Aggressive alternative splicing events discovered in cecum ligation and puncture induced lung injury.

AIMS: Acute lung injury (ALI) induced by sepsis and its complications have high morbidity and mortality rates globally. The objective of this study was to enhance our understanding of the underlying mechanism of ALI by identifying potential splicing events that are regulated in this condition. MATERIALS AND METHODS: The CLP mouse model was utilized for mRNA sequencing, and the expression and splicing data were analyzed. Verification of the changes in expression and splicing induced by CLP was conducted using qPCR and RT-PCR. RESULTS: Our results showed that splicing-related genes were regulated, suggesting that splicing regulation may be a key mechanism in ALI. We also found that more than 2900 genes displayed alternative splicing in the lungs of mice with sepsis. Using RT-PCR, we verified that TLR4 and other genes had differential splicing isoforms in the lungs of mice with sepsis. We confirmed the presence of TLR4-s in the lungs of mice with sepsis using RNA-fluorescence in situ hybridization. CONCLUSION: Our results suggest that sepsis-induced ALI can significantly alter splicing in the lungs of mice. The list of DASGs and splicing factors is valuable for further study in the search for new treatment approaches for sepsis-induced ALI.

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience.

BACKGROUND: Systemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines (interleukin-17 [IL-8], IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post-cardiac arrest period. METHODS: This was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated "survivors". The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays. RESULTS: Plasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC. CONCLUSION: These results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients. TRIAL REGISTRATION: Clinicaltrial.govNCT02297776, 2014-11-21.

MicroRNA Regulation of Endothelial Junction Proteins and Clinical Consequence.

Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional varieties, cellular junctions include tight junctions, adherens junctions, focal adhesion junctions, and tissue specific junctions such as PECAM-1 junctions in endothelial cells (EC), desmosomes in epithelial cells, and hemidesmosomes in EC. Cellular junction dysfunction and deterioration are indicative of clinical diseases. MicroRNAs (miRNA) are ~20 nucleotide, noncoding RNAs that play an important role in posttranscriptional regulation for almost all genes. Unsurprisingly, miRNAs regulate junction protein gene expression and control junction structure integrity. In contrast, abnormal miRNA regulation of junction protein gene expression results in abnormal junction structure, causing related diseases. The major components of tight junctions include zonula occluden-1 (ZO-1), claudin-1, claudin-5, and occludin. The miRNA regulation of ZO-1 has been intensively investigated. ZO-1 and other tight junction proteins such as claudin-5 and occludin were positively regulated by miR-126, miR-107, and miR21 in different models. In contrast, ZO-1, claudin-5, and occludin were negatively regulated by miR-181a, miR-98, and miR150. Abnormal tight junction miRNA regulation accompanies cerebral middle artery ischemia, brain trauma, glioma metastasis, and so forth. The major components of adherens junctions include VE-cadherin, ß-catenin, plakoglobin, P120, and vinculin. VE-cadherin and ß-catenin were regulated by miR-9, miR-99b, miR-181a, and so forth. These regulations directly affect VE-cadherin-ß-catenin complex stability and further affect embryo and tumor angiogenesis, vascular development, and so forth. miR-155 and miR-126 have been shown to regulate PECAM-1 and affect neutrophil rolling and EC junction integrity. In focal adhesion junctions, the major components are integrin ß4, paxillin, and focal adhesion kinase (FAK). Integrin ß4 has been regulated by miR-184, miR-205, and miR-9. Paxillin has been regulated by miR-137, miR-145, and miR-218 in different models. FAK has been regulated by miR-7, miR-138, and miR-135. Deregulation of miRNAs is caused by viral infections, tumorigenesis, and so forth. By regulation of posttranscription, miRNAs manipulate junction protein expression in all cellular processes and further determine cellular fate and development. Elucidation of these regulatory mechanisms will become a new alternative therapy for many diseases, such as cancers and inflammatory diseases.

