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Abstract Treating psoriasis presents a major clinical challenge because of the limitations associated with traditional topical glucocorticoid therapy. This study introduced a drug delivery system utilizing zinc-doped mesoporous silica nanoparticle (Zn-MSN) and microneedle (MN), designed to enhance drug utilization for prolonged anti-inflammatory and anti-itch effects. The MN system facilitated the transdermal delivery of betamethasone dipropionate (BD), allowing its slow release. The BD@Zn-MSN-MN system promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, achieving superior anti-inflammatory effects compared to the clinically used BD cream. Additionally, this study demonstrated that BD@Zn-MSN-MN could further alleviate itching in psoriasis-afflicted mice by decreasing the excitability of the transient receptor potential vanilloid V1 (TRPV1) ion channel positive neurons and reducing the release of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG). These findings offer new insights and effective therapeutic options for the future design of transdermal drug delivery for psoriasis.

Stress is a nonspecific response that occurs when the body is stimulated by internal and external stimuli. When the stress levels exceed the body´s tolerance threshold, physiological and biochemical changes occur that affect homeostasis within the internal environment. Takifugu fasciatus is an important cultured fish species in China, and its demand in the aquatic market has increased in recent years. Stress is extremely harmful to T. fasciatus farming, and cortisol is considered an essential marker for determining the stress response of fish, as it changes significantly within the organism under stress. The intestine is a contact medium between fish and the external environment and can respond to physiological stress levels. Although the study of fish intestinal responses to stress is a global research focus, the role of the T. fasciatus intestinal tract in response to stress remains unclear. In this study, intestinal epithelial cells of T. fasciatus were cultured using four different methods: Trypsin (0.25%) with DMEM, trypsin (0.25%) with RPMI 1640, typeⅠcollagenase (1 mg/mL) in DMEM, and typeⅠcollagenase (1 mg/mL) in RPMI 1640 to establish an in vitro culture method for primary intestinal epithelial cells of T. fasciatus. The effects of different concentrations of cortisol on oxidative stress, apoptosis, and lipid metabolism were investigated. The study methodology involved disinfecting of T. fasciatus with 75% alcohol and subsequently anesthetizing with MS-222. Furthermore, the intestines were removed and cleansed using PBS containing 100 IU/mL penicillin and 100 μg/mL streptomycin. The intestines were then sectioned into 1.5 mL centrifuge tubes with digestive solutions and digested at 28 ℃ for 30 min. Cells were subsequently centrifuged at 1 000 r/min for 5 min at 4 ℃, and resuspended in a new complete medium (DMEM containing 20% fetal bovine serum, 100 IU/mL penicillin, and 100 μg/mL streptomycin). The proliferation rate of intestinal epithelial cells under the four culture methods was determined within 5 d using the CCK-8 method, and cell growth was observed under a microscope after 24 h of culture. Cortisol solutions at varying concentrations were diluted with complete medium, and the cell viability of T. fasciatus was measured using the CCK-8 method after cortisol treatment (0, 100, 1 000, 2 000, 3 000, and 5 000 nmol/L) for 24 h. The morphological structure of intracellular mitochondria was observed through transmission electron microscopy after cortisol treatment (0, 10, 100, and 1 000 nmol/L) for 24 h. After cortisol treatment (0, 10, 100, and 1 000 nmol/L) for 3, 6, 12, and 24 h, the expression patterns of oxidative stress-related genes, apoptosis-related genes, and lipid metabolism-related genes in intestinal epithelial cells were measured by real-time fluorescence-based quantitative PCR (qRT-PCR). Cell apoptosis was measured using the Annexin V-FITC/PI method, and the contents of triglycerides, total cholesterol, and free fatty acids were measured using kits from Nanjing Jiancheng Co. The results showed that the intestinal epithelial cells cultured with trypsin (0.25%) digestion and DMEM had the highest cell proliferation rate among the four culture methods, with predominantly fibroblast-like cell morphology and the best apposition. At a cortisol concentration of 1 000 nmol/L, the intestinal epithelial cell viability was 0.8 times that of the control group, with no significant difference between the 1 000 nmol/L cortisol-treated group and the 2 000 nmol/L cortisol-treated group. However, the cell viability significantly decreased when the cortisol concentration exceeded 2 000 nmol/L (P < 0.05). Thus, 1 000 nmol/L or lower was selected for cortisol treatment. Transmission electron microscopy revealed that the mitochondrial structure of intestinal epithelial cells was altered in all the cortisol-treated groups, with an increase in the number of mitochondria. The expression of oxidative stress-related genes (sod, cat, and gsh-px) and apoptotic index significantly increased with increasing cortisol treatment concentration and time. Pro-apoptotic genes (caspase-3, caspase-7, caspase-9, bax and p53) increased significantly, while anti-apoptotic gene bcl-2 expression decreased significantly with the increase of cortisol treatment concentration (P < 0.05). The expression of lipid synthesis-related genes (g6pd, 6gpd, pparγ, fas and acc) decreased significantly and lipolysis-related genes (hsl, pparα, lpl and cpt-1) increased significantly with increasing cortisol treatment concentration (P < 0.05). Triglyceride and total cholesterol contents decreased significantly, whereas the free fatty acids content increased significantly with increasing cortisol treatment concentration and time (P < 0.05). These results indicate that trypsin (0.25%) digestion with DMEM is optimal for culture of primary intestinal epithelial cells of T. fasciatus. Cortisol promotes oxidative stress, apoptosis, and lipid decomposition but suppresses lipid synthesis in intestinal epithelial cells of T. fasciatus. This study established the optimal isolation and culture method for primary intestinal epithelial cells of T. fasciatus and investigated the mechanism of the intestinal response to cortisol stress in T. fasciatus, thus providing a theoretical basis for the subsequent anti-stress culture of fish.

Abstract Morphine has been suggested to affect cancer cell dynamics and decrease survival rates in lung cancer patients at specific doses, but the precise mechanisms poorly understood. In this study, we aimed to investigate the molecular mechanisms by which morphine modulates the malignant characteristics of non-small cell lung cancer. Cell proliferation was assessed via the Cell Counting Kit-8 assay, and cell migration and invasion were examined via wound healing and Transwell assays. We employed immunofluorescence staining to evaluate E-cadherin expression in A549 and Lewis lung cancer (LLC) cell lines and immunohistochemistry to evaluate E-cadherin expression in nude mice tumours. Additionally, the in vivo effects of morphine on lung cancer progression were explored in a xenograft tumour experiments, in which naloxone was used as a morphine antagonist. Western blot analysis was performed to detect E-cadherin, phosphorylated mTOR (p-mTOR), mTOR, phosphorylated AKT (p-AKT), AKT, phosphorylated PI3K (p-PI3K), and PI3K protein levels in A549 and LLC cells as well as in tumour samples. Morphine (10 µM) significantly increased the proliferation of A549 and LLC cells in vitro (p

BackgroundOsteoporosis is characterized by diminished bone density and quality, compromised bone microstructure, and increased bone fragility, culminating in a heightened risk of fracture. Relatively few attempts have been made to survey the breadth of osteoporosis research using bibliometric approaches. This study aims to delineate the current landscape of osteoporosis research, offering clarity and visualization, while also identifying potential future directions for investigation.MethodsWe retrieved and filtered articles and reviews pertaining to osteoporosis from the Web of Science Core Collection database, specifically the Science Citation Index Expanded (SCI-E) edition, spanning the years 2014 to 2023. Informatics tools such as CiteSpace and VOSviewer were employed to dissect the intellectual framework, discern trends, and pinpoint focal points of interest within osteoporosis research.ResultsOur dataset comprised 33,928 osteoporosis-related publications, with a notable surge in annual publication numbers throughout the last decade. China and the United States lead in terms of research output. The University of California System contributed substantially to this body of work, with Amgen demonstrating the highest degree of centrality within the network. Cooper Cyrus emerged as a pivotal figure in the field. An analysis of highly-cited studies, co-citation networks, and keyword co-occurrence revealed that recent years have predominantly concentrated on elucidating mechanisms underlying osteoporosis, as well as its diagnosis, prevention, and treatment strategies. Burst detection analyses of citations and keywords highlighted osteoblasts, sarcopenia, gut microbiota, and denosumab as contemporary hotspots within osteoporosis research.ConclusionThis bibliometric analysis has provided a visual representation of the fundamental knowledge structure, prevailing trends, and key focal areas within osteoporosis research. The identification of osteoblasts, sarcopenia, gut microbiota, and denosumab as current hotspots may guide future research endeavors. Continued efforts directed at understanding the mechanisms, fracture outcomes, diagnostics, and therapeutics related to osteoporosis are anticipated to deepen our comprehension of this complex disease.

