Efficacy and safety of telitacicept in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled, phase 2 trial.

OBJECTIVE: To evaluate the efficacy and safety of telitacicept in adult patients with primary SS (pSS) in a phase II randomized double-blind placebo-controlled trial. METHODS: Patients with pSS with positive anti-SSA antibody and ESSDAI ≥ 5 were randomly assigned, in a 1:1:1 ratio, to receive weekly subcutaneous telitacicept 240 mg, 160 mg, or placebo for 24 weeks. The primary end point was the change from baseline in the ESSDAI at week 24. Safety was monitored. RESULTS: A total of 42 patients were enrolled and randomized (n = 14 per group). Administration of telitacicept 160 mg resulted in a significant reduction in ESSDAI score from baseline to week 24 compared with placebo (P < 0.05). The placebo-adjusted least-squares mean change from baseline was -4.3 (95% CI -7.0, -1.6; P = 0.002). While, mean change of ESSDAI in telitacicept 240 mg was -2.7(-5.6-0.1) with no statistical difference when compared that in placebo group (P = 0.056). In addition, MFI-20 and serum immunoglobulins decreased significantly (P < 0.05) at week 24 in both telitacicept groups compared with placebo. No serious adverse events were observed in the telitacicept treating group. CONCLUSION: Telitacicept showed clinical benefits and good tolerance and safety in the treatment of pSS. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04078386.

Identification of large yellow croakers (Larimichthys crocea) scavenger receptor genes: Involvement in immune response to Pseudomonas plecoglossicida infection and hypoxia-exposure experiments.

Scavenger receptors (SRs) are pattern recognition receptors involved in the innate immune defense against pathogen infection in fish. However, there has not been much research done on teleosts. In this study, 18 members of the SR gene family were found in large yellow croaker. The identification of the SR gene family showed that the protein length of SR members in large yellow croaker were quite different, and most SR genes were distributed in nuclear and endoplasmic. The evolutionary relationship, exon/intron structure and motif analysis revealed that members of the SR gene family were highly conserved. The results of the expression profiles after Pseudomonas plecoglossicida infection and hypoxia-exposure demonstrated that SR members were involved in inflammatory reactions. Especially, COLEC12 and SCARF1 exhibited substantial changes in response to both P. plecoglossicida and hypoxia stress, indicating their possible immunological functions. The result of this study revealed that SR genes played a vital part in the innate immune response of large yellow croaker, and would give important details for a deeper comprehension of the SR gene family's regulation mechanism under various conditions in large yellow croaker.

Genome-wide identification and characterization of large yellow croaker (Larimichthys crocea) suppressors of cytokine signaling (SOCS) in immune response to Pseudomonas plecoglossicida infection and acute hypoxia stress.

The suppressor of cytokine signaling (SOCS) gene family is a group of genes involved in the negative regulation of cytokine signal transduction. The members of this family play a crucial role in regulating immune and inflammatory processes. However, comprehensive investigations of these genes have not yet been conducted in the economically significant fish large yellow croaker (Larimichthys crocea). In this study, a total of 13 SOCS genes (LcSOCS1a, LcSOCS1b, LcSOCS2, LcSOCS3a, LcSOCS3b, LcSOCS4, LcSOCS5a, LcSOCS5b, LcSOCS6, LcSOCS7a, LcSOCS7b, LcCISHa and LcCISHb) were identified and analyzed in L. crocea. The phylogenetic tree revealed a high conservation of SOCS genes in evolution, and the gene structure and motif analysis indicated a high similarity in the structure of LcSOCSs in the same subfamily. In addition, the expression patterns of LcSOCSs showed that LcSOCS1b was significantly down-regulated in all time under acute hypoxia stress, but it was markedly up-regulated throughout the entire process after P. plecoglossicida infection, revealing its different immune effects to two stresses. Besides, LcSOCS2a, LcSOCS6 and LcSOCS7a only participated in acute hypoxic stress, while LcSOCS5a was more sensitive to P. plecoglossicida infection. In summary, these results indicated that SOCS genes were involved in stress responses to both biological and non-biological stimuli, setting the foundation for deeper study on the functions of SOCS genes.

