A multicenter, randomized, double-blinded, placebo-controlled, phase â ¢ study evaluating the efficacy and safety of Xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Xeligekimab is a fully human monoclonal antibody that selectively neutralizes IL-17A and had shown potential efficacy in preliminary trials. OBJECTIVE: To evaluate the efficacy and safety of Xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg Xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by extending the treatment schedule to GR1501 every 4 weeks for further 40 weeks. Efficacy was assessed by evaluating the Physician's Global Assessment (PGA) 0/1 and Psoriasis Area and Severity Index (PASI) 75/90/100 improvement. The safety profile was also evaluated. RESULTS: At week 12, The PASI 75/90/100 were achieved in 90.7%/74.4%/30.2%% patients in GR1501 group compared with 8.6%/1.4%/0% patients in placebo group, respectively. The PGA 0/1 were achieved in 74.4% patients of GR1501 group and 3.6% patients in placebo group, respectively. The PASI 75 and PGA 0/1 maintained until week 52. No unexpected adverse events were observed. CONCLUSION: Xeligekimab showed high efficacy and is well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

Design and Force/Angle Independent Control of a Bionic Mechanical Ankle Based on an Artificial Muscle Matrix.

Inspired by the natural skeletal muscles, this paper presents a novel shape memory alloy-based artificial muscle matrix (AMM) with advantages of a large output force and displacement, flexibility, and compactness. According to the composition of the AMM, we propose a matrix control strategy to achieve independent control of the output force and displacement of the AMM. Based on the kinematics simulation and experiments, we obtained the output displacement and bearing capacity of the smart digital structure (SDS) and confirmed the effectiveness of the matrix control strategy to achieve force and displacement output independently and controllably. A bionic mechanical ankle actuated by AMM was proposed to demonstrate the actuating capability of the AMM. Experimental results show that the angle and force of the bionic mechanical ankle are output independently and have a significant gradient. In addition, by using a self-sensing method (resistance self-feedback) and PD control strategy, the output angle and force of the bionic mechanical ankle can be maintained for a long time without overheating of the AMM.

The Ethylene Response Factor ERF5 Regulates Anthocyanin Biosynthesis in 'Zijin' Mulberry Fruits by Interacting with MYBA and F3H Genes.

Ethylene promotes ripening in fruits as well as the biosynthesis of anthocyanins in plants. However, the question of which ethylene response factors (ERFs) interact with the genes along the anthocyanin biosynthesis pathway is yet to be answered. Herein, we conduct an integrated analysis of transcriptomes and metabolome on fruits of two mulberry genotypes ('Zijin', ZJ, and 'Dashi', DS, with high and low anthocyanin abundance, respectively) at different post-flowering stages. In total, 1035 upregulated genes were identified in ZJ and DS, including MYBA in the MBW complex and anthocyanin related genes such as F3H. A KEGG analysis suggested that flavonoid biosynthesis and plant hormone signaling transduction pathways were significantly enriched in the upregulated gene list. In particular, among 103 ERF genes, the expression of ERF5 showed the most positive correlation with the anthocyanin change pattern across both genotypes and in the post-flowering stages, with a Pearson correlation coefficient (PCC) of 0.93. Electrophoresis mobility shift assay (EMSA) and luciferase assay suggested that ERF5 binds to the promoter regions of MYBA and F3H and transcriptionally activates their gene expression. We elucidated a potential mechanism by which ethylene enhances anthocyanin accumulation in mulberry fruits and highlighted the importance of the ERF5 gene in controlling the anthocyanin content in mulberry species. This knowledge could be used for engineering purposes in future mulberry breeding programs.

JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis.