Pain sensitivity varies depending on both the state and age of an individual. For example, chronic pain is more common in older individuals, but the underlying mechanisms remain unknown. This study revealed that 18-month-old mice (aged) experienced more severe and long-lasting allodynia and hyperalgesia in the chronic constriction injury (CCI)-induced pain state compared to 2-month-old mice. Interestingly, the aged mice had a higher baseline mechanical pain threshold than the adult mice. The expression of spinal receptor-active modification protein 1 (RAMP1), as a key component and regulator of the calcitonin gene-related peptide (CGRP) receptor for nociceptive transmission from the periphery to the spinal cord, was reduced in the physiological state but significantly increased after CCI in the aged mice compared to the adult mice. Moreover, when RAMP1 was knocked down using shRNA, the pain sensitivity of adult mice decreased significantly, and CCI-induced allodynia in aged mice was reduced. These findings suggest that spinal RAMP1 is involved in regulating pain sensitivity in a state- and age-dependent manner. Additionally, interfering with RAMP1 could be a promising strategy for alleviating chronic pain in older individuals.

Background Acute respiratory distress syndrome (ARDS) is a severe complication that can lead to fatalities in multiple trauma patients. Nevertheless, the incidence rate and early prediction of ARDS among multiple trauma patients residing in high-altitude areas remain unknown. Methods This study included a total of 168 multiple trauma patients who received treatment at Shigatse People’s Hospital Intensive Care Unit (ICU) between January 1, 2019 and December 31, 2021. The clinical characteristics of the patients and the incidence rate of ARDS were assessed. Univariable and multivariable logistic regression models were employed to identify potential risk factors for ARDS, and the predictive effects of these risk factors were analyzed. Results In the high-altitude area, the incidence of ARDS among multiple trauma patients was 37.5% (63/168), with a hospital mortality rate of 16.1% (27/168). Injury Severity Score (ISS) and thoracic injuries were identified as significant predictors for ARDS using the logistic regression model, with an area under the curve (AUC) of 0.75 and 0.75, respectively. Furthermore, a novel predictive risk score combining ISS and thoracic injuries demonstrated improved predictive ability, achieving an AUC of 0.82. Conclusions This study presents the incidence of ARDS in multiple trauma patients residing in the Tibetan region, and identifies two critical predictive factors along with a risk score for early prediction of ARDS. These findings have the potential to enhance clinicians’ ability to accurately assess the risk of ARDS and proactively prevent its onset.

Abstract Purpose Opioids are currently the most frequently prescribed analgesics in clinical practice. However, their effect on cancer progression remains a topic of debate. Opioid receptors (ORs) are present in various types of tumor cells and their expression levels vary depending on the type of tumor. This study aims to explore and preliminarily characterize the association between four different ORs (μ, δ, κ, and nociception/orphanin FQ peptide receptor) and the prognosis of different types of tumors for comparison, with a focus on nociception/ orphanin FQ peptide receptor. Methods The expression levels of four ORs in normal tissues and immune cells were obtained from Human Protein Atlas (HPA) RNA-seq dataset, Monaco dataset, and Consensus dataset. Pan-cancer analysis was performed using the The Cancer Genome Atlas (TCGA) dataset, which included the expression of four ORs in different cancer types, significant copy-number alterations (sCNA), gene mutations of the four ORs, survival analysis, co-expression genes analysis, functional enrichment analyses, and correlations between ORs and immune cell infiltration levels. Based on the results of bioinformatic analysis, we selected 10 cancer cell lines for validation in vitro using specific agonists for the four ORs. Results OPRL1 (opioid related nociceptin receptor 1 gene) exhibited the highest abundance across different types of cancers, while OPRM1 (opioid receptor mu 1 gene) and OPRD1 (opioid receptor delta 1 gene) were barely detectable in multiple cancer types. Pan-cancer survival analysis revealed the overall worse/better prognosis of the four ORs in certain cancer types. Elevated levels of OPRM1 appear to be associated with poorer outcomes in breast invasive carcinoma and kidney renal clear cell carcinoma. Elevated OPRD1 levels are connected to worsen outcomes in kidney renal clear cell carcinoma and liver hepatocellular carcinoma, but better prognosis in bladder urothelial carcinoma. Increased OPRK1 (opioid receptor kappa 1 gene) expression is linked to a poorer prognosis in kidney renal papillary cell carcinoma. Furthermore, high OPRL1 expression relates to worse outcomes in bladder urothelial carcinoma and liver hepatocellular carcinoma, but better outcomes in breast invasive carcinoma and pancreatic adenocarcinoma. Functional enrichment analyses found that immune-related pathways were enriched in OPRK1 and OPRL1, with OPRL1 exhibiting the highest correlation with immune cell infiltration. Different effects on cell growth, migration, and invasion were observed in different cancer types upon the administration of agonists for the four ORs. Conclusion OPRL1 may play a vital role in monocytes and regulating the immune response and tumor-infiltrating macrophages. Due to its high abundance in different types of tumors, it may hold greater clinical significance for oncology patients. OPRK1 also participates in immune-related pathways. OPRL1 could potentially serve as therapeutic targets for different types of cancers. Graphical Abstract

Abstract Purpose While coronavirus disease 2019 (COVID-19) has emerged as a global pandemic, millions of patients with COVID-19 have recovered and returned to their families and work, although the key factors of sequela-free survival remain unknown. Here we determine key factors associated with sequela-free survival of patients with COVID-19. Methods Sequela-free survival is defined as having none of the long-term sequelae measured with the Activity of Daily Living (ADL) Scale, modified Medical Research Council (mMRC) Dyspnoea Scale, New York Heart Association (NYHA) classification, Self-rating Depression Scale (SDS), Carcinologic Handicap Index (CHI) and Modified Telephone Interview for Cognitive Status (TICS-M). Multivariable logistic regression was used to examine the key factors of sequela-free survival. Results The follow-up period for the 464 patients was 10 August to 30 September 2020. Of these, 424 patients completed the assessment of all scales. 30.2% (128 of 424) were categorised as sequela-free at follow-up. The most common sequelae were psychosocial problems (254 [57.7%]), respiratory function abnormality (149 [32.6%]) and cardiac function abnormality (98 [21.5%]). Risk factors associated with COVID-19 sequelae were anaemia on admission, longer duration from the onset of symptoms to admission and increasing of age, whereas anaemia treatment was a protective factor against sequelae. A haemoglobin level of

Abstract The rapid reversal of deep neuromuscular blockade (NMB) is important but remains challenging. This study aimed to evaluate the efficacy and safety of adamgammadex versus sugammadex in reversing deep rocuronium‐induced NMB. This multicenter, randomized, phase IIb study included 80 patients aged 18–64 years, American Society of Anesthesiologists (ASA) grade 1–2, undergoing elective surgery under general anesthesia with rocuronium. Patients were randomized to the adamgammadex 7, 8, and 9 mg/kg group or the sugammadex 4 mg/kg group. The primary efficacy variable was the time to recovery of train‐of‐four ratio (TOFr) to 0.9. The secondary efficacy variables were the time to recovery of TOFr to 0.7, antagonistic success rate of the recovery of TOFr to 0.9 within 5 min, and incidence rate of recurarization within 30 min after drug administration. The explorative efficacy variable was the time to recovery of the corrected TOFr to 0.9 (actual/baseline TOF ratio). Adamgammadex 7, 8, and 9 mg/kg and sugammadex 4 mg/kg groups did not significantly differ in all efficacy variables. Importantly, adamgammadex 9 mg/kg permitted reversal within a geometric mean of 2.9 min. According to the safety profile, adamgammadex achieved good tolerance and low incidence of drug‐related adverse events compared with the 4 mg/kg sugammadex. Adamgammadex 7, 8, and 9 mg/kg facilitated rapid reversal of deep rocuronium‐induced NMB and had good tolerance and low incidence of drug‐related adverse events. Therefore, adamgammadex is a potential and promising alternative to sugammadex.

Abstract Background Microglial polarization is one of the most promising therapeutic targets for multiple central nervous system (CNS) disorders, including ischemic stroke. However, detailed transcriptional alteration of microglia following cerebral ischemic stroke remains largely unclear. Methods Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) for 60 min in mice. Single-cell RNA sequencing (scRNA-seq) was performed using ischemic brain tissues from tMCAO and sham mice 3 days after surgery. Ch25h −/− mice were used to investigate the role of specific microglia subcluster on post-stroke infarct volume and neuroinflammation. Results We identified a relatively homeostatic subcluster with enhanced antigen processing and three “ischemic stroke associated microglia” (ISAM): MKI67+, CH25H+ and OASL+ subclusters. We found the MKI67+ subcluster undergo proliferation and differentiation into CH25H+ and OASL+ subclusters. CH25H+ microglia was a critical subcluster of ISAM that exhibited increased phagocytosis and neuroprotective property after stroke. Ch25h −/− mice developed significantly increased infarct volume following ischemic stroke compared to Ch25h +/−. Meanwhile, the OASL+ subcluster accumulated in the ischemic brain and was associated with the evolving of neuroinflammation after stroke, which was further aggravated in the aged mice brain. Conclusions Our data reveal previously unrecognized roles of the newly defined CH25H+ and OASL+ microglia subclusters following ischemic stroke, with novel insights for precise microglia modulation towards stroke therapy.

