Organellophagy regulates cell death:A potential therapeutic target for inflammatory diseases.

BACKGROUND: Dysregulated alterations in organelle structure and function have a significant connection with cell death, as well as the occurrence and development of inflammatory diseases. Maintaining cell viability and inhibiting the release of inflammatory cytokines are essential measures to treat inflammatory diseases. Recently, many studies have showed that autophagy selectively targets dysfunctional organelles, thereby sustaining the functional stability of organelles, alleviating the release of multiple cytokines, and maintaining organismal homeostasis. Organellophagy dysfunction is critically engaged in different kinds of cell death and inflammatory diseases. AIM OF REVIEW: We summarized the current knowledge of organellophagy (e.g., mitophagy, reticulophagy, golgiphagy, lysophagy, pexophagy, nucleophagy, and ribophagy) and the underlying mechanisms by which organellophagy regulates cell death. KEY SCIENTIFIC CONCEPTS OF REVIEW: We outlined the potential role of organellophagy in the modulation of cell fate during the inflammatory response to develop an intervention strategy for the organelle quality control in inflammatory diseases.

Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury.

Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Studies have indicated that immune dysfunction plays a central role in the pathogenesis of sepsis. Dendritic cells (DCs) play a crucial role in the emergence of immune dysfunction in sepsis. The major manifestations of DCs in the septic state are abnormal functions and depletion in numbers, which are linked to higher mortality and vulnerability to secondary infections in sepsis. Apoptosis is the most widely studied pathway of number reduction in DCs. In the past few years, there has been a surge in studies focusing on regulated cell death (RCD). This emerging field encompasses various forms of cell death, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death (ADCD). Regulation of DC's RCD can serve as a possible therapeutic focus for the treatment of sepsis. Throughout time, numerous tactics have been devised and effectively implemented to improve abnormal immune response during sepsis progression, including modifying the functions of DCs and inhibiting DC cell death. In this review, we provide an overview of the functional impairment and RCD of DCs in septic states. Also, we highlight recent advances in targeting DCs to regulate host immune response following septic challenge.

Unveiling the regulatory mechanism of poly-γ-glutamic acid on soil characteristics under drought stress through integrated metagenomics and metabolomics analysis.

It is of utmost importance to understand the characteristics and regulatory mechanisms of soil in order to optimize soil management and enhance crop yield. Poly-γ-glutamic acid (γ-PGA), a stress-resistant amino acid polymer, plays a crucial role in plant drought stress resistance. However, little is known about the effects of γ-PGA on soil characteristics during drought treatments. In this study, the effects of different forms of γ-PGA on soil texture and basic physical and chemical properties under short-term drought conditions were investigated. Furthermore, the impact of γ-PGA on the microbial community and metabolic function of maize was analyzed. Under drought conditions, the introduction of γ-PGA into the soil resulted in notable improvements in the mechanical composition ratio and infiltration capacity of the soil. Concurrently, this led to a reduction in soil bulk density and improved soil organic matter content and fertility. Additionally, metagenomic analysis revealed that under drought conditions, the incorporation of γ-PGA into the soil enhanced the soil microbiota structure. This shift led to the predominance of bacteria that are crucial for carbon, nitrogen, and phosphorus cycles in the soil. Metabolomics analysis revealed that under drought treatment, γ-PGA affected soil metabolic patterns, with a particular focus on alterations in amino acid and vitamin metabolism pathways. Correlation analysis between the soil metagenome and metabolites showed that microorganisms played a significant role in metabolite accumulation. These results demonstrated that γ-PGA could improve soil characteristics under drought conditions and play an important role in soil microorganisms and microbial metabolism, providing further insights into the changes in soil characteristics under drought conditions.

Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

The crosstalk between mitochondrial quality control and metal-dependent cell death.

Mitochondria are the centers of energy and material metabolism, and they also serve as the storage and dispatch hubs of metal ions. Damage to mitochondrial structure and function can cause abnormal levels and distribution of metal ions, leading to cell dysfunction and even death. For a long time, mitochondrial quality control pathways such as mitochondrial dynamics and mitophagy have been considered to inhibit metal-induced cell death. However, with the discovery of new metal-dependent cell death including ferroptosis and cuproptosis, increasing evidence shows that there is a complex relationship between mitochondrial quality control and metal-dependent cell death. This article reviews the latest research results and mechanisms of crosstalk between mitochondrial quality control and metal-dependent cell death in recent years, as well as their involvement in neurodegenerative diseases, tumors and other diseases, in order to provide new ideas for the research and treatment of related diseases.

Impact of the method of calculating 30-day readmission rate after hospitalization for heart failure. Data from the VancOuver CoastAL Acute Heart Failure (VOCAL-AHF) registry.