Perceptions and experiences of Generation Z nursing students during their practicum in an intensive care unit: A qualitative study.

Background: Influenced by socio-cultural and world events, Chinese society has significant intergenerational differences. With rapid economic and cultural development, the unique characteristics of Generation Z nursing students in China may influence the clinical education environment. However, the research on Generation Z in China is still in its infancy. Objectives: This study aimed to explore the experiences and perceptions of Generation Z nursing students during their practicum in an intensive care unit (ICU) in the context of China's unique cultural and historical background. Methods: A phenomenological approach was used in this qualitative study. Semi-structured, face-to-face interviews were conducted with fifteen Generation Z nursing students doing practicum in the ICU in a third-level hospital in Shanghai, China. The data were analyzed using Colaizzi's seven-step method. Result: Three themes emerged: intelligent medical services empowering critical care, perception of multiple challenges, and affirmation of the teaching work in the ICU. Conclusions and implications: The clinical instructors should use a combination of online and offline pedagogy, give positive guidance through role modeling, and develop the self-learning skills of Generation Z nursing students. This might help Generation Z nursing students relieve the stress of practicum in the ICU, more quickly adapt to the clinical environment, and enter nursing positions. The result of this research provided valuable information to help clinical practicum programs in China effectively educate Generation Z nursing students. Good education ensures that health care is safe and effective, making it easier for patients to get better.

Post-traumatic growth experiences of emergency and critical care nurses after the COVID-19 pandemic: A qualitative meta-synthesis.

Objective: The previous coronavirus disease 2019(COVID-19) epidemic inflicted significant psychological trauma on emergency and critical care nurses due to various factors, potentially leading to job burnout. Despite the rise of positive psychology, little is known about the post-traumatic growth experience of these nurses after the pandemic. The aim of this study was to assess the experience of post-traumatic growth among emergency and critical care nurses, in order to provide managerial insights for developing effective strategies and facilitating the transformation of nurses' negative emotions into positive ones. Design: A qualitative review. Data sources: PubMed, EBSCO, Medline, Elsvier, Cochrane Library, CINAHL, Web of Science, Embase, and Ovid and Chinese databases include the following: Chinese National Knowledge Infrastructure (CNKI), Wanfang Database (CECDB), VIP Database and China Biomedical Database (CBM). Review methods: All articles about emergency and critical care nurses' post-traumatic growth after the COVID-19 pandemic were included after searching and screening 13 databases. The meta-synthesis method was used to integrate and evaluate the included literature in qualitative research. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) was used as a basis for reporting the review. The literature was selected and evaluated by two researchers, and then meta-integration was used for analysis. Results: From a total of 11 articles, 90 main results were presented, eight new categories were integrated, and three themes were formed: stress period, adjustment period and growth period. These three themes include eight sub-themes: negative emotion, psychological gap, self adjusting, social support, improvement of personal ability, increased sense of professional belonging, spiritual awakening and extended thinking, look ahead. Conclusion: Post-traumatic growth in emergency and critical care nurses is dynamic. Managers should monitor the psychological changes experienced by emergency and critical care nurses following traumatic events, offering targeted support at different stages, providing enhanced professional development opportunities, refining management strategies, guiding nurses in self-adjustment and active coping with trauma, and promoting their physical and mental well-being to ensure a positive mindset for effectively addressing future public health crises.

Causal Relationship between Mitochondrial-Associated Proteins and Sepsis in ICU Patients: A Mendelian Randomization Study.

