Assessment of Perfusion Volumes by a New Automated Software for Computed Tomography Perfusion.

INTRODUCTION: To compare the perfusion volumes assessed by a new automated CT perfusion (CTP) software iStroke with the circular singular value decomposition software RAPID and determine its predictive value for functional outcome in patients with acute ischaemic stroke (AIS) who underwent endovascular treatment (EVT). METHODS: Data on patients with AIS were collected from four hospitals in China. All patients received CTP followed by EVT with complete recanalisation within 24 hours of symptom onset. We evaluated the agreement of CTP measures between the two softwares by Spearman's rank correlation tests and kappa tests. Bland-Altman plots were used to evaluate the agreement of infarct core volume (ICV) on CTP and ground truth on diffusion-weighted imaging (DWI). Logistic regression models were used to test the association between ICV on these two softwares and functional outcomes. RESULTS: Among 326 patients, 228 had DWI examinations and 40 of them had infarct volume >70 mL. In all patients, the infarct core and hypoperfusion volumes on iStroke had a strong correlation with those on RAPID (ρ=0.68 and 0.66, respectively). The agreement of large infarct core (volume >70 mL) was substantial (kappa=0.73, p<0.001) between these two softwares. The ICV measured by iStroke and RAPID was significantly correlated with independent functional outcome at 90 days (p=0.009 and p<0.001, respectively). In patients with DWI examinations and those with an ICV >70 mL, the ICV of iStroke and RAPID was comparable on individual agreement with ground truth. CONCLUSION: The automatic CTP software iStroke is a reliable tool for assessing infarct core and mismatch volumes, making it clinically useful for selecting patients with AIS for acute reperfusion therapy in the extended time window.

Clinical significance of the Microbleed Anatomical Rating Scale score in ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: Conflicting results were shown on the relationship between cerebral microbleeds (CMBs) burden and functional outcomes in patients treated with intravenous tissues plasminogen activator (IV tPA). We aimed to investigate the relationship between CMBs burden and functional outcomes using the Microbleed Anatomical Rating Scale (MARS) and determine its optimal cutoff value. METHODS: A retrospective study was conducted to include patients treated with IV tPA in our stroke center, and the MARS was used to assess the CMBs burden. Other clinical data including demographic factors, stroke severity, vascular risk factors, and clinical outcomes were also documented. Another mediation analysis was performed to investigate whether early neurological improvement could mediate the association between MARS and functional outcomes. RESULTS: A total of 408 patients were included. A cutoff value of 1.5 could predict functional outcomes in patients treated with IV tPA. Based on that cutoff value, MARS showed an independent relationship with functional outcomes [adjusted OR (Odds Ratio) 0.841, 95% confidence interval (CI) 0.720-0.982, P = .029]. A shift analysis showed that higher MARS score (MARS ≥1.5) was related with poor functional outcome according to mRS score distribution (OR = 0.519, 95% CI 0.336-0.803, P = .003). Total effect (indirect + direct effect) was calculated and showed in figure. Early neurological improvement mediated 24% of the effect of MARS score on functional outcomes. CONCLUSION: Our study showed that MARS could be a potential method to assess the functional outcome based on CMBs in patients treated with IV tPA, and MARS score ≥ 1.5 might be an optimal threshold for poor functional outcome.

Evaluation of a population-based breast cancer screening in North China.

