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Background Non-Langerhans cell histiocytosis, including Erdheim–Chester disease (ECD), Rosai–Dorfman disease (RDD), indeterminate cell histiocytosis (ICH), and unclassified histiocytosis, is a rare disorder lacking a standard treatment strategy. We report our experience using intermediate-dose cytarabine as the first or subsequent therapy in non-Langerhans cell histiocytosis. Results Nine ECD patients, 5 RDD patients, 1 ICH patient and 1 unclassified histiocytosis patient were enrolled. Intermediate-dose cytarabine therapy was administered as 0.5–1.0 g/m2 of intravenous cytarabine every 12 h for 3 days every 5 weeks. The median age at cytarabine initiation was 47.5 years (range 18–70 years). The median number of cycles of cytarabine administered was 5.5 (range 2–6). The overall response rate (ORR) was 87.5% in the overall cohort, including 12.5% with complete response and 75.0% with partial response. One patient experienced disease recurrence 19 months after cytarabine therapy. The median follow-up duration for the entire cohort was 15.5 months (range 6–68 months). The estimated 2-year progression-free survival and overall survival rates were 85.6% and 92.3%, respectively. The most common toxicity was haematological adverse events, including grade 4 neutropenia and grade 3–4 thrombocytopenia. No treatment-related deaths occurred. Conclusions Intermediate-dose cytarabine is an efficient treatment option for non-Langerhans cell histiocytosis patients, especially for those with CNS involvement.

Bone-tissue defects affect millions of people worldwide. Despite being common treatment approaches, autologous and allogeneic bone grafting have not achieved the ideal therapeutic effect. This has prompted researchers to explore novel bone-regeneration methods. In recent decades, the development of bone tissue engineering (BTE) scaffolds has been leading the forefront of this field. As researchers have provided deep insights into bone physiology and the bone-healing mechanism, various biomimicking and bioinspired BTE scaffolds have been reported. Now it is necessary to review the progress of natural bone physiology and bone healing mechanism, which will provide more valuable enlightenments for researchers in this field. This work details the physiological microenvironment of the natural bone tissue, bone-healing process, and various biomolecules involved therein. Next, according to the bone physiological microenvironment and the delivery of bioactive factors based on the bone-healing mechanism, it elaborates the biomimetic design of a scaffold, highlighting the designing of BTE scaffolds according to bone biology and providing the rationale for designing next-generation BTE scaffolds that conform to natural bone healing and regeneration., Graphical abstract Bone-tissue engineering has become a promising treatment strategy for large bone defects. This work first introduces the advanced knowledge of bone biology, including the physiological microenvironment and healing process. Based on this concept, it further details the current biomimetic and bioactive bone-tissue engineering scaffolds promoting the healing process. Finally, it provides the future perspective in this field.Image 1, Highlights • Elaborate the advanced knowledge of bone physiological microenvironment and healing process. • Summary the biomolecules involved in the natural bone healing process which could be applied to BTE materials and scaffolds. • Detail the current biomimetic and bioinspired scaffolds based on the bone physiological microenvironment. • Review the delivery of bioactive factors based on the bone healing mechanism. • Discuss the current limitations that still need to be solved, and the feasible improvement and outlooks are proposed.

BACKGROUND Decreased ovarian reserve function is an ovarian hypofunction disease that occurs in women before 40 years of age, leading to a decline in fertility and perimenopausal symptoms, such as irregular menstruation, amenorrhea, infertility, decreased libido, and autonomic nervous dysfunction. Fenmatong (FMT) is a compound mixture of estradiol tablets and estradiol didroxyprogesterone tablets, which can improve ovarian reserve function by supplementation of exogenous estrogen. However, this treatment has also been shown to cause breast pain, gastrointestinal discomfort, irregular vaginal bleeding, and changes in sexual desire. In severe cases, FMT can promote the development of breast cancer, endometrial cancer, and venous embolic disease. AIM To observe the effects of Kuntai capsules and FMT on endocrine indexes and uterine artery blood circulation in patients with decreased ovarian reserve function. METHODS Patients (130) with decreased ovarian reserve function, who were treated in our hospital from May 2018 to May 2020, were divided into two groups: The FMT group, in which patients were treated with FMT, and the observation group, in which patients were treated with Kuntai capsules. Chinese medicine symptom scores, uterine artery blood flow parameters, ovarian ultrasound test indexes, pictorial blood loss assessment chart (PBAC) scores, and hormone levels were recorded, and total effective rates were calculated for both groups. RESULTS The total effective rate in the observation group was higher than that in the FMT group (P < 0.05).After treatment, primary symptoms, including low menstrual volume, delayed menstruation, red color and thick consistency of menses, dizziness, palpitation, weakness at the waist and knee, insomnia and excessive dreaming, irritability, and dryness and astringency of the pudendal canal in the observation group decreased, and scores for primary and secondary symptoms in the observation group were significantly lower than those in the FMT group (P < 0.05).The systolic peak flow rate (PSV), end-diastolic flow rate (EDV), ovarian diameter, sinus follicle count, and resistance index (RI) of the uterine arteries in the observation group and FMT group increased after treatment. Notably, the PSV, EDV, ovarian diameter, and antral follicle count in the observation group were higher than those in the FMT group, whereas the RI in the observation group was lower than that in the FMT group (P < 0.05).The PBAC scores in the observation and FMT groups increased after treatment, with that in the observation group becoming significantly higher than that in the FMT group (P < 0.05). After treatment, estradiol (E2) and anti-Mullerian hormone (AMH) levels increased, whereas follicle-stimulating hormone (FSH) levels decreased in the observation group and FMT group; E2 and AMH levels became significantly higher and FSH levels became significantly lower in the observation group than in the FMT group (P < 0.05). CONCLUSION Compared with FMT, Kuntai capsules promoted uterine artery blood circulation, improved menstruation, relieved symptoms, regulated endocrine function, and improved curative effects.