BACKGROUND: The alarming mortality rate of sepsis in ICUs has garnered significant attention. The precise etiology remains elusive. Mitochondria, often referred to as the cellular powerhouses, have been postulated to have a dysfunctional role, correlating with the onset and progression of sepsis. However, the exact causal relationship remains to be defined. METHOD: Employing the Mendelian randomization approach, this study systematically analyzed data from the IEUOpenGWAS and UKbiobank databases concerning mitochondrial function-related proteins and their association with sepsis, aiming to delineate the causal relationship between the two. RESULTS: The findings underscored a statistically significant association of GrpE1 with sepsis, registering a P value of 0.005 and an OR of 0.499 (95% CI: 0.307-0.810). Likewise, HTRA2, ISCU, and CUP3 each manifested significant associations with sepsis, yielding OR values of 0.585, 0.637, and 0.634, respectively. These results suggest potential implications of the aforementioned proteins in the pathogenesis of sepsis. CONCLUSION: The present study furnishes novel evidence elucidating the roles of GrpE1, HTRA2, ISCU, and CUP3 in the pathophysiology of sepsis. Such insights pave the way for a deeper understanding of the pathological mechanisms underpinning sepsis and hint at promising therapeutic strategies for the future.

Post-traumatic growth among emergency nurses after COVID-19 in Shanghai, China: a qualitative study.

OBJECTIVES: This study aims to investigate the post-traumatic growth of emergency nurses (ENs) in Shanghai, China, in 2022 following the COVID-19 pandemic. DESIGN: A phenomenological qualitative research approach was employed, with 17 ENs being interviewed between July and August 2022. Data collection was conducted through semistructured, in-depth interviews, and data analysis was carried out using the Colaizzi's seven-step analysis method. SETTING: A third-level hospital in Shanghai. PARTICIPANTS: A total of 17 ENs were interviewed through face-to-face, semistructured, in-depth interviews. RESULTS: Three main themes and eight subthemes were extracted from the data: (a) stress, (b) restructuring and (c) growth. CONCLUSION: Significant stress was imposed on ENs by the Shanghai COVID-19 pandemic, but cognitive restructuring was successfully undergone by them, leading to the experience of growth. It is recommended that post-traumatic growth levels be enhanced through professional psychological counselling and tailored support measures for different stages.

Exploring promotion factors of resilience among emergency nurses: a qualitative study in Shanghai, China.

OBJECTIVE: To qualitatively explore the factors that enhance resilience among emergency nurses (ENs). DESIGN: This study is an exploratory qualitative investigation. Semistructured in-depth interviews were used for data collection, while qualitative content analysis was applied for data analysis. SETTING: A grade A tertiary hospital in Shanghai, China. PARTICIPANTS: The study subjects comprised 17 ENs, who were selected using a purposive sampling method. RESULTS: Three main themes and the nine subthemes emerged from the study, that is, individual resources, including competency, personality traits and occupational benefits; family resources, including close parent-child attachment and supportive family dynamics; social resources, including peer support, organisational support, resilient leadership and popular support. CONCLUSION: This qualitative study explored the factors promoting resilience among ENs and provided a reference for managers to formulate future management strategies. From the perspective of positive psychology, nurses should receive comprehensive support, focusing on improving their professional accomplishment and role ability while prioritising the development of resilient leadership. These efforts are expected to drive progress and growth across the emergency care team.

Nafamostat mesylate versus regional citrate anticoagulation for continuous renal replacement therapy in patients at high risk of bleeding: a retrospective single-center study.

PURPOSE: The choice of continuous renal replacement therapy (CRRT) anticoagulation program for patients at high risk of bleeding has always been a complex problem in clinical practice. Clinical regimens include regional citrate anticoagulation (RCA) and nafamostat mesylate (NM). This study aimed to evaluate the efficacy and safety of these two anticoagulants for CRRT in patients at high risk of bleeding to guide their clinical use better. PATIENTS AND METHODS: Between January 2021 and December 2022, 307 patients were screened for this study. Forty-six patients were finally enrolled: 22 in the regional citrate anticoagulation group and 24 in the nafamostat mesylate group. We collected patients' baseline characteristics, laboratory indicators before CRRT, and CRRT-related data. We then performed a statistical analysis of the data from both groups of patients. RESULTS: In our study, the baseline characteristics did not differ significantly between the two groups; the baseline laboratory indicators before CRRT of patients in the two groups were not significantly different. The duration of CRRT was 600 min in the regional citrate anticoagulation (RCA) group, 615 min in the nafamostat mesylate (NM) group; the success rate was 90.7% in the RCA group, and 85.6% in the NM group, the anticoagulant efficacy between the two groups was comparable. There was no significant difference in the safety of anticoagulation between the two groups. We used Generalized Estimating Equations (GEE) to test whether different anticoagulation methods significantly affected the success rate of CRRT and found no statistical difference between RCA and NM. CONCLUSION: Our study suggests that nafamostat mesylate's anticoagulant efficacy and safety are not inferior to regional citrate anticoagulation for continuous renal replacement therapy in patients at high risk of bleeding.

