[Is monitoring of anti-factor Xa levels required for low molecular weight heparin prophylaxis of venous thromboembolism in critically ill patients?]

The incidence and mortality of venous thromboembolism (VTE) are high in critically ill patients, and there is still a risk of VTE and bleeding after the use of fixed-dose low molecular weight heparin (LMWH) for prophylaxis. The level of anti-factor Xa is not up to standard after LMWH prophylaxis in patients with surgery or trauma. The condition of critically ill patients is complicated, and the proportion of patients with low antithrombin III is high, which can affect the prophylactic efficacy of LMWH and contribute to VTE occurrence. There is currently no consensus on whether adjusting LMWH dose according to anti-factor Xa levels can reduce VTE occurrence in critically ill patients. High-quality multicenter randomized controlled studies are needed in the future to establish new approaches for precise prevention of VTE in critically ill patients.

Prototype or Exemplar Representations in the 5/5 Category Learning Task.

Theories of category learning have typically focused on how the underlying category structure affects the category representations acquired by learners. However, there is limited research as to how other factors affect what representations are learned and utilized and how representations might change across the time course of learning. We used a novel "5/5" categorization task developed from the well-studied 5/4 task with the addition of one more stimulus to clarify an ambiguity in the 5/4 prototypes. We used multiple methods including computational modeling to identify whether participants categorized on the basis of exemplar or prototype representations. We found that, overall, for the stimuli we used (schematic robot-like stimuli), learning was best characterized by the use of prototypes. Most importantly, we found that relative use of prototype and exemplar strategies changed across learning, with use of exemplar representations decreasing and prototype representations increasing across blocks.

Serum transactive response DNA binding protein 43 associates with poor short-term neurologic outcome after return of spontaneous circulation following cardiac arrest.

OBJECTIVE: To explore the association of serum transactive response DNA binding protein 43 (TDP-43) with 28-day poor neurologic outcome in patients with return of spontaneous circulation (ROSC) after cardiac arrest. METHODS: We performed a study between January and December, 2023. Eligible patients with ROSC following cardiac arrest were enrolled. Their baseline characteristics were collected and serum levels of TDP-43, tumor necrosis factor-α, interleukin-6 and -10, C-reactive protein, and neuron-specific enolase (NSE) at 24 h after ROSC were measured. The neurological function was assessed by the cerebral performance category scores on day 28 after ROSC. RESULTS: A total of 92 patients were included, with 51 and 41 patients in the good and poor neurological outcome groups, respectively. Serum TDP-43 was significantly higher in the poor than the good neurologic outcome group (P < 0.05). Univariate and multivariate logistic regression analyses showed that TDP-43, Witnessed CA, IL-6, and NSE were associated with poor 28-day neurologic outcome (all P < 0.05). Restricted cubic spline analysis revealed that TDP-43 at the serum level of 11.64 pg/mL might be an ideal cutoff value for distinguishing between good and poor neurologic outcomes. Area Under Curve of serum TDP-43 (AUC = 0.78) was close to that of serum NSE (AUC = 0.82). A dynamic nomogram prediction model that combined TDP-43, Witnessed CA, IL-6, and NSE was constructed and validated. CONCLUSION: Elevated serum TDP-43 level was associated with and could be used together with Witnessed CA, IL-6, and NSE to predict poor 28-day neurologic outcome in patients after ROSC following cardiac arrest.

An Underwater Source Localization Method Using Bearing Measurements.

Angle-of-arrival (AOA) measurements are often used in underwater acoustical localization. Different from the traditional AOA model based on azimuth and elevation measurements, the AOA model studied in this paper uses bearing measurements. It is also often used in the Ultra-Short Baseline system (USBL). However, traditional acoustical localization needs additional range information. If the range information is unavailable, the closed-form solution is difficult to obtain only with bearing measurements. Thus, a localization closed-form solution using only bearing measurements is explored in this article. A pseudo-linear measurement model between the source position and the bearing measurements is derived, and considering the nonlinear relationship of the parameters, a weighted least-squares optimization equation based on multiple constraints is established. Different from the traditional two-step least-squares method, the semidefinite programming (SDP) method is designed to obtain the initial solution, and then a bias compensation method is proposed to further minimize localization errors based on the SDP result. Numerical simulations show that the performance of the proposed method can achieve Cramer-Rao lower bound (CRLB) accuracy. The field test also proves that the proposed method can locate the source position without range measurements and obtain the highest positioning accuracy.

