Cardiac involvement in eosinophilic granulomatosis with polyangiitis: acute eosinophilic myocarditis and chronic inflammatory cardiomyopathy.

OBJECTIVES: Currently, cardiac involvement is used to describe all eosinophilic granulomatosis with polyangiitis (EGPA) cardiac problems. However, heterogeneity exists among them. We aimed to depict the disease spectrum of EGPA cardiac involvement and identify high-risk population. METHODS: We included EGPA patients hospitalized in our center from 2012 to 2023 and in public databases. Based on the cardiac enzymes, cardiac magnetic resonance imaging, and endomyocardial biopsy results, the patients were divided into 3 groups: eosinophilic myocarditis (EGPA-EM), chronic inflammatory cardiomyopathy (EGPA-ICM) and EGPA-Control. Their clinical, laboratory, imaging results and prognoses were collected and compared. RESULTS: A total of 193 EGPA patients were included, 118 with cardiac involvement (74 EGPA-EM, 44 EGPA-ICM) and 75 control. Among EGPA-control, EGPA-ICM and EGPA-EM, eosinophil increased (6.12/8.71/10.42 × 109/l, p< 0.01), ANCA positivity decreased (41.33/31.82/14.86%, p< 0.01), and lung involvement reduced (73.33/72.73/43.24%, p= 0.02). In EGPA-EM, cardiac troponin further elevated (0.27 vs 6.00 ng/ml, p< 0.01), ejection fractions decreased (57.79 vs 33.20%, p< 0.01), while more ST-T abnormality was observed (41.89 vs 20.45%, p= 0.02). The prognosis of EGPA-EM was significantly worse, with 14.86% death rate, and 2-year event-free survival rate below 50%. Further, we proposed a LATE-EAST diagnostic score (7 items, 9 points) to discriminate EGPA-EM from EGPA-ICM using 4 points as threshold [AUC 0.85 (95%CI 0.78-0.92), sensitivity 0.78, specificity 0.86]. CONCLUSIONS: We first proposed different subtypes of cardiac involvement in EGPA. Identification and treatment of EGPA-EM needs improvement. LATE-EAST score could recognize the high-risk EGPA-EM effectively. Multi-disciplinary treatment is warranted, immunosuppressive therapy should be given timely and anti-IL-5 antibodies be tested in trials.

Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants.

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069-1081.

Burnout among radiology residents: a systematic review and meta-analysis.

OBJECTIVE: To analyze the prevalence of burnout among radiology residents. METHOD: Five databases (PubMed, Web of Science, Embase, PsycINFO, and Scopus) were searched for studies reporting burnout in radiology residents for the period up to November 7, 2022. RESULTS: A total of 423 studies were identified, and eventually, 16 studies were selected for the qualitative analysis, of which 11 studies were used in the meta-analysis. There was a total of 2164 radiology residents. Six studies reported the prevalence of burnout but the data could not be pooled due to their inconsistent definitions of burnout. The mean scores of three burnout subscales indicated a moderate to high degree of severity: emotional exhaustion = 25.2 (95% CI, 22.1-28.3; I2 = 94.4%), depersonalization = 10.2 (95% CI, 8.5-11.9; I2 = 93.0%), and low perception of personal accomplishment = 32.9 (95% CI, 30.5-35.4; I2 = 94.4%). The pooled prevalence of high-degree emotional exhaustion was 49.9% (95% CI, 43.6-56.1%; I2 = 55.7%), high-degree depersonalization was 45.1% (95% CI, 38.3-52.0%; I2 = 63.2%), and high-degree diminished personal accomplishment was 58.2% (95% CI, 36.0-77.6%; I2 = 84.9%). The impact of the COVID-19 pandemic on radiology residents was not investigated. In addition, there are inconsistent findings on the effects of female sex, seniority, and social support on burnout. CONCLUSIONS: About half of the radiology residents showed at least one of the three burnout manifestations (emotional exhaustion, depersonalization, and personal accomplishment), with a moderate to high degree of severity. CLINICAL RELEVANCE STATEMENT: Such a high prevalence and severity of burnout among radiology residents warrant the attention of residency program directors. KEY POINTS: • Burnout, not uncommon among radiology residents, has not been effectively analyzed. • Nearly half of the radiology residents experience at least one of the three manifestations of burnout to a moderate to high degree. • The high prevalence and severe degree of burnout among radiology residents warrant the attention of residency program directors.

