Evidence-based Clinical Chinese Medicine:What Has Changed Over the Past 20 Years

Chinese medicine has been used for centuries to treat a range of health conditions.This history has produced a wealth of classical literature,case studies and clinical research data detailing its use and effectiveness.However,high-quality and conclusive evidence that meets modern requirements for clinical decision support is lacking.This evidence gap limits the integration of Chinese medicine with contemporary medicine,which in turn limits global access and acceptance of Chinese medicine as a form of safe and effective health care.Over the past 20 years,researchers and organisations around the world,including the World Health Organization(WHO)and United Nations,have worked to support the integration of traditional medicines,such as Chinese medicine,with conventional medicines to improve global health care.This paper provides an overview of Chinese medicine studies published in the top four general medical journals(BMJ,JAMA,Lancet and New England Journal of Medicine)from February 2005 to February 2024 in the past 20 years to highlight the progress in the development of this evidence base.It also highlights key actions taken to promote evidence-based clinical Chinese medicine,including product and practitioner regulation,formalising education standards,and international collaborations.Research conducted at the China-Australia International Research Centre for Chinese Medicine demonstrates the benefits of such a collaboration.Through development of its unique and inclusive‘whole-evidence’approach,plus clinical studies and systematic reviews,the Centre has significantly contributed to the evidence base for clinical Chinese medicine.In addition,its high-impact papers and groundbreaking monographs have been cited in international conventional medicine guidelines.While progress has certainly been made during the past 20 years to build a stronger evidence base for clinical Chinese medicine,there is still a considerable gap that limits its integration with conventional medicine.Future funding and research are needed to continue this work and achieve to safe,effective and accessible traditional medicine as part of the WHO’s Universal Health Coverage strategy.

Comparative efficacy and safety of Chinese patent medicines of iron deficiency anemia during pregnancy:A network meta-analysis

BACKGROUND Iron deficiency anemia(IDA)is a prevalent nutritional disorder during pregnancy.Clinical studies indicate that incorporating Chinese patent medicines(CPMs)with oral iron(OI)in treating IDA in pregnancy can reduce adverse effects and improve clinical outcomes.Nonetheless,the comparative efficacy of different CPMs remains unclear.AIM To assess the safety and effectiveness of different CPMs for treating IDA during pregnancy using network meta-analysis.METHODS We conducted a search for randomized controlled trials(RCTs)that combined CPM and OI for IDA treatment in pregnancy,spanning from 2013 to the present.Data analysis was performed using Rev Man 5.3 and Stata 14.0 on literature that satisfied the quality criteria.RESULTS The analysis included 45 RCTs,encompassing 4422 pregnant patients with IDA.Six CPMs were examined,including Shengxuebao Mixture,Shengxuening Tablets(SXN),Yiqi Weixue CPMs(YQWX),Jianpi Shengxue CPMs(JPSX),Yiqi Buxue Tablets,and Compound Hongyi Buxue Oral Liquid(FFHY).Findings indicated that FFHY+OI significantly improved the clinical effective rate.SXN+OI was most effective in boosting red blood cells counts and hemoglobin levels.YQWX+OI showed superior results in improving serum ferritin,and SXN+OI was most effective in increasing serum iron levels.JPSX+OI was optimal in reducing adverse pregnancy outcomes,while YQBX+OI effectively minimized adverse events.A cluster analysis suggested that SXN+OI could be the potentially optimal therapeutic regimen for IDA in pregnancy.CONCLUSION This study demonstrates that the combination of OI with CPMs offers better outcomes than OI alone.Based on clinical efficacy and other measured outcomes,SXN+OI emerges as the most effective treatment modality for improving the health of pregnant patients with IDA.

Research progress of traditional Chinese medicine in the treatment of endocrine metabolic diseases in 2023

This study aimed to provide a comprehensive review of the research progress in Chinese medicine in the treatment of endocrine metabolic diseases in 2023,covering traditional Chinese medicine(TCM)monomers,TCM extracts,and TCM combinations,including non-alcoholic fatty liver disease,type 2 diabetes mellitus and its complications,obesity,hyperuricaemia,and thyroid disorders.After systematic sorting and summary,we found that in 2023,the research focusing on the application of TCM for endocrine metabolic diseases was still on the mechanism of action at the cellular and molecular levels,which not only influenced the classical pathways of lipid metabolism,but also delved into the key mechanisms of anti-inflammation,anti-oxidation,anti-insulin resistance,and so on.Additionally,TCM has shown remarkable results in the treatment of endocrine metabolic diseases by improving intestinal flora disorders and abnormal cellular iron death.These research results provide valuable ideas,methods,and tools for TCM in the prevention and treatment of endocrine metabolic diseases,and provide important references and guidance for future research and practice.