In this work, we propose a Fractional-order Residual Convolutional Neural Network (FRCNN) for Low-Dose CT (LDCT) denoising. As increasing the dose of radiation is harmful to the patient, how to trade off between reducing the radiation dose and improving the quality of the CT image has become a challenging problem. To this end, this paper proposes a new approach for LDCT image denoising using Convolutional Neural Network (CNN) with Fractional-order Total Variation (FTV) loss, as well as residual learning. Firstly, this paper introduced the FTV loss function for structural details enhancement. Secondly, skip connections were added to optimize the network. Thirdly, extensive experimental analysis was used to evaluate the capacity of this method in suppressing noise and preserving detailed information. The FTV loss can retain essential structural details while suppressing noise, generating high-quality CT images ready for interpretation by radiologists. Compared with state-of-the-art methods, our method obtained better results visually and numerically, especially in structural details preservation. These promising results will significantly improve the usability of LDCT images.

We propose a “sensory verb effect” whereby the use of sensory verbs increases purchase intention and the mediating role of mental simulation. Using secondary data and multiple experiments, we provide supportive evidence for the sensory verb effect, support its underlying mechanism via mental simulation, and identify its boundary conditions due to the various type of advertisement. Finally, we demonstrate the downstream consequences of the sensory verb effect on purchase intention.

The purpose of the present study was to examine the protective action and mechanisms of quercetin on the blood-brain barrier (BBB) in rats subjected to transient middle cerebral artery occlusion (tMCAO) and reperfusion. Quercetin (10, 30, 50 mg/kg) was intraperitoneally administered at the onset of reperfusion. The results showed that quercetin significantly reduced cerebral infarct volume, neurological deficit, BBB permeability and ROS generation via Sirt1/Nrf2/HO-1 signaling pathway. Moreover, EX527, a selective inhibitor of Sirt1, reversed these neuroprotective effects. Our findings indicate that quercetin has neuroprotective effects against cerebral ischemia-reperfusion injury by protecting BBB through Sirt1 signaling pathway in MCAO rats.

Erythropoietic protoporphyria (EPP) is a rare autosomal recessive disease presented with protoporphyrin deposition, photosensitivity and even liver damage. Avatrombopag, a thrombopoietin receptor agonists, has been applied for immune thrombocytopenia and periprocedural thrombocytopenia in patients with chronic liver disease. Here, we reported the first case of a 19-year-old man with acquired aplastic anemia associated with congenital EPP. EPP has led to a severe cirrhosis and liver dysfunction in this patient, which limited hematopoietic stem cell transplantation and immunosuppressive therapy to cure aplastic anemia. We administered Avatrombopag as the first-line therapy. After 8 months, we observed that avatrombopag induced complete response of aplastic anemia safely.

We report a successful transcatheter aortic valve implantation in an high-risk elderly patient with pure aortic regurgitation and type III endoleak after thoracic endovascular aortic repair.

Atrial fibrillation (AF) is the most common cardiac arrhythmia; it has been known to increase the risk of stroke and heart failure. The association between air pollutants and AF has remained to be controversial. Thus, in this study, we sought to undertake a systematic review and meta-analysis in order to assess the short- and long-term effects of ambient air pollution on AF.We searched PubMed, Web of Science, Embase, and Ovid for all related studies up to October 2019. We used the random-effects model to estimate the excess risk percentage (ER%) and confidence intervals (CI) for particulate matter with diameter ≤ 2.5 (PM2.5) and ≤ 10 μm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO). Results were further analyzed by subgroups according to location, age, outcome, and gender.In total, 18 studies were included in our meta-analysis: 5 evaluated for long-term effects, 12 for short-term effects, and 1 for both long- and short-term effects. For the short term, ER per 10 μg/m3 increase of pollutants was 1.8% (0%-3.7%) for PM2.5 and 1.1% (-0.2%-2.4%) for PM10; per 10 parts per billion (ppb) increment of gaseous pollutions was 3.2% (0.6%-5.8%) for NO2, 2.9% (0.3%-5.7%) for SO2, 0.5% (-3.4%-4.7%) for O3, and 2.0% (-1.3%-5.4%) for CO per 1000 ppb change. The subgroup analysis showed the short-term effect was significantly different by region, gender, outcome, and age. Meanwhile, in the long term, except for O3, a statistically significant association was noted between AF incidence and all pollutants.Our meta-analysis suggests that short-term exposure to part of pollutants (PM2.5, SO2, and NO2) increases AF attack. Further, long-term exposure to air pollution can significantly contribute to the incidence of AF in a healthy population.

We investigate the scattering properties of an array of plasmonic structure consisting of a bright atom and a gain assisted dark atom. In light of the Lorentz model analysis, we demonstrate perfect electromagnetically induced transparency (EIT) like resonance with high Q factor when proper amount of gain is introduced. The non-Hermitian physics associated with the proposed structure can greatly enrich the electromagnetic property of it. Ultra-high transmission and reflection of a finite bandwidth are reported at the EIT resonance frequency when the gain level is increased to a critical point. Furthermore, we find that by introducing extra loss into one strip and equal amount of gain into another strip in the dark atom simultaneously, enhanced absorption of the incident wave is achieved. In addition to incorporating material gain to balance the loss, we propose that coherent pump waves can introduce effective gain in the dark mode. Compared to utilizing gain medium, such a route is much easier to implement. The demonstrated high-Q EIT resonance, lasing and enhanced absorption effects may find their applications in sensing, switching, absorbing, nonlinear optics and spaser areas.

