White Matter Hyperintensity is Associated with Malignant Cerebral Edema in Ischemic Stroke Treated with Thrombectomy.

BACKGROUND: White matter hyperintensity (WMH) burden may lead to poor clinical outcomes after endovascular thrombectomy (EVT). But the relationship between WMH burden and cerebral edema (CED) is unclear. PURPOSE: To examine the association between WMH burden and CED and functional outcome in patients treated with EVT. STUDY TYPE: Retrospective. SUBJECT: 344 patients with acute anterior circulation large-vessel occlusion stroke who received EVT at two comprehensive stroke centers. Mean age was 62.6 ± 11.6 years and 100 patients (29.1%) were female. FIELD STRENGTH/SEQUENCE: 3T, including diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) images. ASSESSMENT: The severity of WMH was evaluated using the Fazekas scale on a FLAIR sequence before EVT. The severity of CED was assessed using CED score (three for malignant cerebral edema [MCE]) and net water uptake (NWU)/time on post-EVT cranial CT. The impact of WMH burden on MCE, NWU/time, and 3-month poor outcome (modified Rankin scale >2) after EVT were assessed. STATISTICAL TESTS: Pearson's chi-squared test, Fisher exact test, 2-tailed t test, Mann-Whitney U test, multivariable logistic regression, multivariate regression analysis, Sobel test. A P value <0.05 was considered statistically significant. RESULTS: WMH burden was not significantly associated with MCE and parenchymal hemorrhage (PH) in the whole population (P = 0.072; P = 0.714). WMH burden was significantly associated with an increased risk of MCE (OR, 1.550; 95% CI, 1.128-2.129), higher NWU/time (Coefficient, 0.132; 95% CI, 0.012-0.240), and increased risk of 3-month poor outcome (OR, 1.434; 95% CI, 1.110-1.853) in the subset of patients without PH. Moreover, the connection between WMH burden and poor outcome was partly mediated by CED in patients without PH (regression coefficient changed by 29.8%). DATA CONCLUSION: WMH burden is associated with CED, especially MCE, and poor outcome in acute ischemic stroke patients treated with EVT. The association between WMH burden and poor outcome may partly be attributed to postoperative CED. TECHNICAL EFFICACY: Stage 5.

Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid.

OBJECTIVE: This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA. METHODS: We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group. RESULTS: The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 µg/mL) compared with that before co-administration (88.8 ± 13.6 µg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 µg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291). CONCLUSIONS: In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020.

High Systemic Inflammatory Protein Index Is Associated with Clinically Ineffective Reperfusion in Acute Anterior Circulation Ischemic Stroke Patients Undergoing Endovascular Treatment.

Nearly half of the patients undergoing endovascular treatment (EVT) do not have favorable outcomes despite successful recanalization of the occluded artery, which is also known as clinically ineffective reperfusion. We proposed a novel index-the systemic inflammatory protein index (SIPI), based on albumin, globulin, and C-reaction protein (CRP). We aimed to evaluate the relationship between inflammatory biomarkers at varying time points and the 90-day functional outcomes and investigate inflammatory biomarkers' dynamic changes during hospitalization in acute ischemic stroke (AIS) patients of anterior circulation undergoing EVT. We retrospectively recruited consecutive patients diagnosed with AIS of anterior circulation and treated with EVT from January 2018 to June 2022 in Nanfang Hospital. Albumin, globulin, and CRP were recorded on admission, 1 day, 3 days, and 7 days after EVT. An unfavorable functional outcome was defined as 90-day modified Rankin Scale (mRS) of 3-6. Albumin-to-globulin ratio (AGR), C-reactive protein-to-albumin ratio (CAR), and SIPI were calculated as follows: AGR = albumin/globulin; CAR = CRP/albumin; SIPI = CRP × globulin/albumin. A total of 238 consecutive anterior circulation AIS patients with EVT were included, among which 145 (60.9%) patients had unfavorable outcomes. After adjusting for confounding factors, admission globulin, admission AGR, 1-day AGR, 3-day albumin, 3-day CRP, 3-day CAR, 3-day SIPI, 7-day albumin, 7-day CRP, 7-day CAR, and 7-day SIPI showed an independent association with 90-day functional outcome. Of them, 3-day SIPI had the most robust discriminative ability with an area under the curve of 0.719 (CI 0.630-0.808, p < 0.001). There were differences in the dynamic change of inflammatory biomarkers between the subjects with favorable and unfavorable functional outcomes. Inflammatory biomarkers, including albumin, globulin, CRP, AGR, CAR, and SIPI, are independent predictors of 90-day unfavorable outcomes in anterior circulation AIS patients with EVT. SIPI of day 3 has the highest predictive value.

