Automated quantification of wrist bone marrow oedema, pre- and post-treatment, in early rheumatoid arthritis.

Objective: Bone inflammation (osteitis) in early RA (ERA) manifests as bone marrow oedema (BME) and precedes the development of bone erosion. In this prospective, single-centre study, we developed an automated post-processing pipeline for quantifying the severity of wrist BME on T2-weighted fat-suppressed MRI. Methods: A total of 80 ERA patients [mean age 54 years (s.d. 12), 62 females] were enrolled at baseline and 49 (40 females) after 1 year of treatment. For automated bone segmentation, a framework based on a convolutional neural network (nnU-Net) was trained and validated (5-fold cross-validation) for 15 wrist bone areas at baseline in 60 ERA patients. For BME quantification, BME was identified by Gaussian mixture model clustering and thresholding. BME proportion (%) and relative BME intensity within each bone area were compared with visual semi-quantitative assessment of the RA MRI score (RAMRIS). Results: For automated wrist bone area segmentation, overall bone Sørensen-Dice similarity coefficient was 0.91 (s.d. 0.02) compared with ground truth manual segmentation. High correlation (Pearson correlation coefficient r = 0.928, P < 0.001) between visual RAMRIS BME and automated BME proportion assessment was found. The automated BME proportion decreased after treatment, correlating highly (r = 0.852, P < 0.001) with reduction in the RAMRIS BME score. Conclusion: The automated model developed had an excellent segmentation performance and reliable quantification of both the proportion and relative intensity of wrist BME in ERA patients, providing a more objective and efficient alternative to RAMRIS BME scoring.

Gut microbiota facilitate chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) comes with gut dysbiosis, but its relevance remains elusive. Here we use metagenomics sequencing and short-chain fatty acids metabolomics and assess the effects of human CSU fecal microbial transplantation, Klebsiella pneumoniae, Roseburia hominis, and metabolites in vivo. CSU gut microbiota displays low diversity and short-chain fatty acids production, but high gut Klebsiella pneumoniae levels, negatively correlates with blood short-chain fatty acids levels and links to high disease activity. Blood lipopolysaccharide levels are elevated, link to rapid disease relapse, and high gut levels of conditional pathogenic bacteria. CSU microbiome transfer and Klebsiella pneumoniae transplantation facilitate IgE-mediated mast cell(MC)-driven skin inflammatory responses and increase intestinal permeability and blood lipopolysaccharide accumulation in recipient mice. Transplantation of Roseburia hominis and caproate administration protect recipient mice from MC-driven skin inflammation. Here, we show gut microbiome alterations, in CSU, may reduce short-chain fatty acids and increase lipopolysaccharide levels, respectively, and facilitate MC-driven skin inflammation.

Integrative lipidomic features identify plasma lipid signatures in chronic urticaria.

Chronic urticaria (CU) is a chronic inflammatory skin disease mainly mediated by mast cells. Lipids exert essential functions in biological processes; however, the role of lipids in CU remains unclear. Nontargeted lipidomics was performed to investigate the differential lipid profiles between CU patients and healthy control (HC) subjects. Functional validation studies were performed in vitro and in vivo including ß-hexosaminidase release examination from mast cells and passive cutaneous anaphylaxis (PCA) mouse model. We detected dramatically altered glycerophospholipids in CU patients compared with HCs. Phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG) were increased, while phosphatidylcholine (PC) was reduced in CU patients. The reduction in PC was related to a high weekly urticaria activity score (UAS7), while PS was positively associated with the dermatology life quality index (DLQI). We also identified the differential lipid profiles between chronic spontaneous urticaria (CSU), symptomatic dermographism (SD), and CSU coexist with SD. CU patients were classified into two subtypes (subtype 1 and subtype 2) based on consensus clustering of lipid profiling. Compared with patients in subtype 2, patients in subtype 1 had elevated levels of PC (18:0e/18:2) and PE (38:2), and lower urticaria control test (UCT) scores indicated worse clinical efficiency of secondary generation H1 antihistamines treatment. Importantly, we found that supplementation with PC could attenuate IgE-induced immune responses in mast cells. In general, We described the landscape of plasma lipid alterations in CU patients and provided novel insights into the role of PC in mast cells.

