Increased serum interleukin-41 correlates with disease severity in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease mediated by pathogenic antibodies produced by abnormally activated B cells, resulting in neuromuscular junction transmission dysfunction. Interleukin-41 (IL-41) is a novel immunomodulatory cytokine that has been implicated in various metabolic, inflammatory, and autoimmune diseases. The role of IL-41 in MG is still unclear up to now, our study aimed to investigate the level of IL-41 in MG patients and its correlation with clinical features and inflammatory indicators. METHODS: Totally, 60 MG patients and 30 healthy controls (HC) were recruited. Baseline data and laboratory parameters were routinely recorded through electronic medical systems. IL-41 levels were measured by enzyme-linked immunosorbent assay. Proportions of T-cell and B-cell subsets and natural killer cells were analyzed by flow cytometry. The correlation between serum IL-41 and MG related parameters was investigated, and the clinical value of IL-41 in the diagnosis of MG was evaluated by receiver operator characteristic curve (ROC) analysis. RESULTS: Serum IL-41 levels in MG patients were higher than in HC, and were higher in Myasthenia Gravis Foundation of America (MGFA) III + IV group than that in MGFA I + II group. Serum IL-41 was positively correlated with MG-specific activities of daily living scale (MG-ADL), MGFA classification, platelet to lymphocyte ratio (PLR), and proportion of CD19+ B cells, while it was negatively correlated with high-sensitive C-reactive protein (hs-CRP) and circulatory plasma cells in MG patients. Serum IL-41 levels increased in patients who were treated with efgartigimod during the first cycle of therapy. However, compared to disease initiation, serum IL-41 levels decreased when clinical features steadily improved. ROC analysis showed that IL-41 had a diagnostic value for MG. CONCLUSION: The present findings suggested that serum IL-41 was increased in MG patients and was positively associated with the severity of the disease. IL-41 may be essential to the immunopathological mechanism of MG and a potential biomarker for MG.

Rescue treatment with add-on efgartigimod in a patient with impending myasthenic crisis: a case report.

Myasthenia gravis (MG) is an autoimmune disorder characterized by fluctuating muscle weakness. Severe patients may develop life-threatening respiratory failure and experience crisis. Plasma exchange or intravenous immunoglobulin (IVIg) is the first-line treatment option for myasthenia crisis, but some patients still poorly respond to them. Here, we first reported a generalized MG patient from China who was in a state of impending myasthenic crisis and did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. Especially, we also detected meaningful changes in T-cell and B-cell subsets after efgartigimod, promoting a potential role of efgartigimod in re-establishing immune homeostasis.

Comparative effectiveness of warfarin in cirrhotic patients with non-symptomatic portal vein thrombosis: a multicenter, randomized controlled trial.

The effectiveness and risks of anticoagulant therapy in cirrhotic patients with non-symptomatic portal vein thrombosis (PVT) remain unclear. We conducted a multicenter, Zelen-designed randomized controlled trial to determine the effectiveness of warfarin in cirrhotic patients with non-symptomatic PVT during a one-year follow-up. In brief, 64 patients were 1:1 randomly divided into the anticoagulation group or the untreated group. The probability of recanalization was significantly higher in the anticoagulation group than those untreated in both ITT analysis (71.9% vs 34.4%, p = 0.004) and PP analysis (76.7% vs 32.4%, p < 0.001). Anticoagulation treatment was the independent predictor of recanalization (HR 2.776, 95%CI 1.307-5.893, p = 0.008). The risk of bleeding events and mortality were not significantly different. A significantly higher incidence of ascites aggravation was observed in the untreated group (3.3% vs 26.5%, p = 0.015). In conclusion, warfarin was proved to be an effective and safe as an anticoagulation therapy for treating non-symptomatic PVT in cirrhotic patients.

New Insights into Alzheimer's Disease: Novel Pathogenesis, Drug Target and Delivery.

Alzheimer's disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid ß protein (Aß) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aß and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aß cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aß aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aß- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood-brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aß-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aß assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.

Design and Analysis of Lithium-Niobate-Based Laterally Excited Bulk Acoustic Wave Resonator with Pentagon Spiral Electrodes.

