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Mammalian target of rapamycin (mTOR) inhibitors (sirolimus or everolimus) have been demonstrated effective in reducing the size of tuberous sclerosis complex (TSC)-associated retinal astrocytic hamartoma (RAH) in short term. To investigate the long-term efficacy and safety of sirolimus on TSC-associated RAH, 13 TSC-associated RAH patients (59 RAH lesions) who received sirolimus therapy for at least 2 years were retrospectively enrolled in this study. Changes in the maximal thickness (MT) of RAH on optical coherence tomography and the longest base diameter (LBD) of RAH on color fundus photography were assessed. The results showed that for a mean follow-up of 39 months, sirolimus was associated with a mean reduction of 14.6% in MT and 6.8% in LBD of RAHs. The main impacts of sirolimus occurred within the first 6–12 months, with 14.8% reduction in MT and 4.7% reduction in LBD. Mouth ulceration (10 [76.9%]) and acne (9 [69.2%]) were the most common adverse events. These follow-up data support the long-term use of sirolimus in TSC-associated RAH patients, and persistent use of sirolimus possibly prevents tumor regrowth.

BackgroundOpportunely screening for diabetes is crucial to reduce its related morbidity, mortality, and socioeconomic burden. Machine learning (ML) has excellent capability to maximize predictive accuracy. We aim to develop ML-augmented models for diabetes screening in community and primary care settings.Methods8425 participants were involved from a population-based study in Hubei, China since 2011. The dataset was split into a development set and a testing set. Seven different ML algorithms were compared to generate predictive models. Non-laboratory features were employed in the ML model for community settings, and laboratory test features were further introduced in the ML+lab models for primary care. The area under the receiver operating characteristic curve (AUC), area under the precision-recall curve (auPR), and the average detection costs per participant of these models were compared with their counterparts based on the New China Diabetes Risk Score (NCDRS) currently recommended for diabetes screening.ResultsThe AUC and auPR of the ML model were 0·697and 0·303 in the testing set, seemingly outperforming those of NCDRS by 10·99% and 64·67%, respectively. The average detection cost of the ML model was 12·81% lower than that of NCDRS with the same sensitivity (0·72). Moreover, the average detection cost of the ML+FPG model is the lowest among the ML+lab models and less than that of the ML model and NCDRS+FPG model.ConclusionThe ML model and the ML+FPG model achieved higher predictive accuracy and lower detection costs than their counterpart based on NCDRS. Thus, the ML-augmented algorithm is potential to be employed for diabetes screening in community and primary care settings.

Urolithiasis is a common urological disease with increasing incidence and a high recurrence rate, whose etiology is not fully understood. The application of sequencing and culturomics has revealed that urolithiasis is closely related to the urinary microbiome (urobiome), shedding new light on the pathogenesis of stone formation. In this study, we recruited 30 patients with unilateral stones and collected their renal pelvis urine from both sides. Then, we performed 2bRAD-M, a novel sequencing technique that provides precise microbial identification at the species level, to characterize the renal pelvis urobiome of unilateral stone formers in the both sides. We first found that the urobiome in the stone side could be divided into two clusters (Stone1 and Stone2) based on distance algorithms. Stone2 harbored higher microbial richness and diversity compared to Stone1. The genera Cupriavidus and Sphingomonas were overrepresented in Stone1, whereas Acinetobacter and Pseudomonas were overrepresented in Stone2. Meanwhile, differential species were identified between Stone1 and Stone2. We further constructed a random forest model to discriminate two clusters which achieved a powerful diagnostic potential. Moreover, the urobiome of the non-stone side (Control1/2) was compared with that of the stone side (Stone1/2). Stone1 and Control1 showed different microbial community distributions, while Stone2 was similar to Control2 based on diversity analysis. We also identified differentially abundant species among all groups. We assumed that there might be different mechanisms of how microbiota contribute to stone formation in two clusters. Our findings might assist in the selection of suitable medical treatments for urolithiasis.

The electrocatalytic conversion of biomass into high-value-added chemicals is one of the effective methods of green chemistry. Conventional metal catalysts have disadvantages, such as low atomic utilization and small surface areas. Catalyst materials derived from metal–organic frameworks (MOFs) have received much attention due to their unique physicochemical properties. Here, an MOF-derived non-precious metal CoxNiyS electrocatalyst was applied to the oxidation of biomass-derivative 5-hydroxymethylfurfural (HMF). The HMF oxidation reaction activities were modulated by regulating the content of Co and Ni bimetals, showing a volcano curve with an increasing proportion of Co. When the Co:Ni ratio was 2:1, the HMF conversion rate reached 84.5%, and the yield of the main product, 2,5-furandicarboxylic acid (FDCA), was 54%. The XPS results showed that the presence of high-valent nickel species after electrolysis, which further proved the existence and reactivity of NiOOH, as well as the synergistic effect of Co and Ni promoted the conversion of HMF. Increasing the content of Ni could increase the activity of HMF electrochemical oxidation, and increasing the content of Co could reduce the increase in the anodic current. This study has important significance for designing better HMF electrochemical catalysts in the future.

Abstract There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow‐up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non‐metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third‐line to the first‐line of treatment for different patient groups with detailed notes are provided.