Combining Bulk RNA-seq and scRNA-seq data to identify RNA m5C methyltransferases NSUN1: a rising star as a biomarker for cancer diagnosis, prognosis and therapy.

Background: RNA 5-methylcytosine (m5C) methyltransferases NSUN1 is a member of the NOP2/SUN (NSUN) RNA methyltransferase family. Studies have found that the expression of NSUN1 is elevated in breast and colon cancer and can predict poor prognosis. However, the NSUN1 gene has only been studied in a few tumors. Methods: Single-cell RNA sequencing (scRNA-seq) and Bulk RNA-seq data were used for comprehensive analysis of NSUN1 in cancers. The Human Protein Atlas (HPA) database was used to identify the gene location. Immunofluorescence staining was used to detect NSUN1 subcellular distribution within the nucleus, endoplasmic reticulum (ER), and microtubules of A-431, U-2, U-251 cells. The cBioPortal tool was used to analyze the alteration frequency and mutation type. The epigenetic profile of NSUN1 also was analyzed by using the University of Alabama at Birmingham CANcer data analysis Portal (UCLCAN). Tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint expression in cancers were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform enrichment and visualization. The study was based on online resources and public databases. Results: Elevated NSUN1 expression had been observed in most human cancers. Analysis of scRNA-seq data showed that NSUN1 was highly expressed in immune cells such as T cells, B cells, and dendritic (DC) cells. High NSUN1 expression indicated poor overall survival (OS) and disease-free survival (DFS). The characteristics of genetic alteration, methylation and phosphorylation of NSUN1 were analyzed and higher levels of phosphorylation in tumor tissues were found. In addition, the expression of NSUN1 was closely related to tumor-infiltrating immune cells. At the same time, the expression of NSUN1 was positively correlated with the expression of multiple immune checkpoints. Conclusions: The gene expression profile, survival status, genetic alteration, methylation, phosphorylation and infiltrating immune cells of NSUN1 in human cancers were comprehensively analyzed. The results herein implied that NSUN1 may be an effective biomarker for early cancer diagnosis, prognosis and therapy.

Anti-factor Xa level monitoring of low-molecular-weight heparin for prevention of venous thromboembolism in critically ill patients (AXaLPE): protocol of a randomised, open-label controlled clinical trial.

INTRODUCTION: Whether and when to monitor the amount of anti-factor Xa (aFXa) activity in critically ill patients with complex diseases to prevent venous thromboembolism (VTE) remain unclear. This study is a randomised controlled trial to investigate the effect of aFXa level monitoring on reducing VTE and to establish a new method for accurately preventing VTE in critically ill patients with low-molecular-weight heparin (LMWH). METHODS AND ANALYSIS: A randomised controlled trial is planned in two centres with a planned sample size of 858 participants. Participants will be randomly assigned to three groups receiving LMWH prophylaxis at a 1:1:1 ratio: in group A, peak aFXa levels will serve as the guide for the LMWH dose; in group B, the trough aFXa levels will serve as the guide for the LMWH dose; and in group C, participants serving as the control group will receive a fixed dose of LMWH. The peak and trough aFXa levels will be monitored after LMWH (enoxaparin, 40 mg, once daily) reaches a steady state for at least 3 days. The monitoring range for group A's aFXa peak value will be 0.3-0.5 IU/mL, between 0.1 and 0.2 IU/mL is the target range for group B's aFXa trough value. In order to reach the peak or trough aFXa levels, groups A and B will be modified in accordance with the monitoring peak and trough aFXa level. The incidence of VTE will serve as the study's primary outcome indicator. An analysis using the intention-to-treat and per-protocol criterion will serve as the main outcome measurement. ETHICS AND DISSEMINATION: The Xuanwu Hospital Ethics Committee of Capital Medical University and Peking University First Hospital Ethics Committee have approved this investigation. It will be released in all available worldwide, open-access, peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05382481.

