Identification of common mechanisms and biomarkers of atrial fibrillation and heart failure based on machine learning.

AIMS: Atrial fibrillation (AF) is the most common arrhythmia. Heart failure (HF) is a disease caused by heart dysfunction. The prevalence of AF and HF were progressively increasing over time. The co-existence of AF and HF presents a significant therapeutic challenge. In order to provide new ideas for the diagnosis of AF and HF, it is necessary to carry out biomarker related studies. METHODS AND RESULTS: The training set and validation set data of AF and HF patient samples were downloaded from the GEO database, 'limma' was used to compare the differences in gene expression levels between the disease group and the normal group to screen for differentially expressed genes (DEGs). Weighted correlation network analysis (WGCNA) identified the modules with the highest positive correlation with AF and HF. Functional enrichment and PPI network construction of key genes were carried out. Biomarkers were screened by machine learning. The infiltration of immune cells in AF and HF groups was evaluated by R-packet 'CIBERSORT'. The miRNA network was constructed and potential therapeutic agents for biomarker genes were predicted through the drugbank database. Through WGCNA analysis, it was found that the modules most positively correlated with AF and HF were MEturquoise (r = 0.21, P value = 0.09) and MEbrown (r = 0.62, P value = 8e-12), respectively. We screened 25 genes that were highly correlated with both AF and HF. Lasso regression analysis results showed 7 and 20 core genes in AF and HF groups, respectively. The top 20 important genes in AF and HF groups were obtained as core genes by RF model analysis. Four biomarkers were obtained after the intersection of core genes in four groups, namely, GLUL, NCF2, S100A12, and SRGN. The diagnostic efficacy of four genes in AF validation sets was good (AUC: GLUL 0.76, NCF2 0.64, S100A12 0.68, and SRGN 0.76), as well as in the HF validation set (AUC: GLUL 0.76, NCF2 0.84, S100A12 0.92, and SRGN 0.68). The highest correlation with neutrophils was observed for GLUL, NCF2, and S100A12, while SRGN exhibited the strongest correlation with T cells CD4 memory resting in the AF group. GLUL, NCF2, S100A12, and SRGN were most associated with neutrophils in the HF group. A total of 101 miRNAs were predicted by four genes, and GLUL, NCF2, and S100A12 predicted a total of 10 potential therapeutic agents. CONCLUSIONS: We identified four biological markers that are highly correlated with AF and HF, namely, GLUL, NCF2, S100A12, and SRGN. Our findings provide theoretical basis for the clinical diagnosis and treatment of AF and HF.

Local delivery of stem cell spheroids with protein/polyphenol self-assembling armor to improve myocardial infarction treatment via immunoprotection and immunoregulation.

Stem cell therapies have shown great potential for treating myocardial infarction (MI) but are limited by low cell survival and compromised functionality due to the harsh microenvironment at the disease site. Here, we presented a Mesenchymal stem cell (MSC) spheroid-based strategy for MI treatment by introducing a protein/polyphenol self-assembling armor coating on the surface of cell spheroids, which showed significantly enhanced therapeutic efficacy by actively manipulating the hostile pathological MI microenvironment and enabling versatile functionality, including protecting the donor cells from host immune clearance, remodeling the ROS microenvironment and stimulating MSC's pro-healing paracrine secretion. The underlying mechanism was elucidated, wherein the armor protected to prolong MSCs residence at MI site, and triggered paracrine stimulation of MSCs towards immunoregulation and angiogenesis through inducing hypoxia to provoke glycolysis in stem cells. Furthermore, local delivery of coated MSC spheroids in MI rat significantly alleviated local inflammation and subsequent fibrosis via mediation macrophage polarization towards pro-healing M2 phenotype and improved cardiac function. In general, this study provided critical insight into the enhanced therapeutic efficacy of stem cell spheroids coated with a multifunctional armor. It potentially opens up a new avenue for designing immunomodulatory treatment for MI via stem cell therapy empowered by functional biomaterials.

The efficacy and safety of using a combination of rocuronium and sugammadex for awake craniotomy anesthesia: A randomized clinical trial.

