Risk factors for mortality in patients undergoing continuous renal replacement therapy after cardiac surgery.

BACKGROUND: To investigate the risk factors for mortality in patients with acute kidney injury requiring continuous renal replacement therapy (AKI-CRRT) after cardiac surgery. METHODS: In this retrospective study, patients who underwent AKI-CRRT after cardiac surgery in our centre from January 2015 to January 2020 were included. Univariable and multivariable analyses were performed to identify the risk factors for in-hospital mortality. RESULTS: A total of 412 patients were included in our study. Of these, 174 died after AKI-CRRT, and the remaining 238 were included in the survival control group. Multivariable logistic regression analysis revealed that EuroSCORE > 7 (odds ratio [OR], 3.72; 95% confidence interval [CI], 1.92-7.24; p < 0.01), intraoperative bleeding > 1 L (OR, 2.14; 95% CI, 1.19-3.86; p = 0.01) and mechanical ventilation time > 70 h (OR, 5.03; 95% CI, 2.40-10.54; p < 0.01) were independent risk factors for in-hospital mortality in patients who had undergone AKI-CRRT. Our study also found that the use of furosemide after surgery was a protective factor for such patients (odds ratio, 0.48; 95% confidence interval, 0.25-0.92; p = 0.03). CONCLUSIONS: In summary, the mortality of patients with AKI-CRRT after cardiac surgery remains high. The EuroSCORE, intraoperative bleeding and mechanical ventilation time were independent risk factors for in-hospital mortality. Continuous application of furosemide may be associated with a better outcome.

Diagnosis Value of Procalcitonin Variation on Early Pneumonia after Adult Cardiac Surgery.

BACKGROUND: Postoperative pneumonia (PP) is a complication after cardiac surgery. This study aimed to investigate the ability of procalcitonin (PCT) variation to diagnose postoperative pneumonia. METHOD: In this prospective observational study, patients with PP and age- and sex-matched cases in our center from October 10, 2020, to January 31, 2021, were included. Patients diagnosed with PP in this study met both clinical and microbiological diagnostic criteria. Blood samples were collected in all patients from the first postoperative day (POD1) to POD5 to measure PCT, white blood cells (WBCs), and C-reactive protein (CRP). PCT variation was calculated by the equation: (PCTdelayed - PCTPOD1)/PCTPOD1. The receiver operating characteristic and area under the curve (AUC) analyses were used to evaluate the diagnostic performance of different biomarkers. RESULTS: Our study enrolled 272 patients, including 24 patients with PP and 248 age- and sex-matched cases. From POD1 to POD5, the absolute value of PCT showed diagnostic significance for pneumonia (P < .05), WBC showed no differences, and CRP had no diagnostic value until POD4. Furthermore, PCT variation showed the best diagnostic value among those biomarkers (AUC 0.84, 95% confidence interval [CI] 0.71, 0.91). Multivariable logistic regression showed that PCT variation on POD2 had significant value to predict PP (odds ratio 5.602, 95% CI 2.178, 14.409, P < .01). CONCLUSION: Compared with PCT level, WBC count, and CRP level, PCT variation had the best diagnostic value in predicting PP.

Orthogonal strategy development using reversed macroporous resin coupled with hydrophilic interaction liquid chromatography for the separation of ginsenosides from ginseng root extract.

Ginsenosides have been widely conceded as having various biological activities and are considered to be the active ingredient of ginseng. Nowadays, preparative high-performance liquid chromatography is considered to be a highly efficient method for ginseng saponins purification and preparation. However, in the process of practical application, due to the complex and varied composition of natural products and relatively simple pretreatment process, it is likely to block the chromatographic column and affect the separation efficiency and its service life. In this work, an orthogonal strategy was developed; in the first-dimension separation, reverse-phase macroporous resin was applied to remove impurities in ginseng crude extracts and classified ginseng extracts into protopanaxatriol and protopanaxadiol fractions. In the second-dimension separation, the obtained fractions were further separated by a preparative hydrophilic column, and finally yielded 11 pure compounds. Eight of them identified as ginsenoside Rh1 , Rg2 , Rd, Rc, Rb2 , Rb1 , Rg1 , and Re by standards comparison and electrospray ionization mass spectrometry. The purity of these ginsenosides was assessed by high-performance liquid chromatography with UV detection.

