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OBJECTIVE: To access the efficacy and safety of the double-ProGlide technique for the femoral vein access-site closure in cryoballoon ablation with uninterrupted oral anticoagulants (OAC), and its impact on the electrophysiology laboratory time as well as hospital stay after the procedure in this observational study. METHODS: Patients with atrial fibrillation undergoing cryoballoon ablation with uninterrupted OAC at Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China from May 2019 to May 2021 were enrolled in this study. From October 2020, double-ProGlide technique was consistently used for hemostasis (ProGlide group), and before that conventional manual compression was utilized (manual compression group). The occurrence of vascular and groin complications was accessed during the hospital stay and until the three-month follow-up. RESULTS: A total of 140 participants (69.30% of male, mean age: 59.21 ± 10.29 years) were evaluated, 70 participants being in each group. Immediate hemostasis was achieved in all the patients with ProGlide closure. No major vascular complications were found in the ProGlide group while two major vascular complications were occurred in the manual compression group. The incidence of any groin complication was obviously higher in subjects with manual compression than patients with ProGlide devices (15.71% vs. 2.86%, P = 0.009). In addition, compared with the manual compression group, the ProGlide group was associated with significantly shorter total time in the electrophysiology laboratory [112.0 (93.3–128.8) min vs. 123.5 (107.3–158.3) min, P = 0.006], time from sheath removal until venous site hemostasis [3.8 (3.4–4.2) min vs. 8.0 (7.6–8.5) min, P < 0.001], bed rest time [8.0 (7.6–8.0) h vs. 14.1 (12.0–17.6) h, P < 0.001] and hospital stay after the procedure [13.8 (12.5–17.8) h vs. 38.0 (21.5–41.0) h, P < 0.001]. CONCLUSIONS: Utilization of the double-ProGlide technique for hemostasis after cryoballoon ablation with uninterrupted OAC is feasible and safe, which has the clinical benefit in reducing the total electrophysiology laboratory time and the hospital stay length after the procedure.

Hai-Liang Yuan,1 Xian Zhang,2 Dong-Zhu Peng,1 Guan-Bin Lin,1 Hui-Hui Li,1 Fang-Xian Li,1 Jing-Jing Lu,1 Wei-Wei Chu1 1Department of Gastroenterology, Beilun Branch of the First Affiliated Hospital of Zhejiang University, Ningbo, Zhejiang, People’s Republic of China; 2Department of Endocrinology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Wei-Wei Chu, Department of Gastroenterology, Beilun Branch of the First Affiliated Hospital of Zhejiang University, No. 1288, Lushan East Road, Beilun District, Ningbo, Zhejiang Province, People’s Republic of China, Tel +86-134 56123811, Fax +86- 574 86100266, Email chuweiwei920@163.comPurpose: Constipation is a common complication of diabetic patients, which has a negative impact on their own health. This study aims to establish and internally validate the risk nomogram of constipation in patients with type 2 diabetes mellitus (T2DM) and to test its predictive ability.Patients and Methods: This retrospective study included 746 patients with T2DM at two medical centers. Among the 746 patients with T2DM, 382 and 163 patients in the Beilun branch of the First Affiliated Hospital of Zhejiang University were enrolled in the training cohort and the validation cohort, respectively. A total of 201 patients in the First Affiliated Hospital of Nanchang University were enrolled in external validation cohorts. The nomogram was established by optimizing the predictive factors through univariate and multivariable logistic regression analysis. The prediction performance of the nomogram was measured by the area under the receiver operating characteristic curve (AUROC), the calibration curve, and the decision curve analysis (DCA). Furthermore, its applicability was internally and independently validated.Results: Among the 16 clinicopathological features, five variables were selected to develop the prediction nomogram, including age, glycated hemoglobin (HbA1c), calcium, anxiety, and regular exercise. The nomogram revealed good discrimination with an area under the receiver operating characteristic curve (AUROC) of 0.908 (95% CI = 0.865– 0.950) in the training cohort, and 0.867 (95% CI = 0.790– 0.944) and 0.816 (95% CI = 0.751– 0.881) in the internal and external validation cohorts, respectively. The calibration curve presented a good agreement between the prediction by the nomogram and the actual observation. The DCA revealed that the nomogram had a high clinical application value.Conclusion: In this study, the nomogram for pretreatment risk management of constipation in patients with T2DM was developed which could help in making timely personalized clinical decisions for different risk populations.Keywords: constipation, type 2 diabetes mellitus, model, nomogram, prediction