Background: Systemic sclerosis (SSc) is a rare disabling connective tissue disease with few available treatment options. Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality. A previous experiment has shown that JAK2 inhibitor can significantly improve skin fibrosis in bleomycin (BLM)-induced murine model, including reducing dermal thickening and collagen accumulation. We aimed to describe the efficacy of oral JAK1/2 inhibitor baricitinib in SSc patients, especially focusing on skin fibrosis and microvascular manifestations. Methods: We described the different effects of oral selective JAK1, JAK2, or JAK3 inhibitor treatment in a BLM-induced skin fibrosis mouse model. Furthermore, 10 adult patients with dcSSc were treated with baricitinib. We assessed the changes in modified rodman skin score (mRSS) and digital ulcer net burden at week 12 and 24 from baseline. We also compared the absolute changes in scores on the Scleroderma Health Assessment Questionnaire (SHAQ) and a total score on the St. George's Respiratory Questionnaire (SGRQ) over a 24-week period. Results: In the experimental mouse model of skin fibrosis, a JAK1 and JAK2 inhibitor ameliorated skin fibrosis, and a JAK2 inhibitor had the most obvious effect. Treatment with the JAK2 inhibitor also blunted the capillary rarefaction. We demonstrated that skin fibrosis and digital ulcers were significantly relieved in 10 SSc patients treated with baricitinib. The mRSS significantly improved at week 12 from baseline, with a mean change in mRSS of -8.3 [95% confidence interval (CI), -12.03 to -4.574; p = 0.0007] and improved greater at week 24 to -11.67 (95% CI, -16.84 to -6.496; p = 0.0008). Among the four patients with digital ulcers (DU), three were completely healed at week 24, the number of ulcers in another patient was significantly reduced, and there was no patient with new ulcers. Only one adverse event (AE) of herpes zoster was observed. Conclusions: Our results indicate that selective JAK1 and JAK2 inhibitor alleviates skin fibrosis, and oral JAK1/2 inhibitor baricitinib is a potentially effective treatment for dcSSc patients with skin fibrosis and DU. Baricitinib was well-tolerated by most patients in this study. Additional large clinical trials are needed to confirm our pilot findings. Chinese Clinical Trial Registry Number: ChiCTR2000030995.

A Feature Selection Approach Guided an Early Prediction of Anthocyanin Accumulation Using Massive Untargeted Metabolomics Data in Mulberry.

Identifying the early predictive biomarkers or compounds represents a pivotal task for guiding a targeted agricultural practice. Despite the various available tools, it remains challenging to define the ideal compound combination and thereby elaborate an effective predictive model fitting that. Hence, we employed a stepwise feature selection approach followed by a maximum relevance and minimum redundancy (MRMR) on the untargeted metabolism in four mulberry genotypes at different fruit developmental stages (FDSs). Thus, we revealed that 7 out of 226 differentially abundant metabolites (DAMs) explained up to 80% variance of anthocyanin based on linear regression model and stepwise feature selection approach accompanied by an MRMR across the genotypes over the FDSs. Among them, the phosphoenolpyruvate, d-mannose and shikimate show the top 3 attribution indexes to the accumulation of anthocyanin in the fruits of these genotypes across the four FDSs. The obtained results were further validated by assessing the regulatory genes expression levels and the targeted metabolism approach. Taken together, our findings provide valuable evidences on the fact that the anthocyanin biosynthesis is somehow involved in the coordination between the carbon metabolism and secondary metabolic pathway. Our report highlights as well the importance of using the feature selection approach for the predictive biomarker identification issued from the untargeted metabolomics data.

Corrigendum: JAK1/2 inhibitor baricitinib improves skin fibrosis and digital ulcers in systemic sclerosis.

[This corrects the article DOI: 10.3389/fmed.2022.859330.].

Interferon-α activates interleukin-1 receptor-associated kinase 1 to induce regulatory T-cell apoptosis in patients with systemic lupus erythematosus.