Efficacy and safety of mineralocorticoid receptor antagonists for patients with heart failure and diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to systematically assess the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) for patients with heart failure (HF) and diabetes mellitus (DM). METHODS: We conducted a comprehensive search for controlled studies that evaluated the efficacy and safety of MRAs in patients with DM and HF. Medline, Embase and Cochrane databases were searched. Two reviewers independently identified citations, extracted data and evaluated quality. Risk estimations were abstracted and pooled where appropriate. RESULTS: Four observational studies were included. MRAs use was associated with reduced mortality compared with controls (RR = 0.78; 95% CI: 0.69-0.88; I(2) = 0%; P < 0.001). Increased risk of developing hyperkalaemia was observed in those patients taking MRAs (RR = 1.74; 95% CI: 1.27-2.38; I(2) = 0%; P = 0.0005). CONCLUSIONS: The current cumulative evidence suggests that MRAs can improve clinical outcomes but increase the risk of hyperkalaemia in patients with DM and HF. TRIAL REGISTRATION: PROSPERO CRD42015025690 .

Biphasic regulation of A20 gene expression during human cytomegalovirus infection.

BACKGROUND: The A20 ubiquitin-editing enzyme is a target of nuclear factor kappa B (NF-κB) and also plays a key role in regulating the NF-κB signaling pathway. NF-κB activity is increased during human cytomegalovirus (HCMV) infection and HCMV appears to be adapted to this change. To better understand the regulation of NF-κB signaling during HCMV infection, we investigated how A20 expression is controlled during HCMV infection. METHODS: The expression level of A20 in human fibroblast cells infected with HCMV or UV-inactivated virus (UV-HCMV) was measured by immunoblot analysis, cell staining, and quantitative real-time PCR. Changes of histone modifications on the A20 promoter were determined by chromatin immunoprecipitation assays. Lentiviral vectors were used to knockdown A20 in fibroblast cells. RESULTS: A20 expression was increased at early times after HCMV infection. This increase of the A20 protein level was promoted by viral gene expression under low viral load conditions. The viral IE1 protein, which is known to activate NF-κB, increased the A20 promoter activity through the upstream NF-κB sites in reporter assays, suggesting that IE1 is at least partly involved in A20 induction. Analysis of A20 expression with a high viral load demonstrated that the A20 regulation by HCMV was biphasic; both A20 protein and mRNA levels were increased at the early stage of infection, but decreased at the late stage. Under high viral load conditions, A20 upregulation was more profound with UV-HCMV than with HCMV, indicating a role of the viral gene product(s) in limiting A20 induction. Consistently, more histone modifications for euchromatin were found on the A20 promoter during UV-HCMV infection than with HCMV infection. A20 knockdown by shRNA reduced HCMV growth. CONCLUSION: These results suggest that the biphasic regulation of A20 expression may be important for productive HCMV infection.

Efficient synthesis of mibefradil analogues: an insight into in vitro stability.

This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation.

Blocking the interaction between circTNRC18 and LIN28A promotes trophoblast epithelial-mesenchymal transformation and alleviates preeclampsia.

Defects in migration and invasion caused by dysregulation of trophoblastic epithelial-mesenchymal transformation (EMT) play a vital role in preeclampsia (PE). We have previously shown that circTNRC18 inhibits the migration and EMT of trophoblasts; however, its role in PE remains unknown. Herein, we demonstrate that circTNRC18 interacts with an RNA-binding protein, lin-28 homolog A (LIN28A), and this interaction is enhanced in PE placental tissue. LIN28A overexpression suppresses circTNRC18-mediated inhibition of trophoblast migration, invasion, and EMT, whereas LIN28A knockdown promotes them. The intracellular distribution of LIN28A is regulated by circTNRC18, where it promotes the expression of insulin-like growth factor II by stabilizing its mRNA. circTNRC18 also promotes complex formation between GATA-binding factor 1 (GATA1) and sine oculis homeobox 1 (SIX1) by inhibiting LIN28A-GATA1 interaction. GATA1-SIX1 promotes transcription of grainyhead-like protein 2 homolog and circTNRC18-mediated regulation of cell migration and invasion. Moreover, blocking circTNRC18-LIN28A interaction with antisense nucleotides alleviates PE in a mouse model of reduced uterine perfusion pressure. Thus, targeting the circTNRC18-LIN28A regulatory axis may be a novel PE treatment method.

A Nomogram for Predicting Physical Restraint of Patients in Intensive Care Unit.

