Chen Shigong,Founder of“TCM Orthodox School of External Medicine”

Chen Shigong,styled name Yuren,was also known by the literary name Ruoxu.Coming from Donghaichongchuan(present Nantong City,Jiangsu Province)he was a famous traditional Chinese medicine(TCM)specialist of external medicine of the Ming Dynasty(1368-1644).The Orthodox Lineage of External Medicine(Wai Ke Zheng Zong)written by him has been valued as the founder of the TCM Orthodox School of External Medicine.

The Making of a Health Profession:How Chinese Medicine Became a Nationally Registered Allied Health Profession in Australia

In 2012, traditional Chinese medicine(TCM) practitioners in Australia became nationally-registered allied health professionals in three categories: acupuncturist, Chinese herbal medicine practitioner, and Chinese herbal medicine dispenser. Australia was the first Western country to introduce national registration for Chinese medicine, followed by Portugal and, recently, New Zealand. The practice of TCM in Australia can be traced back to the beginning of Chinese immigration to Australia during the Victorian Gold Rush which began in the 1850s. The process which led to national registration commenced in the early 1970s with the establishment of the first acupuncture courses. Decades of gradual development of courses from unaccredited part-time diplomas to accredited bachelor degrees, and the development, by the profession, of national consensus on educational standards were essential elements in the process which led to registration. Professional associations, such as the Australian Acupuncture and Chinese Medicine Association Ltd.(AACMA), also developed a framework of professional selfregulation, including Codes of Ethics, Codes of Conduct, ongoing professional development requirements and Infection Control Guidelines, and provided leadership in the development of the profession. After decades of tribalism and division within the TCM profession, the National Academic Standards Committee brought almost all stakeholders together to reach a consensus on the Australian Guidelines for Traditional Chinese Medicine Education which were published by AACMA in 2001. Professional associations also collaborated on joint submissions to the government in support of registration, which was introduced first in the state of Victoria in 2000, and subsequently became national in 2012. Despite national registration, some barriers still remain, and professional associations continue to lobby the federal government for inclusion in Medicare, chronic disease management scheme, and Veterans Affairs.

Integrative analysis of bone-formation associated genes and immune cell infiltration in osteoporosis, and the prediction of active ingredients in targeted traditional Chinese medicine

Objective To explore the differential expression and mechanisms of bone formation-related genes in osteoporosis(OP)leveraging bioinformatics and machine learning methodologies;and to predict the active ingredients of targeted traditional Chinese medicine(TCM)herbs.Methods The Gene Expression Omnibus(GEO)and GeneCards databases were employed to conduct a comprehensive screening of genes and disease-associated loci pertinent to the pathogenesis of OP.The R package was utilized as the analytical tool for the identification of differentially expressed genes.Least absolute shrinkage and selection operator(LASSO)logis-tic regression analysis and support vector machine-recursive feature elimination(SVM-RFE)algorithm were employed in defining the genetic signature specific to OP.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses for the selected pivotal genes were conducted.The cell-type identification by estimating rela-tive subsets of RNA transcripts(CIBERSORT)algorithm was leveraged to examine the infiltra-tion patterns of immune cells;with Spearman’s rank correlation analysis utilized to assess the relationship between the expression levels of the genes and the presence of immune cells.Coremine Medical Database was used to screen out potential TCM herbs for the treatment of OP.Comparative Toxicogenomics Database(CTD)was employed for forecasting the TCM ac-tive ingredients targeting the key genes.AutoDock Vina 1.2.2 and GROMACS 2020 softwares were employed to conclude analysis results;facilitating the exploration of binding affinity and conformational dynamics between the TCM active ingredients and their biological targets.Results Ten genes were identified by intersecting the results from the GEO and GeneCards databases.Through the application of LASSO regression and SVM-RFE algorithm;four piv-otal genes were selected:coat protein(CP);kallikrein 3(KLK3);polymeraseγ(POLG);and transient receptor potential vanilloid 4(TRPV4).GO and KEGG pathway enrichment analy-ses revealed that these trait genes were predominantly engaged in the regulation of defense response activation;maintenance of cellular metal ion balance;and the production of chemokine ligand 5.These genes were notably associated with signaling pathways such as ferroptosis;porphyrin metabolism;and base excision repair.Immune infiltration analysis showed that key genes were highly correlated with immune cells.Macrophage M0;M1;M2;and resting dendritic cell were significantly different between groups;and there were signifi-cant differences between different groups(P<0.05).The interaction counts of resveratrol;curcumin;and quercetin with KLK3 were 7;3;and 2;respectively.It shows that the interac-tions of resveratrol;curcumin;and quercetin with KLK3 were substantial.Molecular docking and molecular dynamics simulations further confirmed the robust binding affinity of these bioactive compounds to the target genes.Conclusion Pivotal genes including CP;KLK3;POLG;and TRPV4;exhibited commendable significant prognostic value;and played a crucial role in the diagnostic assessment of OP.Resveratrol;curcumin;and quercetin;natural compounds found in TCM;showed promise in their potential to effectively modulate the bone-forming gene KLK3.This study provides a sci-entific basis for the interpretation of the pathogenesis of OP and the development of clinical drugs.