Background Subclinical hypothyroidism (SCH) is the most common thyroid dysfunction, and its relationship with blood pressure (BP) has been controversial. The aim of the study was to analyze the association between SCH and newly-diagnosed hypertension. Methods Based on data from the Thyroid disease, Iodine nutrition and Diabetes Epidemiology (TIDE) study, 49,433 euthyroid individuals and 7,719 SCH patients aged ≥18 years were enrolled. Patients with a history of hypertension or thyroid disease were excluded. SCH was determined by manufacturer reference range. Overall hypertension and stage 1 and 2 hypertension were diagnosed according to the guidelines issued by the American College of Cardiology/American Heart Association in 2017. Results The prevalence of overall hypertension (48.7%), including stage 1 (28.9%) and 2 (19.8%) hypertension, increased significantly in SCH patients compared with euthyroid subjects. With elevated serum thyroid stimulating hormone (TSH) level, the hypertension prevalence also increased significantly from the euthyroid to different SCH subgroups, which was more profound in females or subjects aged

Lung cancer is the malignant tumor with high invasion and metastasis, which seriously threatens public health. Previous study showed that NLRP3 could promote the occurrence of lung tumors in B(a)P-induced mice. MicroRNAs are closely related to the progression and metastasis of lung cancer by regulating target genes. However, which miRNAs affect the migration and invasion of lung cancer cells through regulating NLRP3 remains poorly defined. In this study, the miRNAs targeting NLRP3 were selected from TargetScan and miRDB database and finally miR-223-3p was chosen due to the consistent expression in both A549 and H520 cells. Then, the migration and invasion of lung cancer cells were detected with miR-223-3p mimic and inhibitor using Transwell assay, at the same time the expression of NLRP3, cleaved caspase-1, IL-1β and IL-18 was determined using Western Blot and immunohistochemistry assay. Our data demonstrated that miR-223-3p was upregulated in both A549 and H520 cells. Furthermore, the migration and invasion of A549 and H520 cells were promoted after inhibiting miR-223-3p. Besides, the levels of NLRP3, cleaved caspase-1, IL-1β and IL-18 were increased in the two lung cancer cells. And the corresponding results were contrary in miR-223-3p mimic group. Taken together, miR-223-3p attenuates the migration and invasion of NSCLC cells by regulating NLRP3, which provides evidence for the prevention and targeted treatment of NSCLC.

BackgroundProgression of freezing of gait (FOG), a common pathological gait in Parkinson’s disease (PD), has been shown to be an important risk factor for falls, loss of independent living ability, and reduced quality of life. However, previous evidence indicated poor efficacy of medicine and surgery in treating FOG in patients with PD. Music-based movement therapy (MMT), which entails listening to music while exercising, has been proposed as a treatment to improve patients’ motor function, emotions, and physiological activity. In recent years, MMT has been widely used to treat movement disorders in neurological diseases with promising results. Results from our earlier pilot study revealed that MMT could relieve FOG and improve the quality of life for patients with PD.ObjectiveTo explore the effect of MMT on FOG in patients with PD.Materials and methodsThis was a prospective, evaluator-blinded, randomized controlled study. A total of 81 participants were randomly divided into music-based movement therapy group (MMT, n = 27), exercise therapy group (ET, n = 27), and control group (n = 27). Participants in the MMT group were treated with MMT five times (1 h at a time) every week for 4 weeks. Subjects in the ET group were intervened in the same way as the MMT group, but without music. Routine rehabilitation treatment was performed on participants in all groups. The primary outcome was the change of FOG in patients with PD. Secondary evaluation indicators included FOG-Questionnaire (FOG-Q) and the comprehensive motor function.ResultsAfter 4 weeks of intervention, the double support time, the cadence, the max flexion of knee in stance, the max hip extension, the flexion moment of knee in stance, the comprehensive motor function (UPDRS Part III gait-related items total score, arising from chair, freezing of gait, postural stability, posture, MDS-UPDRS Part II gait-related items total score, getting out of bed/a car/deep chair, walking and balance, freezing), and the FOG-Q in the MMT group were lower than that in the control group and ET group (p < 0.05). The gait velocity, the max ankle dorsiflexion in stance, ankle range of motion (ROM) during push-off, ankle ROM over gait cycle, the knee ROM over gait cycle, and the max extensor moment in stance (ankle, knee) in the MMT group were higher than that in the control group and ET group (p < 0.05). However, no significant difference was reported between the control group and ET group (p > 0.05). The stride length and hip ROM over gait cycle in the MMT group were higher than that in the control group (p < 0.05), and the max knee extension in stance in the MMT group was lower than that in the control group (p < 0.05). Nevertheless, there was no significant difference between the ET group and MMT group (p > 0.05) or control group (p > 0.05).ConclusionMMT improved gait disorders in PD patients with FOG, thereby improving their comprehensive motor function.