Covalent organic framework based cytoprotective therapy after ischemic stroke.

Cytoprotection has emerged as an effective therapeutic strategy for mitigating brain injury following acute ischemic stroke (AIS). The sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel plays a pivotal role in brain edema and neuroinflammation. However, the practical use of the inhibitor glyburide (GLB) is hindered by its low bioavailability. Additionally, the elevated reactive oxygen species (ROS) after AIS exacerbate SUR1-TRPM4 activation, contributing to irreversible brain damage. To overcome these challenges, GLB and superoxide dismutase (SOD) were embedded in a covalent organic framework (COF) with a porous structure and great stability. The resulting S/G@COF demonstrated significant improvements in survival and neurological functions. This was achieved by eliminating ROS, preventing neuronal loss and apoptosis, suppressing neuroinflammation, modulating microglia activation, and ameliorating blood-brain barrier (BBB) disruption. Mechanistic investigations revealed that S/G@COF concurrently activated the Wnt/ß-catenin signaling pathway while suppressing the upregulation of SUR1-TRPM4. This study underscores the potential of employing multi-target therapy and drug modification in cytoprotective strategies for ischemic stroke.

Glymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke.

BACKGROUND: Blood-brain barrier damage has traditionally been considered to determine the occurrence and development of poststroke brain edema, a devastating and life-threatening complication. However, no treatment strategy targeting blood-brain barrier damage has been proven clinically effective in ameliorating brain edema. METHODS: In mice with stroke models induced by transient middle cerebral artery occlusion (MCAO), the changes in glymphatic system (GS) function impairment were detected by ex vivo fluorescence imaging, 2-photon in vivo imaging, and magnetic resonance imaging within 1 week after MCAO, and the effects of GS impairment and recovery on the formation and resolution of brain edema were evaluated. In addition, in patients with ischemic stroke within 1 week after onset, changes in GS function and brain edema were also observed by magnetic resonance imaging. RESULTS: We found that the extravasation of protein-rich fluids into the brain was not temporally correlated with edema formation after MCAO in mice, as brain edema reabsorption preceded blood-brain barrier closure. Strikingly, the time course of edema progression matched well with the GS dysfunction after MCAO. Pharmacological enhancement of the GS function significantly alleviated brain edema developed on day 2 after MCAO, accompanied by less deposition of Aß (amyloid-ß) and better cognitive function. Conversely, functional suppression of the GS delayed the absorption of brain edema on day 7 after MCAO. Moreover, patients with ischemic stroke revealed a consistent trend of GS dysfunction after reperfusion as MCAO mice, which was correlated with the severity of brain edema and functional outcomes. CONCLUSIONS: GS is a key contributor to the formation of brain edema after ischemic stroke, and targeting the GS may be a promising strategy for treating brain edema in ischemic stroke. REGISTRATION: URL: https://www.chictr.org.cn/showproj.html?proj=162857; Unique identifier: NFEC-2019-189.

White matter hyperintensity burden and functional outcomes in acute ischemic stroke patients after mechanical thrombectomy: A systematic review and meta-analysis.