In this paper, we present a comprehensive study on the propagation and dispersion characteristics of A1 mode propagating in Z-cut LiNbO3 membrane. The A1 mode resonators with pentagon spiral electrodes utilizing Z-cut lithium niobate (LiNbO3) thin film are designed and fabricated. The proposed structure excites the A1 mode waves in both x- and y-direction by utilizing both the piezoelectric constants e24 and e15 due to applying voltage along both the x- and y-direction by arranging pentagon spiral electrode. The fabricated resonator operates at 5.43 GHz with no spurious mode and effective electromechanical coupling coefficient (Keff2) of 21.3%, when the width of electrode is 1 µm and the pitch is 5 µm. Moreover, we present a comprehensive study of the effect of different structure parameters on resonance frequency and Keff2 of XBAR. The Keff2 keeps a constant with varied thickness of LiNbO3 thin film and different electrode rotation angles, while it declines with the increase of p from 5 to 20 µm. The proposed XBAR with pentagon spiral electrodes realize high frequency response with no spurious mode and tunable Keff2, which shows promising prospects to satisfy the needs of various 5 G high-band application.

Preparation, Characterization, and Application of AlN/ScAlN Composite Thin Films.

Piezoelectric aluminum nitride (AlN) thin film, as a commonly used material for high-frequency acoustic resonators, has been a research hotspot in the RF field. Doping Sc elements in AlN is one of most effective methods to improve the piezoelectricity of the material. In this work, the first principal calculation and Mori-Tanaka model are used to obtain the piezoelectric constants of AlN, ScAlN, and AlN/ScAlN composites. Then, five types of AlN/ScAlN thin films are prepared on 8 inch silicon substrates. The crystal quality, roughness, and stress distribution are measured to characterize the film quality. The results show that composite film can effectively solve the problem of abnormal grains and reduce the roughness. Finally, a lamb wave resonator with an AlN/Sc0.2Al0.8N composite working at 2.33 GHz is fabricated. The effective electromechanical coupling coefficient Keff2 is calculated to be 6.19%, which has the potential to design high-frequency broadband filters.

Aluminum Nitride-Based Adjustable Effective Electromechanical Coupling Coefficient Film Bulk Acoustic Resonator.

The arrival of the 5G era has promoted the need for filters of different bandwidths. Thin-film bulk acoustic resonators have become the mainstream product for applications due to their excellent performance. The Keff2 of the FBAR greatly influences the bandwidth of the filter. In this paper, we designed an AlN-based adjustable Keff2 FBAR by designing parallel capacitors around the active area of the resonator. The parallel capacitance is introduced through the support column structure, which is compatible with conventional FBAR processes. The effects of different support column widths on Keff2 were verified by finite element simulation and experimental fabrication. The measured results show that the designed FBAR with support columns can achieve a Keff2 value that is 25.9% adjustable.

A High-Sensitivity Gravimetric Biosensor Based on S1 Mode Lamb Wave Resonator.

The development of MEMS acoustic resonators meets the increasing demand for in situ detection with a higher performance and smaller size. In this paper, a lithium niobate film-based S1 mode Lamb wave resonator (HF-LWR) for high-sensitivity gravimetric biosensing is proposed. The fabricated resonators, based on a 400-nm X-cut lithium niobate film, showed a resonance frequency over 8 GHz. Moreover, a PMMA layer was used as the mass-sensing layer, to study the performance of the biosensors based on HF-LWRs. Through optimizing the thickness of the lithium niobate film and the electrode configuration, the mass sensitivity of the biosensor could reach up to 74,000 Hz/(ng/cm2), and the maximum value of figure of merit (FOM) was 5.52 × 107, which shows great potential for pushing the performance boundaries of gravimetric-sensitive acoustic biosensors.

Transcriptomic Profiles of Splenic CD19+ B Cells in Mice Chronically Infected With the Larval Echinococcus granulosus.

Background: We previously reported that the larval Echinococcus granulosus (E. granulosus) infection can expand the population of regulatory B cells in mice, thereby inhibiting the anti-infective immunity. However, the underlying mechanism is still largely unknown. This study further investigated the holistic transcriptomic profiles of total splenic B cells following the chronic infection of the parasite. Methods: The infection model of larval E. granulosus was established by intraperitoneal inoculation with 2000 protoscolexes. Magnetic-Activated Cell Separation (MACS) was used to isolate the total splenic B cells. RNA sequencing was performed to screen the differentially expressed genes (DEGs) after infection. The expression of selected DEGs was verified using qRT-PCR. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Co-expression network analysis were applied to predict these DEGs' underlying biological processes, pathways, and interactions respectively. Results: A total of 413 DEGs were identified in larval E. granulosus infected B cells, including 303 up- and 110 down-regulated genes. Notably, most DEGs related to inflammation and chemotaxis were significantly upregulated after infection. In line with these changes, significant expression upregulation of DEGs associated with fatty acid oxidation, lipid synthesis, lipolysis, lipid transport, and cholesterol biosynthesis, were observed in infected B cells. Co-expression network analysis showed an intimate interaction between these DEGs associated with immune and metabolism. Conclusions: The present study revealed that the larval E. granulosus infection induces metabolic reprogramming of B cells, which provides a novel clue to clarify the immunoregulatory mechanism of B cells in parasitic infection.