Qiang Yang,1 Yanghao Zhou,1 Jin Chen,1 Ning Huang,1 Zhigang Wang,2 Yuan Cheng1 1Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 2Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaCorrespondence: Yuan ChengDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaTel +86 023 63693540Email chengyuan@hospital.cqmu.edu.cnBackground: Therapy for glioblastoma (GBM) has always been very challenging, not only because of the presence of the blood-brain barrier (BBB) but also due to susceptibility to drug resistance. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) has revolutionized gene editing technology and is capable of treating a variety of genetic diseases, including human tumors, but there is a lack of safe and effective targeting delivery systems in vivo, especially in the central nervous system (CNS).Methods: Lipid-polymer hybrid nanoparticles (LPHNs-cRGD) were constructed for efficient and targeting delivery of CRISPR/Cas9 plasmids targeting O6-methylguanine-DNA methyltransferase (MGMT), a drug-resistance gene to temozolomide (TMZ). Focused ultrasound (FUS)-microbubbles (MBs) were used to non-invasively and locally open the BBB to further facilitate gene delivery into glioblastoma in vivo. The gene editing efficiency and drug sensitivity changes were evaluated both in vitro and in vivo.Results: The gene-loaded LPHNs-cRGD were successfully synthesized and could protect pCas9/MGMT from enzyme degradation. LPHNs-cRGD could target GBM cells and mediate the transfection of pCas9/MGMT to downregulate the expression of MGMT, resulting in an increased sensitivity of GBM cells to TMZ. MBs-LPHNs-cRGD complexes could safely and locally increase the permeability of the BBB with FUS irradiation in vivo and facilitated the accumulation of nanoparticles at the tumor region in orthotopic tumor-bearing mice. Furthermore, the FUS-assisted MBs-LPHNspCas9/MGMT-cRGD enhanced the therapeutic effects of TMZ in glioblastoma, inhibited tumor growth, and prolonged survival of tumor-bearing mice, with a high level of biosafety.Conclusion: In this work, we constructed LPHNs-cRGD for targeting delivery of the CRISPR/Cas9 system, in combination with FUS-MBs to open the BBB. The MBs-LPHNs-cRGD delivery system could be a potential alternative for efficient targeting gene delivery for the treatment of glioblastoma.Keywords: CRISPR/Cas9, LPHNs, FUS, microbubbles, glioblastoma

Background: Thyroid function is increasingly recognized as an important modifiable factor for atrial fibrillation (AF); however, it is unclear if the changes in thyroid hormones, even within the normal range, are associated with AF recurrence after catheter ablation. Methods: Consecutive paroxysmal AF patients who underwent catheter ablation were enrolled. Patients with abnormal thyroid hormones or previous thyroid illnesses were excluded. Patients were followed for 12 months or until they presented with the first episode of atrial tachyarrhythmia after a blanking period. Results: The study included 448 patients with a mean age of 61 (14) years, and 46% were women. After a 1-year follow-up, 104 (23.2%) patients experienced atrial tachyarrhythmia recurrences after an ablation procedure. Recurrence was significantly different among quartile groups of thyroid function, with highest FT4 and FT3 levels associated with the greatest risk of recurrence (p < 0.001 and p = 0.024, respectively). FT4 and FT3 levels were independent predictors of atrial tachyarrhythmia recurrence (hazard ratio 1.07 per 1 pmol/L increase in FT4, 95% confidence interval [CI] 1.01–1.15, p = 0.036 and 1.31 per 1 pmol/L increase in FT3, 95% CI 1.01–1.71, p = 0.032). Conclusions: High-normal FT3 and FT4 levels are associated with AF recurrence after catheter ablation in this Chinese population. Attention to thyroid hormones could be valuable to assist in the management of AF.

The objective of this study was to evaluate the therapy effects of a novel biological scaffold containing heparin, collagen and vascular endothelial growth factor (VEGF) in treating traumatic brain injury (TBI). In our research, a functional composite scaffold constituted by collagen, heparin and vascular endothelial growth factor was used to stimulate angiogenesis and improve nerve-tissue regeneration in a rat model of TBI. The composite scaffold possessed excellent mechanical properties and good porosity, and could effectively control the release rate of VEGF. Motor and cognitive functions such as motor evoked potential, Morris water maze test and modified neurological severity score were evidently improved after the scaffold was grafted onto the injury site in the rat TBI model. There was clearly improved restoration of damaged nerve tissue at the injured site. Furthermore, brain edema and inflammatory reactions were significantly alleviated. Newly formed neurons with associated synaptic structures, nerve fibers, myelin sheaths and functional angiogenesis with intact endothelium at the injury site were observed. In conclusion, our data revealed that the collagen/heparin scaffold combined with VEGF could create excellent microenvironment stimuli for damaged nerve-tissue regeneration, providing a potential strategy for treating TBI.

Tianyi Rong,* Min He,* Yun Hua, Deyan Chen, Miao Chen Department of Neurology, Shidong Hospital of Yangpu District, Shanghai 200438, People’s Republic of China*These authors contributed equally to this workCorrespondence: Miao ChenDepartment of Neurology, Shidong Hospital of Yangpu District, Shanghai 200438, People’s Republic of ChinaEmail marcy_cm@163.comBackground: Timely diagnosis and treatment are crucial to improve prognosis of ischemic stroke, making exploring factors associated with prognosis essential. Blood pressure variability (BPV) was reported to be associated with neurologic outcome, and basic researches on cardiovascular diseases found abnormal expression patterns of several factors including interleukin 10 (IL-10), matrix metallopeptidase 9 (MMP-9), and legumain which might be related to abnormal BPV but yet to prove in ischemic stroke. The study aimed to investigate whether IL-10, MMP-9, and legumain are associated with BPV and neurologic outcome of patients with ischemic stroke.Patients and Methods: Newly diagnosed ischemic stroke patients admitted to the department of neurology, Shidong Hospital of Yangpu District in Shanghai between July 2017 and January 2019 were enrolled. IL-10, MMP-9, and legumain were detected and BPV was assessed within 72 hours after admission. All the patients were followed for neurologic outcomes at discharge and 6 months after admission based on the Modified Rankin Scale (MRS). Correlations of IL-10, MMP-9, and legumain with BPV were examined by Spearman correlation coefficient, and their associations with neurologic outcomes were evaluated by multivariable linear regression.Results: A total of 349 patients with ischemic stroke were enrolled with an average age of 72.97± 11.47 years. Compared with non-progressive ischemic stroke, patients with progressive ischemic stroke had significantly higher IL-10, MMP-9, and legumain on admission. MMP-9 was found to be positively correlated with BPV while no significant correlation was found for IL-10 and legumain with BPV. MMP-9 was associated with progressive ischemic stroke [β=0.23 (95% CI 0.11– 0.35) per SD increase for MRS at discharge, and β=0.32 (95% CI 0.20– 0.43) per SD increase for MRS at 6 months after admission].Conclusion: Increased MMP-9 was associated with increased BPV and progressive ischemic stroke for patients with ischemic stroke, which might partially explain the effect of BPV on neurologic outcomes.Keywords: interleukin 10, matrix metallopeptidase 9, legumain, blood pressure variability, ischemic stroke

