BACKGROUND:Cardiac arrest (CA) is a widespread public health problem with high mortality, severe neurological sequelae, and limited pharmacological therapies. We investigated the neuroprotective effect of a novel drug, FPS-ZM1 (FPS), on CA and explored its potential mechanism. METHODS:A potassium chloride-induced CA was induced for 9.5 min in mice, with i.p. injections of FPS or vehicle administered 24 and 1 h before induction. Postoperative assessments included survival rate, body weight change, neurological scores, and neuronal pathological damage. The expression levels of the high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) axis, pyroptosis-related molecules, oxidative stress markers, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis were evaluated. RESULTS:Post-CA brain injury (PCABI) activated the HMGB1/RAGE axis, triggering intensified oxidative stress and aggravated pyroptosis. In contrast, pretreatment with FPS attenuated CA-induced injuries. FPS pretreatment was found to suppress the activation of the HMGB1/RAGE axis, alleviate pyroptosis and the release of associated inflammatory mediators, and enhance the Nrf2/HO-1 antioxidant axis after PCABI. CONCLUSION:FPS pretreatment mitigated PCABI by concurrently modulating the HMGB1/RAGE inflammatory axis and the Nrf2/HO-1 antioxidant pathway, suggesting that RAGE antagonism represents a promising therapeutic strategy for PCABI.

Background Neuroinflammation plays a pivotal role in the pathogenesis of brain injury following cardiac arrest(CA), primarily mediated by microglial activation. The stimulator of interferon genes (STING) has been demonstrated to play a pivotal role in regulating anti-tumor immunity and inflammatory diseases. However, the functional impact and underlying mechanisms of STING in regulating microglial polarization following brain injury after cardiac arrest remain poorly understood. Methods In this study, we employed an in vivo model of hyperkalemic cardiac arrest and an in vitro BV2 microglial oxygen-glucose deprivation/reperfusion (OGD/R) model to simulate brain injury following cardiac arrest (CA). STING was specifically inhibited using H151 or gene silencing. A range of techniques, including neurological function scoring, RNA sequencing, western blotting, immunofluorescence, FJB and TUNEL staining, HE and Nissl staining, ELISA, and flow cytometry, were applied in both in vivo and in vitro settings to evaluate the outcomes. Results We observed that STING expression in microglia was significantly upregulated following CA or OGD/R. Pharmacological inhibition of STING with H151 improves survival rate and neurological function in mice following CA and attenuates neuronal degeneration and apoptosis. Furthermore, H151 induces a phenotypic shift in microglia from the pro-inflammatory M1 state to the anti-inflammatory M2 state. These results are also associated with reduced production of pro-inflammatory cytokines, including IL-6 and TNF-α, as well as increased levels of anti-inflammatory cytokines such as IL-10 and TGF-β. Mechanistically, both in vivo and in vitro experiments demonstrate that STING activation promotes microglial polarization toward the pro-inflammatory M1 phenotype while suppressing the anti-inflammatory M2 phenotype through downstream signaling pathways involving interferon regulatory factor 3 and nuclear factor κB (NF-κB). Conversely, inhibition of STING—achieved either pharmacologically using the inhibitor H151 or genetically via gene silencing—results in the opposite effects. Conclusions Inhibition of the cGAS/STING/NF-κB signaling pathway shifts microglial polarization toward the M2 phenotype, thereby attenuating neuroinflammation, as well as neuronal degeneration and apoptosis. These findings suggest that STING is a promising therapeutic target for reducing neuroinflammation and neuronal damage, ultimately contributing to the alleviation of brain injury after CA.