Calycosin-7-O-ß-D-glucoside attenuates palmitate-induced lipid accumulation in hepatocytes through AMPK activation.

Calycosin-7-O-ß-D-glucoside (CG) is the major component of Astragali Radix (AR), a traditional Chinese drug. As reported, CG could attenuate cerebral ischemia/reperfusion injury, protect blood-brain barrier integrity, and ameliorate myocardial infarction. To date, whether CG has a protective effect on metabolic diseases remains to be elucidated. In the present study, CG could attenuate palmitate-induced lipid accumulation in hepatocytes in a dose-dependent manner, with down-regulation of lipogenesis related genes expression and up-regulation of lipids ß-oxidation related genes expression. CG could decrease the triglyceride (TG) content from 0.30 mmol/g protein to 0.21 mmol/g protein and reduce the total cholesterol (TC) content from 0.39 mmol/g protein to 0.26 mmol/g protein. Moreover, CG stimulated the phosphorylation of AMP-activated protein kinase (AMPK), and the protective effect of CG on hepatocytes was partially reversed both by the inhibitor of AMPK signaling pathway and overexpression of AMPK-DN. Our findings revealed that CG could ameliorate palmitate-induced lipids accumulation in hepatocytes via AMPK activation and it may be a promising therapeutic medicine for hepatic steatosis.

Design and Optimization of the Dual-Mode Lamb Wave Resonator and Dual-Passband Filter.

Radio frequency (RF) filters with multiple passbands can meet the needs of miniaturization and integration for 5G communications. This paper reports a dual-mode Lamb wave resonator (DLWR) and a dual-passband filter based on DLWRs. The DLWR consists of a piezoelectric film and two interdigital electrode (IDT) arrays with different thicknesses, which leads to the coexistence of two main modes in the resonator. The resonance frequencies of the two modes can be adjusted separately by changing the thicknesses of the IDTs, which greatly satisfies the requirements of the dual-passband filter. Four DLWRs with different electrode configurations are designed, and the influences of the periodic length and thicknesses of the IDTs on the performance of the DLWR are studied. When the thickness of the piezoelectric layer is 0.75 µm and the two thicknesses of the IDTs are 0.1 µm and 0.3 µm, the resonance frequency of the second main mode is 1.27 GHz higher than the resonance frequency of the first main mode in the DLWR. Furthermore, a dual-passband filter based on the proposed DLWRs is demonstrated with an insertion loss less than 1 dB and a band rejection of about 15 dB. Moreover, two passbands at 2.45 GHz and 3.88 GHz with bandwidths of 66 MHz and 112 MHz, respectively, are achieved. The presented DLWR shows a potential application that can be used to obtain RF filters with adjustable dual passbands.

Dual-ratiometric fluorescence probe for viscosity and hypochlorite based on AIEgen with mitochondria-targeting ability.

Viscous microenvironments are ubiquitous in living organisms. An oxidative stress attack could cause the fluctuation of lymph or blood viscosity, which is closely related to many common diseases. However, the dual-function detection of reactive oxygen species and viscosity is still ineffective due to design defects. Herein, by rational linking a propeller-shaped triphenylamine rotator and a rigid planar anthracene, we report the first dual-ratiometric-response probe for ClO- and viscosity detection. The probe itself shows weak fluorescence background in low-viscous solution or at non-aggregate state, which can largely switch on its blue (414 nm) and yellow fluorescence (600 nm) respectively in response to ClO- and viscosity. Their sensing mechanisms were elucidated through the interruption of FRET and TICT processes for ClO- and viscosity detection, respectively. In addition to its mitochondria targeting ability, TPP-AN was employed for mitochondrial viscosity and ClO- imaging in HeLa cells, providing a potentially useful probe for clinical assays.

The non-oral infection of larval Echinococcus granulosus induces immune and metabolic reprogramming in the colon of mice.

