Pepsin-mediated inflammation in laryngopharyngeal reflux via the ROS/NLRP3/IL-1ß signaling pathway.

BACKGROUND: Laryngopharyngeal reflux (LPR) is one of the most common disorders in otorhinolaryngology, affecting up to 10% of outpatients visiting otolaryngology departments. In addition, 50% of hoarseness cases are related to LPR. Pepsin reflux-induced aseptic inflammation is a major trigger of LPR; however, the underlying mechanisms are unclear. The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome has become an important bridge between stimulation and sterile inflammation and is activated by intracellular reactive oxygen species (ROS) in response to danger signals, leading to an inflammatory cascade. In this study, we aimed to determine whether pepsin causes LPR-associated inflammatory injury via mediating inflammasome activation and explore the potential mechanism. METHODS: We evaluated NLRP3 inflammasome expression and ROS in the laryngeal mucosa using immunofluorescence and immunohistochemistry. Laryngeal epithelial cells were exposed to pepsin and analyzed using flow cytometry, western blotting, and real-time quantitative PCR to determine ROS, NLRP3, and pro-inflammatorycytokine levels. RESULTS: Pepsin expression was positively correlated with ROS as well as caspase-1 and IL-1ß levels in laryngeal tissues. Intracellular ROS levels were elevated by increased pepsin concentrations, which were attenuated by apocynin (APO)-a ROS inhibitor-in vitro. Furthermore, pepsin significantly induced the mRNA and protein expression of thioredoxin-interacting protein, NLRP3, caspase-1, and IL-1ß in a dose-dependent manner. APO and the NLRP3 inhibitor, MCC950, inhibited NLRP3 inflammasome formation and suppressed laryngeal epithelial cell damage. CONCLUSION: Our findings verified that pepsin could regulate the NLRP3/IL-1ß signaling pathway through ROS activation and further induce inflammatory injury in LPR. Targeting the ROS/NLRP3 inflammasome signaling pathway may help treat patients with LPR disease.

A brain tumor reporting and data system to optimize imaging surveillance and prognostication in high-grade gliomas.

BACKGROUND AND PURPOSE: High-grade glioma (HGG), including glioblastoma, is the most common primary brain neoplasm and has a dismal prognosis. After initial treatment, follow-up decisions are guided by longitudinal MRI performed at routine intervals. The Brain Tumor Reporting and Data System (BT-RADS) is a proposed structured reporting system for posttreatment brain MRIs. The purpose of this study is to determine the relationship between BT-RADS scores and overall survival in HGG patients. METHODS: Chart review of grade 4 glioma patients who had an MRI at a single institution from November 2018 to November 2019 was performed. BT-RADS scores, tumor characteristics, and overall survival were recorded. Likelihood of improvement, stability, or worsening on the subsequent study was calculated for each score. Survival analysis was performed using Kaplan-Meier method, log-rank test, and a time-dependent cox model. Significance level of .05 was used. RESULTS: The study identified 91 HGG patients who underwent a total of 538 MRIs. Mean age of patients was 57 years old. Score with the highest likelihood for worsening on the next follow-up was 3b. The risk of death was 53% higher with each incremental increase in BT-RADS scores (hazard ratio, 1.53; 95% confidence interval [CI], 1.07-2.19; p = .019). The risk of death was 167% higher in O-6-methylguanine-DNA-methyltransferase unmethylated tumors (hazard ratio, 2.67; 95% CI, 1.34-5.33; p = .005). CONCLUSIONS: BT-RADS scores can be used as a reference guide to anticipate whether patients' subsequent MRI will be improved, stable, or worsened. The scoring system can also be used to predict clinical outcomes and prognosis.

Stabilizing the Unstable: Chromium Coating on NiMo Electrode for Enhanced Stability in Intermittent Water Electrolysis.