BACKGROUND: Despite mammography-based screening for breast cancer has been conducted in many countries, there are still little data on participation and diagnostic yield in population-based breast cancer screening in China. METHODS: We enrolled 151,973 eligible women from four cities in Hebei Province within the period 2013-2021 and followed up until December 31, 2021. Participants aged 40-74 who assessed as high risk were invited to undergo breast ultrasound and mammography examination. Overall and group-specific participation rates were calculated. Multivariable analyses were used to estimate the factors associated with participation rates. The diagnostic yield of both screening and no screening groups was calculated. We further analyzed the stage distribution and molecular subtype of breast cancer cases by different modes of cancer detection. RESULTS: A total of 42,547 participants were evaluated to be high risk of breast cancer. Among them, 23,009 subjects undertook screening services, with participation rate of 54.08%. Multivariable logistic regression model showed that aged 45-64, high education level, postmenopausal, current smoking, alcohol consumption, family history of breast cancer, and benign breast disease were associated with increased participation of screening. After median follow-up of 3.79 years, there were 456 breast cancer diagnoses of which 65 were screen-detected breast cancers (SBCs), 27 were interval breast cancers (IBCs), 68 were no screening cancers, and 296 were cancers detected outside the screening program. Among them, 92 participants in the screening group (0.40%) and 364 in the non-screening group (0.28%) had breast cancer detected, which resulted in an odds ratio of 1.42 (95% CI 1.13-1.78; P = 0.003). We observed a higher detection rate of breast cancer in the screening group, with ORs of 2.42 (95% CI 1.72-3.41) for early stage (stages 0-I) and 2.12 (95% CI 1.26-3.54) for luminal A subtype. SBCs had higher proportion of early stage (71.93%) and luminal A subtype (47.22%) than other groups. CONCLUSIONS: The significant differences in breast cancer diagnosis between the screening and non-screening group imply an urgent need for increased breast cancer awareness and early detection in China.

Event-Triggered Consensus of Uncertain Euler-Lagrange Multiagent Systems Over Jointly Connected Digraphs.

In this article, a fully distributed event-triggered protocol is proposed to solve the consensus problem of uncertain Euler-Lagrange (EL) multiagent systems (MASs) under jointly connected digraphs. First, distributed event-based reference generators are proposed to generate continuously differentiable reference signals via event-based communication under jointly connected digraphs. Unlike some existing works, only the states of agents rather than virtual internal reference variables need to be transmitted among agents. Second, adaptive controllers are exploited based on the reference generators so that each agent can track the reference signals. The uncertain parameters converge to their real values under an initially exciting (IE) assumption. It is proved that the uncertain EL MAS achieves state consensus asymptotically under the proposed event-triggered protocol composed of the reference generators and the adaptive controllers. A unique feature of the proposed event-triggered protocol is its fully distributed property: the protocol does not depend on global information about the jointly connected digraphs. Meanwhile, a minimum interevent time (MIET) is guaranteed. Finally, two simulations are conducted to show the validity of the proposed protocol.

Intravenous thrombolysis for acute ischemic stroke during two COVID-19 outbreaks in China: Wuhan pandemic and Beijing pandemic.

INTRODUCTION: The COVID-19 pandemic has had an impact on the emergency department (ED). Door-to-needle time (DNT) could be prolonged for intravenous thrombolysis (IVT) treatment. We aimed to investigate the impact of two COVID-19 pandemics on the workflow of IVT in our neurovascular ED. METHOD: We performed a retrospective analysis of patients who received IVT treatment in the neurovascular ED of Beijing Tiantan Hospital, Beijing, from January 20, 2020, to October 30, 2020, covering two COVID-19 pandemics in China. The time-based performances of IVT treatment including onset-to-arrival time, arrival-to-CT time, CT-to-needle time, door-to-needle time, and onset-to-needle time were recorded. Data on clinical characteristics and imaging information were also collected. RESULTS: Four hundred forty patients that received IVT were enrolled in this study. The number of patients admitted to our neurovascular ED began to decrease in December 2019 and was the lowest in April 2020 (n = 95). Longer DNT (Wuhan pandemic: 49.00 [35.00, 64.00] min; Beijing pandemic: 55.00 [45.50, 77.00] min) interval delays were observed during the two pandemics (p = .016). More patients admitted during the two pandemics had an 'unknown' subtype (Wuhan pandemic: 21.8%; Beijing pandemic: 31.4%. p = .008). The percentage of the cardiac embolism subtype was higher during the Wuhan pandemic (20.0%) than during other periods. The median admission NIHSS score increased during the Wuhan pandemic and the Beijing pandemic (8.00 [4.00, 12.00], 7.00 [4.50, 14.00], respectively, p < .001). CONCLUSION: The number of patients who received IVT decreased during the Wuhan pandemic. Higher admission NIHSS scores and prolonged DNT intervals were also observed during the Wuhan pandemic and the Beijing pandemic.