In this paper, the following work is done: The application of genetic algorithms in games is discussed, and based on reading relevant references, the design of the algorithm is explained in detail; the current situation of combining algorithms with games is analyzed; the novelty of combining algorithms with games is explained; and the paper concludes with a summary of the considerations and the scope of application of using genetic algorithms in games. The aim of the study is to reduce the cost of consultation and understanding for game makers and researchers, allowing them to focus on the specific application of genetic algorithms in games to make the AI of the game evolvable and intelligent to the level of the players.

Xiao-Hui Zhao, Hai-Liang Li, Chen-Yang Guo, Quan-Jun Yao, Wei-Li Xia, Hong-Tao Hu Department of Minimally-Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou City, People’s Republic of ChinaCorrespondence: Hong-Tao Hu, Department of Minimally-Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan Province, 450008, People’s Republic of China, Tel +86-135-9264-6376, Email huhongtaogy@163.comBackground and Objectives: Trans-arterial chemoembolization (TACE) combined with 125I seed implantation is an effective treatment modality for hepatocellular carcinoma (HCC) with a portal vein tumor thrombus (PVTT). However, there are no reports on the effectiveness of radiofrequency ablation (RFA) after downstaging in such patients. This study aimed to investigate the efficacy and safety of TACE in combination with 125I seed implantation and RFA for the treatment of HCC complicated by PVTT.Methods: 49 patients diagnosed with HCC with PVTT between February 2015 and December 2016 were included. All patients were clinically or pathologically diagnosed with advanced HCC, intrahepatic lesions ≤ 3, and a single tumor diameter ≤ 70 mm, total diameter ≤ 100 mm. PVTT was limited to the unilateral portal vein branches. All the patients were treated with TACE combined with PVTT 125I seed implantation. The size and activity of intrahepatic lesions and PVTT were evaluated using enhanced magnetic resonance imaging 3 months after treatment, and other indicators were combined to determine the success of downstaging.Results: A total of 31 patients were successfully downstaged, while 18 patients did not achieve downstaging owing to the progression of intrahepatic lesions or PVTT activity/progression, the success rate of the downstaging was 63.27%. All 31 patients with successful downstaging underwent RFA for intrahepatic lesions. The 1-, 2-, and 3-year survival rates were 90.3%, 80.6%, and 48.4%, respectively. The median overall survival was 36 months (95% CI: 24.7– 47.3).Conclusion: 125I seed implantation in combination with TACE can effectively inactivate PVTT and achieve downstaging. Furthermore, the addition of RFA can significantly improve patient survival.Keywords: hepatocellular carcinoma, portal vein tumor thrombus, 125I seed, transcatheter arterial chemoembolization, downstaging treatment

Lithium-rich manganese-based oxides (Li1.2Mn0.54Ni0.13Co0.13O2, LMNCO) as cathode materials were prepared by the sol-gel method. Then, LMNCO was coated with γ-basic manganese oxide (γ-MnOOH) to form the composite cathodes. Through the structural characterization and performance test, it is found that the composite cathode with 10% γ-MnOOH coating exhibits the best electrochemical performance. After 50 cycles at 0.1 C (1 C = 200 mA g-1), the specific discharge capacity is 264.4 mAh g-1 with capacity retention of 96.1%. Even at a high current density of 1C, its discharge capacity reaches up to 200.5 mAh g-1 after 30 cycles, which suggests that surface coating of γ-MnOOH is an effective strategy for further enhancing the electrochemical performance of LMNCO.

