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White matter disruption plays an important role in disorders of consciousness (DOC). The aim of this study was to analyze the connectometry between DOC patients and healthy controls and to explore the relationship between diffusion connectometry and levels of consciousness. Fourteen patients with DOC and 13 sex- and age-matched controls were included in this study. The participants underwent diffusion magnetic resonance imaging (MRI) and T1-weighted structural MRI at 7 Tesla. Diffusion MRI connectometry was performed to investigate the differences between groups, and to subsequently study the correlation between Coma Recovery Scale-Revised (CRS-R) indexes and white matter integrity. In DOC patients, the quantitative anisotropy (QA) was significantly reduced in deep white matter tracts, whereas significantly higher QA values were found in the bilateral cerebellum compared with healthy controls. Moreover, the QA values in many tracts within the right hemisphere were higher in patients in a minimally conscious state compared to those in vegetative state/unresponsive wakefulness syndrome, which was reflected by the correlation between diffusion connectometry and CRS-R indexes. These results indicate that the cerebellum may play an important role in DOC, and the lateralization of the cerebral hemisphere in affected patients may suggest neural compensation.

We designed a nanoplatform TMPD coated with metal-phenolic networks for the co-delivery of Mn2+ and DOX with the aim to amplify the STING signal and potentiate cancer therapy. This nanoplatform induced a robust innate and adaptive immunity response.

Objective To investigate the influence of different volume of interest (VOI) delineation strategies on machine learning-based predictive models for discrimination between low and high nuclear grade clear cell renal cell carcinoma (ccRCC) on dynamic contrast-enhanced CT. Methods This study retrospectively collected 177 patients with pathologically proven ccRCC (124 low-grade; 53 high-grade). Tumor VOI was manually segmented, followed by artificially introducing uncertainties as: (i) contour-focused VOI, (ii) margin erosion of 2 or 4 mm, and (iii) margin dilation (2, 4, or 6 mm) inclusive of perirenal fat, peritumoral renal parenchyma, or both. Radiomics features were extracted from four-phase CT images (unenhanced phase (UP), corticomedullary phase (CMP), nephrographic phase (NP), excretory phase (EP)). Different combinations of four-phasic features for each VOI delineation strategy were used to build 176 classification models. The best VOI delineation strategy and superior CT phase were identified and the top-ranked features were analyzed. Results Features extracted from UP and EP outperformed features from other single/combined phase(s). Shape features and first-order statistics features exhibited superior discrimination. The best performance (ACC 81%, SEN 67%, SPE 87%, AUC 0.87) was achieved with radiomics features extracted from UP and EP based on contour-focused VOI. Conclusion Shape and first-order features extracted from UP + EP images are better feature representations. Contour-focused VOI erosion by 2 mm or dilation by 4 mm within peritumor renal parenchyma exerts limited impact on discriminative performance. It provides a reference for segmentation tolerance in radiomics-based modeling for ccRCC nuclear grading. Key points • Lesion delineation uncertainties are tolerated within a VOI erosion range of 2 mm or dilation range of 4 mm within peritumor renal parenchyma for radiomics-based ccRCC nuclear grading. • Radiomics features extracted from unenhanced phase and excretory phase are superior to other single/combined phase(s) at differentiating high vs low nuclear grade ccRCC. • Shape features and first-order statistics features showed superior discriminative capability compared to texture features.

Berberine (BBR), an alkaloid produced by a traditional Chinese plant, was recently attributed multiple effects on lipometabolism, inflammation, and fibrosis. Thyroid-associated ophthalmopathy (TAO) is highly associated with these pathologic changes. Thus, we aimed to examine the potential therapeutic effect of BBR in an in vitro model of TAO.Orbital fibroblasts (OFs) obtained from control donors (n = 6) or patients with TAO (n = 6) were cultured. The CCK-8 assay was conducted for assessing the optimal concentration range. Oil Red O staining, Western blotting, and quantitative RT-PCR (qRT-PCR) were conducted to assess adipogenesis in OFs. RNA sequencing (RNA-seq) was used to screen the key pathways of the antiadipogenic effect mediated by BBR. Along with incremental concentrations of BBR, IL-1β-induced expression of proinflammatory molecules was determined by ELISA and qRT-PCR. In addition, TGF-β-induced hyaluronan (HA) production and fibrosis were evaluated by ELISA, qRT-PCR, and Western blotting.TAO-OFs, but not control fibroblasts (CON-OFs), were readily differentiated into adipocytes with the commercial medium. Intracellular lipid accumulation was dose-dependently decreased by BBR, and adipogenic markers were also downregulated. Moreover, the PPARγ and AMPK pathways were screened out by RNA-seq and their downstream effectors were suppressed by BBR. Besides, BBR attenuated IL-1β-induced expression of proinflammatory molecules in both TAO-OFs and CON-OFs by blocking nuclear factor-κB signaling. BBR's inhibitory effect on TGF-β-mediated tissue remodeling was also confirmed in OFs.These findings demonstrate BBR has outstanding capabilities of controlling adipogenesis, inflammation, HA production, and fibrosis in OFs, highlighting its potential therapeutic role in TAO management.

