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Yuhong Tang,1,* Jun Cao,1,* Rui Peng,1 Xingkang Mao,1 Bingbing Su,1 Hao Tang,1 Daoyuan Tu,1 Jie Zhou,1 Guoqing Jiang,1 Shengjie Jin,1 Qian Wang,1 Chen Zhang,2 Renjie Liu,1 Chi Zhang,1,3 Dousheng Bai1,3 1Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China; 2The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 3General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dousheng Bai; Chi Zhang, Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Road, Yangzhou, 225000, People’s Republic of China, Email drbaidousheng@yzu.edu.cn; zc17212850@163.comIntroduction: Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them.Methods: A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein–protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments.Results: GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage.Conclusion: A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.Keywords: ubiquitination, growth factor receptor-binding protein 2, liver cancer, tumour-infiltrating immune cells

Xiaomin Ren,1 Dingqun Bai,2 Yuan Zhang,3 Haidan Lin,2 Shu Zhang,2 Danyang Li,1 Hui Wei,1 Shouwei Yue1 1Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Physical Medicine & Rehabilitation, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Shouwei Yue; Hui Wei, Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China, Tel +18560086655 ; +18560083563, Fax +531 82166115, Email shouweiy@sdu.edu.cn; 83926275@qq.comBackground and Purpose: Epidemiological studies on low back pain in residents living in mountainous areas are scarce. The study was aimed at investigating the prevalence and associated factors of low back pain in Chongqing, relatively impoverished mountainous areas of China.Materials and Methods: This was a cross-sectional study conducted at selected community or village health service centers in Chongqing over a 2-month period (May 2021 to June 2021), which included adults of Chongqing aged > 18 years with or without low back pain (N=1820) chosen by stratified, cluster-sampling. Associated factors of low back pain including sociodemographic characteristics, lifestyle, and occupational features were collected, along with medical history, Oswestry Disability Questionnaire (ODI), and Numerical Rating Scale (NRS) of patients with low back pain, and carried out for at least 20 minutes per respondent. Univariate and multivariate logistic regression models were utilized for statistical analysis.Results: Overall, 30.5% of 1704 respondents presented with low back pain, with 26.3% living in flat areas and 35.6% in mountainous areas. The associated factors of low back pain were mountainous area residence (OR 1.4, 95% CI 1.1– 1.8), advanced age (OR 1.8, 95% CI 1.3– 2.5 for those aged 45– 59 years, OR 2.3, 95% CI 1.6– 3.4 for those aged 60– 74 years, and OR 2.1, 95% CI 1.2– 3.6 for those aged ≥ 75 years), married or remarried (OR 1.9, 95% CI 1.1– 3.2), divorced or widowed (OR 2.7, 95% CI 14– 5.4), moderate labor intensity (OR 1.4, 95% CI 1.1– 1.8), frequent stoop (OR 1.6, 95% CI 1.1– 2.4), and depressed mood (OR 1.6, 95% CI 1.2– 2.1). Residents in the mountainous areas had a higher score on Oswestry Disability Questionnaire (8.3 [SD 6.3] vs 6.2 [SD 4.3]) than those in flat areas.Conclusion: Mountainous areas in Chongqing had higher prevalence of low back pain as 35.6%, compared with 26.3% in flat areas, with more severe dysfunction in low back pain patients. Multifactorial analysis found that the factors associated with low back pain in Chongqing residents included mountain residence, labor intensity, stoop, psychological factors and frequency of exercise.Keywords: low back pain, prevalence, associated factors, China