Echocardiographic features of right ventricle in septic patients with elevated central venous pressure.

BACKGROUND: Elevated central venous pressure (CVP) is deemed as a sign of right ventricular (RV) dysfunction. We aimed to characterize the echocardiographic features of RV in septic patients with elevated CVP, and quantify associations between RV function parameters and 30-day mortality. METHODS: We retrospectively reviewed a cohort of septic patients with CVP ≥ 8 mmHg in a tertiary hospital intensive care unit. General characteristics and echocardiographic parameters including tricuspid annular plane systolic excursion (TAPSE), pulmonary vascular resistance (PVR) as well as prognostic data were collected. Associations between RV function parameters and 30-day mortality were assessed using Cox regression models. RESULTS: Echocardiography was performed in 244 septic patients with CVP ≥ 8 mmHg. Echocardiographic findings revealed that various types of abnormal RV function can occur individually or collectively. Prevalence of RV systolic dysfunction was 46%, prevalence of RV enlargement was 34%, and prevalence of PVR increase was 14%. In addition, we collected haemodynamic consequences and found that prevalence of systemic venous congestion was 16%, prevalence of RV-pulmonary artery decoupling was 34%, and prevalence of low cardiac index (CI) was 23%. The 30-day mortality of the enrolled population was 24.2%. In a Cox regression analysis, TAPSE (HR:0.542, 95% CI:0.302-0.972, p = 0.040) and PVR (HR:1.384, 95% CI:1.007-1.903, p = 0.045) were independently associated with 30-day mortality. CONCLUSIONS: Echocardiographic findings demonstrated a high prevalence of RV-related abnormalities (RV enlargement, RV systolic dysfunction and PVR increase) in septic patients with elevated CVP. Among those echocardiographic parameters, TAPSE and PVR were independently associated with 30-day mortality in these patients.

Evolution Characteristics of Void in the Caving Zone Using Fiber Optic Sensing.

Addressing the issue of low filling efficiency in gangue slurry backfilling due to unclear evolution characteristics of voids in the overlying collapsed rock mass during mining, this study utilizes fiber optic sensing technology to monitor real-time strain changes within the rock mass. It proposes a void zoning method based on fiber optic sensing for mining the overlying rock and, in combination with physical model experiments, systematically investigates the dimensions, distribution, and deformation characteristics of rock mass voids. By analyzing fiber optic sensing data, the correlation between the rate of void expansion and the stress state of the rock mass is revealed. The research results demonstrate that as mining progresses, the internal voids of the rock mass gradually expand, exhibiting complex spatial distribution patterns. During the mining process, the expansion of voids within the overlying collapsed rock mass is closely related to the stress state of the rock mass. The rate of void expansion is influenced by changes in stress, making stress regulation a key factor in preventing void expansion and rock mass instability. The application of fiber optic sensing technology allows for more accurate monitoring of changes in rock mass voids, enabling precise zoning of voids in the overlying collapsed rock mass during mining. This zoning method has been validated against traditional theoretical calculations and experimental results. This research expands our understanding of the evolution characteristics of voids in overlying collapsed rock mass and provides valuable reference for backfilling engineering practices and backfilling parameter optimization.

Overview of Health-Monitoring Technology for Long-Distance Transportation Pipeline and Progress in DAS Technology Application.

There are various health issues associated with the different stages of long-distance pipeline transportation. These issues pose potential risks to environmental pollution, resource waste, and the safety of human life and property. It is essential to have real-time knowledge of the overall health status of pipelines throughout their entire lifecycle. This article investigates various health-monitoring technologies for long-distance pipelines, providing references for addressing potential safety issues that may arise during long-term transportation. This review summarizes the factors and characteristics that affect pipeline health from the perspective of pipeline structure health. It introduces the principles of major pipeline health-monitoring technologies and their respective advantages and disadvantages. The review also focuses on the application of Distributed Acoustic Sensing (DAS) technology, specifically time and space continuous monitoring technology, in the field of pipeline structure health monitoring. This paper discusses the process of commercialization development of DAS technology, the main research progress in the experimental field, and the open research issues. DAS technology has broad application prospects in the field of long-distance transportation pipeline health monitoring.