Background:Age-related macular degeneration (AMD) is the primary cause of visual impairment among the elderly. It mainly affects the macular region of the fundus oculi. Studies have shown that macular and extramacular region's gene expression differs considerably. This may be the reason for regional specificity and different phenotypic outcomes of the AMD. The non-coding RNA (ncRNAs) is a RNAs that cannot encode proteins in the human transcribed genome. However, they are involved in many life events as regulatory molecules. NcRNAs were identified to play a vital role in AMD. But the molecular mechanism underlying ncRNAs in AMD remains unclear. In the current study, we explored the differences in the macular and extramacular regions of the retina gene expression in AMD patients. We investigated the function of ncRNAs by constructing the lncRNA-miRNA-mRNA network.Results:A total of 4491 DE-mRNAs and 18 DE-lncRNAs were discovered in the macular and the retina region of the retina of AMD patients. In the lncRNA-miRNA-mRNA network, 18 lncRNAs, 41 miRNAs, and 404 mRNAs were established through target gene prediction. Co-expression analysis showed that 51 pairs of lncRNAs and mRNAs in the lncRNA-miRNA-mRNA network had a positive co-expression. GO and KEGG pathway analysis indicated that mRNAs involved in the lncRNA-miRNA-mRNA network were mainly enriched in the apoptotic signaling pathway, negative regulation of nitrogen compound metabolic process, cellular response to chemical stimulus, and MAPK signaling pathway, endocytosis, PI3K-Akt signaling pathway, cellular senescence, hepatitis, axon guidance, microRNAs in cancer, mTOR signaling pathway, AMPK signaling pathway, and longevity regulating pathway. In addition, DO enrichment indicated that 18 DE-lncRNAs were enriched in 266 diseases.Conclusions:In this study, we constructed the lncRNA-miRNA-mRNA network consisting of 18 lncRNAs, 41 miRNAs, and 404 mRNAs. In addition, 51 pairs of lncRNAs and mRNAs presented a positive co-expression relationship.

The objective of this study was to compare the efficacy of ofloxacin ear drops, vaseline gauze (VG) and dry gelfoam alone on the large traumatic perforations of tympanic membrane (TM).A randomized prospective analysis was performed for the treatment of traumatic perforation larger than 25 % of the entire TM. The closure rate, closure time, and hearing gain between ofloxacin ear drops, VG and gelfoam alone groups were compared at 3 months.Final analysis was performed on 70 patients. The closure rates of perforation in the ofloxacin ear drops, VG, and dry gelfoam patch groups were 100.0 %, 92.0 %, and 87.5 %, respectively (P = 0.41).The mean closure times were 8.67 ± 3.1, 10.65 ± 4.2, and 14.33 ± 7.5 days for the ofloxacin ear drops, VG, and gelfoam patch alone groups, respectively. The closure times among the 3 groups were significantly different (P = 0.003). In addition, there was a significant difference between the ofloxacin ear drops and gelfoam patch alone groups with regard to closure time (P = 0.003), while there was no significant difference between the ofloxacin ear drops and VG groups (P = 0.080) or VG and gelfoam patch groups (P = 0.056).The mean hearing gain was 11.4 ± 2.3 dB for the ofloxacin ear drops group, 11.7 ± 4.1 dB for the VG group, and 12.2 ± 1.6 dB for the gelfoam patch group (P = 0.69).The repairing of traumatic perforations didn't require an exogenous biological scaffold. Ofloxacin ear drops and VG were a deal material for repairing traumatic perforation in otology clinic, which not only was readily available and inexpensive but also showed faster closure compared with dry gelfoam alone.

Purpose: To characterize the macula microvasculature using fractal dimension (FD) in hypertensive white matter hyperintensity (WMH) participants and explore the association between the microvascular changes and serum uric acid levels. Methods: Thirty-eight WMH participants were dementia and stroke-free, and 37 healthy controls were enrolled. Optical coherence tomographic angiography (OCTA) was used to image the superficial vascular complex (SVC), deep vascular complex (DVC), and inner vascular complex (IVC) in a 2.5-mm diameter concentric circle (excluding the foveal avascular zone FAZ). A commercial algorithm was used to quantify the complexity and density of the three capillary layers by fractal analysis. Results: WMH participants showed significantly lower FD value in the SVC (P = 0.002), DVC (P < 0.001) and IVC (P = 0.012) macula microvasculature compared with control group. After adjusting for risk factors (hypertension, diabetes, age and gender) SVC (P = 0.035) and IVC (P = 0.030) significantly correlated with serum uric acid. Conclusions: Serum uric acid levels are associated with microvascular changes in WMH. Fractal dimension based on OCTA imaging could help quantitatively characterize the macula microvasculature changes in WMH and may be a potential screening tool to detect serum uric acid level changes.

Developing novel activatable photosensitizers with excellent plasma membrane targeting ability is urgently needed for smart photodynamic therapy (PDT). Herein, a tumor acidity-activatable photosensitizer combined with a two-step bioorthogonal pretargeting strategy to anchor photosensitizers on the plasma membrane for effective PDT is developed. Briefly, artificial receptors are first anchored on the cell plasma membrane using cell-labeling agents (Az-NPs) via the enhanced permeability and retention effect to achieve the tumor cell labeling. Then, pH-sensitive nanoparticles (S-NPs) modified with dibenzocyclooctyne (DBCO) and chlorin e6 (Ce6) accumulate in tumor tissue and disassemble upon protonation of their tertiary amines in response to the acidic tumor environment, exposing the contained DBCO and Ce6. The selective, highly specific click reactions between DBCO and azide groups enable Ce6 to be anchored on the tumor cell surface. Upon laser irradiation, the cell membrane is severely damaged by the cytotoxic reactive oxygen species, resulting in remarkable cellular apoptosis. Taken together, the membrane-localized PDT by our bioorthogonal pretargeting strategy to anchor activatable photosensitizers on the plasma membrane provides a simple but effective method for enhancing the therapeutic efficacy of photosensitizers in anticancer therapy.