Constitution identification model in traditional Chinese medicine based on multiple features

Objective To construct a precise model for identifying traditional Chinese medicine(TCM)constitutions;thereby offering optimized guidance for clinical diagnosis and treatment plan-ning;and ultimately enhancing medical efficiency and treatment outcomes.Methods First;TCM full-body inspection data acquisition equipment was employed to col-lect full-body standing images of healthy people;from which the constitutions were labelled and defined in accordance with the Constitution in Chinese Medicine Questionnaire(CCMQ);and a dataset encompassing labelled constitutions was constructed.Second;heat-suppres-sion valve(HSV)color space and improved local binary patterns(LBP)algorithm were lever-aged for the extraction of features such as facial complexion and body shape.In addition;a dual-branch deep network was employed to collect deep features from the full-body standing images.Last;the random forest(RF)algorithm was utilized to learn the extracted multifea-tures;which were subsequently employed to establish a TCM constitution identification mod-el.Accuracy;precision;and F1 score were the three measures selected to assess the perfor-mance of the model.Results It was found that the accuracy;precision;and F1 score of the proposed model based on multifeatures for identifying TCM constitutions were 0.842;0.868;and 0.790;respectively.In comparison with the identification models that encompass a single feature;either a single facial complexion feature;a body shape feature;or deep features;the accuracy of the model that incorporating all the aforementioned features was elevated by 0.105;0.105;and 0.079;the precision increased by 0.164;0.164;and 0.211;and the F1 score rose by 0.071;0.071;and 0.084;respectively.Conclusion The research findings affirmed the viability of the proposed model;which incor-porated multifeatures;including the facial complexion feature;the body shape feature;and the deep feature.In addition;by employing the proposed model;the objectification and intel-ligence of identifying constitutions in TCM practices could be optimized.

The enlightenment of artificial intelligence large-scale model on the research of intelligent eye diagnosis in traditional Chinese medicine

Eye diagnosis is a method for inspecting systemic diseases and syndromes by observing the eyes.With the development of intelligent diagnosis in traditional Chinese medicine(TCM);artificial intelligence(AI)can improve the accuracy and efficiency of eye diagnosis.However;the research on intelligent eye diagnosis still faces many challenges;including the lack of standardized and precisely labeled data;multi-modal information analysis;and artificial in-telligence models for syndrome differentiation.The widespread application of AI models in medicine provides new insights and opportunities for the research of eye diagnosis intelli-gence.This study elaborates on the three key technologies of AI models in the intelligent ap-plication of TCM eye diagnosis;and explores the implications for the research of eye diagno-sis intelligence.First;a database concerning eye diagnosis was established based on self-su-pervised learning so as to solve the issues related to the lack of standardized and precisely la-beled data.Next;the cross-modal understanding and generation of deep neural network models to address the problem of lacking multi-modal information analysis.Last;the build-ing of data-driven models for eye diagnosis to tackle the issue of the absence of syndrome dif-ferentiation models.In summary;research on intelligent eye diagnosis has great potential to be applied the surge of AI model applications.