The incidence and risk factors of unplanned removal of peripherally inserted central catheters among adult patients: A multi-centre cohort study.

AIMS AND OBJECTIVES: (i) To estimate the national incidence of unplanned removal of peripherally inserted central catheters (PICCs) in China. (ii) To explore the associated risk factors to provide evidence for the prevention. DESIGN: A multi-centre prospective cohort study. METHODS: A representative sample of 3222 Chinese adult patients with successful PICC insertion was recruited for the PICC Safety Management Research (PATH) using a two-stage cluster sampling method from December 2020 to June 2022. Sixty hospitals from seven Chinese provinces representing all geographical regions were selected. Demographic information and PICC characteristics were collected using a standard online case report form. Risk factors for the unplanned removal of PICCs were assessed using a cause-specific hazard model and verified using a sub-distribution hazard model. STROBE guidelines were followed in reporting this study. RESULTS: Three thousand one hundred and sixty-six patients were included in the final analysis with a mean age of 59 years and a total of 344,247 catheter days. The incidence of unplanned removal was 10.04%. Female, with thrombosis history, PICC insertion due to infusion failure, valved catheter and double-lumen catheter were risk factors, whereas longer insertion and exposure length were protective factors in the cause-specific hazard model. Higher BMI became an independent risk factor in the sub-distribution hazard model. CONCLUSIONS: Unplanned removal of PICCs is a serious clinical challenge in China. Our findings call for prevention strategies targeting the identified risk factors. RELEVANCE TO CLINICAL PRACTICE: Our study characterised the epidemiology of unplanned removal of PICCs among Chinese adult inpatients, highlighting the need for prevention among this population and providing a basis for the formulation of relevant prevention strategies. PATIENT OR PUBLIC CONTRIBUTION: Patients contributed through sharing their information required for the case report form. Healthcare professionals who provide direct care to the patient at each medical centre contributed by completing the online case report form.

P38-DAPK1 axis regulated LC3-associated phagocytosis (LAP) of microglia in an in vitro subarachnoid hemorrhage model.

BACKGROUND: The phagocytosis and homeostasis of microglia play an important role in promoting blood clearance and improving prognosis after subarachnoid hemorrhage (SAH). LC3-assocaited phagocytosis (LAP) contributes to the microglial phagocytosis and homeostasis via autophagy-related components. With RNA-seq sequencing, we found potential signal pathways and genes which were important for the LAP of microglia. METHODS: We used an in vitro model of oxyhemoglobin exposure as SAH model in the study. RNA-seq sequencing was performed to seek critical signal pathways and genes in regulating LAP. Bioparticles were used to access the phagocytic ability of microglia. Western blot (WB), immunoprecipitation, quantitative polymerase chain reaction (qPCR) and immunofluorescence were performed to detect the expression change of LAP-related components and investigate the potential mechanisms. RESULTS: In vitro SAH model, there were increased inflammation and decreased phagocytosis in microglia. At the same time, we found that the LAP of microglia was inhibited in all stages. RNA-seq sequencing revealed the importance of P38 MAPK signal pathway and DAPK1 in regulating microglial LAP. P38 was found to regulate the expression of DAPK1, and P38-DAPK1 axis was identified to regulate the LAP and homeostasis of microglia after SAH. Finally, we found that P38-DAPK1 axis regulated expression of BECN1, which indicated the potential mechanism of P38-DAPK1 axis regulating microglial LAP. CONCLUSION: P38-DAPK1 axis regulated the LAP of microglia via BECN1, affecting the phagocytosis and homeostasis of microglia in vitro SAH model. Video Abstract.