Background: Despite its ethical implications, physical restraint (PR) is widely used in the intensive care unit (ICU) to guarantee the safety of patients. This study investigated the frequency and risk factors of PR use for patients in the ICU to establish a predictive nomogram. Methods: Clinical parameters of patients admitted to the ICU of Jiangsu Province Hospital from January 2021 to July 2021 were retrospectively collected. Independent risk factors of PR were analyzed by univariate and multivariate logistic regression analyses. The R software was used to establish the nomogram. Model performance was validated using the concordance-index (C-index) and calibration curves. Results: The rate of PR use was 46.32% (233/503 patients). Age (B = 0.036, odds ratio [OR]: 1.037, 95% confidence interval [CI]: 1.022-1.052, P < 0.001), consciousness disorder (B = 0.770, OR: 2.159, 95% CI: 1.216-3.832, P=0.009), coma (B = -1.666, OR: 0.189, 95% CI: 0.101-0.353, P < 0.001), passive activity (B = 1.014, OR: 2.756, 95% CI: 1.644-4.618, P < 0.001), delirium (B = 0.993, OR: 2.699, 95% CI: 1.097-6.642, P=0.031), -3 < Richmond Agitation Sedation Scale (RASS) score <2 (B = 0.698, OR: 2.009, 95% CI: 1.026-3.935, P=0.042), RASS score ≥2 (B = 1.253, OR: 3.499, 95% CI: 1.126-10.875, P=0.030), and mechanical ventilation (B = 1.696, OR: 5.455, 95% CI: 2.804-10.611, P < 0.001) were identified as independent risk factors for PR in the ICU (P < 0.05) and included in the nomogram. The C-index was 0.830, and the calibration curve indicated good discriminatory ability and accuracy (mean absolute error: 0.026). Conclusion: The prediction nomogram model of PR in ICU was established based on age, mobility, delirium, consciousness, RASS score, and mechanical ventilation. It showed good discrimination and accuracy. This nomogram may predict the probability of PR use in the ICU and guide nurses in developing precise interventions to reduce the rate of PR.

[Expert consensus on implementation strategy of awake prone positioning for non-intubated patients in China (2023)].

The awake prone position plays an important role in the treatment of hypoxemia and the improvement of respiratory distress symptoms in non-intubated patients. It is widely used in clinical practice because of its simple operation, safety, and economy. To enable clinical medical staff to scientifically and normatively implement prone position for awake patients without intubation, the committees of consensus formulation, guided by evidence-based methodology and Delphi method, conducted literature search, literature quality evaluation and evidence synthesis around seven topics, including indications and contraindications, evaluation, implementation, monitoring and safety management, termination time, complication prevention and health education of awake prone position. After two rounds of expert letter consultation, Expert consensus on implementation strategy of awake prone positioning for non-intubated patients in China (2023) was formulated, and provide guidance for clinical medical staff.

Human cytomegalovirus infection causes degradation of Sp100 proteins that suppress viral gene expression.

The interferon-inducible Sp100 proteins are thought to play roles in the chromatin pathway and in transcriptional regulation. Sp100A, the smallest isoform, is one of the major components of PML nuclear bodies (NBs) that exhibit intrinsic antiviral activity against several viruses. Since PML NBs are disrupted by the immediate-early 1 (IE1) protein during human cytomegalovirus (HCMV) infection, the modulation of Sp100 protein expression or activity during infection has been suggested. Here, we show that Sp100 proteins are lost largely in the late stages of HCMV infection. This event required viral gene expression and involved posttranscriptional control. The mutant virus with deletion of the sequence for IE1 (CR208) did not have Sp100 loss. In CR208 infection, PML depletion by RNA interference abrogated the accumulation of SUMO-modified Sp100A and of certain high-molecular-weight Sp100 isoforms but did not significantly affect unmodified Sp100A, suggesting that the IE1-induced disruption of PML NBs is not sufficient for the complete loss of Sp100 proteins. Sp100A loss was found to require proteasome activity. Depletion of all Sp100 proteins by RNA silencing enhanced HCMV replication and major IE (MIE) gene expression. Sp100 knockdown enhanced the acetylation level of histones associated with the MIE promoter, demonstrating that the repressive effect of Sp100 proteins may involve, at least in part, the epigenetic control of the MIE promoter. Sp100A was found to interact directly with IE1 through the N-terminal dimerization domain. These findings indicate that the IE1-dependent loss of Sp100 proteins during HCMV infection may represent an important requirement for efficient viral growth.

Effects of sea salt intake on metabolites, steroid hormones, and gut microbiota in rats.