Hydrogen production through water electrolysis is a promising method to utilize renewable energy in the context of urgent need to phase out fossil fuels. Nickel-molybdenum (NiMo) electrodes are among the best performing non-noble metal-based electrodes for hydrogen evolution reaction in alkaline media (alkaline HER). Albeit exhibiting stable performance in electrolysis at a constant power supply (i.e., constant electrolysis), NiMo electrodes suffer from performance degradation in electrolysis at an intermittent power supply (i.e., intermittent electrolysis), which is emblematic of electrolysis powered directly by renewable energy (such as wind and solar power sources). Here we reveal that NiMo electrodes were oxidized by dissolved oxygen during power interruption, leading to vanishing of metallic Ni active sites and loss of conductivity in MoOx substrate. Based on the understanding of the degradation mechanism, chromium (Cr) coating was successfully applied as a protective layer to inhibit oxygen reduction reaction (ORR) and significantly enhance the stability of NiMo electrodes in intermittent electrolysis. Further, combining experimental and Molecular Dynamics (MD) simulations, we demonstrate that the Cr coating served as a physical barrier inhibiting diffusion of oxygen, while still allowing other species to pass through. Our work offers insights into electrode behavior in intermittent electrolysis, as well as provides Cr coating as a valid method and corresponding deep understanding of the factors for stability enhancement, paving the way for the successful application of lab-scale electrodes in industrial electrolysis powered directly by renewable energy.

Academic Radiology in the United States: Defining Gender Disparities in Faculty Leadership and Academic Rank.

RATIONALE AND OBJECTIVES: Female physicians in academic medicine have faced barriers that potentially affect representation in different fields and delay promotion. Little is known about gender representation differences in United States academic radiology departments, particularly within the most pursued subspecialties. PURPOSE: To determine whether gender differences exist in United States academic radiology departments across seven subspecialties with respect to academic ranks, departmental leadership positions, experience, and scholarly metrics. MATERIALS AND METHODS: In this cross-sectional study from November 2018 to June 2020, a database of United States academic radiologists at 129 academic departments in seven subspecialties was created. Each radiologist's academic rank, departmental leadership position (executive-level - Chair, Director, Chief, and Department or Division Head vs vice-level - vice, assistant, or associate positions of executive level), self-identified gender, years in practice, and measures of scholarly productivity (number of publications, citations, and h-index) were compiled from institutional websites, Doximity, LinkedIn, Scopus, and official NPI profiles. The primary outcome, gender composition differences in these cohorts, was analyzed using Chi2 while continuous data were analyzed using Kruskal-Wallis rank sum test. The adjusted gender difference for all factors was determined using a multivariate logistic regression model. RESULTS: Overall, 5086 academic radiologists (34.7% women) with a median 14 years of practice (YOP) were identified and indexed. There were 919 full professors (26.1% women, p < 0.01) and 1055 executive-level leadership faculty (30.6% women, p < 0.01). Within all subspecialties except breast imaging, women were in the minority (35.4% abdominal, 79.1% breast, 12.1% interventional, 27.5% musculoskeletal, 22.8% neuroradiology, 45.1% pediatric, and 19.5% nuclear; p < 0.01). Relative to subspecialty gender composition, women full professors were underrepresented in abdominal, pediatric, and nuclear radiology (p < 0.05) and women in any executive-level leadership were underrepresented in abdominal and nuclear radiology (p < 0.05). However, after adjusting for h-index and YOP, gender did not influence rates of professorship or executive leadership. The strongest single predictors for professorship or executive leadership were h-index and YOP. CONCLUSION: Women academic radiologists in the United States are underrepresented among senior faculty members despite having similar levels of experience as men. Gender disparities regarding the expected number of women senior faculty members relative to individual subspecialty gender composition were more pronounced in abdominal and nuclear radiology, and less pronounced in breast and neuroradiology. Overall, h-index and YOP were the strongest predictors for full-professorship and executive leadership among faculty. KEY RESULTS: ● Though women comprise 34.7% of all academic radiologists, women are underrepresented among senior faculty members (26.1% of full professors and 30.6% of executive leadership) ● Women in junior faculty positions had higher median years of practice than their male counterparts (10 vs 8 for assistant professors, 21 vs 13 for vice leadership) ● Years of practice and h-index were the strongest predictors for full professorship and executive leadership.