Abstract Unlike physiological stress, which carries survival value, pathological stress is widespread in modern society and acts as a main risk factor for visceral pain. As the main stress-responsive nucleus in the brain, the locus coeruleus (LC) has been previously shown to drive pain alleviation through direct descending projections to the spinal cord, but whether and how the LC mediates pathological stress-induced visceral pain remains unclear. Here, we identified a direct circuit projection from LC noradrenergic neurons to the rostral ventromedial medulla (RVM), an integral relay of the central descending pain modulation system. Furthermore, the chemogenetic activation of the LC-RVM circuit was found to significantly induce colorectal visceral hyperalgesia and anxiety-related psychiatric disorders in naïve mice. In a dextran sulfate sodium (DSS)-induced visceral pain model, the mice also presented colorectal visceral hypersensitivity and anxiety-related psychiatric disorders, which were associated with increased activity of the LC-RVM circuit; LC-RVM circuit inhibition markedly alleviated these symptoms. Furthermore, the chronic restraint stress (CRS) model precipitates anxiety-related psychiatric disorders and induces colorectal visceral hyperalgesia, which is referred to as pathological stress-induced hyperalgesia, and inhibiting the LC-RVM circuit attenuates the severity of colorectal visceral pain. Overall, the present study clearly demonstrated that the LC-RVM circuit could be critical for the comorbidity of colorectal visceral pain and stress-related psychiatric disorders. Both visceral inflammation and psychological stress can activate LC noradrenergic neurons, which promote the severity of colorectal visceral hyperalgesia through this LC-RVM circuit.

Abstract Background Hypoxia is a very common adverse event that occurs during gastrointestinal endoscopy under sedation, especially in older patients, owing to limited reservation of heart, brain, lung, and other organs. Prolonged or severe hypoxia can cause ischemia of the coronary artery and permanent nervous system damage, and even result in death. Hence, it is imperative to reduce or prevent hypoxia during gastrointestinal endoscopy under sedation in older patients. Although several oxygen delivery methods would reduce hypoxia during this procedure, early detection of respiratory depression and early administration of intervention would be the best method to reduce or even confirm the hypoxia. Capnographic monitoring is reportedly more sensitive for detecting respiratory depression before the onset of hypoxia than the current clinical routine monitoring of pulse oxygen saturation; however, its effect is controversial. Therefore, in this study, we aimed to improve the safety of gastrointestinal endoscopy under sedation in older patients. Methods A multicenter, randomized, single-blind, two-arm parallel-group, controlled with an active comparator, interventional superiority clinical trial will be conducted to evaluate the impact of an additional capnographic monitoring-based intervention on the incidence of hypoxia in older patients. Patients (n = 1800) scheduled for gastrointestinal endoscopy with propofol sedation will be randomly assigned to either a control or interventional arm, wherein standard or capnographic monitoring is implemented, respectively. Discussion This study primarily aims to examine whether an additional capnographic monitoring-based intervention can reduce the incidence of hypoxia in older patients during gastrointestinal endoscopy under propofol and sufentanil sedation. The results of this study may extensively impact gastrointestinal endoscopy under sedation and the development of associated guidelines. Trial registration ClinicalTrials.gov NCT05030870. Registered on September 1, 2021.

Abstract Background μ‐opioid receptor agonists (MORAs) are indispensable for analgesia in bladder cancer (BC) patients, both during surgery and for chronic pain treatment. Whether MORAs affect BC progression and metastasis remains largely unknown. This study focused on the effects of MORAs on the formation of circulating tumor cells (CTCs) in BC and aimed to provide potential therapeutic targets, which would retain the pain‐relieving effects of MORAs in BC patients without sacrificing their long‐term prognosis. Methods Different preclinical models were used to identify the effects of MORAs on the progression of BC. A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients. Bioinformatic analyses, total transcriptome sequencing, and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines. Results Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment. A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients. Mechanistically, MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway, hereby promoting the epithelial‐mesenchymal transition (EMT) of BC cells, as knockdown of MOR, Slug or blockade of PI3K inhibited the EMT process and CTC formation. Conclusion MORAs promoted BC metastasis by facilitating CTC formation. The EMT‐CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumor metastasis or recurrence in BC patients.

Hepatic ischemia-reperfusion injury (HIRI) is a complex pathological phenomenon dominated by the innate immune system and involves a variety of immune cells. This condition frequently occurs during hepatectomy, liver transplantation or hemorrhagic shock. HIRI represents an important factor in the poor prognosis of patients after liver surgery. However, there is still a lack of effective intervention to reduce the incidence of HIRI. In this study, we aimed to describe the overall structure of scientific research on HIRI over the past 20 years and provide valuable information and guidelines for future researchers. Bibliometric analysis was used to comprehensively review developments in HIRI and changes in our understanding of HIRI over the past two decades. We identified a total of 4267 articles on HIRI that were published over the past 20 years of which basic research was predominant. Collaboration network analysis revealed that China, the University of California Los Angeles, and Ronald W Busuttil were the most influential country, institute, and scholar, respectively. Co-occurrence cluster analysis revealed that ischemic preconditioning, liver cirrhosis, hepatic I/R injury, autophagy, acute liver failure, oxygen, donation after circulatory death, Nlrp3, remote organ, and microdialysis were the top 10 clusters. Keyword burst detection indicated that autophagy, inflammation, and early allograft dysfunction represent the current research hotspots. In summary, this is the first bibliometric analysis of HIRI research. Our timely analysis of these hotpots and research trends may provide a framework for future researchers and further promote research on the key mechanisms and therapeutic measures in this field.

BackgroundPediatric liver transplantation is an important modality for treating biliary atresia. The overall survival rate of pediatric liver transplantation has significantly improved. The incidence of perioperative cardiac events was evaluated, and risk factors were also investigated in adult patients undergoing liver transplantation in previous studies. To the best of our knowledge, this is the first case of a cardiac event during a pediatric living-donor liver transplantation.Case summaryOur report describes the management of cardiac events during a liver transplantation in a 7-month-old girl. The ST segment began to increase to 3.0 mm immediately after reperfusion, with peak ST-segment elevation reaching 13.2 mm after 45 min. The procedure ended uneventfully after continuous symptomatic and etiological treatment. It was considered to be the occurrence of an acute air embolism complication during the procedure based on the electrocardiograph and biomarkers. An echocardiogram during follow-up showed a patent foramen ovale with a left-to-right shunt tract width of 2.7 mm.DiscussionPediatric liver transplantation has become a state-of-the-art treatment for children with end-stage liver disease and can improve the quality of life to some extent. These children may be complicated with congenital heart disease, which increases the risk of surgery. Application of echocardiogram, close monitoring, and appropriate management may reduce the incidence of perioperative cardiac events.

BackgroundSleep is an important biological process and has been linked to many diseases; however, very little is known about which and how genes control and regulate sleep. Although technology has seen significant development, this issue has still not been adequately resolved. Therefore, we conducted a bibliometric analysis to assess the progress in research on sleep quality and associated genes over the past 2 decades. Through our statistical data and discussions, we aimed to provide researchers with better research directions and ideas, thus promoting the advancement of this field.MethodsOn December 29, 2022, we utilized bibliometric techniques, such as co-cited and cluster analysis and keyword co-occurrence, using tools such as CiteSpace, VOSviewer, and the Online Analysis Platform of Literature Metrology (http://bibliometric.com/), to conduct a thorough examination of the relevant publications extracted from the Web of Science Core Collection (WoSCC). Our analysis aimed to identify the emerging trends and hot spots in this field while also predicting their potential development in future.ResultsCluster analysis of the co-cited literature revealed the most popular terms relating to sleep quality and associated genes in the manner of cluster labels; these included genome-wide association studies (GWAS), circadian rhythms, obstructive sleep apnea (OSA), DNA methylation, and depression. Keyword burst detection suggested that obstructive sleep apnea, circadian clock, circadian genes, and polygenic risk score were newly emergent research hot spots.ConclusionBased on this bibliometric analysis of the publications in the last 20 years, a comprehensive analysis of the literature clarified the contributions, changes in research hot spots, and evolution of research techniques regarding sleep quality and associated genes. This research can provide medical staff and researchers with revelations into future directions of the study on the pathological mechanisms of sleep-related diseases.

BackgroundHepatocellular carcinoma (HCC), one of the most common cancers worldwide, exhibits high immune heterogeneity and mortality. Emerging studies suggest that copper (Cu) plays a key role in cell survival. However, the relationship between Cu and tumor development remains unclear.MethodsWe investigated the effects of Cu and cuproptosis-related genes (CRGs) in patients with HCC in the TCGA-LIHC (The Cancer Genome Atlas-Liver cancer, n = 347) and ICGC-LIRI-JP (International Cancer Genome Consortium-Liver Cancer-Riken-Japan, n = 203) datasets. Prognostic genes were identified by survival analysis, and a least absolute shrinkage and selection operator (Lasso) regression model was constructed using the prognostic genes in the two datasets. Additionally, we analyzed differentially expressed genes and signal pathway enrichment. We also evaluated the effects of CRGs on tumor immune cell infiltration and their co-expression with immune checkpoint genes (ICGs) and performed validation in different tumor immune microenvironments (TIMs). Finally, we performed validation using clinical samples and predicted the prognosis of patients with HCC using a nomogram.ResultsA total of 59 CRGs were included for analysis, and 15 genes that significantly influenced the survival of patients in the two datasets were identified. Patients were grouped by risk scores, and pathway enrichment analysis suggested that immune-related pathways were substantially enriched in both datasets. Tumor immune cell infiltration analysis and clinical validation revealed that PRNP (Prion protein), SNCA (Synuclein alpha), and COX17 (Cytochrome c oxidase copper chaperone COX17) may be closely correlated with immune cell infiltration and ICG expression. A nomogram was constructed to predict the prognosis of patients with HCC using patients’ characteristics and risk scores.ConclusionCRGs may regulate the development of HCC by targeting the TIM and ICGs. CRGs such as PRNP, SNCA, and COX17 could be promising targets for HCC immune therapy in the future.