BACKGROUND: The influence of white matter hyperintensity (WMH) on clinical outcomes in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT) remains controversial. We performed a systematic review and meta-analysis to examine whether WMH burden is associated with clinical outcomes in AIS patients after MT. METHODS: PubMed, Embase, and Web of Science were searched from inception to Sep 03, 2023. The registration number for PROSPERO is CRD42022340568. Studies reporting an association between the burden of WMH in AIS patients and clinical outcomes after MT were included in the meta-analysis. A random-effects model was used for meta-analysis. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Additionally, the presence of imprecise-study effects was evaluated using Egger's test and funnel plot. RESULTS: Fifteen studies with 3,456 patients were enrolled in this meta-analysis. Among AIS patients who underwent MT, moderate/severe WMH had higher odds of 90-day unfavorable functional outcomes (odds ratio [OR] 2.72, 95% confidence interval [CI] 2.14-3.44; I2 = 0.0%; 95% CI 0.0%-42.7%), 90-day mortality (OR 1.94, 95% CI 1.45-2.60; I2 = 19.5%; 95% CI 0.0%-65.2%) and futile recanalization (OR 2.99, 95% CI 1.42-6.28; I2 = 69.7%; 95% CI 0.0%-91.0%) compared with none/mild WMH. However, the two groups had no significant difference in successful recanalization, symptomatic hemorrhagic transformation, and hemorrhagic transformation. A subset analysis of patients from 3 articles showed that WMH volume was not significantly associated with these outcomes. A notable limitation is that this meta-analysis lacks direct adjustment for imbalances in important baseline covariates. CONCLUSIONS: Patients with moderate/severe WMH on baseline imaging are associated with substantially increased odds of 90-day unfavorable outcomes, futile recanalization, and 90-day mortality after MT. This association suggests that moderate/severe WMH may contribute to the prediction of clinical outcomes in AIS patients after MT.

RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer.

RNF43 is a tumor suppressor for various cancers and is considered to drive carcinogenesis when mutated. However, the correlation between RNF43 mutation and colorectal cancer (CRC) immunotherapy remains unreported. We evaluated the role of RNF43 using publicly available data from the Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). In addition, further analysis was performed on an internal validation cohort (hcohort). The mutant profiles of RNF43 were analyzed in 873 Chinese CRC patients. The relationship between clinical pathologic features and RNF43 were analyzed using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics were associated with overall survival using Cox regression and the Kaplan-Meier method. We found that RNF43 mutation was significantly associated with high TMB and high MSI score (all p-values < 0.05) in the MSKCC cohort. Additionally, RNF43 mutation was found to be enriched in MSI instability. Kaplan-Meier survival analysis revealed that patients with RNF43 mutation had better OS compared to RNF43 wild-type (not reached vs. 13 months, HR, 0.12; 95% CI 0.03 to 0.49; P = 0.0034). However, no association was observed between RNF43 and OS in the TCGA cohort (HR, 1.83; 95% CI 0.66 to 5.07; P = 0.2479). Our CRC hcohort confirmed the significance of RNF43 mutation in predicting better clinical outcomes, including ORR (45% vs. 21%, P = 0.0468). RNF43 mutation correlated with a high tumor mutation burden (P < 0.001). The mutation frequency of RNF43 in CRC patients was 8.4% (73/873); RNF43 G659Vfs*41 was found to be the most frequent mutation site. In patients with RNF43 mutations, TP53, KRAS, and TGFBR2 were genes with a high frequency of mutations. Compared with RNF43 wild-type patients, those with RNF43 mutations had a higher TMB score and a greater proportion of MSI-H, but no difference in PD-L1 expression. Moreover, the content of immune-related B cells, CD8+ T cells, neutrophils, and dendritic cells was higher in the RNF43 mutant group than in the wild-type group. Our results suggest that RNF43 mutation may correlate with better OS in CRC patients receiving PD-1/PD-L1 inhibitors. The exact mechanisms underlying RNF43 require further investigation.

In Situ Ratiometric Determination of Cerebral Ascorbic Acid after Ischemia Reperfusion.