Impaired regulatory T-cell (Treg) responses and upregulated interleukin-1 receptor-associated kinase 1 (IRAK1) expression are associated with the development of human systemic lupus erythematosus (SLE). Here, we show that the levels of upregulated IRAK1 expression in circulating Tregs are correlated with the percentages of apoptotic Tregs, Systemic Lupus Erythematosus Disease Activity Index scores, and serum complement C3 levels in SLE patients. High levels of plasma interferon (IFN)-α in SLE patients induced IRAK1 phosphorylation to trigger Treg apoptosis, which was mitigated by IRAK1 inhibitor (IRAK-Inh) treatment. Bioinformatics indicated that IRAK1 activation was related to the IFN-α/ß and mitogen-activated protein kinase (MAPK) signaling in Tregs and IFN-α treatment induced the p38 and MAPK/ERK kinase 3/6 phosphorylation, which was attenuated by IRAK-Inh in Tregs. Treatment with IRAK-Inh effectively alleviated renal injury and promoted the survival of lupus-prone B6.MRL-Faslpr /Nju mice. Therefore, IFN-α induced IRAK1 activation to promote Treg apoptosis, contributing to the pathogenesis of SLE and IFN-α/IRAK1 may be therapeutic targets for SLE.

Does Radical Hysterectomy for Clinically Apparent Stage II Endometrial Cancer Affect Risk of Local Recurrence?

OBJECTIVE: Compare recurrence-free survival (RFS) and morbidity between radical hysterectomy (RH) and simple hysterectomy (SH) for clinically diagnosed stage II endometrial cancer. METHODS: A multicentre, retrospective study, from 2000 to 2015, involving patients with endometrial cancer with cervical involvement preoperatively and stromal invasion on final pathology. Wilcoxon rank-sum test, Fisher exact test, Kaplan-Meier survival functions, and Cox proportional hazards models were used for analysis. RESULTS: Ninety of 1613 patients had clinical stage II endometrial cancer; 57 underwent RH and 33 underwent SH, with no difference in adjuvant treatment or morbidity. About half of patients (51%) had pathologic stage III-IV disease. Mean follow-up was 3.3 and 3.8 years for SH and RH, respectively. Thirty-three percent of patients with RH and SH experienced a recurrence. Most recurrences were distant: 90% with SH and 79% with RH. There was no difference in RFS between groups (2-year: SH 65% vs. RH 75%; 5-year: SH 54% vs. RH 63%; P = 0.72). Controlling for stage, adjuvant treatment, and margin status, RH was not associated with RFS (HR 0.62; 95% CI 0.28-1.35). Among 44 patients with pathologic stage II disease, 7 had a recurrence (4 SH and 3 RH); 6 of 7 had distant recurrences. CONCLUSIONS: Fifty-one percent of patients with clinical stage II endometrial cancer had advanced disease on final pathology, highlighting the importance of surgical staging. RH was not associated with RFS or reduced morbidity. Most recurrences were distant. Although RH could be performed to achieve negative surgical margins, SH may be sufficient for central, small tumours given the high risk of advanced disease and distant recurrence. Research efforts should further elucidate the ideal management of these patients.

Endometriosis-associated Ovarian Cancer is a Subset With a More Favorable Outcome and Distinct Clinical-pathologic Characteristics.

There is a controversy about whether endometriosis-associated ovarian cancer (EAOC) might represent a different entity from the corresponding ovarian cancer occurring de novo, in the absence of endometriosis. This study investigated the clinical-pathologic characteristics and outcome of EAOC compared with other ovarian carcinomas that are not associated with endometriosis (non-EAOC) in a large cohort. Seven hundred two patients meeting the inclusion criteria were further subclassified as group I when patients had ovarian carcinoma associated with or arising within endometriosis (EAOC) and group II when patients had non-EAOC. Age, gross features, histologic type, International Federation of Gynecology and Obstetrics stage, and disease-free survival (DFS) were compared between the groups. One hundred sixty-eight (23.9%) patients had EAOC, whereas 534 (76.1%) patients had non-EAOC. EAOCs were mostly endometrioid and clear cell type. Patients with EAOC were younger, present early, and had a lower rate of recurrence when compared with patients with non-EAOC, P<0.001. Patients with EAOC had longer DFS time, 51.9 mo (95% confidence interval, 44.9-58.8) versus 30.5 mo (95% confidence interval, 27.7-33.3) in non-EAOC patients. The 5 yr Kaplan-Meier estimate of DFS rate was 70% in 166 patients of group I and was 39.3% in 532 patients of group II, P<0.001. On multivariate analysis, International Federation of Gynecology and Obstetrics staging, histologic type, and treatment were the only significant factors affecting the hazards of recurrence. Patients with tumors associated with endometriosis are usually, younger, present early, have lower rate of recurrence, longer DFS, and their tumors are of lower grade and are more likely endometrioid or clear cell carcinoma.