Atrial fibrillation (AF) is the most common sustained arrhythmia. Renin-angiotensin system (RAS) inhibitors were reported to modify the arrhythmia substrate and reverse atrial remodeling. However, the role of RAS inhibitors on AF recurrence after catheter ablation remains much more controversial. In this study, a meta-analysis was performed to explore the effect of RAS inhibitors on AF recurrence after catheter ablation.We searched PubMed, Cochrane Library, EMBASE, and Web of Science for all articles published up to July 2019 on the effect of RAS inhibitors on AF recurrence rate after ablation. We used the random-effects model to estimate the odds ratios (ORs) and confidence intervals (CI). The I2 statistic was used to evaluate statistical heterogeneity. A two-tailed P value of

Ischemic stroke represents one of the leading causes of mortality worldwide and especially in developing countries. It is crucial for finding effective therapeutic targets that protect the brain against ischemic injury. Long noncoding RNAs (lncRNAs) have emerged as major regulators of neurological diseases, and clarifying their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke. We aimed to investigate the role of lncRNA-XLOC_035088 in middle cerebral artery occlusion (MCAO)-induced rat brain injury and oxygen-glucose deprivation (OGD)-reperfusion treated hippocampal neurons. In our findings, we found that XLOC_035088 expression was significantly upregulated in OGD-reperfusion treated hippocampal neurons and in different brain regions of MCAO-treated rats. XLOC_035088 silencing protected against MCAO-induced ischemic brain injury in vivo and OGD-induced hippocampal neuronal apoptosis in vitro. Intrahippocampal silencing of XLOC_035088 significantly decreased brain XLOC_035088 expression, reduced brain infarct size, and improved neurological function through inhibiting NOTCH1 following derepression of presenilin 2 (PSEN2). Taken together, this study provides evidence that the lncRNA XLOC_035088/PSEN2/Notch1 axis is involved in the pathogenesis of ischemic brain injury, and presents a promising therapeutic route for ischemic stroke.

Aim β-blockers are commonly used to treat hypertension that arises during pregnancy. However, reproductive safety concerns have been expressed. Here, we investigated whether the use of β-blockers during early pregnancy increased the risk of congenital malformations. Methods A systematic literature search was performed in PubMed, Embase, and Cochrane Library to identify relevant studies published from database inception until February 2020. Observational studies evaluating associations between maternal β-blocker use and congenital malformations were included in this meta-analysis. Two reviewers independently extracted data and assessed study quality. Meta-analysis of outcomes was performed and a summary odds ratio (OR) was calculated with consideration of heterogeneity. Results Twenty observational studies were identified. β-blocker use during early pregnancy was not associated with an increased risk of congenital malformations (OR=1.01, 95% confidence interval [CI]=0.93-1.09). Subgroup analysis of organ-specific malformations revealed that β-blocker use was associated with an increased risk of heart malformations (OR=1.29, 95% CI=1.02-1.63) and an increased risk of cleft lip or palate (OR=1.5, 95% CI=1.18-1.91); however, these associations (OR=1.11, 95% CI=0.94-1.32 for heart malformations; OR=1.34, 95% CI=0.98-1.85 for cleft lip or palate) disappeared when the adjusted data were pooled. β-blocker use was not associated with increased risks of central nervous system malformations, neural tube defects, or hypospadias. Conclusion Exposure to β-blockers during early pregnancy does not appear to be associated with congenital malformations or heart malformations in offspring. Other organ-specific congenital malformations should be evaluated in further studies.

Recently, safety protection research on the risk of flammable gas leakage and deflagration between adjacent offshore facilities is easy to be ignored and the fire and explosion accidents are also h...

This paper endeavors to reveal the squeezing failure mechanism of roof‐coal masses and its correlation with the movement of the roof strata. An integrated method incorporating field instruments and numerical modeling was conducted. The borehole camera detection revealed that the development degree and scope of cracks in the roof strata on the coal pillar side are significantly larger than that on the panel rib side, and the fracture line of the main roof occurred above the coal pillar. A rigorous modeling procedure verified the borehole camera detection results and also found that the vertical and horizontal displacement of the roof‐coal mass exhibited asynchronous development characteristics at various heights. Subsequently, a comprehensive control strategy was proposed to prevent the squeezing failure behavior of roof‐coal masses in DUOS gob‐side entry. This study provides a basis for understanding the squeezing failure behavior of roof‐coal masses, and the proposed control strategy can potentially be applied in other similar mining projects.

Acquired pure red cell aplasia (PRCA) is a disorder characterized by normocytic anemia associated with reticulocytopenia and an absence of erythroblasts. The gene mutation profile in acquired PRCA is not defined yet. In this study, we aimed to identify the gene mutation spectrum of patients with acquired PRCA and the correlation between gene mutations and response to immunosuppressive therapy (IST). Thirty newly diagnosed acquired PRCA patients were enrolled in this study, and then whole-exome sequencing were performed among these patients and a panel with 93 candidate genes which associated with other bone marrow failure for the following analysis. Subsequently patients were treated with IST for at least 2 years. When treated with IST, there were thirteen complete response, ten partial response (ORR 76.7%), and seven no response at a medium of 8 (6–10) months. Totally twenty-three mutations in fifteen genes were detected in sixteen patients (53%). The mutated genes were associated with transcription, signal transduction, and epigenetic regulation pathways. The most frequent transitions in the point mutations were C > T. Age, gender, hemoglobin level at diagnosis, and gene mutation or not did not influence the response to IST. However, although patients with BCOR or BCORL1 mutations had a similar response to IST compared with those without mutation (P = 0.235), they had a better response than those with other gene mutations (P = 0.0193). In conclusion, patients with acquired PRCA may have clonal gene mutations. The patients with BCOR and BCORL1 mutations may suggest a better response to IST compared with those with other mutations.