Multi-omic profiling reveals potential biomarkers of hepatocellular carcinoma prognosis and therapy response among mitochondria-associated cell death genes in the context of 3P medicine.

Background: Cancer cell growth, metastasis, and drug resistance are major challenges in treating liver hepatocellular carcinoma (LIHC). However, the lack of comprehensive and reliable models hamper the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) strategy in managing LIHC. Methods: Leveraging seven distinct patterns of mitochondrial cell death (MCD), we conducted a multi-omic screening of MCD-related genes. A novel machine learning framework was developed, integrating 10 machine learning algorithms with 67 different combinations to establish a consensus mitochondrial cell death index (MCDI). This index underwent rigorous evaluation across training, validation, and in-house clinical cohorts. A comprehensive multi-omics analysis encompassing bulk, single-cell, and spatial transcriptomics was employed to achieve a deeper insight into the constructed signature. The response of risk subgroups to immunotherapy and targeted therapy was evaluated and validated. RT-qPCR, western blotting, and immunohistochemical staining were utilized for findings validation. Results: Nine critical differentially expressed MCD-related genes were identified in LIHC. A consensus MCDI was constructed based on a 67-combination machine learning computational framework, demonstrating outstanding performance in predicting prognosis and clinical translation. MCDI correlated with immune infiltration, Tumor Immune Dysfunction and Exclusion (TIDE) score and sorafenib sensitivity. Findings were validated experimentally. Moreover, we identified PAK1IP1 as the most important gene for predicting LIHC prognosis and validated its potential as an indicator of prognosis and sorafenib response in our in-house clinical cohorts. Conclusion: This study developed a novel predictive model for LIHC, namely MCDI. Incorporating MCDI into the PPPM framework will enhance clinical decision-making processes and optimize individualized treatment strategies for LIHC patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00362-8.

Screening and risk factors of exocrine pancreatic insufficiency in critically ill adult patients receiving enteral nutrition.

INTRODUCTION: Malnutrition is a frequent problem associated with detrimental clinical outcomes in critically ill patients. To avoid malnutrition, most studies focus on the prevention of inadequate nutrition delivery, whereas little attention is paid to the potential role of exocrine pancreatic insufficiency (EPI). In this trial, we aim to evaluate the prevalence of EPI and identify its potential risk factors in critically ill adult patients without preexisting pancreatic diseases. METHODS: In this prospective cross-sectional study, we recruited 563 adult patients with critical illnesses. All details of the patients were documented, stool samples were collected three to five days following the initiation of enteral nutrition, and faecal elastase 1 (FE-1) concentrations were assayed using an enzyme-linked immunosorbent assay kit. Blood samples were also taken to determine serum amylase and lipase activity. RESULTS: The percentages of recruited patients with EPI (FE-1 concentration <200 µg/g) and severe EPI (FE-1 concentration <100 µg/g) were 52.2% and 18.3%, respectively. The incidences of steatorrhea were significantly different (P < 0.05) among the patients without EPI, with moderate EPI (FE-1 concentration = 100 to 200 µg/g) and severe EPI (FE-1 concentration < 100 µg/g). Both multivariate logistic regression analysis and z-tests indicated that the occurrence of EPI was closely associated with shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis. CONCLUSIONS: More than 50% of critically ill adult patients without primary pancreatic diseases had EPI, and nearly one-fifth of them had severe EPI. The risk factors for EPI included shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis. TRIAL REGISTRATION: NCT01753024.