BACKGROUND: Thirty-day readmission rate after heart failure (HF) hospitalization is widely used to evaluate healthcare quality. Methodology may substantially influence estimated rates. We assessed the impact of different definitions on HF and all-cause readmission rates. METHODS: Readmission rates were examined in 1,835 patients discharged following HF hospitalization using 64 unique definitions derived from five methodological factors: (1) ICD-10 codes (broad vs narrow), (2) index admission selection (single admission only first-in-year vs. random sample; or multiple admissions in year with vs. without 30-day blanking period), (3) variable denominator (number alive at discharge vs. number alive at 30-days), (4) follow-up period start (discharge date vs day following discharge), and (5) annual reference-period (calendar vs fiscal). The impact of different factors was assessed using linear-regression. RESULTS: The calculated 30-day readmission rate for HF varied more than 2-fold depending solely on the methodological approach (6.5% to 15.0%). All-cause admission rates exhibited similar variation (18.8% to 29.9%). The highest rates included all consecutive index admissions (HF 11.1-15.0%, all-cause 24.0-29.9%), and lowest only one index admission per patient per year (HF 6.5-11.3%, all-cause 18.8-22.7%). When including multiple index admissions and compared to blanking the 30-days post-discharge, not blanking was associated with 2.3% higher readmission rates. Selecting a single admission per year with a first-in-year approach lowered readmission rates by 1.5%, while random-sampling admissions lowered estimates further by 5.2% (p<0.001). CONCLUSION: Calculated 30-day readmission rates varied more than 2-fold by altering methods. Transparent and consistent methods are needed to ensure reproducible and comparable reporting.

Ferritinophagy: A novel insight into the double-edged sword in ferritinophagy-ferroptosis axis and human diseases.

Nuclear receptor coactive 4 (NCOA4), which functions as a selective cargo receptor, is a critical regulator of the particularly autophagic degradation of ferritin, a process known as ferritinophagy. Mechanistically, NCOA4-mediated ferritinophagy performs an increasingly vital role in the maintenance of intracellular iron homeostasis by promoting ferritin transport and iron release as needed. Ferritinophagy is not only involved in iron-dependent responses but also in the pathogenesis and progression of various human diseases, including metabolism-related, neurodegenerative, cardiovascular and infectious diseases. Therefore, ferritinophagy is of great importance in maintaining cell viability and function and represents a potential therapeutic target. Recent studies indicated that ferritinophagy regulates the signalling pathway associated with ferroptosis, a newly discovered type of cell death characterised by iron-dependent lipid peroxidation. Although accumulating evidence clearly demonstrates the importance of the interplay between dysfunction in iron metabolism and ferroptosis, a deeper understanding of the double-edged sword effect of ferritinophagy in ferroptosis has remained elusive. Details of the mechanisms underlying the ferritinophagy-ferroptosis axis in regulating relevant human diseases remain to be elucidated. In this review, we discuss the latest research findings regarding the mechanisms that regulate the biological function of NCOA4-mediated ferritinophagy and its contribution to the pathophysiology of ferroptosis. The important role of the ferritinophagy-ferroptosis axis in human diseases will be discussed in detail, highlighting the great potential of targeting ferritinophagy in the treatment of diseases.

Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

SUPPLEMENTATION WITH NICOTINAMIDE RIBOSIDE ATTENUATES T CELL EXHAUSTION AND IMPROVES SURVIVAL IN SEPSIS.

ABSTRACT: T cell exhaustion is the main cause of sepsis-induced immunosuppression and is associated with the poor prognosis. Nicotinamide adenine dinucleotide (NAD + ) is well known for its anti-aging effect, but its role in sepsis-induced T cell exhaustion remains to be elucidated. In the present study, using a classic septic animal model, we found that the levels of NAD + and its downstream molecule, which is sirtuins 1 (SIRT1), in T cells in sepsis were decreased. Supplementation with nicotinamide ribose (NR), the precursor of NAD + , right after cecal ligation and puncture significantly increased the levels of NAD + and SIRT1. Supplementation with NR alleviated the depletion of mononuclear cells and T lymphocytes in spleen in sepsis and increased the levels of CD3 + CD4 + and CD3 + CD8 + T cells. Interestingly, both Th1 and Th2 cells were expanded after NR treatment, but the balance of Th1/Th2 was partly restored. Nicotinamide ribose also inhibited the regulatory T cells expansion and programmed cell death 1 expression in CD4 + T cells in sepsis. In addition, the bacteria load, organ damage (lung, heart, liver, and kidney), and the mortality of septic mice were reduced after NR supplementation. In summary, these results demonstrate the beneficial effect of NR on sepsis and T cell exhaustion, which is associated with NAD + /SIRT1 pathway.