PREDICTIVE VALUE OF NEUTROPHIL EXTRACELLULAR TRAP COMPONENTS FOR 28-DAY ALL-CAUSE MORTALITY IN PATIENTS WITH CARDIAC ARREST: A PILOT OBSERVATIONAL STUDY.

ABSTRACT: Background: Ischemia-reperfusion after cardiac arrest (CA) activates peptidyl arginine deiminase and citrullinated histone H3 (CitH3), which leads to the formation of neutrophil extracellular traps (NETs). This study attempted to determine the alterations in NET components in post-CA patients as well as analyze the association of NETs with 28-day all-cause mortality. Methods : In this study, 95 patients with restoration of spontaneous circulation (ROSC) after CA were included. They were categorized into the survivor group (n = 32) and the nonsurvivor group (n = 63) according to their 28-day survival statuses. The control group comprised 20 healthy individuals. The blood samples were collected from the patients on days 1, 3, and 7 after ROSC and from the control subjects at the time of enrollment. The serum cell-free DNA (cfDNA) level was determined using the fluorescent labeling method, and the serum concentrations of NET components, including CitH3, myeloperoxidase, neutrophil elastase, and nucleosomes, were estimated using the enzyme-linked immunosorbent assay. Results : Compared with the control group, the serum NET components were significantly increased in the patients 1 week after ROSC (all P < 0.05). These components were significantly higher in the nonsurvivor group than in the survivor group (all P < 0.05). Spearman correlational analysis revealed that the components were positively correlated with Acute Physiology and Chronic Health Evaluation II scores (both P < 0.05). Binary logistic regression analysis indicated that serum cfDNA, CitH3, and nucleosomes on days 1 and 3 after ROSC were independent predictors of 28-day all-cause mortality. Furthermore, these parameters on day 1 after ROSC had the biggest areas under the receiver operating characteristic curves (0.876, 0.862, and 0.861, respectively). Conclusions: Elevated serum levels of cfDNA, CitH3, myeloperoxidase, neutrophil elastase, and nucleosomes were positively correlated with disease severity after ROSC. However, only serum CitH3, cfDNA, and nucleosomes on day 1 after ROSC showed a good predictive value for 28-day all-cause mortality.

The role of organoids in cancer research.

Organoids are established through in vitro 3D culture, and they can mimic the structure and physiological functions of organs or tissues in vivo. Organoids have attracted much attention in recent years. They can provide a reliable technology platform for cancer research and treatment and are a valuable preclinical model for academic research and personalized medicine. A number of studies have confirmed that organoids have great application prospects in new drug development, drug screening, tumour mechanism research, and precision medicine. In this review, we mainly focus on recent advances in the application of organoids in cancer research. We also discussed the opportunities and challenges facing organoids, hoping to indicate directions for the development of organoids in the future.

Improvement of Core-Shell Lightweight Aggregate by Modifying the Cement-EPS Interface.

To improve the interfacial compatibility between cement matrix and expanded polystyrene (EPS) in core-shell lightweight aggregates (CSLA), the effects of sodium silicate, polyvinyl acetate (PVA) emulsion, vinyl acetate-ethylene (VAE) emulsion, acrylic acid, and acetic acid on the cement-EPS interface were investigated. The density of the interface was studied by scanning electron microscopy (SEM), and the effect of interfacial agents on the hydration process of cement was studied by the heat of hydration and induction resistivity. The macroscopic properties of the interface of the CSLA were characterized by the "leak-white" rate, drop resistance, and numerical crushing strength. The results show that the sodium silicate densifies the interface by generating hydration products on the EPS surface. At the same time, organic acid enhances the interfacial properties of EPS and cement by increasing the surface roughness, and allowing hydration products to grow in the surface micropores. In terms of the cement hydration process, both interfacial agents delay the cement hydration. Above all, with comprehensive interface properties, "leak-white" rate, and mechanical properties, VAE emulsion and sodium silicate can achieve the best performance with a final crushing resistance of 5.7 MPa, which had a 46% increase compared with the reference group.

A Robust INS/USBL/DVL Integrated Navigation Algorithm Using Graph Optimization.