Clinical research report on traditional Chinese patent medicines and traditional Chinese classic famous prescriptions(2022)

Objective:The paper is to comprehensively summarize and analyze the basic situation and methodological quality of clinical randomized controlled trials(RCTs)of traditional Chinese patent medicines and traditional Chinese classic famous prescriptions published in 2022,to provide evidence and reasonable suggestions for the advancement of clinical research and the formulation of policies and guidelines.Methods:The Evidence Database System of clinical evidence-based evaluation of traditional Chinese medicine was searched,and data from China National Knowledge Infrastructure(CNKI),PubMed,and other databases were supplemented.The search duration was from January 1,2022,to December 31,2022.RCTs of traditional Chinese patent medicines and traditional Chinese classic famous prescriptions were included as the source of clinical evidence,and published information,sample size,intervention,control measures,treatment course,methodological quality,and key link report were analyzed and evaluated.Results:A total of 1,464 RCTs of traditional Chinese patent medicines were included,which comprised 667 types of traditional Chinese patent medicines;“traditional Chinese patent medicines+Western medicine vs.Western medicine”was the most widely used intervention and control setting,involving 417 RCTs(28.48%).A total of 245 RCTs of traditional Chinese classic famous prescriptions were included,comprising 55 types of traditional Chinese classic famous prescriptions.“Decoction+conventional treatment vs.conventional treatment”was the most widely used intervention and control setting,with 87 RCTs(35.51%).Published RCTs on traditional Chinese patent medicines and traditional Chinese classic famous prescriptions were limited by the study design and implementation.Most“allocation concealment”and“blinding of patients and personnel”were rated as medium to high risk.There are insufficient reports on key research links such as experimental registration and ethical approval.Conclusions:The number of RCTs on traditional Chinese patent medicines has decreased in 2022,but there has been a slight improvement in the research quality and impact.There are relatively few studies on traditional Chinese classic famous prescriptions.Measures must be taken to improve clinical trial design,implementation,and reporting.Methodological experts should be invited to provide professional technical guidance on the trial design.In the research implementation process,attention should be paid to quality control,particularly the standardization of the randomized execution.

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.

Molecular mechanism and research progress of traditional Chinese medicine in the treatment of prostate cancer

Prostate cancer(PCa)is one of the most common malignant tumors in the male genitourinary system,ranking second in incidence worldwide.Traditional Chinese medicine(TCM),as an important component of complementary and alternative medicine,shows unique advantages in cancer treatment.Chinese herbal medicine is usually composed of multiple ingredients and involves multiple signaling pathways,which showed function of inducing apoptosis of cancer cells,arresting the cell cycle,inhibiting invasion and metastasis,reducing drug resistance,and regulating immune function.Physical therapy is also an important treatment of TCM.Currently,Physical therapy such as acupuncture or Tai Chi and Qigong are gaining increased recognition in the management of PCa,particularly in addressing issues like urinary incontinence and bone metastasis-related pain.This article reviews the TCM treatment and therapy of PCa,in order to provide new research avenues and treatment options for the treatment of PCa with TCM and improve the quality of life of patients.

Mechanism of traditional Chinese medicine in the treatment of psoriasis with depression:A review

Psoriasis is a kind of immune-mediated, chronic, inflammatory skin disease, which is often associated with different degrees of psychological disorders. Specifically, there is a significant correlation between psoriasis and depression, and they show the relationships of reciprocal causation and mutual promotion. Psoriasis with depression is more harmful than simple psoriasis, and its prognosis is worse, which brings a huge burden to the family and society and is worthy of clinical attention. Based on the pathogenic factors of western medicine and pathogenesis of traditional Chinese medicine in psoriasis with depression, the paper summarized and elaborated the research progress on the mechanism of traditional Chinese medicine in the treatment of psoriasis with depression, in order to provide new ideas for clinical treatment.