PurposeThe aim of this study was to assess the safety and efficacy of microwave ablation combined with apatinib [vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor] and camrelizumab [anti-programmed death-1 (PD-1) antibody] in patients with advanced hepatocellular carcinoma (HCC).Patients and methodsPatients (age, >18 years) with histologically confirmed HCC and refractory to at least the standard first-line therapy were enrolled from 2 September 2018 to 17 January 2022. They first received ultrasound-guided subtotal microwave ablation. Then, beginning at 7–14 days after ablation, they were given apatinib (250 mg once daily) and camrelizumab (200 mg once every 2 weeks) until unacceptable toxicity or disease progression or death. The coprimary end points were progression-free survival (PFS) and overall survival (OS).ResultsFourteen HCC patients with Barcelona Clinic of Liver Cancer (BCLC) B and C stages were retrospectively enrolled. At data cutoff, follow-up period ranged from 3.8 to 41.3 months (median, 17.4 months), and the median (95% confidence interval) duration of exposure (DE) was 6.4 (4.0–8.9) months. The PFS and OS were 10.8 (0–23.5) months and 19.3 (2.4–36.2) months, respectively. Three (21.4%) patients achieved a confirmed complete response (CR). Confirmed partial response (PR), stable disease (SD), and progression of disease (PD) were achieved in four (28.6%), four (28.6%), and three (21.4%) patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were 50.0% (20.0%-80.0%) and 78.6% (54.0%-100%), respectively. The serious treatment-related adverse events included one (7.1%) case with reactive capillary hemangiomas (grade 4), one (7.1%) with hypertension (grade 3), two (14.3%) with elevated transaminase and bilirubin (grade 4), one (7.1%) with platelet count decrease (grade 4), one (7.1%) with hepatic failure (grade 4), and two (14.3%) with gastrointestinal bleeding (grades 3 and 4).ConclusionsMicrowave ablation combined with apatinib and camrelizumab treatment in advanced HCC patients demonstrated intriguing clinical activity and resulted in durable antitumor responses and significantly improved PFS and OS. The combination therapy is well tolerated, enabling further clinical studies.

Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is the first enzyme in the de novo purine nucleotide synthesis pathway and is essential for cell development. However, the effect of PRPS1 on melanoma proliferation and metastasis remains unclear. This study aimed to investigate the regulatory mechanism of PRPS1 in the malignant progression of melanoma. Here, we found PRPS1 was upregulated in melanoma and melanoma cells. In addition, our data indicated that PRPS1 could promote the proliferation and migration and invasion of melanoma both in vitro and in vivo. PRPS1 also could inhibit melanoma cell apoptosis. Furthermore, we found NRF2 is an upstream transcription factor of PRPS1 that drive malignant progression of melanoma.

Background Intravenous thrombolysis with alteplase is widely used in patients with acute ischemic stroke presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared with alteplase. This study investigates whether intravenous tenecteplase is noninferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial (AcT [Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke]) with blinded end point assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, maximum dose 25 mg) is noninferior to intravenous alteplase (0.9 mg/kg body weight; maximum dose, 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a noninferiority margin of 5%, assuming incidence of the 90‐day modified Rankin Scale score of 0 to 1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate

The objective of this study is to explore the effect and mechanism of ultrasound on chitin extraction from shrimp shells powder (SSP) by the co-fermentation of Bacillus subtilis and Acetobacter pasteurianus. After pre-treating the SSP with high-intensity ultrasound (HIU) at 800 W, the protease activity in the fermentation solution reached 96.9 U/mL on day 3, which was significantly higher than for SSP that had not been pre-treated with ultrasound (81.8 U/mL). The fermentation time of the chitin extraction process was 5.0 d without ultrasound pre-treatment, while it was shortened to 4.5 d when using ultrasound at 800 W to treat SSP. However, there were no obvious differences when we applied ultrasound at low power (200 W, 400 W). Furthermore, chitin purified from shrimp shells pre-treated with HIU at 800 W exhibited lower molecular weight (11.2 kDa), higher chitin purity (89.8%), and a higher degree of deacetylation (21.1%) compared to SSP with no ultrasound pre-treatment (13.5 kDa, 86.6%, 18.5%). Results indicate that HIU peels off the protein/CaCO3 matrix that covers the SSP surface. About 9.1% of protein and 4.7% of Ca2+ were released from SSP pre-treated with HIU at 800 W. These figures were both higher than with no ultrasound pre-treatment (4.5%, 3.2%). Additionally, the amount of soluble protein extracted from SSP through HIU at 800 W was 50% higher than for the control sample. SDS-PAGE analysis indicated that the soluble protein was degraded to the micromolecule. It also revealed that HIU (600, 800 W) induced the secondary and tertiary structure destruction of protein extracted from SSP. In conclusion, HIU-induced degradation and structural damage of protein enhances the protein/CaCO3 matrix to be peeled off from SSP. Also, in the co-fermentation process, an increase of protease activity further accelerates deproteinization.

