis-related metabolism of RPL dMΦs toward oxidative phosphorylation and exacerbated the disruption of the IL-33/ST2 signaling pathway. Metabolic disorders also lead to dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and secondary necrosis. We also screened the efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback axis of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation with mouse IL-33 reduced the embryo losses. These findings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for homeostasis of the microenvironment at the maternal-fetal interface.

Cumulative experience improves the procedures of mechanical thrombectomy.

BACKGROUND: Mechanical thrombectomy has been widely performed for large vessel occlusion stroke. The present study aimed to determine whether cumulative experience could improve thrombectomy outcomes. METHODS: In this retrospective single-center analysis, patients who underwent mechanical thrombectomy with the Solitaire stent in 3 years from 25 April 2015 were enrolled in the current study. Patients' characteristics, durations of admission and treatment, recanalization rates, clinical outcomes, and hemorrhage transformation rates were compared among the 3 years. Logistic analysis was used to analyze the independent correlation of the years and procedural outcomes. RESULTS: A total of 222 patients underwent mechanical thrombectomy in the 3 years: 50 in the first year, 68 in the second year, and 104 in the third year. Door-to-puncture time (P < 0.001) and puncture-to-recanalization time (P = 0.033) decreased significantly among the 3 years, while successful recanalization rates increased (P = 0.001). Logistic regression analysis showed an independent increase in the successful recanalization rates in the second year and third year (P = 0.020, P = 0.001) as compared to that in the first year. CONCLUSIONS: Cumulative experience might improve the procedures of mechanical thrombectomy. The current findings suggested a potential benefit for centralization in the treatment of large vessel occlusion stroke.

Clinical characteristics and risk factors for a prolonged length of stay of patients with asymptomatic and mild COVID-19 during the wave of Omicron from Shanghai, China.

BACKGROUND: This study aims to investigate the clinical characteristics and the length of hospital stay (LOS), as well as risk factors for prolonged LOS in a cohort of asymptomatic and mild COVID-19 patients infected with the Omicron variant. METHODS: A total of 1166 COVID-19 patients discharged from the inpatient ward of the largest makeshift hospital (May 8-10, 2022) in Shanghai, China, were included. The demographics, medical history, and the lowest and admission cycle threshold (Ct) values of the RT-PCR tests for SARS-CoV-2 genes of the open reading frame 1ab (Ct-ORF) and the nucleocapsid protein (Ct-N) during hospitalization were recorded. Patients with LOS > 7 days, or LOS ≤ 7 days were included in the Prolonged group or the Control group, separately. The clinical characteristics and LOS of the participants in the two groups were described and compared. Multivariate Logistic and linear regression analyses were applied to explore the risk factors for prolonged LOS. The diagnostic efficacy of the lowest and admission Ct values for the Prolonged group was tested via the receiver operating characteristic (ROC) curve analysis. RESULTS: The median LOS was 6 days in the total study population. The age was older (45.52 ± 14.78 vs. 42.54 ± 15.30, P = 0.001), while both the lowest and admission Ct-ORF (27.68 ± 3.88 vs. 37.00 ± 4.62, P < 0.001; 30.48 ± 5.03 vs. 37.79 ± 3.81, P < 0.001) and Ct-N (25.79 ± 3.60 vs. 36.06 ± 5.39, P < 0.001; 28.71 ± 4.95 vs. 36.95 ± 4.59, P < 0.001) values were significantly lower in the Prolonged group. There were more mild cases in the Prolonged group (23.8% vs. 11.5%, P < 0.001). The symptom spectrum differed between the two groups. In multivariate analyses, age, disease category, and the lowest Ct-N values were shown to be associated with prolonged LOS. Besides, both the lowest and admission Ct-ORF (AUC = 0.911 and 0.873) and Ct-N (AUC = 0.912 and 0.874) showed robust diagnostic efficacy for prolonged LOS. CONCLUSIONS: Our study firstly reports the clinical characteristics and risk factors for prolonged LOS during the wave of the Omicron epidemic in Shanghai, China. These findings provide evidence for the early identification of asymptomatic and mild COVID-19 patients at a high risk of prolonged hospitalization who may require early intervention, and long-term monitoring and management.

The association of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and lymphocyte to monocyte ratio with post-thrombolysis early neurological outcomes in patients with acute ischemic stroke.

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.

Gastrin, via activation of PPARα, protects the kidney against hypertensive injury.

Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.