The resilience of emergency and critical care nurses: a qualitative systematic review and meta-synthesis.

Background: Due to the unique work environment, emergency and critical care departments nurses face high job pressure, often resulting in burnout and a high turnover rate. Public health emergencies such as the Corona Virus Disease 2019 pandemic tend to exacerbate these problems further. Therefore, improving the resilience of nurses is crucial to enhance their retention rates. Objective: This systematic review and meta-synthesis of qualitative studies on the resilience of emergency and critical nurses were conducted to provide a reference for clinical managers to develop strategies for improving the resilience of nurses. Methods: Following databases were searched for relevant studies: CINAHL Plus, Elsevier, Cochrane Library, Embase, Medline, OVID, Pubmed, Science Direct, LWW and Web of Science, China National Knowledge Network (CNKI), Wanfang Database (CECDB), VIP Database, and Sinomed. Google Scholar and Opengrey were used to search for gray literature. The literature search period was from the establishment of the database to April 2023. The systematic review of qualitative studies followed the Joanna Briggs Institute (JBI) approach, including critical appraisal using the JBI Checklist and synthesis through meta-synthesis. Confidence of evidence was assessed with JBI's ConQual process. Results: A total of 12 articles were identified, with 59 main results and 9 new integrated categories. Also, 3 themes, i.e., risk factors, protective factors, and personal growth, and 9 sub-themes, i.e., working pressure, negative emotion, an organizational issue, active learning, sense of occupational benefit, social support, self-cognition and regulation, learn to adapt, and self-actualization, were formed. Conclusion: The resilience of emergency and critical care nurses depends on various factors. Managers should prioritize the mental health of nurses and implement measures to enhance their resilience through social support, team building, and psychological capital development. Additionally, management models can be updated based on domestic and international experience to improve nurses' job involvement, optimize nursing quality, and promote the advancement of the nursing profession.

Causal associations of gut microbiota and metabolites on sepsis: a two-sample Mendelian randomization study.

Background: Sepsis stands as a dire medical condition, arising when the body's immune response to infection spirals into overdrive, paving the way for potential organ damage and potential mortality. With intestinal flora's known impact on sepsis but a dearth of comprehensive data, our study embarked on a two-sample Mendelian randomization analysis to probe the causal link between gut microbiota and their metabolites with severe sepsis patients who succumbed within a 28-day span. Methods: Leveraging data from Genome-wide association study (GWAS) and combining it with data from 2,076 European descendants in the Framingham Heart Study, single-nucleotide polymorphisms (SNPs) were employed as Instrumental Variables (IVs) to discern gene loci affiliated with metabolites. GWAS summary statistics for sepsis were extracted from the UK Biobank consortium. Results: In this extensive exploration, 93 distinct genome-wide significant SNPs correlated with gut microbial metabolites and specific bacterial traits were identified for IVs construction. Notably, a substantial link between Coprococcus2 and both the incidence (OR of 0.80, 95% CI: 0.68-0.94, P=0.007) and the 28-day mortality rate (OR 0.48, 95% CI: 0.27-0.85, P=0.013) of sepsis was observed. The metabolite α-hydroxybutyrate displayed a marked association with sepsis onset (OR=1.08, 95% CI: 1.02-1.15, P=0.006) and its 28-day mortality rate (OR=1.17, 95% CI: 1.01-1.36, P=0.029). Conclusion: This research unveils the intricate interplay between the gut microbial consortium, especially the genus Coprococcus, and the metabolite α-hydroxybutyrate in the milieu of sepsis. The findings illuminate the pivotal role of intestinal microbiota and their metabolites in sepsis' pathogenesis, offering fresh insights for future research and hinting at novel strategies for sepsis' diagnosis, therapeutic interventions, and prognostic assessments.