The prevalence and prognosis of asymptomatic intracranial atherosclerosis in a community-based population: Results based on high-resolution magnetic resonance imaging.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic disease (ICAD) is a major cause of ischemic stroke in China, but the prevalence and prognosis of asymptomatic ICAD detected using high-resolution magnetic resonance imaging (HR-MRI) is largely unknown. The aim of this study was to investigate the prevalence and prognosis in order to guide neurologists in interpreting ICAD detected on HR-MRI. METHODS: We included stroke-free participants from a community-based prospective cohort (Shunyi study participants) who underwent HR-MRI between July 2014 and April 2016. The participants were divided into two groups: those with or without ICAD (ICAD+ and ICAD- , respectively). ICAD included intracranial artery stenosis and non-stenotic plaque. The primary outcome was ischemic stroke. Cox proportional hazard models were used to evaluate the association between ICAD and event outcomes. RESULTS: A total of 1060 stroke-free participants evaluated by HR-MRI were included from the Shunyi study. The median age at HR-MRI was 56 years and 64.7% were female. The ICAD prevalence was 36.3% (n = 385). The ICAD+ group was older and had more cerebrovascular risk factors. The rates of ischemic stroke in the ICAD- and ICAD+ groups were 1.3% (n = 9) and 5.2% (n = 20), respectively, with a median follow-up time of 54 months. ICAD was associated with an increased risk of ischemic stroke in the unadjusted and adjusted Cox models, with hazard ratios of 4.12 (95% confidence interval [CI] 1.87-9.05) and 2.50 (95% CI 1.05-5.94), respectively. The greatest risk of an event outcome was observed in participants with ≥70% stenosis or occlusion. The features of high-risk plaques were also identified. CONCLUSIONS: We found that ICAD detected using HR-MRI increases the long-term risk of a first-ever ischemic stroke in a stroke-free population, suggesting that the current primary prevention protocol of stroke awaits further optimization.

Self-enhanced peroxidase-like activity in a wide pH range enabled by heterostructured Au/MOF nanozymes for multiple ascorbic acid-related bioenzyme analyses.

Nanozymes, a class of catalytic nanomaterials, have shown great potential to substitute natural enzymes in various applications. Nevertheless, the pursuit of high-efficiency peroxidase-like activity in a wide pH range is one of the major challenges existing in designing nanozymes. A feasible strategy is to construct an artificial active center by using porous materials as stable supporting structures, which can actively modulate biocatalytic activities via their porous atomic structures and more active sites. Herein, a gold nanoparticles/metal-organic framework (MOF) heterostructure was prepared using UiO-66 as a stable support structure (Au NPs/UiO-66), which demonstrates enhanced peroxidase-like activity, ∼8.95 times higher than that of pure Au NPs. Strikingly, Au NPs/UiO-66 exhibits excellent stability (maintains above 80% activity at 40-70 °C and retains 93% activity after 3 months of storage) and sustained high relative activity (above 90%) over a pH range of 5.0-9.0 due to the homogeneous dispersibility of free-ligand Au NPs and the strong chemical interaction between the Au NPs and the UiO-66 host. Moreover, a colorimetric assay of ascorbic acid (AA) and three AA-related biological enzymes was developed based on Au NPs/UiO-66 nanozyme, which has a good linear detection range and excellent anti-interference ability. This work provides important guidance for the expansion of metal NPs/MOF heterostructure nanozymes and their application prospects in the development of biosensors.