The rostral ventromedial medulla (RVM) is a bulbospinal nuclei in the descending pain modulation system, and directly affects spinal nociceptive transmission through pronociceptive ON cells and antinociceptive OFF cells in this area. The functional status of ON and OFF neurons play a pivotal role in pain chronification. As distinct pain modulative information converges in the RVM and affects ON and OFF cell excitability, neural circuits and transmitters correlated to RVM need to be defined for an in-depth understanding of central-mediated pain sensitivity. In this review, neural circuits including the role of the periaqueductal gray, locus coeruleus, parabrachial complex, hypothalamus, amygdala input to the RVM, and RVM output to the spinal dorsal horn are discussed. Meanwhile, the role of neurotransmitters is concluded, including serotonin, opioids, amino acids, cannabinoids, TRPV1, substance P and cholecystokinin, and their dynamic impact on both ON and OFF cell activities in modulating pain transmission. Via clarifying potential specific receptors of ON and OFF cells, more targeted therapies can be raised to generate pain relief for patients who suffer from chronic pain.

PurposeTo explore the potential therapeutic strategies of different types of neuropathic pain (NP) and to summarize the cutting-edge novel approaches for NP treatment based on the clinical trials registered on ClinicalTrials.gov.MethodsThe relevant clinical trials were searched using ClinicalTrials.gov Dec 08, 2022. NP is defined as a painful condition caused by neurological lesions or diseases. All data were obtained and reviewed by the investigators to confirm whether they were related to the current topic.ResultsA total of 914 trials were included in this study. They were divided into painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), sciatica (SC), peripheral nerve injury-related NP (PNI), trigeminal neuralgia (TN), chemotherapy-induced NP (CINP), general peripheral NP (GPNP) and spinal cord injury NP (SCI-NP). Potential novel therapeutic strategies, such as novel drug targets and physical means, were discussed for each type of NP.ConclusionNP treatment is mainly dominated by drug therapy, and physical means have become increasingly popular. It is worth noting that novel drug targets, new implications of conventional medicine, and novel physical means can serve as promising strategies for the treatment of NP. However, more attention needs to be paid to the challenges of translating research findings into clinical practice.

The rostral ventromedial medulla (RVM) exerts bidirectional descending modulation of pain attributable to the activity of electrophysiologically identified pronociceptive ON and antinociceptive OFF neurons. Here, we report that GABAergic ON neurons specifically express G protein–coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, but their ablation abrogated, pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain, and ameliorated morphine analgesia through desensitizing μ-type opioid receptor–mediated (MOR-mediated) activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia, and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly indicate that GPER is a marker for GABAergic ON cells and illuminate the mechanisms underlying hormonal regulation of pain and analgesia, thus highlighting GPER as a promising target for the treatment of pain and opioid tolerance.

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease. MAFLD is a major risk factor for end-stage liver disease including cirrhosis and primary liver cancer. The pathogenesis of MAFLD is complex and has not yet been clarified. To the best of our knowledge, few studies have conducted quantitative bibliometric analysis to evaluate published MAFLD research. In this study, we conducted a comprehensive analysis of MAFLD publications over the past decade to summarize the current research hotspots and predict future research directions in this field.MethodsArticles into MAFLD published from 2012 to 2021 were identified from the Science Citation Index-Expanded of Web of Science Core Collection. CiteSpace software, VOSviewer, the “bibliometrix” R package, and the Online Analysis Platform of Literature Metrology were used to analyze the current publication trends and hotspots.ResultsWe retrieved 13959 English articles about MAFLD published from 2012 to 2021. Primary sites of publication were dominated by the United States until 2014, when China became the source of most published MAFLD-related research papers. The United States was found to be the most engaged country in international cooperative efforts. Shanghai Jiao Tong University was the most productive institution. Loomba R was the most productive author with 123 articles. The co-cited keyword cluster tag showed ten main clusters: #0 liver fibrosis, #1 hemoglobin, #2 metabolic associated fatty liver disease, #3 egcg, #4 myocardial infarction, #5 heart disease, #6 pnpla3, #7 hepatocellular carcinoma, #8 noninvasive marker, and #9 children. Keyword burst analysis showed that gut microbiota was the highest-intensity research hotspot.ConclusionIn the past decade, the number of publications on MAFLD increased dramatically, especially in the last three years. Gut microbiota became an important research direction for etiological and therapeutic investigations into MAFLD. Insulin resistance was also a key factor in studying the development of MAFLD in recent years. Liver fibrosis was an important focus of disease development. This study provides systematic information, helps guide future research, and helps to identify mechanisms and new treatment methods for MAFLD.

BackgroundAcute respiratory distress syndrome (ARDS) is a serious organ failure and postoperative complication. However, the incidence rate, early prediction and prevention of postoperative ARDS in patients undergoing hepatectomy remain unidentified.MethodsA total of 1,032 patients undergoing hepatectomy between 2019 and 2020, at the Eastern Hepatobiliary Surgery Hospital were included. Patients in 2019 and 2020 were used as the development and validation cohorts, respectively. The incidence rate of ARDS was assessed. A logistic regression model and a least absolute shrinkage and selection operator (LASSO) regression model were used for constructing ARDS prediction models.ResultsThe incidence of ARDS was 8.8% (43/490) in the development cohort and 5.7% (31/542) in the validation cohort. Operation time, postoperative aspartate aminotransferase (AST), and postoperative hemoglobin (Hb) were all critical predictors identified by the logistic regression model, with an area under the curve (AUC) of 0.804 in the development cohort and 0.752 in the validation cohort. Additionally, nine predictors were identified by the LASSO regression model, with an AUC of 0.848 in the development cohort and 0.786 in the validation cohort.ConclusionWe reported the incidence of ARDS in patients undergoing hepatectomy and developed two simple and practical prediction models for early predicting postoperative ARDS in patients undergoing hepatectomy. These tools may improve clinicians’ ability to early estimate the risk of postoperative ARDS and timely prevent its emergence.

Abstract Background Emergence agitation (EA) after general anesthesia is a common complication in the post-anesthesia care unit (PACU). Once EA occurs, there are still no guidelines established for the treatment in adults. Propofol is excessively used in managing agitated patients in the PACU, but it lacks analgesia and can result in apnea. Intraoperative infusion of dexmedetomidine has been proven to have a preventive effect on EA, but the treatment effect of dexmedetomidine on EA remains unknown. This study aims to compare the effects between dexmedetomidine and propofol on relieving EA in adult patients after general anesthesia in the PACU. Methods In this randomized, superiority, controlled clinical study, a total of 120 adult patients aged 18–65 years of both genders, with American Society of Anesthesiologists (ASA) classification I or II developing EA in the PACU after general anesthesia, will be enrolled. Patients will be randomized at a 1:1 ratio into two groups, receiving either a single dose of dexmedetomidine (0.7μg/kg) or propofol (0.5 mg/kg). The primary outcome is the proportion of patients having a recurrent EA within 15 min after intervention in the PACU. Discussion Previous studies have focused on premedication for preventing EA, while therapeutics for reliving EA have rarely been reported. To our knowledge, this study is the first randomized, superiority, controlled trial to compare a bolus of dexmedetomidine with the current routine care for this indication. Trial registration ClinicalTrials.gov NCT04142840 . Registered on October 26, 2019

Background and aimsThe gut microbiota is involved in the regulation of pain, which is proved by plenty of evidence. Although a substantial quantity of research on the link between the gut microbiota and pain has emerged, no study has focused on the bibliometric analysis of this topic. We aim to present a bibliometric review of publications over the past 20 years and predict research hot spots.MethodsRelevant publications between 2002 and 2021 were extracted from the Science Citation Index-Expanded (SCI-EXPANDED) of the Web of Science Core Collection (WoSCC) database on April 22, 2022. CiteSpace (version 5.8 R3c), VOSviewer, the Online Analysis Platform of Literature Metrology, and the R package bibliometrix were used to analyze and visualize.ResultsA total of 233 articles have been published between 2002 and 2021. The number of publication outputs increased rapidly since 2016. The collaboration network revealed that the USA, Baylor College of Medicine, and Vassilia Theodorou were the most influential country, institute, and scholar, respectively. Alimentary pharmacology and therapeutics and Gut were the most co-cited journal and Neurogastroenterology and Motility was the most productive journal. Visceral sensitivity, fibromyalgia, gastrointestinal, chronic pain, stress, gut microbiome, LGG, brain-gut axis, SLAB51, and sequencing were the top 10 clusters in co-occurrence cluster analysis. Keyword burst detection indicated that the brain-gut axis and short-chain fatty acid were the current research hot spots.ConclusionResearch on the links between the gut microbiota and pain has increased rapidly since 2016. The current research focused on the brain-gut axis and short-chain fatty acid. Accordingly, the SCFAs-mediated mechanism of pain regulation will be a research direction of great importance on the links between the gut microbiota and pain. This study provided instructive assistance to direct future research efforts on the links between the gut microbiota and pain.