Xu Chen,1,2,* Xuan Hou,3,* Daisy Bai,4 Rosanne Lane,5 Chong Zhang,6 Carla Canuso,7 Gang Wang,1,2 Dong-Jing Fu7 1The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of China; 3Clinical Development, Janssen China Research & Development, Shanghai, People’s Republic of China; 4Statistics, Janssen China Research & Development, Shanghai, People’s Republic of China; 5Statistics, Janssen US Research & Development, Titusville, NJ, USA; 6Clinical Pharmacology, Janssen China Research & Development, Shanghai, People’s Republic of China; 7Neuroscience, Janssen US Research & Development, Titusville, NJ, USA*These authors contributed equally to this workCorrespondence: Gang Wang, The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital and Advanced Innovation Center for Human Brain Protection, Capital Medical University, 5 Ankang Hu Tong, Beitaipingzhuang, Xicheng District, Beijing, 100035, People’s Republic of China, Tel +86 010-58303189, Email gangwangdocvip@163.com Dong-Jing Fu, Neuroscience, Janssen US Research & Development, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA, Tel +1 609 730 4312, Email dfu@its.jnj.comPurpose: This Phase 3, multicenter study (NCT03434041) was conducted in primarily Chinese patients with treatment-resistant depression (TRD) to support the registration of esketamine nasal spray in China.Patients and Methods: This randomized, double-blind, active-controlled study was conducted in China and the United States (US) in patients with TRD (single or recurrent episode). Eligible patients were randomized 1:1 to receive intranasal esketamine or matching placebo, each in conjunction with a newly initiated oral antidepressant (AD; duloxetine, escitalopram, sertraline, and venlafaxine extended release) (ie, esketamine plus AD or AD plus placebo). The primary endpoint, change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Day 28, was analyzed using a mixed-effects model for repeated measures. Secondary endpoints including safety were also evaluated.Results: Of 252 randomized patients (China, 224; US, 28), 214 completed the double-blind treatment phase. The difference between treatment groups at Day 28 was not statistically significant (difference in least-square means [95% CI]: − 2.0 [− 4.64, 0.55]; 2-sided p = 0.123). However, esketamine plus AD demonstrated a clinically meaningful treatment difference compared with AD plus placebo in MADRS total score at 24 hours after first dose for the study overall population and China sub-population (difference in least-square mean [95% CI]: − 3.3 [− 5.33, − 1.33] and − 2.6 [− 4.64, − 0.60], respectively). No new safety signals were observed.Conclusion: Esketamine plus AD was not statistically superior to AD plus placebo in improving depressive symptoms in TRD patients at Day 28. Rapid reduction in depressive symptoms within 24 hours was observed for TRD patients treated with esketamine plus AD in the overall population and China sub-population. Safety was consistent with the established safety profile of esketamine.Keywords: intranasal, major depressive disorder, MDD, TRD

Jun Luo,1 Qing Liu,2 Zhujizhaba Gama,3 Deji Gesang,3 Ying Zhu,2 Lining Yang,2 Dingqun Bai,2 Qinghua Zhao,4 Mingzhao Xiao1 1Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Rehabilitation Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Rehabilitation Medicine, Tibet Autonomous Region People’s Hospital, Tibet, People’s Republic of China; 4Department of Nursing, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Mingzhao Xiao, 1st Youyi Road, Chongqing, 400016, People’s Republic of China, Tel +86 13608399433, Email xmz.2004@163.comPurpose: To investigate the current situation of assistive device (AD) usage among seniors in Tibet, China, and explore its influencing factors.Methods: A mixed-methods design was used. Cognition, attitude, behavior, and preference toward ADs were assessed by a self-designed questionnaire. Additionally, participants responded to the open-ended questions. Anderson’s behavior model analyzed the impacts of the prerequisite factors, enabling factors, and demand factors influencing the utilization of ADs by Tibetan seniors.Results: Of the 211 Tibetan seniors, 149 (70.6%) Tibetan seniors expressed the willingness to utilize ADs. Binary Logistic regression analysis showed that one prerequisite factor: age; one enabling factor: care situation, and one demand factor: dysfunctional condition were factors influencing the utilization of ADs. Qualitative comments described: psychological, physical environment, and social support factors were the main influencing factors.Conclusion: This study presents the current situation to utilize ADs by Tibetan seniors on the Qinghai-Tibet Plateau, incorporates Anderson’s behavioral model for quantitative analysis, and combines qualitative research to explore the facilitating and hindering factors, to provide reference and basis for the development of ADs for seniors and policy formulation. The sample size of this study is relatively small and limited to ethnic groups, and we plan to increase the sample size and include more ethnic groups in the future study.Keywords: assistive devices, seniors, Qinghai-Tibet Plateau, mixed-methods research

