key: cord-291934-pm3ns6ge authors: jiang, ronglin; wang, kungen; mao, wei; zhu, wei; hu, weihang; huang, liquan title: chinese herbal experience for the 2019 novel coronavirus date: 2020-07-21 journal: crit care doi: 10.1186/s13054-020-03170-4 sha: doc_id: 291934 cord_uid: pm3ns6ge nan the novel coronavirus (covid-19) has spread rapidly and become a severe global threat, with a reported acute respiratory distress syndrome (ards) incidence up to 40% [1] . according to a large survey, more than 14% patients were transferred to the intensive care unit care (icu), and among those who received invasive mechanical ventilation, the mortality was as high as 88.1% [2] . here we presented the data from a single icu of tianyou hospital in wuhan, and according our experience, the overall mortality decreased in patients receiving chinese herb therapy. from january 11, 2020, to march 17, 2020, a total of 37 patients confirmed with covid-19 infection were admitted to icu (table 1) , of whom seven patients were transferred to other hospitals and were excluded from this analysis. the general treatment regimens included glucocorticoids, antibiotics, hydroxychloroquine, and arbidol; however, the overall mortality rate remains as high as 78.1%. chinese herb was applied in these patients since feb 17. thus, a total of nine patients received chinese herbal therapy during the whole disease course (admitted to icu after feb 17), five patients received chinese herbal therapy for a period of the whole disease course, and the rest fourteen patients had not received chinese herbal therapy. despite with limited sample size, the mortality rate decreased significantly after applying chinese herbal to these patients (4/9 vs. 5/5 vs. 14/16, p = 0.033), especially in patients who received chinese herbal therapy during the whole disease course. further, these patients were also divided into two groups according to whether they had used chinese herbal; a decreased trend of mortality was also observed (9/14 vs. 14/16, p = 0.134). we understand our finding is unstable due to the limited sample size and potential cofounders. however, in china, chinese herbal therapy has been fully applied to patients with covid-19 infection in the middle stage of this epidemic and the effect is positive. the following content is the risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-287118-30s0a27q authors: idrovo, alvaro javier; manrique-hernández, edgar fabián title: data quality of chinese surveillance of covid-19: objective analysis based on who’s situation reports date: 2020-05-14 journal: asia pac j public health doi: 10.1177/1010539520927265 sha: doc_id: 287118 cord_uid: 30s0a27q was there quality in the chinese epidemiological surveillance system during the covid-19 pandemic? using data of world health organization’s situation reports (until situation report 55), an objective analysis was realized to answer this important question. fulfillment of benford’s law (first digit law) is a rapid tool to suggest good data quality. results suggest that china had an acceptable quality in its epidemiological surveillance system. furthermore, more detailed and complete analyses could complement the evaluation of the chinese surveillance system. good epidemiological surveillance systems are essential for epidemic management. one of its functions is to provide data with quality that serve to make decisions based on evidence. 1 unfortunately, it is not easy to know the quality of data during public health emergencies of international concern such as the covid-19 pandemic. during the influenza a(h1n1) pandemic, benford's law was proposed as an objective and fast way to assess the performance of surveillance systems during epidemics. 2 its usefulness was also evidenced in the dengue epidemic in paraguay (2009-2011) 3 and the zika epidemic in american countries. 4 benford's law, 5 also called "law of the first digits," "newcomb-benford law," or "law of anomalous numbers," states that for a determined set of numbers, those whose first digit is 1 will appear more frequently (30.103%) than those beginning with other digits, following in order from 2 to 9 (17.609%, 12.494%, 9.691%, 7.918%, 6.695%, 5.799%, 5.115%, and 4.576%, respectively). 6 a very good explanation of benford's law is the following: "the good fit of the newcomb-benford law to empirical data can be explained by the fact that in many cases the frequency with which objects occur in "nature" is an inverse function of their size. very small objects occur much more frequently than do small ones, which in turn occur more frequently than do large ones and so on." 7 the covid-19 pandemic began in wuhan (hubei, china) in early december 2019. 8 from there, it had a rapid spread through asia, europe, america, and africa. at the end of march 2020, there were more than 850 000 cases and 40 000 deaths around the world. 9 this brief report presents the results of an objective evaluation of data quality of the chinese epidemiological surveillance system during the ongoing epidemic. to obtain evidence on the level of performance of the chinese epidemiological surveillance system, we used data included in situations reports 1 to 55 of the world health organization (who) website (january 21 to march 15, 2020). 10 in these situational reports are found the number of confirmed cases, suspected cases, and deaths in the past 24 hours, and cumulated confirmed cases and deaths, in each chinese province, region, and city. given that by march 16, the numbers of cases and deaths outside china had overtaken the total number of cases in china, the who decided not to report separately the situation in the chinese territories. cumulative cases reported by chinese provinces, regions, and cities were evaluated according to how closely they followed the distribution of benford's law using log-likelihood ratio test. results of these analyses are presented in table 1 . as can be seen, in the first situation reports, the information did not maintain a standard nor did the data show stable quality. since the situation report 13, the data improved its quality in a more stable way. in figure 1 is the benford distribution of the last situation report analyzed, and a detailed analysis of each digit with the χ 2 test ( table 2 ). the results suggest that the chinese epidemiological surveillance system has had good data quality during the current health emergency. this must be understood in a pandemic context, and being the country where it originated. in these circumstances, it is highly probable that the reported data are underestimated in great magnitudes, as presented in recent publications. 11 it is frequent in these contexts that only most severe cases are reported. with well-designed population studies, the numerator and denominator of the proportions of the actual occurrence of the infection will be better known. previous experiences such as lassa fever in africa suggests that infections with initial high fatality diminish the severity with widespread epidemiological studies. 12 however, this evaluation did not incorporate all the elements of the health system involved in the management of the current covid-19 pandemic. a comprehensive evaluation of the chinese surveillance system should add to the data quality, characteristics of simplicity, flexibility, acceptability, sensitivity, positive predictive value, representativeness, timeliness, and stability. 1 however, this rapid evaluation serves to provide feedback to officials of the chinese surveillance system. this type of ongoing evaluation is possible in other countries, and it will allow officials in charge to make relevant decisions to improve epidemiological surveillance systems and the response of health care services. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) received no financial support for the research, authorship, and/or publication of this article. alvaro javier idrovo https://orcid.org/0000-0001-9579-1463 updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group performance of public health surveillance systems during the influenza a(h1n1) pandemic in the americas: testing a new method based on benford's law monitoring the paraguayan epidemiological dengue surveillance system (2009-2011) using benford's law global performance of epidemiologic surveillance of zika virus: rapid assessment of an ongoing epidemic the law of anomalous numbers the first digit phenomenon the newcomb-benford law in its relation to some common distributions clinical features of patients infected with 2019 novel coronavirus in wuhan an interactive web-based dashboard to track covid-19 in real time world health organization. coronavirus disease (covid-2019) situation reports average detection rate of sars-cov-2 infections is estimated around six percent the covid19 pandemic: public health and epidemiology key: cord-008692-y61sg1q9 authors: congdon, nathan g.; aung, tin title: a tale of two systems: health reform in china and the united states date: 2010-02-25 journal: ophthalmology doi: 10.1016/j.ophtha.2010.01.025 sha: doc_id: 8692 cord_uid: y61sg1q9 nan the 9-province survey of zhao et al, 1 provides new evidence of the burden of vision disability facing rural china. the prevalence of presenting blindness among persons 50 years of age and older exceeds 2%, while 1 in 10 persons are visually impaired. mild impairment, in the range of 20/40 to 20/63, is of increasing importance in an age when the ability to drive and read a computer screen are requirements of day-to-day life for many chinese citizens; more than a quarter of persons in the economic vanguard guangdong province suffer from such impairment. women and those without formal education are at the highest risk for all levels of visual disability. 1 a major underlying reason for high rates of blindness in china is likely the low cataract surgical rate (csr), estimated at 460/million/year in 2004. 2 this is among the lowest in east asia, and roughly 1/10 of the rate in neighboring india. reasons for this low surgical output have included the disincentive of poor outcomes, particularly in rural areas, 3, 4 lack of knowledge about cataract among patients, 5 and unaffordable prices, despite a demonstrated willingness to pay modest amounts for surgery even among rural-dwellers in poor areas. 6 like the united states, china has recently embarked on major efforts to reform its healthcare system, and as with the us, much of this reform has been aimed at reducing the proportion of citizens without health insurance. china's new cooperative medical scheme (ncms) 7 was launched in the wake of the 2003 severe acute respiratory syndrome (sars) epidemic to replace the old cooperative medical scheme (cms), abandoned in the early 1980s as part of deng xiaoping's economic reforms. the ncms system now covers more than 90% of rural citizens, paying 40%-70% of the cost of cataract surgery, for example. as with the american medicare system in the 1960s, ncms promises to introduce a significant new revenue stream for doctors and hospitals. the impact on eye care in china is already highly visible: the growth of private, forprofit chains such as ai'er (http://www.aierchina.com/en/ index.htm) and bright eyes (http://www.purui.cn) has accelerated. competition has improved the service level at public hospitals as well. routine eye examinations are available at most clinics 7 days per week, all year round. investment in new technology has provided many hospitals even in mid-sized chinese cities with electronic medical record systems, for example, that would put many of the top centers in the united states to shame. urban-rural partnerships and cataract outreach screening programs are burgeoning, motivated by the higher rates of reimbursement obtained from ncms when cataract surgeries are performed locally at county hospitals rather than tertiary centers. tiered pricing is the rule, with cataract surgeries priced from us $100 to more than $500 even at rural centers, depending on the type of intraocular lens and surgical approach. the availability of ncms reimbursements has allowed prices to rise while reducing the out-of-pocket cost to patients. the activities of the chinese government in eye care have not been limited to improving the insurance landscape. the ambitious million cataract surgeries for the poor program plans 1 million free surgeries nationwide over the next 3 years, concentrated on poor, rural areas. governmentaffiliated organizations such as the disabled people's federation are active in nearly every county nationwide, partnering with local providers to carry out large-scale cataract screening activities and free or low-cost surgery. in many cases (though not all), hospitals receive payments of roughly $100 per operation for providing surgeries free of charge in these government programs. although all of these activities seem likely to boost china's csr, and to ameliorate some of the burden of poor vision highlighted in zhao's article, 1 deep-set institutional problems remain with vision care in china. a major reason for the slow dissemination of surgical knowledge in china (only some half of china's ophthalmologists perform surgery 8 ) is the fact that residents and young doctors are rarely given any chance to learn surgery, spending much of their time preparing needlessly detailed charts that may balloon to 50 pages for a routine cataract extraction. organized ophthalmology and the national government need to promulgate national qualification examinations and standards for training, and hold doctors and hospitals to them. drawing a lesson from the pages of american medical history, china's training programs need the kind of wholesale house-cleaning precipitated in the united states during the early 20th century by the flexner report. 