Influence of continuous renal replacement therapy on the plasma concentration of tigecycline in patients with septic shock: A prospective observational study.

Objective: The influence of continuous renal replacement therapy (CRRT) on the steady-state plasma concentration of high-dose tigecycline was investigated in septic shock patients to provide references for drug dosing. Methods: In this prospective observational study, 17 septic shock patients presenting with severe infections needing a broad-spectrum antibiotic therapy with high-dose tigecycline (100 mg per 12 h) in the intensive care unit were included and divided into CRRT group (n = 6) or non-CRRT group (n = 11). The blood samples were collected and plasma drug concentration was determined by SHIMADZU LC-20A and SHIMADZU LCMS 8040. The steady-state plasma concentration was compared between groups using unpaired t-test. Furthermore, between-groups comparisons adjusted for baseline value was also done using multivariate linear regression model. Results: Peak concentration (Cmax) of tigecycline was increased in CRRT group compared to non-CRRT group, but there were no statistical differences (505.11 ± 143.84 vs. 406.29 ± 108.00 ng/mL, p-value: 0.129). Trough concentration (Cmin) of tigecycline was significantly higher in CRRT group than in non-CRRT group, with statistical differences (287.92 ± 41.91 vs. 174.79 ± 33.15 ng/mL, p-value: 0.000, adjusted p-value: 0.000). In safety, Cmin was reported to be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL. In our studies, Cmin of all patients in CRRT group was lower than 474.8 ng/mL. Conclusion: The plasma concentration of tigecycline was increased in septic shock patients with CRRT treatment and only Cmin shown statistical differences. No dose adjustment seems needed in the view of hepatotoxicity. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2000037475.

Solid lipid nanoparticles of anticancer drugs against MCF-7 cell line and a murine breast cancer model.

To develop some promising anticancer drug loaded solid lipid nanoparticles (SLN) for further clinical application, SLN carrying mitoxantrone (MTO), paclitaxel (PCT), methotrexate (MTX) were prepared and their cytotoxic effects on the human breast cancer cell line, MCF-7 were investigated. The 50 % inhibitory concentration (IC50) values were interpolated from growth curves obtained by MTT assay. Moreover, the inhibition effects of the drugs incorporated in SLN on a murine breast cancer model induced by MCF-7 cells were further examined. In vitro cytotoxicity of MTO loaded SLN (IC50/72h=1.25 +/- 0.19 microM vs 2.13 +/- 0.37 microM) and MTX loaded SLN (IC50/72h = 93.80 +/- 6.54 nM vs 153.16 +/- 11.54 nM) was higher than that of free drug formulations. In vitro cytotoxicity of PCT-loaded SLN and free drug formulation IC50/72 h were similar. Then, the MCF-7 breast cancer model in mice was established. In mice treated with SLN injections for a month, tumor was significantly inhibited. Mean tumor size of mice treated with SLN was significantly smaller than that with free drug (P<0.05). Additionally, the percent inhibition of mice treated with SLN was obviously lower than that with free drug (P<0.05). Therefore, the conclusion can be drawn that anticancer drugs carried by SLN, including mitoxantrone, methotrexate and paclitaxel, may be more effective than free anticancer drugs for breast cancer treatment.

Population Pharmacokinetics of Tigecycline: A Systematic Review.

Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide tigecycline dosing in different patient subpopulations through comparing the published population pharmacokinetic models of tigecycline, as well as summarizing and determining the potential covariates that markedly influence tigecycline pharmacokinetics. In this review, literature was systematically searched from the PubMed database from inception to March 2022. The articles focusing on population pharmacokinetics for tigecycline in healthy volunteers or patients were included; finally, a total of eight studies were included in this review. NONMEM methods were used in five studies to generate the population pharmacokinetic models. Tigecycline pharmacokinetics were mostly described by a two-compartment model in these included studies. Estimated clearance and volumes of distribution of tigecycline at steady state (Vss) varied widely in different target patient populations, with a range of 7.5-23.1 L/h and 212.7-1087.7 L, respectively. Body-weight and creatinine clearance were the most important predictors of clearance in these studies, while other predictors include age, gender, bilirubin and aspartate aminotransferase. In conclusion, this review showed the large variability of tigecycline population pharmacokinetics, which can provide guide dosing in different target populations. For clinicians, the individual dosing adjustment should be based not only on the indication and pathogen susceptibility but also on the potential important predictors. However, more studies were needed to confirm the necessity of modified dosage regimens in different patient subpopulations.