Aim: A blockchain provides data consistency and builds a fair mining environment for a network by using a consensus mechanism such as proof of work (PoW) and proof of stake. However, selfish mining is a well-known mining attack. It can reduce the fairness and destabilize the network, especially for a PoW-based blockchain. Therefore, in this paper, we propose a new approach, named the adaptive mining difficulty adjustment protocol, which can deter a selfish attack. Methods: We propose using the unit profit as an improved version of the relative revenue, because it is more flexible for calculating the miners’ profits in different periods and can be used to analyze repeated mining games. Based on the unit profit, we propose using the adaptive mining-difficulty adjustment protocol to reduce an attacker’s profit. Our protocol evaluates the effective hash power in a network more accurately and corrects the mining difficulty. Moreover, we introduce the discount factor and model the long-term profit to analyze the impact of a miner’s patience on its future profit. Results: We used an open-source simulator to simulate the competition between a selfish miner and an honest miner and determined their profits under different protocols. Our experimental results show that our protocol can effectively raise the attack threshold, but it reduces the total network profit if the attacker still attacks. However, the long-term profit model shows that a more patient attacker needs to invest more hash power and pay increased mining costs to maintain its attack. Conclusion: We conclude that, under our protocol, selfish attackers will tend to become honest miners if their hash power does not exceed the threshold, which means that our protocol can effectively deter selfish attacks and some variants of selfish attacks. Briefly, our protocol can correct the mining difficulty and leads to a more stable and fairer mining environment for a PoW-based blockchain.

The PedsQL 3.0 End Stage Renal Disease (ESRD) Module is a well-accepted instrument internationally but it is not available in the local language. We aimed to validate the Bahasa Melayu (Malay language) version and determine the health-related quality of life (HRQoL) scores amongst children with CKD in Malaysia.The source questionnaire in English was translated into Bahasa Melayu. Linguistic validation guidelines by the MAPI Research Institute were followed. The already validated Bahasa Melayu PedsQL 4.0 Generic Core Scales was used for comparison. Sociodemographic data were collected during the interview. Statistical analyses were performed using SPSS version 25.0.Sixty-nine children aged 8 to 18 with CKD stages 4 and 5, with or without dialysis, and their caregivers were recruited. Mean age was 12.62 ± 2.77 (SD). Evaluation of the PedsQL 3.0 ESRD Module Bahasa Melayu version demonstrated good internal consistency (Cronbach alpha 0.82). There was good agreement between child self-report and parent proxy report in all domains; average intraclass correlation coefficients (ICC) were 0.78, 95% CI (0.71, 0.84). Scores obtained from Generic 4.0 scales correlated with the disease-specific ESRD 3.0 scale, Spearman's rho = 0.32, p = 0.007. The Kruskal-Wallis H test indicated that there were no significant differences between stages of CKD and their respective mean HRQoL score, χThe PedsQL 3.0 ESRD Module Bahasa Melayu version is a reliable and feasible tool for cross-cultural adaptation. A longer prospective study may help better illustrate the quality of life in this group of children.