An Exploration of Traditional Chinese Cultural Programs:The Construction of Rituals,Narrative Strategies,and Experiential Insights

In the context of the cultural development of the new era and the burgeoning spiritual demands of the people,there has been a remarkable surge in the proliferation of traditional Chinese cultural programs.The“Chinese Festivals”series,produced by Henan TV,standing out as an engaging TV program that showcases traditional Chinese culture,has rapidly captivated a diverse audience across different age groups,creating a rich,multi-dimensional,and cross-media cultural communication ecosystem.The program strategically selects symbolic elements by systematically categorizing and organizing traditional Chinese cultural symbols to create a rich cultural space.It employs cutting-edge scientific and technological methods to enrich viewer immersion,crafting media rituals with both temporal significance and a profound sense of media ritual.This approach boosts the program’s popularity and sets a benchmark for industry innovation.By fostering an interactive narrative between mainstream media and the public,the program continuously broadens the scope of the“story world,”fostering a harmonious and structured national cultural community through the creative interpretation of traditional Chinese culture and the evocative crafting of the aesthetic sensibilities inherent in Chinese art.It is worth noting that the phenomenon of aesthetic fatigue besets the development of this serial program.To address this issue and further improve the appeal of the program,a comprehensive approach is required to develop a cohesive narrative mode for the“story world.”This involves harmonizing the interplay between artistic endeavors and technological advancements,synchronizing sensory experiences with the foundational ritualistic elements,and enhancing the effectiveness of the media communication matrix to construct a brand of media culture that has social significance,aesthetic value,and economic profits in the new era.

The potential of Chinese herbal medicines in treating anxiety disorders

In recent years,there has not been much progress in developing anxiolytic drugs.Amongst the barriers are the lack of clarity on the pathogenesis of anxiety disorders,low product conversion rates for developing drugs targeting the receptors,and species variability.Some scientists have focused on natural medicines,especially herbal medicines in traditional Chinese medicine.New drugs with excellent anxiolytic activity are hoped to be found in herbal medicines with anxiolytic effects.This mini-review summarised three Chinese herbal medicines with anxiolytic effects and anxiolytic herbal formulas used in the traditional Chinese medicine clinic.Several key issues that block the development of new anxiolytic drugs are also discussed.We hope to provide some ideas for researching and developing new anxiolytic drugs and studying anxiolytic components in traditional Chinese medicine.

Pioneering a New Realm of Human Rights Civilization in the Chinese Path to Modernization——An Overview of the Symposium on“The Chinese Path to Modernization and the Promotion of Free and Comprehensive Human Development”

On October 14,2023,a symposium themed“The Chinese Path to Modernization and the Promotion of Free and Comprehensive Human Development”was held in Changchun,Jilin Province,China.More than fifty experts,scholars,and researchers from national institutions and universities engaged in discussions and exchanges on human rights on the Chinese path to modernization,including the path,practice,knowledge systems,and civilization forms of human rights.This symposium played a significant role in advancing the construction of the disciplinary system,academic system,and discourse system of human rights in China.

Review of Research on English Translation of Chinese Running Sentences

In order to convey complete meanings,there is a phenomenon in Chinese of using multiple running sentences.Xu Jingning(2023,p.66)states,“In communication,a complete expression of meaning often requires more than one clause,which is common in human languages.”Domestic research on running sentences includes discussions on defining the concept and structural features of running sentences,sentence properties,sentence pattern classifications and their criteria,as well as issues related to translating running sentences into English.This article primarily focuses on scholarly research into the English translation of running sentences in China,highlighting recent achievements and identifying existing issues in the study of running sentence translation.However,by reviewing literature on the translation of running sentences,it is found that current research in the academic community on non-core running sentences is limited.Therefore,this paper proposes relevant strategies to address this issue.

“Chineseness”:A Discussion on Cases Related to Tulou in Contemporary Chinese Architecture

The article delves into the concept of“Chineseness”in contemporary Chinese architecture,a strategic tool for creating distinctive styles rooted in Chinese identity.It serves not only to distinguish projects from market-driven trends but also to establish a pivotal position in the global architectural landscape.“Chineseness”among 24 identified keywords represents a practical strategy embraced by many young architects with international exposure.The traditional Chinese dwelling,a symbol of familial and cultural essence,particularly in the context of home culture,is a primary inspiration for contemporary architects.The research adopts a case study approach,focusing on Tulou-related cases from the last fifteen years,encompassing various building types.The Tulou,a mountain-dwelling with rich cultural connotations,is introduced,reflecting ancient Chinese philosophies in its architectural principles.The case studies,including URBANUS’s“Tulou Collective Housing 2008”and Chengdu’s“Tulou Theater,”demonstrate how Tulou prototypes can be creatively adapted.These designs not only replicate forms but also capture the communal spirit inherent in traditional dwellings.“Stepped Courtyards”by OPEN Architecture reinterprets Tulou typology for a staff dormitory,emphasizing community awareness.In conclusion,the concept of“Chineseness”emerges as a prominent topic,showcasing the dynamic and adaptable nature of traditional Chinese culture and modern architectural expressions.The cases illustrate the evolving intersection between traditional Chinese culture and modern architecture,offering insights into the future trajectory of Chinese architectural culture.The interrelated keywords highlight the nuanced and evolving nature of“Chineseness”in architectural practices.