Efficacy and safety of dabigatran and rivaroxaban in atrial fibrillation patients with impaired liver function: a multicenter retrospective cohort study.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients with impaired liver function (ILF) have not been sufficiently studied. The aim of this study was to evaluate the efficacy and safety of DOACs for stroke prevention in patients with AF and ILF. METHOD: This study was based on data from 15 centers in China, including 4,982 AF patients. The patients were divided into 2 subgroups based on their liver function status: patients with normal liver function (NLF)(n = 4213) and patients with ILF (n = 769). Logistic regression analysis was used to investigate the risk of total bleeding, major bleeding, thromboembolism, and all-cause deaths in AF patients with NLF and ILF after taking dabigatran or rivaroxaban, respectively. RESULTS: Among AF patients treated with dabigatran or rivaroxaban, patients with ILF were associated with significantly higher major bleeding, compared with NLF patients (aOR: 4.797; 95% CI: 2.224-10.256; P < 0.001). In patients with NLF, dabigatran (n = 2011) had considerably lower risk of total bleeding than rivaroxaban (n = 2202) (aOR: 1.23; 95% CI: 1.002-1.513; P = 0.049). In patients with ILF, dabigatran (n = 321) significantly favored lower risks of major bleeding compared with rivaroxaban(n = 448) (aOR: 5.484; 95% CI: 1.508-35.269; P = 0.026). CONCLUSION: After using dabigatran or rivaroxaban, patients with ILF had remarkably increased risk of major bleeding compared with patients with NLF. In AF patients with NLF, dabigatran had the distinct strength of significantly reduced risk of total bleeding compared with rivaroxaban. In patients with AF and ILF, dabigatran use was associated with lower risk for major bleeding compared with rivaroxaban.

Preliminary study on toxicological mechanism of golden cuttlefish (Sepia esculenta) larvae exposed to cd.

BACKGROUND: Cadmium (Cd) flows into the ocean with industrial and agricultural pollution and significantly affects the growth and development of economic cephalopods such as Sepia esculenta, Amphioctopus fangsiao, and Loligo japonica. As of now, the reasons why Cd affects the growth and development of S. esculenta are not yet clear. RESULTS: In this study, transcriptome and four oxidation and toxicity indicators are used to analyze the toxicological mechanism of Cd-exposed S. esculenta larvae. Indicator results indicate that Cd induces oxidative stress and metal toxicity. Functional enrichment analysis results suggest that larval ion transport, cell adhesion, and some digestion and absorption processes are inhibited, and the cell function is damaged. Comprehensive analysis of protein-protein interaction network and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore S. esculenta larval toxicological mechanisms, and we find that among the 20 identified key genes, 14 genes are associated with neurotoxicity. Most of them are down-regulated and enriched to the neuroactive ligand-receptor interaction signaling pathway, suggesting that larval nervous system might be destroyed, and the growth, development, and movement process are significantly affected after Cd exposure. CONCLUSIONS: S. esculenta larvae suffered severe oxidative damage after Cd exposure, which may inhibit digestion and absorption functions, and disrupt the stability of the nervous system. Our results lay a function for understanding larval toxicological mechanisms exposed to heavy metals, promoting the development of invertebrate environmental toxicology, and providing theoretical support for S. esculenta artificial culture.

Validation of diagnostic criteria for atopic dermatitis and proposal of novel diagnostic criteria for adult and elderly Chinese populations: a multicentre, prospective, clinical setting-based study.