Leuprolide acetate microspheres developed by Shanghai Livzon Pharmaceutical Co., Ltd. (T) have been marketed in China for more than 10 years, benefiting a large number of patients, and will continue to play an important role in China. However, as a generic drug, it is unclear whether there is a difference in efficacy between T and the original product Enantone® (R). This study compared the differences in efficacy and safety of two 1-month depot formulations in 48 healthy Chinese male subjects by comparing multiple pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The main research indicators were the PK parameters of leuprolide (Cmax, AUC0-t, AUC0-D7, and AUCD7-t) and the PD parameters of testosterone (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) after 42 days of administration. The Cmax, AUC0-t, AUC0-D7 and AUCD7-t of leuprolide were slightly higher in the T group than in the R group with 90% confidence intervals (CIs) of 94.43–118.53%, 109.13–141.88%, 109.53–139.54%, and 105.17–145.74%, respectively. No significant differences in the PD parameters (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) existed between the T and R groups, and 90% CIs were 62.80–93.57%, 88.17–110.55, 95.72%–118.50%, and 79.77–105.63, respectively. At 672 h (D28), the castration rate of T was 91.30% (21/23) and that of R was 60.87% (14/23). The PK characteristics were consistent and the inhibitory effects on testosterone levels were similar in both T and R groups; further, clinical safety was observed for both T and R formulations, suggesting that these two products can replace each other in clinical practice.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier CTR20200641.

Single atom catalysts (SACs) are constituted by isolated active metal centers, which are heterogenized on inert supports such as graphene, porous carbon, and amorphous carbon. The thermal stability, electronic properties, and catalytic activities of the metal center can be controlled via manipulating the neighboring heteroatoms such as nitrogen, oxygen, and sulfur. Due to the atomical dispersion of the active catalytic centers, the amount of metal required for catalysis can be decreased. Furthermore, new possibilities are offered to easily control the selectivity of a given transformation process as well as to improve turnover frequencies and turnover numbers of target reactions. Among them, Fe–N–C single atom catalysts own special electronic structure, and have been widely used in many fields of electrocatalysis. This review aims to summarize the synthesis of Fe–N–C based on anchoring individual iron atoms on carbon/graphene. The spin-related properties of Fe–N–C catalysts are described, including the relation between spin and electron structure of Fe–Nx as well as the coupling between electronic structure of Fe–Nx and electronic (orbit) of CO2, N2 and O2. Next, mechanistic investigations conducted to understand the specific behavior of Fe–N–C catalysts are highlighted, including C, N, O electro-reduction. Finally, some issues related to the future developments of Fe–N–C are put forward and corresponding feasible solutions are offered.

Abstract The information on crustal thickness in Antarctica can provide significant constraints on its crustal deformation and tectonic evolution. To generate reliable images of crustal features, we investigate the model of Moho depth and crustal thickness beneath Antarctica by applying the Bott‐Parker's formulas based on the Gauss‐fast Fourier transform method through a comprehensive analysis of gravity data, ice and sediment thicknesses and bedrock elevation, combined with seismic constraints. Tests with synthetic data indicate that the iterative inversion algorithm can yield a highly accurate Moho topography. Ultimately, inverted crustal thickness reveals a more detailed crustal image by clearly identifying more tectonic elements at different scales than previous results and correlates well with major tectonic provinces. Airy isostasy and flexural isostasy models are used to assess the crustal isostatic compensation. The distinctive negative isostatic anomalies are observed in the Transantarctic Mountains and the East Antarctic areas of the great escarpment in the Dronning Maud Land and Aurora and Wilkes Subglacial Basin, indicating that the low density of the uppermost mantle and lithospheric strength may play important roles in compensating for their elevations. Variations in crustal thickness in interior East Antarctica are analyzed; the thickened crust from Dronning Maud Land to the Gamburtsev Subglacial Mountains may be associated with the collision of continental blocks and is interpreted as the fossil sutures. We compare the relationship between the Moho and Curie interfaces and find that the uppermost mantle is magnetized in some areas of East Antarctica, which may indicate preserved Precambrian cratonic roots.

Abstract. Background:. The basis of individualized treatment should be individualized mortality risk predictive information. The present study aimed to develop an online individual mortality risk predictive tool for acute-on-chronic liver failure (ACLF) patients based on a random survival forest (RSF) algorithm. Methods:. The current study retrospectively enrolled ACLF patients from the Department of Infectious Diseases of The First People's Hospital of Foshan, Shunde Hospital of Southern Medical University, and Jiangmen Central Hospital. Two hundred seventy-six consecutive ACLF patients were included in the present study as a model cohort (n = 276). Then the current study constructed a validation cohort by drawing patients from the model dataset based on the resampling method (n = 276). The RSF algorithm was used to develop an individual prognostic model for ACLF patients. The Brier score was used to evaluate the diagnostic accuracy of prognostic models. The weighted mean rank estimation method was used to compare the differences between the areas under the time-dependent ROC curves (AUROCs) of prognostic models. Results:. Multivariate Cox regression identified hepatic encephalopathy (HE), age, serum sodium level, acute kidney injury (AKI), red cell distribution width (RDW), and international normalization index (INR) as independent risk factors for ACLF patients. A simplified RSF model was developed based on these previous risk factors. The AUROCs for predicting 3-, 6-, and 12-month mortality were 0.916, 0.916, and 0.905 for the RSF model and 0.872, 0.866, and 0.848 for the Cox model in the model cohort, respectively. The Brier scores were 0.119, 0.119, and 0.128 for the RSF model and 0.138, 0.146, and 0.156 for the Cox model, respectively. The nonparametric comparison suggested that the RSF model was superior to the Cox model for predicting the prognosis of ACLF patients. Conclusions:. The current study developed a novel online individual mortality risk predictive tool that could predict individual mortality risk predictive curves for individual patients. Additionally, the current online individual mortality risk predictive tool could further provide predicted mortality percentages and 95% confidence intervals at user-defined time points.