ZIF-8 derived hollow carbon to trap polysulfides for high performance lithium-sulfur batteries.

Lithium-sulfur batteries (LSBs) have a high theoretical energy density and are low cost. However, the undesirable shuttle effect with the solid discharge product, Li2S, greatly impedes their market penetration. Conductive carbon materials with functional elements are beneficial in controlling the shuttle effect and can reactivate the Li2S, leading to improved long term cycling performance of LSBs. Herein, we report zinc (Zn) and nitrogen (N) co-doped ZIF-8 derived hollow carbon (ZHC) as a promising separator coating for LSBs to control the shuttle effect. The hollow area in the ZHC is identified to be around 250 nm with a carbonized outer surface thickness of approximately 50 nm. The presence of Zn and N in the nanohollow carbon structure helps to mitigate polysulfide (PS) diffusion in LSBs. Furthermore, the hollow interior of the carbon acts as a PS pocket to physically capture the PS and in addition Zn and N chemically attract the PS through polar-polar and metal sulfide interactions. The ZHC with its unique architecture and functional groups shows a promising performance with an initial specific capacity (S.cap) of 842 mA h g-1 at 4.80 mg cm-2 and cycling stability until 400 cycles, which is considerably higher in comparison with the cycling performance of parent ZIF-8.

Tocilizumab in the treatment of severe and refractory parenchymal neuro-Behçet's syndrome: case series and literature review.

OBJECTIVES: This study aimed to investigate the efficacy and safety of tocilizumab (TCZ) in severe and refractory parenchymal neuro-Behçet's syndrome (p-NBS). METHODS: We retrospectively analyzed five patients with p-NBS treated with TCZ in our center between 2013 and 2020, and six cases from literature research with the index terms "neuro-Behçet's syndrome" and "tocilizumab" on PubMed NCBI. RESULTS: A total of 11 patients with p-NBS were enrolled (5 males, 6 females), with a mean age of 34.5 ± 8.0 years at the onset. All the patients had parenchymal neurological lesions, six patients (54.5%) suffered from multiple lesions, and nine patients (81.8%) were disabled. Before TCZ administration, all the patients had failed conventional therapy, eight patients (72.7%) received two or more immunosuppressants, and five patients showed insufficient response or intolerance to other biologics. TCZ was administrated at 8 mg/kg every 4 weeks, with background glucocorticoids (GCs) and immunosuppressants. After a median follow-up of 13 (interquartile range, 3.5-23.5) months, all the patients achieved both clinical and radiological improvements, and the Behçet's Disease Current Activity Form score improved significantly (3 versus 0, median, p = 0.004), the Rankin score also decreased (4 versus 2, median, p = 0.005). Levels of interleukin-6 in the cerebrospinal fluid decreased significantly in five patients (533.4 ± 389.7 pg/ml versus 34.5 ± 27.1 pg/ml, p = 0.048), after a median of two (interquartile range, 1-4) times of TCZ infusions. Furthermore, the GC dosage (per os) reduced from 69.2 ± 16.9 mg/d to 16.4 ± 16.2 mg/d (p = 0.000), and immunosuppressants were tapered in number and dosage in seven (63.6%) and four (36.3%) patients, respectively. No serious adverse events or deaths were observed during follow-up. CONCLUSIONS: TCZ is well tolerated and effective in severe and refractory p-NBS, with a favorable GC- and immunosuppressant-sparing effect. Cerebrospinal fluid interleukin-6 might be used to monitor the effects of TCZ in p-NBS.

Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis.

Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14+ monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AAD+annexin V+), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1ß and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.