Aim:Post-cardiac arrest brain injury (PCABI) is the leading cause of death and disability after resuscitation. This study aimed to investigate the pathogenesis and novel biomarkers for monitoring the progression and early prognostication of PCABI. Methods:Mouse model of PCABI was induced by hyperkalemia-induced asystole and successful resuscitation. Young adult male C57BL/6 mice were randomized into sham-operation or asystole/resuscitation. The sham-operated mice were selected as control. Neurological examinations were performed at 24 h after resuscitation, and three groups were set: control (n = 4), severe PCABI (n = 3), and mild PCABI (n = 3). Cerebral cortexes were collected for data-independent acquisition-proteomic analyses. The pathogenesis and potential biomarkers were identified through the pairwise comparisons of three subgroups and subsequent bioinformatics analyses. Human serum proteomes profiles, extracted from a published work of the second analysis of TTM-trial, were used for joint analyses to identify the common and clinically relevant biomarkers at the same timepoint. Experimental and external validation were performed to verify the association between novel biomarkers and neural death in PCABI. Results:The proteomic analysis identified and quantified 7,745 proteins. The most prominent proteomic changes were related to response to external stimulus, stress response, regulation of biological and metabolic process, endomembrane system, and inflammatory response in the PCABI progression. 10 potential biomarkers were identified by the pairwise comparisons of three groups, and lipocalin-2 and angiotensinogen are common biomarkers with human studies at 24 h after resuscitation. Experimental validation verified that lipocalin-2 was closely associated with neurodegeneration in PCABI. Conclusions:Stress, inflammatory, and metabolic responses play important roles in the progression of PCABI. Lipocalin-2 is a novel biomarker for monitoring and early neuroprognostication at 24 h after resuscitation.

Excessive formation of neutrophil extracellular traps (NETs) significantly impedes diabetic wound healing. Although conditioned medium of mesenchymal stem cells (MSC-CM) has shown therapeutic potential due to its anti-inflammatory, antioxidant, and immunosuppressive properties, its regulatory effects on NETs remain poorly understood. Herein, this study systematically investigates the impact of MSC-CM, particularly conditioned medium of hypoxia-conditioned MSCs (HCM), on NET formation and diabetic wound repair. Transcriptomic analysis and public database mining revealed that circadian clock dysfunction drives aberrant NET formation. Notably, HCM exhibited superior efficacy over conditioned medium of normoxia-conditioned MSCs (NCM) in suppressing reactive oxygen species (ROS) production and NET formation while accelerating diabetic wound healing. Mechanistically, HCM-derived prostaglandin E2 (PGE2) upregulated brain and muscle ARNT-Like protein 1 (BMAL1), a core circadian regulator, through PGE2 receptor 2 (EP2)-EP4 signaling, thereby reducing ROS accumulation and subsequent NET formation. To achieve non-invasive, on-demand delivery of HCM bioactive components (especially PGE2), we developed a multifunctional hydrogel composed of phenylboronic acid-grafted quaternized soy protein isolate, sodium alginate and HCM (BQSA-HCM). This hydrogel system features glucose/ROS responsiveness, self-healing capability, injectability and excellent biocompatibility, enabling controlled PGE2 release. Importantly, HCM incorporation endows the hydrogel with immunomodulatory properties. In vivo experiments demonstrated that BQSA-HCM hydrogel significantly enhanced BMAL1 expression, suppressed NET formation, and promoted diabetic wound healing. This study clarifies the critical role of BMAL1 in regulating NET formation, validates the therapeutic potential of HCM in targeting NET-related diabetic wounds, and presents an innovative controlled-release hydrogel platform for advanced diabetic wound therapy.

Cardiac arrest (CA) is one of the most common illnesses worldwide. Post-CA brain injury (PCABI) is a major cause of death and poor recovery in CA patients and the current CA treatments are not very effective. The microbiome-gut-brain axis has been found to significantly affect brain ischemia injury. Furthermore, in ischemic stroke patients, short-chain fatty acids (SCFA), especially sodium butyrate (SB), have been observed to promote neuroprotective effects by modulating inflammatory response and microglial polarization in the cortex. However, the precise mechanism of SB on CA-induced injury remains elusive. Therefore, this research study established an oxygen–glucose deprivation and reoxygenation (OGD/R) model using BV-2 microglial and HT22 cells to simulate cerebral ischemia/reperfusion injury in vitro and a potassium chloride-induced CA mouse model to mimic CA in vivo. The data revealed that SB markedly improved neurological scores and reduced neuronal death and apoptosis. Moreover, it reduced M1 microglia and neuroinflammation in CA mice. In addition, SB increased intestinal integrity and alleviated systemic inflammation. The 16S rDNA sequencing analysis indicated that SB intervention mitigated CA-induced gut microbiota dysbiosis and SCFA depletion. It was also observed that CA mice’s brain and OGD/R-exposed BV2 cells had substantially increased levels of MyD88, phosphorylated NF-κB p65, and TLR4 proteins, which were reduced after SB treatment. In summary, this study revealed that SB can protect against cerebral ischemia–reperfusion injury by controlling microglia polarization and microbiome-gut-brain axis to inhibit brain inflammation via the TLR4/MyD88/NF-κB pathway.