9 other systemic inefficiencies remain: most chinese patients will spend 2 to 4 days in the hospital for a routine cataract operation, and a decade after studies questioned the value of routine preoperative medical testing in the us, 10 virtually all chinese cataract patients undergo an electrocardiogram, chest x-ray, and laboratory examinations including hepatitis and human immunodeficiency virus testing. while important differences exist between the us and china (high prevalence of hepatitis b, the need for some rural patients to travel long distances for surgery), the preponderance of available data suggests that a practice of universal admission and extensive preoperative laboratory testing for cataract surgical patients is unlikely to be beneficial. given the potential for substantial cost savings, these policies, which are driven largely by insurance requirements, should either be reconsidered or ideally subjected to careful study. lifeline express (http://www.lifeline-express.com/index. html, accessed on october 15, 2009) and other local and international non-governmental organizations bring in surgeons from urban centers to carry out "campaigns" of free cataract surgery in poor rural areas, often offering little economic benefit or even training to local surgeons, while undercutting the sustainability of local services. non-governmental organizations and the chinese government need to limit free surgery to those few areas where patients are truly unable to pay, and to involve local rural surgeons in all programs. finally, as china's population continues to age, the government must grapple with the same demographic realities now faced by washington. by 2050, china's population older than 80 years of age will increase to 83 million, 11 raising significant financial challenges to the long-term sustainability of activities such as the million cataract project, and even such critical programs as ncms. nonetheless, as americans contend with the thorny problem of reforming our own healthcare system, we have much to learn from beijing's recent successes in providing insurance to the vast majority of china's much-larger population. prevalence of vision impairment in older adults in rural china: the china nine-province survey statistics yearbook on the undertakings of people with disabilities in china a survey of blindness and cataract surgery in doumen county, china visual acuity and quality of life outcomes in patients with cataract in shunyi county, china a two-site, population-based study of barriers to cataract surgery in rural china willingness to pay for cataract surgery in rural southern china the chinese health system at a crossroads prevention of blindness: priorities in china american medical education 100 years after the flexner report the value of routine preoperative medical testing before cataract surgery. study of medical testing for cataract surgery national population and family planning commission of china key: cord-287262-gkolbiil authors: li, yulin; xu, haonan; lang, hui; li, jing; bi, lin; li, yanqing; dong, liang; zhang, lin; liang, xin; zhu, hongqiu title: the efficacy and safety of chinese traditional medicine injections on patients with coronavirus disease 2019: a protocol for systematic review and meta analysis date: 2020-07-31 journal: medicine (baltimore) doi: 10.1097/md.0000000000021024 sha: doc_id: 287262 cord_uid: gkolbiil introduction: the pandemic caused by the coronavirus disease 2019 (covid-19) infection has exposed vulnerable populations to an unprecedented global health crisis. research reported that chinese traditional medicine injections were used in patients with covid-19 infection and showed significant effects, and there have been no systematic review and meta-analyses to investigate the effects and safety of chinese traditional medicine injections. materials and methods: this systematic review and meta-analysis protocol is based on the preferred reporting items for systematic review and meta-analysis protocols 2015 statement. the literature search will involve cochran library, web of science, pubmed, medline, embase, china biology medicine database, china national knowledge infrastructure database, vip, wang fang database, and china clinical trial registration center for articles and research published form december 2019. this search will include randomized controlled trials and nonrandomized studies. the cochrane collaboration's tool for randomized controlled trial studies and the quality assessment tool for quantitative studies for nonrandomized studies will be used to assess the risk of bias among the studies included in the systematic review. review manager 5.3 software will be used for the meta-analysis, and odds ratio are calculated as the primary outcomes. subgroup analyses will then be performed based on the characteristics of the interventions and populations included in the studies examined. ethics and dissemination: this systematic review protocol is designed to provide evidence regarding the effects and safety of chinese traditional medicine injections on patients with covid-19, such evidence may be useful and important for clinical treatment decisions. the results should be disseminated through publication in a peer-reviewed journal. since the data and results used in the systematic review will be extracted exclusively from published studies, approval from an ethics committee will not be required. novel coronavirus (2019-ncov) is raging all around the world, resulting in the death toll surging to 139,515 and confirmed cases spiking to 2,078,605, as of 2:00 am cest, april 17, 2020, reported to who. [1] coronavirus disease 2019 belongs to the coronavirus of genus b; however, its infection mechanism is not yet completely clear. on account of the long incubation period and highly infectivity of covid-19 novel coronavirus poses great challenges to the prevention and treatment of diseases, while there exist no special medicine proved to be effective. [2, 3] chinese traditional medicine injections are recommended by the chinese clinical guidance of covid-19 pneumonia diagnosis and treatment (7th edition) published by china national health commission on march 4, 2020, which is including xiyanping injection, xuebijing injection, reduning injection, tanreqing injection, xingnaojing injection, shenfu injection, shengmai injection, and shenmai injection for critical ill patients. [4] chinese traditional medicine is widely used in clinical treatment. reports show that chinese traditional medicine injections have a certain effect in new covid-19. the early use of traditional chinese medicine injections can significantly shorten the course of the disease, alleviating the clinical symptoms of patients, and reducing the conversion of ordinary type to heavy and critical. [5] [6] [7] although the guideline [4] mentions these traditional chinese medicine injections can be used to treat severe patients with covid-19, and some clinical research reported the efficiency, there is no systematic review and meta-analyses to investigate the effects and safety of chinese traditional medicine injections. as far as the current registration situation is concerned, many clinical randomized controlled trial (rct) trials are about to be carried out. considering this, the present study aims to completely review the effects and safety, which will be of great significance to the clinical treatment of covid-19. the study aims to investigate whether it is effective and safe to apply chinese traditional medicine injections on patients with covid-19, including effective rate, all-cause mortality clinical recovery time negative time of novel coronavirus nucleic acid, etc. the results will provide evidence-based evidence for clinical treatment decisions. this is a systematic review and meta-analysis protocol, which is based on the preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015 statement [8] and cochrane collaboration handbook. [9] the data and results used in this paper are form online databases. those who meet one of the following conditions can be regarded as critical patients. adults meet any of the following criteria: online databases that will be searched are as follows: cochran library, web of science, pubmed, medline, embase, china biology medicine database, china national knowledge infrastructure database, vip, and wang fang database. the literature will be search from december 2019 with language restriction in english and chinese. the related reference will be retrieved as well. in addition, chinese clinical trial registry centre will also be searched. the process of identification, selection, and the inclusion/ exclusion of articles will follow the prisma flowchart (shown in fig. 1 ). first, endnote x9 software will be used to filter duplicate studies. after the deduplication study, the 2 commentators will filter the literature again by reading the title, abstract and other information of the article according to the inclusion and exclusion criteria. according to the results obtained, the full text of the target article is obtained through the database, and then 2 reviewers read the full text of the research that meets the screening criteria, reread the full text, and conduct the screening again. in case of repeated literature results, the results with the largest sample size or the longest follow-up time should be selected. when reviewers are unable to confirm the repeat study, they will contact the author for judgment. then, the review team generated a unified data extraction table (excel spreadsheet). the extracted content includes the following information: research characteristics: research year, publication time, country, research background, publication type, research design, research method, and research population. patient baseline characteristics, intervention information: dose and treatment plan, duration, route of administration; assessment results; study measurement details; bias risk assessment, and other information. the reviewers will then conduct more detailed screening and data extraction of the study. in the process of data extraction, all disagreements of reviewers will be solved through discussion with the 3rd reviewer. after extracting data and information, professional research design tools will be used to assess research quality and bias risk. two reviewers will use the double-blind method to independently assess and check the bias risk. if there are differences between the reviewers, they will be resolved through discussion. at the same time, they will discuss with the third party reviewer to solve the bias risk difference. two researchers will use the methods and cross checks recommended by cochrane collaboration handbook to independently assess the bias risk of each study [10] : random sequence generation, task hiding, blind method, incomplete result data, selective result reporting, and other biases. in these 6 areas, we make "yes (low bias)," "no (high bias)," and "unclear (lack of information or bias uncertainty)" judgments to assess the risk of bias in each study. the quality assessment tool for quantitative studies [11] will be used to assess the quality of pre-post studies and non-rcts. this tool evaluates 7 domains: selection bias, study design, confounders, blinding, data collection method, withdrawals, and dropouts. commentators will summarize the risks of biased judgment in each of the areas listed in different studies. reviewers will review against the cochrane collaboration tool to assess the risk of bias. table 1 search strategy for the medline database. searches results 1 xiyanping injection 29 2 xuebijing injection 129 3 reduning injection 49 4 tanreqing injection 43 5 xingnaojing injection 31 6 shenfu injection 137 7 shengmai injection 68 8 shenmai injection 154 9 chinese traditional medicine injection 3 10 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 618 11 new coronavirus 213 12 novel search strategy for chinese clinical trial registry centre. "xiyanping injection" and novel coronaviruses 4 2 "xuebijin injection" and novel coronaviruses 2 3 "reduning injection" and novel coronaviruses 1 4 "tanreqing injection" and novel coronaviruses 1 5 "shenfu injection" and novel coronaviruses 1 li et al. medicine (2020) 99:31 www.md-journal.com researchers will summaries the main characteristics of each included study, including the general profile of the study, the methods, the characteristics of participants, interventions, controls, and the outcomes. a meta-analysis will be performed on studies that showed effective rate, mortality rate, or other outcomes. for studies for which a meta-analysis is appropriate, review manager 5.3 software will be used to combine the odds ratio or rr with 95% confidence intervals. a fixed effects model will be used if there is no evidence of heterogeneity and a random-effects model will be used if there is significant of heterogeneity. study heterogeneity will be assessed using the i 2 statistic. specifically, i 2 values will be stratified as follows: might not be important (0-40%), may represent moderate heterogeneity (30-60%), may represent substantial heterogeneity (50-90%), and considerable heterogeneity (75-100%), the corresponding p values will also be taken into account. [8] at the time of data collection, if subgroup analysis can be performed, the reviewer will analyze according to the age and gender of the patient, intervention (different injections, different doses), controls and whether the patient has other chronic diseases. if the interaction test between related subgroups is <0.05, the reviewer will analyze and adjust it to eliminate deviation and risk, so as to ensure the stability of evidence. sensitivity analysis will examine the reliability and heterogeneity of the results of the mate analysis and examine the bias of the samples. the study of eliminating the risk of high bias and reducing bias can ensure the stability of the analysis results. following the method proposed by sterne et al, [12] funnel chart was used to measure publication bias, and review manager 5.3 software was used to measure publication bias. if no bias is published, the results show a symmetrical funnel-shaped reversal shape. this systematic review protocol is designed to provide evidence regarding the effects and safety of chinese traditional medicine injections on patients with covid-19, such evidence may be useful and important for clinical treatment decisions. the results should be disseminated through publication in a peer-reviewed journal. since the data and results used in the systematic review will be extracted exclusively from published studies, approval from an ethics committee will not be required. in chinese traditional medicine aspect, covid-19 is expressed as the inclusion of cold and heat, complex of dryness and wetness, and the pathologic nature of both reality and deficiency. the pathogenesis is characterized by "poison, dryness, dampness, cold, deficiency, stasis," and inflammation as well as respiratory distress. [13] chinese traditional medicine injections were firstly recommended by the chinese clinical guidance of covid-19 pneumonia diagnosis and treatment (4th edition) published by china national health commission on february 4, 2020, which suggested to apply xiyanping injection in the mid-term clinical treatment, while shenfu injection and shengmai injection in the critical stage. xuebijing injection can apply in both of the period. [14] in the chinese clinical guidance of covid-19 pneumonia diagnosis and treatment (7th edition), there are 8 injections totally, including xiyanping injection, xuebijing injection, reduning injection, tanreqing injection, xingnaojing injection, shenfu injection, shengmai injection, and shenmai injection for severe and critical patients with covid-19. and it also recommended to combine 0.9% sodium chloride injection 250 ml with xiyanping injection 100 mg bid, or reduning injection 20 ml, or tanreqing injection 40 ml bid, to patients with viral infection or mild bacterial infection. novel coronavirus and sars-cov are both belong to coronavirus of genus b. it is reported that 2019-ncov is about 79% genetically similar to sars-cov. [15] researches have demonstrated that chinese traditional medicine injections were applied in patients with sars-cov infection, which played a great role in ameliorating the clinical symptoms, improving the body's immunity, reducing complications, and shortening the course of disease. [16] [17] [18] [19] thirty-four patients with covid-19 who were treated by the combination of traditional chinese and western medicine in hubei province were treated with traditional chinese medicine on the basis of western medicine, including xuebijing injection, tanreqing injection, shengmai injection, and shen annotation injection. the results of clinical treatment show that the use of traditional chinese medicine decoction and injection before the patient's admission or lung injury is more helpful to the overall recovery of patients. [5] treatment of covid-19 with xuebijing in dongfeng hospital affiliated to hubei medical college, the results of retrospective analysis on the clinical efficacy of xuebijing showed that on the basis of routine antiviral treatment, the combination of xuebijing injection can promote the absorption of pulmonary lesions and improve the efficacy, reduce the incidence of severe cases, which may be related to the improvement of microcirculation and the effective reduction of mortality of septic shock. [20] however, it is not obvious in improving the inflammation index and promoting the negative transformation of nucleic acid, and the reason needs further research. [21] from 2013 to 2016, the "centralized monitoring research on clinical safety of xuebijing injection" was carried out in 93 second-class (including) hospitals nationwide. [22] in this study, 96 cases of adverse reactions of xuebijing injection were detected, and the incidence of adverse reactions was 0.30%, which belonged to the level of occasional study. the results showed that xuebijing injection had a high safety, a slight degree of adverse reactions and a good outcome under the condition of clinical rational use. [23] although the guideline mentions these traditional chinese medicine injections including xiyanping injection, xuebijing injection, reduning injection, tanreqing injection, xingnaojing injection, shenfu injection, and shengmai injection can be used to treat severe patients with covid-19, and some clinical research reported the efficiency, there is no systematic review and meta-analyses to investigate the effects and safety of chinese traditional medicine injections. as far as the current registration situation is concerned, many clinical rct trials are about to be carried out. considering this, the present study aims to completely review the effects and safety, which will be of great significance to the clinical treatment of covid-19. clinical features of patients infected with 2019 novel coronavirus in wuhan, china early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia national health commission of the people's republic of china clinical study on 34 cases of new coronavirus pneumonia treated with integrated traditional chinese and western medicine cognition and thinking of new coronavirus pneumonia in traditional chinese medicine xuebijing injection versus placebo for critically ill patients with severe community-acquired pneumonia: a randomized controlled trial preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015 statement cochrane handbook for systematic reviews of interventions. version 5.1.0 [updated the cochrane collaboration's tool for assessing risk of bias in randomised trials national collaborating centre for methods and tools. quality assessment tool for quantitative studies systematic reviews in health care: investigating and dealing with publication and other biases in meta analysis analysis on the treatment of pneumonia infected by new coronavirus (2019-ncov) from the cold epidemic national health commission of the people's republic of china medicine (2020) 99:31 www.md-journal genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding application of chinese medicine injection in the treatment of sars chinese pharmaceutical association: academic affairs department of chinese pharmaceutical association analysis on the application of chinese patent medicines for the treatment of sars clinical study on treatment of severe acute respiratory syndrome with integrated traditional chinese and western medicine clinical study on 71 cases of sars patients with interventional treatment of traditional chinese medicine thoughts on the rational use of traditional chinese medicine injection in the treatment of new coronavirus pneumonia (covid-19) observation of the clinical efficacy of xuebijing in the treatment of new coronavirus pneumonia a real-world study on adverse drug reactions to xuebijing injection: hospital intensive monitoring based on93 hospitals (31,913 cases) xuebijing injection in the treatment of new coronavirus infected pneumonia (covid-19) evidence base and research prospects key: cord-018699-gri4vybv authors: tobias, michael charles; morrison, jane gray title: china declares global state of emergency: an urgent telegram from taihu date: 2014-06-10 journal: why life matters doi: 10.1007/978-3-319-07860-1_27 sha: doc_id: 18699 cord_uid: gri4vybv may 18th, 2013, china’s 4th most powerful politician, yu zhengsheng, chairman of the national committee of the cppcc (chinese people’s political consultative conference) opened the second conference of the (carbon-neutralized) taihu world cultural forum in hangzhou, a city 1 h by speed train southwest of shanghai. “what kind of a planet will we leave to our descendants? this is an urgent subject which deserves the collective attention of the whole world,” he said with a sincere air of emergency. percentage of the 30,000 or so endemic plants (8 % of the world's total). over 27 % of china's 6347 vertebrates (including 581 mammal, 1244 avian and 660 reptile and amphibian species) are at risk of extinction, including the largest number of threatened primates, from rare snub-nosed monkeys of the genus rhinopithecus to the hainan gibbon. as for the estimated 20,000 chinese marine species-into whose in-shore and oceanic biomes the vast majority of chinese chemical toxins are dumped-disappearing pink, and yangtze river dolphins are unambiguous indicator species. other such bio-indicator species include père david's deer, snow leopards, the chinese alligator, pangolin, and the world's largest number of endemic pheasants, not to mention a quarter of the world's unique rhododendron species, rare ferns and other bryophytes, and-last but surely not least, the giant panda and-most tragically, the south china tiger [3] , deemed by the iucn to be "functionally extinct" although it once ranged through the beautiful forests of hangzhou (fig. 27.3) . while in situ legislation is rapidly evolving (dating back to 1988 with the law on the protection of wildlife, order number 9), and baseline data sets are increasingly refined for the country's vast biodiversity, abetted by all of the state-of-the-art science, geo-and bio-technologies that have so brilliantly powered china's applied engineering renaissance and economic miracles, there remains an undiminished, if brutal truth: china has the most wilderness left to lose of any country on the planet, roughly 28 % of her remaining wild countryside. or, one might say, china has the most wilderness yet to safeguard. that is, of course, assuming her new leadership under president xi jinping will maintain focus on this priority. indeed, statistics now show that a true and lasting environmental movement has taken hold across the country. says yang zhaofei, vice-chair of the chinese society for environmental sciences, "the number of environmental protests [4] has increased by an average of 29 % every year since 1996, while in 2011 the number of major environmental incidents rose 120 %." while the taihu conference was taking place over the course of two days, cadmium-tainted rice and baby food scandals, as well as chinese h7n9 virus humanto-human transmission prospects were making headlines. four months earlier, beijing-which maintains a sophisticated air quality index focusing on minute particulate matter smaller in diameter than 2.5 μm (the "invisible killer") [5] -had seen three days of the worst air pollution [6] -in the city's documented history reaching for the first time ever, the "orange" [7] level of risk. travelers to china are by now accustomed to seeing people wearing masks as particulate matter far exceeds on any given day world health organization recommended acceptable thresholds. among the salient components fueling such pollution are the fundamentally exponential gdp(s) driven by a human population explosion across the nation's 31 provinces poised to hit between 1.4-and-(in the most sobering projections) 2 billion chinese. then there is the dust, and the dust storms from the deforestation largely along the north china plain where water levels are dangerously diminishing