BACKGROUND: Awake craniotomy (AC) is a neurosurgical method for the resection of brain lesions located in eloquent areas to achieve maximal and safe resection. A patient's arousal quality is essential for the success of the operation. This study compared the arousal time and quality after AC achieved by 2 different drug combinations: rocuronium with sugammadex and propofol with remifentanil. METHODS: This prospective, randomized, controlled trial included 42 adult patients undergoing AC with a laryngeal mask, who were randomly assigned to either a rocuronium-sugammadex group (RS; n = 21) or a propofol-remifentanil without muscle relaxant group (nRS; n = 21). The primary outcomes were the arousal time and arousal quality. The secondary outcomes included the number of laryngeal mask airway (LMA) adjustments and diaphragmatic excursion length. RESULTS: This study included 42 participants. The median (IQR) arousal time was 13.5 minutes (7-20) in the RS group and 21 minutes (16.5-26.5) in the nRS group (P = .005). There was no significant difference in arousal quality between the 2 groups (P = .229). LMA adjustments were significantly less frequent in the nRS group than in the RS group [0.25 times (±0.62) vs 1.26 times (±1.17), P = .001]. Adverse events, such as spontaneous movements and brain swelling, were more frequent in the nRS group than in the RS group. CONCLUSIONS: Using a combination of rocuronium and sugammadex with propofol and remifentanil may shorten the awakening time, reduce the duration of laryngeal mask adjustment, and do not affect the arousal quality and postoperative outcomes for patients undergoing awake craniotomy, compared to propofol and remifentanil alone.

Development of target-based cell membrane affinity ultrafiltration technology for a simplified approach to discovering potential bioactive compounds in natural products.

Target-based drug discovery technology based on cell membrane targets has gained significant traction and has been steadily advancing. However, current methods still face certain limitations that need to be addressed. One of the challenges is the laborious preparation process of screening materials, which can be time-consuming and resource-intensive. Additionally, there is a potential issue of non-specific adsorption caused by carrier materials, which can result in false-positive results and compromise the accuracy of the screening process. To address these challenges, this paper proposes a target-based cell membrane affinity ultrafiltration technology for active ingredient discovery in natural products. In this technique, the cell membranes of human lung adenocarcinoma epithelial cells (A549) with a high expression of epidermal growth factor receptor (EGFR) were incubated with candidate drugs and then transferred to an ultrafiltration tube. Through centrifugation, components that interacted with EGFR were retained in the ultrafiltration tube as "EGFR-ligand" complex, while the components that did not interact with EGFR were separated. After thorough washing and eluting, the components interacting with EGFR were dissociated and further identified using LC-MS, enabling the discovery of bioactive compounds. Moreover, the target-based cell membrane affinity ultrafiltration technology exhibited commendable binding capacity and selectivity. Ultimately, this technology successfully screened and identified two major components from the Curcumae Rhizoma-Sparganii Rhizoma (CS) herb pair extracts, which were further validated for their potential anti-tumor activity through pharmacological experiments. By eliminating the need for laborious preparation of screening materials and the potential non-specific adsorption caused by carriers, the development of target-based cell membrane affinity ultrafiltration technology provides a simplified approach and method for bioactive compounds discovery in natural sources.

Butterflies in the gut: the interplay between intestinal microbiota and stress.

Psychological stress is a global issue that affects at least one-third of the population worldwide and increases the risk of numerous psychiatric disorders. Accumulating evidence suggests that the gut and its inhabiting microbes may regulate stress and stress-associated behavioral abnormalities. Hence, the objective of this review is to explore the causal relationships between the gut microbiota, stress, and behavior. Dysbiosis of the microbiome after stress exposure indicated microbial adaption to stressors. Strikingly, the hyperactivated stress signaling found in microbiota-deficient rodents can be normalized by microbiota-based treatments, suggesting that gut microbiota can actively modify the stress response. Microbiota can regulate stress response via intestinal glucocorticoids or autonomic nervous system. Several studies suggest that gut bacteria are involved in the direct modulation of steroid synthesis and metabolism. This review provides recent discoveries on the pathways by which gut microbes affect stress signaling and brain circuits and ultimately impact the host's complex behavior.

Fgf21-Dubosiella axis mediates the protective effects of exercise against NAFLD development.