Advances in Research Methods of Pharmacodynamic Substances in Traditional Chinese Medicines and Their Application in the Teaching of Traditional Chinese Medicine Analysi

With the continuous progress of science and technology,the research methods of pharmacodynamic substances in traditional Chinese medicine are developing,and the application of these methods in teaching is becoming more and more extensive.By introducing these research methods into the classroom,teachers can help students to deeply understand the nature and mechanism of action of pharmacodynamic substances in traditional Chinese medicine,and improve their interest in and knowledge of traditional Chinese medicine.This paper introduces the definition of pharmacodynamic substances in traditional Chinese medicine,research methods,and their application in the teaching of traditional Chinese medicine analysis.

An exploration of the origin and flow of the development of traditional Chinese medicine orthopedic and chiropractic massage

Traditional Chinese medicine(TCM)chiropractic massage is a kind of orthopedic therapy that corrects the abnormal anatomical position of bone or joint and corrects the dislocation of joint by manipulation so that the bone is soft and the Qi and blood are reconciled(Qi:The intangible,high-mobility nutritive substance that maintains vital activities).Manipulation treatment is the first of the four major orthopedic diseases.At the same time,TCM chiropractic massage is also an essential part of TCM.TCM orthopedic chiropractic practice originated from the struggle between humanity and nature,sprouted from the Warring States period to the two Han Dynasty,formed in the Sui,Tang,and Song Dynasties,matured in the Ming and Qing Dynasties,and flourished in the modern era.In more than 2,000 years of development,many practical techniques have been produced,which have profoundly influenced the inheritance and development of modern techniques,making the TCM orthopedic chiropractic massage in the contemporary era form the characteristics of“tendon and bone”and“point-line-face combination”.At present,the development of TCM chiropractic massage is facing the great challenges of modern medicine and modern advanced science and technology such as American chiropractic and the limitations of its development.Therefore,in the future,the development direction of Chinese medicine orthopedic chiropractic massage should be“hybrid to treat”.In the face of modern medicine,we should take its essence to its dross,eclectic,organically integrate its advantages into itself,enrich its theoretical framework,and strengthen the construction of disciplines and departments to enhance its competitiveness.It is believed that Chinese medicine orthopedic chiropractic massage can have better development in the future and can make more contributions to the health of the world’s people.

The Historical Evolution of Chinese Education in the United States

Chinese education in America is a cultural product of Chinese immigrants to the United States.In 1848,the California Gold Rush attracted many Chinese to the United States,and gradually formed Chinese communities in the local area,and then spontaneously produced Chinese education.At that time,San Francisco Chinatown was the largest Chinatown in the United States,and its Chinese education showed representative characteristics.By studying the origin and development of Chinese education in San Francisco,this paper analyzes the characteristics of Chinese education in the United States,in order to provide experience and reference for contemporary Chinese education in the United States.

A Study on the Pedagogical Application of Chinese New Year Culture in International Chinese Language Education

Culture teaching is an inseparable part of International Chinese Language Education,and it has great significance in international Chinese language teaching.Students can enhance their interest in Chinese language learning and improve their learning effect through understanding the excellent traditional Chinese culture,at the same time,culture teaching can help to disseminate the Chinese culture and promote the development of a multicultural world.Taking the teaching of Chinese New Year culture as an example,we analyze the current teaching materials involving Chinese New Year culture with high popularity and acceptance,put forward effective teaching methods matching the feasibility of teaching Chinese New Year culture,and then present the specific teaching design of Chinese New Year culture,in order to provide references for the teaching of culture in International Chinese Language Education.

Exploration of Teaching Reform of TCM Dispensing Technology in Higher Vocational Colleges Based on Traditional Chinese Medicine Skills Competition

This paper aims to thoroughly explore the teaching reform of Traditional Chinese Medicine(TCM)dispensing technology in higher vocational colleges,with a focus on the Traditional Chinese Medicine Skills Competition.By analyzing the current teaching status and main challenges of TCM dispensing technology,and aligning with the requirements of the skills competition,a series of detailed and practical teaching reform measures are proposed.These measures are designed to comprehensively improve the teaching quality of TCM dispensing technology in higher vocational colleges,enhance students’practical skills and professional qualities,and ultimately meet the demand for high-quality,skilled talents in the field of TCM.