and forests denuded. but the most obvious contributor is the nation's vast consumption of coal (china is said to possess some 13 % of the world's recoverable coal reserves [8] for the generation of her more than 1,000 gw of currently needed electrical capacity, and with it an estimated abstraction of 12.6 m 3 of groundwater for every ton of coal across the fossil fuel's entire supply chain. add to these, china's rapacious appetite for animals on breakfast, lunch and dinner plates; what one commentator has likened to a kind of "revenge" eating of meat to make up for famines in past years. writes nicola davison for the important bi-lingual magazine, "chinadialogue" (whose founder and editor attended the taihu world forum, ms. isabel hilton, a renowned china expert and member of the royal institute of international affairs), "in 1980 the average chinese person ate 14 kg of meat. today that person eats over four times more…." moreover, says davison, "pork is china's favourite meat [9] : last year the country produced 50 million tons--more than half the world's total." with increased income generation, more pigs will be slaughtered, more effluent emitted, contributing to the overall groundwater and air pollution drama deeply embedded in everybody's life across china ( fig. 27.4) . professor peter li [10] has elsewhere stated that "china surpassed the us as the world's biggest meat producer in 1990, and the chinese authorities have long looked to the industrialized west as the object of emulation in meat production." but, at the same time, "china has lagged behind the industrialized nations in animal protection law-making for more than 180 years ( fig. 27 .5)." china has also exported this lack of animal welfare in the same name of consumption, whether by driving the market for ivory and corresponding slaughter of elephants; or in the insatiable desire-often delusional-for aphrodisiacs or any number of other alleged animal-derived medicinals, resulting in the near extinction of rhinos and tigers, and the abominable torture and killing of bears for their bile which contains ursodeoxycholic acid and is believed to help with human digestion and the dissolution of gallstones. add to this the melting of glaciers and the looming grain crisis. china's $ 120 billion annual surplus will not be enough to produce the 400 million tons of grain needed each year from an already arable land base whose productivity and soil nutrient turn-over rates are facing utter exhaustion and extraordinary nitrogenous fertilizer overshoot. ecological schizophrenia captures both the upside and colossal downside of human affairs in china. on the one hand, there is the current construction of the shanghai tower, second tallest and smartest building in the world, engineered at the most formidably green standards ever devised. moreover, china has long embarked on the largest reforestation program and national strategic plant conservation initiatives in human history. but the biodiversity hotspots and coldspots are increasingthose areas with the largest aggregates of species, populations and genetic diversity at risk that would, otherwise, service-hopefully humanely, wisely and sustainably-the agricultural and medical needs of future chinese generations. all that on top of the greatest need of all: our species' humility before the far greater vastness of millions of other species which give us essential physiological, emotional and psychological health and solace (fig. 27.6 ). this is a universal quotient of ecology, by no means unique to china. what is unique-and what characterized the dominant theme of the taihu world cultural forum-is the risk to which our species, and our species alone, has exposed the rest of the creation. the chinese know this, both in terms of their glorious shan-shui landscape aesthetic traditions (from confucius, mencius, buddha, lao tzu, hseigh ling-yun, han-shan, li cheng, kuo hsi, and so many other luminaries of chinese literature, painting and philosophy) to the environmental awareness that pervades chinese rural culture with much the same contemporary reverence and sensitivity one might find in countries as diverse as china's neighboring bhutan, or in great britain, switzerland, ecuador or the united states. to some, who know only the pollution of beijing, the nightlife and commerce of hong kong, or the skyscrapers of shanghai, this might seem off center, but it is not. china is brilliantly in tune with nature and has exactly what it takes to be a world ecological leader. that is both my personal view, and the overall assessment that emerged at the second world cultural forum, though not without rigorous self-reflection voiced openly at taihu, all in a clear effort to make future taihu gatherings the ecological equivalent of the davos economic forum. with an eight-part proclamation signed by the delegates, taihu promises to usher in what is hoped to be a new "ecological civilization" and one which ambassador jean-jacques subrenat (representing former french prime minister jean-pierre raffarin) described as the precursor for much "action" in as much as "awareness is not neutral," or, as prime minister samaras eloquently suggested, what is needed is a move from environmental protection to environmental improvement. such invocations from both the chinese and their guests were the order of the day at taihu. this year being the 30th anniversary of bilateral relations between china and mozambique, president armando emilio guebuza's opening keynote address made it abundantly clear that a flourishing biodiversity-whether in his native african nation, in china, or anywhere on earth-is "the bedrock… of human civilization." that should we fail to halt climate change, the many "unknown consequences" will, among other things, impede our ability to enjoy "blue skies," a metaphor the president employed with unmistakable and fitting poignancy, thus setting the subsequent tone for the entire conference, both by his gravity and his great heart; his ebullience and unwavering "hope" for the world (fig. 27.7) . the litany of concerns and concomitant convictions raised in taihu's two days transcended, even, the june 2012 un rio+20 density of wake-up calls, perhaps because there was no time, nor intention to haggle and negotiate. with maui's brilliantly astute, affable and practical mayor alan moriyoshi arakawa sharing the podium with pierre laconte, president of the foundation for the urban environment in belgium (who stressed the necessity of walking at least 30 min every day) and others, this was a conference focused upon getting the job done; human survival; spiritual freedom; core values of sustainability that transcend greed and economic disparities; that overcome weapons of ecological mass destruction and extinction, redeem biological integrity for all sentient beings, redress what has gone wrong, re-wild our hearts, re-attune our compasses, achieve the achievable, live and let live before it is too late (fig. 27.8) . former dutch prime minister ruud lubbers, a great environmentalist, human rights champion and original member of the earth charter commission, reflected on how the word "culture" had changed in china during his many years visiting the country; from the days of the "cultural revolution" to the new ecological culture sweeping china and so much in evidence at taihu. delegates from outside china-russia, estonia, cuba, across the european union and the united states-were not a little stunned by the remarkable candor aired by chinese politicians, scientists, philosophers and cultural historians who each touched upon spirituality and religion; international collaboration; personal emotion; family life and the roots of all cultures as seminal to the enormous challenge of engendering a green, circular, low-carbon, equitable and biologically-restored planet. may 18th was named the official world ecological civilization day. "we must restore the balance of man and nature-[this is] our dream in china," yan zhaozhu gently intoned (executive chairman and secretary-general of the entire forum). while ye xiaowen, vice president of the academy of chinese culture, likened this challenge to the "renaissance," but one that must get beyond industrialization, urbanization and the consumption of fossil fuels. those were the vehicles, he described, that delivered prosperity to some but turned humans into "enemies of nature," a syndrome that today is manifested in poisonous wastes, the measurement of moribund health in parts per million, and outbreaks like sars coronavirus. the sum total of all that prosperity, said ye xiaowen, has become "an ecological crisis plaguing the world." this world view, said matthew hodes, director of the united nations alliance of civilizations, is paramount to a constellation of eco-crises "beyond debate." hodes reminded participants that the first three words of the united nations charter are "we the peoples" and sounded a cautionary note by invoking the un millennium development goal #7 [11] focused on environmental sustainability, particularly for the tens-of-millions of environmental refugees and economically marginalized peoples of the world. hodes underscored the ecological interdependency of a climate-challenged global population by pointing to the fact that china had just joined the arctic council, noting that between 2010 and 2012, arctic maritime commerce had witnessed ten times the ships and tens times the tonnage of commercial goods, as the ice continued to vanish (fig. 27.9 ). such cautions were furthered by dr. roy morrison, director of the office for sustainable development at southern new hampshire university, who referenced a world of "ghost cities" and marshaled acute logic on behalf of a "business proposition [that] is simple"-to extract trillions of dollars from obsolete, polluting mechanisms, and mine "savings streams" for natural capital, not destruction. utilizing citywide utility scales and energy efficiencies, morrison predicted that we could well hit zero emissions as a civilization within 20 years if we really set our minds and hearts to it, utilizing such instruments as a tax administered by the un for all per capita emissions exceeding three tons. ultimately, the chinese ecological position was delivered in unadulterated form by dr. qu geping, chairman of the environmental and resources protection committee of the national people's congress. i first met dr. qu geping at his offices in beijing in the early 1990s when he was the chairman of the 8th environmental and resources protection committee of the npc, a position equivalent to the head of the epa. back then he told me that the chinese had widespread awareness of environmental crises sweeping the nation and that laws were quickly coming into being (fig. 27.10) . but here in taihu his message was terse: "i have noticed some progress… [but, so far,] we have failed to avoid the old path. i can say that the situation in china today is extremely severe. china must make tremendous and extra efforts." or, as dr. ervin laszlo warned, humanity will become the "first self-endangered species. [but] humanity can evolve and mutate culturally. the nature of crisis is also an opportunity... ." this biodiversity crisis, involving animal rights and human rights; this overwhelming and unprecedented crisis was the focus of taihu-an urgent telegram to all of china, to all of the world. will people read the telegram? i, too, was a delegate at taihu along with jane gray morrison. in my address, i expressed the belief that 'we need to be compassionate and non-violent; to be focused upon the biological bottom-line.' i suggested that hangzhou become a global biodiversity corridor, in keeping with her traditional garden of eden ethos; a greenbelt like that surrounding kyoto, teeming with gardens and wildlife; or like devonport, new zealand-the first nuclear-free zone in the world; or denmark's samsø, a nearly carbon-neutral island; organic mendocino, organic wine and olive regions in spain-andalusia and la mancha-or the haa valley of bhutan. a green space like the vast majority of the nation of suriname, or any jain monastery across india where gross national happiness and a reverence for all living beings reigns supreme. is this possible in china? i believe it is. this is a nation whose ancient philosophers echoed century after century that heaven and humanity can be one. princess of the netherlands) who concluded with deep but unyielding emotion 2nd world cultural forum (taihu, china) kicks off in hangzhou international union for conservation of nature and natural resources, red list (2013) panthera tigris ssp. amoyensis (south china tiger china's new "middle class" environmental protests china central television (2013) pm2.5: invisible killer world air quality.info, insdio prod (nd) beijing air pollution: real-time air quality index (aqi) beijing adopts emergency measures for "hazardous" pollution china's growing appetite for pork creates new pollution animal