Abstract Background As a new type of molecular marker, microRNAs (miRNAs) can be used for early diagnosis and prognosis prediction of malignant tumors, and has broad clinical application prospects. This paper mainly studies the important role of miR-889 in the occurrence and development of hepatocellular carcinoma and the prognostic significance of miR-889 in hepatocellular carcinoma. Methods Quantitative real-time PCR analysis detected the expression levels of miR-889 in hepatocellular carcinoma tissues and cell lines. Kaplan-Meier curve and Cox regression analysis were used to explore the prognostic significance of miR-889 in hepatocellular carcinoma. The CCK-8 and Transwell assays assay were used to assess cell proliferation, migration, and invasion abilities ability. Results The expression of miR-889 in hepatocellular carcinoma tissues was significantly higher than that in adjacent tissues. Overexpression of miR-889 was significantly associated with TNM stage, hepatitis B virus infection, and cirrhosis. Patients with high miR-889 expression had shorter overall survival than those with low miR-889 expression. And functional studies in two hepatocellular carcinoma cell lines have shown that overexpression of miR-889 significantly promoted cell proliferation, migration, and invasion in vitro. Conclusions Overall, miR-889 was upregulated in hepatocellular carcinoma tissues and cell lines, and overexpression of miR-889 promoted cell proliferation, migration, and invasion in hepatocellular carcinoma cells. Based on our findings, high expression of miR-889 may promote the progression of hepatocellular carcinoma, and high expression of miR-889 is also forecasted for an unfavorable prognosis in hepatocellular carcinoma.

Abstract Aims/Introduction To explore the potential role of irisin in the outcomes of newly diagnosed prediabetes. Materials and Methods Data were obtained from the Guiyang subcenter of the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. A total of 2,530 participants had newly diagnosed prediabetes at baseline and completed follow up. The nested 1:1 case–control study included 161 participants who developed diabetes mellitus at follow up, and 161 age‐ and sex‐matched controls. The follow‐up study included 86 matched case–control pairs. Fasting serum irisin levels were measured using enzyme‐linked immunosorbent assay. Results Baseline serum irisin levels were higher in the cases than in the controls (P = 0.002); high baseline serum irisin levels were an independent risk factor for the development of diabetes (odds ratio 1.235, 95% confidence interval 1.025–1.488). After adjustment for age, sex, body mass index, glycated hemoglobin (HbA1c), smoking, exercise, and family history of diabetes, subjects in the highest quartile of irisin levels had a higher risk of diabetes than those in the lowest quartile (odds ratio 3.065, 95% confidence interval 1.511–6.218). The extent of decrease in irisin levels during follow‐up was greater in the cases than in the controls (P

Abstract Background Progression of freezing of gait, a common pathological gait in Parkinson’s disease, is an important risk factor for diagnosing the disease and has been shown to predispose patients to easy falls, loss of independent living ability, and reduced quality of life. Treating Parkinson’s disease with freezing of gait is very difficult, while the use of medicine and operation has been ineffective. Music exercise therapy, which entails listening to music as you exercise, has been proposed as a treatment technology that can change patients’ behavior, emotions, and physiological activity. In recent years, music exercise therapy has been widely used in treatment of motor disorders and neurological diseases and achieved remarkable results. Results from our earlier pilot study revealed that music exercise therapy can improve the freezing of gait of Parkinson’s patients and improve their quality of life. Therefore, we aim to validate clinical efficacy of this therapy on freezing of gait of Parkinson’s patients using a larger sample size. Methods/design This three-arm randomized controlled trial will evaluate clinical efficacy of music exercise therapy in improving the freezing of gait in Parkinson’s patients. We will recruit a total of 81 inpatients with Parkinson’s disease, who meet the trial criteria. The patients will randomly receive music exercise with and without music as well as routine rehabilitation therapies, followed by analysis of changes in their gait and limb motor function after 4 weeks of intervention. We will first use a three-dimensional gait analysis system to evaluate changes in patients’ gait, followed by assessment of their limb function, activity of daily living and fall risk. Discussion The findings of this trial are expected to affirm the clinical application of this therapy for future management of the disease. Trial registration Chinese Clinical Trial Registry ChiCTR1900026063 . Registered on September 20, 2019