This cross-sectional study focused on the association between heart rate variability (HRV) and early repolarization pattern (ERP). It included 1236 patients categorized into three groups: ERP type 1: J-point elevation with notched/slurred QRS; ERP type 2: ST elevation without dominant J-wave; and non-ERP group. Analyzing time-domain indexes include standard deviation of NN (normal-to-normal) RR intervals (SDNN), root mean square of successive difference in NN RR intervals (RMSSD), and proportion of consecutive NN intervals that differ by more than 50 ms (PNN50), there were significant differences between any two groups (all P 0.01). All time-domain indexes showed: ERP type 2ERP type 1non-ERP. Multivariate logistic regression analysis revealed that SDNN at nighttime and gender were independently associated with the maximum magnitude of J-point elevation ≧ 0.2 mV. The findings strongly suggested that based on electrocardiogram characteristics, parasympathetic tone denoted by HRV may be related to different types of ERP.

No agreement had been reached on the treatment of patients with pure red cell aplasia (PRCA) secondary to indolent malignancies. Data was collected from patients with acquired PRCA from May, 2014 to May, 2018 in Peking Union Medical College Hospital. Tumor-associated PRCA and primary PRCA patients were matched at a ratio of 1:2 with compatible baseline characteristics. All patients had been treated with CsA or sirolimus for at least 6 months with the efficacy and adverse events recorded. Twelve tumor-associated PRCA patients (3 thymoma, 8 lymphoproliferative disorders, and 1 smoldering multiple myeloma) with stable underling disease and 24 acquired primary PRCA patients were selected. 83.3% tumor-associated PRCA patients and 100% primary PRCA patients (P = 0.436) responded to immunosuppression therapy (IST) at a median of 2.5 and 3.5 months (P = 0.137), respectively. No different was found in side effects. The ORR at the end of a median of 21.5-month follow-up was 75% and 70.8% (P = 0.795), respectively. No tumor progression was reported except one secondary patient had lymphoma relapse after 2 years of IST and was given chemotherapy again. These results suggested IST had similar effect, safety on patients with tumor-associated, and primary PRCA patients when the tumors were stable.

Objectives To systematically evaluate the effect of the surgery-first approach (SFA) on oral health-related quality of life (OHRQoL) in patients with dentofacial deformities. Materials and Methods An electronic database search and hand search of selected journals and references were carried out. Studies investigating the OHRQoL of patients receiving SFA with or without a control group were included. The risk of bias was assessed by the Cochrane risk of bias tool in randomized clinical trials (RCTs) and the Newcastle-Ottawa Scale in non-RCTs. Results A total of seven articles met the eligible criteria and were included, of which six were cohort studies and one was an RCT, and six assessed the OHRQoL of the SFA with conventional orthodontic–surgical treatment (COST) as a control and one without. A total of 214 patients were examined, with sample sizes in studies ranging from 9 to 50. A total of 3 articles successfully measured the OHRQoL both before and after treatment in both the SFA and conventional orthodontic–surgical treatment groups. A total of six cohort studies were classified as low to moderate risk of bias, and the RCT was classified as high. Conclusions The SFA could improve the OHRQoL of patients with dentofacial deformities similar to conventional orthodontic–surgical treatment at the end of complete treatment. In addition, it increases OHRQoL immediately at the beginning of treatment without a deterioration.

Cervical cancer is an aggressive cutaneous malignancy, illuminating the molecular mechanisms of tumorigenesis and discovering novel therapeutic targets are urgently needed. KMT2A is a transcriptional co-activator regulating gene expression during early development and hematopoiesis, but the role of KMT2A in cervical cancer remains unknown. Here, we demonstrated that KMT2A regulated cervical cancer growth via targeting VADC1. Knockdown of KMT2A significantly suppressed cell proliferation and migration and induced apoptosis in cervical cancer cells, accompanying with activation of PARP/caspase pathway and inhibition of VADC1. Overexpression of VDAC1 reversed the KMT2A knockdown-mediated regulation of cell proliferation, migration and apoptosis. The in vivo results from a cervical cancer xenograft mouse model also validated that KMT2A knockdown suppressed tumor growth by inhibiting VDAC1, whereas KMT2A overexpression promoted cervical cancer growth. Moreover, analyses of Biewenga cervix database and clinical samples showed that both KMT2A and VDAC1 were upregulated in cervix squamous cell carcinoma compared with cervix uteri tissues, and their expression was negatively correlated with the differentiation grade of cervical cancer. Our results therefore indicated that the KMT2A/VDAC1 signaling axis may be a potential new mechanism of cervical carcinogenesis.

BACKGROUND Fulminant lupus myocarditis is a rare but fatal manifestation of systemic lupus erythematosus. Aggressive immunosuppressive treatments are important in its successful management. However, they can significantly damage the immunity and are associated with a considerable risk of infection development and spread. We present a rare and complicated case of a 20-year-old female diagnosed with fulminant lupus myocarditis accompanied by pneumonia. The patient was successfully treated with plasma exchange (PE) for fulminant lupus myocarditis. CASE SUMMARY A 20-year-old Chinese woman presented to the Hematology Department complaining of fatigue and knee pain. Blood test showed anemia and thrombocytopenia. On the second day of hospitalization, she was transferred to the ICU due to dyspnea and hypotension. Autoimmune profiles showed hypocomplementemia and positive antinuclear antibodies. Computer tomography showed an enlarged heart and pneumonia. Ultrasound revealed an enlarged heart with a low left ventricular ejection fraction. Fulminant lupus myocarditis with cardiogenic shock was initially considered. Due to the accompanying pneumonia, aggressive immunosuppression was contraindicated. Her cardiac function remained critical after the initial therapy of intravenous immunoglobulin and corticosteroids at a conventional dose, but she responded well to later PE therapy plus corticosteroids administration. The patient fully recovered with normal cardiac function. CONCLUSION This case indicates that PE is a valuable treatment choice without adverse effects of immunosuppression in patients with fulminant lupus myocarditis and coexisting infection.