Role of GRK4 in the regulation of the renal ETB receptor in hypertension.

The endothelin receptor type B (ETBR) regulates water and electrolyte balance and blood pressure, in part, by inhibiting renal sodium transport. Our preliminary study found that the ETBR-mediated diuresis and natriuresis are impaired in hypertension with unknown mechanism. Persistently increased activity of G protein-coupled receptor kinase 4 (GRK4), caused by increased expression or genetic variants (eg, GRKγ142V), impairs the ability of the kidney to excrete a sodium load, in part, by impairing renal dopamine D1 receptor function through persistent phosphorylation. Our present study found that although renal ETBR expression was not different between Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), renal ETBR phosphorylation was higher in SHRs. The role of hyper-phosphorylation in impaired ETBR-function was supported by results in human (h) GRK4γ transgenic mice. Stimulation of ETBR by BQ3020-induced natriuresis in human (h) GRK4γ wild-type (WT) mice. However, in hGRK4γ 142V transgenic mice, the renal ETBR was hyperphosphorylated and ETBR-mediated natriuresis and diuresis were not evident. There were co-localization and co-immunoprecipitation of ETBR and GRK4 in renal proximal tubule (RPT) cells from both WKY and SHRs but was greater in the latter than the former group. SiRNA-mediated downregulation of GRK4 expression, recovered the impaired inhibitory effect of ETBR on Na+ -K+ -ATPase activity in RPT cells from SHR. In vivo downregulation of renal GRK4 expression, via ultrasound-targeted microbubble destruction, decreased ETBR phosphorylation and restored ETBR-mediated natriuresis and diuresis in SHRs. This study provides a mechanism by which GRK4, via regulation of renal ETBR function, participates in the pathogenesis of hypertension.

Admission blood cell counts are predictive of stroke-associated infection in acute ischemic stroke patients treated with endovascular therapy.

Stroke-associated infection (SAI) is a major medical complication in acute ischemic stroke patients (AIS) treated with endovascular therapy (EVT). Three hundred thirty-three consecutive patients with AIS caused by a large vessel occlusion in the anterior circulation who received EVT (142 (42.6%) of them were given IV tPA as bridging therapy) and 337 AIS patients who received IV tPA only (non-EVT) were enrolled in the study and evaluated to determine the association of inflammatory factors on admission with SAI. Among the 333 AIS patients undergoing EVT, SAI occurred in 219 (65.8%) patients. Patients with SAI had higher baseline National Institutes of Health Stroke Scale (NIHSS) total scores, white blood cell (WBC) and neutrophil counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) than those without SAI (P < 0.05). The multivariable logistic regression analyses showed that older age in addition to higher diastolic blood pressure (DBP), NIHSS score, fasting blood glucose, WBC and neutrophil counts, NLR, and PLR were significantly associated with SAI (P < 0.05). However, these associations were not revealed in 337 non-EVT AIS patients. Furthermore, based on the inflammatory markers, we developed a nomogram that provided the opportunity for more accurate predictions (compared with conventional factors) and appeared a better prognostic tool for SAI according to the decision curve analysis. In summary, if proven externally valid, our nomogram that included WBC count, NLR, and PLR may be a useful tool for SAI prediction in clinical practice.

Safe standard remnant liver volume after hepatectomy in HCC patients in different stages of hepatic fibrosis.

BACKGROUND: To determine the standard remnant liver volume (SRLV) threshold to avoid postoperative hepatic insufficiency inpatients in different stages of hepatic fibrosis who undergo right hemi-hepatectomy. METHODS: Data for 85 patients at our single medical center were analysed prospectively to examine whether the following factors differed significantly between those who experienced postoperative hepatic insufficiency and those who did not: height, prothrombin time, remnant liver volume, SRLV or hepatic fibrosis stage. RESULTS: Logistic regression showed SRLV and hepatic fibrosis stage to be independent risk factors for postoperative hepatic insufficiency. The threshold SRLV for predicting insufficiency was 203.2 ml/m2 across all patients [area under receiver operating characteristic curve (AUC) 0.778, sensitivity 66.67%, specificity 83.64%, p<0.0001), 193.8 ml/m2 for patients with severe hepatic fibrosis (AUC 0.938, sensitivity 91.30%, specificity 85.71%, p<0.0001), and 224.3 ml/m2 for patients with cirrhosis (AUC 0.888, sensitivity 100%, specificity 64.29%, p<0.0001). CONCLUSIONS: Right hemi-hepatectomy may be safer in Chinese patients when the standard remnant liver volume is more than 203.2 ml/m2 in the absence of hepatic fibrosis or cirrhosis, 193.8 ml/m2 in the presence of severe hepatic fibrosis or 224.3 ml/m2 in the presence of cirrhosis.