Background: Recent studies have demonstrated that programmed necrosis (necroptosis) is a delayed component of ischemic neuronal injury and our previous study has shown that pannexin 1 channel is involved in cerebral ischemic injury and cellular inflammatory response. Here, we examined whether the pannexin 1 channel inhibitor, 10panx, could reduce focal ischemic brain injury in rats by inhibiting cellular necroptosis and the associated inflammation. Male Sprague–Dawley rats were randomly divided into sham-operated, MCAO (transient middle cerebral artery occlusion) group, and 10panx-treated groups. We investigated the effect of 10panx by assessing infarct volume and neurological deficit. Further, we determined the potential mechanism using immunofluorescent staining, Western blotting, enzyme-linked immunosorbent assay (ELISA) and TUNEL assay. We demonstrated that 10panx reduced infarct volume and alleviated neurological deficit in the MCAO injury model. 10panx ameliorated post-ischemic neuronal death, but it did not reduce the TUNEL positive neurons and expression of cleaved-caspase3. In contrast, expression of necroptosis related protein receptor-interacting protein 3 (RIP3) was significantly decreased. Furthermore, 10panx reduced the release of high mobility group box 1 (HMGB1) from neurons and inhibited microglial activation and secretion of pro-inflammatory factors. Immunent co-labeling of RIP3 with HMGB1 showed that RIP3 protein was closely related with the release of HMGB1 from nucleus to cytoplasm. Our data suggested that 10panx treatment may ameliorate MCAO injury by reducing RIP3-mediated necroptosis, HMGB1 release and associated inflammatory response. RIP3 may play an important role in the release of HMGB1 and inflammation after stroke.

IgG4-related disease (IgG4-RD) affects multiple organs and is characterized by immune-mediated inflammation and fibrosis; IgG-RD affecting orbital tissue is known as IgG4-related ophthalmic disease (IgG4-ROD). This research is aimed at exploring whether symptom duration and common serologic factors, such as IgG, IgE, and eosinophils, are potential risk factors for IgG4-ROD patient relapse after surgery and identifying possible causes of the positive correlation between symptom duration and relapse. This retrospective cohort study included 40 IgG4-ROD patients after surgery. Auxiliary inspection results were obtained before surgery and during follow-up, and relapse risk factors were identified based on previous studies. We used the Spearman rank correlation test to reveal the relationship between symptom duration and relapse time and identified the optimal cutoff value for symptom duration by X-tile. Then, we divided the patients into the long-duration and short-duration groups. Kaplan–Meier survival analyses and log-rank tests were performed to identify the relationship between symptom duration and relapse using X-tile software. Finally, we studied the relationship between previously studied relapse risk factors and symptom duration. The survival curves of the long-duration and short-duration groups were obviously different, and the baseline serum IgG, IgE, and eosinophil levels and asthma concomitant rate were significantly different between the long-duration and short-duration groups. Furthermore, the baseline serum IgG ( r = 0.485 , P = 0.002 ), IgE ( r = 0.350 , P = 0.037 ), and eosinophil ( r = 0.6535 , P < 0.0001 ) levels were positively correlated with symptom duration. Our study shows that IgG4-ROD symptom duration is significantly positively correlated with relapse rate and negatively correlated with relapse time. Symptom duration was positively correlated with serum baseline IgG4, IgE, and eosinophil levels and asthma history, which were potential risk factors for disease relapse. We recommended that IgG4-ROD patients with symptom durations greater than 96 months continue to receive maintenance steroid therapy longer than 1 year postsurgery to reduce the relapse rate.

The objective of this was to evaluate anatomical and hearing results of modified inlay butterfly perichondrium-cartilage myringoplasty for repairing central perforation in an office setting.We performed a prospective study in 81 patients with chronic central perforations who underwent modified inlay butterfly perichondrium-cartilage myringoplasty in an office setting. The graft success rate, hearing outcome, and complications were evaluated at postoperative 3, 6 and 24 months.81 patients with 81chronic perforations were included in this study. The graft success rate was 100.0% (81/81) at postoperative 3 months. At postoperative 24 months, 16 patients lost follow-up, the graft success rate was 98.5% (64/65). The mean preoperative ABG was 23.0 ± 2.6 dB, while the mean postoperative ABG postoperatively 12 months was 11.4 ± 3.1 dB; the difference between these values was significant (P .05). No graft-related complications (e.g., graft lateralization, graft medialization, graft keratin pearl, middle ear cholesteatoma) were encountered during the follow-up period. In addition, excess perichondrium lateral to the superficial layer of TM remnant became necrotic and crust at postoperative 2-3 months. However, graft keratin pearl and intra-tympanic cholesteatoma/epithelial inclusion cyst weren't found in any patients at postoperative 24 months. Granular myringitis with minimal moistness but without infection has been noted in 6 patients.Modified inlay butterfly perichondrium-cartilage myringoplasty is a viable and less invasive option for closure of central perforations in an office setting because this technique does not require tympanomeatal flap elevation and general anesthesia.