BACKGROUND: A previous validation study showed a very low sensitivity and higher specificity associated with Hanifin and Rajka criteria (H&R) and the UK Working Party criteria (UKWP) in diagnosing AD vs. the Chinese criteria of atopic dermatitis (AD) for children (CCAD). However, their diagnostic efficacy in adult and elderly Chinese populations remains unknown. OBJECTIVES: To validate the diagnostic efficacy of three sets of AD criteria in adult and elderly Chinese populations in a hospital setting. METHODS: A total of 1034 patients (aged 19-95 years) from five university hospital dermatological clinics were recruited. Medical history, dermatological examination, AD diagnosis and evaluation of AD severity were done by dermatologists. Each patient was investigated by two dermatologist panels, one to establish a clinical diagnosis, and the other to identify and record the major or minor signs of H&R criteria, UKWP criteria and CCAD. Taking clinical diagnosis as the reference, the diagnostic efficacy of three sets of diagnostic criteria was evaluated. The χ2 test or rank sum test were used for between-groups comparisons. RESULTS: CCAD had a higher sensitivity (84.0%), especially among mild and moderate cases of AD (72.7% and 90.3%, respectively), than the H&R (58.0%; P < 0.001) and UKWP criteria (56.0%; P < 0.001) in diagnosing AD. The specificity of CCAD (92.7%) was slightly lower than the H&R (97.3%; P < 0.001) or UKWP criteria (97.4%; P < 0.001). The CCAD had the highest Youden index (0.77), accuracy rate (0.90) and Kappa value (0.76) of the three sets of diagnostic criteria. CONCLUSIONS: Consistent with results in a population of Chinese children, although the H&R and UKWP criteria had a high specificity for diagnosing AD, their low sensitivity limited their use in adult and elderly Chinese patients. Based on the high sensitivity and favourable diagnostic efficacy, the CCAD is proposed for AD diagnosis in adult and elderly Chinese populations, especially for cases of mild and moderate AD.

Characterization of Japanese flounder (Paralichthys olivaceus) STAT members: An immune-related gene family involved in Edwardsiella tarda and temperature stress.

The signal transducer and activator of transcription (STAT) family members are not only the transcriptional activators, but also play important roles in regulating inflammatory response. Some members have been reported to be involved in innate bacterial and antiviral immunity in aquatic organisms. However, no systematic research on STATs has been found in teleost. In this present study, we characterized six STAT genes in Japanese flounder based on bioinformatics methods, namely PoSTAT1, PoSTAT2, PoSTAT3, PoSTAT4, PoSTAT5 and PoSTAT6. The phylogenetic analysis of STATs in fish indicated that STATs were highly conserved and revealed an absence of STAT5 in a few species. Further analysis of gene structures and motifs showed STAT proteins shared a similar structure and probably had similar functionality in Japanese flounder. The expression profiles of different development stages and tissues demonstrated that PoSTATs exhibited specificity in temporality and spatiality as well as PoSTAT4 was highly expressed in gill. The transcriptome data analysis of E. tarda and temperature stress showed that PoSTAT1 and PoSTAT2 were more respective to these two kinds of stress. In addition, the results also demonstrated that these PoSTATs might regulate immune response in different ways, manifested by up-regulation in E. tarda infection and down-regulation in temperature stress. In a word, this systematic analysis of PoSTATs would provide valuable information about the phylogenetic relationship of STATs in fish species and help understand the role of STAT genes in the immune response of Japanese flounder.

Genome-wide identification of TNF receptor-associated factors in Japanese flounder (Paralichthys olivaceus) and functional analysis of resistance to temperature and Edwardsiella tarda stress.