Intravenous thrombolysis for mild stroke: NIHSS 3-5 Versus NIHSS 0-2.

BACKGROUND AND PURPOSE: Studies have shown that mild stroke patients with National Institutes of Health Stroke Scale (NIHSS) score 3-5 but not 0-2 may benefit from the intravenous thrombolysis when compared with antiplatelet therapy. We aimed to compare the safety and effectiveness of thrombolysis in mild stroke with NIHSS score of 0-2 vs. 3-5 and identify the predictors of an excellent functional outcome in a real world longitudinal registry. METHODS: In a prospective thrombolysis registry, we identified patients with acute ischemic stroke who presented within 4.5 hours of symptom onset and had initial NIHSS scores ≤ 5. Demographic data, medical history, pre-stroke medications, imaging data, and laboratory measures were collected. The outcome of interest was modified Rankin Scale score of 0 to 1 at discharge. Safety outcome was evaluated by syptomatic intracrerebral hemorrhage defined as any decline in neurologic status due to hemorrhage within 36 h. Multivariable regression models were performed to explore the safety and effectiveness in the alteplase-treated patients with admission NIHSS 0-2 vs. 3-5 and identify factors independently associated with an excellent functional outcome. RESULTS: Of a total of 236 eligible patients, those with an admission NIHSS score of 0-2 (n=80) had a better functional outcome at discharge compared with NIHSS 3-5 group (n=156) (81.3% vs. 48.7%, adjusted odds ratio [aOR] 0.40, 95% confidential interval [CI] 0.17 - 0.94, P=0.04) without increasing the rate of symptomatic intracerebral hemorrhage and mortality. Non-disabling stroke (Model 1: aOR 0.06, 95%CI 0.01-0.50, P=0.01; Model 2: aOR 0.06, 95% CI 0.01-0.48, P=0.01) and prior statin therapy (Model 1: aOR 3.46, 95% CI 1.02-11.70, P=0.046; Model 2: aOR 3.30, 95% CI 0.96-11.30, P=0.06) were independent predictors of excellent outcomes. CONCLUSIONS: Acute ischemic stroke patients with admission NIHSS 0-2 was associated with better functional outcomes at discharge compared with NIHSS 3-5 within the 4.5-hour time window. Minor stroke severity, non-disabling stroke and prior statin therapy were independent predictors for funcitonal outcomes at discharge. Further studies with large sample size are needed to confirm the findings.

Machine learning for predicting the survival in osteosarcoma patients: Analysis based on American and Hebei Province cohort.

Osteosarcoma, a rare malignant tumor, has a poor prognosis. This study aimed to find the best prognostic model for osteosarcoma. There were 2912 patients included from the SEER database and 225 patients from Hebei Province. Patients from the SEER database (2008-2015) were included in the development dataset. Patients from the SEER database (2004-2007) and Hebei Province cohort were included in the external test datasets. The Cox model and three tree-based machine learning algorithms (survival tree [ST], random survival forest [RSF] and gradient boosting machine [GBM]) were used to develop the prognostic models by 10-fold cross-validation with 200 iterations. Additionally, performance of models in the multivariable group was compared with the TNM group. The 3-year and 5-year cancer specific survival (CSS) were 72.71% and 65.92% in the development dataset, respectively. The predictive ability in the multivariable group was superior to that in the TNM group. The calibration curves and consistency in the multivariable group were superior to those in the TNM group. The Cox and RSF models performed better than the ST and GBM models. A nomogram was constructed to predict the 3-year and 5-year CSS of osteosarcoma patients. The RSF model can be used as a nonparametric alternative to the Cox model. The constructed nomogram based on the Cox model can provide reference for clinicians to formulate specific therapeutic decisions both in America and China.

Event-Triggered Cooperative Output Regulation of Heterogeneous Multiagent Systems Under Switching Directed Topologies.