Improve the dupilumab therapy evaluation with dermoscopy and high-frequency ultrasound in moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory disease. Monoclonal antibody dupilumab was approved to treat moderate-to-severe AD in recent years. An objective assessment of treatment response by skin imaging modality is adjuvant for clinical evaluations. This study aimed to explore the value of dermoscopy and high-frequency ultrasound (HFUS) imaging characteristics in treatment evaluation for moderate-to-severe AD patients treated with dupilumab. METHODS: Moderate-to-severe AD patients refractory to conventional therapy were enrolled in the study. All patients went through at least a 16-week standardized treatment of dupilumab. Clinical scores (eczema area scoring index [EASI], SCOARD, numerical rating scale of pruritus, dermatology life quality index), dermoscopy, and HFUS examinations were conducted at 0, 2, 4, 8, 12, and 16 weeks of treatment. Erythema, scales, erosion, and pigmentation under dermoscopy were scored, and subepidermal low-echogenic band (SLEB) thickness under HFUS was measured as quantitative indexes. Descriptive analysis and mixed effect linear regression models were used for statistical analysis. RESULTS: Sixteen patients were enrolled in the study and their average age was 45.63 ± 18.18 years. All clinical scores decreased with significant difference after 16-week treatment compared with baseline. All patients achieved EASI 50 (EASI score decreased by 50% or more), and 9/16 patients reached EASI 75 after 16-week treatment. Dermoscopy evaluation of erythema, scales and erosion scores were decreased, and the sign of pigmentation score was increased after treatment. For HFUS, the mean SLEB value was 0.51 ± 0.29 mm and decreased to 0.27 ± 0.15 mm after 16-week treatment (p < 0.01). SLEB value decreased linearly with treatment time and correlated with clinical scores. However, SLEB values of two patients were 0.57 and 0.68 mm at week 16, respectively, which were higher than the average, and one of the patients showed EASI 75. CONCLUSION: Dermoscopy and HFUS were able to reveal deeper inflammation response than clinical scores in AD and can be an effective method to evaluate and monitor clinical improvement during dupilumab treatment for AD patients. The preliminary value of imaging methods for predicting the treatment endpoint of dupilumab remains to be verified.

Research on Similarity Simulation Experiment of Mine Pressure Appearance in Surface Gully Working Face Based on BOTDA.

In order to study the mountain deflection characteristics and the pressure law of the working face after the mining of a shallow coal seam under the valley terrain, a geometric size of 5.0 × 0.2 × 1.33 m is used in the physical similarity model. Brillouin optical time domain analysis (BOTDA) technology is applied to a similar physical model experiment to monitor the internal strain of the overlying rock. In this paper, the strain law of the horizontal optical fiber at different stages of the instability of the mountain structure is analyzed. Combined with the measurement of the strain field on the surface of the model via digital image correlation (DIC) technology, the optical fiber strain characteristics of the precursor of mountain instability are given. The optical fiber characterization method of working face pressure is proposed, and the working face pressures at different mining stages in gully terrain are characterized. Finally, the relationship between the deflection instability of the mountain and the strong ground pressure on the working face is discussed. The sudden increase in the strain peak point of the horizontally distributed optical fiber strain curve can be used to distinguish the strong ground pressure. At the same time, this conclusion is verified by comparing the measured underground ground pressure values. The research results can promote the application of optical fiber sensing technology in the field of mine engineering.

Different Types of Circulatory Inflammatory Biomarkers Associated with Cerebral Arterial Atherosclerosis and Dolichoectasia.

BACKGROUND: Although inflammation is found to be related to arteriopathy pathogenesis, it is yet to be determined the distinct correlations of specific inflammatory biomarker types contributing to different cerebral large vessel diseases. We aimed to investigate the association between multiple inflammatory biomarkers and cerebral atherosclerosis and dolichoectasia in a community-based sample. METHODS: A total of 960 participants of the Shunyi study were included. A panel of 14 circulatory inflammatory biomarkers was assessed and then grouped in three sets as systemic, endothelial-related, and media-related inflammation, based on underlying different inflammatory cascades. Intracranial atherosclerotic stenosis (ICAS), dolichoectasia estimated by magnetic resonance angiography, and carotid plaques estimated by ultrasound were also performed. RESULTS: Endothelial-related inflammatory group was related to the presence of ICAS (R2 = 0.215, p = 0.024) and carotid plaques (R2 = 0.342, p = 0.013). Backward stepwise elimination showed that E-selectin was prominent (ß = 0.67, 95% CI: 0.54-0.85, p = 0.001; ß = 0.79, 95% CI: 0.68-0.93, p = 0.005). Systemic inflammatory group was associated with an increased basilar artery diameter (R2 = 0.051, p < 0.001), and backward stepwise elimination showed that IL-6 was prominent (ß = 0.07, 95% CI: 0.03-0.11, p < 0.001). CONCLUSION: Different types of inflammatory biomarkers were associated with atherosclerosis and dolichoectasia, respectively, implying dissimilar inflammatory processes. Further confirming of their distinct anti-inflammatory roles as potential therapeutic targets is warrant.