High salt intake is positively linked to many health problems, but the effect of mineral-rich sea salt (SS) has rarely been studied. To better understand the physiological effects of SS intake, the changes in general characteristics, metabolites, steroid hormones, and gut microbiota of SS-fed rats were investigated. Male rats were fed either a normal diet (ND, control) or ND containing 1% SS or 4% SS for 5 weeks. SS intake decreased fat, spleen, liver, and body weight, and increased blood urea nitrogen (BUN), water intake, and gut salt content. Accumulated gut salt content led to a decrease in beneficial bacteria, such as Lachnospiraceae and Lactobacillus, but an increase in potentially harmful bacteria, resulting in a change in lipid metabolites associated with gut health. Interestingly, most renal lysophosphatidylcholines (LPCs) associated with many renal functions were dramatically decreased and female hormones, such as estrogens, were significantly more altered than the male hormones by high SS intake. Although further investigation is needed, these data suggest that high SS intake could be positively linked to kidney dysfunction and gut health problems, and salt-related physiological changes may be sex-specific. Additionally, these data will be useful to better under-stand the physiological effects of SS intake.

[Expert consensus on prevention and management of enteral nutrition therapy complications for critically ill patients in China (2021 edition)].

Enteral nutrition plays an irreplaceable role in the nutritional treatment of critically ill patients. In order to help clinical medical staff to manage the common complications during the implementations of enteral nutrition for critically ill patients, the consensus writing team carried out literature retrieval, literature quality evaluation, evidence synthesis. Several topics such as diarrhea, aspiration, high gastric residual volume, abdominal distension, etc. were assessed by evidence-based methodology and Delphi method. After two rounds of expert investigations, Expert consensus on prevention and management of enteral nutrition therapy complications for critically ill patients in China (2021 edition) developed, and provided guidance for clinical medical staff.

Bilirubin adsorption versus plasma exchange for hyperbilirubinemia in patients after cardiac surgery: a retrospective study.

OBJECTIVE: Hyperbilirubinemia after cardiac surgery increases in-hospital mortality and is associated with poor prognosis. Our present study aimed to compare the efficacy of bilirubin adsorption (BA) and plasma exchange (PEX) in patients with hyperbilirubinemia after cardiac surgery. METHODS: We retrospectively included patients who underwent BA treatment or PEX treatment due to severe hyperbilirubinemia after cardiac surgery at our center from 2015 to 2020. We collected results from urine and liver function tests before and after treatment and compared the in-hospital mortality and morbidity between the two treatment groups. RESULTS: A total of 56 patients were enrolled in this study: 14 patients received BA treatment, and 42 patients received PEX treatment. Compared to the PEX group, the BA group exhibited a statistically significant reduction in total bilirubin (p = 0.016) and direct bilirubin (p = 0.036) levels. The in-hospital mortality was 85.7% (48/56) in the whole group, and the BA group had a lower mortality than the PEX group (71.4% vs. 90.5%, p = 0.078). The BA group showed better circulatory support, including lower risks of IABP (21.4% vs. 52.4%, p = 0.044), ECMO (21.4% vs. 50.0%, p = 0.061), reintubation (64.3% vs. 40.5%, p = 0.122) and ventricular arrhythmias (64.3% vs. 45.2%, p = 0.217). The in-hospital mortality was still lower in the BA treatment group than in the PEX treatment group (71.4% vs. 100%, p = 0.049) in the matched cohort. CONCLUSIONS: Compared to PEX treatment, BA treatment had a higher bilirubin removal ability in patients with hyperbilirubinemia and could reduce the mortality and risks of poor clinical outcomes. BA treatment should be considered an effective treatment method for patients with higher total bilirubin or direct bilirubin levels.

Synthesis and biological evaluation of 1,4-diazepane derivatives as T-type calcium channel blockers.

We have synthesized and biologically evaluated 1,4-diazepane derivatives as T-type calcium channel blockers. In this study, we discovered compound 4s, a potential T-type calcium channel blocker with good selectivity over hERG and N-type calcium channels. In addition, it exhibited favorable pharmacokinetic characteristics for further investigation of T-type calcium channel related diseases.

Correlation between fluorodeoxyglucose positron emission tomography and magnetic resonance imaging findings of non-suppurative meningoencephalitis in 5 dogs.

This study characterized the [(18)F]2-deoxy-2-fluoro-D-glucose positron emission tomography (FDG-PET) findings of encephalitis in dogs and assessed the role of FDG-PET in the diagnosis of meningoencephalitis. The medical records, magnetic resonance (MR), and FDG-PET images of 3 dogs with necrotizing meningoencephalitis (NME), 1 dog with granulomatous meningoencephalitis (GME), and 1 dog with meningoencephalitis of unknown etiology (MUE) were reviewed. On the FDG-PET, glucose hypometabolism was identified in the dog with NME, whereas hypermetabolism was noted in the dog with GME. The T2-weighted images (WI) and fluid attenuated inversion recovery (FLAIR) images were characterized by hyperintensity, whereas the signal intensity of the lesions on the T1-WI images was variable. The metabolic changes on the brain FDG-PET corresponded well to the hyper- and hypointense lesions seen on the MR imaging. This type of tomography (FDG-PET) aided in the differentiation of different types of inflammatory meningoencephalitis when the metabolic data was combined with clinical and MR findings.