The Autonomous Underwater Vehicle (AUV) is usually equipped with multiple sensors, such as an inertial navigation system (INS), ultra-short baseline system (USBL), and Doppler velocity log (DVL), to achieve autonomous navigation. Multi-source information fusion is the key to realizing high-precision underwater navigation and positioning. To solve the problem, a fusion scheme based on factor graph optimization (FGO) is proposed. Due to multiple iterations and joint optimization of historical data, FGO could usually show a better performance than the traditional Kalman filter. In addition, considering that USBL and DVL are usually heavily influenced by the environment, outliers are often present. A robust integrated navigation algorithm based on a maximum correntropy criterion and FGO scheme is proposed. The proposed algorithm solves the problem of multi-sensor fusion and non-Gaussian noise. Numerical simulations and field tests demonstrate that the proposed FGO scheme shows a better performance and robustness than the traditional Kalman filter. Compared with the traditional Kalman filtering, the positioning accuracy is improved by 5.3%, 9.1%, and 5.1% in the east, north, and height directions. It can realize a more accurate navigation and positioning of underwater multi-sensors.

Recent developments and controversies in therapeutic hypothermia after cardiopulmonary resuscitation.

Therapeutic hypothermia was recommended as the only neuroprotective treatment in comatose patients after return of spontaneous circulation (ROSC). With new evidence suggesting a similar neuroprotective effect of 36 °C and 33 °C, the term "therapeutic hypothermia" was substituted by "targeted temperature management" in 2011, which in turn was replaced by the term "temperature control" in 2022 because of new evidence of the similar effects of target normothermia and 33 °C. However, there is no clear consensus on the efficacy of therapeutic hypothermia. In this article, we provide an overview of the recent evidence from basic and clinical research related to therapeutic hypothermia and re-evaluate its application as a post-ROSC neuroprotective intervention in clinical settings.

Roles of exosomes as drug delivery systems in cancer immunotherapy: a mini-review.

Exosomes can be released by a variety of cells and participate in intercellular communication in many physiological processes in the body. They can be used as carriers of cancer therapeutic drugs and have natural delivery capabilities. Some biologically active substances on exosomes, such as major histocompatibility complex (MHC), have been shown to be involved in exosome-mediated anticancer immune responses and have important regulatory effects on the immune system. Exosome-based drug delivery systems hold great promise in future cancer immunotherapy. However, there are still substantial challenges to be overcome in the clinical application of exosomes as drug carriers. This article reviews the biological characteristics of exosome drug delivery systems and their potential applications and challenges in cancer immunotherapy.

New Insights Into PTBP3 in Human Cancers: Immune Cell Infiltration, TMB, MSI, PDCD1 and m6A Markers.

Polypyrimidine tract binding protein 3 (PTBP3) plays a critical role in post-transcriptional regulation. The role of PTBP3 in various human tumours was explored and analysed in this study based on the Cancer Genome Atlas and Gene Expression Omnibus datasets. PTBP3 was highly expressed in most tumours, such as breast invasive carcinoma, colon adenocarcinoma and hepatocellular carcinoma. PTBP3 overexpression generally predicts poor overall survival and disease-free survival in patients with adrenocortical carcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma. However, low PTBP3 expression predicts poor prognosis in kidney renal clear cell carcinoma. We also explored PTBP3 genetic alterations in different tumour tissues. The result found that the frequency of PTBP3 alteration (>4%) was the highest in uterine tumours with "mutation" as the primary type. Furthermore, we found a significant correlation between PTBP3 expression and tumour mutational burden and microsatellite instability in various human tumours, and found that PTBP3 expression was positively correlated with TMB in ACC, STAD, PAAD, LUAD, and SARC. Two enhanced phosphorylation levels of S30 and S426 in colon cancer, ovarian cancer, and uterine corpus endometrial carcinoma were found. Further analysis indicated that PTBP3 expression was positively correlated with the cancer-associated fibroblasts for most tumour types. This study also found a relationship between immune checkpoints and N6-methyladenosine-related markers and PTBP3 expression. Moreover, the "mRNA surveillance pathway" and "RNA degradation" were involved in the functional mechanisms of PTBP3. These results provide new insights for molecular studies, and integrative analysis provided a framework for determining the predictive, prognostic, and therapeutic relevance of PTBP3 in cancer patients.