Tumor necrosis factor receptor-associated factors (TRAFs), as the signaling mediators of the tumor necrosis factor (TNFR) superfamily, toll-like receptors (TLR) and interleukin-1 receptor (IL-1R) superfamily, can activate downstream signal transduction pathways and play an important role in the body's immune process. In this study, six TRAF genes, namely PoTRAF2a, PoTRAF2b, PoTRAF3, PoTRAF4, PoTRAF6 and PoTRAF7, were identified and annotated in Japanese flounder by using bioinformatics methods. Phylogenetic analysis confirmed that TRAF genes can be divided into seven groups. Analysis of motif composition and gene structure demonstrated that all PoTRAF members were evolutionarily conserved. The expression patterns of PoTRAF genes were then further investigated in six different developmental stages and eleven tissues of healthy fish, and it was found that there were spatial and tissue specificities among the members. To investigate the immune response of Japanese flounder to abiotic and biotic stresses, we further analyzed the expression profile of PoTRAFs after temperature stress and pathogen challenge. The result showed that PoTRAF3 and PoTRAF4 were observably differentially expressed under temperature stress, indicating that they were involved in the immune response after temperature stress. The expression of PoTRAF2a, PoTRAF2b and PoTRAF4 was significantly different after E. tarda infection, suggesting that they might have antibacterial effects. These results would help to clarify the molecular roles of PoTRAF genes in the regulation of immune and inflammatory responses in Japanese flounder.

Characterisation, evolution and expression analysis of the interferon regulatory factor (IRF) family from olive flounder (Paralichthys olivaceus) in response to Edwardsiella tarda infection and temperature stress.

Interferon regulatory factor (IRF) family involves in the transcriptional regulation of type I Interferons (IFNs) and IFN-stimulated genes (ISGs) and plays a critical role in cytokine signaling and immune response. However, systematic identification of the IRF gene family in teleost has been rarely reported. In this study, twelve IRF members, named PoIRF1, PoIRF2, PoIRF3, PoIRF4a, PoIRF4b, PoIRF5, PoIRF6, PoIRF7, PoIRF8, PoIRF9, PoIRF10 and PoIRF11, were identified from genome-wide data of olive flounder (Paralichthys olivaceus). Phylogenetic analysis indicated that PoIRFs could be classified into four clades, including IRF1 subfamily (PoIRF1, PoIRF11), IRF3 subfamily (PoIRF3, PoIRF7), IRF4 subfamily (PoIRF4a, PoIRF8, PoIRF9, PoIRF10) and IRF5 subfamily (PoIRF5, PoIRF6). They were evolutionarily related to their counterparts in other fish. Gene structure and motif analysis showed that PoIRFs protein sequences were highly conserved. Under normal physiological conditions, all PoIRFs were generally expressed in multiple developmental stages and healthy tissues. After E. tarda attack and temperature stress, twelve PoIRFs showed significant and different changes in mRNA levels. The expression of PoIRF1, PoIRF3, PoIRF4a, PoIRF5, PoIRF7, PoIRF8, PoIRF9, PoIRF10 and PoIRF11 could be markedly induced by E. tarda, indicating that they played a key role in the process of antibacterial immunity. Besides, temperature stress could significantly stimulate the expression of PoIRF3, PoIRF5, PoIRF6 and PoIRF7, indicating that they could transmit signals rapidly when the temperature changes. In conclusion, this study reported the molecular properties and expression analysis of PoIRFs, and explored their role in immune response, which laid a favorable foundation for further studies on the evolution and functional characteristics of the IRF family in teleost fish.

Genome-wide identification of olive flounder (Paralichthys olivaceus) SOCS genes: Involvement in immune response regulation to temperature stress and Edwardsiella tarda infection.

The suppressors of cytokine signaling (SOCS) gene family participates in development and immunity through negative regulation of cytokine signaling pathways. Although the immune response of SOCS gene family members has been extensively characterized in teleost, no similar study has been reported in olive flounder yet. In our present study, a total of 13 SOCSs in olive flounder were identified and characterized systematically. By querying the SOCS sequences of ten teleost fish species, we found there were exactly more members of SOCSs in fish than mammals, which indicated that there were more duplication events occurred in fish than in higher vertebrates. Phylogenetic analysis clearly illuminated that SOCS genes were highly conserved. The analysis of gene structure and motif showed SOCS proteins of olive flounder shared a high level of sequence similarity strikingly. The expression profiles of tissues and developmental stages indicated that SOCS members had a kind of specificity in temporality and spatiality. RNA-Seq analysis of temperature stress and E. Tarda infection demonstrated SOCS members were involved in inflammatory response. In a word, our results would provide a further reference for understanding the mechanism of SOCS genes in olive flounder.