Ginsenoside Rb1 administration attenuates focal cerebral ischemic reperfusion injury through inhibition of HMGB1 and inflammation signals.

High-mobility group box 1 (HMGB1) is released after focal cerebral ischemia/reperfusion (I/R), and aggravates brain tissue damage. Ginsenoside Rb1 (Rb1), isolated from Panax ginseng, has been reported to inhibit I/R-induced cell death in the brain. The present study aimed to investigate the protective ability of GRb1 on focal cerebral I/R rats and to explore its further mechanisms. A middle cerebral artery occlusion (MCAO) rat model was established and treated with different doses of Rb1. The neurological deficits were examined after reperfusion, and TTC staining was applied to assess the infarct volume. Histology and TUNEL staining were performed to evaluate pathological changes and neuronal cell apoptosis in brain tissues. HMGB1 and levels of inflammatory factors and proteins, were examined by ELISA or western blotting. Rb1 treatment notably improved the neurological deficits in an MCAO model, accompanied by decreased infarct volume in the brain tissues. Histological examination revealed that the necrotic tissue area in MCAO rats was also diminished by Rb1 treatment. Apoptosis induced by cerebral I/R was also attenuated by Rb1 treatment via downregulation of cleaved caspase-3 and caspase-9 levels. HMGB1 release was inhibited by Rb1 treatment in MCAO rats, and the levels of nuclear factor-κB, tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase and nitric oxide were also decreased. The present study suggests that Rb1 serves a protective role in I/R-induced cerebral-neuron injury, due to the decreased cerebral infarct volume of brain tissue. The mechanisms underlying these effects may be associated with the inhibition of HMGB1 inflammatory signals.

Comprehensive Clinicopathologic and Updated Immunohistochemical Characterization of Primary Ovarian Mucinous Carcinoma.

The distinction of primary mucinous ovarian carcinoma (PMOC) from other primaries or secondaries is essential for selecting therapeutic options and prognostication. We aimed to characterize the immunohistochemical profile of 36 PMOCs using an extended immunohistochemical panel, with clinicopathologic features and outcome. PAX8 was negative in 30 (83.3%), and SATB2 was negative in 32/35. HNF1B, AMACR, and napsin-A were detected in 33 (91.7%), 35 (97.2%), and 0 (0%), respectively. MMR proteins and ARID1A were retained in 100%; PTEN was lost in 4 (11.1%). P53 was aberrant in 10 (27.8%); none overexpressed p16. HER2 was positive in 6/35 (17.1%). Most PMOCs had a favorable outcome. However, recurrence is usually fatal. The typical tumor profile was CK7+, CK20+/-, CDX2+/-, PAX8-, ER-, PgR-, and SATB2-. HER2 positivity suggests a possible target for therapy in advanced disease.

Response of soil microbial community to application of biochar in cotton soils with different continuous cropping years.

The bacterial community in soils of cotton that have continuously been cropped for 2 years, 6 years, 11 years and 14 years and treated with biochar (B0, 0 t·ha-1; B1, 12.5 t·ha-1; and B2, 20 t·ha-1) was investigated using next-generation sequencing. Of the 45 bacterial genera (relative abundance ratio of genera greater than 0.3%), 21 genera were affected (p < 0.05) by the biochar treatment, whereas 20 genera were affected by the continuous cropping. Between the soils that have been continuously cropped for 2 years and 14 years, 12 different genera were significantly observed (p < 0.05), and 6 genera belonged to the phylum Acidobacteria. The relative abundance of Sphingomonas and Pseudomonas in the biochar-treated soils was significantly higher than that in the soil without biochar treatment (p < 0.05), and the relative abundance of Sphingomonas and Pseudomonas in soils that have been continuously cropped for 2 years and 6 years was significantly higher than that in the soils continuously cropped for 11 years and 14 years (p < 0.05). The results suggest that the biochar application has a significant impact on the soil bacterial community, which may improve the microbial diversity of continuous cropping systems in cotton soils.