Ascorbic acid (AA) is significant in protecting the brain from further damage and maintaining brain homeostasis after ischemia stroke (IS); however, the dynamic change of cerebral AA content after different degrees of ischemic stroke is still unclear. Herein, carboxylated single-walled carbon nanotube (CNT-COOH)- and polyethylenedioxythiophene (PEDOT)-modified carbon fiber microelectrodes (CFEs) were proposed to detect in situ cerebral AA with sensitivity, selectivity, and stability. Under differential pulse voltammetry scanning, the CFE/CNT-COOH/PEDOT gave a ratiometric, electrochemically responsive signal. The internal standard peak at -310 mV was from the reversible peak of O2 reduction and the deprotonation and protonation of quinone groups, while AA was oxidized at -70 mV. In vivo experimental results indicated that the cerebral AA level gradually increased with the ischemic time increasing in different middle cerebral artery occlusion (MCAO) model mice. This work implies that the increasing cerebral AA level may be highly related to the glutamate excitotoxicity and ROS-led cell apoptosis and paves a new way for further understanding the release and metabolic mechanisms of AA during ischemia reperfusion and IS.

Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): a randomized, double-blind, placebo-controlled trial.

Background: Glibenclamide alleviates brain edema and improves neurological outcomes in experimental models of stroke. We aimed to assess whether glibenclamide improves functional outcomes in patients with acute ischemic stroke treated with recombinant tissue plasminogen activator (rtPA). Methods: In this randomized, double-blind, placebo-controlled trial, patients with acute ischemic stroke were recruited to eight academic hospitals in China. Patients were eligible if they were aged 18-74 years, presented with a symptomatic anterior circulation occlusion with a deficit on the NIHSS of 4-25, and had been treated with rtPA within 4.5 h of symptom onset. We used web-based randomization (1:1) to allocate eligible participants to the glibenclamide or placebo group, stratified according to endovascular treatment and baseline stroke severity. Glibenclamide or placebo was taken orally or via tube feeding at a loading dose of 1.25 mg within 10 h after symptom onset, followed by 0.625 mg every 8 h for 5 days. The primary outcome was the proportion of patients with good outcomes (modified Rankin Scale of 0-2) at 90 days, assessed in all randomly assigned patients who had been correctly diagnosed and had begun study medication. The study is registered with ClinicalTrials.gov, NCT03284463, and is closed to new participants. Findings: Between January 1, 2018, and May 28, 2022, 305 patients were randomly assigned, of whom 272 (142 received glibenclamide and 130 received placebo) were included in the primary efficacy analysis. 103 (73%) patients in the glibenclamide group and 94 (72%) in the placebo group had a good outcome (adjusted risk difference 0.002, 95% CI -0.098 to 0.103; p = 0.96). 12 (8%) patients allocated to glibenclamide and seven (5%) patients allocated to placebo died from any cause at 90 days (p = 0.35). The number and type of adverse events were similar between the two groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: The addition of glibenclamide to thrombolytic therapy did not increase the proportion of patients who achieved good outcomes after stroke compared with placebo, but it did not lead to any safety concerns. Funding: Southern Medical University and Nanfang Hospital.

Vertical Layering of Quantized Neural Networks for Heterogeneous Inference.

Although considerable progress has been obtained in neural network quantization for efficient inference, existing methods are not scalable to heterogeneous devices as one dedicated model needs to be trained, transmitted, and stored for one specific hardware setting, incurring considerable costs in model training and maintenance. In this paper, we study a new vertical-layered representation of neural network weights for encapsulating all quantized models into a single one. It represents weights as a group of bits (i.e., vertical layers) organized from the most significant bit (also called the basic layer) to less significant bits (i.e., enhance layers). Hence, a neural network with an arbitrary quantization precision can be obtained by adding corresponding enhance layers to the basic layer. However, we empirically find that models obtained with existing quantization methods suffer severe performance degradation if they are adapted to vertical-layered weight representation. To this end, we propose a simple once quantization-aware training (QAT) scheme for obtaining high-performance vertical-layered models. Our design incorporates a cascade downsampling mechanism with the multi-objective optimization employed to train the shared source model weights such that they can be updated simultaneously, considering the performance of all networks. After the model is trained, to construct a vertical-layered network, the lowest bit-width quantized weights become the basic layer, and every bit dropped along the downsampling process act as an enhance layer. Our design is extensively evaluated on CIFAR-100 and ImageNet datasets. Experiments show that the proposed vertical-layered representation and developed once QAT scheme are effective in embodying multiple quantized networks into a single one and allow one-time training, and it delivers comparable performance as that of quantized models tailored to any specific bit-width.