Objectives This study aims to analyze the expression profile of osteoclasts (OCs) following the stimulation with interleukin 23 (IL-23) in mice, which would imply the underlying effects of IL-23 on the function of OCs in inflammatory arthritis. Materials and methods Mature OCs were induced from bone marrow mononuclear cells of 5 male mice (age 6 weeks; weighing 18-20 g) in the presence of macrophage-colony stimulating factor (50 ng/mL) and receptor activator of nuclear factor kappa B ligand (30 ng/mL) in vitro. The Agilent SurePrint G3 Mouse GE V2.0 Microarray was used to analyze the gene expression profile of OCs stimulated with IL-23 (30 ng/mL) or vehicle. The four major IL-23-modulated genes were validated by quantitative real-time polymerase chain reaction (qPCR) analysis. Results The expression levels of 23 genes were up-regulated and 32 genes were down-regulated by IL-23 stimulation (fold change ≥1.5 and p value

Psoriatic arthritis (PsA) is a type of chronic inflammatory arthritis which is associated with psoriasis. The early recognition and treatment for PsA are of critical importance. Janus kinase (JAK) inhibitors, as a kind of orally small molecules, have emerged as an encouraging class of drug in PsA treatment. This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA. There are three JAK inhibitors approved for use in autoimmune diseases, for example, tofacitinib, baricitinib, and upadacitinib, and only tofacitinib has been approved in PsA treatment. The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing. The efficacy and safety of these agents were briefly discussed. Although there are still issues in terms of their efficacy and safety currently, JAK inhibitors are expected to benefit more PsA patients in future.

AIMS Atrial fibrillation is the most common sustained arrhythmia in the general population, and circumferential pulmonary vein isolation has emerged as a cornerstone in the treatment of drug-resistant atrial fibrillation. However, there is a paucity of data regarding the CHA2DS2-VASc and SAMe-TT2R2 scores as predictors of outcomes among patients with nonvalvular atrial fibrillation on vitamin K antagonists after radiofrequency catheter ablation (RFCA). METHODS The current prospective observational study enrolled 304 consecutive patients with atrial fibrillation who underwent RFCA. Warfarin was maintained for at least 3 months after RFCA. The 1-year atrial fibrillation recurrence rate was documented. RESULTS Persistent atrial fibrillation (P = 0.003), heart failure (P

Background: Metastatic colorectal cancer (CRC) is a lethal disease; however, the underlying molecular mechanisms remain unclear and require further study. Methods: RNA-Seq, PCR, Western blotting, immunohistochemistry, ChIP and RNAi assays were performed to investigate Rho GTPase-activating protein 5 (ARHGAP5, aslo known as p190RhoGAP-B, p190-B) expression and the clinical relevance, functional roles and regulatory mechanisms of this protein using human CRC cells and tissues. In vivo, two cell-based xenograft models were used to evaluate the roles of ARHGAP5 in CRC metastasis. Results: Here, we report that ARHGAP5 expression is significantly increased in metastatic CRC tissues and is inversely associated with patient overall survival. The suppression of ARHGAP5 reduces CRC cell metastasis in vitro and in cell-based xenograft models. Furthermore, we show that ARHGAP5 promotes CRC cell epithelial-mesenchymal transition by negatively regulating RhoA activity. Mechanistically, cAMP response element-binding protein (CREB1) transcriptionally upregulates ARHGAP5 expression, and decreased miR-137 further contributes to ARHGAP5 mRNA stability in CRC. Conclusions: Overall, our study highlights the crucial function of ARHGAP5 in CRC metastasis, thus suggesting novel prognostic biomarkers and hypothetical therapeutic targets.

Mucociliary epithelium lining the upper and lower respiratory tract constitutes the first line of defense of the airway and lungs against inhaled pollutants and pathogens. The concerted beating of multiciliated cells drives mucociliary clearance. Abnormalities in both the structure and function of airway cilia have been implicated in obstructive lung diseases. Emerging evidence reveals a close correlation between lung diseases and environmental stimuli such as sulfur dioxide and tobacco particles. However, the underlying mechanism remains to be described. In this review, we emphasize the importance of airway cilia in mucociliary clearance and discuss how environmental pollutants affect the structure and function of airway cilia, thus shedding light on the function of airway cilia in preventing obstructive lung diseases and revealing the negative effects of environmental pollutants on human health.

Online controlled experimentation is widely adopted for evaluating new features in the rapid development cycle for web products and mobile applications. Measurement of the overall experiment sample is a common practice to quantify the overall treatment effect. In order to understand why the treatment effect occurs in a certain way, segmentation becomes a valuable approach to a finer analysis of experiment results. This paper introduces a framework for creating and utilizing user behavioral segments in online experimentation. By using the data of user engagement with individual product components as input, this method defines segments that are closely related to the features being evaluated in the product development cycle. With a real-world example, we demonstrate that the analysis with such behavioral segments offered deep, actionable insights that successfully informed product decision-making., 2017 IEEE International Conference on Data Science and Advanced Analytics (DSAA). IEEE, 2017

Background Surgical delay can improve flap viability, leading to vasodilation, neovascularization, and vessel reorganization. Experiments suggest a similar positive effect of botulinum toxin type A on pedicled flap viability. However, whether it may convert choke anastomoses into true anastomoses and how to identify the optimal timing for flap transfer remain unclear. Methods One hundred fifty-four Sprague-Dawley rats were divided into a control group, three saline injection groups, and three botulinum toxin type A injection groups defined by time of injection (2, 3, and 4 weeks before flap harvest). A pedicled 11 × 3-cm flap was marked on the unilateral dorsum of each rat. Before flap harvest, the flap donors were assessed by infrared thermal imaging, postmortem arteriography, immunohistochemical staining of CD31, and enzyme-linked immunosorbent assay. Flap survival area percentage was measured on postoperative day 7. Results In the control and saline groups, infrared thermography showed three independent white hotspots interspaced by red zones over flaps, whereas it presented a continuous white band in the botulinum toxin type A groups. There was a significant increase in flap survival area, flap surface temperatures, numbers of identifiable vessels in the choke zones, microvascular density, and vascular endothelial growth factor concentration in the botulinum toxin type A groups. Conclusions Botulinum toxin type A can convert choke anastomoses into true anastomoses, and its preconditioning effect cannot increase over time; it is appropriate to choose the timing point when the infrared thermal images show a continuous white band existing over flaps for flap transfer.