Intravenous thrombolysis for ischemic stroke with hyperdense middle cerebral artery sign: A meta-analysis.

Hyperdense middle cerebral artery sign (HMCAS) on admitting to neuroimaging is reported to have prognostic value for poor outcomes after thrombolysis, while evidence from studies comprising a sufficiently large sample size is limited. To detect prognostic predictors after thrombolysis could help improve therapeutic clinical strategies for acute ischemic stroke. We included prospective and retrospective studies of stroke patients that were treated with intravenous thrombolysis, in which functional outcomes (ie, a modified Rankin scale [mRS]) and systematic intracranial hemorrhage (sICH) were assessed in relation to HMCAS during pretreatment head CT. Random-effects models were used to calculate pooled risk ratios (RR) of poor outcomes and sICH for HMCAS patients as compared to patients without HMCAS. Eleven studies permitted identification of 11 818 patients. The risk of poor outcome at 3 months in the HMCAS-positive group was 1.56-fold the negative group (RR, 1.56; 95% CI 1.50-1.62; P < .001). The sICH risk when comparing both groups was found to be non-significant. Sensitivity analysis regarding studies performing thrombolysis within 3 hours also exhibited significant differences in their functional outcomes (RR, 1.56, 95% CI 1.49-1.62; P < .001) in patients with HMCAS as compared to non-HMCAS patients, although this was true for sICH risk. The presence of HMCAS on pretreatment CT predicts a poor outcome at 3 months after intravenous thrombolysis, while its relationship with the incidence of sICH was found to have no statistic value. Our study implies that more aggressive treatment should be considered for HMCAS patients.

MG53 protects against contrast-induced acute kidney injury by reducing cell membrane damage and apoptosis.

Mitsugumin 53 (MG53) is a tripartite motif family protein that has been reported to attenuate injury via membrane repair in different organs. Contrast-induced acute kidney injury (CI-AKI) is a common complication caused by the administration of iodinated contrast media (CM). While the cytotoxicity induced by CM leading to tubular cell death may be initiated by cell membrane damage, we wondered whether MG53 alleviates CI-AKI. This study was designed to investigate the effect of MG53 on CI-AKI and the underlying mechanism. A rat model of CI-AKI was established, and CI-AKI induced the translocation of MG53 from serum to injury sites on the renal proximal tubular (RPT) epithelia, as illustrated by immunoblot analysis and immunohistochemical staining. Moreover, pretreatment of rats with recombinant human MG53 protein (rhMG53, 2 mg/mL) alleviated iopromide-induced injury in the kidney, which was determined by measuring serum creatinine, blood urea nitrogen and renal histological changes. In vitro studies demonstrated that exposure of RPT cells to iopromide (20, 40, and 80 mg/mL) caused cell membrane injury and cell death, which were attenuated by rhMG53 (10 and 50 µg/mL). Mechanistically, MG53 translocated to the injury site on RPT cells and bound to phosphatidylserine to protect RPT cells from iopromide-induced injury. In conclusion, MG53 protects against CI-AKI through cell membrane repair and reducing cell apoptosis; therefore, rhMG53 might be a potential effective means to treat or prevent CI-AKI.

Elevated heme impairs macrophage phagocytosis in endometriosis.

Endometriosis (EMS) is a chronic inflammatory disease characterized by the presence of extrauterine endometrial tissues. It has been previously reported that the refluxed blood containing viable endometrial tissues and the defective elimination of peritoneal macrophages in the pelvic cavity may involve in EMS pathogenesis. However, the mechanism by which macrophages exhibit attenuated phagocytic capability in EMS remains undetermined. Herein, we found that heme, the byproduct of lysed erythrocytes, accumulated abnormally in the peritoneal fluid (PF) of patients with EMS (14.22 µmol/L, 95% confidence interval (CI): 12.54-16.71), compared with the EMS-free group (9.517 µmol/L, 95% CI: 8.891-10.1053). This abnormal accumulation was not associated with the color of PF, phase of the menstrual cycle or severity of the disease. The reduced phagocytic ability of peritoneal macrophages (pMφs) was observed in the EMS group. Consistently, a high-concentration (30 µmol/L) heme treatment impaired EMS-pMφs phagocytosis more than a low-concentration (10 µmol/L) heme treatment. A similar phenomenon was observed in the EMS-free control pMφs (Ctrl-pMφs) and the CD14+ peripheral monocytes (CD14+ Mos). These results indicated that a high heme concentration exhibits a negative effect on macrophage phagocytosis, which supplements the mechanism of impaired scavenger function of pMφs in EMS.