Seatbelt use to save money: Impact on hospital costs of occupants who are involved in motor vehicle crashes.

OBJECTIVE: Seatbelt use is the single most effective way to save lives in motor vehicle crashes (MVC). However, although safety belt laws have been enacted in many countries, seatbelt usage throughout the world remains below optimal levels, and educational interventions may be needed to further increase seatbelt use. In addition to reducing crash-related injuries and deaths, reduced medical expenditures resulting from seatbelt use are an additional benefit that could make such interventions cost-effective. Accordingly, the objective of this study was to estimate the correlation between seatbelt use and hospital costs of injuries involved in MVC. METHODS: The data used in this study were from the Nebraska CODES database for motor vehicle crashes that occurred between 2004 and 2013. The hospital cost information and information about other factors were obtained by linking crash reports with hospital discharge data. A multivariable regression model was performed for the association between seatbelt use and hospital costs. RESULTS: Mean hospital costs were significantly lower among motor vehicle occupants using a lap-shoulder seatbelt ($2909), lap-only seatbelt ($2289), children's seatbelt ($1132), or booster ($1473) when compared with those not using any type of seatbelt ($7099). After adjusting for relevant factors, there were still significantly decreased hospital costs for motor vehicle occupants using a lap-shoulder seatbelt (84.7%), lap-only seatbelt (74.1%), shoulder-only seatbelt (40.6%), children's seatbelt (95.9%), or booster (82.8%) compared to those not using a seatbelt. CONCLUSION: Seatbelt use is significantly associated with reduced hospital costs among injured MVC occupants. The findings in this study will provide important educational information for emergency department nurses who can encourage safety belt use for vehicle occupants.

Non-seatbelt use and associated factors among passengers.

Seatbelt use is the most effective way to save lives and reduce severe injuries. However, the percentage of non-seatbelt use is still high among drivers and passengers. Although the factors related to non-seatbelt use among drivers have been widely studied, the factors associated with non-seatbelt use among passengers have not been well documented. In addition, recent surveys showed that the driver's attitude has a significant impact on the passenger's seatbelt use. However, the lower response rate and less accurate of self-reported seatbelt use in survey studies, especially among participants who had a high level perception of penalty for non-seatbelt use. Therefore, we examined the association between passenger's seatbelt use and driver's seatbelt use with a statewide injury surveillance system. 36,012 passengers who were involved in motor vehicle crashes (MVC) in 2004-2013 were included in this study. Our results showed that if a driver wore a seatbelt, 92.6% of his/her passengers also wore seatbelts while if a driver did not wear a seatbelt, only 19.1% of his/her passengers wore seatbelts. Compared to the passenger whose driver wore a seatbelt, the passenger had a significantly higher probability of non-seatbelt use (odds ratio = 46.7; 95% confidence intervals, 42.7-51.1) if his/her driver did not wear a seatbelt. The driver has the greatest influence on the passenger's seatbelt use. The findings will provide important information for future public health practices to increase seatbelt use at the highest possible rate for passengers, such as educational interventions for drivers and seatbelt reminders use.

Uterine Clear Cell Carcinoma: Does Adjuvant Chemotherapy Improve Outcomes?