The Role of Crosstalk of Immune Cells in Pathogenesis of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is defined as recurrent episodes of spontaneous wheal development and/or angioedema for more than six weeks and at least twice a week. The core link in the pathogenesis of CSU is the activation of mast cells, T cells, eosinophils, and other immune cells infiltrating around the small venules of the lesion. Increased vascular permeability, vasodilatation, and recruitment of inflammatory cells directly depend on mast cell mediators' release. Complex regulatory systems tightly influence the critical roles of mast cells in the local microenvironment. The bias toward Th2 inflammation and autoantibodies derived from B cells, histamine expressed by basophils, and initiation of the extrinsic coagulation pathway by eosinophils or monocytes exerts powerful modulatory influences on mast cells. Cell-to-cell interactions between mast cells and eosinophils/T cells also are regulators of their function and may involve CSU's pathomechanism. This review summarizes up-to-date knowledge regarding the crosstalk between mast cells and other immune cells, providing the impetus to develop new research concepts and treatment strategies for CSU.

Efficacy and Safety of Dupilumab in Chinese Patients With Atopic Dermatitis: A Real-World Study.

Background: Atopic dermatitis (AD) is a common skin disease, but treatment of this disease has been challenging. Dupilumab is a new biological agent for AD that has been proven to be safe and effective in clinical trials. Although dupilumab was approved for listing in China in June 2020, real-world data about the application of dupilumab in China are lacking. This study aimed to collect and analyze real-world data on dupilumab among Chinese AD patients. Methods: Demographic and clinical data for 116 AD patients receiving dupilumab treatment were reviewed. The Eczema Area and Severity Index (EASI), SCORing Atopic Dermatitis (SCORAD), Numerical Rating Scale (NRS), Patient Oriented Eczema Measure (POEM), and Dermatology Quality of Life Index (DLQI) of patients were evaluated every 2 weeks from baseline to 16 weeks of treatment. Any adverse events during treatment were recorded. Results: Among the 116 patients in this study, baseline levels of IgE, eosinophils, and LDH were elevated in 62.79% (n = 86), 45.30% (n = 86), and 54.20% of patients (n = 48), respectively. The SCORAD index and POEM, DLQI, and NRS scores were significantly improved in all patients at 2 weeks (p < 0.0001), 4 weeks (p < 0.01), and 16 weeks (p < 0.001). EASI scores also improved significantly in all patients at 2 weeks (p < 0.01), 4 weeks (> 0.05), and 16 weeks (p < 0.01). However, 11 patients (9.48%) had no response. IgE and LDH levels (p > 0.05), Eosinophil counts (p < 0.01) in blood increased temporarily in the first 4 weeks and then decreased and stabilized during dupilumab treatment. Conjunctivitis was the most common adverse event (2.59%) among the patients. We found that the curative efficacy of dupilumab at 4th weeks was related to the patient's age and course of disease. Nevertheless, there is no relationship between levels of eosinophils, IgE, LDH and the therapeutic efficacy of dupilumab. Conclusion: The real-world data in China showed that dupilumab can effectively treat AD and is well tolerated with a low incidence of adverse events.

[Numerical Analysis of Two-stage Axial Blood Pump Based on Blood Damage].

The implantable miniaturized axial blood pump works at a high rotational speed,which increases the risk of blood damage.In this article,we aimed to reduce the possibility of hemolysis and thrombosis by designing a twostage axial blood pump.Under the operation conditions of flow rate 5L/min and outlet pressure of 100 mm Hg,we carried out the numerical simulation on the two-stage and single-stage blood pumps to compare the hemolysis and platelet activation state.The results turned out that the hemolysis index of two-stage axial blood pump was better while the platelet activation state was worse than those of single stage design.On the index of hemolysis level and platelet activation state,the design of the two-stage pump with the low and high-head impeller combination was better than the two-stage pump with the equal heads,or the high and low-head impeller combination.In terms of reducing the risk of blood damage for implantable miniaturized axial blood pump,the research result can provide some theoretical basis and new design ideas.