Abstract Background Despite recent advances in diagnostic and therapeutic approaches for gastric cancer (GC), the survival of patients with advanced GC remains very low. Islet-1 (ISL1) is a LIM-homeodomain transcription factor, which is upregulated and promotes cell proliferation in GC. The exact mechanism by which ISL1 influences GC development is unclear. Methods Co-immunoprecipitation (co-IP) and glutathione S-transferase (GST)-pulldown assays were employed to evaluate the interaction of ISL1 with CDK1. Western blot and immunohistochemistry analyses were performed to evaluate the ability of CDK1 to phosphorylate ISL1 at Ser 269 in GC cell and tissue specimens. Chromatin immunoprecipitation (ChIP), ChIP re-IP, luciferase reporter, and CCK-8 assays were combined with flow cytometry cell cycle analysis to detect the transactivation potency of ISL1-S269-p and its ability to promote cell proliferation. The self-stability and interaction with CDK1 of ISL1-S269-p were also determined. Results ISL1 is phosphorylated by CDK1 at serine 269 (S269) in vivo. Phosphorylation of ISL1 by CDK1 on serine 269 strengthened its binding on the cyclin B1 and cyclin B2 promoters and increased its transcriptional activity in GC. Furthermore, CDK1-dependent phosphorylation of ISL1 correlated positively with ISL1 protein self-stability in NIH3T3 cells. Conclusions ISL1-S269-p increased ISL1 transcriptional activity and self-stability while binding to the cyclinB1 and cyclinB2 promoters promotes cell proliferation. ISL1-S269-p is therefore crucial for tumorigenesis and potentially a direct therapeutic target for GC.

The spatial distribution pattern of urban spatial structure affects air flow and local meteorological conditions, which in turn influence the diffusion of air pollutants. This study built the urban spatial structure index system based on DEM, urban road networks, and big data. The ordinary kriging interpolation method was used to analyze the spatial distribution of gaseous pollutant concentrations in Jinan City. Correlation analysis, stepwise regression analysis, and bivariate global spatial autocorrelation analysis were used to study the influence of the urban spatial structure index on the spatial distribution of gaseous pollutant concentration. The main conclusions were as follows: (1) Evident spatial and temporal differences were observed in the concentration distribution of gaseous pollutants in Jinan. The spatial distribution of NO2 and CO concentrations showed a gradual decrease from north to south. Spatial heterogeneity was observed in the distribution of SO2 and O3 concentrations. (2) The urban spatial structure indicators had varying effects on the spatial distribution of different gaseous pollutant concentrations. The important factors that influenced the spatial distribution of urban gaseous pollutant concentrations included terrain elevation, building density, building volume, and floor area ratio. The greater the terrain undulation, the denser the building distribution, the greater the difference in building volume, and the greater the plot ratio, the greater the impact on the diffusion and spatial distribution of urban gaseous pollutants. (3) The spatial distribution of urban gaseous pollutant concentrations was significantly affected by the urban spatial structure indicators in the surrounding areas. Furthermore, the spatial distributions of NO2, SO2, CO, and O3 concentrations had a significant negative spatial correlation with the average DEM and standard deviation of the surrounding adjacent areas and a significant positive spatial correlation with the average and standard deviation of building height, standard deviation of building area, and building density in the surrounding adjacent areas (in June).

The permanent magnet synchronous motor (PMSM) has been widely used in the field of ship electric propulsion due to its advantages of a small size, light weight, low loss, and high efficiency. In this paper, a 100 kW ship-side thruster motor was taken as the research object, and the problem of the high harmonic content of the air gap magnetic flux density in the motor was addressed by designing a rotor eccentricity. On this basis, the hybrid Taguchi method of genetic algorithm was used to optimize the rotor structural parameters with increasing the efficiency and reducting the cost of the motor as the optimization objectives. The results show that the performance and economy of the motor have been greatly improved after optimization. Finally, the motor weight reduction hole was designed, and a prototype was manufactured and tested. The test data are within the allowable range compared with the simulation data, verifying the effectiveness of the multiobjective optimization algorithm proposed in this paper.

Abstract Generalized auto-calibrating partially parallel acquisitions (GRAPPA) and other parallel Magnetic Resonance Imaging (pMRI) methods restore the unacquired data in k-space by linearly calculating the undersampled data around the missing points. In order to obtain the weight of the linear calculation, a small number of auto-calibration signal (ACS) lines need to be sampled at the center of the k-space. Therefore, the sampling pattern used in this type of method is to full sample data in the middle area and undersample in the outer k-space with nominal reduction factors. In this paper, we propose a novel reconstruction method with a multiple variable density sampling (MVDS) that is different from traditional sampling patterns. Our method can significantly improve the image quality using multiple reduction factors with fewer ACS lines. Specifically, the traditional sampling pattern only uses a single reduction factor to uniformly undersample data in the region outside the ACS, but we use multiple reduction factors. When sampling the k-space data, we keep the ACS lines unchanged, use a smaller reduction factor for undersampling data near the ACS lines and a larger reduction factor for the outermost part of k-space. The error is lower after reconstruction of this region by undersampled data with a smaller reduction factor. The experimental results show that with the same amount of data sampled, using NL-GRAPPA to reconstruct the k-space data sampled by our method can result in lower noise and fewer artifacts than traditional methods. In particular, our method is extremely effective when the number of ACS lines is small.