Construction of a unique fluorescent probe for rapid and highly sensitive detection of glutathione in living cells and zebrafish.

A rhodamine-based fluorescent probe (Rho-GSH) was rationally designed and synthesized, using nitrobenzene as recognition group for monitoring and imaging GSH in vitro and in vivo. In the presence of GSH, Rho-GSH undergoes sequential nucleophilic substitution and spiro-ring-opening reaction, resulting the fluorescence increase of probe, which enables quantitative detection of GSH with "off-on" fluorescence. The cascade reaction also enables Rho-GSH to rapidly detect GSH (3 s). In addition, Rho-GSH exhibited outstanding selectivity in detecting GSH vs cysteine (Cys) and homocysteine (Hcy). Based on the outstanding detection performance and superior biocompatibility of Rho-GSH, it was used to visualize GSH in vitro and in vivo, demonstrating its highly selectivity for GSH detection (with respect to Cys and Hcy). Rho-GSH can help visually distinguishing cancer cells from normal cells by fluorescence imaging, demonstrating the overexpression of GSH in cancer cells. Because of the outstanding analytical capabilities of Rho-GSH for GSH detection, Rho-GSH may be useful for cancer diagnosis and clinical evaluation.

An N-nitrosation reaction-based fluorescent probe for detecting nitric oxide in living cells and inflammatory zebrafish.

Nitric oxide (NO), an essential biological messenger molecule, participates in various physiological and pathological processes. The sensitive and specific detection of NO is of great significance for understanding the biological function of NO. Here, we synthesized a fluorescent probe (Rho-NO) for highly selective detection of NO both in vitro and in vivo. The high selectivity of Rho-NO is attributed to the fact that NO is easily replaced by electron donor amino group to form N-nitrosation products, causing rhodamine spiro ring open and fluorescence emit. Rho-NO showed a good linear response to NO (0-100 µM) with a low detection limit (0.06 µM). Importantly, it exhibited excellent specificity for NO detection in human serum and was also applied for imaging NO in living cells and inflammatory model of zebrafish. This work proves the potential of Rho-NO in pathological research and disease diagnosis.

The diagnostic accuracy of mid-regional pro-adrenomedullin for sepsis: a systematic review and meta-analysis.

INTRODUCTION: The incidence and mortality of sepsis are high, and common biomarkers are not perfect. To identify a biomarker with high specificity and sensitivity for sepsis, we evaluated the current literature on the performance of mid-regional pro-adrenomedullin (MR-proADM) in the diagnosis of sepsis. EVIDENCE ACQUISITION: According to appropriate eligibility and exclusion criteria, PubMed, EMBASE, Cochrane Library, China Journal full-text Database, Wanfang Database and Chinese Journal Full Text Database were searched for "mid-regional pro-adrenomedullin," "MR-proADM," "sepsis," "pyemia," "pyohemia," "septicemia," and "blood poisoning." The publication dates considered for the search were from inception until August 31st, 2020. The risk of bias was assessed according to QUADAS-2 criteria. EVIDENCE SYNTHESIS: Eleven studies involving 2038 cases were included. MR-proADM had high sensitivity and specificity in the diagnosis of sepsis, with values of 0.83 (95% CI: 0.79-0.87) and 0.90 (95% CI: 0.83-0.94), respectively. The odds ratio of a combined diagnosis was 41.35, and the area under the curve (AUC) was 0.91. The best cut-off value for MR-proADM diagnosis of sepsis is 1-1.5 nmol/L. MR-proADM may also have value in distinguishing pathogens and identifying sepsis severity and organ failure. CONCLUSIONS: MR-proADM is an excellent biomarker for the diagnosis of sepsis with high sensitivity and specificity. The best cut-off value for MR-proADM diagnosis of sepsis is 1-1.5 nmol/L.

CT assessment of preoperative nutritional status in gastric cancer: severe low skeletal muscle mass and obesity-related low skeletal muscle mass are unfavorable factors of postoperative complications.