OBJECTIVES: Women with uterine clear cell carcinoma (UCCC) are at high risk of relapse. Adjuvant chemotherapy (CT) is often recommended, although its effectiveness remains controversial. Our objective was to evaluate treatment-related outcomes of patients with UCCC, particularly those treated with adjuvant CT. METHODS: In this retrospective cohort study, patients diagnosed with UCCC at 2 academic cancer centers from 2000 to 2014 were included. Clinical, surgical, and pathological data were collected. Survival estimates were obtained using the Kaplan-Meier method and compared by log rank test. Multivariable analysis was used to determine the effect of CT and radiation therapy (RT) on overall survival (OS) and progression-free survival (PFS). RESULTS: We included 146 patients with UCCC, with a median follow-up of 27 months (range, 1-160). Ninety-five (65%) patients presented with stage I to II disease and 51 (35%) with stage III to IV disease. Forty-six percent of patients with clinical stage I were upstaged after surgery: 29% were upstaged to stages III and IV. Thirty-one percent of patients with early-stage disease and 70% with advanced-stage received CT. Among recurrences, the majority had distant relapse in both early-stage (61.5%) and advanced-stage (96.3%) diseases. In both patients with early-stage and advanced-stage diseases, adjuvant CT did not improve OS or PFS. On multivariate analysis, CT was not a significant factor associated with improved PFS (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.69-2.71; P = 0.37) or OS (HR, 0.58; 95% CI, 0.24-1.38; P = 0.22), whereas RT was associated with improved PFS (HR, 0.51; 95% CI, 0.29-0.90; P = 0.02) and OS (HR, 0.19; 95% CI, 0.09-0.42; P < 0.001). CONCLUSIONS: The high rate of upstaging after surgery highlights the importance of lymph node assessment. The high rate of distant recurrence questions the effectiveness of current CT regimens and warrants the development of novel systemic approaches. The role of adjuvant RT deserves further study.

Comorbid Conditions are Associated With Emergency Department Visits, Hospitalizations, and Medical Charges of Patients With Systemic Lupus Erythematosus.

BACKGROUND/OBJECTIVES: In addition to increase mortality, comorbidities can increase medical costs for systemic lupus erythematosus (SLE). Healthcare utilization can dramatically increase medical costs. It is essential to better understand the comorbidities that can lead to healthcare utilization, such as emergency department visit and/or hospitalization, for SLE patients. Therefore, the objective of this study was to examine the associations between comorbidities and healthcare utilization and medical charges of patients with SLE. METHODS: Nebraska statewide emergency departments (ED) discharge and hospitals discharge data from 2007 to 2012 were used to study the comorbid conditions of patients with SLE. SLE was defined using the standard International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes (710.0). RESULTS: There were more comorbid conditions in patients with SLE than patients without SLE. Comorbid conditions were majorly related to ED visits and hospitalizations of patients with SLE. Chest pain, abdominal pain, injury, acute respiratory infections, symptoms of digestive systems, headache, myalgia and myositis, noninfectious gastroenteritis and colitis, and symptoms of skin and other integumentary systems are common comorbid conditions for ED visits. Infections, cardiovascular diseases, fractures, chronic obstructive pulmonary disease (COPD) and allied conditions, cerebrovascular diseases, and episodic mood disorder are common comorbid conditions for hospitalizations of patients with SLE. In addition, the numbers of comorbid conditions were significantly associated with the length of hospital stay and hospital charges for SLE patients. CONCLUSION: The findings in this study indicated that comorbid conditions are associated with healthcare utilization and medical charges of patients with SLE.

Response of Bacteria Community to Long-Term Inorganic Nitrogen Application in Mulberry Field Soil.

The bacterial community and diversity in mulberry field soils with different application ages of inorganic nitrogen fertilizer (4Y, 4-year-old; 17Y, 17-year-old; 32Y, 32-year- old) were investigated using next-generation sequencing. The results demonstrated that the application ages of nitrogen fertilizer significantly altered soil bacterial community and diversity. Soil bacterial Shannon diversity index and Chao 1 index decreased with the consecutive application of nitrogen fertilizer, and the 4Y soil exhibited the highest bacterial relative abundance and diversity. Of 45 bacterial genera (relative abundance ratio of genera greater than 0.3%), 18 were significantly affected by the plant age, and seven belong to Acidobacteria. The relative abundances of Acidobacteria Gp 1, Gp4 and Gp6 in the 4Y soil were significantly lower than that of in the 17Y and 32Y soils. However, the relative abundance of Pseudononas sp. in the 4Y soil was significantly higher than that of in the 17Y and 32Y soils. Most microbial parameters were significantly affected by soil pH and organic matter content which were significantly changed by long-term application of inorganic nitrogen fertilizer.