A digital fluorescence detector (DFD), a handheld fluorescence detection device, can convert the fluorescence signal of samples into the corresponding fluorescer concentration. Herein, by adopting a DFD as the readout, a novel intelligent platform was developed based on a ratiometric paper-based device (RPD) for multiple aminoglycoside detection. There are five layers and four parallel channels contained in the designed RPD, functioning as reagent storage, fluidic path control and signal processing, respectively. The rationale of this design lies in the fact that aptamer/graphitic carbon nitride nanosheet (Apt/g-C3N4 NS) modified layers can catalyze o-phenylenediamine to fluorescent 2,3-diaminophenazine (DAP) in the presence of H2O2. When Apt was removed from nanosheets via the Apt-target reaction, the peroxidase-like activity would be decreased, thus decreasing the production of DAP. All the changes of the fluorescence DAP signal can be read out using a portable DFD. Based on the DFD signal change related to the concentration of the target, a quantitative reaction platform was established. Furthermore, the sample flow and Apt-target reaction time can be reasonably regulated using the H2O2-cleavable hydrophobic compound modified layer placed between the target recognition region and detection region. Then, the practicality of this platform was verified through realizing sensitive analysis of streptomycin, tobramycin, and kanamycin simultaneously. Overall, with merits including portability and ease of operation, the platform shows great potential in on-site simultaneous detection of multiple targets, especially in resource-limited settings.

Diabetic osteoporosis is a common complication in diabetic patients, leading to increased fracture risk and impaired bone healing. As a member of the peroxisome proliferator-activated receptor (PPAR) family, PPARβ/δ agonist is suggested as a therapeutic target for the treatment of metabolic syndrome, and has been reported to positively regulate bone turnover by improving osteogenesis. However, its regulatory role in diabetic osteoporosis has not been reported yet. Here, we explored the therapeutic effects and potential mechanisms of PPARβ/δ agonist to the osteoporotic phenotypes of diabetic mice. Our results indicated that the osteoporotic phenotypes could be significantly ameliorated in diabetic mice by the administration of PPARβ/δ agonists. In vitro experiments suggested that PPARβ/δ agonist treatment could alleviate the abnormal increase of osteoclast activity in diabetic mice by rectifying high glucose-mediated macrophage dysfunction instead of directly inhibiting osteoclast differentiation. Mechanistically, Angptl4 may act as a downstream target of PPARβ/δ to regulate macrophage polarization. In conclusion, our study demonstrates the potential of PPARβ/δ agonist as a therapeutic target for the treatment of osteoporosis and immune homeostasis disorder in diabetic patients.

The optimal method of tumor burden evaluation in newly diagnosed multiple myeloma (NDMM) is yet to be determined. This study aimed to compare the value of 11C-acetate positron-emission tomography (PET)/computed tomography (CT) (AC-PET and 18F-fluorodeoxyglucose PET/CT (FDG-PET) in the assessment of tumor burden in NDMM. This study evaluated 64 NDMM patients between February 2015 and July 2018. AC-PET and FDG-PET were used to assess myeloma lesions. The clinical data, imaging results, and their correlations were analyzed. Diffuse bone marrow uptake in AC-PET was significantly correlated with biomarkers for tumor burden, including serum hemoglobin (P = 0.020), M protein (P = 0.054), the percentage of bone marrow plasma cells (P P = 0.007). The maximum standard uptake value (SUVmax) of focal lesions and high diffuse bone marrow uptake in AC-PET showed stronger correlations with high-risk disease (P = 0.017, P = 0.013) than those in FDG-PET. Moreover, the presence of diffuse bone marrow uptake, more than ten focal lesions, and an SUVmax of focal lesions of > 6.0 in AC-PET, but not in FDG-PET, predicted a higher probability of disease progression and shorter progression-free survival (P

Objective: The ongoing coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic. Currently, supportive care measures remain the standard of care for severe and critical COVID-19 patients, such as ventilation oxygenation, fluid management and blood purification. In this study, we aimed to evaluate the effects of early blood purification therapy upon severe and/or critical COVID-19 patients.Patients and Methods: From January 31, 2020 to March 1, 2020, a total 5 patients with COVID-19 (3 critical type cases and 2 severe type cases) received early blood purification treatment in the intensive care unit (ICU) of Affiliated Hospital of Zunyi Medical University. Clinical indexes, including oxygen concentration, blood gas analysis, oxygenation index, and laboratory test as well as disease scores were recorded and analyzed before and after the treatment with blood purification.Results: Among the 5 patients, 4 were males ranging from 35 to 80 year old (Mean age = 63 ± 17.87). All cases with characteristics of OI Conclusion: Continuous blood purification therapy held promising prospects for alleviating the deteriorative progression of severe and critical types of COVID-19 in the early stage, together with ameliorating the accumulation of inflammatory cytokine and the concomitant symptoms and complications by efficacious immunoadsorption.Trial Registration:www.chictr.org.cn, Identifier (ChiCTR2000031930).

Miao Chen,1,2 Weimin Lin,1 Jianru Yi,1,2 Zhihe Zhao1,2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Jianru Yi; Zhihe Zhao Tel +86-28-85503040; +86-28-85503645Email jianruyi@scu.edu.cn; zhzhao@scu.edu.cnPurpose: Genetic factors in type 2 diabetes (T2D) pathogenesis have been widely explored by the genome-wide association studies (GWAS), identifying a great amount of susceptibility loci. With the development of high-resolution sequencing, the N(6)-methyladenosine (m6A) RNA modification has been proved to be affected by genetic variation. In this study, we identified the T2D-associated m6A-SNPs from T2D GWAS data and explored the underlying mechanism of the pathogenesis of T2D.Methods: We examined the association of m6A-SNPs with T2D among large-scale T2D GWAS summary statistics and further performed multi-omics integrated analysis to explore the potential role of the identified m6A-SNPs in T2D pathogenesis.Results: Among the 15,124 T2D-associated m6A-SNPs, 71 of them reach the genome-wide significant threshold (5.0e-05). The leading SNP rs4993986 (C>G), which is located near the m6A modification site at the 3ʹ end of the HLA-DQB1 transcript, is expected to participate in the pathogenesis of T2D by influencing m6A modification to regulate the HLA-DQB1 expression.Conclusion: The current study has suggested a potential correlation between m6A-SNPs and T2D pathogenesis and also provided new insights into the pathogenic mechanism of the T2D susceptibility loci identified by GWAS.Keywords: type 2 diabetes, single nucleotide polymorphism, epigenetics, m6A, genome-wide association study