Retinal Vascular Image Segmentation Using Improved UNet Based on Residual Module.

In recent years, deep learning technology for clinical diagnosis has progressed considerably, and the value of medical imaging continues to increase. In the past, clinicians evaluated medical images according to their individual expertise. In contrast, the application of artificial intelligence technology for automatic analysis and diagnostic assistance to support clinicians in evaluating medical information more efficiently has become an important trend. In this study, we propose a machine learning architecture designed to segment images of retinal blood vessels based on an improved U-Net neural network model. The proposed model incorporates a residual module to extract features more effectively, and includes a full-scale skip connection to combine low level details with high-level features at different scales. The results of an experimental evaluation show that the model was able to segment images of retinal vessels accurately. The proposed method also outperformed several existing models on the benchmark datasets DRIVE and ROSE, including U-Net, ResUNet, U-Net3+, ResUNet++, and CaraNet.

Single-cell transcriptome profiling of sepsis identifies HLA-DRlowS100Ahigh monocytes with immunosuppressive function.

BACKGROUND: Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. METHODS: We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9-/- mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. RESULTS: ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DRlowS100Ahigh monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. CONCLUSIONS: This study identifies HLA-DRlowS100Ahigh monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.

Mutation-Driven S100A8 Overexpression Confers Aberrant Phenotypes in Type 1 CALR-Mutated MPN.

Numerous pathogenic CALR exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; CALRDEL) and type 2 (5bp insertion; CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by various CALR mutants, it is unclear why different CALR mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in CALRDEL but not in CALRINS MPN-model cells. The expression of S100a8 could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting S100a8 promoter region in CALRDEL cells as compared to CALRINS cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in CALRDEL cells. Clinical validation showed significantly enhanced S100A8 expression in CALRDEL-mutated MPN patients compared to CALRINS-mutated cases, and thrombocytosis was less prominent in those with S100A8 upregulation. This study provides indispensable insights into how different CALR mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.

The impact of sarcopenia on overall survival in patients with pan-RAS wild-type colorectal liver metastasis receiving hepatectomy.

Sarcopenia has been associated with conventional chemotherapy-related toxicity, postoperative complications and poor overall survival in patients with genotype-unselected metastatic colorectal cancer (mCRC). This study aimed to evaluate the prognostic implications of sarcopenia and its change after perioperative cetuximab plus doublet chemotherapy and hepatectomy in patients with RAS wild-type colorectal liver metastasis (CRLM). Patients with CRLM from 2007 to 2018 in Chang Gung Research Database were retrospectively analyzed. Baseline characteristics as well as skeletal muscle index (SMI) at baseline and dynamic changes after interventions were collected. A multivariate Cox proportional hazard model was used to evaluate the effect of each parameter on overall survival (OS), and the Kaplan-Meier method was used to establish survival curves. A two-sided p value < 0.05 was considered statistically significance. Of 214 RAS wild-type mCRC patients who received both cetuximab and doublet chemotherapy, 77 who received upfront or subsequent hepatectomy were included in this study. The median follow-up time was 2.3 years. The rate of sarcopenia was higher in the patients who received neoadjuvant cetuximab-containing regimens than in those who received upfront hepatectomy (95% versus 63%, p = 0.001). Increased SMI after perioperative systemic therapy remained independently associated with better OS in multivariate analysis [hazard ratio (HR) = 0.27/10% increase, p = 0.013). The patients with sarcopenia had a trend of worse OS than those without sarcopenia (median OS: 4.5 versus 3.6 years, log-rank p = 0.282). Improvement in sarcopenia ([SMI after intervention - initial SMI]/initial SMI × 100%) is an important prognostic factor for OS. Future research is warranted to investigate direct interventions for sarcopenia and the impact on OS.

Nuclear fragile X mental retardation-interacting protein 1-mediated ribophagy protects T lymphocytes against apoptosis in sepsis.