An interpretability model for syndrome differentiation of HBV-ACLF in traditional Chinese medicine using small-sample imbalanced data

Objective Clinical medical record data associated with hepatitis B-related acute-on-chronic liver failure(HBV-ACLF)generally have small sample sizes and a class imbalance.However,most machine learning models are designed based on balanced data and lack interpretability.This study aimed to propose a traditional Chinese medicine(TCM)diagnostic model for HBV-ACLF based on the TCM syndrome differentiation and treatment theory,which is clinically interpretable and highly accurate.Methods We collected medical records from 261 patients diagnosed with HBV-ACLF,including three syndromes:Yang jaundice(214 cases),Yang-Yin jaundice(41 cases),and Yin jaundice(6 cases).To avoid overfitting of the machine learning model,we excluded the cases of Yin jaundice.After data standardization and cleaning,we obtained 255 relevant medical records of Yang jaundice and Yang-Yin jaundice.To address the class imbalance issue,we employed the oversampling method and five machine learning methods,including logistic regression(LR),support vector machine(SVM),decision tree(DT),random forest(RF),and extreme gradient boosting(XGBoost)to construct the syndrome diagnosis models.This study used precision,F1 score,the area under the receiver operating characteristic(ROC)curve(AUC),and accuracy as model evaluation metrics.The model with the best classification performance was selected to extract the diagnostic rule,and its clinical significance was thoroughly analyzed.Furthermore,we proposed a novel multiple-round stable rule extraction(MRSRE)method to obtain a stable rule set of features that can exhibit the model’s clinical interpretability.Results The precision of the five machine learning models built using oversampled balanced data exceeded 0.90.Among these models,the accuracy of RF classification of syndrome types was 0.92,and the mean F1 scores of the two categories of Yang jaundice and Yang-Yin jaundice were 0.93 and 0.94,respectively.Additionally,the AUC was 0.98.The extraction rules of the RF syndrome differentiation model based on the MRSRE method revealed that the common features of Yang jaundice and Yang-Yin jaundice were wiry pulse,yellowing of the urine,skin,and eyes,normal tongue body,healthy sublingual vessel,nausea,oil loathing,and poor appetite.The main features of Yang jaundice were a red tongue body and thickened sublingual vessels,whereas those of Yang-Yin jaundice were a dark tongue body,pale white tongue body,white tongue coating,lack of strength,slippery pulse,light red tongue body,slimy tongue coating,and abdominal distension.This is aligned with the classifications made by TCM experts based on TCM syndrome differentiation and treatment theory.Conclusion Our model can be utilized for differentiating HBV-ACLF syndromes,which has the potential to be applied to generate other clinically interpretable models with high accuracy on clinical data characterized by small sample sizes and a class imbalance.

Clinical Observation of the Hot and Humid Compress Therapy of Traditional Chinese Medicine in the Treatment of Qi Stagnation and Blood Stasis Type of Lumbar Disc Herniation

Background: Although a number of studies have reported that the hot and humid compress from traditional Chinese medicine (TCM) is effective in treating lumbar disc herniation (LDH) with qi stagnation and blood stasis, clinical evidence is limited. Objective: The purpose of this study is to provide high-quality evidence to support the effectiveness of the traditional Chinese hot and humid compress in the treatment of LDH with qi stagnation and blood stasis. Methods: From October 2021 to November 2023, 86 patients with LDH of qi stagnation and blood stasis type were recruited in our hospital and divided into a control (n = 43) and an observation group (n = 43) according to the random number table method. The control group was given routine clinical treatment, and the observation group was treated with the hot and humid compress therapy for two weeks. The visual analogue scale (VAS) score, Japanese Orthopaedic Association (JOA) score, TCM syndrome score, serum interleukin-6 (IL-6), serum interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were observed and compared between the two groups before and after treatment, and the clinical efficacy of the two groups was evaluated. Results: After treatment, the VAS score, TCM symptom score, and serum IL-6, IL-1β, and TNF-α levels decreased in both groups (P P P P P Conclusions: The hot and humid compress of traditional Chinese medicine can effectively relieve pain, restore lumbar function, improve TCM syndromes, reduce the level of inflammatory factors, and have a curative effect in treating LDH.