Abstract A new strategy for designing single‐band and dual‐band balanced bandpass filters (BPFs) based on a circular patch resonator is proposed in this study. By altering the output balanced ports of the balanced BPFs to inhibit or transport the TM31 mode of the circular patch resonator under the differential‐mode (DM) excitation, a single‐band or dual‐band balanced BPF can be realized. As the odd modes could be restrained under the common‐mode (CM) excitation, the balanced BPFs could feature high CM suppression in the DM passbands. Meanwhile, several perturbing tactics are introduced to improve the performance of the balanced BPFs. Specifically, perturbation vias are presented to disturb the electric field distribution to enhance the CM suppression in the DM passbands, and slots are applied on the circular patch resonators to perturb the current distribution to amend the second DM passband of the dual‐band balanced BPF. The proposed single‐band and dual‐band balanced BPFs are fabricated and characterized. Good agreement can be achieved between the simulated and measured results of the fabricated balanced BPFs, which validates the feasibility of the proposed design method.

BackgroundThe status of circulating tumor cells (CTCs) is related to the recurrence of hepatocellular carcinoma (HCC), which is also one of the reasons for the poor prognosis of HCC. The purpose of this study was to explore whether CTCs can help guide the choice of treatment methods for HCC.MethodsThis study is a multicenter retrospective study, including 602 patients with HCC. CTCs were detected in the overall cohort before operation. There were 361 patients in the training cohort and 241 patients in the validation cohort. Patients were divided into CTC-negative group (CTCs = 0/5 mL) and the CTC-positive group (CTCs ≥ 1/5 mL) according to CTCs status. Subgroup analysis was performed according to CTCs status. We compared overall survival, and recurrence outcomes for HCC patients with different CTC statuses after undergoing radiofrequency ablation (RFA) or surgical resection (SR)ResultsThere was no significant difference in overall survival (OS) and recurrence-free survival (RFS) between the RFA group and SR group for CTC-negative patients in both the training cohort and the validation cohort (P > 0.05). However, among CTC-positive patients, the clinical outcome of patients in the SR group was significantly better than those in the RFA group. CTC-positive patients who underwent RFA had increased early recurrence compared to those who underwent SR. RFA is an independent risk factor for survival and recurrence in CTC-positive HCC patientsConclusionsThe CTC status could serve as an indicator to guide the choice between surgical resection or radiofrequency ablation for early hepatocellular carcinoma. Surgical resection is recommended for CTC-positive patients.

Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders.

Regulation of chromatin structure and accessibility determines the transcription activities of genes, which endows the host with function-specific patterns of gene expression. Upon viral infection, the innate immune responses provide the first line of defense, allowing rapid production of variegated antiviral cytokines. Knowledge on how chromatin accessibility is regulated during host defense against viral infection remains limited. Our previous work found that the nuclear matrix protein SAFA surveilled viral RNA and regulated antiviral immune genes expression. However, how SAFA regulates the specific induction of antiviral immune genes remains unknown. Here, through integration of RNA-seq, ATAC-seq and ChIP-seq assays, we found that the depletion of SAFA specifically decreased the chromatin accessibility, activation and expression of virus induced genes. And mutation assays suggested that the RNA-binding ability of SAFA was essential for its function in regulating antiviral chromatin accessibility. RIP-seq results showed that SAFA exclusively bound with antiviral related RNAs following viral infection. Further, we combined the CRISPR-Cas13d mediated RNA knockdown system with ATAC-qPCR, and demonstrated that the binding between SAFA and according antiviral RNAs specifically mediated the openness of the corresponding chromatin and following robust transcription of antiviral genes. Moreover, knockdown of these associated RNAs dampened the accessibility of related genes in an extranuclear signaling pathway dependent manner. Interestingly, VSV infection cleaved SAFA protein at the C-terminus which deprived its RNA binding ability for immune evasion. Thus, our results demonstrated that SAFA and the interacting RNA products collaborated and remodeled chromatin accessibility to facilitate antiviral innate immune responses.

Chalkiness, which is highly affected by nitrogen (N) management during grain filling, is critical in determining rice appearance quality and consumer acceptability. We investigated the effects of N application rates 75 (N1), 150 (N2), and 225 (N3) kg ha−1 on the source-sink carbohydrate accumulation and grain filling characteristics of two indica hybrid rice cultivars with different chalkiness levels in 2019 and 2020. We further explored the relationship between grain filling and formation of chalkiness in superior and inferior grains. In this study, carbohydrates in the functional leaves and grains of the two varieties, and grain filling parameters, could explain 66.2%, 68.0%, 88.7%, and 91.6% of the total variation of total chalky grain rate and whole chalkiness degree, respectively. They were primarily concentrated in the inferior grains. As the N fertilizer application rate increased, the chalky grain rate and chalkiness degree of both the superior and inferior grains decreased significantly. This interfered with the increase in total chalky grain rate and chalkiness. Moreover, the carbohydrate content in the functional leaves increased significantly in N2 and N3 compared with that in N1. The transfer of soluble sugar from the leaves to the grains decreased the soluble sugar and increased total starch contents, accelerated the development of grain length and width, increased grain water content, and effectively alleviated the contradiction between source and sink. These changes promoted the carbohydrate partition in superior and inferior grains, improved their average filling rate in the middle and later stages, optimized the uniformity of inferior grain fillings, and finally led to the overall reduction in rice chalkiness.