(1) To evaluate the diagnostic performance of radiomics in differentiating high-grade glioma from brain metastasis and how to improve the model. (2) To assess the methodological quality of radiomics studies and explore ways of embracing the clinical application of radiomics.Studies using radiomics to differentiate high-grade glioma from brain metastasis published by 26 July 2021 were systematically reviewed. Methodological quality and risk of bias were assessed using the Radiomics Quality Score (RQS) system and Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool, respectively. Pooled sensitivity and specificity of the radiomics model were also calculated.Seventeen studies combining 1,717 patients were included in the systematic review, of which 10 studies without data leakage suspicion were employed for the quantitative statistical analysis. The average RQS was 5.13 (14.25% of total), with substantial or almost perfect inter-rater agreements. The inclusion of clinical features in the radiomics model was only reported in one study, as was the case for publicly available algorithm code. The pooled sensitivity and specificity were 84% (95% CI, 80-88%) and 84% (95% CI, 81-87%), respectively. The performances of feature extraction from the volume of interest (VOI) or (semi) automatic segmentation in the radiomics models were superior to those of protocols employing region of interest (ROI) or manual segmentation.Radiomics can accurately differentiate high-grade glioma from brain metastasis. The adoption of standardized workflow to avoid potential data leakage as well as the integration of clinical features and radiomics are advised to consider in future studies.• The pooled sensitivity and specificity of radiomics for differentiating high-grade gliomas from brain metastasis were 84% and 84%, respectively. • Avoiding potential data leakage by adopting an intensive and standardized workflow is essential to improve the quality and generalizability of the radiomics model. • The application of radiomics in combination with clinical features in differentiating high-grade gliomas from brain metastasis needs further validation.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disorder that causes significant changes in brain connectivity and visual impairment. Degree centrality (DC), a graph-based assessment of network organization was performed to explore the connectivity changes in NMOSD patients and their correlation with clinical consequences.Twenty-two NMOSD patients and 22 healthy controls (HC) were included. Participants underwent visual acuity examination and resting-state functional magnetic resonance imaging (fMRI) of the brain. We first performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity (FC) with other voxels. DC was calculated by the fMRI graph method and comparison between the two groups was done by two-sample t-test. GraphPad Prism was used to assess the association between DC changes and clinical consequences.Out of the 22 NMOSD patients, 7 (31.82%) had ON once while 15 (68.18%) had ON twice or more. Decreased DC value (P 0.001) in the left frontal superior orbital gyrus (ORBsup), left angular gyrus (ANG) and right parietal superior gyrus (SPG) was found in NMOSD patients when compared with healthy controls respectively. Reduced visual acuity significantly correlated (RNMOSD patients experience neural network dysfunction which may be associated with their clinical implications.

Simple Summary Glioblastoma multiforme (GBM) and solitary brain metastasis (SBM) are common brain tumors in adults. The two tumors often pose a diagnostic dilemma owing to their similar features on conventional magnetic resonance imaging (MRI). Ability to discriminate the two tumors is critical as it informs clinical treatment strategies. This pilot study attempts to employ the machine learning technique to identify GBM and SBM by fusing radiomics features of multiple MRI sequences and multiple models. A multiparametric MR-based RadioFusionOmics (RFO) model was developed and has demonstrated promising prediction accuracy for the identifications of GBM and SBM. Abstract This study aimed to evaluate the diagnostic potential of a novel RFO model in differentiating GBM and SBM with multiparametric MR sequences collected from 244 (131 GBM and 113 SBM) patients. Three basic volume of interests (VOIs) were delineated on the conventional axial MR images (T1WI, T2WI, T2_FLAIR, and CE_T1WI), including volumetric non-enhanced tumor (nET), enhanced tumor (ET), and peritumoral edema (pTE). Using the RFO model, radiomics features extracted from different multiparametric MRI sequence(s) and VOI(s) were fused and the best sequence and VOI, or possible combinations, were determined. A multi-disciplinary team (MDT)-like fusion was performed to integrate predictions from the high-performing models for the final discrimination of GBM vs. SBM. Image features extracted from the volumetric ET (VOIET) had dominant predictive performances over features from other VOI combinations. Fusion of VOIET features from the T1WI and T2_FLAIR sequences via the RFO model achieved a discrimination accuracy of AUC = 0.925, accuracy = 0.855, sensitivity = 0.856, and specificity = 0.853, on the independent testing cohort 1, and AUC = 0.859, accuracy = 0.836, sensitivity = 0.708, and specificity = 0.919 on the independent testing cohort 2, which significantly outperformed three experienced radiologists (p = 0.03, 0.01, 0.02, and 0.01, and p = 0.02, 0.01, 0.45, and 0.02, respectively) and the MDT-decision result of three experienced experts (p = 0.03, 0.02, 0.03, and 0.02, and p = 0.03, 0.02, 0.44, and 0.03, respectively).