In this article, the cooperative output regulation problem of heterogeneous linear multiagent systems under jointly connected digraphs is addressed. The event-triggered control protocols based on state feedback and output feedback are proposed, respectively. It is shown that the output tracking errors of the resulting closed-loop control systems converge to 0 exponentially via the proposed protocols. One of the key advantages of the proposed event-triggering mechanism is that the information transmissions induced by event triggerings and topology switchings are independent, and data transmissions among agents are thus reduced. Furthermore, an explicit minimum interevent time is provided for all the agents so that the Zeno-behavior is excluded strictly. Finally, three numerical examples are provided to verify the effectiveness of the proposed protocols.

Establishment and validation of a prognostic model for gastric cancer patients of Hebei Province in China.

BACKGROUND: Hebei Province is a high-risk area for gastric cancer in China, and there is currently no survival prediction model for gastric cancer patients in Hebei Province. This study aimed to build the best survival prediction model for gastric cancer patients in Hebei Province. METHODS: The development dataset included 1,993 hospitalized gastric cancer patients from the Hebei Cancer Registration Project during 2016 and 2017. Three tree-based machine learning methods [survival trees (ST), random survival forests (RSF), and gradient boosting machines (GBM)] and Cox, were used to develop the models by ten-fold cross validation with 200 iterations. California Chinese hospitalized gastric cancer patients were used as external test models. In addition, we compared the multivariable group with the Tumor Node Metastasis (TNM) group. RESULTS: The 3- and 5-year cancer-specific survival (CSS) rates of the development dataset were 57.07% and 44.48%, respectively. For predicting the 3-year CSS rates of gastric cancer patients of multivariable group, the C-indexes in train datasets were 0.75, 0.72, 0.79 and 0.76 for Cox, ST, RSF and GBM. Multivariable group performed better than TNM group. The predictive ability of Cox and RSF were superior to ST and GBM. A nomogram was established to predict the 3- and 5-year CSS rates of gastric cancer patients. CONCLUSIONS: The nomogram was useful for facilitating clinicians to predict the survival of gastric cancer patients, and identifying high-risk patients so as to adopt more reasonable treatment plans.

Clinical Significance of Stress Hyperglycemic Ratio and Glycemic Gap in Ischemic Stroke Patients Treated with Intravenous Thrombolysis.

Objective: The clinical significance of different glycemic parameters has been rarely investigated in ischemic stroke patients treated with intravenous tissue plasminogen activator (IV tPA). This study was aimed to investigate the association between different glycemic parameters and favorable functional outcome in patients treated with IV tPA. Methods: Patients with ischemic stroke who received IV tPA therapy at our stroke center were retrospectively enrolled. Four glycemic parameters were collected including admission glucose, HbA1c, stress hyperglycemia ratio (SHR) and glycemic gap (GG). Additional information was also recorded including demographics, medical history, stroke severity, imaging measures and mRS score at discharge. We used 5 machine learning models to investigate the predictive value of glycemic parameters. Results: Our study included 294 patients treated with IV tPA. SHR and GG were independently associated with favorable functional outcome (adjusted OR for SHR 0.03, 95% CI 0.01-0.72, P = 0.03; adjusted OR for GG 1.024, 95% CI 1.00-1.05, P = 0.04). Conclusion: SHR and GG were associated with functional outcomes in acute ischemic stroke patients with intravenous thrombolysis.

Association Between Neutrophil-to-Lymphocyte Ratio/Lymphocyte-to-Monocyte Ratio and In-Hospital Clinical Outcomes in Ischemic Stroke Treated with Intravenous Thrombolysis.