Ketogenic diet and ß-Hydroxybutyrate alleviate ischemic brain injury in mice via an IRAKM-dependent pathway.

Ketogenic diet (KD) is a classical nonpharmacological therapy that has recently been shown to benefit cerebral ischemia, but the mechanism remains unclear. This study investigated the neuroprotective effects of KD pretreatment and ß-hydroxybutyrate (BHB, bioactive product of KD) post-treatment in a mouse model of temporary middle cerebral artery occlusion (tMCAO). Neurological function, infarct volume, as well as inflammatory reactions are evaluated 24 h after ischemia. Results showed that both KD pretreatment or BHB post-treatment improved the Bederson score and Grip test score, reduced infarct volume and the extravasation of IgG, suppressed the over-activation of microglia, and modulated the expression of cytokines. Mechanically, we found that both KD pretreatment or BHB post-treatment significantly stimulated the expression of interleukin-1 receptor-associated kinase M (IRAKM) and then inhibited the nuclear translocation of NF-κB. IRAKM deletion (Irakm-/-) exacerbated tMCAO-induced neurovascular injuries, and aggravated neuroinflammatory response. Moreover, KD pretreatment or BHB post-treatment lost their neuroprotection in the tMCAO-treated Irakm-/- mice. Our results support that KD pretreatment and BHB post-treatment alleviate ischemic brain injury in mice, possibly via an IRAKM-dependent way.

Expression Profiles, Prognosis, and ceRNA Regulation of SRY-Related HMG-Box Genes in Stomach Adenocarcinoma.

Aberrant expression of the SRY-related HMG-box (SOX) genes contributes to tumor development and progression. This research aimed to identify the regulation of the SOX genes in stomach adenocarcinoma (STAD). Expression profiles downloaded from The Cancer Genome Atlas (TCGA) were conducted to analyze the expression and function of the SOX genes. A competing endogenous RNAs (ceRNA) network mediated by the SOX genes was effectively constructed consisting of 64 lncRNAs, 29 miRNAs, and 11 SOX genes based on predicted miRNAs shared by lncRNAs and mRNAs using miRDB, TargetScan, miRTarBase, miRcode, and starBase v2.0. SOX9 was identified as a prognostic signature, which showed the usefulness of diagnosis and prognosis of STAD by the receiver operating characteristic (ROC) and Kaplan-Meier curves. SOX9 was also shown specifically in STAD and identified as highly expressed in the gastrointestinal tract. Gene Ontology (GO) enrichment analysis showed that SOX9 might influence the genes related to the pattern specification process, sodium ion homeostasis, and potassium ion transport, mainly including FEZF1, HOXC13, HOXC10, HOXC9, HOXA11, DPP6, ATP4B, CASQ2, KCNA1, ATP4A, and SFRP1. Furthermore, HOTAIR knockdown, miR-206-mimic transfection, the Cell Count Kit-8 (CCK-8) assay were performed to verify the function of HOTAIR/miR-206/SOX9 axis, which was identified in the ceRNA network analysis. HOTAIR could induce proliferation potentially by competitively binding miR-206/SOX9 axis in STAD. These findings provide new clues with prognostic and therapeutic implications in STAD and suggest that HOTAIR/miR-206/SOX9 might be a potential new strategy for therapeutic targeting of gastric cancer.

An end-to-end multi-task system of automatic lesion detection and anatomical localization in whole-body bone scintigraphy by deep learning.