BACKGROUND Cardiac arrest (CA) and successful cardiopulmonary resuscitation (CPR) cause post-CA brain injury (PCABI) and extracerebral multiple organ dysfunction (EMOD), leading to low survival and disability in resuscitated patients. The pathogenesis of PCABI is still poorly understood, and no therapeutic-related factors have been identified to improve survival and neurological outcomes to date. Bumetanide is a promising pharmaceutical intervention for some neurological disorders that have some common pathophysiology with PCABI, and it also exhibit systemic protective effects on vital organs under pathological conditions. This study aims to investigate the protective effects of bumetanide on PCABI and EMOD after CA/CPR, and uncover the pathogenesis and biomarkers of PCABI at protein level.METHODS We generated a hyperkalemia-induced asystole CA/CPR mouse model with bumetanide/vehicle treatment after resuscitation. Survival, neurological outcome, functional outcome, key pathophysiological process underlying PCABI, and injury level of EMOD were evaluated. Proteomics analysis of cerebral cortex was performed for investigating mechanisms of PCABI.RESULTS Bumetanide significantly improved outcomes after CA/CPR and reduced the main pathophysiological processes of PCABI, including seizures, neurodegeneration, neuroinflammation, decreased cerebral blood flow, blood-brain barrier disruption, and oxidative stress. CA/CPR-induced injury in heart, lung, liver, kidney, spleen, adrenal gland, spinal cord, pennis, and urinary bladder were also alleviated by bumetanide. Proteomic study and experimental verification identified LCN2/NGAL is a potential biomarker for early neuroprognostication and has association with PCABI severity.CONCLUSIONS Systemic administration of bumetanide improved outcomes and prevented multiple organ dysfunction after CA/CPR. LCN2/NGAL is a novel biomarker for early neuroprognostication at 24 hours after CA/CPR.Clinical Perspective 1. What Is New? 2. What Are the Clinical Implications? ### Competing Interest StatementThe authors have declared no competing interest.* BBB : blood-brain barrier BUM : bumetanide CA : cardiac arrest CBF : cerebral blood flow CNS : central nervous system COG : cluster ortholog groups CPR : cardiopulmonary resuscitation CVC : central venous catheterization DEPs : differentially expressed proteins DHE : dihydroethidium DIA : data-independent acquisition EMOD : extracerebral multiple organ dysfunction FJB : Fluoro-Jade B GFAP : glial fibrillary acidic protein GO : gene ontology HE : hematoxylin-eosin HIBI : hypoxic ischemic brain injury Iba1 : ionized calcium-binding adaptor molecule 1 LCN2 : lipocalin-2 LSCI : laser speckle contrast imaging MODS : multiple organ dysfunction syndrome NGAL : neutrophil gelatinase-associated lipocalin NKCC1 : sodium-potassium-chloride cotransporter 1 PAS : periodic acid-Schiff PCABI : post-cardiac arrest brain injury PCAMD : post-cardiac arrest myocardial dysfunction PCAS : post-cardiac arrest syndrome PPI : protein-protein interaction PPP : persistent precipitating pathology ROS : reactive oxygen species ROSC : return of spontaneous circulation SDF : sidestream dark field SEM : standard error of the mean SIRR : systemic ischemia/reperfusion response Veh : vehicle

Subarachnoid hemorrhage (SAH) is a stroke subtype with high mortality, and its severity is closely related to the short-term prognosis of SAH patients. S100 calcium-binding protein A9 (S100A9) has been shown to be associated with some neurological diseases. In this study, the concentration of S100A9 in clinical cerebrospinal fluid samples was detected by enzyme-linked immunosorbent assay (ELISA), and the relationship between S100A9 and the prognosis of patients was explored. In addition, WT mice and S100A9 knockout mice were used to establish an