Comprehensive effects of traditional Chinese medicine treatment on heart failure and changes in B-type natriuretic peptide levels: A meta-analysis

BACKGROUND Heart failure(HF),a common cardiovascular condition,is characterized by significant morbidity and mortality.While traditional Chinese medicine(TCM)is often used as a complementary approach in HF management,systematic evalua-tions of its impact on clinical outcomes,TCM syndrome scores,and B-type natriuretic peptide(BNP)levels are lacking.This study fills this gap through a comprehensive analysis of randomized controlled trials(RCTs)focusing on TCM for HF treatment.It encompasses an assessment of methodological quality,a meta-analysis,and an evaluation of evidence quality based on established standards.The results offer crucial insights into the potential advantages and constraints of TCM in HF management.RCTs on TCM for HF treatment published since the establishment of the database were searched in four Chinese and English databases,including China National Knowledge Infrastructure,Wanfang,VIP Information Chinese Science and Technology Journal,and PubMed.Methodological quality was assessed for the included studies with the Cochrane risk-of-bias assessment tool,and the meta-analysis and publication bias assessment was performed with the RevMan5.3 software.Finally,the quality of evidence was rated according to the GRADE criteria.RESULTS A total of 1098 RCTs were initially retrieved.After screening,16 RCTs were finally included in our study,which were published between 2020 and 2023.These RCTs involved 1660 HF patients,including 832 in the TCM group[TCM combined with conventional Western medicine(CMW)treatment]and 828 in the CWM group(CWM treatment).The course of treatments varied from 1 wk to 3 months.TCM syndrome differentiation was analyzed in 11 of the included RCTs.In all included RCTs,outcome indicators included comprehensive clinical outcomes,TCM syndrome scores,and BNP levels.The meta-analysis results showed significant differences between the TCM and CWM groups in terms of comprehensive clinical outcomes[risk ratio=-0.54;95%confidence interval(CI)=-0.61,-0.47;P<0.00001],TCM syndrome scores[weighted mean difference(WMD)=-142.07;95%CI=-147.56,-136.57;P<0.00001],and BNP levels(WMD=-142.07;95%CI=-147.56,-136.57;P<0.00001).According to the GRADE criteria,RCTs where"TCM improves clinical comprehensive outcomes"were rated as low-quality evidence,and RCTs where"TCM reduces TCM syndrome scores"or"TCM decreases BNP levels"were rated as medium-quality evidence.CONCLUSION TCM combined with CWM treatment effectively improves comprehensive clinical outcomes and diminishes TCM syndrome scores and BNP levels in HF patients.Given the low and medium quality of the included RCTs,the application of these results should be cautious.

海外中医药译写专著的“他塑”研究——以Between Heaven and Earth:A Guide to Chinese Medicine为例

基于亚马逊平台热销中医专著Between Heaven and Earth:A Guide to Chinese Medicine (《天地之间:中医指南》),举例分析其巧用“取象比类”思维、借用现代医学术语、采用图示辅助理解、创新中医文化表达的4种译写策略,并借助调查问卷佐证这4种译写策略的有效性与可取性,希望通过借鉴学习“他塑”,完善中医国际形象的“自塑”。同时检查“他塑”出现的文化误读,反观“自塑”的不足,从而调整中医传播策略,促进中医药文化的海外传播。

The Significance of Constructing TCM Psychosomatic Medicine from the Holistic View of the Unity of Nature and Man

With the development of medical technology, the problem of fragmentation of medical research has become increasingly prominent, and a series of iatrogenic diseases, drug-induced diseases and drug toxicity and side effects have resulted in an increase in the number of diseases. In the face of these problems, the medical concept has been re-examined and re-thought. The concept of the holistic view of the unity of nature and man in traditional Chinese medicine has certain enlightenment for dealing with the problems in the current medical development. Based on the holistic view of the unity of nature and man, the overall connection between human’s heart and body and nature is explained, and the further construction of TCM psychosomatic medicine is conducive to guiding the diagnosis and treatment of clinical diseases, and providing new enlightenment for the current medical concept thinking and clinical disease research.