Hops, the dried female clusters from Humulus lupulus L., have traditionally been used as folk medicines for treating insomnia, neuralgia, and menopausal disorders. However, its pharmacological action on iron overload induced nerve damage has not been investigated. This study aims to evaluate the protective effects of hops extract (HLE) and its active constituent xanthohumol (XAN) on nerve injury induced by iron overload in vivo and in vitro, and to explore its underlying mechanism. The results showed that HLE and XAN significantly improved the memory impairment of iron overload mice, mainly manifested as shortened latency time, increased crossing platform times and spontaneous alternation ratio, and increased the expression of related proteins. Additionally, HLE and XAN significantly increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities, and remarkably decreased malondialdehyde (MDA) level in hippocampus. Also, HLE and XAN apparently reduced reactive oxygen species (ROS) content of PC12 cells induced by iron dextran (ID), and improved the oxidative stress level. Moreover, HLE and XAN significantly upregulated the expression of nuclear factor E2-related factor (Nrf2), NAD(P)H quinone oxidoreductase (NQO1), heme oxygenase-1 (HO-1), SOD, phosphorylated AKT (p-AKT), and phosphorylated GSK3β (p-GSK3β) both in hippocampus and PC12 cells. These findings demonstrated the protective effect of HLE and XAN against iron-induced memory impairment, which is attributed to its antioxidant profile by activation of AKT/GSK3β and Nrf2/NQO1 pathways. Also, it was suggested that hops could be a potential candidate for iron overload-related neurological diseases treatment.

It is urgent to identify the development of the Corona Virus Disease 2019 (COVID-19) in countries around the world. Therefore, visualization is particularly important for monitoring the COVID-19. In this paper, we visually analyze the real-time data of COVID-19, to monitor the trend of COVID-19 in the form of charts. At present, the COVID-19 is still spreading. However, in the existing works, the visualization of COVID-19 data has not established a certain connection between the forecast of the epidemic data and the forecast of the epidemic. To better predict the development trend of the COVID-19, we establish a logistic growth model to predict the development of the epidemic by using the same data source in the visualization. However, the logistic growth model only has a single feature. To predict the epidemic situation in an all-round way, we also predict the development trend of the COVID-19 based on the Susceptible Exposed Infected Removed epidemic model with multiple features. We fit the data predicted by the model to the real COVID-19 epidemic data. The simulation results show that the predicted epidemic development trend is consistent with the actual epidemic development trend, and our model performs well in predicting the trend of COVID-19.

CELSR1 gene, encoding cadherin EGF LAG seven-pass G-type receptor 1, is mainly expressed in neural stem cells during the embryonic period. It plays an important role in neurodevelopment. However, the relationship between CELSR1 and disease of the central nervous system has not been defined. In this study, we performed trios-based whole-exome sequencing in a cohort of 356 unrelated cases with partial epilepsy without acquired causes and identified CELSR1 variants in six unrelated cases. The variants included one de novo heterozygous nonsense variant, one de novo heterozygous missense variant, and four compound heterozygous missense variants that had one variant was located in the extracellular region and the other in the cytoplasm. The patients with biallelic variants presented severe epileptic phenotypes, whereas those with heterozygous variants were associated with a mild epileptic phenotype of benign epilepsy with centrotemporal spikes (BECTS). These variants had no or low allele frequency in the gnomAD database. The frequencies of the CELSR1 variants in this cohort were significantly higher than those in the control populations. The evidence from ClinGen Clinical-Validity Framework suggested a strong association between CELSR1 variants and epilepsy. These findings provide evidence that CELSR1 is potentially a candidate pathogenic gene of partial epilepsy of childhood.

RNase H1-dependent phosphorothioate oligonucleotides (PS-ASOs) have been developed to treat various diseases through specific degradation of target RNAs. Although many factors or features of RNA and PS-ASOs have been demonstrated to affect antisense activity of PS-ASOs, little is known regarding the roles of RNase H1-associated proteins in PS-ASO performance. In this study, we report that two nucleolar proteins, NAT10 and DDX21, interact with RNase H1 and affect the potency and safety of PS-ASOs. The interactions of these two proteins with RNase H1 were determined using BioID proximity labeling in cells and confirmed biochemically. Reduction of NAT10 and DDX21 decreased PS-ASO activity in cells, and purified NAT10 and DDX21 proteins enhanced RNase H1 cleavage rates, indicating that these two proteins facilitate RNase H1 endoribonuclease activity. Consistently, reduction of these proteins increased the levels of R-loops, and impaired pre-rRNA processing. In addition, reduction of the two proteins increased the cytotoxicity of toxic PS-ASOs, and treatment of toxic PS-ASOs also altered the localization of these proteins. Together, this study shows for the first time that NAT10 and DDX21 interact with RNase H1 protein and enhance its enzymatic activity, contributing to the potency and safety of PS-ASOs.