rights in china millennium development goal # 7 -ensure environmental sustainability: how are we doing? key: cord-262936-yo6jf3ng authors: deng, jia-gang; hou, xiao-tao; zhang, tie-jun; bai, gang; hao, er-wei; chu, justin jang hann; wattanathorn, jintanaporn; sirisa-ard, panee; soo ee, ch'ng; low, john; liu, chang-xiao title: carry forward advantages of traditional medicines in prevention and control of outbreak of covid-19 pandemic date: 2020-06-02 journal: chin herb med doi: 10.1016/j.chmed.2020.05.003 sha: doc_id: 262936 cord_uid: yo6jf3ng members of the china-asean joint laboratory for international cooperation in traditional medicine research used the video conference platform to exchange and discuss the advantages of traditional medicine through the form of score exchange and report, and research and develop the amount and issues of the therapeutic covid-19 products of concern. this paper manly reviews the achievements of the implementation of the epidemic prevention and control plan, advances of scientific basic studies on sars-cov-2, analysis and screening of potential targets and pathways of antiviral compounds based on network pharmacology and development of antiviral food dual-use products. the authors believe that the declaration of the (10+3) special meeting of national leaders on epidemic prevention and control should raise the medical and pharmaceutical issues of common concern. it is the responsibility of our joint laboratory members to accelerate the development of traditional medicine research and industry. also the authors believe that this exchange will certainly promote the development of the cause of cooperation. the world is facing unprecedented health threats, social and economic shocks from covid-19. world health organization (who) is to address the global impact of the covid-19 pandemic. who reported that the world has now been more than 3.5 million cases of covid-19 (who, 2020) . around the world, the pandemic has caused severe disruption to essential health services, including to community-based health care, and in many countries trained members of the community play a vital role in delivering essential health services like vaccination, drug screening, clinical detection, prevention and management of the diseases. we must address this now and in the long-term by prioritizing diagnosis and care for those who are most at risk. the who will help communities most at risk by scaling up local medical and public health efforts and better protect people around the world from future pandemics. at this grim time, the timely convening of the asia-pacific (10+3) special video-meeting demonstrates the responsibility of countries in the asia-pacific region. the statement and declaration of the special session pointed the way to how our co-laboratory could exploit the advantages of traditional medicines. the commitment to strengthen solidarity, enhance cooperation and mutual support among the apt countries to control and contain the spread of the pandemic, addressing the adverse impact of the pandemic on our societies and economies. the asean countries hereby resolve to 18 terms. the strengthen 5 points out that "scientific cooperation in epidemiological research, including through the apt field epidemiology training network, coordination, including with the private sector, towards rapid, research, development, manufacturing and distribution of diagnostics anti-viral medicines and vaccines, adhering to the objectives of efficiency, safety, equity accessibility and affordability", and the strengthen 15 points out that "efforts to stabilize the manufacturing and supply of essential goods and services, including vital medical supplies, critical agricultural products, maintain necessary flow of goods and services and sustain supply …… in order to support economic development, reaffirming our commitment described in the joint leader's statement on the regional comprehensive economic partnership released in 2019" (china daily, 2020) . we learned from the conference documents that the two articles had great responsibilities for experts in joint laboratories engaged in the research, development and application of traditional medicines. we are also holding a joint laboratory work meeting on this important day (5 th may) to share research advances and innovations in the fight against the epidemic using traditional drug services in the asia-pacific region. during the epidemic, we also carried out some theoretical and applied studies and published several papers (liu 2020a; liu 2020b; liu, wang & yan, 2020; liu wang & zang et al., 2020a; liu, wang & zang et al.,2020b; liu, yi & wang et al., 2020; han et al., 2020; qin et al., 2020) . this article will focus on the expert discussion and reports contents. nankai university was involved in the development of diagnostic reagents and techniques to combat with covid-19, and developed covid-19 igm/igg antibody detection kit. by integrating ai technology and ct images, the new diagnostic technique was successfully used in clinical detection of covid-19. in order to rapidly discover lead compounds for clinical use, researchers identified a mechanism-based inhibitor, n3, by computer-aided drug design and subsequently determined the crystal structure of covid-19 virus mpro (3clpro) in complex with this compound. an initiated program of combined structure-assisted is used for drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the covid-19 virus main protease was designed (jin et al., 2020) . the rna-dependent rna polymerase (rdrp, also named nsp12) is the central component of coronaviral replication/transcription machinery and appears. researchers also report the cryo-em structure of covid-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-å resolution. a comparative analysis model shows how remdesivir binds to this polymerase. the structure provides a basis for the design of new antiviral therapeutics targeting viral rdrp (gao et al. 2020) . by actively carrying out joint research, the structure of covid-19 key proteases, 3clpro and rdrp have been published in science and nature. a series of lead compounds were screened for covid-19 related targets from natural product compound library. mangiferin is well-known xanthone in mango fruits, barks, peel, leaves and stone. the compound has potential pharmacological effects, such as antioxidant, antiaging, antiviral, hepatoprotective, analgesic and immunomodulatory activities (imran et al. 2017) . mangiferin is a natural miracle bioactive compound against lifestyle related disorders. baicalin is derived compound from the plant scutellaria baicalensis georgi. it is famous in many countries, including the russian federation, european countries and several east asian countries, for its potential pharmacological properties including anti-inflammation effect, apoptosis modulation, autophagy induction, cell cycle arrest, metastasis suppression and oxidative stress inhibition and so on (li et al, 2019) . from the pharmacological actions of them, we suggested that the two compounds maybe have relation with antivirus of sars-cov-2. prof. bai's team at nankai university in china used the pymol software to display the 3d map of the interaction of mangiferin with mpro (pdb: 6lu7). the interactions between the mangiferin and the protein include hydrogen bond interactions with leu141, ser-144, ). the software was also used to display the 3d map of the interaction of baicalin ( chinese academy of engineering (cae) to protest the development of a major project "lanzhi bacteriostatic solution" (research and development of new chinese medicine sprayers based on covid-19 tcm prevention and control strategies) has been approved by academician chang-xiao liu and the chinese medicine team of tianjin institute of pharmaceutical research (tjipr). based on the epidemic characteristics and prevention and control countermeasures and traditional chinese medicine for external use in fire prevention theory and experience, design suppresses environmental pathogenic microorganisms and human conditioning qi activity for the principle formula, in raw materials, logistics, testing, processing is very difficult to special circumstances, complete chinese medicine epidemic prevention and control product "lanzhi antibacterial liquid (spray type)", complete the production of 20000 bottles of products, and giving the epidemic area. after the outbreak of covid-19, the research team of gxucm responded actively, and the application for two special science and technology projects to prevent and control pneumonia caused by sars-cov-2 in guangxi in 2020 was approved, including sino-singapore cooperation for evaluating the effectiveness and application of guangxi zhuang/yao medicines against undertook sub-topics. this formula can be used to treat the deficiency of spleen and lung, deficiency of qi and yin, shortness of breath, tiredness, tolerance and vomiting, or low heat, dry cough with less phlegm, dry mouth, thirst, palpitations, excessive sweat, insufficient sleep, weak stool and irritated stools during the recovery period after discharge. tongue light fat or dry tongue less fluid, moss white greasy or less moss, veins fine or weak and so on. it can also be used as a source of qi-yin deficiency or yin deficiency holding wet constitution people daily conditioning drinking. the early symptoms sars-cov-2 infection was fever, dry cough, sore throat, fatigue, etc. at the beginning, patients were mainly with the plague rage infringement throat, causing acute inflammation. at present, the oral preparations are the preferential therapy. the guangxi project team developed a contain gargle solution "antipyretic wet nurse liquid", for the epidemic prevention and control. using six kinds of traditional chinese and ethnic medicines including atractylodis rhizoma (artemisia annua l. and aractylodes lancea (thunb.) dc.) etc., in chinese medicine and national medicine formula. the preparation is given locally in the mouth, which can increase the contact surface between the drug and the lesion, enhance the efficacy of clearing heat, changing humidity, and improving pharyngeal protection. currently, the product prescription and process research have been completed, and the simple archival materials of traditional chinese medicine and ethnic medicine preparations have been submitted to the food and drug administration of guangxi zhuang autonomous region, china. the national university of singapore has established the state of the art bsl3-core facility in the yong loo lin school of medicine as a screening technology platform for drug discovery research against sars-cov-2. the bsl-3 core facility, led by associate professor justin chu, has successfully isolated and cultured the sars-cov2 from covid-19 patients from the hospitals .in view of the coronavirus replication cycle, 54 chemical components in the library of gxucm and 461 chemical components in the library of ace2 receptor inhibitors are being screened for anti-sars-cov-2 virus activity. after screening the active compounds, a human ace2 transgenic mouse model will be established to study the anti-sars-cov-2 virus activity in vivo. with this platform, target prediction was carried out to achieve high-throughput screening (fig. 3) and screening scheme design (fig. 4) to obtain valuable information. the project team searched the domestic and foreign literatures, screened the reported compounds with anti-coronavirus, influenza virus and hiv, and prepared 54 active chemical components through purchase and isolation. the team studied the chemical composition analysis of potential targets and pathways of 54 potential antiviral preparations, and screened and found the total of 87 potential targets in the database. they also obtained information on the protein and the protein interaction network, download protein-protein interaction information using cytoscape software, according to the network topology parameters selected is greater than 2 times the average degree of targets, the targets play a pivotal role in the network, key targets for received 49. the network topological parameters of compounds and targets were visualized by cytoscape software. the results showed that the top five compounds were resveratrol, genistein, estradiol, berberine and baicalein. the top five targets were tp53, akt1, bcl2, nos3 and cdkn1a. they also detected the neutralization activity of the pseudovirus, and initially found four compounds with potential antiviral activity, and one compound extract of traditional chinese medicine. currently, a cell based assay is being used for activity validation in the nus medicine biosafety level 3 research facility, a research unit in the national university of singapore. during january 20, 2020 to march 23, 2020, the project team has collected 25 guiding documents, such as the latest version of diagnosis and treatment plans, prevention and treatment plan, and technical guidelines, which have been published by the