Time-dependent immune injury induced by short-term exposure to nanoplastics in the Sepia esculenta larvae.

Marine organisms are threatened by various environmental contaminants, and nanoplastics (NPs) is one of the most concerned. Studied have shown that NPs has a certain impact on marine organisms, but the specific molecular mechanism is still unclear. At present, researches on the effect of NPs on marine life mostly focus on crustaceans, gastropods, and bivalves. In this study, cephalopod Sepia esculenta larvae were first used to investigate the potential immune response molecular mechanisms caused by PS-NPs (50 nm, 50 mg/L) short-term exposure (4 and 24 h). Through S. esculenta larvae transcriptome profile of gene expression analysis, 548 and 1990 genes showed differential expression at 4 and 24 h after NPs exposure, respectively. GO and KEGG enrichment analysis were performed to find immune related DEGs. Then, the interaction relationship between the immune related DEGs after NPs exposure was known through the constructed protein-protein interaction network. 20 hub genes were found on the base of KEGG pathway numbers involved and protein-protein interaction numbers. This research supply valuable genes for the study of cephalopod immune response caused by NPs, which can help us further uncover the molecular mechanisms of organism against NPs.

Identification of olive flounder (Paralichthys olivaceus) toll-like receptor genes: Involvement in immune response to temperature stress and Edwardsiella tarda infection.

Toll-like receptor (TLR) genes are best known for their roles in the innate immune defense. However, studies focusing on the reaction mechanisms of TLR genes in olive flounder (Paralichthys olivaceus) immune responses are still limited. In this study, 11 TLR family members (PoTLRs) were identified and classified from P. olivaceus genome. Phylogenetic analysis showed that PoTLRs were highly conserved in olive flounder. The analysis of motif prediction and gene structure indicated that TLRs had high sequence similarity. The expression patterns in developmental stages and different tissues showed that TLR members were spatially and temporally specific. RNA-Seq analysis of temperature stress and Edwardsiella tarda infection suggested that TLR members were involved in inflammatory responses, PoTLR5b and PoTLR22 showed significant differences in response to both temperature stress and E. tarda stress, indicating their potential immune functions. The results of this study suggested that TLR genes played important roles in the innate immune response of olive flounder, and would provide a solid basis for further study of their functions.

Gene network analyses of Sepia esculenta larvae exposed to copper and cadmium: A comprehensive investigation of oxidative stress, immune response, and toxicological mechanisms.

Copper (Cu) and Cadmium (Cd), prevalent heavy metals in marine environments, have known implications in oxidative stress, immune response, and toxicity in marine organisms. Sepia esculenta, a cephalopod of significant economic value along China's eastern coastline, experiences alterations in growth, mobility, and reproduction when subjected to these heavy metals. However, the specific mechanisms resulting from heavy metal exposure in S. esculenta remain largely uncharted. In this study, we utilized transcriptome and four oxidative, immunity, and toxicity indicators to assess the toxicological mechanism in S. esculenta larvae exposed to Cu and Cd. The measurements of Superoxide Dismutase (SOD), Malondialdehyde (MDA), Glutathione S-Transferase (GST), and Metallothioneins (MTs) revealed that Cu and Cd trigger substantial oxidative stress, immune response, and metal toxicity. Further, we performed an analysis on the transcriptome data through Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) network analysis. Our findings indicate that exposure methods and duration influence the type and the extent of toxicity and oxidative stress within the S. esculenta larvae. We took an innovative approach in this research by integrating WGCNA and PPI network analysis with four significant physiological indicators to closely examine the toxicity and oxidative stress profiles of S. esculenta upon exposure to Cu and Cd. This investigation is vital in decoding the toxicological, immunological, and oxidative stress mechanisms within S. esculenta when subjected to heavy metals. It provides foundational insights capable of advancing invertebrate environmental toxicology and informs S. esculenta artificial breeding practices.