Multidrug Resistance of Gastric Cancer: The Mechanisms and Chinese Medicine Reversal Agents.

Chemotherapy is the main clinical treatment method of gastric cancer. Multidrug resistance (MDR) has become a common phenomenon with the development of tumors, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of survival rate of advanced gastric cancer. Therefore, the exploration of MDR reversal agents for gastric cancer is the focus and also the difficulty of current treatment. Currently, the researches on the mechanisms of drug resistance in gastric cancer have been continuously deepened, which reveal different pathways and targets of MDR, laying a solid foundation for studying reversal agents. As a kind of natural medicine, traditional Chinese medicine (TCM) owns the characteristics of low toxicity, high safety and effectiveness. It can inhibit the occurrence, growth and metastasis of tumors, and reverse MDR via multiple pathways and mechanisms, the pathological function of which has become a research hotspot in recent years. TCM reversers are mainly divided into Chinese medicine monomers, Chinese patent medicines, and Chinese herbal compounds. With certain quantity and advantage, TCM reversers for MDR play an important role in the clinical treatment and show great potential in gastric cancer.

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox-Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA.

Abnormal ossification as a cause the progression of adolescent idiopathic scoliosis.

Although, there is no generally accepted scientific theory for the etiology of adolescent idiopathic scoliosis (AIS), the relative anterior spinal column overgrowth has been postulated as a mechanism of AIS progression by many morphological studies. The normal spinal growth involves both kinds of ossification: endochondral and membranous ossification. Considering the uncoupled anterior-posterior column growth of AIS patients, the uncoupled endochondral-membranous ossification could possibly play an important role in the progression of AIS. Meanwhile, other observations found that the uncoupling of ossification was not limited to the spinal column, but rather a systemic phenomenon. This consideration leads us to carefully dissect the underlying abnormal molecular pathways, cytokines or receptors of ossification, such as BMP-Smads, Runx2, FGFR-3, and will raise the hope to detect the AIS progression potentiality and help to formulate the appropriately personalized treatment strategy for patients.

Three-dimensional time-of-flight magnetic resonance angiography of intracranial vessels in a canine model of ischemic stroke with permanent occlusion of the middle cerebral artery.

The purpose of this study was to evaluate the potential efficacy of 3-dimensional time-of-flight magnetic resonance angiography (TOF-MRA) to validate a canine ischemic stroke model. Ischemic stroke was induced through permanent middle cerebral artery occlusion (MCAO) in 5 healthy Beagle dogs. T2-turbo spin echo images and TOF-MRA were obtained with a 1.5-T magnetic resonance system before and 3 and 10 d after MCAO. In 3 dogs, angiograms of the brain obtained at 3 d after MCAO showed complete occlusion of the MCA; in addition, T2 hyperintensities were present unilaterally in the striatocapsular and cerebral cortex lesions. Partial occlusion of the proximal part of the MCA was identified in the 2 remaining dogs, with T2 hyperintensities present only in the striatocapsular lesions. The occluded sites were confirmed at necropsy. The results of this study demonstrate the potential of TOF-MRA to provide a detailed description of intracranial arteries and aid in the evaluation of flow impairment in a canine MCAO model.

18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging findings of primary intracranial histiocytic sarcoma in a dog.

A 10-year-old, neutered male, Maltese dog presented with a three week history of intention tremor, right hind limb rigidity, poor coordination, and occasional circling to the left. On magnetic resonance imaging (MRI) of the brain, a mass was identified in the right occipital lobe and cerebellum. Three weeks after the initial MRI scan, we performed an (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) of the brain. The FDG-PET demonstrated areas of hypermetabolism in the right occipital lobe, cerebellum, pons, and medulla oblongata. When the standardized uptake value was calculated, the hypermetabolic lesion was higher than the gray matter values. The anatomical location of the hypermetabolic lesion was more precisely identified by the PET-MRI fusion images. The dog was definitively diagnosed as a primary histiocytic sarcoma of the brain. This is the first report of PET findings of an intracranial histiocytic sarcoma in a dog.