national health commission and the health commissions of 24 provinces, autonomous regions and municipalities directly under the central government. collection of treatment prescription information in each program, the establishment of a database, including prescription name, drug name, efficacy classification, sexual taste, efficacy indications, treatment, disease stage and other information. using excel, graphpad 8.0, spss modeler18.0 and other software, the paper made a statistical analysis on the usage frequency, classification frequency, properties and compatibility characteristics of all kinds of traditional chinese medicines. a total of 137 prescriptions of traditional chinese medicine for treating covid-19 were collected, and 178 herbs were included. chinese medicine with the functions of clearing heat, tonifying deficiency, resolving phlegm, relieving cough and asthma, relieving exterior syndrome, resolving dampness, clearing damp and promoting diuresis were the mainly used chinese medicine, in which types of resolving phlegm, relieving cough and asthma, resolving dampness, clearing damp and promoting diuresis accounted for 35.78%. there were also a considerable number of medicines with the function of removing dampness in the types of clearing heat, tonifying deficiency and relieving exterior syndrome. it can be seen that the medicines with the function of removing dampness was the first choice in the treatment of covid-19 with chinese medicine. the chinese medicine with the function of aromatic resolving dampness, clearing heat and drying dampness, drying dampness and tonifying spleen qi, drying dampness and removing phlegm, promoting diuresis and relieving swelling, promoting diuresis and relieving exterior syndrome were mainly used chinese medicine for removing dampness. among them, the most frequently used medicine was tianjin institute of pharmaceutical research carried out the development of special medical food. according to the needs of covid-19 nutrition support, the institute seizes the time to develop new special medical food "yiyiyuan" during the epidemic and has completed the production of 20,000 boxes of finished products that was donated to hubei epidemic areas, china. dr. panee sirisa-ard, associate professor, university of chiangmai, thailand, studied a kind of medicinal mushroom that can improve the immunity of patients. it has the application of resistance to h1n1 virus. at present, the mechanism of action of this mushroom has been studied. it is looking forward to funding the research. keding international co., ltd. aponte, which is mainly made of ganoderma lucidum in tiger milk, has a good effect on pulmonary infection. are almost cheap kitchen "medicine" one of the world's most countries, especially southeast asian countries like to eat. they contain antibacterial and antiviral compounds, anti-inflammatory, antioxidant, anti-tumor effects, but also conducive to the human body to improve immunity, to fight against "pathogen invasion". garlic and onions contain 70 phytochemicals that reduce the risk of hypertension. ginger has a warm and spicy taste, which can enhance blood circulation, stimulate gastric juice secretion, stimulate the intestines and promote digestion. it can play sweating, cooling, and relieve fatigue, fatigue, anorexia, insomnia, abdominal distension, abdominal pain, and so on. the antioxidant, anti-inflammatory and immune-modulation effects are beneficial in improving initial symptoms for covid-19 patients. the prevention and control of the covid-19 epidemic is a top priority for the world. who recognizes that traditional, complementary and alternative medicine has many benefits in public health care. we know that the traditional herbal products are very value for treatment and prevention of covid-19, but note that it needs to research and select traditional medicine products in clinical efficacy and safety for covid-19 treatment. who welcomes every opportunity to collaborate with countries and researchers to develop new therapies and encourages such collaboration for the development of effective and safe therapies. it concerns not only the safety of the people, but also the stability and development of the world. the members of the china-asean joint laboratory of traditional medicine use the video conference platform to exchange and discuss the advantages of traditional medicine through the form of score exchange and report, and research and develop covid-19 product amount and issues of concern to research and development. in summary, this paper manly contents achievements of the implementation of the epidemic prevention and control plan, advance of scientific basic studies on sars-cov-2, analysis and screening of potential targets and pathways of antiviral compounds based on network pharmacology and development of antiviral food dual-use products. the authors believe that the declaration of the (10+3) special meeting of national leaders on epidemic prevention and control should raise the issue of medical and pharmaceutical issues of common concern. it is the responsibility of our joint laboratory members to accelerate the development of traditional medicine research and industry. therefore, we believe that this exchange will certainly promote the development of the cause of cooperation in traditional medicines. the authors declare no conflict of interests. joint statement of the special asean plus three (apt) summit on coronavirus diseases-2019 (covid 2019) structure of the rna-dependent rna polymerase from covid-19 virus mechanism of tanreqing capsule on treatment of coronavirus disease 2019 based on network pharmacology mangiferin: a natural miracle bioactive compound against lifestyle related disorders structure of mpro from covid-19 virus and discovery of its inhibitors baicalin mitigated mycoplasma gallisepticum-induced structural damage and attenuated oxidative stress and apoptosis in chicken thymus through the nrf2/ho-1 defence pathway pay attention to situation of sars-cov-2 and tcm advantages in treatment of novel coronavirus infection drug-therapy for novel coronavirus infection: compassionate use and its implications understanding novel coronavirus pneumonia, paying attention to research and development of epidemic prevention and control drugs using "compartment model" dynamics to understand the transmission regularity of coronavirus disease 2019 (covid-19) during the outbreak period attach importance to research and development of chinese materia medica based on prevention and control needs of sars-cov-2 infection understanding coronavirus (sars-cov-2) and thinking about strategy of antiviral drug development. drug evaluation research screening active components of anti-sars-cov-2 from yao medicine named "eighteen zuan" by literature mining and molecular docking technology who (2020) director-general's opening remarks at the media briefing on covid-19 -6 authors thank for the support of the science foundation projects: (1) chinese academy of key: cord-002583-cgcf7mgj authors: zhuo, xun-hui; sun, hong-chao; huang, bin; yu, hai-jie; shan, ying; du, ai-fang title: evaluation of potential anti-toxoplasmosis efficiency of combined traditional herbs in a mouse model date: 2017-06-01 journal: journal of zhejiang university-science b doi: 10.1631/jzus.b1600316 sha: doc_id: 2583 cord_uid: cgcf7mgj toxoplasma gondii is a worldwide spread protozoan and is able to infect almost all warm-blood animals. no effective drugs are available clinically on toxoplasmosis. chinese traditional herbal medicines have provided remedies for many health problems. there exists a possibility that chinese herbs may provide protection against t. gondii. this work aims to assess the protective efficacy of combined chinese herbs against t. gondii. we screened five herbal medicines that have different pharmacological effects and combined them into a prescription according to the traditional chinese medicine compatibility principle. the drug potential and protective efficacy were evaluated through a mouse model by determining the survival time, the parasite load in blood and tissues, the change of cell proportions in blood and histological detection. the results showed that the survival time of mice in the 500 mg chinese herbs group and sulfadiazine group was significantly longer than that of the pbs control group. also the parasite load in blood and tissues of 500 mg chinese herbs and sulfadiazine groups was significantly lower than that of pbs group at 7 days post infection (dpi), which was in accordance with the result of histological detection. monocyte and neutrophil of infected mice were remarkably increased while lymphocyte was dramatically decreased compared to that of blank group at 7 dpi. the results demonstrated that the 500 mg dosage of our chinese herbs could slow down the replication of t. gondii and prolong the survival time of mice and could be considered as possible candidate drug against toxoplasmosis. toxoplasmosis caused by the intracellular protozoan toxoplasma gondii is a ubiquitous worldwide parasitic zoonotic disease (innes, 2010a) . it is usually asymptomatic in immune-competent individuals but may occasionally lead to severe ocular and neurological disorders (furtado et al., 2013) . when it comes to immune-compromised and congenitally infected individuals, toxoplasmosis can result in lethal systemic disease and eventually death (shen et al., 2016) . currently, the control of t. gondii mainly depends on chemotherapy, such as the combination of sulfadiazine and pyrimethamine, but these drugs have serious side effects (petersen and schmidt, 2003) . even though many antigens including rhoptry, surface, and dense granule excreted-secreted antigens were evaluated as potential vaccines (kur et al., 2009) , there is no licensed vaccine against t. gondii infection clinically making the situation even worse (jongert et al., 2009; innes, 2010b) . therefore, new efficient drugs and safe protective therapies are needed. artemisinin isolated from a chinese traditional medicine artemisia annua is now included in standard treatment worldwide for plasmodium falciparum malaria. subsequent to that, interest in chinese traditional medicine has risen to be considered for providing therapeutic reagents for many infectious diseases. the radix clematidis extract is reported to be a potent inhibitor of matrix metalloproteinase-9 (mmp-9) and notably blocks the nuclear factor-κb (nf-κb) pathway in breast carcinoma cells (noh et al., 2011). na-bangchang and karbwang (2014) found that a chinese traditional medicine atractylodes possesses various pharmacological effects with anticancer, anti-inflammatory and antimicrobial activity, and is now a potential chemotherapeutic for cholangiocarcinoma found in southeast asia. artemisia anomala has been widely and in long-term used for the treatment of inflammatory diseases in china. recent findings suggested that it manifests its antiinflammatory effects through inhibiting the expression of inducible nitric oxide synthase (inos) (tan et al., 2014) . glycyrrhizin, extracted from liquorice, was reported to have antiviral activity through inhibiting replication of the pathogen (cinatl et al., 2003) . throughout history, chinese traditional herbal medicines have provided many remedies for many health problems. the use of most herbal medicines dates back almost 2000 years in shennong's materia medica. however, limited information is available on their pharmacological activity since the use of herbal medicine has been based mainly on empirical treatment. as a consequence, there exists a possibility that many herbal medicines may have unknown effects on different health problems. in this study, we screened five herbal medicines that have different pharmacological effects and combined them into a prescription according to the traditional chinese medicine compatibility principle. we evaluated the protective efficacy provided by the different dosages of this prescription against the challenge of rh strain of t. gondii in a mouse model. female icr mice (6-8 weeks old) were kept in an animal experimentation laboratory under standard conditions according to the guidelines of the regulation for the administration of affairs concerning experimental animals of the people's republic of china. these experiments on mice were approved by zhejiang university experimental animal ethics committee (no. zju201308-1-10-072). tachyzoites of t. gondii rh strain were maintained in icr mice by intraperitoneal (i.p.) serial passage at regular 72 h intervals. the parasites were washed three times by phosphate-buffered saline (pbs) and centrifuged at 1000g for 5 min as previously described (mack and mcleod, 1984) . five kinds of chinese herbal medicines were purchased from huqingyu tang pharmaceutical co., ltd., hangzhou, china. according to the traditional chinese medicine compatibility principle, they were combined as follows: r. clematidis (10 g), fructus ulmi macrocarpae (8 