Gene network analyses of larvae under different egg-protecting behaviors provide novel insights into immune response mechanisms of Amphioctopus fangsiao.

Amphioctopus fangsiao was a representative economic species in cephalopods, which was vulnerable to marine bacteria. Vibrio anguillarum was a highly infectious pathogen that have recently been found to infect A. fangsiao and inhibit its growth and development. There were significant differences in the immune response mechanisms between egg-protected and egg-unprotected larvae. To explore larval immunity under different egg-protecting behaviors, we infected A. fangsiao larvae with V. anguillarum for 24 h and analyzed the transcriptome data about egg-protected and egg-unprotected larvae infected with 0, 4, 12, and 24 h using weighted gene co-expression networks (WGCNA) and protein-protein interaction (PPI) networks. Network analyses revealed a series of immune response processes after infection, and identified six key modules and multiple immune-related hub genes. Meanwhile, we found that ZNF family, such as ZNF32, ZNF160, ZNF271, ZNF479, and ZNF493 might play significant roles in A. fangsiao immune response processes. We first creatively combined WGCNA and PPI network analysis to deeply explore the immune response mechanisms of A. fangsiao larvae with different egg-protecting behaviors. Our results provided further insights into the immunity of V. anguillarum infected invertebrates, and laid the foundation for exploring the immune differences among cephalopods with different egg protecting behaviors.

Sequencing-based network analysis provides a core set of genes for understanding hemolymph immune response mechanisms against Poly I:C stimulation in Amphioctopus fangsiao.

Aquatic viruses can spread rapidly and widely in seawater for their high infective ability. Polyinosinic-polycytidylic acid (Poly I:C), a viral dsRNA analog, is an immunostimulant that has been proved to activate various immune responses of immune cells in invertebrate. Hemolymph is a critical site that host immune response in invertebrates, and its transcriptome information obtained from Amphioctopus fangsiao stimulated by Poly I:C is crucial for understanding the antiviral molecular mechanisms of this species. In this study, we analyzed gene expression data in A. fangsiao hemolymph tissue within 24 h under Poly I:C stimulation and found 1082 and 299 differentially expressed genes (DEGs) at 6 and 24 h, respectively. Union set (1,369) DEGs were selected for subsequent analyses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were carried out for identifying DEGs related to immunity. Several significant immune-related terms and pathways, such as toll-like receptor signaling pathways term, inflammatory response term, TNF signaling pathway, and chemokine signaling pathway were identified. A protein-protein interaction (PPI) network was constructed for examining the relationships among immune-related genes. Finally, 12 hub genes, including EGFR, ACTG1, MAP2K1, and other nine hub genes, were identified based on the KEGG enrichment analysis and PPI network. The quantitative RT-PCR (qRT-PCR) was used to verify the expression profile of 12 hub genes. This research provides a reference for solving the problem of high mortality of A. fangsiao and other mollusks and provides a reference for the future production of some disease-resistant A. fangsiao.

Transcriptome analysis preliminary reveals the immune response mechanism of golden cuttlefish (Sepia esculenta) larvae exposed to Cd.

As a well-known marine metal element, Cd can significantly affect bivalve mollusk life processes such as growth and development. However, the effects of Cd on the molecular mechanisms of the economically important cephalopod species Sepia esculenta remain unclear. In this study, S. esculenta larval immunity exposed to Cd is explored based on RNA-Seq. The analyses of GO, KEGG, and protein-protein interaction (PPI) network of 1,471 differentially expressed genes (DEGs) reveal that multiple immune processes are affected by exposure such as inflammatory reaction and cell adhesion. Comprehensive analyses of KEGG signaling pathways and the PPI network are first used to explore Cd-exposed S. esculenta larval immunity, revealing the presence of 16 immune-related key and hub genes involved in exposure response. Results of gene and pathway functional analyses increase our understanding of Cd-exposed S. esculenta larval immunity and improve our overall understanding of mollusk immune functions.