Traditional Chinese Medicine's Spleen Strengthening and Intestinal Microecology

The"spleen"in traditional Chinese medicine is the"acquired foundation"and the"source of qi and blood biochemistry".Strengthening the"spleen"is one of the important treat‐ment methods in traditional Chinese medicine;The gut microbiota has been a hot topic in modern scientific research in recent years,and its nutritional and immune functions correspond to some of the functions of the spleen in traditional Chinese medicine.In terms of philosophy,traditional Chinese medicine emphasizes the balance between the spleen and the gut microbiota,emphasizing the importance of supporting the right and eliminating evil,preventing diseases before they occur,seeking the root cause of treat‐ment,and adapting measures to the three causes;Clinically,the treatment of obesity,con‐stipation,diarrhea and other diseases by invigorating the spleen and the treatment mechanism of acupuncture and moxibustion,chiropractic and invigorating the spleen are all related to microecology.This article combines relevant literature on traditional Chinese medicine's"spleen"and"spleen health"to explore the treatment concept,clinical application,and correlation with intestinal microbiota of traditional Chinese medicine's"spleen health".It also elaborates on the latest literature,aiming to exchange ideas with peers and promote research on the microbiota of traditional Chinese medicine's"spleen".

Five commonly used traditional Chinese medicine formulas in the treatment of ulcerative colitis:A network meta-analysis

BACKGROUND Currently,traditional Chinese medicine(TCM)formulas are commonly being used as adjunctive therapy for ulcerative colitis in China.Network meta-analysis,a quantitative and comprehensive analytical method,can systematically compare the effects of different adjunctive treatment options for ulcerative colitis,providing scientific evidence for clinical decision-making.AIM To evaluate the clinical efficacy and safety of commonly used TCM for the treatment of ulcerative colitis(UC)in clinical practice through a network metaanalysis.METHODS Clinical randomized controlled trials of these TCM formulas used for the adjuvant treatment of UC were searched from the establishment of the databases to July 1,2022.Studies that met the inclusion criteria were screened and evaluated for literature quality and risk of bias according to the Cochrane 5.1 standard.The methodological quality of the studies was assessed using ReviewManager(RevMan)5.4,and a funnel plot was constructed to test for publication bias.ADDIS 1.16 statistical software was used to perform statistical analysis of the treatment measures and derive the network relationship and ranking diagrams of the various intervention measures.RESULTS A total of 64 randomized controlled trials involving 5456 patients with UC were included in this study.The adjuvant treatment of UC using five TCM formulations was able to improve the clinical outcome of the patients.Adjuvant treatment with Baitouweng decoction(BTWT)showed a significant effect[mean difference=36.22,95%confidence interval(CI):7.63 to 65.76].For the reduction of tumor necrosis factor in patients with UC,adjunctive therapy with BTWT(mean difference=−9.55,95%CI:−17.89 to−1.41),Shenlingbaizhu powder[SLBZS;odds ratio(OR)=0.19,95%CI:0.08 to 0.39],and Shaoyao decoction(OR=−23.02,95%CI:−33.64 to−13.14)was effective.Shaoyao decoction was more effective than BTWT(OR=0.12,95%CI:0.03 to 0.39),SLBZS(OR=0.19,95%CI:0.08 to 0.39),and Xi Lei powder(OR=0.34,95%CI:0.13 to 0.81)in reducing tumor necrosis factor and the recurrence rate of UC.CONCLUSION TCM combined with mesalazine is more effective than mesalazine alone in the treatment of UC.

Synergistic effects of carbon cycle metabolism and photosynthesis in Chinese cabbage under salt stress

Chinese cabbage(Brassica rapa ssp. pekinensis) has a long cultivation history and is one of the vegetable crops with the largest cultivation area in China. However, salt stress severely damages photosynthesis and hormone metabolism, nutritional balances, and results in ion toxicity in plants. To better understand the mechanisms of salt-induced growth inhibition in Chinese cabbage, RNA-seq and physiological index determination were conducted to explore the impacts of salt stress on carbon cycle metabolism and photosynthesis in Chinese cabbage. Here, we found that the number of thylakoids and grana lamellae and the content of starch granules and chlorophyll in the leaves of Chinese cabbage under salt stress showed a time-dependent response, first increasing and then decreasing. Chinese cabbage increased the transcript levels of genes related to the photosynthetic apparatus and carbon metabolism under salt stress, probably in an attempt to alleviate damage to the photosynthetic system and enhance CO_(2) fixation and energy metabolism. The transcription of genes related to starch and sucrose synthesis and degradation were also enhanced;this might have been an attempt to maintain intracellular osmotic pressure by increasing soluble sugar concentrations. Soluble sugars could also be used as potential reactive oxygen species(ROS) scavengers, in concert with peroxidase(POD)enzymes, to eliminate ROS that accumulate during metabolic processes. Our study characterizes the synergistic response network of carbon metabolism and photosynthesis under salt stress.