SUMMARY: Limited by spatial resolution and visual contrast, bone scintigraphy interpretation is susceptible to subjective factors, which considerably affects the accuracy and repeatability of lesion detection and anatomical localization. In this work, we design and implement an end-to-end multi-task deep learning model to perform automatic lesion detection and anatomical localization in whole-body bone scintigraphy. A total of 617 whole-body bone scintigraphy cases including anterior and posterior views were retrospectively analyzed. The proposed semi-supervised model consists of two task flows. The first one, the lesion segmentation flow, received image patches and was trained in a supervised way. The other one, skeleton segmentation flow, was trained on as few as five labeled images in conjunction with the multi-atlas approach, in a semi-supervised way. The two flows joint in their encoder layers so each flow can capture more generalized distribution of the sample space and extract more abstract deep features. The experimental results show that the architecture achieved the highest precision in the finest bone segmentation task in both anterior and posterior images of whole-body scintigraphy. Such an end-to-end approach with very few manual annotation requirement would be suitable for algorithm deployment. Moreover, the proposed approach reliably balances unsupervised labels construction and supervised learning, providing useful insight for weakly labeled image analysis. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Three-Dimensional Digital Reconstruction of the Cerebellar Cortex: Lobule Thickness, Surface Area Measurements, and Layer Architecture.

The cerebellum is ontogenetically one of the first structures to develop in the central nervous system; nevertheless, it has been only recently reconsidered for its significant neurobiological, functional, and clinical relevance in humans. Thus, it has been a relatively under-studied compared to the cerebrum. Currently, non-invasive imaging modalities can barely reach the necessary resolution to unfold its entire, convoluted surface, while only histological analyses can reveal local information at the micrometer scale. Herein, we used the BigBrain dataset to generate area and point-wise thickness measurements for all layers of the cerebellar cortex and for each lobule in particular. We found that the overall surface area of the cerebellar granular layer (including Purkinje cells) was 1,732 cm2 and the molecular layer was 1,945 cm2. The average thickness of the granular layer is 0.88 mm (± 0.83) and that of the molecular layer is 0.32 mm (± 0.08). The cerebellum (both granular and molecular layers) is thicker at the depth of the sulci and thinner at the crowns of the gyri. Globally, the granular layer is thicker in the lateral-posterior-inferior region than the medial-superior regions. The characterization of individual layers in the cerebellum achieved herein represents a stepping-stone for investigations interrelating structural and functional connectivity with cerebellar architectonics using neuroimaging, which is a matter of considerable relevance in basic and clinical neuroscience. Furthermore, these data provide templates for the construction of cerebellar topographic maps and the precise localization of structural and functional alterations in diseases affecting the cerebellum.

Dynamic changes of neutrophil-to-lymphocyte ratio in brain-dead donors and delayed graft function in kidney transplant recipients.

OBJECTIVES: Neutrophil-to-lymphocyte ratio (NLR) is a simple parameter implying the inflammatory status. We aimed to explore the association of brain-dead donor NLR change with delayed graft function (DGF) in kidney transplant recipients. METHODS: We retrospectively analyzed the data on 102 adult brain-dead donors and their corresponding 199 kidney transplant recipients (2018 - 2021). We calculated ΔNLR by subtracting the NLR before evaluating brain death from the preoperative NLR. Increasing donor NLR was defined as ΔNLR > 0. RESULTS: Forty-four (22%) recipients developed DGF after transplantation. Increasing donor NLR was significantly associated with the development of DGF in recipients (OR 2.8, 95% CI 1.2 - 6.6; p = .018), and remained significant (OR 2.6, 95% CI 1.0 - 6.4; p = .040) after adjustment of confounders including BMI, hypertension, diabetes, and the occurrence of cardiac arrest. When acute kidney injury (AKI) was included in the multivariable analysis, increasing donor NLR lost its independent correlation with DGF, while AKI remained an independent risk factor of recipient DGF (OR 4.5, 95% CI 2.7 - 7.6; p < .001). The area under the curve of combined increasing NLR and AKI in donors (0.873) for predicting DGF was superior to increasing donor NLR (0.625, p = .015) and AKI alone (0.859, p < .001). CONCLUSIONS: Dynamic changes of donor NLR are promising in predicting post-transplant DGF. It will assist clinicians in the early recognition and management of renal graft dysfunction. Validation of this new biomarker in a large study is needed.