A COACHS Nomogram to Predict the Probability of Three-Month Unfavorable Outcome after Acute Ischemic Stroke in Chinese Patients.

BACKGROUND: Accurate prognostication of unfavorable outcome made at the early onset of stroke is important to both the clinician and the patient management. This study was aimed to develop a nomogram based on the integration of parameters to predict the probability of 3-month unfavorable functional outcome in Chinese acute ischemic stroke patients. METHODS: We retrospectively collected patients who underwent acute ischemic stroke at Stroke Center of the Nanjing First Hospital (China) between May 2013 and May 2018. After exclusion, the study population includes 1,025 patients for nomogram development. The main outcome measure was 3-month unfavorable outcome (modified Rankin Scale > 2). Multivariable logistic regression analysis was used to develop the predicting model, and stepwise logistic regression with the Akaike information criterion was utilized to find best-fit nomogram model. We incorporated the creatinine, fast blood glucose, age, previous cerebral hemorrhage, previous valvular heart disease, and NHISS score (COACHS), and these factors were presented with a nomogram. We assessed the discriminative performance by using the area under curve (AUC) of receiver-operating characteristic (ROC) and calibration of risk prediction model by using the Hosmer-Lemeshow test. RESULTS: Multivariate analysis of the 1,025 patients for logistic regression helped identify the independent factors as National Institutes of Health Stroke Scale score on admission, age, previous valvular heart disease, fasting blood glucose, creatinine, and previous cerebral hemorrhage, which were included in the COACHS nomogram. The AUC-ROC of nomogram was 0.799. Calibration was good (p = 0.1376 for the Hosmer-Lemeshow test). CONCLUSIONS: The COACHS nomogram may be used to predict unfavorable outcome at 3 months after acute ischemic stroke in Chinese population. It may be also a reliable tool that is effective in its clinical utilization to risk-stratify acute stroke patients.

A NADE nomogram to predict the probability of 6-month unfavorable outcome in Chinese patients with ischemic stroke.

BACKGROUND: Early prediction of unfavorable outcome after ischemic stroke is of great significance to the clinical and therapeutic management. A nomogram is a better visual tool than earlier models and prognostic scores to predict clinical outcomes, which incorporates different factors to develop a graphic continuous scoring system and calculates accurately the risk probability of poor outcome entirely based on individual characteristics. However, to date, no nomogram models have been found to predict the probability of 6-month poor outcome after ischemic stroke. We aimed to develop and validate a nomogram for individualized prediction of the probability of 6-month unfavorable outcome in Chinese patients with ischemic stroke. METHODS: Based on the retrospective stroke registry, a single-center study which included 499 patients from May, 2013 to May, 2018 was conducted in Nanjing First Hospital (China) for ischemic stroke within 12 h of symptoms onset. The main outcome measure was 6-month unfavorable outcome (mRS > 2). To generate the nomogram, NIHSS score on admission, Age, previous Diabetes mellitus and crEatinine (NADE) were integrated into the model. We assessed the discriminative performance by using the area under the curve (AUC) of receiver-operating characteristic (ROC) and calibration of risk prediction model by using the Hosmer-Lemeshow test. RESULTS: A visual NADE nomogram was constructed that NIHSS score on admission (OR: 1.190, 95%CI: 1.125-1.258), age (OR: 1.068, 95%CI: 1.045-1.090), previous diabetes mellitus (OR: 1.995, 95%CI: 1.236-3.221) and creatinine (OR: 1.010, 95%CI: 1.002-1.018) were found to be significant predictors of 6-month unfavorable outcome after acute ischemic stroke in Chinese patients. The AUC-ROC of nomogram was 0.791. Calibration was good (p = 0.4982 for the Hosmer-Lemeshow test). CONCLUSION: The NADE is the first nomogram developed and validated in Chinese ischemic stroke patients to provide an individual, visual and precise prediction of the risk probability of 6-month unfavorable outcome.