Ning Zhao,1,2 Yan Ma,3 Xiaoxue Liang,2 Yu Zhang,4 Dacheng Hong,5 Ying Wang,2 Dong Bai2 1Department of Pharmacy, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Formula-Syndrome Research Center, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 3Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; 4Beijing Xiuzheng Pharmaceutical Company, Beijing, People’s Republic of China; 5Department of Pharmaceutical Sciences, University of Vienna, Vienna, AustriaCorrespondence: Dong Bai, Tel +86 13552343081, Fax +8610 64089002, Email baidong2000@126.comPurpose: To study the efficacy of Qianshan Huoxue Gao (QS) in treating acute coronary syndrome (ACS) and to explore the mechanism of action from the perspective of intestinal flora regulation.Methods: Male Sprague–Dawley rats were divided into control, model, QS, and atorvastatin groups; except for the control group, rats underwent ligation of the left anterior descending branch of the coronary artery. Following treatment for 28 days, cardiac function was evaluated using an echocardiographic assay; ELISAs for serum creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-2 (IL-2), IL-6, and tumor necrosis factor-α (TNF-α); assessment of cardiac enzymes and inflammatory response; hematoxylin and eosin (HE) staining for histopathological changes in the heart, skin, and viscera; 16S rRNA gene sequencing for intestinal flora diversity and structural differences analysis; and we further investigated intestinal contents using metabolomics.Results: Compared with controls, CK-MB and cTnI were increased (P< 0.01); ejection factor and fractional shortening were decreased (P< 0.01); left ventricular internal end-diastolic dimension and left ventricular internal end-systolic dimension were increased (P< 0.01); and IL-2, IL-6, TNF-α, and hs-CRP were increased in the model group. Myocardial damage and inflammation were also observed by HE staining. QS improved these indexes, similar to the atorvastatin group; therefore, QS could effectively treat ACS. QS modulates the structure and abundance of the intestinal flora in ACS model rats, among which Bacteroides, Lactobacillus, and Rikenellaceae_RC9_gut_group are associated with cardiovascular disease. Metabolomics revealed that the intestinal metabolite content changed in ACS, with ethanolamine (EA) being the most relevant metabolite for ACS treatment by QS. EA was significantly positively correlated with Eubacterium xylanophilum group, Ruminococcus, unclassified f__Oscillospiraceae, Intestinimonas, Eubacterium siraeum group, Lachnospiraceae NK4A136 group, and norank f__Desulfovibrionaceae.Conclusion: QS can effectively treat ACS and can restore regulation of the intestinal flora. EA may be the primary metabolite of QS, exerting a therapeutic effect in ACS.Keywords: traditional Chinese medicine, acute coronary syndrome, 16S rRNA, ethanolamine, topical paste