Objective: Investigations on neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) in patients with ischemic stroke are insufficient. We aimed to investigate the relationship of NLR and LMR with in-hospital clinical outcomes at different time points in ischemic stroke patients treated with intravenous tissues plasminogen activator (IV tPA). Methods: We retrospectively enrolled patients who received IV tPA therapy within 4.5 hours from symptoms onset. Demographics, clinical characteristics, imaging measures, and the in-hospital clinical outcomes including early neurological improvement (ENI, defined as NIHSS score reduction within 24 hours ≥4 points or decreased to the baseline) and favorable functional outcome (defined as modified Rankin scale 0-1) were collected. Multivariable logistic regression analyses were performed to test whether NLR or LMR was an independent predictor for the in-hospital clinical outcomes. Results: One hundred and two patients treated with IV tPA were included. NLR at 24 hours proved to be an independent predictor of ENI (adjusted OR=0.85, 95% CI=0.75-0.95, P=0.04). NLR at 48 hours and LMR at 48 hours proved to be independent predictors of mRS 0-1 at discharge (NLR at 48 hours: adjusted OR=0.64, 95% CI=0.49-0.83, P=0.01; LMR at 48 hours: adjusted OR=1.50, 95% CI=1.08-2.09, P=0.02). The AUC of NLR at 48 hours to predict favorable functional outcome at discharge was 0.79 (95% CI=0.70-0.88, P<0.001) and the optimal cut-off was 5.69 (sensitivity=0.52, specificity=0.63). Conclusion: In our study, NLR at 24 hours was correlated with ENI. Both NLR and LMR at 48 hours were closely associated with favorable functional outcomes at discharge.

In-hospital clinical outcomes in diffusion weighted imaging-negative stroke treated with intravenous thrombolysis.

OBJECTIVE: We aimed to investigate whether negative diffusion weighted imaging (DWI) is related to the in-hospital clinical outcomes for ischemic stroke patients with intravenous tissues plasminogen activator (IV tPA). METHODS: We retrospectively enrolled patients who received IV tPA therapy within 4.5 hours from symptoms onset. The classification of DWI-positive or negative was based on post-IV tPA MR scan. Demographic factors, stroke characteristics, imaging information, and the in-hospital clinical outcomes including early neurological improvement (ENI) and favourable functional outcome were collected. Multivariable logistic regression and sensitivity analyses were conducted to test whether negative DWI imaging was an independent predictor of the in-hospital clinical outcomes. RESULTS: In the final study population, 437 patients treated with IV tPA were included and 12.36% of them had negative DWI imaging at the first MR scan post IV tPA. In the DWI-negative group, 51.9% (28/54) of the patients achieved ENI at 24 hours and 74.1% (40/54) of the patients achieved favourable clinical outcome at discharge. DWI-negative was not related to ENI (adjusted odds ratio 0.93, 95% confidence interval 0.17-4.91) or favourable clinical outcome (adjusted odds ratio 2.40, 95% confidence interval 0.48-11.95). Additional sensitivity analyses yielded similar results. CONCLUSION: DWI-negative is not associated with ENI or favourable functional outcome at discharge.

Clinical Significance and Dynamic Change of Coagulation Parameters in Ischemic Stroke Patients Treated with Intravenous Thrombolysis.

OBJECTIVE: Investigations on coagulation parameters including fibrinogen (Fbg), fibrinogen degradation products (FDP), and D-dimer in ischemic stroke patients treated with intravenous thrombolysis are insufficient. We aimed to investigate the association between in-hospital clinical outcomes and the coagulation parameters at different time points in ischemic stroke patients treated with intravenous tissues plasminogen activator (IV tPA). METHODS: We retrospectively enrolled patients who received IV tPA therapy within 4.5 h from symptoms onset. Demographics, clinical characteristics, imaging measures, and the discharge mRS score were collected. Multivariable logistic regression analyses were performed to test whether coagulation parameters were independent predictors for the in-hospital clinical outcomes. We also employed machine learning models to investigate whether coagulation parameters were able to improve the prediction of favorable functional outcomes. RESULTS: One hundred and fifty-two patients treated with IV tPA were included. Among the coagulation parameters, low D-dimers at 48 h proved to be an independent predictor of favorable functional outcome (adjusted odd ratio 0.24, 95% confidential intervals 0.06-0.92, P = 0.04). The AUC of D-dimer at 48 h to predict favorable functional outcome was 0.73 (0.60-0.87) and the optimal cut-off value was 0.92 (sensitivity 0.69, specificity 0.78). Machine learning models with D-dimer at 48 h had superior performance in predicting favorable functional outcomes and among the input variables in the machine learning models, D-dimer at 48 h showed the highest weight in predicting mRS 0-1 at discharge (38.44%). CONCLUSION: Increased levels of D-dimer at 48 h was associated with lower proportion of favorable functional outcomes in acute ischemic stroke patients with intravenous thrombolysis.