Subarachnoid hemorrhage (SAH) is a stroke subtype with high mortality, and its severity is closely related to the short-term prognosis of SAH patients. S100 calcium-binding protein A9 (S100A9) has been shown to be associated with some neurological diseases. In this study, the concentration of S100A9 in clinical cerebrospinal fluid samples was detected by enzyme-linked immunosorbent assay (ELISA), and the relationship between S100A9 and the prognosis of patients was explored. In addition, WT mice and S100A9 knockout mice were used to establish an in vivo SAH model. Neurological scores, brain water content, and histopathological staining were performed after a specified time. A co-culture model of BV2 and HT22 cells was treated with heme chloride to establish an in vitro SAH model. Our study confirmed that the expression of S100A9 protein in the CSF of SAH patients is increased, and it is related to the short-term prognosis of SAH patients. S100A9 protein is highly expressed in microglia in the central nervous system. S100A9 gene knockout significantly improved neurological function scores and reduced neuronal apoptosis. S100A9 protein can activate TLR4 receptor, promote nuclear transcription of NF-κB, increase the activation of inflammatory body, and ultimately aggravate nerve injury.

Acute respiratory distress syndrome (ARDS), a fatal critical disease, is induced by various insults. ARDS represents a major global public health burden, and the management of ARDS continues to challenge healthcare systems globally, especially during the pandemic of the coronavirus disease 2019 (COVID-19). There remains no confirmed specific pharmacotherapy for ARDS, despite advances in understanding its pathophysiology. Debate continues about the potential role of glucocorticoids (GCs) as a promising ARDS clinical therapy. Questions regarding GC agent, dose, and duration in patients with ARDS need to be answered, because of substantial variations in GC administration regimens across studies. ARDS heterogeneity likely affects the therapeutic actions of exogenous GCs. This review includes progress in determining the GC mechanisms of action and clinical applications in ARDS, especially during the COVID-19 pandemic.

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD. Single nucleotide polymorphisms regulating PM20D1 expression are associated with changed risk of PD. Dopamine (DA) metabolism and DA metabolites have been reported to regulate α-Syn pathology. Here we report that PM20D1 catalyzes the conversion of DA to N-arachidonoyl dopamine (NADA), which interacts with α-Syn and inhibits its aggregation. Simultaneously, NADA competes with α-Syn fibrils to regulate TRPV4-mediated calcium influx and downstream phosphatases, thus alleviating α-Syn phosphorylation. The expression of PM20D1 decreases during aging. Overexpression of PM20D1 or the administration of NADA in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. These observations support the protective effect of the PM20D1-NADA pathway against the progression of α-Syn pathology in PD.

Cardiac arrest and successful resuscitation cause whole-body ischemia and reperfusion, leading to brain injury and extracerebral multiple organ dysfunction. Brain injury is the leading cause of death and long-term disability in resuscitated survivors, and was conceptualized and treated as an isolated injury, which has neglected the brain-visceral organ crosstalk. Extracerebral organ dysfunction is common and is significantly associated with mortality and poor neurological prognosis after resuscitation. However, detailed description of the characteristics of post-resuscitation multiple organ dysfunction is lacking, and the bidirectional interactions between brain and visceral organs need to be elucidated to explore new treatment for neuroprotection. This review aims to describe current concepts of post-cardiac arrest brain injury and specific characteristics of post-resuscitation dysfunction in cardiovascular, respiratory, renal, hepatic, adrenal, gastrointestinal, and neurohumoral systems. Additionally, we discuss the crosstalk between brain and extracerebral organs, especially focusing on how visceral organ dysfunction and other factors affect brain injury progression. We think that clarifying these interactions is of profound significance on how we treat patients for neural/systemic protection to improve outcome.