BACKGROUND: Computed tomography (CT) has become an important technique for assessing skeletal muscle mass. Low skeletal muscle mass (LSMM) is considered an unfavorable factor for postoperative complications in patients with gastric cancer (GC). METHODS: Patients who underwent laparoscopic gastrectomy for GC were included. Skeletal muscle mass at the third lumbar vertebra (L3) level was measured by preoperatively using CT. The patients were divided into an LSMM group and a non-LSMM group and the intergroup differences were analyzed. Furthermore, we divided the LSMM group into mild and severe LSMM subgroups. The study also analyzed the influence of obesity-related LSMM on postoperative complications. RESULTS: A total of 409 patients were enrolled; of them, 265 had LSMM and 41 had severe LSMM. LSMM was associated with age, body mass index, and Nutritional Risk Screening 2002 score. In the multivariate analysis, LSMM was not related to postoperative complications. Further analysis revealed that severe LSMM was a risk factor for postoperative complications. The study also found that the risk of postoperative complications was significantly increased in patients with obesity-related LSMM. CONCLUSIONS: LSMM was not significantly correlated with postoperative complications. Severe LSMM and obesity-related LSMM are unfavorable factors for postoperative complications with GC after gastrectomy.

A near-infrared fluorescent probe for monitoring and imaging of ß-galactosidase in living cells.

ß-Galactosidase (ß-gal) which is overexpressed in primary ovarian cancer can be employed as a valuable biomarker for ovarian cancer. Thus, monitoring and imaging endogenous ß-gal in living cells is of great importance. Herein, a dicyanoisophorone-based near-infrared (NIR) fluorescent probe 2-(5,5-dimethyl-3-((E)-4-(((2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)styryl)cyclohex-2-en-1-ylidene)malononitrile named DP-ßgal, was rationally designed and synthesized for the monitoring of ß-gal activity in living cells. In the presence of ß-gal, with the breaking of the glycosidic bond, the NIR fluorescence of the dicyanoisophorone derivative gradually recovered, enabling the fluorescence "off-on" quantitative determination of ß-gal activity. DP-ßgal has the advantages of good selectivity and high sensitivity for the detection of ß-gal, with the limit of detection (LOD) of 3.2 × 10-3 U. Furthermore, based on its advantages of long-wavelength emission and excellent biocompatibility, the practical applications of DP-ßgal in NIR imaging of ß-gal in living ovarian cancer cells (SKOV-3) were demonstrated.

Risk of Dyslipidemia Associated with VEGF/VEGFR Inhibitors: A Meta-Analysis.

OBJECTIVE: This meta-analysis was performed to investigate hyperlipidemia in patients with carcinoma treated with vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors. METHODS: We searched for eligible phase II and III studies using PubMed and Embase databases. We then summarized reported occurrences of hyperlipidemia in patients with different cancers. Relative risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by Revman 5 software in meta-analysis. RESULTS: Eleven trials (4760 subjects) were included in this meta-analysis. Overall, VEGF/VEGFR inhibitors had similar incidence of hypertriglyceridemia (RR = 0.56, 95% CI = 0.24%-1.32%, P = .19), hypercholesterolemia (RR = 1.15, 95% CI = 0.42%-3.16%, P = .78), and LDL elevation (RR = 4.58, 95% CI = 0.80%-26.25%, P = .09) than control drugs, under high heterogeneity. Moreover, subgroup analyses found VEGF/VEGFR inhibitors had higher incidence of hypertriglyceridemia (RR = 1.86, 95% CI = 1.37%-2.52%, P < .001) and hypercholesterolemia (RR = 2.95, 95% CI = 2.02%-4.30%, P = .006) than blank control or placebo control drugs (placebo-controlled-group), although with lower incidence of hypertriglyceridemia (RR = 0.29, 95% CI = 0.12%-0.69%, P < .001) and hypercholesterolemia (RR = 0.39, 95% CI = 0.28%-0.56%, P < .001) than positive control drugs (positive-controlled-groups). CONCLUSION: The use of VEGF/VEGFR inhibitors, especially the multitargeted VEGFR tyrosine kinase inhibitors (VEGFR-TKIs), was associated with higher risk of hyperlipidemia than the use of placebo, but this risk was less than that associated with mTOR or FGFR inhibitors. It indicated that clinicians need to pay close attention to the occurrence of hyperlipidemia in VEGFR-TKIs therapies.