Objective The purpose of this study was to reevaluate the high-risk breast non-mass-like lesions (NMLs) in mammography (MG) by target ultrasound (US) and Automated breast ultrasonography (ABUS), and to analyze the correlation between different imaging findings and the factors influencing the classification of lesions. Methods A total of 161 patients with 166 breast lesions were recruited in this retrospectively study. All cases were diagnosed as BI-RADS 4 or 5 by MG and as NML on ultrasound. While all NMLs underwent mammography, target US and ABUS before breast surgery or biopsy in the consistent position of breast. The imaging and pathological features of all cases were collected. All lesions were classified according to the lexion of ACR BI-RADS®. Results There were significant differences between benign and malignant breast NML in all the features of target US and ABUS. US, especially ABUS, was superior to MG in determining the malignant breast NML. There was a significant difference in the detection rate of calcification between MG and Target US (P P Conclusions Target US, especially ABUS, can significantly improve the sensitivity, specificity and accuracy of the diagnosis of high-risk NMLs in MG. The features of Target US and ABUS such as blood supply, hyperechogenicity, ductal changes, peripheral changes and coronal features could be employed to predict benign and malignant lesions. The coronal features of ABUS were more sensitive than those of Target HHUS in showing structural abnormalities. Target US was less effective than MG in local micro-calcification.

Aim: The structural and electrical changes in the atrium, also known as atrial remodeling, are the main characteristics of atrial fibrillation (AF). Fibroblast growth factor 21 (Fgf21) is an important endocrine factor, which has been shown to play an important role in cardiovascular diseases. However, the effects of Fgf21 on atrial remodeling have not been addressed yet. The purpose of the present study is to evaluate the effects of Fgf21 on atrial remodeling.Methods and Results: Adult mice were treated with Ang II, and randomly administrated with or without Fgf21 for 2 weeks. The susceptibility to AF was assessed by electrical stimulation and optical mapping techniques. Here, we found that Fgf21 administration attenuated the inducibility of atrial fibrillation/atrial tachycardia (AF/AT), improved epicardial conduction velocity in the mice atria. Mechanistically, Fgf21 protected against atrial fibrosis and reduced oxidative stress of the atria. Consistently, in vitro study also demonstrated that Fgf21 blocked the upregulation of collagen by Tgf-β in fibroblasts and attenuated tachypacing-induced oxidative stress including reactive oxygen species (ROS), Tgf-β, and ox-CaMKII in atrial myocytes. We further found that Fgf21 attenuated oxidative stress by inducing antioxidant genes, such as SOD2 and UCP3. Fgf21 also improved tachypacing-induced myofibril degradation, downregulation of L-type calcium channel, and upregulation of p-RyR2, which implicated protective effects of Fgf21 on structural and electrical remodeling in the atria. Moreover, Nrf2 was identified as a downstream of Fgf21 and partly mediated Fgf21-induced antioxidant gene expression in atrial myocytes.Conclusion: Fgf21 administration effectively suppressed atrial remodeling by reducing oxidative stress, which provides a novel therapeutic insight for AF.

Herein we report a framework nucleic acid programmed strategy to develop nanocarriers to precisely and independently package multiple homo- and heterogeneous cargos in vitro and in vivo, thereby enabling multiplexed analysis of aptamer-ligand complexes to distinguish normal people and patients with prostate enlargement via simple serum tests, as well as favorable imaging and discrimination of MCF-7, PC-3 and A549 cancer cells and normal QSG-7701 cells.

BackgroundHNSCC is a heterogeneous disease, which arises from distinct anatomic subsites, associates with various risk factors and possesses diverse molecular pathological features. Generally, HNSCC is considered as an immunosuppressive disease, characterized by abnormal tumor immune microenvironment. The TNF family plays a crucial role in the survival, proliferation, differentiation, and effector functions in both immune and non-immune cells. However, the expression patterns of TNF in HNSCC remains to be systematically analyzed.MethodsWe downloaded transcriptional profile data of HNSCC from TCGA and GEO datasets. Unsupervised clustering methods were used to identify different TNF patterns and classify patients for further analysis. PCA was conducted to construct a TNF relevant score, which we called risk score.ResultsIn this study, we systematically evaluated the patterns of TNF family and tumor immune microenvironment characteristics of HNSCC patients by clustering the expression of 46 members of TNF family. We identified two subtypes with distinct clinical and immune characteristics in HNSCC and constructed a risk scoring system based on the expression profile of TNF family genes.ConclusionRisk score serves as a reliable predictor of overall survival, clinical characteristics, and immune cell infiltration, which has the potential to be applied as a valuable biomarker for HNSCC immunotherapy.

Background: Although some observational studies have shown that physical activity may have a positive relationship with cardiovascular diseases, the causal effect remains uncertain. We conducted a Mendelian randomization (MR) study to identify the potential causal effect between physical activity and cardiovascular diseases.Methods: Summary statistics of genome-wide association studies on four physical activity phenotypes and cardiovascular diseases were utilized. MR analysis was performed using inverse-variance weighted (IVW) and multivariable MR. Multiple sensitivity analysis was further conducted to identify the robustness of our results.Results: Genetically predicted self-reported vigorous physical activity (VPA) was significantly associated with lower risk of myocardial infarction (IVW OR: 0.24, 95% CI: 0.08–0.68, p-value: 0.007). Additionally, the causal effect of VPA with myocardial infarction was robust after adjusting for several cardiovascular risk factors through using the multivariable MR. There were no apparent causal associations between physical activity with other cardiovascular diseases. Results were consistent with the sensitivity analysis.Conclusion: The present study supports a protective role of self-reported vigorous physical activity in the initiation of myocardial infarction and highlights the importance of activity levels of physical activity. Further studies are required to elucidate the potential biological pathways of physical activity with cardiovascular diseases.