Background : Post-cardiac arrest brain injury (PCABI) is the leading cause of death in survivors of cardiac arrest (CA). Carbon monoxide-releasing molecule (CORM-3) is a water -soluble exogenous carbon monoxide that has been shown to have neuroprotection benefits in several neurological disease models. However, the effects of CORM-3 on PCABI is still unclear. Methods : A mice model combined asystole with hemorrhage was used. Mice were anesthetized and randomized into 4 groups (n = 12/group) and underwent either 9.5 min CA followed by cardiopulmonary resuscitation (CPR) or sham surgery. CORM-3 (30 mg/kg) or vehicle (normal saline) were administered at 1 h after return of spontaneous circulation or sham surgery. Survival, neurologic deficits, alterations in the permeability of the brainblood barrier and cerebral blood flow, changes of oxidative stress level, level of neuroinflammation and neuronal degeneration, and the activation of Nrf2/HO-1 signaling pathway were measured. Results : In CORM-3 treated mice that underwent CA/CPR, significantly improved survival (75.00% vs. 58.33%, P = 0.0146 (24 h) and 66.67% vs. 16.67%, P < 0.0001 (72 h)) and neurological function were observed at 24 h and 72 h after ROSC ( P < 0.05 for each). Additionally, increased cerebral blood flow, expression of tight junctions, and reduced reactive oxygen species generation at 24 h after ROSC were observed ( P < 0.05 for each). CORM-3 treated mice had less neuron death and alleviated neuroinflammation at 72 h after ROSC ( P < 0.05 for each). Notably, the Nrf2/HO-1 signaling pathway was significantly activated in mice subjected to CA/CPR with CORM-3 treatment. Conclusions : CORM-3 could improve survival and exert neuroprotection after CA/CPR in mice. CORM-3 may be a novel and promising pharmacological therapy for PCABI.

1 early brain injury after subarachnoid hemorrhage by 2 activating the TLR4/MYD88/NF-κB pathway 3 Guijun Wang, Kesheng Huang, Zhan Zhang , Yujia Guo, Qi Tian, Chengli 4 Liu , Zhijie Li, Zhui Yu*, Mingchang Li* 5 Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, 6 Hubei Province, China. 7 Department of Critical Care Medicine, Renmin Hospital of Wuhan University, 8 Wuhan 430060, Hubei Province, China. 9 Department of Rehabilitation Medicine, Renmin Hospital of Wuhan University, Wuhan 10 430060, Hubei Province, China. 11 These authors contribute equally to this study 12 * Corresponding authors: 13 Zhui Yu, Department of Critical Care Medicine, Renmin Hospital of Wuhan University, 14 Wuhan 430060, Hubei Province, China. Email: yuzhui@whu.edu.cn 15 Mingchang Li, Department of Neurosurgery, Renmin Hospital of Wuhan University, 16 Wuhan 430060, Hubei Province, China. Email: mingcli@whu.edu.cn 17 Address: 99 ziyang road, Wuhan, Hubei Province, 430060, China 18