BackgroundThe prevalence of metabolic associated fatty liver disease (MAFLD) presented a booming growth over recent years in the whole world. MAFLD was associated with a higher risk of end-stage liver disease, hepatocellular carcinoma and liver transplantation. Accumulating evidence indicated that gut microbiota and MAFLD were interrelated and interacted with each other. However, to the knowledge of the authors, no bibliometric quantitative analysis has been carried out to evaluate the links between the gut microbiota and MAFLD. This study aimed to use bibliometric analysis to evaluate current publication trends and hotspots in the links between the gut microbiota and MAFLD, in order to advance research in this field.MethodsThe articles regarding the links between gut microbiota and MAFLD from 2002 to 2021 were identified from the Science Citation Index-Expanded of Web of Science Core Collection. CiteSpace software, Vosviewer, the R package “bibliometrix” and the Online Analysis Platform of Literature Metrology were used to analyze current publication trends and hotspots in this field.ResultsA total of 707 articles were retrieved regarding the links between gut microbiota and MAFLD from 2002 to 2021. The USA occupied the leading role until 2015 and the dominance of China started in 2016. The USA was the most frequently involved country in international cooperation. Shanghai Jiao Tong University was the most productive institution. Ina Bergheim was the most productive author, publishing 14 articles. The co-citation keywords cluster label displayed ten main clusters: probiotics, bile acid, immune function, adolescents, nutritional genomics, high fat diet, systems biology, lipopolysaccharides, phosphatidylcholine, and oxidative stress. Keyword bursts analysis indicated that diet induced obesity, metabolic syndrome, ppar alpha, and lactobacillus were the research hotspots with high strength.ConclusionThe number of publications covering the links of gut microbiota and MAFLD increased dramatically in the past decade and especially became exponential growth in the last 3 years. Probiotics and bile acid will be the research direction of great importance in the etiology and novel treatment for MAFLD. This study provided systematic information and instructive assistance for future research work, that helped to discover the mechanisms and new treatments of MAFLD.

Background: Liver hepatocellular carcinoma (LIHC) is a complicated disease with poor survival and lack of viable treatment options. The roles of ferroptosis and immunotherapy in LIHC are increasingly prominent, but the interplay of ferroptosis with the tumor microenvironment (TME) in LIHC is currently under-investigated.Methods: In this study, we analyzed normal liver tissues and tumor tissues from the TCGA and GTEx databases to obtain differentially expressed ferroptosis-related genes (FRGs). We then clustered LIHC based on the expression levels of selected FRGs and acquired distinct subtypes with significant heterogeneity regarding survival prognoses, PD-L1 expression, and immune cell infiltration. The correlation of those FRGs with TME in LIHC and pan-cancer analysis was also investigated. GO functional annotations and KEGG pathway analyses were performed to investigate the potential reactions of the obtained differentially expressed genes (DEGs). Further external validation was performed using microarrays on the GEO database and the key ferroptosis regulator SLC7A11 expression between LIHC and normal cells was detected by Western blotting.Results: A large proportion of genes were upregulated in the LIHC group. Among three clusters, cluster 3 had the worst prognosis combined with the highest PD-L1 expression and was positively correlated with various immune cells. Subsequently, survival analysis and Cox regression analysis screened out SLC7A11 as an independent prognostic factor in LIHC featured strong PD-L1 expression and unfavorable survival time. We filter out SLC7A11 as an independent prognostic signature in LIHC patients with strongly associated PD-L1 expression and unfavorable survival probability. In the pan-cancer analysis, high expression of SLC7A11 showed poor overall survival in seven cancers, while the correlation between immune checkpoints (ICs) and SLC7A11 varied by cancer type, indicating the potential therapeutic effects of SLC7A11 in cancers other than LIHC. Western blot was further employed to verify the expression of SLC7A11 in LIHC in vitro.Conclusion: Ferroptosis and TME synergistically play key roles in oncogenesis and progression of LIHC, and SLC7A11 can be used as a predictive biomarker for customized immunotherapy.

Multi-functionalization of wound dressings with natural polymers is meaningful and remains a challenge. The combination of natural polyanions and polycations appears to be a promising strategy. Still, its performances based on current layer-by-layer self-assembly or homogeneous complexation are mutable and limited. Herein, Ca2+-incorporated carboxymethyl cellulose (Ca/Na-CMC) and hydroxypropyltrimethyl ammonium chloride chitosan (HACC) are adopted as the model polyanion and polycation, respectively, to develop multi-functionalized dressings based on interfacial complexation. The dressings exhibit a multilayer structure composed of a polyanion layer (Ca/Na-CMC) for hemostasis and promotion of cell proliferation, a formed polyelectrolyte complex (PEC) layer for structural stability, and a polycation layer (HACC) for antibiosis. Compared to the dressing based on homogeneous complexation, the multilayer dressings show stronger moisture penetrability (around 1,150 g/m2/24 h), higher hemostatic activity, and higher antibacterial rate (up to 100%) and promoted effect on cell proliferation. An in vivo evaluation using a rat full-thickness skin defect model reveals that the multilayer dressings can accelerate wound healing in 2 weeks. Overall, owing to interfacial complexation resulting in separate layers, the performances of polyanions and polycations after combination are more predictable, and their biological functions can be effectively preserved. These findings not only support the extensive application of multilayer dressings but also offer an alternative strategy for multi-functionalizing wound dressings with natural polyanions and polycations.

Abstract The utilization of local anesthetics for postoperative analgesia represents an effective approach, but generally suffers from short half‐lives and brachychronic local neurotoxicity. A desirable anesthetic with controllable and sustainable drug‐releasing performance for adequate analgesia effect is highly required. In this work, the core/shell‐structured two‐dimenional (2D) silicene nanosheets coated with mesoporous silica layer (abbreviated as Silicene@MSNs) have been rationally constructed as localized drug‐delivery system in sciatic nerve block to achieve on‐demand release of loaded ropivacaine (RP) in mesoporous silica layer for local analgesia. Based on the specific photothermal performance of 2D silicene core, this local anesthesia system can be triggered by near‐infrared laser to release the loaded RP, resulting in on‐demand and long‐lasting regional anesthesia. The analgesia effect is assessed by pain behavior tests, which demonstrates that the RP‐loaded Silicene@MSNs core/shell nanosystem behaves almost five times longer analgesia effect than free RP. Furthermore, the activation of pain‐related neurons in nerve conduction pathways is tested to explore the underlying analgesia mechanism, revealing that the designed nanosystem can improve the pain threshold, reduce the activation of neurons in dorsal root ganglion and excitability in spinal substantia gelatinosa neurons. This designed anesthetic nanomedicine provides a facile but effective methodology for long‐lasting regional anesthesia.