AIM: To explore the mechanism of gut microbiota mediates protective effects of exercise against non-alcoholic fatty liver disease (NAFLD) development. MAIN METHODS: The male C57BL/6 mice were fed with high fat food (HFD) or normal diet (CON) respectively, and the obese mice were randomly divided into sedentariness (HFD) and exercise groups (HFD + Exe). The total intervention period was 18 weeks. Antibiotic treatment and fecal microbiota transplantation were applied to evaluate gut microbiota mediates the protective effects of exercise against NAFLD development. 16S rDNA profiling of gut microbiota and extracorporeal rehydration of Dubosiella newyorkensis were performed to identify the crucial role of Dubosiella in NAFLD improvement during exercise training. FGF21 knock-out mice were used to reveal the potential mechanism of exercise increased the abundance of Dubosiella. RT-PCR, Western blot, Histopathological examinations and Biochemical testing were performed to evaluate the lipid deposition and function in the liver. KEY FINDINGS: Treadmill exercise significantly ameliorated hepatic function and mitigated lipid accumulation in NAFLD mice, and these hepatoprotective benefits were mostly mediated by the Dubosiella. In addition, the increased abundance of Dubosiella during exercise training was modulated by FGF21 specifically. SIGNIFICANCE: In short, Dubosiella, chiefly regulated by FGF21 signaling during exercise training, has been discovered to govern the protective impacts of exercising counter to the development of NAFLD and exhibits a promising treatment target for NAFLD.

Association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus: A prospective study of the Hong Kong Diabetes Register.

AIMS: To examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D). METHODS: Between July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia. RESULTS: After excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association. CONCLUSIONS: Insomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D.

Significance of alkaline Phosphatase After Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma.

BACKGROUND: The inexpensive and readily available biomarkers for cytokine release syndrome (CRS) grading and prognosis assessment in chimeric antigen receptor (CAR)-T therapy are currently lacking. This study examined the significance of alkaline phosphatase (ALP) after CAR-T therapy in patients with relapsed/refractory multiple myeloma (MM). METHODS: This cohort study included 27 patients with relapsed/refractory MM who were treated with CAR-T cells between December 2017 and October 2021. Patients were classified into 2 groups: normal ALP group (peak ALP <125 U/L, n = 10) and high ALP group (peak ALP ≥125 U/L, n = 17). RESULTS: Within 1 month of CAR-T cell infusion, the incidence of ALP increases was 63%. We found that ALP levels began to rise in the second week, peaked in the third and fourth weeks, and began to decline in the second month. Moreover, the ALP levels in previous chemotherapy-responsive period were significantly lower than those after CAR-T therapy. Statistical analysis found that patients with increased ALP exhibited higher alanine aminotransferase and aspartate aminotransferase levels, higher and longer CAR-T cell proliferation, more serious CRS, higher cytokine and ferritin levels, and higher initial response rates. In addition, the duration of ALP increase was parallel to the duration of CAR-T expansion. Multivariable Cox-regression analysis showed that peak ALP was the independent predictor for progression-free survival (PFS) (HR = 0.029, 95% CI: 0.002-0.369). CONCLUSIONS: Our results suggest that the ALP levels after CAR-T therapy could serve as a suitable biomarker for monitoring CAR-T cell proliferation, CRS grading, and prognosis in patients with MM.

Progress in molecular mechanisms of coronary microvascular dysfunction.

Coronary microvascular dysfunction is a high-risk factor for many cardiovascular events. However, because of multiple risk factors and limited understanding about its underlying pathophysiological mechanisms, it was easily misdiagnosed. Therefore, its clinical diagnosis and treatment were greatly restricted. Coronary microcirculation refers to microvessels that play an important role in the physiological regulation of myocardial perfusion and regulating blood flow distribution, fulfilling myocardial metabolic needs and moderating peripheral vascular resistance. In coronary microvascular dysfunction, vascular endothelial celldamage is a critical link. The main feature of early coronary microvascular dysfunction is the impairment of endothelial cell proliferation, adhesion, migration, apoptosis, and secretion. Moreover, coronary microvascular dysfunction risk factors include hyperglycemia, lipid metabolism disorders, ischemia-reperfusion injury, aging, and hypertension, similar to coronary atherosclerosis. There are various mechanisms by which these risk factors harm endothelial function and cause microcirculatory disturbances. Therefore, we reviewed coronary microvascular dysfunction's risk factors and pathogenesis in this article.