中医药团体标准评价体系(SCORE-TCM)解读

本文全面解读了中医药团体标准评价体系(System of Consortium Standards Rating and Evaluation of Traditional Chinese Medicine,SCORE-TCM)。SCORE-TCM是结合定性与定量评价,全面评估中医药团体标准在制定主体、文本编写、技术内容、推广应用和实施效益等几方面特征的综合评价工具。文中详述了SCORE-TCM的构建目的、定义和构建过程,解释了评价指标体系中的各项指标,并对每项指标的评价材料进行介绍。本文旨在帮助中医药团体标准的制定者、第三方评价机构和其他相关方更好地理解SCORE-TCM各评价条目的含义,更有效地运用于中医药团体标准的自评价或第三方评价,SCORE-TCM将为《中医药团体标准管理办法》的贯彻实施,以及中医药团体标准的高质量发展提供技术支持。

基于SCORE-TCM的中医药团体标准抽样评价方案设计

目前,各社会团体积极参与中医药标准的制定和发布,特别是“十四五”以来,中医药团体标准化工作更是迎来了提质增效的关键阶段。深入评估社会团体发布的中医药标准质量,是推进中医药团体标准工作的关键环节和重点任务。前期已研制并形成了中医药团体标准评价体系(System of Consortium Standards Rating and Evaluation of Traditional Chinese Medicine, SCORETCM)。在上述背景下,本研究通过专家共识法,设计了一套基于SCORE-TCM的中医药团体标准抽样评价方案,应用场景为对于特定社会团体发布的标准,或各团体发布的特定技术类别的标准进行快速评估。该方案涵盖了标准抽样、材料收集、标准评价、结果解读的完整流程,为中医药团体标准的抽样评价工作提供了参考方案。

My Relationship with TCM

A Spanish businessman becomes a dedicated advocate of traditional Chinese medicine after witnessing its effects in treating his terminally ill young son.MY relationship with traditional Chinese medicine(TCM)-and with China-began in 1988,when I traveled to Beijing with my two-year-old son Joan.He was suffering from an extremely rare disease called leukoencephalopathy,in which the brain is affected,and we wanted to explore treatment possibilities.

Proposal of translation of commonly-used acupuncture and moxibustion terminology by Beijing University of Chinese Medicine

General Secretary Xi Jinping points out“traditional Chinese medicine(TCM)is a treasure of the Chinese nation.We must pro-tect,explore,develop and inherit it well.”According tothe latest in-formation,1 TCM has spread to 196 countries and regions around the world,indicating that it enjoys a good development abroad,especially the development of acupuncture and moxibustion.

Integration and implementation of precision medicine in the multifaceted inflammatory bowel disease

Inflammatory bowel disease(IBD)is a complex disease with variability in genetic,environmental,and lifestyle factors affecting disease presentation and course.Precision medicine has the potential to play a crucial role in managing IBD by tailoring treatment plans based on the heterogeneity of clinical and temporal variability of patients.Precision medicine is a population-based approach to managing IBD by integrating environmental,genomic,epigenomic,transcriptomic,proteomic,and metabolomic factors.It is a recent and rapidly developing medicine.The widespread adoption of precision medicine worldwide has the potential to result in the early detection of diseases,optimal utilization of healthcare resources,enhanced patient outcomes,and,ultimately,improved quality of life for individuals with IBD.Though precision medicine is promising in terms of better quality of patient care,inadequacies exist in the ongoing research.There is discordance in study conduct,and data collection,utilization,interpretation,and analysis.This review aims to describe the current literature on precision medicine,its multiomics approach,and future directions for its application in IBD.

Investigation on the cognitive status and the infiltration path of Traditional Chinese Medicine among residents in Liaoning Province

To understand citizens’awareness,trust and attitude towards Tradition Chinese medicine(TCM),to seek the best penetration path of TCM products and culture,to analyze their influencing factors,and to provide suggestions and countermeasures,a non-probabilistic judgment sampling method was used to conduct a survey among 459 people online with the help of Questionnaire Star and 434 valid questionnaires were collected.The survey shows that residents have a high degree of recognition and identification of Chinese medicine;citizens are rational when choosing TCM products,and the recognition of the emerging TCM culture infiltration path is low.Different social and demographic factors affect citizens’awareness,trust and attitude towards TCM,as well as the choice of infiltration path(P<0.05).