Safety and efficacy of direct oral anticoagulation in patients with and without radiofrequency ablation of non-valvular atrial fibrillation: a multicenter retrospective cohort study.

BACKGROUND: Based on the few available studies on the prognostic benefit of using direct oral anticoagulants (DOACs) after atrial fibrillation (AF) ablation. Therefore, this study aimed to evaluate the prognostic differences between patients who underwent radiofrequency ablation (RFA) and those without RFA taking DOACs. METHODS: This is a multicenter retrospective cohort study enrolling 6137 patients with non-valvular AF (NVAF) at 15 hospitals in China. Patient information was collected through a mean follow-up of 10 months and medical record queries. Clinical outcomes included major bleeding, total bleeding, thrombosis, all-cause death, and a composite endpoint of bleeding, thrombosis, and all-cause death. RESULTS: After adjusting for confounders and propensity score matching (PSM), patients with RFA of NVAF had a significantly lower risk of major bleeding [OR 0.278 (95% CI, 0.150-0.515), P<0.001], thrombosis [OR 0.535 (95% CI, 0.316-0.908), P=0.020] and the composite endpoint [ OR 0.835 (95% CI, 0.710-0.982), P=0.029]. In the RFA PSM cohort, dabigatran was associated with reduced all-cause death in patients with RFA of NVAF [OR 0.420 (95% CI, 0.212-0.831), P=0.010]. In the no RFA PSM cohort, rivaroxaban was associated with a reduction in major bleeding [OR 0.521 (95% CI, 0.403-0.673), P<0.001], total bleeding [OR 0.114 (95% CI, 0.049-0.266), P<0.001], and the composite endpoint [OR 0.659 ( 95% CI, 0.535-0.811), P<0.001]. CONCLUSION: Among patients with NVAF treated with DOACs, RFA was a negative correlate of major bleeding, thrombosis, and composite endpoints but was not associated with total bleeding or all-cause mortality.

Safety and efficacy of direct oral anticoagulants in stroke prevention in patients with atrial fibrillation complicated with anemia and/or thrombocytopenia: a retrospective cohort study.

BACKGROUND: There are limited data about the clinical benefits and harm of direct oral anticoagulants (DOACs) in stroke prevention in patients with atrial fibrillation (AF) complicated with anemia or thrombocytopenia. METHODS: This is a multi-center retrospective cohort study involving 5469 AF patients from 15 hospitals in China. Patients were divided into three groups according to hemoglobin and platelet levels: Group 1 (hemoglobin male ≥ 130 g/L; female ≥ 120 g/L and platelet ≥ 100 × 109/L), Group 2 (hemoglobin male < 130 g/L; female < 120 g/L or platelet < 100 × 109/L), and Group 3 (hemoglobin male < 130 g/L; female < 120 g/L and platelet < 100 × 109/L). Patients in each category are further divided into two groups according to their stroke prevention strategies: rivaroxaban or dabigatran. Clinical results include major, minor, total bleeding, thrombosis, and the composite outcome of major bleeding and thrombosis. RESULTS: Higher hemoglobin levels were associated with a reduced risk of total bleeding and major bleeding, while platelet counts were not associated with any event. Compared with Group 1, Group 2 had a higher risk of major bleeding (aOR 1.70, 95%CI 1.12-2.57, P = 0.012), and the composite endpoint of major bleeding and thrombosis (aOR 1.70, 95%CI 1.19-2.44, P = 0.004). Compared with Group 1, Group 3 had a higher total bleeding risk (aOR 2.15, 95%CI 1.14-4.05, P = 0.018). Compared with dabigatran, rivaroxaban was associated with higher composite risk in Group 1 (aOR 2.91, 95% CI 1.66-5.16, P < 0.001) and Group 2 (aOR 3.05, 95%CI 1.46-6.39, P = 0.003), but there was no significant difference in Group 3 (aOR 1.78, 95%CI 0.23-13.54, P = 0.577). CONCLUSIONS: Higher hemoglobin levels are associated with a reduced risk of total bleeding and major bleeding in patients with AF. Dabigatran was associated with better clinical outcomes than rivaroxaban in patients with anemia or thrombocytopenia but not in those with anemia and thrombocytopenia.