Photodynamic therapy (PDT) is a promising non-invasive and selective cancer treatment. However, its efficacy is curtailed by tumor hypoxia and high levels of glutathione (GSH) in the tumor and addressing both limitations simultaneously remain challenging. Here, an all-in-one nanoplatform was designed using a GSH-responsive nitric oxide (NO) nano-prodrug that synchronously depletes GSH and relieves hypoxia in tumors, enhancing PDT efficacy. The nano-prodrug PEG-PAMAM-PA/SNO was prepared by integrating the GSH-sensitive NO and pheophorbide A (PA) prodrugs N-acetyl-d-penicillamine thiolactone and PAMAM-PA into polyethylene glycol (PEG), and the NP

Purpose: We examined the macular microvascular changes of the macula in neuromyelitis optica spectrum disorder (NMOSD) patients and its association with their disability and other clinical variables.Methods: Thirty-four NMOSD (13 patients without optic neuritis, NMOSD-NON, and 21 patients with a history of optic neuritis, NMOSD-ON) and 44 healthy controls (HCs) were included in the study. Optical coherence tomographic angiography (OCTA) was used to image the superficial (SCP), deep (DCP), and whole capillary plexus (WCP) in a 2.5-mm-diameter concentric circle [excluding the foveal avascular zone (FAZ)]. An algorithm (Dbox) was used to quantify the complexity of the three capillary layers by fractal analysis. We also evaluated the expanded disability scale status (EDSS).Results: Dbox values were significantly reduced in SCP (p < 0.001), DCP (p < 0.001), and WCP (p = 0.003) of NMOSD when compared with HCs. Dbox values were significantly reduced in NMOSD eyes with optic neuritis when compared with healthy controls (p < 0.001) and eyes without optic neuritis (p = 0.004) in the SCP. In the DCP, eyes with optic neuritis showed significantly reduced Dbox values when compared with eyes without optic neuritis (p = 0.016) and healthy controls (p < 0.001); eyes without optic neuritis showed significantly reduced Dbox values (p = 0.007) in the DCP when compared with healthy controls. A significant negative correlation (Rho = −0.475, p = 0.005) was shown between the superficial macula Dbox values and the EDSS in NMOSD patients. Additionally, a negative correlation (Rho = −0.715, p = 0.006) was seen in the superficial Dbox values in [e]eyes without optic neuritis and EDSS.Conclusions: Macular microvascular damage in the superficial plexus is associated with disability in NMOSD. Macular microvascular alterations arise independently of the occurrence of ON in NMOSD.

The Qilong capsule (QLC) is a Chinese patented medicine characterized by an equal emphasis on replenishing Qi and activating blood circulation. In 2000, China's FDA approved the use of QLC for ischemic stroke (IS). However, there is not yet much high-quality evidence of the clinical effectiveness of QLC combined with conventional treatment (CT) for IS with Qi deficiency and blood stasis syndrome.In this study, we conducted a prospective, multicenter, non-randomized controlled trial at 7 hospitals in China to investigate the clinical effectiveness of QLC combined with CT for IS with Qi deficiency and blood stasis syndrome.Participants aged 35 to 80 years old diagnosed as IS with Qi deficiency and blood stasis syndrome in TCM were recruited. Participants were treated with QLC (intervention group) or non-QLC (control group). The intervention course of QLC was 12 weeks. All participants in two groups received standard treatment. All participants returned for in-person follow-up visits at the 12th week and 24th week. Primary outcome measures included a modified Rankin Scale (mRS), the National Institute of Health Stroke Scale (NIHSS), and the Barthel Index (BI). Secondary outcome measures included TCM syndromes (Qi deficiency syndrome score, blood stasis syndrome score), psychological index (self-rating depression scale, SDS; self-rating anxiety scale, SAS), blood lipid index, blood coagulation index, homocysteine, and favorable functional outcome (mRS 0 - 3). Multiple imputations were used for any missing data. Propensity score matching (PSM) was used to deal with any confounding factors (age, gender, scale score, etc.). Rank alignment transformation variance analysis (ART ANOVA) and generalized linear mixed model (GLMM) were introduced to improve the scientific and accuracy of repeated measurement data. All statistical calculations were carried out with R 3.6.1 statistical analysis software.A total of 2468 participants were screened from November 2016 to January 2019. Finally, 2302 eligible participants were included in the analysis. There were 1260 participants in the intervention group (QLC group) and 1042 participants in the control group (non-QLC group). After PSM matching, sub-samples of 300 participants in the QLC group and 300 participants in the non-QLC group were finally formed. The final results of clinical effectiveness are the same results shared by the total samples and sub-samples after PSM. In the 24th week after treatment, QLC combined with CT proved to be significantly better than CT alone in reducing the scores of mRS (p 0.05), NIHSS (p 0.001), Qi deficiency syndrome (p 0.01), and blood stasis syndrome (p 0.001), SAS (p 0.05), as well as in improving BI score (p 0.05). The favourable functional outcome (mRS score of 0 to 3 at week 12) was statistically different between QLC and non-QLC group in the sub-samples (p 0.01, 97% vs 91.7%). The results of the ART ANOVA showed that the improvement of mRS (p 0.01), BI (p 0.05) and NIHSS (p 0.001) in QLC group was better than non-QLC group when the interaction effect was considered. The results of GLMM showed that the reduction of mRS and NIHSS scores of patients in the QLC group were better than those of the non-QLC group (p 0.001). The BI score of the QLC group in the sub-samples after PSM increased more than the non-QLC group (p 0.001). There was no evidence showing that QLC can cause serious adverse reactions (ADRs) in treating patients with IS.QLC combined with CT was better than CT alone in reducing mRS score, NIHSS score, Qi deficiency syndrome score, blood stasis syndrome score, and SAS score, as well as improving BI score after treatment. Further high-quality RCTs are needed to confirm the positive results. The study protocol was embedded in a registry study that registered in the Clinical Trials USA Registry (registration No. NCT03174535).