Cancer immunotherapy has significantly improved patient survival. Yet, half of patients do not respond to immunotherapy. Gut microbiomes have been linked to clinical responsiveness of melanoma patients on immunotherapies; however, different taxa have been associated with response status with implicated taxa inconsistent between studies. We used a tumor-agnostic approach to find common gut microbiome features of response among immunotherapy patients with different advanced stage cancers. A combined meta-analysis of 16S rRNA gene sequencing data from our mixed tumor cohort and three published immunotherapy gut microbiome datasets from different melanoma patient cohorts found certain gut bacterial taxa correlated with immunotherapy response status regardless of tumor type. Using multivariate

In this paper, we study certain determinants over finite fields. Let $\mathbb{F}_q$ be the finite field of $q$ elements and let $a_1,a_2,\cdots,a_{q-1}$ be all nonzero elements of $\mathbb{F}_q$. Let $T_q=\left[\frac{1}{a_i^2-a_ia_j+a_j^2}\right]_{1\le i,j\le q-1}$ be a matrix over $\mathbb{F}_q$. We obtain the explicit value of $\det T_q$. Also, as a consequence of our result, we confirm a conjecture posed by Zhi-Wei Sun.

Non-CpG PS-ASOs can activate the innate immune system, leading to undesired outcomes. This response can vary—in part—as a function of 2′modifications and sequence. Here we investigated the molecular steps involved in the varied effects of PS-ASOs on the innate immune system. We found that pro-inflammatory PS-ASOs require TLR9 signaling based on the experimental systems used. However, the innate immunity of PS-ASOs does not correlate with their binding affinity with TLR9. Furthermore, the innate immune responses of pro-inflammatory PS-ASOs were reduced by coincubation with non-inflammatory PS-ASOs, suggesting that both pro-inflammatory and non-inflammatory PS-ASOs can interact with TLR9. We show that the kinetics of the PS-ASO innate immune responses can vary, which we speculate may be due to the existence of alternative PS-ASO binding sites on TLR9, leading to full, partial, or no activation of the pathway. In addition, we found that several extracellular proteins, including HMGB1, S100A8 and HRG, enhance the innate immune responses of PS-ASOs. Reduction of the binding affinity by reducing the PS content of PS-ASOs decreased innate immune responses, suggesting that PS-ASO–protein complexes may be sensed by TLR9. These findings thus provide critical information concerning how PS-ASOs can interact with and activate TLR9.

We herein report a Ni-catalyzed three-component cross-electrophile coupling of 1,3-dienes with aldehydes and aryl bromides using manganese metal as the reducing agent. This efficient protocol accomplishes dicarbofunctionalization of 1,3-dienes to synthesize diverse structural 1,4-disubstituted homoallylic alcohols by forming two new C-C bonds in one time. Mechanistic study suggests that an allyl-nickel(I) species is involved in the catalytic cycle.

Phosphorothioate modified antisense oligonucleotides (PS-ASOs) can reduce gene expression through hybridization to target RNAs and subsequent cleavage by RNase H1. Target reduction through this mechanism is influenced by numerous features of the RNA, which modulate PS-ASO binding affinities to the RNA target, and how the PS-ASO-RNA hybrid is recognized by RNase H1 for RNA cleavage. Endogenous RNAs are frequently chemically modified, which can regulate intra- and intermolecular interactions of the RNA. The effects of PS-ASO modifications on antisense activity have been well studied; however, much less is known regarding the effects of RNA modifications on PS-ASO hybridization and RNase H1 cleavage activity. Here, we determine the effects of three different RNA modifications on PS-ASO binding and antisense activity in recombinant and cell-based systems. Some RNA modifications can reduce PS-ASO hybridization, the cleavage activity of RNase H1, or both, while other modifications had minimal effects on PS-ASO function. In addition to these direct effects, RNA modifications can also change the RNA structure, which may affect PS-ASO accessibility in a cellular context. Our results elucidate the effects of three prevalent RNA modifications on PS-ASO-mediated RNase H1 cleavage activity, and such findings will help improve PS-ASO target site selection.