Yue Zhu,1,* Rongjia Zhu,2,* Kun Liu,3,* Xin Li,1 Dezhong Chen,4 Dunyao Bai,5 Jieli Luo,5 Yixun Liu,6 Yan Zhang,7 Li Li,8 Junfang Hu,9 Dayong Xu,10 Yan Liu,10 Robert Chunhua Zhao2,11 1Stem Cell Lab, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, People’s Republic of China; 3Otorhinolaryngology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 5Molecular Laboratory, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 6Gonadal Biology Research Group, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China; 7National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China; 8The Ministry of Science and Education, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 9Department of Pharmacy, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 10Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 11School of Life Sciences, Shanghai University, Shanghai 200444, People’s Republic of China*These authors contributed equally to this workCorrespondence: Robert Chunhua ZhaoInstitute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, People’s Republic of ChinaEmail zhaochunhua@vip.163.comYan LiuStem Cell Lab, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of ChinaEmail liuyan@wust.edu.cnBackground: COVID-19 (coronavirus disease 2019) has become a global public health emergency since patients were first detected in Wuhan, China, in December 2019. Currently, there are no satisfying antiviral medications and vaccines available.Case Presentation: We reported the treatment process and clinical outcome of a 48-year-old man critically ill COVID-19 patient who received transfusion of allogenic human umbilical cord mesenchymal stem cells (UC-MSCs).Conclusions: We proposed that UC-MSC transfusion might be a new option for critically ill COVID-19. Although only one case we were shown, more similar clinical cases are inquired for further evidence providing the potential effectiveness of UC-MSC treatment.Keywords: COVID-19, UC-MSCs, critically ill, cell transplantation, case report

Lu Yuan,1 Qingzhao Li,1 Disi Bai,2 Xueliang Shang,2 Fen Hu,3 Zhenfei Chen,4 Tianyang An,5 Yajing Chen,6 Xiujun Zhang1 1College of Public Health; 2College of Psychology; 3College of Life Sciences; 4Environmental Monitoring Center Tang Shan, Tangshan 063210, Hebei, People’s Republic of China; 5College of Ji Tang; 6College of Pharmacy of North China University of Science and Technology, Tangshan 063210, Hebei, People’s Republic of ChinaCorrespondence: Xiujun ZhangNorth China University of Science and Technology, Bohai Avenue 21, Tangshan 063210, Hebei, People’s Republic of ChinaTel +86-315-3726335Fax +86-315-3726341Email xiujunzhang66@126.comDisi BaiCollege of Psychology, North China University of Science and Technology, Bohai Avenue 21, Tangshan 063000, People’s Republic of ChinaEmail baidisi@163.comPurpose: Lanthanum oxide (La2O3) nanoparticles (NPs) have been widely used in catalytic and photoelectric applications, but the reproductive toxicity is still unclear. This study evaluated the reproductive toxicity of two different-sized La2O3 particles in the testes.Materials and Methods: Fifty Kunming mice were randomly divided into five groups. Mice were treated with La2O3 NPs by repeated intragastric administration for 90 days (control, nano-sized with 5, 10, 50 mg/kg BW and micro-sized with 50 mg/kg BW). Mice in the control group were treated with de-ionised water without La2O3 NPs. Sperm parameters, testicular histopathology, TEM assessment, hormone assay and nuclear factor erythroid 2-related factor 2 (Nrf-2) pathway were performed and evaluated.Results: The body weight of mice treated with La2O3 NPs or not had no difference; sperm parameters and histological assessment showed that La2O3 NPs could induce reproductive toxicity in the testicle. Serum testosterone and gonadotropin-releasing hormone (GnRH) in the NH (nano-sized with 50 mg/kg BW) group were markedly decreased relative to control group, and an increase of luteinizing hormone (LH) in NH group was detected . Additionally, transmission electron microscopy revealed that the ultrastructural abnormalities induced by La2O3 NPs were more severe than La2O3 MPs in the testes. Furthermore, La2O3 NPs treatment inhibited the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), hemeoxygenase 1 (HO-1) and (glutathione peroxidase) GSH-Px, thus abrogating Nrf-2-mediated defense mechanisms against oxidative stress.Conclusions: The results of this study demonstrated that La2O3 NPs improved the spermatogenesis defects in mice. La2O3 NPs inhibited Nrf-2/ARE signaling pathway that resulted in apoptosis in the mice testes.Keywords: La2O3 nanoparticles, reproductive toxicity, inflammation, Nrf-2/ARE signaling pathway, apoptosis