As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H2O2) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe3+)/gadolinium ions (Gd3+) via chelation reactions between Fe3+/Gd3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H2O2, followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide, CA and Fe3+, downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd3+ may serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. Statement of significance : Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.

White matter disruption plays an important role in disorders of consciousness (DOC). The aim of this study was to analyze the connectometry between DOC patients and healthy controls and to explore the relationship between diffusion connectometry and levels of consciousness. Fourteen patients with DOC and 13 sex- and age-matched controls were included in this study. The participants underwent diffusion magnetic resonance imaging (MRI) and T1-weighted structural MRI at 7 Tesla. Diffusion MRI connectometry was performed to investigate the differences between groups, and to subsequently study the correlation between Coma Recovery Scale-Revised (CRS-R) scores and white matter integrity. In DOC patients, the quantitative anisotropy (QA) was significantly reduced in deep white matter tracts, whereas significantly higher QA values were found in the bilateral cerebellum compared with healthy controls. Moreover, the QA values in many tracts within the right hemisphere were higher in patients in a minimally conscious state compared to those in vegetative state/unresponsive wakefulness syndrome. In contrast, many tracts within the left hemisphere of the latter group showed higher QA than the former, which was reflected by the correlation between diffusion connectometry and CRS-R scores. These results indicate that the cerebellum may play an important role in DOC, and the lateralization of the cerebral hemisphere in affected patients may suggest neural compensation.

Shengsheng Lai,1,* Lei Sun,2,* Jialiang Wu,3 Ruili Wei,4 Shiwei Luo,4 Wenshuang Ding,5 Xilong Liu,6 Ruimeng Yang,4 Xin Zhen2 1School of Medical Equipment, Guangdong Food and Drug Vocational College, Guangzhou, Guangdong, 510520, People’s Republic of China; 2School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 3Department of Radiology, The University of Hong Kong Shenzhen Hospital, Shenzhen, Guangdong, 518000, People’s Republic of China; 4Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of China; 5Department of Pathology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of China; 6Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ruimeng YangDepartment of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of ChinaTel +86-20-81048873Email eyruimengyang@scut.edu.cnXin ZhenSchool of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaTel +86-20-62789323Email xinzhen@smu.edu.cnObjective: To investigate the predictive performance of different machine learning models for the discrimination of low and high nuclear grade clear cell renal cell carcinoma (ccRCC) by using multiphase computed tomography (CT)-based radiomic features.Materials and Methods: A total of 137 consecutive patients with pathologically proven ccRCC (including 96 low-grade [grade 1 or 2] and 41 high-grade [grade 3 or 4] ccRCC) from January 2011 to January 2019 were enrolled in this retrospective study. Target region of interest (ROI) delineation followed by texture extraction was performed on a representative slice with the largest section of the tumor on the four-phase (unenhanced phase [UP], corticomedullary phase [CMP], nephrographic phase [NP] and excretory phase [EP]) CT images. Fifteen concatenations of the four-phase features were fed into 176 classification models (built with 8 classifiers and 22 feature selection methods), the classification performances of the 2640 resultant discriminative models were compared, and the top-ranked features were analyzed.Results: Image features extracted from the unenhanced phase (UP) CT images demonstrated a dominant classification performance over features from the other three phases. The discriminative model “Bagging + CMIM” achieved the highest classification AUC of 0.75. The top-ranked features from the UP included one shape-based feature and five first-order statistical features.Conclusion: Image features extracted from the UP are more effective than other CT phases in differentiating low and high nuclear grade ccRCC based on machine learning–based classification modeling.Keywords: clear cell renal cell carcinoma, Fuhrman nuclear grade, computed tomography, machine learning, classification

Background Orbital invasive aspergillosis infection is rare life-threatening infection, most commonly seen in immunocompromised patients and extremely rare in individuals without risk factors. Here we present a rare case of bilateral cellulitis caused by invasive aspergillosis associated with bilateral intraorbital abscesses in a female patient. Case presentation A 49-year-old woman presented with a 3-month history of painful proptosis and periorbital swelling of bilateral eyes. She was initially diagnosed as bilateral orbital cellulitis complicated with cavernous sinus thrombosis and was treated with antibiotic medication for 1 month, but her symptoms persisted. MRI demonstrated orbital masses behind both globes. The lesion in right orbit was biopsied with a diagnosis of orbital granulomatosis with invasive aspergillosis infection. The patient was healed after receiving antifungal treatment. Conclusions This is an unusual case about bilateral orbital abscesses with invasive fungal infection. Fungal infection of the orbit should be considered when patient does not respond to combination of anti-inflammatory and antibiotic therapies, even in some cases without any risk factors.