Objective:To study the crosstalk between the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) - X-box binding protein 1 (XBP1) pathway in oxygen-glucose deprivation/reoxygenation (OGD/R)-injured mouse hippocampal neuronal cell line HT22.Methods:The OGD/R-injured HT22 cell model was used to observe the changes of the indicators of endoplasmic reticulum stress (ERS), cell viability, and apoptosis at different OGD/R time points (0, 3, 6, 12, and 24 hours). HT22 cells in the logarithmic growth phase were randomized into blank control group, control+ATF6 activator (AA147) group, control+IRE1 inhibitor (4μ8c) group, OGD/R model group, OGD/R+AA147 group and OGD/R+4μ8c group (10 μmol/L AA147 or 16 μmol/L 4μ8c was given during the whole process in the AA147 group and 4μ8c group). Western blotting was used to detect the expression of ERS-related proteins [glucose-regulated protein 78 (GRP78), phosphorylated-inositol-requiring enzyme 1 (p-IRE1), and phosphorylated-eukaryotic translation initiation factor-2α (p-eIF2α)], and apoptosis-related proteins (Bcl-2, Bax, caspase-3, and cleaved caspase-3). The mRNA of ERS-related genes, and ATF6 [homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (Herpud1), protein disulfide isomerase associated 4 (Pdia4) and Sel-1 suppressor of lin-12-like (Sel1L)] and spliced XBP1 [XBP1s, include DnaJ heat shock protein family member B9 (Erdj4), Sec24 related gene family, member D (Sec24d) and signal sequence receptor, gamma (Ssr3)] induced transcriptional response-related genes were measured by real-time quantitative polymerase chain reaction (RT-qPCR). A cell counting kit-8 (CCK-8) assay was used to detect the viability of HT22 cells. Immunofluorescence was utilized to test the expression of cleaved caspase-3.Results:Compared with the blank control group, the expression of ERS-related proteins p-IRE1 and p-eIF2α were significantly increased at 12 hours and 3 hours following OGD/R, respectively (p-IRE1/β-actin: 2.09±0.10 vs. 1.00±0.00, p-eIF2α/β-actin: 1.39±0.11 vs. 1.00±0.00, both P < 0.01). The mRNA expressions of ERS-related genes [ATF6, XBP1s, unspliced XBP1 (XBP1u), activating transcription factor 4 (ATF4), CCAAT/EBP homologous protein (CHOP)] were also upregulated in different OGD/R timepoint in HT22 cells, which indicated ERS was activated in OGD/R-stimulated HT22 cells. Compared with the OGD/R model group, the expression of protein p-IRE1 was not changed, but the mRNA of XBP1s and XBP1u were obviously downregulated in the OGD/R+AA147 group [XBP1s (2 -ΔΔCt): 0.76 (0.71, 0.92) vs. 1.13 (1.03, 1.29), XBP1u (2 -ΔΔCt): 0.29±0.05 vs. 0.52±0.04, both P < 0.01], whereas the expressions of XBP1s-induced transcriptional response downstream genes did not change significantly. Compared with the OGD/R model group, the protein of short-form ATF6 (sATF6) and GRP78 were not changed after administration of 4μ8c, neither was the mRNA expression of ATF6-induced transcriptional response-related genes. These results showed that the mRNA expression of XBP1s and XBP1u were inhibited by AA147-induced activation of ATF6, but no crosstalk was observed between the transcriptional response induced by ATF6 and XBP1s. Compared with the blank control group, the cell viability decreased significantly at OGD/R 3 hours [(44.64±5.12) % vs. (99.13±5.76) %, P < 0.01], the ratios of apoptosis-related proteins Bax/Bcl-2 and cleaved caspase-3/caspase-3 were significantly increased at OGD/R 3 hours and OGD 0 hour, respectively (Bax/Bcl-2: 6.15±1.65 vs. 1.00±0.00, cleaved caspase-3/caspase-3: 17.48±2.75 vs. 1.00±0.00, both P < 0.01), which indicated that apoptosis was activated in OGD/R-treated HT22 cells. Compared with the OGD/R model group, the cell viability decreased significantly [(36.52±17.78)% vs. (69.90±9.43)%, P < 0.01], and the ratios of Bax/Bcl-2 and cleaved caspase-3/caspase-3 were significantly upregulated in the OGD/R+AA147 group in HT22 cells (Bax/Bcl-2: 2.06±0.31 vs. 1.10±0.25, cleaved caspase-3/caspase-3: 3.35±0.59 vs. 0.55±0.09, both P < 0.01). Conclusion:Under our experimental conditions, no obvious crosstalk between the transcriptional response induced by ATF6 and XBP1s was observed, while ATF6 activation induced by AA147 suppressed mRNA expression of XBP1s and XBP1u and promoted cell death in OGD/R-treated HT22 cells.

BACKGROUND:Remimazolam is a novel ultra-short-acting sedative, but its safety and adverse events (AEs) in high-risk patients in the intensive care unit (ICU) setting remain unknown.METHODS:This was a single-center, retrospective study that compared remimazolam to propofol and midazolam in patients undergoing upper gastrointestinal endoscopy. The primary outcome was the incidence of treatment-related AEs. The secondary outcomes were the time to extubation, the length of ICU stay, and the average cost of sedative per case.RESULTS:Of the 88 patients analyzed, 47 were treated with remimazolam (mean dose, 7.90±4.84 mg), and 41 were treated with propofol (21.19±17.98 mg) or midazolam (3.08±2.17 mg). There was no statistically significant difference in the average duration of the endoscopic procedure (35.89±13.37 min vs. 44.51±21.68 min, P=0.133) or the time to extubation (15.00±9.75 h vs. 20.59±18.71 h, P=0.211) in the remimazolam group (group I) compared to the propofol or midazolam group (group II). ICU stays (5.40±2.93 d vs. 4.63±3.31 d, P=0.072) and treatment-related AEs (48.61% vs. 51.38%, P=0.056) were similar between groups. The average cost of sedative per case was significantly lower in the group I than in the group II (RMB 16.07±10.58 yuan vs. RMB 24.37±15.46 yuan, P=0.016).CONCLUSION:Remimazolam-based sedation was noninferior to the classic sedatives and had lower average cost per case, indicating that it may be used as a promising sedative for high-risk patients during endoscopic procedures in the ICU setting.