g), atractylodes (15 g), a. anomala (10 g), and glycyrrhizae (6 g). on the basis of the traditional chinese medicine decoction method, herbal drugs were boiled for 3 h in water (1 l) followed by concentrating through a rotary evaporator into 2 g/ml of the whole drugs. sulfadiazine as a positive control drug was purchased from novartis (beijing, china). a total of 140 female mice were randomly divided into seven groups (a to g). mice in groups b-g were i.p. infected with 1×10 3 tachyzoites of t. gondii rh strain. different medical administrations were carried out after infection with t. gondii rh strain as follows: group a, blank control; group b, pbs control; group c, mice were treated with 10 mg/d of sulfadiazine through oral gavage; mice in groups d-g were treated with chinese herbs through oral gavage in single dosages of 300, 400, 500, and 600 mg/d, respectively, according to the chinese pharmacopoeia (national pharmacopoeia committee, 2010). the animals were observed daily for mortality. a total of three mice in each group were euthanized at 3 and 7 days post infection (dpi), when whole blood was collected for a blood routine test; liver, spleen, and lung tissues were collected for quantitative realtime polymerase chain reaction (pcr) and histological section assay. the presence of t. gondii dna was investigated by real-time pcr based on the sag1 gene as described previously (yu et al., 2013) . the genomic dna of blood, liver, spleen, and lung tissues was extracted using a universal genomic dna extraction kit (takara, china) according to the manufacturer's instructions. the forward and reverse primer sequences used in this study were 5'-ctgatgtcg ttcttgcgatgtggc-3' and 5'-gtgaagtggt tctccgtcggtgt-3', respectively, designed by the primer express software (pe applied biosystem), which could amplify a 128-bp fragment under predetermined conditions. sybr ® green was then used to detect fluorescence using the iq5™ real-time pcr system (bio-rad). sterile water and genomic dna of t. gondii tachyzoites were included as negative and positive controls in each run. in addition, a plasmid pmd-sag1 was constructed based on pmd18-t vector using the same primers. to establish standard curves, plasmid pmd-sag1 was tenfold serially diluted ranging from 2×10 4 to 2×10 9 copies per milliliter tested in each independent experiment for t. gondii quantification. each sample had three parallel wells and was detected three times. at least 30 µl of anticoagulated blood samples collected from mice of different groups at 3 and 7 dpi were applied to an idexx procyte dx ® hematology analyzer. each blood sample was read three times. the data were analyzed using the software spss 16.0 for windows (spss inc., chicago, il, usa) and statistical difference was accepted at the level of p<0.05. liver, spleen, and lung tissue specimens from different groups were first fixed in 10% (v/v) buffered formalin and then processed to paraffin for embedding. tissue sections were obtained at approximately 5-µm thickness and stained with haematoxylin and eosin (h & e) stains as described previously (fischer et al., 2008) . sections were examined under light microscopy. in order to determine whether these combined chinese herbs could provide effective protection against t. gondii rh infection, mortality was recorded daily following the t. gondii challenge until all mice were dead and survival curves of all groups were generated as shown in fig. 1 . the survival time of mice in the sulfadiazine group ((13.5±2.0) d) and 500 mg chinese herb group ((9.8±0.69) d) were significantly longer than that in the pbs control group (6.9±0.18 d) (p<0.05). the average survival time of mice in the 300, 400, and 600 mg chinese herb groups was all under 8 d which was slightly longer than that of pbs group, but the difference was not statistically significant (p>0.05). blood and tissue samples were collected from different experimental groups at 3 and 7 dpi with t. gondii, and then dna was extracted as the template for sag1-based real-time pcr to evaluate the parasite loads and dna copy number in t. gondiiinfected mice (fig. 2) . every blood and tissue dna sample was tested in triplicate and no amplification products were observed in wells from the blank control group. results from the blood are shown in fig. 2a . parasite loads in all groups at 7 dpi were survival rate of mice treated with sulfadiazine and different dosages of chinese herbs after challenge with 1×10 3 tachyzoites of t. gondii rh strain. mice treated with pbs were included as negative control and mice infected with no t. gondii were included as blank control. survival rate was monitored daily until all infected-mice died (n=10 mice per group) almost double that at 3 dpi, but no significant difference was observed among these groups. results of spleen, lung, and liver tissues presented a similar pattern in that parasite loads were all largely increased from 3 to 7 dpi, and mice of the pbs control group had statistically significantly higher parasite load compared with sulfadiazine and 500 mg chinese herb groups (p<0.05). however, the parasite loads of mice in 300, 400, and 600 mg chinese herb groups were all fewer than those in the pbs control group but not at a statistically significant level. blood samples were collected from different groups at 3 and 7 dpi directly into a 1-ml tube containing 0.3 mg dipotassium ethylenediamine tetraacetic acid (k 2 edta) and analyzed by an idexx procyte dx ® hematology analyzer. no significant increases were observed in eosinophil among the different t. gongdii-infected groups (fig. 3a) . the proportion of monocyte of infected mice was remarkably increased compared to that of the blank group at 7 dpi ( fig. 3b ; p<0.05). however, lymphocytes of the infected groups were dramatically decreased compared with the blank control group (fig. 3c) and those of the sulfadiazine and 500 mg chinese herb groups were significantly low compared to the other four infected groups (p<0.05). as shown in fig. 3d , neutrophil in the infected groups was increased more than double compared to the blank control group at 7 dpi (p<0.05), and the sulfadiazine and 500 mg chinese herb groups also increased significantly higher among these groups. blood (a), spleen (b), lung (c), and liver (d) tachyzoite burdens at 3 and 7 d after challenge. the dna copies of t. gondii (per milliliter blood or per gram tissue) in blood and tissues of mice after challenge with 1×10 3 tachyzoites of t. gondii rh strain per mouse. the counting of dna copies of t. gondii has been done in triplicate for each tissue and for three mice from each group. values are expressed as mean±sd. columns with different letters present statistical difference (p<0.05) pathological studies were performed through histological sections of liver, lung, and spleen tissues which were collected at 7 dpi from all groups. the livers of sulfadiazine and 500 mg chinese herbs-treated mice displayed few changes compared to normal mice (figs. 4c and 4f), but the livers of the pbs group mice showed a clear cellular separation, which revealed its morphologically incomplete and hepatocellular dysfunction (fig. 4b) , and the livers of 300, 400, and 600 mg chinese herbs-treated mice showed slightly more cellular separation . the lungs of all t. gondii-infected mice represented interstitial pneumonia at different degrees with much thicker alveolar walls compared to that of the blank control group (figs. 4i-4n) , and more severe cellular damage was observed in 300 and 600 mg chinese herbs-treated mice and the pbs control group. the spleen of the pbs group was extensively necrotic with few lymphoid cells and plenty of scattered cells observed. lymphoid follicles were also absent (fig. 4p) . the spleens of other groups also had evidence of necrosis and degeneration with small scattered nodules of dead lymphoid cells (figs. 4q-4u), but they were not as deteriorated as that of the pbs group shown in fig. 4p . t. gondii can infect almost all warm-blooded animals, but no available drugs can eliminate this pathogen from its host without any clinical side effects. the discovery of artemisinin, isolated from a. annua, which can provide effective treatment worldwide against p. falciparum malaria, raises the the results showed the percentage of cells in blood at 3 and 7 d after challenge with 1×10 3 tachyzoites of t. gondii rh strain per mouse. eosinophil (a), monocyte (b), lymphocyte (c), and neutrophil (d) cell percentages were analyzed by idexx procyte dx ® hematology analyzer at 3 and 7 dpi. blood samples were collected from three mice at each group at 3 and 7 dpi, respectively. values are expressed as mean±sd. columns with different letters present statistical difference (p<0.05) question as to whether chinese traditional medicines could afford protection against t. gondii. therefore, five herbal medicines that have different pharmacological effects were screened and combined into a prescription according to the traditional chinese medicine compatibility principle and then the drug potential and protective efficacy were evaluated through a mouse model. molecular methods, particularly real-time pcr, have been treated as sensitive and reliable tools for determining the parasite loads of t. gondii (bell and ranford-cartwright, 2002; li et al., 2012) . hence, we applied an sag1-based real-time pcr method to determine the parasite loads in blood and tissues. we found t. gondii dna could be detected in blood and tissues from all infected groups at 3 dpi with a relatively high level and was almost all doubled from 3 to 7 dpi while no significant difference was observed among these groups. the level of the parasite load of the liver of sulfadiazine and 500 mg chinese herbs-treated groups was lower than that of the pbs control group (p< 0.05). we also found the livers of sulfadiazine and 500 mg chinese herbs-treated mice displayed few changes while a clear cellular separation could be observed in the liver of pbs group mice that presented a morphologically incomplete and hepatocellular dysfunction. the lungs of sulfadiazine and chinese herbs-treated mice possessed a significantly lower parasite load than that of the pbs control group (p<0.05) and the histological result verified this from the morphological perspective. the lungs of all t. gondii-infected mice displayed interstitial pneumonia which had much thicker alveolar walls compared to those of the blank control group. however, the situations of the pbs group, the 300 and 600 mg chinese herbs-treated groups were the worst such that no complete pulmonary alveoli structure could be observed. this revealed the fact that the lungs barely functioned and resulted in rapid death at 7 dpi as shown in the survival curve. as for the spleen, the parasite in sulfadiazine and 500 mg chinese herbstreated groups was at a significantly lower level than that in the pbs group at 7 dpi (p<0.05). the spleens of all infected mice showed necrosis and degeneration. lymphoid follicles of the pbs group were barely observed, and those of sulfadiazine and 500 mg chinese herbs-treated groups also had evidence of necrosis and degeneration with small scattered nodules of dead lymphoid cells. these results were in accordance with the survival curve that the mice of sulfadiazine and 500 mg chinese herb groups lived much longer than the controls. mice treated with 500 mg chinese herbs ((9.8±0.69) d) showed a pathological examinations were based on h & e-stained 5 µm-thick longitudinal sections of liver, lung, and spleen tissues in each group at 7 dpi. liver (a-g), lung (h-n), and spleen (o-u) were collected from seven groups. scale bars represent 20 µm (a-g) and 50 µm (h-u) significantly longer survival time (p<0.05) than the pbs-treated mice. in addition, the average survival time of 500 mg chinese herbs-treated mice presented a similar level as many studies on dna vaccines; the average survival time of rrop18-immunized icr mice is 11.5 d (qu et al., 2013) and zheng et al. (2013) found that after being immunized with rrop5+ rsag1, mice had prolonged survival time of 12.1 d. we assume that t. gondii was able to move to most tissues of mice through blood based on the fact that dna copies of t. gondii had been detected in blood, liver, spleen, and lung. actually, dadimoghaddam et al. (2014) found t. gondii moved to various tissues within 24 h after i.p. injection and the largest number of parasites was observed in the heart, kidney, and liver. the movement trend of t. gondii and parasite load in tissues have been used mainly to evaluate the vaccine effect, anti-parasite and drug disease severity (bell and ranford-cartwright, 2002; romand et al., 2004) . the results gathered here suggested that these combined chinese herbs could afford efficient protection against acute t. gondii infection. machado et al. (2014) demonstrated that the increased monocytes and lymphocytes could be treated as a relevant hematological biomarker of acute retinochoroidal lesions caused