Accurate prediction of the neurological outcome following hypoxic-ischemic brain injury (HIBI) remains difficult. Diffusion-weighted imaging (DWI) can detect acute and subacute brain abnormalities following global cerebral hypoxia. Therefore, DWI can be used to predict the outcomes of HIBI. To this end, we searched the PubMed, EMBASE, and Cochrane Library databases for studies that examine the diagnostic accuracy of DWI in predicting HIBI outcomes in adult patients between January1995 and September 2019. Next, we conducted a comprehensive meta-analysis using the Meta-DiSc and several complementary techniques. Following the application of inclusion and exclusion criteria, a total of 28 studies were included with 98 data subsets. The overall sensitivity and specificity, with 95% confidence interval, were 0.613(0.599-0.628) and 0.958(0.947-0.967), respectively, and the area under the curve was 0.9090. Significant heterogeneity among the included studies and a threshold effect were observed (p

Immonoglobulin G4‑related ophthalmic disease (IgG4‑ROD) is a IgG4‑RD and exhibits two main characteristics: Fibrosis that is not necessarily marked histopathologically; and frequent formation of germinal centers (GCs). Follicular B helper T (Tfh) cells are now recognized as the true helper cells for B cells in antibody responses. In the present study, the profile and distribution of Tfh cells in involved tissues from patients with IgG4‑ROD was compared to those of type 1 autoimmune pancreatitis (AIP) and patients with IgG4‑related lymphadenopathy (IgG4‑RL). A total of 7 patients with IgG4‑ROD, 7 patients with type 1 AIP or IgG4‑RL and 7 IgG4‑negative controls were evaluated. The expression of Tfh‑cell immunological proteins, the inducible T‑cell costimulator, B‑cell lymphoma 6 protein, C‑X‑C chemokine receptor type 5 (CXCR5) and interleukin‑21 (IL‑21) in affected tissues was analyzed using immunohistochemical staining and dual immunofluorescence. It was demonstrated that patients with IgG4‑RD exhibited a significantly increased number of CD4+CXCR5+ Tfh cells compared with the IgG4‑negative controls. Furthermore, CD4+CXCR5+ Tfh cells were detected in and outside of GCs in patients with IgG4‑ROD and IgG4‑RLF, whereas CD4+CXCR5+ Tfh cells were randomly distributed in areas demonstrating type 1 AIP. Fewer CD4+CXCR5+ Tfh cells were observed in patients with type 1 AIP compared with patients with IgG4‑ROD and IgG4‑RL. In addition, increased expression of IL‑21 was observed in patients with IgG4‑ROD and IgG4‑RL compared with type 1 AIP. IL‑21 expression was positively correlated with the IgG4/IgG ratio in immunohistochemically‑positive cells. The results of the present study indicate that Tfh cells are involved in the histopathological pathogenesis of IgG4‑RD and may serve a different role in IgG4‑ROD and type 1 AIP. Tfh cells may serve a direct role in the IL‑21‑mediated pathogenesis of IgG4‑ROD.

A 43-year-old woman presented with a 4-day history of right limb weakness. While biking 4 days earlier, she felt a weakness in her right hand and leg. She had a history of hypertension for more than 2 years, and was taking extended-release nifedipine tablets (40 mg) and perindopril (4 mg) daily, but her blood pressure was difficult to control (fluctuations of 150–180/90–115 mm Hg). The patient did not smoke or drink alcohol, and had no family history of similar diseases. The authors thank Dr. Haiyan Lou and Dr. Xiaodong Teng for their contributions.

Purpose To achieve fast whole-brain chemical exchange saturation transfer (CEST) imaging with negligible susceptibility artifact. Methods An optimized turbo spin echo readout module, also known as sampling perfection with application optimized contrasts by using different flip angle evolutions (SPACE), was deployed in the CEST sequence. The SPACE-CEST sequence was tested in a phantom, 6 healthy volunteers, and 3 brain tumor patients on a 3T human scanner. A dual-echo gradient echo sequence was used for B0 inhomogeneity mapping. In addition, the proposed SPACE-CEST sequence was compared with the widely used turbo spin echo-CEST sequence for amide proton transfer-weighted (APTw) images. Results The SPACE-CEST sequence generated highly consistent APTw maps to those of the turbo spin echo-CEST sequence in the phantom. In healthy volunteers, the SPACE-CEST sequence yielded whole-brain 2.8-mm isotropic APTw source images within 5 minutes, with no discernible susceptibility artifact. As for the B0 maps in the whole brain, its mean, median, and standard deviation B0 offset values were 5.0 Hz, 5.6 Hz, and 16 Hz, respectively. Regarding the APTw map throughout the whole brain, its mean, median, and standard deviation values were 0.78%, 0.56%, and 1.74%, respectively. The SPACE-CEST sequence was also successfully applied to a postsurgery brain tumor patient, suggesting no disease progression. In addition, on the newly diagnosed brain tumor patients, the SPACE-CEST and turbo spin echo-CEST sequences yielded essentially identical APTw values. Conclusion The proposed SPACE-CEST technique can rapidly generate whole-brain CEST source images with negligible susceptibility artifact.