POM Anolyte for All-Anion Redox Flow Batteries with High Capacity Retention and Coulombic Efficiency at Mild pH.

A highly soluble Li5 BW12 O40 cluster delivers 2 e- redox reaction with fast electron transfer rates (2.5 × 10-2  cm s-1 ) and high diffusion coefficients (≈2.08 × 10-6 cm2 s-1 ) at mild pH ranging from 3 to 8. In-operando aqueous-flowing Raman spectroscopy and density functional theory calculations reveal that Raman shift changing of {BW12} clusters is due to the bond length changing between W-Ob -W and W-Oc -W at different redox states. The structure changing and redox chemistry of Li5 BW12 O40 are highly reversible, which makes the Li5 BW12 O40 cluster versatile to construct all-anion aqueous redox flow batteries (RFBs). The cation-exchange Nafion membrane will also repel the cross permeability of the anion redox couples. Consequently, by coupling with Li3 K[Fe(CN)6 ] catholyte, the aqueous RFB can be operated at pH 8 with a capacity retention up to 95% and an average Coulombic efficiency more than 99.79% over 300 cycles within 0 to 1.2 V. Meanwhile, Li5 BW12 O40 cluster can also be paired with LiI catholyte to form aqueous RFBs at pH 7 and pH 3, the capacity retention of 94% and 90% can be realized over 300 cycles within 0 to 1.3 V.

Molecular mechanism underlying transport and allosteric inhibition of bicarbonate transporter SbtA.

SbtA is a high-affinity, sodium-dependent bicarbonate transporter found in the cyanobacterial CO2-concentrating mechanism (CCM). SbtA forms a complex with SbtB, while SbtB allosterically regulates the transport activity of SbtA by binding with adenyl nucleotides. The underlying mechanism of transport and regulation of SbtA is largely unknown. In this study, we report the three-dimensional structures of the cyanobacterial Synechocystis sp. PCC 6803 SbtA-SbtB complex in both the presence and absence of HCO3- and/or AMP at 2.7 Å and 3.2 Å resolution. An analysis of the inward-facing state of the SbtA structure reveals the HCO3-/Na+ binding site, providing evidence for the functional unit as a trimer. A structural comparison found that SbtA adopts an elevator mechanism for bicarbonate transport. A structure-based analysis revealed that the allosteric inhibition of SbtA by SbtB occurs mainly through the T-loop of SbtB, which binds to both the core domain and the scaffold domain of SbtA and locks it in an inward-facing state. T-loop conformation is stabilized by the AMP molecules binding at the SbtB trimer interfaces and may be adjusted by other adenyl nucleotides. The unique regulatory mechanism of SbtA by SbtB makes it important to study inorganic carbon uptake systems in CCM, which can be used to modify photosynthesis in crops.

Publisher Correction: The oligomeric structures of plant cryptochromes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The oligomeric structures of plant cryptochromes.

Cryptochromes (CRYs) are a group of evolutionarily conserved flavoproteins found in many organisms. In plants, the well-studied CRY photoreceptor, activated by blue light, plays essential roles in plant growth and development. However, the mechanism of activation remains largely unknown. Here, we determined the oligomeric structures of the blue-light-perceiving PHR domain of Zea mays CRY1 and an Arabidopsis CRY2 constitutively active mutant. The structures form dimers and tetramers whose functional importance is examined in vitro and in vivo with Arabidopsis CRY2. Structure-based analysis suggests that blue light may be perceived by CRY to cause conformational changes, whose precise nature remains to be determined, leading to oligomerization that is essential for downstream signaling. This photoactivation mechanism may be widely used by plant CRYs. Our study reveals a molecular mechanism of plant CRY activation and also paves the way for design of CRY as a more efficient optical switch.