Perspectives and Considerations of IABP in the Era of ECMO for Cardiogenic Shock.

The development of mechanical circulatory support (MCS) has been rapid, and its use worldwide in patients with cardiogenic shock is increasingly widespread. However, current statistical data and clinical research do not demonstrate its significant improvement in the patient prognosis. This review focuses on the widely used intra-aortic balloon pumps (IABP) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), analyzing and comparing their characteristics, efficacy, risk of complications, and the current exploration status of left ventricular mechanical unloading. Subsequently, we propose a rational approach to viewing the negative outcomes of current MCS, and look ahead to the future development trends of IABP.

Semi-supervised inference for nonparametric logistic regression.

We consider the problem of estimating the nonparametric function in nonparametric logistic regression under semi-supervised framework, where a relatively small size labeled data set collected by case-control sampling and a relatively large size of unlabeled data containing only observations of predictors are available. This problem arises in various applications when the outcome variable is expensive or difficult to be observed directly. A two-stage nonparametric semi-supervised estimator based on spline method is proposed to estimate the target regression function by maximizing the likelihood function of the labeled case-control data. The unlabeled data are used in the first stage for estimating the density function that involves in the likelihood function. The consistency and functional asymptotic normality of the semi-supervised two-stage estimator are established under mild conditions. The proposed method, by making use of the unlabeled data, produces more efficient estimation of the target function than the traditional supervised counterpart. The performance of the proposed method is evaluated through extensive simulation studies. An application is illustrated with an analysis of a skin segmentation data.

Environmental DNA metabarcoding revealed the impacts of anthropogenic activities on phytoplankton diversity in Dianchi Lake and its three inflow rivers.

Phytoplankton diversity is closely related to environmental variables and has been widely used in ecological health assessment of rivers and lakes. Combining advantages of DNA-based identification and high-throughput sequencing technology, environmental DNA (eDNA) metabarcoding permits a new measurement for biodiversity monitoring in aquatic ecosystems. However, it had rarely been used to explore the variability and similarity of phytoplankton diversity between lake and its inflow rivers and the effects of environmental variables on phytoplankton. This study utilized eDNA metabarcoding to investigate the spatial distribution of phytoplankton and the impacts of environmental variables on the phytoplankton diversity in Dianchi Lake (one of the most polluted urban lakes in China) and its main inflow rivers (Panlong River, Baoxiang River, and Chai River). A total of 243 distinct phytoplankton taxa were detected, covering 9 phyla, 30 classes, 84 orders, and 132 families, and the taxonomic richness of rivers was higher than that of Dianchi Lake. Distinct biodiversity patterns (e.g., community structure, dominant taxon, ɑ-diversity) were exhibited among Dianchi Lake and its three inflow rivers, but similar biodiversity patterns were also observed in Dianchi Lake and the estuarine sites. The patterns of phytoplankton diversity were closely related to environmental variables, which were associated with pollution sources from different anthropogenic activities (e.g., urbanization, water diversion, industrial and agricultural activities). The primary environmental variables correlated with phytoplankton diversity varied in different habitats. The total phosphorus (TP) and chemical oxygen demand (COD) positively correlated with the phytoplankton community structures in Dianchi Lake, whereas negatively correlated in Panlong River and Baoxiang River. The total nitrogen (TN) positively correlated with the phytoplankton community structures in Baoxiang River and Chai River but negatively correlated in Dianchi Lake. Overall, this study provides insights on the phytoplankton diversity monitoring and the conservation of its diversity and healthy management of Dianchi Lake.

TIPE2 regulates the response of BV2 cells to lipopolysaccharide by the crosstalk between PI3K/AKT signaling and microglia M1/M2 polarization.

Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2) is a crucial negative regulator of both adaptive and innate immunity, which helps maintain the dynamic balance of the immune system by negatively regulating the signaling of T-cell receptors (TCR) and Toll-like receptors (TLR). In this study, we aimed to investigate the role and molecular mechanism of TIPE2 using a lipopolysaccharide (LPS)-induced inflammatory injury model in BV2 cells. Specifically, we constructed a BV2 cell line of TIPE2-overexpression or TIPE2-knockdown via lentiviral transfection. Our results demonstrated that overexpression of TIPE2 downregulated the expression of pro-inflammatory cytokines IL-1ß and IL-6, which was reversed by knockdown of TIPE2 in the inflammation model of BV2 cells. In addition, overexpression of TIPE2 resulted in the conversion of BV2 cells to the M2 phenotype, while the knockdown of TIPE2 promoted the transformation of BV2 cells to the M1 phenotype. Notably, our co-culture experiments with neuronal cells SH-SY5Y showed that the overexpression of TIPE2 in inflammation-injured BV2 cells exhibited a protective effect on the neuronal cells. Finally, western blot analysis demonstrated that TIPE2 significantly reduced the expression of p-PI3K, p-AKT, p-p65, and p-IκBα in LPS treated BV2 cells, and inhibited the activation of NF-κB through the dephosphorylation of PI3K/AKT. These results suggest that TIPE2 plays an important role in mediating neuroinflammatory responses and may be involved in neuroprotection by modulating the phenotypic changes of BV2 cells and regulating the pro-inflammatory responses through the PI3K/AKT and NF-κB signaling pathways. In conclusion, our study provides new insights into the crucial role of TIPE2 in regulating neuroinflammatory responses and highlights its potential as a therapeutic target for neuroprotection.

Elemene induces cell apoptosis via inhibiting glutathione synthesis in lung adenocarcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Curcuma wenyujin Y.H. Chen & C. Ling, also known as Wen-E-Zhu, has been used for cancer treatment since ancient times, with roots dating back to the Song Dynasty. Elemene (EE), a sesquiterpene extract with potent anticancer properties, is extracted from Wen-E-Zhu, with ß-elemene (BE) being its main active compound, along with trace amounts of ß-caryophyllene (BC), γ-elemene and δ-elemene isomers. EE has demonstrated broad-spectrum anti-cancer effects and is commonly used in clinical treatments for various types of malignant cancers, including lung cancer. Studies have shown that EE can arrest the cell cycle, inhibit cancer cell proliferation, and induce apoptosis and autophagy. However, the exact mechanism of its anti-lung cancer activity remains unclear and requires further research and investigation. AIM OF THE STUDY: In this study, the possible mechanism of EE and its main active components, BE and BC, against lung adenocarcinoma was investigated by using A549 and PC9 cell lines. MATERIALS AND METHODS: The subcutaneous tumor model of nude mice was constructed to evaluate the efficacy of EE in vivo, then the in vitro half-inhibitory concentration (IC50) of EE and its main active components, BE and BC, on A549 and PC9 cells at different concentrations were determined by CCK-8. Flow cytometry was used to detect the apoptosis and cycle of A549 and PC9 cells treated with different concentrations of BE and BC for 24 h. Non-targeted metabolomics analysis was performed on A549 cells to explore potential target pathways, which were subsequently verified through kit detection and western blot analysis. RESULTS: Injection of EE in A549 tumor-bearing mice effectively suppressed cancer growth in vivo. The IC50 of EE and its main active components, BE and BC, was around 60 µg/mL. Flow cytometry analysis showed that BE and BC blocked the G2/M and S phases of lung adenocarcinoma cells and induced apoptosis, leading to a significant reduction in mitochondrial membrane potential (MMP). Results from non-targeted metabolomics analysis indicated that the glutathione metabolism pathway in A549 cells was altered after treatment with the active components. Kit detection revealed a decrease in glutathione (GSH) levels and an increase in the levels of oxidized glutathione (GSSG) and reactive oxygen (ROS). Supplementation of GSH reduced the inhibitory activity of the active components on lung cancer and also decreased the ROS content of cells. Analysis of glutathione synthesis-related proteins showed a decrease in the expression of glutaminase, cystine/glutamate reverse transporter (SLC7A11), and glutathione synthase (GS), while the expression of glutamate cysteine ligase modified subunit (GCLM) was increased. In the apoptosis-related pathway, Bax protein and cleaved caspase-9/caspase-9 ratio were up-regulated and Bcl-2 protein was down-regulated. CONCLUSIONS: EE, BE, and BC showed significant inhibitory effects on the growth of lung adenocarcinoma cells, and the mechanism of action was linked to the glutathione system. By down-regulating the expression of proteins related to GSH synthesis, EE and its main active components BE and BC disrupted the cellular redox system and thereby promoted cell apoptosis.