Background Subarachnoid hemorrhage (SAH) is a stroke subtype with an extremely high mortality rate, and its severity is closely related to the short-term prognosis of patients with SAH. The S100 calcium-binding protein A9 (S100A9) has been shown to be associated with some neurological diseases, and this study aimed to investigate the relationship between S100A9 and neuroinflammation, as well as its mechanism in SAH. Methods An enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration of S100A9 in clinical cerebrospinal fluid samples. Furthermore, an in vivo mouse SAH model was established using intravascular perforation; S100A9 knockout mice were used for the in vivo experiments. S100A9 recombinant protein was administered via lateral ventricular injection 1 h before SAH model induction. SAH grade, neurological function score, and brain water content were measured after a specific time. BV2 and HT22 cells and co-culture models were treated with heme chloride to establish an in vitro model of SAH. Paquinimod was used to explore the potential neuroprotective mechanisms of S100A9 inhibition. Western blotting and immunofluorescence staining were used to explore microglial activation, inflammatory responses, and its related protein pathways. Results The expression of S100A9 protein in the cerebrospinal fluid of patients with SAH increased and was related to the short-term prognosis of patients with SAH; S100A9 was highly expressed in the microglia. S100A9 knockout significantly improved neurological function scores, reduced brain edema, and reduced neuronal apoptosis. S100A9 inhibition with Paquinimod restrained neuronal apoptosis, while administration of recombinant S100A9 aggravated neuroinflammation, activated the TLR4 receptor, promoted NF-κB nuclear transcription, and ultimately aggravated nerve injury. Conclusion S100A9 protein expression increased after SAH, which induced neuroinflammation and promote neuronal apoptosis by activating the TLR4/MYD88/ NF-κB pathway, ultimately aggravating nerve injury after SAH. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by National Natural Science Foundation of China (Grant /Award Number: 81971870, 82172173 to Mingchang Li). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All animal experiments were approved by the Animal Experiment Center of Wuhan University.The clinical samples were approved by the Ethics Committee of Renmin Hospital of Wuhan University (WDRY2021-K070) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All raw data is provided as required. * SAH : subarachnoid hemorrhage ELISA : enzyme-linked immunosorbent assay TLR4 : toll-like receptor 4 EBI : early brain injury BBB : blood-brain barrier PAMP : pathogen-associated molecular pattern DAMP : damage-associated molecular pattern PRRs : Pattern recognition receptors HSP : heat-shock protein HMGB1 : high mobility group protein B1 RAGE : receptor for advanced glycation end products PBS : phosphate buffer solution MYD88 : myeloid differentiation factor 88 IL-1β : interleukin-1β TNF-α : tumor necrosis factor WT : wild-type Sham : sham-operated PFA : paraformaldehyde DAPI : 4-6-diamidino-2-phenylindole ECL : enhanced chemiluminescence CA : cornu smmonis CSF : cerebrospinal fluid

We explored the pathological changes and the activation of local complement system in COVID-19 pneumonia. Lung paraffin sections of COVID-19 infected patients were analyzed by HE (hematoxylin-eosin) staining. The deposition of complement C3, the deposition of C3b/iC3b/C3d and C5b-9, and the expression of complement regulatory proteins, CD59, CD46 and CD55 were detected by immunohistochemistry. In COVID-19 patients' lung tissues, fibrin exudation, mixed with erythrocyte, alveolar macrophage and shed pneumocyte are usually observed in the alveoli. The formation of an "alveolar emboli" structure may contribute to thrombosis and consolidation in lung tissue. In addition, we also found that compared to normal tissue, the lung tissues of COVID-19 patients displayed the hyper-activation of complement that is represented by extensive deposition of C3, C3b/iC3b/C3d and C5b-9, and the increased expression level of complement regulatory proteins CD55, and especially CD59 but not CD46. The thrombosis and consolidation in lung tissues may contribute to the pathogenesis of COVID-19. The increased expression of CD55 and CD59 may reflect a feedback of self-protection on the complement hyper-activation. Further, the increased C3 deposition and the strongly activated complement system in lung tissues may suggest the rationale of complement-targeted therapeutics in conquering COVID-19.