Contradiction between Traditional Chinese Medicine and Modern Medicine in Understanding and Treating Parkinson’s Disease and Its Solutions

Parkinson’s disease is not a lifelong disease. Although modern medicine cannot cure Parkinson’s disease, I found that traditional Chinese medicine can cure Parkinson’s disease. However, because of the misunderstanding of the treatment ideas of most of Chinese doctors, they failed to achieve the goal of curing Parkinson’s disease. There are differences not only in understanding and treating Parkinson’s disease between traditional Chinese medicine and modern medicine, but also in understanding within the Chinese medicine community. Because they have not been able to cure Parkinson’s disease, they draw the conclusions from modern medicine and also believe that Parkinson’s disease is an incurable lifelong disease. This paper deeply explores the problems existing in modern medicine and traditional Chinese medicine, puts forward new ideas for understanding and treating Parkinson’s disease, and explores the correct way to understand and cure Parkinson’s disease for the medical community to overcome Parkinson’s disease.

Effectiveness of traditional Chinese medicine in treating AIDS related diarrhoea:a meta-analysis

Background:To evaluate the efficacy of traditional Chinese medicine(TCM)in treating Acquired Immune Deficiency Syndrome(AIDS)related diarrhoea.Methods:Chinese and English databases(CBM,CNKI,Wanfang Database,PubMed,Web of Science,Cochrane Library)were searched up to November 2021.Studies that compared TCM with western medicine were included.RevMan 5.4,Stata 17,and Grading of Recommendations Assessment Development and Evaluation system were used for data analyses.The inclusion and exclusion criteria,quality assessment process,and potential biases were specified.Result:24 randomized controlled trial with a total of 1,766 participants of TCM compared with western medicine were included,12 of which reported random assignment methods.Meta-analyses showed that,TCM was more effective than western medicine in treating AIDS-related diarrhoea[RR=1.32,95%CI(1.26,1.39),P<0.01],internal treatment of TCM[RR=1.37,95%CI(1.28,1.46),P<0.01],external treatment of TCM[RR=1.27,95%CI(1.17,1.39)],internal and external treatment of TCM[RR=1.21,95%CI(1.07,1.37),P<0.01],Shenlingbaizhu Powder/Pill[RR=1.25,95%CI(1.13,1.39),P<0.01],Xielikang Capsules[RR=1.57,95%CI(1.33,1.84),P<0.01],Jianpizhixie Recipe[RR=1.31,95%CI(1.05,1.65),P<0.01],Moxibustion[RR=1.19,95%CI(1.07,1.32),P<0.01],Ginger Moxibustion[RR=1.24,95%CI(1.04,1.47),P<0.01],when compared to using western medicine alone and with significant differences.Conclusion:Shenlingbaizhu Powder/Pill,Xielikang Capsules,Jianpizhixie Recipe,Moxibustion and Ginger Moxibustion had certain advantages in improving the effective rate of AIDS-related diarrhoea,they needed to be further validated by high quality clinical trials.

How modern teaching technology affects the transmission of traditional Chinese medicine knowledge: reflections from educators in clinical Chinese pharmaceutical education

Traditional Chinese medicine(TCM)education plays a crucial role in cultivating TCM talents and preserving the profound cultural heritage of the Chinese nation.This paper explores the current situation and problems of TCM education and proposes philosophical reflections on this issue.The analysis shows that the current TCM education faces various challenges,including an unbalanced curriculum,a narrow teaching approach,a lack of practical experience,and an insufficient number of qualified teachers.To enhance the teaching effectiveness and foster a new generation of high-quality Chinese medicine professionals,it is necessary to reform the teaching methods of TCM and integrate the depth of humanities into the teaching process.The paper argues that a philosophical perspective can provide a more comprehensive understanding of TCM education and its role in the development of Chinese medicine.

Treatment of 140 cerebral palsied children with a combined method based on traditional Chinese medicine(TCM)and western medicine

Objective:To observe and evaluate a method that is effective and practical for treatment of cerebral palsied(CP)children in China.Method:The patient's age and disease type and individual specific conditions were considered in choosingtherapy methods accordingly:Chinese herbs,acupuncture,auricnlar seed pressure,point finger pressing,massage,orthopedichand manipulation,physiotherapy,occupational therapy,language therapy,etc.Meanwhile we created a new CP treatment modelthat combines hospitalized treatment with family therapy.Results:The majority of CP patients improved greatly in motor andsocial adaptation capacities after treatment.Wilcoxon paired rank sum test analysis showed that there were significant differencesbetween the data before and after treatment(P<0.01).Conclusion:This combined therapy method,based on traditional Chinesemedicine and western medicine plus family supplemental therapy,is an effective and practical treatment strategy for CP children inChina.