Background: The intestinal tract serves as a critical regulator for nutrient absorption and overall health. However, its involvement in anti-parasitic infection and immunity has been largely neglected, especially when a parasite is not transmitted orally. The present study investigated the colonic histopathology and functional reprogramming in mice with intraperitoneal infection of the larval Echinococcus granulosus (E. granulosus). Results: Compared with the control group, the E. granulosus-infected mice exhibited deteriorated secreted mucus, shortened length, decreased expression of tight junction proteins zonula occludens-1 (ZO-1), and occludin in the colon. Moreover, RNA sequencing was employed to characterize colonic gene expression after infection. In total, 3,019 differentially expressed genes (1,346 upregulated and 1,673 downregulated genes) were identified in the colon of infected mice. KEGG pathway and GO enrichment analysis revealed that differentially expressed genes involved in intestinal immune responses, infectious disease-associated pathways, metabolism, or focal adhesion were significantly enriched. Among these, 18 tight junction-relative genes, 44 immune response-associated genes, and 23 metabolic genes were annotated. Furthermore, mebendazole treatment could reverse the colonic histopathology induced by E. granulosus infection. Conclusions: Intraperitoneal infection with E. granulosus induced the pathological changes and functional reprogramming in the colon of mice, and mebendazole administration alleviated above alternations, highlighting the significance of the colon as a protective barrier against parasitic infection. The findings provide a novel perspective on host-parasite interplay and propose intestine as a possible target for treating parasitic diseases that are not transmitted orally.

Complications and management of elective endoscopic cyanoacrylate injection with lauromacrogol for gastric varices.

OBJECTIVE: To report the complications and evaluate the risk factors of elective endoscopic cyanoacrylate injection with lauromacrogol for gastric varices in cirrhotic patients. METHODS: A total of 583 elective endoscopic tissue adhesives procedures were performed in 439 patients in our hospital from January 2015 to December 2016. The clinical characteristics and complications were retrospectively collected and evaluated. RESULTS: The median age was 56 ± 11 years, and 290 (66.1%) patients were male. The main etiology of liver cirrhosis was hepatitis virus (63.3%). Two hundred fifty-nine (59.0%) patients were classified as Child-Pugh Class A. Bleeding occurred in 44 patients (7.5%) during procedures. Two patients developed distant embolism (0.5%; one pulmonary, one cerebra). In perioperative period, fever was a common complication; however, only 16 cases had high fever and one case had sepsis. Bleeding was observed in 7 (1.2%) patients. Overall incidence of the major perioperative complication was 3.8%. The major postoperative complication rate was 10.4% (60/582, 26 rebleeds, 27 ascites increase, 12 new-onset portal vein thrombosis). The complication-related death was 1.6% (one death from embolism, five deaths from rebleeding, one death from refractory ascites). Injection point was the only factor related to the major perioperative complications [odds ratio (OR) = 1.581, 95% CI, 1.086-2.301; P < 0.05]. Etiology of cirrhosis and injection point were independent risk factors of major postoperative complications (OR = 1.830, 95% CI, 1.005-3.331, P = 0.048; OR = 1.373, 95% CI, 1.089-1.731, P = 0.007). CONCLUSION: The incidence of complications after elective endoscopic cyanoacrylate injection with lauromacrogol for gastric varices was low. The injection point was the risk factor for both perioperative and postoperative complications.

Development and validation of prognostic implications of chromosome abnormalities algorithm for newly diagnosed multiple myeloma.

Fluorescence in situ hybridization (FISH) evaluation is essential for initial risk stratification in multiple myeloma (MM). The presence of specific cytogenetic abnormalities (CA) confers a heterogeneity impact on prognosis. However, the cutoff values among different centers are not uniform. Therefore, we conduct this study to better predict the prognosis of newly diagnosed MM patients based on FISH results. The Kaps method was used to calculate the chromosomal abnormal cutoff values. A total of 533 participants were included in the study. The best cutoff value of overall survival were as follows: 17p- 20.1%, 13q- 85%, 1q21+ 39%, t(11;14) 55.5%, t(14;16) 87%, and t(4;14) 53.5%. The survival analysis showed that 17p- and 1q21+ were the independent factors affecting both OS and progress free survival (PFS) among CA. The analysis based on the cutoff value obtained by Kaps suggested that 13q-, t(14;16), 17p-, and 1q21+ were independent factors affecting OS among CA; t(14;16), 17p-, and 1q21+ were independent factors affecting PFS among CA. The prognostic model was constructed by the Kaps method with the Harrell concordance index (c-index) at 0.719 (95% CI, 0.683-0.756; corrected 0.707), which was higher than that calculated by the European Myeloma Network criteria (0.714; 95% CI, 0.678-0.751; corrected 0.696). In conclusion, chromosomal abnormalities in different proportions and combinations can affect the prognosis of MM patients. Therefore, effective criteria should be formulated to evaluate the prognosis of MM patients better.