The Performances of SNAQ, GLIM, mNICE, and ASPEN for Identification of Neurocritically Ill Patients at High Risk of Developing Refeeding Syndrome.

We previously found that neurocritically ill patients are prone to refeeding syndrome (RFS), a potentially life-threatening complication. However, there is no unified or validated consensus on the screening tool for RFS so far. We aimed to validate and compare the performance of four screening tools for RFS in neurocritically ill patients. We conducted a single-center, observational, retrospective cohort study among neurocritically ill adult patients who were admitted to the neurocritical care unit (NCU), and who received enteral nutrition for 72 h or longer. They were scored on the Short Nutritional Assessment Questionnaire (SNAQ), the Global Leadership Initiative on Malnutrition (GLIM), the modified criteria of the Britain's National Institute for Health and Care Excellence (mNICE), and ASPEN Consensus Recommendations for Refeeding Syndrome (ASPEN) scales to predict RFS risk via admission data. The performance of each scale in predicting RFS was evaluated. Logistic regression analysis was used to identify the independent risk factors for RFS, and they were added to the above scales to strengthen the identification of RFS. Of the 478 patients included, 84 (17.57%) developed RFS. The sensitivity of the SNAQ and GLIM was only 20.2% (12.6-30.7%), although they had excellent specificities of 84.8% (80.8-88.1%) and 86.0% (82.1-89.2%), respectively; mNICE predicted RFS with a sensitivity of 48.8% (37.8-59.9%) and a specificity of 65.0% (60.0-69.9%); ASPEN had the highest Youden index, with a sensitivity and specificity of 53.6% (42.4-64.4%) and 64.7% (59.8-69.4%), respectively. The Area Under the receiver operating characteristic Curves (AUC) of SNAQ, GLIM, mNICE, and ASPEN to predict RFS were 0.516 (0.470-0.561), 0.533 (0.487-0.579), 0.568 (0.522-0.613), and 0.597 (0.551-0.641), respectively. We identified age, Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Glasgow Coma Scale (GCS) score as independent risk factors of RFS, and the combination of GCS and age can improve the AUC of ASPEN to 0.664 (0.620-0.706) for predicting RFS. SNAQ, GLIM, mNICE, and ASPEN do not perform well in identifying neurocritically ill patients at high risk of RFS, although ASPEN appears to have relatively a good validity among them. Combining GCS and age with ASPEN slightly improves RFS recognition, but it still leaves a lot of room for improvement.

Predicting futile recanalization, malignant cerebral edema, and cerebral herniation using intelligible ensemble machine learning following mechanical thrombectomy for acute ischemic stroke.

Purpose: To establish an ensemble machine learning (ML) model for predicting the risk of futile recanalization, malignant cerebral edema (MCE), and cerebral herniation (CH) in patients with acute ischemic stroke (AIS) who underwent mechanical thrombectomy (MT) and recanalization. Methods: This prospective study included 110 patients with premorbid mRS ≤ 2 who met the inclusion criteria. Futile recanalization was defined as a 90-day modified Rankin Scale score >2. Clinical and imaging data were used to construct five ML models that were fused into a logistic regression algorithm using the stacking method (LR-Stacking). We added the Shapley Additive Explanation method to display crucial factors and explain the decision process of models for each patient. Prediction performances were compared using area under the receiver operating characteristic curve (AUC), F1-score, and decision curve analysis (DCA). Results: A total of 61 patients (55.5%) experienced futile recanalization, and 34 (30.9%) and 22 (20.0%) patients developed MCE and CH, respectively. In test set, the AUCs for the LR-Stacking model were 0.949, 0.885, and 0.904 for the three outcomes mentioned above. The F1-scores were 0.882, 0.895, and 0.909, respectively. The DCA showed that the LR-Stacking model provided more net benefits for predicting MCE and CH. The most important factors were the hypodensity volume and proportion in the corresponding vascular supply area. Conclusion: Using the ensemble ML model to analyze the clinical and imaging data of AIS patients with successful recanalization at admission and within 24 h after MT allowed for accurately predicting the risks of futile recanalization, MCE, and CH.