Background and AimRuptured hepatocellular carcinoma (rHCC) is classified as T4 according to the TNM staging system with a very poor (does not achieve expected) prognosis, which has always been controversial. This study aimed at assessing the specific impact of different tumor diameters on the posttreatment prognosis of BCLC stage 0/A rHCC patients.MethodsData from 258 patients with BCLC stage 0/A HCC treated in our center from January 2008 to December 2017 were collected, including 143 rHCC patients and 115 patients with non-ruptured HCC (nrHCC). With the help of X-tile software, we determined the cutoff value of the tumor diameter in patients with rHCC. Using 8 cm as the cutoff, we divided rHCC patients into Small-rHCC (n = 96) and Large-rHCC (n = 47) groups, compared the prognoses of the S-rHCC and L-rHCC groups, as well as the prognoses of the two groups with the nrHCC group using the Kaplan–Meier method, and screened the prognostic factors of rHCC patients using the multivariate Cox risk model.ResultsThe OS of the S-rHCC group was significantly higher than that of the L-rHCC group [HR = 2.41 (1.60–3.63)], and the OS of the nrHCC group was comparable to that of the S-rHCC group (P = 0.204). In patients treated with surgery only, OS and RFS were also comparable in the S-rHCC nrHCC group. Meanwhile, multivariate Cox regression analysis revealed that alpha-fetoprotein (AFP), alkaline phosphatase (ALP), and the main method of treatment were also prognostic factors for OS in patients with rHCC.ConclusionsRuptured HCC with a relatively small diameter (≤8 cm) can also achieve the same prognosis as nrHCC patients after aggressive treatment. It is also not recommended to include all patients with rHCC in stage T4.

BackgroundLarge hepatocellular carcinoma (LHCC) is highly malignant and prone to recurrence, leading to a poor long-term prognosis for patients. There is an urgent need for measures to intervene in postoperative recurrence. Preoperative Transcatheter Arterial Embolization (TACE) is an effective treatment. However, there is a lack of reliable preoperative indicators to guide the application of preoperative TACE. We, therefore, investigated whether the preoperative status of circulating tumor cells (CTCs) could be used to guide preoperative TACE for HCC treatment.MethodsThis study recruited 361 HCC patients and compared recurrence-free survival (RFS) and overall survival (OS) in patients treated with TACE prior to surgery and those not treated with TACE. Patients were divided into CTC-positive group and CTC-negative group according to CTC status, and the effect of preoperative TACE on RFS and OS was compared in each subgroup.ResultsIn CTC-positive patients, preoperative TACE reduces early recurrence and improves long-term survival. However, HCC patients did not benefit from preoperative TACE for the overall population and CTC-negative patients.ConclusionsPreoperative CTC testing is a reliable indicator of whether HCC patients received TACE preoperatively. CTC positivity was associated with early tumor recurrence, and preoperative TACE could reduce early recurrence and long-term prognosis in CTC-positive patients.

Abstract Background Association of arterial stiffness and osteoporosis has been well documented in elderly population. However, it is not clear whether they co-progress from the early stages through common mechanisms. The object of this study was to evaluate possible associations between arterial stiffness and osteoporosis by measuring brachial-ankle pulse wave velocity (baPWV) and the Osteoporosis Self-Assessment Tool for Asia (OSTA) index among a healthy population of Chinese aged 40 years and older. Whether baPWV can be used as a predictor of osteoporosis on OSTA was further assessed. Methods This study was cross-sectional in design. Of 3984 adults aged 40 years and older in the Yunyan district of Guiyang (Guizhou, China) who underwent both OSTA and baPWV measurements within 1 month, 1407 were deemed eligible for inclusion (women, 1088; men, 319). Results The mean baPWV was 1475 ± 302 cm/s (range,766–3459 cm/s). baPWV in 110 individuals with high risk of osteoporosis (OSTA index < − 4) was higher than that of individuals with non-high risk (1733 ± 461 cm/s vs. 1447 ± 304 cm/s, P < 0.001). OSTA index was negatively correlated with baPWV(ρ = − 0.296, P < 0.001) after adjusting for age, sex, body mass index, waist circumference, diastolic blood pressure, and creatinine clearance rate. baPWV was an independent predictor for the presence of high risk of osteoporosis (β = − 0.001, P < 0.001) and was consistent across age and sex subgroups, and the optimal baPWV cutoff value for predicting the presence of high risk of osteoporosis and fracture was 1693 cm/s. The AUC was 0.722 (95% confidence interval [CI], 0.667–0.777; P < 0.001, sensitivity of 52.8% and specificity of 83.6%). Conclusions We conclude that arterial stiffness measured by baPWV is well correlated with the severity of osteoporosis evaluated by OSTA. baPWV index may be a valuable tool for identifying individuals with risk of developing osteoporosis.

The pneumonia caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)abbreviated as Coronavirus Disease 2019(COVID-19)has been classified as a Class B infectious disease under the management of Class A infectious diseases in China. COVID-19 caused by hospital-related transmission is not uncommon and poses a serious threat to clinical medical staff and inpatients. This article introduces that ophthalmologists should master the epidemiological characteristics and clinical manifestations of COVID-19, how ophthalmologists cope with the emergency patients in ophthalmology, focus on the key points of infection prevention and control in ophthalmology emergency and surgery, and strengthen specific prevention and control measures, so as to provide reference for infection prevention and control in ophthalmology medical care in the front line of war epidemics.