Ultrasensitive detection of vitamin E by signal conversion combined with core-satellite structure-based plasmon coupling effect.

The rapid and sensitive surface-enhanced Raman scattering (SERS) detection of molecular biomarkers from real samples is still a challenge because the intrinsically trace analytes may have a low molecular affinity for metal surfaces. Herein, we develop a smart signal conversion and amplification strategy based on silver-gold-silica core-satellite structure nanoparticles (Ag@Au@SiO2 NPs) to sensitively detect low adsorptive vitamin E using SERS, which has been considered a biomarker of neuromuscular disorders when its abnormal content is measured in the serum of patients. Through the reducibility of vitamin E, Ag+ ions are rapidly reduced to Ag atoms, resulting in the epitaxial growth of Ag nanocrystals on gold nanoparticles forming satellite particle-particle gap-narrowed Ag@Au@SiO2 NPs. The generated strong plasmonic field dramatically enhances the Raman signal of the Raman reporter molecule 4-aminothiophenol (4-ATP) and the detected vitamin E molecules at an estimated level of 58.19 nmol L-1. The sensitivity of this operational SERS strategy provides tremendous prospects for the screening of neuromuscular disorders.

Prognostic value of left atrial mechanics in cardiac light-chain amyloidosis with preserved ejection fraction: a cohort study.

BACKGROUND: Light-chain amyloidosis is a plasma cell disorder associated with poor outcomes, especially when the heart is involved. The characteristics of left atrial (LA) function and its prognostic implications in cardiac amyloidosis (CA) have not been fully investigated. METHODS: Between April 2014 and June 2019, 93 patients with a diagnosis of CA, normal left ventricular ejection fraction (LVEF) and sinus rhythm were included. Their clinical, baseline echocardiographic and follow-up data were investigated. LA function, including LA strain and strain rate, was assessed using 2D speckle tracking echocardiography in different LA functional phases. RESULTS: Among all patients, 38 (40.9%) died. Multivariate Cox regression analyses showed that LA mechanics regarding LA reservoir and booster pump functions were independent predictors for overall survival. Traditional echocardiographic parameters for LA structure like LA volume index and LA width were not associated with mortality. Moreover, LA strain and strain rate in reservoir and contractile phases improved the discrimination and goodness of fit of the conventional prognostic model, the Mayo criteria 2004 and 2012, in our study population. Decreased LA mechanics were associated with impaired left ventricular (LV) systolic and diastolic function, and LA reservoir and contractile functions were associated with LA structure. CONCLUSIONS: Assessment of LA reservoir and contractile functions via 2D speckle tracking echocardiographic LA mechanical indices provide clinical and prognostic insights into cardiac light-chain amyloidosis patients, especially those with preserved EF and sinus rhythm. Emphasizing the monitoring of LA function may be beneficial for the prognosis prediction of CA.

Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis.

Janus kinase (JAK) inhibitors have become promising treatments for atopic dermatitis (AD), however no study directly comparing JAK inhibitors with each other has been reported. We conducted this network meta-analysis to determine the comparative efficacy and safety of three common oral JAK inhibitors including abrocitinib, baricitinib, and upadacitinib for moderate-to-severe AD. We first identified eligible studies from published meta-analyzes, then we searched PubMed to obtain additional studies published between February and July 2021. Clinical efficacy and safety were evaluated as primary and secondary outcome, respectively. After extracting data and assessing methodological quality, we utilized ADDIS 1.4 software to conduct pair-wise and network meta-analyzes. Ten eligible studies were included in the final analysis. Pooled results that abrocitinib, baricitinib, and upadacitinib obtained higher investigator global assessment (IGA), eczema area, and severity index (EASI) response, however abrocitinib and upadacitinib caused more treatment-emergent adverse events (TEAEs) regardless of doses, compared with placebo. Network meta-analyzes revealed that upadacitinib 30 mg was superior to all regimens and upadacitinib 15 mg was better than remaining regimens except for abrocitinib 200 mg in terms of IGA and EASI response. Moreover, abrocitinib 200 mg was superior to abrocitinib 100 mg, baricitinib 1 mg, 2 mg, and 4 mg for clinical efficacy. However, upadacitinib 30 mg caused more TEAEs. Abrocitinib, baricitinib, and upadacitinib were consistently effective therapies in adult and adolescent patients with AD; however, upadacitinib 30 mg may be the optimal option in short-term studies. More efforts should be done to reduce the risk of TEAEs caused by upadacitinib 30 mg.