The role of alerting in the attentional boost effect.

Stimuli presented simultaneously with behaviorally relevant events (e.g., targets) are better memorized, an unusual effect defined as the attentional boost effect (ABE). We hypothesized that all types of behaviorally relevant events, including attentional cues, can promote the encoding process for the stimuli paired with them, and the attentional alerting network can amplify the ABE. The two experiments we conducted demonstrated that not all behaviorally relevant events, including alerting cues, benefit the processing of concurrently paired stimuli. We also found that the presence of a cue prior to a target can extend the memory advantage produced by target detection, but this advantage can only be observed within a limited range of time. Overall, our study provides the first evidence that the alerting network plays an important role in the ABE.

Novel biofortification candidate: MTP1 increases microelement contents and decreases toxic heavy metal accumulation in grains.

Decreases in microelement contents and increases in toxic element levels seriously affect crop growth and human health. Thus, improving the elemental content of food crops is an important environmental issue for enhancing crop production and quality. Previous research showed that metal tolerance protein 1 (MTP1) is localized at the vacuole membrane, wherein it mediates the translocation of heavy metal ions. Therefore, LmMTP1 was isolated from annual ryegrass (Lolium multiflorum). Real-time quantitative PCR analyses revealed LmMTP1 expression increased significantly in the roots after Zn, Co, and Cd treatments. Confocal microscopy images indicated LmMTP1 was localized at the vacuole membrane. The expression of LmMTP1 in transgenic yeast and rice resulted in increased Zn, Co, and Cd tolerance. The examination of heavy metal contents detected increases in the Zn and Co contents, but decreases in the Cd contents, of yeast and rice. Moreover, the grains of LmMTP1-expressing transgenic rice had higher Zn/Co contents and lower Cd contents than wild-type rice grains. These results imply that LmMTP1 influences Zn, Co, and Cd tolerance and accumulation. Furthermore, LmMTP1 might be a novel biofortification-related candidate gene useful for improving the storage of essential elements and eliminating toxic heavy metals from crops.

Risk factors for ASD : Risk Factors for Autism Spectrum Disorder in Shanghai, China: A Population-based Case-control Study.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that brings heavy burdens to families and the society. This case-control study explored risk factors for ASD based on 74,252 children aged 3-12 years who were recruited from general education kindergartens, primary schools, and special education schools in Shanghai, China. One hundred ninety-two children were identified with ASD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition. Male sex, the presence of anoxia or asphyxia at birth, artificial feeding, adverse maternal psychological status, complications during pregnancy and higher paternal education were associated with ASD even after controlling for age, residential district, family history of mental disorders, parental personality, and amount of daily TV viewing.

The correlation factors and prognostic significance of coagulation disorders after chimeric antigen receptor T cell therapy in hematological malignancies: a cohort study.

Background: Along with cytokine release syndrome (CRS) and neurotoxicity, coagulation disorder is a common early complication of chimeric antigen receptor (CAR)-T cell therapy. However, the mechanisms and prognostic significance of CAR-T-related coagulation disorders are not fully known. This study explored the possible correlation factors and prognostic significance of coagulation disorders after CAR-T cell infusion in patients with relapsed/refractory hematological malignancies. Methods: This cohort study included 56 patients with relapsed/refractory hematological malignancies who were treated with CAR-T cells between April 2017 and February 2022. The median follow-up was 26.8 months. Coagulation disorders were defined as the abnormality in at least one coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer. The correlation factors of coagulation disorders were analyzed using Wilcoxon rank-sum test, Fisher's exact test, paired t-test and Spearman correlation coefficient. The prognostic significance of coagulation disorders was analyzed using Kaplan-Meier method and stepwise multivariate Cox regression model. Results: The incidence of coagulation disorders was 59% within 1 month of CAR-T cell infusion. PT prolongation, APTT prolongation, TT prolongation, and D-dimer increase peaked at a median of 6-9 days, and fibrinogen decreased to its lowest value at a median of 12 days. Coagulation disorders in patients with severe CRS were more significant (P<0.001). Abnormality of coagulation parameters was closely related to cytokines, CAR-T cells, liver function parameters, and von Willebrand Factor (VWF) in both peak level and peak time (P<0.05). Statistical analysis showed that coagulation disorders were associated with higher initial response rates (TT, P=0.006; D-dimer, P=0.010) and also longer progression-free survival (PFS) (PT, P=0.017; APTT, P=0.018; TT, P=0.001; Fibrinogen, P=0.003; D-dimer, P<0.001) in CAR-T therapy, with TT prolongation (HR =0.279, 95% CI: 0.099-0.782, P=0.015) and D-dimer increase (HR =0.218, 95% CI: 0.087-0.548, P=0.001) independent predictors for PFS. Conclusions: The protection of liver and endothelial cells may reduce CAR-T-related coagulation disorders. Further, coagulation disorders occurring within 1 month of CAR-T cell infusion can serve as a new predictor for prognosis in patients with hematological malignancies.