随着医学技术的飞速发展,由于医务人员过度关注疾病和器官,忽略患者的感受,医学的人文属性逐渐被弱化.人文素质教育的缺失、边缘化已成为医学教育的重大挑战.叙事医学在回归人本属性的同时,关注患者情感、心理及社会属性,近年来仍处于初步探索阶段.然而,如今焦虑、担忧、迷茫等偏见,似乎已成为重症医学的代名词,而真实的重症医学却充满人间温情、感动、重生及希望.叙事医学与重症医学的结合是医学发展的必然,不仅重新回归"人本"属性,而且也是医学人文情怀的外显.文章旨在探索叙事医学在重症医学领域的教学实践,以别样艺术形式再现ICU重症患者的涅槃重生.

OBJECTIVE:To investigate and compare the regulatory effects of umbilical cord mesenchymal stem cells (MSC) and their conditioned medium (MSC-CM) on gut microbiota of septic mice.METHODS:Twenty-eight six-to-eight-week-old female C57BL/6J mice were randomly divided into sham operation group (Sham group), sepsis model group (CLP group), sepsis+MSC treatment group (CLP+MSC group) and sepsis+MSC-CM treatment group (CLP+MSC-CM group), with seven mice in each group. The septic mouse model was established by cecal ligation and puncture (CLP). In Sham group, CLP were not performed, and other operations were the same as CLP group. Mice in the CLP+MSC group and CLP+MSC-CM group received 0.2 mL 1×106 MSC or 0.2 mL concentrated MSC-CM via intraperitoneal injection 6 hours after CLP, respectively. Sham group and CLP group were given 0.2 mL sterile phosphate buffer saline (PBS) via intraperitoneal injection. Histopathological changes were evaluated by hematoxylin-eosin (HE) staining and colon length. Levels of inflammatory factors in serum were detected by enzyme-linked immunosorbent assay (ELISA). Phenotype of peritoneal macrophages was analyzed by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing.RESULTS:Compared with Sham group, significant inflammatory injury in lung and colon was observed, and shorter colon was detected in CLP group (cm: 6.00±0.26 vs. 7.11±0.09), the level of inflammatory cytokine interleukin-1β (IL-1β) in serum was significantly increased (ng/L: 432.70±17.68 vs. 353.70±17.01), the proportion of F4/80+ peritoneal macrophages was increased [(68.25±3.41)% vs. (50.84±4.98)%], while the ratio of F4/80+CD206+ anti-inflammatory peritoneal macrophages was decreased [(45.25±6.75)% vs. (66.66±3.36)%]. The α diversity sobs index of gut microbiota was downregulated significantly (118.50±23.25 vs. 255.70±6.87), the structure of species composition was altered, and the relative abundance of functional gut microbiota related to transcription, secondary metabolites biosynthesis, transport and catabolism, carbohydrate transport and metabolism, and signal transduction were decreased significantly in CLP group (all P < 0.05). Compared with CLP group, upon MSC or MSC-CM treatment, the pathological injury in lung and colon was alleviated to varying extent, the length of colon was increased (cm: 6.53±0.27, 6.87±0.18 vs. 6.00±0.26), the level of IL-1β in serum was downregulated (ng/L: 382.10±16.93, 343.20±23.61 vs. 432.70±17.68), the ratio of F4/80+ peritoneal macrophages was decreased [(47.65±3.93)%, (48.68±2.51)% vs. (68.25±3.41)%], the ratio of F4/80+CD206+ anti-inflammatory peritoneal macrophages was increased [(52.73±5.02)%, (66.38±4.73)% vs. (45.25±6.75)%], and the α diversity sobs index of gut microbiota was increased (182.50±16.35, 214.00±31.18 vs. 118.50±23.25), and the effects of MSC-CM were more significant (all P < 0.05). At the same time, species composition of gut microbiota was rebuilt, and a tendency of increase in relative abundance of functional gut microbiota was observed upon MSC and MSC-CM treatment.CONCLUSIONS:Both MSC and MSC-CM could alleviate inflammatory injury in tissues, and showed regulatory effects on gut microbiota in septic mouse model, moreover, MSC-CM exhibited superior advantages over MSC.