GSK3ß inhibitor TDZD8 ameliorates brain damage through both ROS scavenging and inhibition of apoptosis in hyperglycaemic subarachnoid haemorrhage rats.

Hyperglycaemia is known to be associated with unfavourable outcomes in subarachnoid haemorrhage (SAH), but the pathogenic mechanism is unclear, and there is also a lack of effective therapeutic drugs in clinical practice. Phosphorylation of GSK3ß at serine 9 can inhibit its activity to further worsen SAH. The aim of the present study was to evaluate the protective effect and the potential mechanism of the GSK3ß inhibitor TDZD8 on brain injury in a hyperglycaemic SAH rat model. Hyperglycaemia was induced by intraperitoneal injection of streptozocin for 3 days. The SAH model was established by injecting fresh autologous femoral artery blood into the prechiasmatic cistern. p-GSK3ß (Ser9) expression was induced by intraperitoneal injection of TDZD8 (30 min post-SAH). The expression levels of GSK3ß, p-GSK3ß, SOD1/2, caspase 3, Bax and Bcl-2 were detected by western blot analysis. Terminal deoxynucleotidyl transferase dUTP nick end-labelling (TUNEL) staining was used to detect neuronal apoptosis of basal temporal lobe. Neurological scores were calculated to determine behavioural recovery. Neuronal survival was detected by Nissl staining. Hyperglycaemia significantly decreased p-GSK3ß expression, further exacerbated neurobehavioural deficits and increased oxidative stress and neuronal apoptosis in the brain after SAH compared to normal glycaemic SAH rats and hyperglycaemic rats. In addition, hyperglycaemic SAH rats had obvious oxidative stress and apoptosis. However, TDZD8 effectively decreased cleaved caspase 3 expression and TUNEL-positive cells and increased the Bcl2/Bax ratio, expression of SOD1/2 and activity of superoxide dismutase (SOD) enzyme compared with hyperglycaemic SAH rats. The GSK3ß inhibitor TDZD8 has therapeutic potential for hyperglycaemic SAH. The neuroprotective effect of TDZD8 appears to be mediated through its antioxidative and antiapoptotic activity.

Study on Quantitative Characterization of Coupling Effect between Mining-Induced Coal-Rock Mass and Optical Fiber Sensing.

The monitoring of mine pressure, division of vertical zoning of the overburden, discrimination of key stratum structure of the overburden and monitoring of advanced abutment pressure are still the main research problems in the field of coal mining. Therefore, the promotion of development of a monitoring technology of mining-induced rock mass deformation has important research value in the mining field. There are many problems to be solved in the application of optical fiber sensing (OFS) to deformation monitoring, such as the corresponding relationship between actual deformation and optical parameters, the coupling relationship between the optical fiber and rock mass and the reasonable division of vertical zoning of the overburden. In this study, a quantitative index of coupling action between the mining rock mass and optical fiber is put forward, and the coupling coefficient of different vertical zonings is quantitatively analyzed and discussed. Based on this, five different media in contact with optical fiber are proposed. The relationship between the strain curve form, the development height of the fracture zone and the activity of key stratum is established. It is of great academic value and research significance to establish a characterization system of displacement, deformation and structural evolution of overlying strata based on optical fiber sensing technology.

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. METHODS: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. RESULTS: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. CONCLUSIONS: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis.

OBJECTIVES: While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. METHODS: We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. RESULTS: Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. CONCLUSION: Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.