Basket trial design

Shortening of the 3′ untranslated regions (3′UTR) of mRNA is an important mechanism for oncogene activation. However, 3′UTR alteration events, their pathologic functions, and underlying mechanisms in human urothelial carcinoma of the bladder (UCB) are not clear. Here, we combine RNA sequencing, bioinformatics, and clinical studies in two independent cohorts of patients with UCB to identify a novel RAC1 shorter 3′UTR isoform that is frequently expressed in UCB and is critical in the tumorigenesis and acquisition of a poor prognostic phenotype in patients. Short 3′UTR isoform of RAC1 substantially upregulated RAC1 expression by escaping from miRNA-targeted repression and played an essential oncogenic role in UCB pathogenesis. An important cleavage/polyadenylation factor, cleavage stimulation factor 2 (CSTF2), induced 3′UTR shortening of RAC1 in UCB by mediating slow transcriptional elongation at RAC1. Cotranscriptional recruitment of CSTF2 on the GUAAU motif at proximal polyadenylation site of RAC1 attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation. CSTF2 regulated the tumorigenic functions of the shorter RAC1 isoform in UCB cells, enhancing cell proliferation, migration, and invasion. The combination of high expression of CSTF2 and high usage of RAC1 short-3′UTR isoform may be used as a powerful biomarker to predict poor prognosis in UCB. Our findings also suggest a CSTF2-regulated RAC1-3′UTR shortening program as an exploitable therapeutic strategy for patients with UCB.Significance: These findings demonstrate that the short isoform of RAC1 is critical in UCB tumorigenesis and may have implications for developing new therapeutic strategies to treat this disease. Cancer Res; 78(20); 5848–62. ©2018 AACR.

Serious treatment-related adverse events

Immune-related adverse events

Purpose:Blockade of immune checkpoint and angiogenesis is an effective treatment strategy for advanced or metastatic renal cell carcinoma (RCC). We report the results of camrelizumab plus famitinib in the RCC cohort of an open-label, multicenter, phase II basket study.Patients and Methods:Eligible patients were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1.Results:Totally, 38 patients were recruited, including 13 (34.2%) treatment-naïve and 25 (65.8%) previously treated patients. With a median duration from enrollment to data cutoff of 16.5 months (range, 6.1–20.4), 23 patients achieved a confirmed objective response, and ORR was 60.5% [95% confidence interval (CI), 43.4–76.0]. Responses in 18 (78.3%) responders were still ongoing, and Kaplan–Meier estimated median duration of response had not been reached yet (range, 1.0+–14.8+ months). Median progression-free survival (PFS) was 14.6 months (95% CI, 6.2–not reached). ORR was 84.6% (95% CI, 54.6–98.1) in treatment-naïve patients and 48.0% (95% CI, 27.8–68.7) in pretreated patients; median PFS had not been reached and was 13.4 months (95% CI, 4.1–not reached), respectively. Most common grade 3 or 4 treatment-related adverse events included proteinuria (18.4%), hypertension (18.4%), decreased neutrophil count (13.2%), palmar-plantar erythrodysesthesia syndrome (10.5%), and hypertriglyceridemia (10.5%). No treatment-related deaths occurred, and no new safety signals were observed.Conclusions:Camrelizumab plus famitinib showed potent and enduring antitumor activity in patients with advanced or metastatic RCC, both in treatment-naïve and previously treated population.

Treatment-related adverse events leading to dose modification

Supplementary Figures + Supplementary Datas