Association of Blood Glucose Variability with Sepsis-Related Disseminated Intravascular Coagulation Morbidity and Mortality.

Purpose: Sepsis-related disseminated intravascular coagulation (DIC) is closely associated with poor prognosis and high mortality. Higher blood glucose (BG) variability indicates an increased risk of mortality in sepsis; however, its relationship with sepsis-related DIC has not been investigated. This study aimed to determine the association between glucose variability and sepsis-related DIC. Patients and Methods: Patients with sepsis admitted to the intensive care unit were enrolled between October 2017 and January 2021. Baseline data and BG records from the first 72 h were collected. We calculated the glucose liability index (GLI), largest amplitude of glucose excursion, BG standard deviation, and coefficient of variation on days 1 and 3. The relationship between GLI and morbidity of sepsis-related DIC was explored using a competing risk model. In subgroup analysis, we divided patients with and without diabetes into three groups according to the BG range. Results: Of the 238 patients enrolled, 28.2% developed DIC during hospitalization (n=67). GLI on day 3 was found to have the closest relationship with DIC incidence as it has the largest area under the ROC curve and the highest associated odds ratio of death per unit change (GLI3-day: AUC=0.891 OR=1.84), also independently increased the occurrence of DIC after adjusting for the competing risk of death (sub-distribution hazard ratios=1.866, p<0.01). In subgroup analysis, patients with diabetes had worse outcomes under hypoglycemia than under hyperglycemia. Patients without diabetes having stable BG had the best outcomes. Conclusion: Our study suggested that a higher GLI in patients with sepsis at 72 h was independently associated with an increased risk of sepsis-related DIC, which was not associated with pre-existing diabetes.

Predictive value of the C-reactive protein/albumin ratio in severity and prognosis of acute pancreatitis.

Aim: To investigate the predictive value of C-reactive protein (CRP) to serum albumin (ALB) ratio in the severity and prognosis of acute pancreatitis (AP), and compare the predictive value of the CRP/ALB ratio with the Ranson score, modified computed tomography severity index (MCTSI) score, and Bedside Index of Severity in Acute Pancreatitis (BISAP) score. Methods: This cohort study retrospectively analyzed clinical data of AP patients from August 2018 to August 2020 in our hospital. Logistic regression analysis was utilized to determine the effects of CRP/ALB ratio, Ranson, MCTSI, and BISAP score on severe AP (SAP), pancreatic necrosis, organ failure, and death. The predictive values of CRP/ALB ratio, Ranson, MCTSI, and BISAP score were examined with the area under the curve (AUC) of the receiver operator characteristic (ROC) curve analysis. DeLong test was used to compare the AUCs between CRP/ALB ratio, Ranson, MCTSI, and BISAP score. Results: Totally, 284 patients were included in this study, of which 35 AP patients (12.32%) developed SAP, 29 (10.21%) organ failure, 30 (10.56%) pancreatic necrosis and 11 (3.87%) died. The result revealed that CRP/ALB ratio on day 2 was associated with SAP [odds ratio (OR): 1.74, 95% confidence interval (CI): 1.32 to 2.29], death (OR: 1.73, 95%CI: 1.24 to 2.41), pancreatic necrosis (OR: 1.28, 95%CI: 1.08 to 1.50), and organ failure (OR: 1.43, 95%CI: 1.18 to 1.73) in AP patients. Similarly, CRP/ALB on day 3 was related to a higher risk of SAP (OR: 1.50, 95%CI: 1.24 to 1.81), death (OR: 1.8, 95%CI: 1.34 to 2.65), pancreatic necrosis (OR: 1.22, 95%CI: 1.04 to 1.42), and organ failure (OR: 1.21, 95%CI: 1.04 to 1.41). The predictive value of CRP/ALB ratio for pancreatic necrosis was lower than that of MCTSI, for organ failure was lower than that of Ranson and BISAP, and for death was higher than that of MCTSI. Conclusion: The CRP/ALB ratio may be a novel but promising, easily measurable, reproducible, non-invasive prognostic score that can be used to predict SAP, death, pancreatic necrosis, and organ failure in AP patients, which can be a supplement of Ranson, MCTSI, and BISAP scores.