Different Prevalence of Neuropathic Pain and Risk Factors in Patients with Knee Osteoarthritis at Stages of Outpatient, Awaiting and after Total Knee Arthroplasty.

OBJECTIVE: Neuropathic pain (NP) plays an important role in patients with knee osteoarthritis (KOA). However, the prevalence of NP at different treatment stages including outpatient, awaiting and after total knee arthroplasty (TKA) have not been compared. The understanding of this issue and identify risk factors can help physicians develop individualized strategies to manage the pain of KOA. Therefore, the aim of the study is to investigate the prevalence and risk factors of NP at different treatment stages of KOA. METHODS: Patients diagnosed as KOA between August 2016 and August 2020 were enrolled in this cross-sectional study and divided into three groups according to treatment stage, including outpatient stage, awaiting TKA stage (pre-TKA) and after TKA stage (post-TKA). A numeric rating scale (NRS) and PainDETECT questionnaire were used to evaluate nociceptive pain and NP. Patient demographics, radiological assessments using Kellgren-Lawrence (K-L) grade, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were analyzed. Data analysis and statistics were processed using SPSS 20.0 and examined by ANOVA with/without Bonferroni correction or Kruskal-Wallis test. A chi-square test was used to determine cross-table data and calculate the odds ratio (OR) value. RESULTS: Of the 921 patients, the prevalence of possible and likely NP was 17.5% (56/320) and 2.5% (8/320) in the pre-TKA group compared with 3.4% (8/233) and 0.4% (1/233) in the outpatient group and 1.4% (5/368) and 0.5% (2/368) in the post-TKA group, respectively. In the pre-TKA group, higher NRS (NRS >3; OR = 10.65, 95% CI: 3.25-34.92, P < 0.001) and WOMAC pain score (score > 10; OR = 4.88, 95% CI: 2.38-10.01, P < 0.001) conferred an increased risk of unclear pain. Age, gender, BMI and K-L grade showed no significant differences among the unlikely, possible and likely NP groups. CONCLUSION: Prevalence of NP is different at stages of out-patient, awaiting and after TKA in patients with KOA. Patients awaiting TKA have the highest prevalence of NP compared with patients in outpatient and post-TKA groups. In the patients waiting for TKA, higher NRS (NRS >3) and WOMAC pain scores (score > 10) are risk factors of NP.

Coupled process of in-situ sludge fermentation and riboflavin-mediated nitrogen removal for low carbon wastewater treatment.

Volatile fatty acid recovery from waste activated sludge (WAS) was highly suggested to supplement carbon source for nitrogen removal. However, it was not easy to separate them from the metabolites under the ex-situ fermentation. In this study, in-situ WAS fermentation combined in the denitrification system was established to treat low carbon wastewater (COD/TN = 4), and riboflavin was employed as a redox mediator. This coupled process could simultaneously enhance the WAS fermentation and nitrogen removal, and riboflavin could significantly enrich the fermentative bacteria (Firmicutes phylum), denitrifying bacteria (Denitratisoma genus) and related functional genes (narGHJI, napABC, nirKS, nosZ, norBC), generating more available carbon sources for efficient nitrogen removal. This resulted in the effluent TN (<15 mg/L) satisfying the required discharge standard in China. This study provided new insights into the efficient nitrogen removal from low carbon wastewater, realizing the carbon-neutral operation of new concept wastewater treatment plant in China.