The association between high-sensitivity C-reactive protein at admission and progressive motor deficits in patients with penetrating artery infarctions.

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.

Leukoaraiosis is associated with poor outcomes after successful recanalization for large vessel occlusion stroke.

BACKGROUND: Leukoaraiosis (LA) is related to the dysfunction of the microcirculation and results in the impairment of the perfusion state. We investigated the association of LA and poor outcomes after successful recanalization by thrombectomy. METHODS: We retrospectively analyzed 97 patients with anterior large-artery occlusion who underwent thrombectomy and had successful recanalization (modified Treatment in Cerebral Ischemia Scale score 2b or 3). All patients underwent magnetic resonance imaging (MRI). LA was evaluated using fluid-attenuated inversion recovery MRI and graded using the Fazekas scale. Poor functional outcome at day 90 and symptomatic intracerebral hemorrhage (sICH) were compared between patients with absent to mild LA and moderate to severe LA. Logistic regression analyses were performed to determine the association of LA severity and outcomes. RESULTS: Moderate and severe LA occurred in 28.9% and 26.8% patients respectively. A higher proportion of poor outcomes were observed in patients with moderate to severe LA compared to patients with absent to mild LA (77.8% vs. 39.5%, p < 0.001). Logistic regression analyses showed patients with moderate to severe LA had 3.77 times (95%CI 1.21-11.76, p = 0.022) higher risk of having poor outcomes compared to patients with absent to mild LA. CONCLUSIONS: LA severity may be associated with poor outcomes after successful recanalization for ischemic stroke with anterior large vessel occlusion.

External Validation of START nomogram to predict 3-Month unfavorable outcome in Chinese acute stroke patients.

BACKGROUND: Recently, the NIHSS STroke Scale score, Age, pre-stroke mRS score, onset-to-treatment Time (START nomogram) predicts 3-month functional outcome after intravenous thrombolysis in ischemic stroke patients. However, this model has not yet been an external validation. We aim to validate the performance of START nomogram. METHODS: Data were derived from the stroke center of the Nanjing First Hospital (China). Patients who lacked the necessary data to calculate the nomogram and missed 3-month modified Ranking scale scores were excluded. Modified Rankin Scale score more than 2 at 3-month was assessed as an unfavorable outcome. We used areas under the receiver operator characteristic curves (AUC-ROC) to quantify the prognostic value. Calibration was assessed by calibration plots and Hosmer-Lemeshow (HL) goodness of fit test. RESULT: The final cohort included 306 eligible patients. For 3-month unfavorable outcome, the AUC-ROC of the START nomogram was .766 (95%CI: .7013-.8304, P < .0001), suggesting good discrimination in the START nomogram. It also showed good calibration (HL goodness of fit test P = .1261) in the external validation sample. CONCLUSION: The START nomogram with good predictive performance is a reliable and simple clinical instrument to predict unfavorable outcome after acute stroke.

Indoleamine 2,3-dioxygenase suppresses the cytotoxicity of 1 NK cells in response to ectopic endometrial stromal cells in endometriosis.

It has been reported that the impaired cytotoxicity of natural killer (NK) cells and abnormal cytokines that are changed by the interaction between ectopic endometrial cells and immune cells is indispensable for the initiation and development of endometriosis (EMS). However, the mechanism of NK cells dysfunction in EMS remains largely unclear. Here, we found that NK cells in peritoneal fluid from women with EMS highly expressed indoleamine 2,3-dioxygenase (IDO). Furthermore, IDO+NK cells possessed lower NKp46 and NKG2D but higher IL-10 than that of IDO-NK. Co-culture with endometrial stromal cells (nESCs) from healthy control or ectopic ESCs (eESCs) from women with EMS led to a significant increase in the IDO level in NK cells from peripheral blood, particularly eESCs, and an anti-TGF-ß neutralizing antibody suppressed these effects in vitro. NK cells co-cultured with ESC more preferentially inhibited the viability of nESCs than eESCs did, and pretreating with 1-methyl-tryptophan (1-MT), an IDO inhibitor, reversed the inhibitory effect of NK cells on eESC viability. These data suggest that ESCs induce IDO+NK cells differentiation partly by TGF-ß, and that IDO further restricts the cytotoxicity of NK cells in response to eESCs, which provides a potential therapeutic strategy for EMS patients, particularly those with a high number of impaired cytotoxic IDO+NK cells.