Recent studies have demonstrated that programmed necrosis (necroptosis) is a delayed component of ischemic neuronal injury and our previous study has shown that pannexin 1 channel is involved in cerebral ischemic injury and cellular inflammatory response. Here, we examined whether the pannexin 1 channel inhibitor

Data on the association between hemoglobin (Hb) levels and poststroke cognitive function are limited. We investigated the relationship between Hb concentrations at admission and poststroke cognitive function using a multicenter database. In total, 1081 patients were recruited from seven Chinese medical centers within 6 months after experiencing ischemic stroke. Cognitive status was evaluated with a series of brief neuropsychological tests. A subgroup of 439 patients from a single center was followed up for 4–6 years and was eventually reassessed with a cognitive test. The association between Hb and cognitive impairment was analyzed by multivariable Tobit regression and logistic regression. The mean age of the 920 eligible participants at study entry was 42.5 years; 311 (34%) were women, and all participants were Chinese nationals who lived locally. After adjustment for multiple covariables, Hb levels at admission remained positively associated with poststroke Mini-Mental State Examination (MMSE) scores, with a 0.37-point increase in the MMSE score for every 1-standard-deviation increase in the Hb level. Moreover, an optimal Hb level above 15.0 g/dl was proposed for preventing or alleviating the development of poststroke cognitive impairment in men. After 4–6 years of rehabilitation, the baseline Hb still correlated with MMSE scores. A significant interaction was found between baseline Hb and change in MMSE scores over time, with higher baseline Hb levels predicting faster recovery of global cognitive performance (β, 0.21; 95% confidence interval, 0.03–0.39).These findings warrant further study of anemia as a risk factor for poststroke cognitive impairment.

In recent years, the stimuli-responsive delivery of drugs based on diselenide-bridged polymeric nanocomposites have gathered significant attention from researchers towards augmented anticancer therapy, owing to the unique dual reactive oxygen species (ROS) as well as glutathione (GSH) redox-responsive diselenide bonds. Despite their success in delivery of diverse therapeutics, the fabrication of such diselenide-bridged polymeric nanocomposites with high performance efficiency is often limited due to the relatively high sensitivity of diselenide bonds to various stimuli such as light, temperature, and both oxidation and reduction. In an attempt to address these attributes, herein, we demonstrate the fabrication of indocyanine green (ICG)-loaded diselenide-containing polymeric nanoparticles using the supercritical fluid (SCF)-assisted rapid and facile synthesis approach for ROS/GSH-responsive drug delivery platform towards augmented anticancer therapy. Initially, the diselenide-containing poly (ethylene glycol)-poly(e-caprolactone)-poly(ethylene glycol) block copolymers (PSe) are synthesized based on stannous octoate initiated ring-opening polymerization and subsequent esterification with carboxylic acid-functionalized polyethylene glycol (PEG-COOH). Further, the ICG molecules are loaded into the copolymer nanocomposites via the incorporation of coprecipitation interactions between PSe and ICG through the convenient and highly effective SCF technology. These nanocomposites afforded high drug loading (up to 48.5%) and encapsulation efficiency (up to 85.1%), along with uniform distribution and desired photo-stability. Finally, various photodynamic therapy (PDT)-related experiments both in vitro and in vivo have shown that the fabricated ROS-responsive drug delivery system based on ICG and PSe is capable of devastating tumor cells.

Many studies have demonstrated the key role of lysosomes in ischemic cell death in the brain and have led to the "lysosomocentric" hypothesis. In this hypothesis, the release of cathepsin-B due to a change of lysosomal membrane permeabilization (LMP) or rupture is critical, and this can be prevented by its inhibitors CA074 and CA074-me. However, the role of CA074-me in neuronal death and its effect on the change of lysosomal membrane integrity after global cerebral ischemia/reperfusion (I/R) injury is not clear, so we investigated this here. Rat hippocampal CA1 neuronal death was evaluated after 20-min global cerebral I/R injury. CA074-me (1 μg, 10 μg) were given intracerebroventricularly 1h before ischemia or 1h post reperfusion. The changes of heat shock protein 70 (Hsp70), cathepsin-B, lysosomal-associated membrane protein 1 (LAMP-1), receptor-interacting protein 3 (RIP3), and the change of lysosomal pH were evaluated respectively. Hippocampal CA1 neuronal programmed necrosis induced by global cerebral I/R injury was prevented by CA074-me both pre-treatment and post-treatment. Diffuse cytoplasmic cathepsin-B and LAMP-1 immunostaining synchronized with the pyknotic nuclear changes 2 days post reperfusion, and a rise of lysosomal pH with the leakage of DND-153, a dye of lysosomes, after oxygen-glucose deprivation (OGD) was detected. Both of these changes demonstrated the rupture of lysosomal membrane and the leakage of cathepsin-B, and this was strongly inhibited by CA074-me pre-treatment. The overexpression and nuclear translocation of RIP3 and the reduction of NAD(+) level after I/R injury were also inhibited, while the upregulation of Hsp70 was strengthened by CA074-me pre-treatment. Delayed fulminant leakage of cathepsin-B due to lysosomal rupture is a critical harmful factor in neuronal programmed necrosis induced by 20-min global I/R injury. In addition to being an inhibitor of cathepsin-B, CA074-me may have an indirect neuroprotective effect by maintaining lysosomal membrane integrity and protecting against lysosomal rupture.