Effects of Fluid Resuscitation on the Occurrence of Organ Failure and Mortality in Patients With Acute Pancreatitis.

OBJECTIVES: Acute pancreatitis (AP) is a serious gastroenterological condition requiring urgent fluid resuscitation and emergent intensive care. However, the benefit of fluid resuscitation is inconsistent. Therefore, this study aimed to examine the effects of fluid resuscitation on the occurrence of organ failure and mortality in patients with AP. METHODS: The data were retrospectively extracted from the Medical Information Mart for Intensive Care III 2002-2012 database. The fluid resuscitation and fluid balance were calculated at 12, 24, 36, and 48 hours after intensive care unit admission. Multivariate analysis models were used. RESULTS: A total of 317 patients with AP were included. Odds of organ failure increased significantly with increased fluid input at 0 to 12 hours [adjusted odds ratio (aOR), 1.124; 95% confidence interval (CI), 1.015-1.244] and with increased fluid balance at 36 to 48 hours (aOR, 1.184; 95% CI, 1.009-1.389). Odds of in-hospital mortality increased significantly with increased fluid balance at 24 to 36 hours (aOR, 1.201; 95% CI, 1.052-1.371). Odds of 30-day mortality increased significantly with increased fluid balance at 24 to 36 hours (aOR, 1.189; 95% CI, 1.039-1.361). CONCLUSIONS: Increased fluid balance was associated with increased risk of organ failure and mortality. Increased fluid output may decrease mortality.

Microarray Analysis of lncRNA and mRNA Reveals Enhanced Lipolysis Along With Metabolic Remodeling in Mice Infected With Larval Echinococcus granulosus.

Parasitic infection improves metabolic homeostasis in "western diet"-induced obesity through the regulation of adipogenesis. However, the underlying mechanism is not yet fully understood. Using microarray analysis, this study investigated the long non-coding RNA (lncRNA) and messenger RNA (mRNA) profiles of subcutaneous adipose tissues from mice infected with Echinococcus granulosus protoscoleces. A total of 1052 mRNA (541 upregulated, 511 downregulated) and 220 lncRNA (126 upregulated, 94 downregulated) transcripts were differentially expressed (fold change ≥2, P < 0.05) in the infected subcutaneous adipose tissues. When compared with the control group, the infected mice showed a decrease in adipose tissue mass and a reduction in adipocyte size. Indirect calorimetry revealed the change in the energy metabolism after infection, characterized by a lower CO2 production and O2 consumption, a sharp decline in carbohydrate oxidation, and a slight increase in fat oxidation. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the parasitic infection reprogrammed a complex metabolic network. Notably, "lipoxygenase" and "arginine and proline metabolism" pathways were significantly upregulated while "glycolysis," "tricarboxylic acid cycle," "de novo lipogenesis," and "lipid droplet" pathways were dramatically downregulated. In addition, several key lncRNAs were associated with insulin resistance and adipocyte differentiation. Overall, the present study suggested that E. granulosus infection could enhance lipolysis. Thus, our findings provide novel insights into parasite-mediated metabolic homeostasis, and into the mechanism of hypertrophic adipocytes in obesity.

The role of a multidisciplinary team in the management of portal hypertension.

BACKGROUND: Gastroesophageal variceal hemorrhage is the most severe complication of portal hypertension, with a high mortality rate. The current recommendations for gastroesophageal varices include pharmacological treatment, endoscopic treatment, transjugular intrahepatic portosystemic shunt (TIPS) placement, and splenectomy with devascularization surgery. Multidisciplinary team (MDT) comprises of a group of medical experts and specialists across a range of disciplines, providing personalized and targeted patient care tailored to each individual's condition, circumstances, and expectations. METHODS: Patients referred to the MDT clinic since its establishment in September 2014 were prospectively enrolled and followed-up for at least 12 months. Patient baseline characteristics, treatment methods, outcome and survival were compared to non-MDT patients retrieved from a prospectively maintained database with propensity score matching. RESULTS: Propensity-score matching (PSM) was carried out to balance available covariates, resulting in 58 MDT patients vs. 111 non-MDT patients. Overall survival and variceal rebleed was compared between the two groups. The rate of variceal rebleed was significantly higher in the non-MDT group, while no difference in overall survival was observed. CONCLUSIONS: This study is the first to investigate the role of a multidisciplinary team in the management of gastroesophageal varices secondary to portal hypertension. Patients treated based on MDT clinic recommendations had a significantly lower risk for variceal rebleed.