The primary function of a network system is to gather information from the observation region and transmit it to the base station. The network life span and congestion are the two major concerns in wireless networks. To enhance the lifespan of the sensor system; multi-hopping has been proved as best in class. Congestion is an important factor to be taken, where multiple nodes forward data to one another in the process of communication. Hence to overcome the issue of congestion in WSN, we proposed a congestion detection and mitigation method along with the multi-hop concept. In this technique, we have considered different routes among communication units that were classified on distance, relative attainment rate (RAR) and node storage occupancy. A utility function (U) has been proposed and calculated using the above illustrated factors for every node that acts as a neighbour to the transmitting node. The Neighbour node with the highest U-valued will be considered as the packet forwarding node's next hop. In this manner, congestion-free nodes are selected for data transmission. [ABSTRACT FROM AUTHOR]

Ding-Ping Bai,1,* Xi-Feng Zhang,2,* Guo-Liang Zhang,3,4 Yi-Fan Huang,1 Sangiliyandi Gurunathan5 1Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, China; 2College of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, China; 3Dong-E-E-Jiao Co., Ltd., Shandong, China; 4National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Shandong, China; 5Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Republic of Korea *These authors contributed equally to this work Background: Zinc oxide nanoparticles (ZnO NPs) are frequently used in industrial products such as paint, surface coating, and cosmetics, and recently, they have been explored in biologic and biomedical applications. Therefore, this study was undertaken to investigate the effect of ZnO NPs on cytotoxicity, apoptosis, and autophagy in human ovarian cancer cells (SKOV3). Methods: ZnO NPs with a crystalline size of 20 nm were characterized with various analytical techniques, including ultraviolet-visible spectroscopy, X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, and atomic force microscopy. The cytotoxicity, apoptosis, and autophagy were examined using a series of cellular assays. Results: Exposure of cells to ZnO NPs resulted in a dose-dependent loss of cell viability, and the characteristic apoptotic features such as rounding and loss of adherence, enhanced reactive oxygen species generation, and loss of mitochondrial membrane potential were observed in the ZnO NP-treated cells. Furthermore, the cells treated with ZnO NPs showed significant double-strand DNA breaks, which are gained evidences from significant number of γ-H2AX and Rad51 expressed cells. ZnO NP-treated cells showed upregulation of p53 and LC3, indicating that ZnO NPs are able to upregulate apoptosis and autophagy. Finally, the Western blot analysis revealed upregulation of Bax, caspase-9, Rad51, γ-H2AX, p53, and LC3 and downregulation of Bcl-2. Conclusion: The study findings demonstrated that the ZnO NPs are able to induce significant cytotoxicity, apoptosis, and autophagy in human ovarian cells through reactive oxygen species generation and oxidative stress. Therefore, this study suggests that ZnO NPs are suitable and inherent anticancer agents due to their several favorable characteristic features including favorable band gap, electrostatic charge, surface chemistry, and potentiation of redox cycling cascades. Keywords: zinc oxide nanoparticles, human ovarian cancer cells SKOV3, mitochondrial membrane potential, apoptosis, DNA fragmentation, autophagy

Commercial hard-drive products utilizing perpendicular magnetic recording technology have recently been announced and introduced. In this paper, we review key magnetic materials characteristics and wafer process attributes in fabricating perpendicular write heads. It becomes increasingly important for write-head materials to possess not only high magnetic moment, but also optimal coercivity, remanence, anisotropy Hk, magnctostriction, and stress in order to meet head performance and reliability requirements. Advanced materials and film architectures discussed in this paper resulted in a significantly improved performance margin, including reduced pole erasure; hence enabling higher recording densities. Novel wafer-processing techniques are required for fabrication of 3-D pole features with controlled shape, and with critical dimensions of less than 150 nm. The advance in wafer process has been driven by rapidly decreasing trackwidth, as well as by the evolving head architecture from unshielded rectangular pole to shielded trapezoidal pole. Index Terms--High moment materials, lamination, perpendicular recording, perpendicular write head, pole erasure, wafer fabrication.