Inhibin subunit beta B (INHBB) is a potential prognostic biomarker for a variety of cancers. However, its role in gastric cancer (GC) remains elusive. The differential expression data of INHBB in tumor and normal tissues were extracted from several databases and genetic alterations of INHBB were assessed by cBioPortal. Kaplan-Meier analysis was used to evaluate the survival rate of patients with GC with INHBB and association with clinical features in GC. Cox regression analysis was used to explore the prognostic value of clinical indicators and INHBB in GC, and a nomogram prognostic model was established. In addition, the predictive validity of the nomogram model was assessed by time-depended receiver operating characteristic (ROC) and calibration curves. Functional enrichment analyses were conducted to functionally annotate INHBB. Notably, we found that the quantitative assessment of immune cell subpopulation infiltration correlated with INHBB expression. INHBB expression is upregulated in GC and is correlated with several clinical features including prognostic indicators and a histological type. Genetic alterations were observed in INHBB, its DNA methylation level was negatively correlated with INHBB expression. High INHBB expression is associated with a poor prognosis and is an independent risk factor for prognosis in GC, along with age and residual tumor. The nomogram model showed a good prediction ability and was validated by time-depended ROC and calibration curves. Functional enrichment analysis indicated that INHBB-associated genes were enriched in tumor microenvironment Gene Ontology (GO) terms and were correlated with tumor-associated pathways. INHBB has a regulatory function in immune cell infiltration, especially macrophage infiltration in GC. Specifically, patients with GC with high INHBB expression and high macrophage infiltration have a worse prognosis. INHBB expression was negatively correlated with the expression of chemokines/chemokine receptors and plays a regulatory role in immunoinhibitor/immunostimulator-involved pathways. INHBB is a potential prognostic biomarker for GC and may drive the abnormal activity of critical cancer-associated pathways, potentially contributing to immune cell infiltration to promote GC development.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with high morbidity and mortality, which accounts for the fourth most common cause of cancer-related deaths. Reports suggest that the neurotransmitter receptor-related genes (NRGs) may influence the tumor microenvironment and the prognosis of patients with HCC.Methods: The clinical information and RNA-seq data of patients with HCC were acquired from the ICGC-LIRI-JP dataset and the TCGA-LIHC dataset. Effects of 115 NRGs on the prognosis of HCC patients were analyzed in the ICGC-LIRI-JP dataset. The least absolute shrinkage and selection operator (LASSO) regression model was utilized to generate a risk score formula based on the critical NRGs. Next, the risk score effectiveness was validated both in the TCGA-LIHC dataset and in our clinical HCC samples. Based on the risk scores, patients with HCC were divided into two groups. Moreover, differentially expressed genes (DEGs) were screened. The gene ontology (GO) was used to analyze the functional enrichments of DEGs and to identify potential signaling pathways. To test the diagnostic effectiveness of our model, the receiver operator characteristic curve (ROC) analysis and nomogram were used. Finally, potential targeted drug prediction was performed based on DEGs of nine clinical HCC samples.Results: Nine NRGs were correlated significantly with the prognosis of patients with HCC, and eight NRGs were successfully included in the LASSO regression model. The Kaplan-Meier analysis of overall survival (OS) suggested that patients in the high-risk score group had worse prognosis; on the other hand, ROC analysis revealed a high prognostic value of the risk score in HCC. Several critical signaling pathways, such as lipid metabolism, organic acid metabolism, cell migration, cell adhesion, and immune response, were enriched both in public datasets and clinical samples. Nomogram results also suggested that the risk scores correlated well with the patients’ prognosis. Potential targeted drugs prediction revealed that tubulin inhibitors might be the promising drugs for patients with HCC who have high risk scores based on the NRGs.Conclusion: We established a prognostic model based on critical NRGs. NRGs show a promising prognostic prediction value in HCC and are potential therapeutic targets for the disease treatment.

Glycolipid metabolic diseases, including type 2 diabetes, non-alcoholic fatty liver disease, obesity, hypertension, dyslipidemia, and atherosclerosis, which have become a major public health concern worldwide, are mainly triggered by hepatic glycolipid metabolism disorder. Bibliometric analysis has provided a comprehensive review of developments in hepatic glycolipid metabolism research and changes in research hotspots over the past 20 years. The articles regarding hepatic glycolipid metabolism from 2002 to 2021 were identified from the Science Citation Index-Expanded of Web of Science Core Collection. Acquired data were then processed by the CiteSpace software and the Online Analysis Platform of Literature Metrology to analyze trends and predict hot spots in this field. A total of 4,856 articles regarding hepatic glycolipid metabolism published from 2002 to 2021 were selected. The leading country was China. The Chinese Academy of Sciences was the most productive institution. Co-citation cluster labels revealed characteristics of ten main clusters: non-alcoholic fatty liver disease, gut microbiota, adiponectin, fructose, fgf21, fatty acid, liver x receptor, nr4a, obese mice, and bile acids. Keyword bursts analysis indicated that management, non-alcoholic fatty liver disease, and modulation were the newly emerging research hot spots. We described the overall structure of scientific research on hepatic glycolipid metabolism and presented systematic information to other researchers. The current focus on NAFLD and gut microbiota is critical to further study and will help explore effective therapeutic strategy for aberrant glycolipid metabolism in liver.

Abstract Background ALI/ARDS is a severe lung injury leading to refractory respiratory failure, accounting for high morbidity and mortality. However, therapeutic approaches are rather limited. Targeting long non-coding RNA MALAT1 and microRNA miR-181a-5p might be potential option for ALI/ARDS intervention. Objective We aimed to investigate the role of MALAT and miR-181a-5p in the pathogenesis of ALI/ARDS, and test the therapeutic effects of targeting MALAT and miR-181a-5p for ALI/ARDS intervention in vitro. Methods MALAT1 and miR-181a-5p levels were measured in plasma from ALI/ARDS patients. In vitro human pulmonary microvascular endothelial cell (HPMEC) injury was induced by LPS treatment, and molecular targets of MALAT1 and miR-181a-5p were explored by molecular biology approaches, mainly focusing on cell apoptosis and vascular inflammation. Interaction between MALAT1 and miR-181a-5p was also detected. Finally, the effects of targeting MALAT1 and miR-181a-5p for ALI/ARDS intervention were validated in a rat ALI/ARDS model. Results MALAT1 upregulation and miR-181a-5p downregulation were observed in ALI/ARDS patients. Transfection of mimic miR-181a-5p into HPMECs revealed decreased Fas and apoptosis, along with reduced inflammatory factors. Fas was proved to be a direct target of miR-181a-5p. Similar effects were also present upon MALAT1 knockdown. As for the interaction between MALAT1 and miR-181a-5p, MALAT1 knockdown increased miR-181a-5p expression. Knocking down of MALAT1 and miR-181a-5p could both improve the outcome in ALI/ARDS rats. Conclusion MALAT1 antagonism or miR-181a-5p could both be potential therapeutic strategies for ALI/ARDS. Mechanistically, miR-181a-5p directly inhibits Fas and apoptosis, along with reduced inflammation. MALAT1 negatively regulates miR-181a-5p.

N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism in eukaryotic cells and is involved in numerous physiological and pathological processes. However, the specific role of m6A modification in sepsis-induced acute respiratory distress syndrome(ARDS) remains unknown. Here, we show that the levels of m6A RNA were significantly decreased in septic lungs and that METTL3 was the main regulator involved in the absence of m6A RNA modification. Pulmonary endothelial barrier damage is a critical process in the pathogenesis of acute lung injury during sepsis. METTL3 regulated endothelial barrier dysfunction and inflammatory responses in sepsis-induced ARDS in vivo and in vitro. Furthermore, we identified tripartite motif-containing (Trim)59 as a key m6A effector and Trim59 deficiency exacerbated lung injury. Mechanistically, METTL3 inhibited endothelial injury in sepsis-induced ARDS through Trim59-associated NF-κB inactivation. Our findings revealed novel insights into epitranscriptional mechanisms in sepsis-induced ARDS via m6A modifications, which has important application value in the diagnosis, prognosis, and molecular-targeted therapy of sepsis-associated lung injury.

PurposeHerpes zoster infection, with its considerable burden to individuals and society, remains a challenge around the world. However, to the knowledge of the authors, little bibliometric quantitative or qualitative analysis has been carried out to evaluate herpes zoster research. This study aimed to use a bibliometric analysis to evaluate current publication trends and hotspots on herpes zoster research worldwide, in order to advance research in this field.MethodsRelevant publications from January 2012 to December 2021 were collected from the Web of Science Core Collection database. Citespace (V5.8.R3) was used to analyze the research points, including publication countries, institutions and authors, cited author, cited reference and their clustering, and keyword co-occurrence, and burst keyword to acquire research trends and hotspots.ResultsA total of 9,259 publications were obtained, with a steady increase in the number of annual publications during the decade. Articles were the main type of publication. The United States is the leading country in this research, and the University of Colorado has the highest influence in this field. Oxman is the most representative author, with a main research interest in herpes zoster vaccines. The top five cited authors' publications focused on herpes zoster vaccines, molecular mechanisms, and postherpetic neuralgia. A co-citation map resulted 19 main clusters, and revealed that vaccines, postherpetic neuralgia, treatments, varicella zoster virus and its mechanisms, and epidemiology of herpes zoster were the current research focus after clustering co-cited publications. Human herpesviruses, antiviral prophylaxis, rheumatoid arthritis, recombinant zoster vaccine, varicella vaccination and postherpetic neuralgia were the top clusters after co-occurrence keywords analysis. Moreover, burst keywords detection showed that the subunit vaccine was the new hotspot in the field of herpes zoster.ConclusionThis bibliometric study defined the overall prospects in the field of herpes zoster and provided valuable instruction for the ongoing research. The keyword “subunit vaccine” indicated that a vaccine for herpes zoster prevention was the hotspot. Efforts to prevent varicella zoster virus infection will be essential to improve herpes zoster outcomes.

BackgroundNowadays, pediatric liver transplantation (PLT) has become an effective strategy for treating various acute or chronic end-stage liver diseases and inherited metabolic diseases. Many experts have already concluded the current challenges and future directions of PLT. However, no detailed analysis of the publication landscape has substantiated these proposed opinions.MethodsThis study presents a bibliometric review of the articles related to PLT between 1997 and 2020. A total of 3,084 publications were analyzed mainly by CiteSpace and VOSviewer.ResultsThe field of PLT has evolved gradually in the past two decades. Articles increased at an average rate of 97 articles every 4 years. University of Pittsburgh (PITT) is the most prolific institution. The three most productive regions are North America, Europe, and East Asia. Currently, interdisciplinary studies on PLT are scarce. The main goal of PLT has shifted from survival rates to long-term outcome. The quality of life, living donor liver transplantation (LDLT), immunological biomarkers, perioperative hemodynamic management, expanding the indications of PLT, etc. are parts of the emerging research fronts. In the past two decades, articles that contain potentials that may lead to transformative discoveries are scarce, and obvious deficits can be seen in the field of new therapies.ConclusionsLong-term outcome and good quality of life represent the principal direction of work concerning PLT. Deficits in new therapies align with the shortage of intellectual milestones, which indicate possible subsequent intellectual milestones may occur as innovations in therapies such as new immunosuppression therapies or liver cell transplantation.