Flufenamic acid improves survival and neurologic outcome after successful cardiopulmonary resuscitation in mice.

BACKGROUND: Brain injury is the main cause of high mortality and disability after successful cardiopulmonary resuscitation (CPR) from sudden cardiac arrest (CA). The transient receptor potential M4 (TRPM4) channel is a novel target for ameliorating blood-brain barrier (BBB) disruption and neuroinflammation. Herein, we tested whether flufenamic acid (FFA), which is reported to block TRPM4 with high potency, could confer neuroprotection against brain injury secondary to CA/CPR and whether its action was exerted by blocking the TRPM4 channel. METHODS: Wild-type (WT) and Trpm4 knockout (Trpm4-/-) mice subjected to 10-min CA/CPR were randomized to receive FFA or vehicle once daily. Post-CA/CPR brain injuries including neurologic deficits, survival rate, histological damage, edema formation, BBB destabilization and neuroinflammation were assessed. RESULTS: In WT mice subjected to CA/CPR, FFA was effective in improving survival and neurologic outcome, reducing neuropathological injuries, attenuating brain edema, lessening the leakage of IgG and Evans blue dye, restoring tight junction protein expression and promoting microglia/macrophages from the pro-inflammatory subtype toward the anti-inflammatory subtype. In comparison to WT mice, Trpm4-/- mice exhibited less neurologic deficiency, milder histological impairment, more BBB integrity and more anti-inflammatory microglia/macrophage polarization. As expected, FFA did not provide a benefit of superposition compared with vehicle in the Trpm4-/- mice after CA/CPR. CONCLUSIONS: FFA mitigates BBB breach and modifies the functional status of microglia/macrophages, thereby improving survival and neurologic deficits following CA/CPR. The neuroprotective effects occur at least partially by interfering with the TRPM4 channel in the neurovascular unit. These results indicate the significant clinical potential of FFA to improve the prognosis for CA victims who are successfully resuscitated.

Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation In Microglia.

Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. However, it remains unknown whether the anti-inflammatory effect of GLB is independent of its role in preventing brain edema, and how GLB inhibits the NLRP3 inflammasome is not fully understood. Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. The Trpm4 siRNA and GLB were injected to block sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel in rats. Western blotting, quantitative real-time polymerase chain reaction, behavioral analysis, and histological examination were used to evaluate the role of GLB in preventing NLRP3-mediated neuroinflammation through inhibiting SUR1-TRPM4, and corresponding neuroprotective effect. To further explore the underlying mechanism, BV2 cells were subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion. Here, in rat model of cardiac arrest with brain edema combined with neuroinflammation, GLB significantly alleviated neurocognitive deficit and neuropathological damage, via the inhibition of microglial NLRP3 inflammasome activation by blocking SUR1-TRPM4. Of note, the above effects of GLB could be achieved by knockdown of Trpm4. In vitro under circumstance of eliminating distractions from brain edema, SUR1-TRPM4 and NLRP3 inflammasome were also activated in BV2 cells subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion, which could be blocked by GLB or 9-phenanthrol, a TRPM4 inhibitor. Importantly, activation of SUR1-TRPM4 in BV2 cells required the P2X7 receptor-mediated Ca2+ influx, which in turn magnified the K+ efflux via the Na+ influx-driven opening of K+ channels, leading to the NLRP3 inflammasome activation. These findings suggest that GLB has a direct anti-inflammatory neuroprotective effect independent of its role in preventing brain edema, through inhibition of SUR1-TRPM4 which amplifies K+ efflux and promotes NLRP3 inflammasome activation.