AFF4 Predicts the Prognosis of Colorectal Cancer Patients and Suppresses Colorectal Cancer Metastasis via Promoting CDH1 Expression.

INTRODUCTION: AF4/FMR2 family member 4 (AFF4) is a core component of super elongation complex (SEC) and regulates the transcription elongation of many genes. AFF4 depletion or amplification is associated with multiple cancers, but its role in colorectal cancer (CRC) has not been investigated so far. METHODS: qRT-PCR and Western blot analyzed AFF4 expression in the paired clinical CRC tissues. The patients' overall survival curve was determined using the Kaplan-Meier plotter. In vitro experiments, such as cell proliferation, migration, and invasion, were used to preliminarily ascertain the role of AFF4 in CRC. A CRC cell liver metastasis animal model was well established. Livers were harvested and examined histologically by a series of indicators, such as tumor nodules, liver weight, ALT/AST activity, and tumor cell identification by hematoxylin-eosin (HE) staining. RESULTS: We firstly examined the expression of AFF4 in colorectal cancer and normal tissues by collecting paired CRC tissues and adjacent normal tissues, revealing that AFF4 was significantly downregulated in CRC patients and lower expression of AFF4 was correlated with poor prognosis. Next, we observed that presence or absence of AFF4 in CRC cells had no effect on cancer cell proliferation, while AFF4 depletion significantly promoted the migration or invasion of CRC cells in vitro. Furthermore, we confirmed that AFF4 deficiency enhanced the metastatic capacity of CRC cells in vivo. Mechanistically, we found that AFF4 upregulated the transcription of CDH1 gene, which encodes E-cadherin and suppresses the epithelial-mesenchymal transition (EMT). Knockdown of AFF4 interfered with CDH1 transcription, resulting in downregulation of E-cadherin expression and the progression of CRC. Moreover, restored CDH1 expression could rescue the phenotype of CRC cells without AFF4. CONCLUSIONS: Collectively, our data demonstrated that AFF4 served as a significant novel regulator of CRC via CDH1 transcriptional regulation and a potential effective therapy target for patients with CRC.

[Modern interpretation of "exterior-interior correlation between lung and large intestine" theory in acute and critical cases].

The "exterior-interior relationship between lung and large intestine" is one of the theories of traditional Chinese medicine, which is scientific in modern medicine. The ancients discovered the specific connection between the lung and large intestine, and constructed the theory of "exterior-interior relationship between lung and large intestine" through the Yin-Yang theory and the meridian attachment. The theory of "exterior-interior relationship between lung and large intestine" has been of great significance in the critical care field since the first study on intestinal tract and acute respiratory distress syndrome (ARDS) was carried out in the emergency medicine in 1980s. This article analyzes the consistence of lung and large intestine in early embryonic development, explains the close connection between the lung and large intestine through the intestinal flora translocation theory in sepsis, and reviews the immunoregulation mechanism of helper T cell 17 (Th17) in intestine and lung, and the possible molecular mechanism of immune response, so as to provide physicians with further exploration of the traditional theory of "exterior-interior relationship between lung and the large intestine".