Light touch can sometimes induce unpleasant itch sensation but the neural correlates of this conversion are not well studied. Here, the authors provide evidence that Tac2 expressing spinal interneurons are connected to gastrin-releasing peptide receptor (GRPR) neurons and form an integral part of the neural circuit underlying touch evoked itch.

Abstract Background Perioperative ischemia/reperfusion (I/R) injury during liver transplantation is strongly associated with early allograft dysfunction (EAD), graft loss, and mortality. Hepatic I/R injury also causes remote damage to other organs including the renal and pulmonary systems. Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist which is used as an adjuvant to general anesthesia, has been shown in preclinical studies to provide organ protection by ameliorating the effects of I/R injury in a range of tissues (including the liver). However, prospective clinical evidence of any potential benefits in improving outcomes in liver transplantation is lacking. This study aimed to verify the hypothesis that the application of dexmedetomidine during the perioperative period of liver transplantation can reduce the incidence of EAD and primary graft non-function (PNF). At the same time, the effects of dexmedetomidine application on perioperative renal function and lung function were studied. Methods This is a prospective, single-center, randomized, parallel-group study. Two hundred participants (18–65 years) scheduled to undergo liver transplantation under general anesthesia will be included in this study. For participants in the treatment group, a loading dose of DEX will be given after induction of anesthesia (1 μg/kg over 10 min) followed by a continuous infusion (0.5 μg/kg /h) until the end of surgery. For participants in the placebo group, an equal volume loading dose of 0.9% saline will be given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. All other supplements, e.g., opioids, sedatives, and muscle relaxant, will be identical in both arms and administered according to routine clinical practice. Discussion The present trial will examine whether DEX confers organoprotective effects in the liver, in terms of reducing the incidence of EAD and PNF in orthotopic liver transplantation recipients. Trial registration ClinicalTrials.gov NCT03770130. Registered on 10 December 2018. https://clinicaltrials.gov/ct2/show/NCT03770130

With the emergence of novel technologies and ground breaking concepts in BBB basic research in the past decades, the researchers’ attention on the critical role of blood brain barrier (BBB) integrity after stroke is surging. The main novelty of this review is that it not only highlights recent findings of the signaling pathways mediating ischemic BBB disruption, such as vascular permeability, lactate transportation failure, mitochondrial crisis and ion channel and water channel disability, endothelial actin polymerization, junctional proteins disassembly and endothelial transcytosis. Evolutional breakthroughs in identification of novel molecules that orchestrates the neuro-vascular unit restoration, immune cells of distinct phenotype that play dualistic roles in the evolution of ischemic brain injury are also included in this review. The aim of this review is to provide intriguing therapeutic targets to protect the BBB after cerebral ischemia.

BackgroundAging is one of the most important risk factors of postoperative cognitive dysfunction (POCD); however, the mechanisms are still not completely understood. In this study, we explore the roles of matrix metalloproteinase-9 (MMP-9) in aged mice with POCD.MethodsAppendectomy was performed in 18-month-old C57BL/6 and MMP-9–/– mice under anesthesia to establish the POCD model. Learning and memory were assessed using the Morris water maze (MWM) or Barnes maze. Protein expression of MMP-9 was measured by Western blotting or enzyme-linked immunosorbent assay (ELISA). To explore the role of neutrophils-derived MMP-9 in POCD, we treated mice with anti-Gr-1 monoclonal antibody to deplete peripheral neutrophils. And the percentage of neutrophils and other leukocytes were detected by flow cytometry. We further used sodium fluorescein (NaFlu) to evaluate the blood–brain barrier (BBB) permeability.ResultsThe spatial learning and memory ability was injured, and expression of MMP-9 increased in both plasma and the hippocampus after anesthesia/surgery. However, cognitive dysfunction was alleviated in both MMP-9–/– and peripheral neutrophils-depleted mice. The permeability of BBB was increased after anesthesia/surgery while recused by anti-Gr-1 antibody administration.ConclusionThese findings suggest that peripheral neutrophils-derived MMP-9 could lead to POCD of aged mice through increasing the BBB permeability.

BackgroundBibliometric analysis is used to gain a systematic understanding of developments in the correlation between neurotransmitters and tumor progression in research hotspots over the past 20 years.MethodsRelevant publications from the Web of Science Core Collection (WoSCC) were downloaded on August 1, 2021. Acquired data were then analyzed using the Online Analysis Platform of Literature Metrology (http://biblimetric.com) and the CiteSpace software to analyze and predict trends and hot spots in this field.ResultsA total of 1310 publications on neurotransmitters and tumor progression were identified, and 1285 qualified records were included in the final analysis. The country leading the research was the United States of America. The University of Buenos Aires featured the highest number of publications among all institutions. Co-citation cluster labels revealed the characteristics of 10 main clusters: beta-adrenergic receptors (β-AR), glutamate, neurotransmitters, serotonin, drd2, histamine, glycine, interleukin-2, neurokinin receptor-1, and nicotinic acetylcholine receptors (AchRs). Keywords and references burst detection indicated that apart from β-AR, dopamine receptor and cancer types like gastric cancer and glioblastoma are the newly emerging research hotspots.ConclusionsThis study analyzed 1285 publications and 39677 references covering the topic of neurotransmitters and tumor progression and showed that while β-AR has always been a hot topic in this field, dopamine receptor is an emerging target for this research field, and gastric cancer and glioblastoma are the top two tumors that have garnered increasing attention and have become the focal point of recent studies.

Abstract Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α2‐AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 μg kg−1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF‐7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF‐7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF‐7 cells. Clinical trial registration: NCT03108937.

Background: Although major joint replacement surgery has a high overall success rate, postoperative cognitive dysfunction (POCD) is a common complication after anesthesia and surgery, increasing morbidity and mortality. Identifying POCD risk factors would be helpful to prevent and decrease the occurrence of POCD. We hypothesized that preoperative chronic pain increases the risk of POCD.Methods: A single-center, observational, prospective cohort study was conducted from January 2018 to March 2020. All consecutive elderly patients (>65 years) who underwent elective total hip arthroplasty or hemiarthroplasty with general anesthesia by the same surgeon were enrolled. The patients underwent neuropsychological testing preoperatively and at 7 days and 2 months after surgery. To determine POCD, a nonsurgical control group was recruited from the general community.Results: Of the 141 patients who finished the neuropsychological testing 7 days after surgery, 61 (43.2%) had preoperative chronic pain. Of the 61 patients, 17 (27.9%) developed POCD; of the 79 patients with no chronic pain, 10 (12.7%) had developed POCD by 7 days after surgery. Multivariate logistic regression analysis identified preoperative chronic pain as a risk factor of POCD assessed 7 days after surgery (odds ratio 6.527; P = 0.009). There was no significant difference in the POCD incidence 2 months after surgery between patients with and without preoperative chronic pain.Conclusion: Preoperative chronic pain was a risk factor of developing POCD within 7 days after surgery in elderly patients following hip joint replacement surgery.Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03393676].

In recent years, the information crosstalk between the central nervous system and the periphery has been a hot topic, such as the brain–gut axis, brain–lung axis, etc. Among them, some studies have shown that brainstem nuclei activity can significantly affect the progression of peripheral tumor; however, regarding lung cancer, our understanding of the basic characteristics of the lung-innervating brain nuclei responsive to lung cancer progression remains deficient. Therefore, we used the pseudorabies virus for retrograde labeling of nerves to study the neural circuits between the lung and brain. We then established a mouse orthotopic lung cancer model and used the expression of the c-Fos gene in brain regions to characterize activated brain circuits and compared these results with those of the control group. We focused on c-Fos activity in nuclei associated with retrograde tracing regions of the brainstem. We found over 16 nuclei in the whole brain with direct or indirect lung innervation through neural retrograde labeling with the pseudorabies virus. We further revealed that the neuronal activity of the rostral ventrolateral reticular nucleus (RVL), caudal nucleus of Raphe (raphe obscurus nucleus, ROb), Raphe pallidus nucleus (RPa), and ventral gigantocellular reticular nucleus (GiV) in the rostral ventromedial and lateral medulla were significantly changed in an orthotopic lung cancer mouse model by the immunostaining of c-Fos early responsive protein. Thus, the distinctive rostroventral medulla area, functionally closely related to the vagus nerve, likely plays a role in central neural interaction with peripheral lung tumors and deserves future investigation.