Association between Body Mass Index and Clinical Outcomes in Patients with Non-valvular Atrial Fibrillation Receiving Direct Oral Anticoagulants: A New Piece of Evidence on the Obesity Paradox from China.

PURPOSE: We conducted a multicenter real-world study in China to assess the association between body mass index (BMI) and clinical outcomes in patients with atrial fibrillation (AF) taking direct oral anticoagulants (DOACs). METHOD: This is a retrospective multicenter cohort study conducted in 15 centers in China. We collected demographic information through the hospital information system and obtained clinical events through follow-up visits to patients or relatives. Clinical outcomes include major, minor, total bleeding, thromboembolism, and all-cause death. RESULT: A total of 6164 patients with non-valvular AF (NVAF) were included in this study. The incidence of major bleeding in patients with NVAF differed significantly by BMI category (P < 0.001), with 5.2% in the underweight group, 2.6% in the normal group, 1.4% in the overweight group, 1.1% in the obese I group, and 1.3% in the obese II group. There was no significant difference in minor, total bleeding, and thrombosis in the five groups (P = 0.493; P = 0.172; P = 0.663). All-cause death was significantly different among the five groups (P < 0.001), with 8.9% in the underweight group, 6.3% in the normal group, 4.8% in the overweight group, 2.2% in the obese I group, and 0.4% in the obese II group. High BMI was negatively associated with major bleeding (OR = 0.353, 95% CI 0.205-0.608), total bleeding (OR = 0.664, 95% CI 0.445-0.991), and all-cause death (OR = 0.370, 95% CI 0.260-0.527). CONCLUSION: In patients with NVAF treated with DOACs, higher BMI was associated with lower major bleeding and better survival. BMI was a negative correlate of total bleeding, but not minor bleeding and thrombosis.

Quantitative Detection of In Vivo Aggregation Degree for Enhanced M2 Macrophage MR Imaging.

In situ self-assembly in vivo can be used in the enhanced diagnosis and therapy of major diseases such as cancer and bacterial infections on the basis of an assembly/aggregation-induced-retention (AIR) effect. However, the aggregation degree (αagg) is a significant parameter for determining the delivery efficiency to lesions in a complex physiological environment and a real-time quantitative calculation of the aggregation degree in vivo is still a great challenge. Here, we developed a magnetic resonance imaging (MRI) method for sensitive and quantitative calculation of αagg with a detection limit of 10-4 M and a bioactivated in vivo assembly (BIVA) magnetic resonance (MR) probe was optimized for enhanced T1-weighted MR imaging of M2 macrophages in tumors. Our MRI quantitative calculation method had a high fitting degree (R2 = 0.987) with the gold standard fluorescence (FL) method. On the basis of the BIVA mechanism of CD206 active targeting and cathepsin B specific tailoring to induce an in situ nanofiber assembly, our optimized BIVA probe exhibited a high intracellular aggregation degree of over 70% and a high in vivo αagg value of over 55%. Finally, the aggregation-enhanced T1 MR signal and the AIR effect both contributed to enhanced T1-weighted MR imaging of M2 macrophages in triple-negative breast cancer. We believe that our αagg real-time quantitative calculation method of MRI will help to further screen and optimize the in vivo enhanced imaging and treatment of the BIVA drug.