Background: Ribophagy is a selective autophagic process that specifically degrades dysfunctional or superfluous ribosomes to maintain cellular homeostasis. Whether ribophagy can ameliorate the immunosuppression in sepsis similar to endoplasmic reticulum autophagy (ERphagy) and mitophagy remains unclear. This study was conducted to investigate the activity and regulation of ribophagy in sepsis and to further explore the potential mechanism underlying the involvement of ribophagy in T-lymphocyte apoptosis. Methods: The activity and regulation of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-mediated ribophagy in T lymphocytes during sepsis were first investigated by western blotting, laser confocal microscopy and transmission electron microscopy. Then, we constructed lentivirally transfected cells and gene-defective mouse models to observe the impact of NUFIP1 deletion on T-lymphocyte apoptosis and finally explored the signaling pathway associated with T-cell mediated immune response following septic challenge. Results: Both cecal ligation and perforation-induced sepsis and lipopolysaccharide stimulation significantly induced the occurrence of ribophagy, which peaked at 24 h. When NUFIP1 was knocked down, T-lymphocyte apoptosis was noticeably increased. Conversely, the overexpression of NUFIP1 exerted a significant protective impact on T-lymphocyte apoptosis. Consistently, the apoptosis and immunosuppression of T lymphocytes and 1-week mortality rate in NUFIP1 gene-deficient mice were significantly increased compared with those in wild-type mice. In addition, the protective effect of NUFIP1-mediated ribophagy on T lymphocytes was identified to be closely related to the endoplasmic reticulum stress apoptosis pathway, and PERK-ATF4-CHOP signaling was obviously involved in downregulating T-lymphocyte apoptosis in the setting of sepsis. Conclusions: NUFIP1-mediated ribophagy can be significantly activated to alleviate T lymphocyte apoptosis through the PERK-ATF4-CHOP pathway in the context of sepsis. Thus, targeting NUFIP1-mediated ribophagy might be of importance in reversing the immunosuppression associated with septic complications.

Variability in Nonvitamin K Oral Anticoagulant Dose Eligibility and Adjustment According to Renal Formulae and Clinical Outcomes in Patients With Atrial Fibrillation With and Without Chronic Kidney Disease: Insights From ORBIT-AF II.

Background Nonvitamin K oral anticoagulants require dose adjustment based on kidney function.The most common estimate of kidney function employed in clinical practice is estimated glomerular filtration rate (eGFR); however, product monographs recommend the use of the Cockcroft-Gault estimated creatinine clearance (eCrCl) for dose adjustment. Methods and Results The authors included patients enrolled in the ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation AF II) trial. Dosing was considered inappropriate when use of eGFR resulted in a lower (undertreatment) or higher (overtreatment) dose than that recommended by the eCrCl. The primary outcome of major adverse cardiovascular and neurological events was a composite of cardiovascular death, stroke or systemic embolism, new-onset heart failure, and myocardial infarction. Among 8727 in the overall cohort, agreement between eCrCl and eGFR was observed in 93.5% to 93.8% of patients. Among 2184 patients with chronic kidney disease (CKD), the agreement between eCrCl and eGFR was 79.9% to 80.7%. Dosing misclassification was more frequent in the CKD population (41.9% of rivaroxaban users, 5.7% of dabigatran users, and 4.6% apixaban users). At 1 year, undertreated patients in the CKD group had significantly greater major adverse cardiovascular and neurological events (adjusted hazard ratio, 2.93 [95% CI, 1.08-7.92]) compared with the group with appropriate nonvitamin K oral anticoagulants dosing (P=0.03). Conclusions The prevalence of misclassification of nonvitamin K oral anticoagulants dosing was high when using eGFR, particularly among patients with CKD. Among patients with CKD, potential undertreatment due to inappropriate and off-label renal formulae may result in worse clinical outcomes. These findings highlight the importance of using eCrCl, and not eGFR, for dose adjustment in all patients with AF receiving nonvitamin K oral anticoagulants.

Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression.

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Worldwide productivity and research trend of publications concerning glioma-associated macrophage/microglia: A bibliometric study.

Glioma-associated macrophage/microglia (GAM) represents a key player in shaping a unique glioma ecosystem to facilitate tumor progression and therapeutic resistance. Numerous studies have been published concerning GAM, but no relevant bibliometric study has been performed yet. Our bibliometric study aimed to comprehensively summarize and analyze the global scientific output, research hotspots, and trendy topics of publications on GAM over time. Data on publications on GAM were collected using the Web of Science (WoS). The search date was 16 January 2022, and the publications were collected from 2002 to 2021. Totally, 1,224 articles and reviews were incorporated and analyzed in the current study. It showed that the annual publications concerning GAM kept increasing over the past 20 years. The United States had the largest number of publications and total citations. Holland, Kettenmann, and Gutmann were the top three authors in terms of citation frequency. Neuro-oncology represented the most influential journal in GAM studies, with the highest H-index, total citations, and publication numbers. The paper published by Hambardzumyan in 2016 had the highest local citations. Additionally, the analysis of keywords implied that "prognosis," "tumor microenvironment," and "immunotherapy" might become research hotspots. Furthermore, trendy topics in GAM studies suggested that "immune infiltration," "immune microenvironment," "bioinformatics," "prognosis," and "immunotherapy" deserved additional attention. In conclusion, this bibliometric study comprehensively analyzed the publication trend of GAM studies for the past 20 years, in which the research hotspots and trendy topics were also uncovered. This information offered scholars critical references for conducting in-depth studies on GAM in the future.