BackgroundBibliometric analysis is used to gain a systematic understanding of developments in the field of the influence of anesthesia on tumor prognosis and changes in research hot spots over the past 20 years.MethodsRelevant publications from the Web of Science Core Collection (WoSCC) were downloaded on May 5, 2021. Acquired data were then analyzed using the Online Analysis Platform of Literature Metrology (http://biblimetric.com) and the CiteSpace software was used to analyze and predict trends and hot spots in this field.Results1,521 publications on the influence of anesthesia on tumor prognosis were identified and 1494 qualifying records were included in the final analysis. The leading country in this field was the United States of America (USA). The University of Texas MD Anderson Cancer Center (Houston, TX, USA) and Pennsylvania State University (State College, PA, USA) featured the highest number of publications among all institutions. Co-citation cluster labels revealed characteristics of ten main clusters: total intravenous anesthesia, opioid growth factor receptor, gastric cancer cell, opioid receptor, murine model, natural killer cell activity, health-related quality, glioma cell, opioid switching and mu-type opioid receptor. Keyword burst detection indicated that randomized controlled trials (RCTs), volatile anesthetics, and ropivacaine were the newly emerging research hot spots.ConclusionsThis study compiled 1494 publications covering anesthesia and tumor prognosis research and showed that the direction of these studies is likely in transition from opioids and their receptors to other anesthetics, and from retrospective studies to prospective randomized controlled trials. It provides guidance for further research and clinical applications on choosing anesthetic methods and drugs.

Background: Rapid reversal of neuromuscular block after surgery and anesthesia is often necessary. Here, we reported the primary efficacy and safety data from a phase IIa study on adamgammadex sodium, a newly developed modified γ-cyclodextrin derivative.Methods: This was a phase IIa, single-center, randomized, open-label, and dose-finding study that enrolled 35 patients under general anesthesia who received the neuromuscular blocking agent rocuronium for induction and maintenance of neuromuscular blockade. The subjects were randomized to one of the five adamgammadex dose groups (2, 4, 6, 8, and 10 mg kg−1) and to the 4 mg kg−1 sugammadex group. Pharmacological efficacy was the recovery time from the start of adamgammadex or sugammadex administration to train-of-four (TOF) ratio ≥0.9, 0.8, and 0.7 among the different dose groups. Adverse events were recorded throughout the study.Results: The efficacy in reversing deep neuromuscular block was the same between 4 mg kg−1 sugammadex and adamgammadex. However, in the lowest dose groups of 2 and 4 mg kg−1 adamgammadex, adequate reversal could not be achieved in all subjects. The recovery time of TOF ratio to 0.9, 0.8, and 0.7 was shorter in the adamgammadex 10 mg kg−1 group than in the sugammadex 4 mg kg−1 group. The average values of the TOF ratio after 3 min of administration of adamgammadex 8 and 10 mg kg−1 and sugammadex 4 mg kg−1 were >90%. There were no serious adverse events after the use of adamgammadex, and no subjects had to be withdrawn from the trial.Conclusions: Adamgammadex enabled quick, predictable, and tolerable reversion of rocuronium-induced deep neuromuscular block in a dose-dependent manner. Adamgammadex doses of 6–10 mg kg−1 might be the recommended dose range for further exploration of efficacy. Clinical Trial Registration: This study was registered at chictr.org.cn, identifier: ChiCTR2000038391.

Abstract Background With the increasing amount of geriatric surgery, it has become a great challenge for anesthesiologists to reduce the incidence of postoperative pulmonary complications (PPCs). The two most popular airway management methods, laryngeal mask airway (LMA) and endotracheal intubation (ETI), both have their unique advantages in specific clinical settings. For the purpose of helping clinicians make better decisions on airway management during geriatric surgery, we designed this multi-center clinical trial to compare the influence of LMA and ETI on PPCs. Methods/design In this multi-center, randomized, parallel clinical trial, a total of 6000 elderly patients, aged ≥ 70 years, with an American Society of Anesthesiologists classification level of 1–2 and a body mass index ≤ 35 kg/m2, undergoing elective surgery will be enrolled and randomized into the LMA or the ETI group. Both groups will receive usual perioperative care except for the adoption of LMA/ETI. Primary outcomes are the occurrence of PPCs and patients’ perioperative mortality rates. Ease of intubation, anesthetics consumption, treatment for PPCs, duration of surgery, anesthesia recovery time and performance, time of PPC onset, postanesthesia care unit stay, intensive care unit admission and stay, in-hospital days, re-admission rates, hospitalization cost, and patients’ satisfactory scores will be secondary outcomes. Follow-up will be conducted through phone-call visits until 12 weeks after discharge. Discussion This trial will assess the possible benefits or disadvantages of perioperative LMA use in elderly patients compared with ETI regarding the occurrence of PPCs and clinical prognosis. We expect that this trial will also add to the current understanding of PPCs in geriatric populations and contribute to the international recommendations of geriatric surgery management. Trial registration ClinicalTrials.gov, NCT02240901 . Registered on 16 September 2014.

BackgroundCholestasis patients often suffer from pain desensitization, resulting in serious complications in perioperative period. This study was aim to investigate the mechanism of bilirubin in cholestasis mediating pain desensitization through 5-hydroxytryptamine 3A (5-HT3A) receptor activation in spinal dorsal horn (SDH).MethodsA cholestasis model was established by bile duct ligation (BDL) in rats. Pain thresholds of rats were measured after BDL or intrathecally injecting bilirubin in the presence or absence of agonist (mCPBG) and antagonists (ondansetron, bicuculline, or CGP55845). Expression of 5-HT3 receptors, and the affinity and binding mode of bilirubin to 5-HT3A receptor were determined. Effects of bilirubin on γ-aminobutyric acid (GABA) pathway and the interactions with 5-HT3A receptor were tested.ResultsBilirubin was elevated significantly in both serum and CSF in BDL rats, accompanied with the up-regulation of pain thresholds. Both of 5-HT3A receptor and GABAA receptor antagonists could reverse the increased pain threshold in BDL rats. Further, 5-HT3A and GABAA receptor expressions were increased in BDL rats or intervention with bilirubin. Molecular docking suggested that bilirubin entered the hydrophobic pocket pre-formed in 5-HT3A receptor with potential hydrogen bonding. Bilirubin also increased GABA concentrations in CSF and GABAergic spontaneous inhibitory postsynaptic current in spinal cord, and directly induced inward currents in HEK293 cells which were overexpressed 5-HT3A receptor by lentivirus.ConclusionIn conclusion, bilirubin induced pain desensitization in cholestasis by activating 5-HT3A receptor in spinal cord. The activation of 5-HT3A receptor might regulate pain threshold by acting on the GABA pathway.

Background: Transnasal humidified rapid insufflation ventilatory exchange (THRIVE) was used to extend the safe apnea time. However, THRIVE is only effective in patients with airway opening. Nasopharyngeal airway (NPA) is a simple device that can help to keep airway opening. This study aimed to investigate the noninferiority of NPA to jaw thrust for airway opening during anesthesia-induced apnea.Methods: This was a prospective randomized single-blinded noninferiority clinical trial on the use of THRIVE in patients with anesthesia-induced apnea. The participants were randomly allocated to receive NPA or jaw thrust. The primary outcomes were PaO2 and PaCO2 at 20 min after apnea, with noninferiority margin criteria of −6.67 and 0.67 kPa, respectively.Results: A total of 123 patients completed the trial: 61 in the NPA group and 62 in the jaw thrust group. PaO2 at 20 min after apnea was 42.9 ± 14.0 kPa in the NPA group and 42.7 ± 13.6 kPa in the jaw thrust group. The difference between these two means was 0.25 kPa (95% CI, −3.87 to 4.37 kPa). Since the lower boundary of the 95% CI was > −6.67 kPa, noninferiority was established because higher PO2 is better. PaCO2 at 20 min after apnea was 10.74 ± 1.09 kPa in the NPA group and 10.54 ± 1.18 kPa in the jaw thrust group. The difference between the two means was 0.19 kPa (95% CI, −0.14 to 0.53 kPa). Since the upper boundary of the 95% CI was

Acute ischemic stroke (AIS) is common in patients with cancer, and mounting clinical evidence suggests that it may shorten the survival of cancer patients. But how stroke affects the progression of cancer remains unclear. We inoculated B16 tumor cells (2 × 105) subcutaneously before distal middle cerebral artery occlusion (dMCAO) or sham surgery in C57BL/6 mice and found that compared to sham operated mice, dMCAO mice developed significantly increased tumor volume and were accompanied by lower survival rate. To explore the underlying mechanism, we performed RNA-sequencing analysis of the tumor tissue from mice with or without stroke and found prominent upregulation of lipocalin 2 (LCN2) in the tumor from stroke mice compared to those from sham mice. Using quantitative reverse transcription-PCR, we confirmed increased mRNA expression of LCN2 as well as anti-inflammatory cytokines-Arg1, IL-10, and decreased mRNA level of pro-inflammatory cytokines-IL-6, IL-23 in the tumor of cancer-bearing stroke mice. Both immunofluorescence staining and flow cytometry analysis revealed that increased expression of LCN2 was mainly derived from the polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) in the tumor. We also found that stroke reduced the PMN-MDSCs in the peripheral blood, but increased PMN-MDSCs in the tumor of the cancer-bearing mice after stroke. In conclusion, cerebral ischemic stroke may exacerbate cancer progression by increasing LCN2 expression in PMN-MDSCs, which turns out to be a promising therapeutic target to suppress cancer progression after ischemic stroke.