by t. gondii. thus we used an idexx procyte dx ® hematology analyzer to determine the changes of cell proportions in blood at 3 and 7 dpi. we found that there was no significant difference among the t. gondii infected groups on eosinophil at 3 or 7 dpi. however, monocytes and neutrophils of infected mice were remarkably increased while lymphocytes were dramatically decreased compared to those of the blank control group at 7 dpi. on the other hand, the significantly lower lymphocyte and slighter lower monocyte of sulfadiazine and 500 mg chinese herbs-treated mice than those of other chinese herbs-treated mice suggests that effective drugs may decrease the cell proportions to hinder the cellular transmission of t. gondii. there are no differences between normal mice and infected mice at 3 dpi. we found t. gondii was capable of escaping the immune system in blood when combining the results of parasite load in blood at 3 dpi. in accordance with the results of machado et al. (2014) , the monocytes were increased drastically at 7 dpi. the recruitment of monocytes is essential in restricting the replication of the t. gondii murine model (mordue and sibley, 2003; robben et al., 2005) . on the other hand, monocytes as well as neutrophils and eosinophils are strong candidates for transport of t. gondii in blood in a way known as a "trojan horse" (lachenmaier et al., 2011) , so the activity of monocyte must be carefully controlled. however, the trend of lymphocytes was opposite to that of machado et al. (2014) . the percentage of lymphocytes was decreased in infected mice mainly because icr mice were sensitive to t. gondii and failed to eliminate the parasite, which was in accordance with the result that all infected mice eventually died. in summary, mice treated with chinese herbal medicines had been showed to elicit partial protection against acute t. gondii infection. moreover, our study indicated that 500 mg chinese herbs could afford more efficient protection than the other three dosages. the results also suggested that our 500 mg chinese herbs could slow down the replication of t. gondii and prolong the survival time of mice. these results demonstrated this combination of chinese herbs could be considered as possible candidate drugs against toxoplasmosis and also that the therapies of traditional chinese herbal medicine can be developed for anti-toxoplasma in the future. real-time quantitative pcr in parasitology glycyrrhizin, an active component of liquorice roots, and replication of sars-associated coronavirus tissue tropism and parasite burden of toxoplasma gondii rh strain in experimentally infected mice. asian pac hematoxylin and eosin staining of tissue and cell sections ocular toxoplasmosis i: parasitology, epidemiology and public health a brief history and overview of toxoplasma gondii vaccination against toxoplasma gondii: an increasing priority for collaborative research? vaccines against toxoplasma gondii: challenges and opportunities current status of toxoplasmosis vaccine development intracellular transport of toxoplasma gondii through the blood-brain barrier development and application of reverse transcription loop-mediated isothermal amplification for detecting live shewanella putrefaciens in preserved fish sample biomarker analysis revealed distinct profiles of innate and adaptive immunity in infants with ocular lesions of congenital toxoplasmosis new micromethod to study the effect of antimicrobial agents on toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin a a novel population of gr-1 + -activated macrophages induced during acute toxoplasmosis traditional herbal medicine for the control of tropical diseases pharmacopoeia of people republic of china radix clematidis extract inhibits tpa-induced mmp-9 expression by suppressing nf-κb activation in mcf-7 human breast cancer cells sulfadiazine and pyrimethamine in the postnatal treatment of congenital toxoplasmosis: what are the options? enhancement of protective immune response to recombinant toxoplasma gondii rop18 antigen by ginsenoside re recruitment of gr-1 + monocytes is essential for control of acute toxoplasmosis usefulness of quantitative polymerase chain reaction in amniotic fluid as early prognostic marker of fetal infection with toxoplasma gondii seroprevalence of toxoplasma gondii infection among hiv/aids patients in eastern china ethyl acetate extract of artemisia anomala s. moore displays potent anti-inflammatory effect evaluation of a real-time pcr assay based on the single-copy sag1 gene for the detection of toxoplasma gondii the virulence-related rhoptry protein 5 (rop5) of toxoplasma gondii is a novel vaccine candidate against toxoplasmosis in mice xun-hui zhuo, hong-chao sun, bin huang, hai-jie yu, ying shan, and ai-fang du declare that they have no conflict of interest.all institutional and national guidelines for the care and use of laboratory animals were followed. key: cord-003612-bp7sray2 authors: hu, guangyu; han, xueyan; zhou, huixuan; liu, yuanli title: public perception on healthcare services: evidence from social media platforms in china date: 2019-04-10 journal: int j environ res public health doi: 10.3390/ijerph16071273 sha: doc_id: 3612 cord_uid: bp7sray2 social media has been used as data resource in a growing number of health-related research. the objectives of this study were to identify content volume and sentiment polarity of social media records relevant to healthcare services in china. a list of the key words of healthcare services were used to extract data from wechat and qzone, between june 2017 and september 2017. the data were put into a corpus, where content analyses were performed using tencent natural language processing (nlp). the final corpus contained approximately 29 million records. records on patient safety were the most frequently mentioned topic (approximately 8.73 million, 30.1% of the corpus), with the contents on humanistic care having received the least social media references (0.43 million, 1.5%). sentiment analyses showed 36.1%, 16.4%, and 47.4% of positive, neutral, and negative emotions, respectively. the doctor-patient relationship category had the highest proportion of negative contents (74.9%), followed by service efficiency (59.5%), and nursing service (53.0%). neutral disposition was found to be the highest (30.4%) in the contents on appointment-booking services. this study added evidence to the magnitude and direction of public perceptions on healthcare services in china’s hospital and pointed to the possibility of monitoring healthcare service improvement, using readily available data in social media. investigating public perception of healthcare services from different perspectives may generate inconsistent results. for example, patient-initiated violence against health workers [1] [2] [3] [4] [5] [6] , and the tension between doctors and patients for their dissatisfaction with the quality of healthcare [7, 8] , were wildly covered in the chinese media. while patient experience surveys on the national level showed that patients were generally satisfied with both in-patient and out-patient services [9] . such differences may result from biases rooted in the survey and media coverage; however, the inconsistency also pointed to the need for additional data sources to monitor public opinions on chinese healthcare services. it has been suggested that social media might be such a data source. rozenblum et al. pointed out that when patient-centered healthcare, the internet, and social media were combined, the current relationship between healthcare providers and consumers might face major changes-thus creating a "perfect storm" [10] . users' posts on the social media platforms would generate a large volume of real-time data regarding public or private issues, among which healthcare related information scatters. therefore, the utilization of social media data for healthcare research becomes a dramatically growing field and already covered various medical and healthcare research fields [11, 12] . sinnenberg and colleagues proposed four ways in which social media data were used in healthcare studies: (1) content analysis, (2) volume surveillance of contents on specific topics, (3) engagement of users with others, and (4) network analysis of users [12] . for the content analysis, most studies focused on measuring public discussion on specific diseases [13] [14] [15] , sentiment analysis for medical interventions (e.g., cancer screening) [16, 17] , identifying safety concerns among health consumers [18] , detecting adverse events of health products [19, 20] . several researchers studied patient experience, based on the comments posted by patients from online health communities in china [21, 22] , but few studies have been conducted to gather information on healthcare services related topics using social media data. meanwhile, although sentiment analysis has been wildly applied to process user sentiments associated with health-related text [23] , the lexical resource and tools designed for doing health-related sentiment analysis in chinese language are few and far between. fast-advancing in technology and economy, social media users and their activities spiked in china, which made social media a promising source for healthcare service monitoring. in china, the internet penetration rate reached 55.8% at the end of 2017 [24] , with local providers dominating the market, rather than facebook and twitter, which are not accessible in china. chinese social media sites have a unique landscape, and it may not only be used as a communication software but also as an entry point for information. as subsidiaries of tencent holdings limited, shenzhen, china, wechat and qzone are two leading social media and networking services platforms. each of them reached more than 938 million and 632 million monthly active user accounts in the first quarter of 2017 [25] . according to the 2016 wechat data report, typical users of wechat were born in the 80s or 90s [26], representing a wide breadth of demographic group in china. besides providing multimedia communication and supporting social networking, wechat also has "official accounts", which serve as channels for publishing articles to the public. any individual or organization can apply for having their own official account to broadcast their ideas and believes. as for qzone, it is a platform bundled with qq, a popular online messaging application in china. qzone allows users to create their own personal page to write blogs and post updates. and users could be able to express their individual opinions and attitudes freely and instantly on the social media platforms. subject to the platforms' terms of service and privacy policy agreed upon by users [27, 28] , three kinds of information were collected, stored, and used by the platforms: (1) personal information; (2) non-personal information; and (3) shared information. the shared information refers to information that is voluntarily shared on the platforms by users freely and instantly, thus providing a valuable perspective and opportunity to gather public opinions on healthcare services. as such, we selected wechat and qzone as the social media platforms to conduct this exploratory study. the objectives of this study are to conduct volume and sentiment analyses base on the extracted social media contents on hospital healthcare services. the study could demonstrate the social media users' perceptions of hospitals healthcare and may shed light on the further utilization of social media as a data source for healthcare research in china. this study consisted of three phases. firstly, we utilized a predefined list of healthcare services categories to devise key words and search strategies accordingly. the data searching strategy would then be used to extract contents from a raw database, which contained publicized posts of wechat and qzone. the extracted materials were then put into a corpus. secondly, we applied natural language processing (nlp) techniques from tencent nlp platform to the corpus and calculated the volume of content concerning different healthcare services topics. thirdly, we conducted sentiment analysis to explore the sentiment polarity of chinese social media users on different healthcare service topics. the detailed process of data collection and analysis is presented in figure 1 the raw databases used for this study come from wechat and qzone of the version only operated in mainland china. the user volumes and data inclusion criteria of the platforms were showed in table 1 . publicly available posted information such as: posted blogs, reviews and articles that are voluntarily shared by individual users from june 2017 to september 2017 were collected from the two platforms. the data collection followed the privacy policy for users of tencent and was subject to the confidentiality and security measures that implemented by the platforms. and the data analyses were supported by technicians in the tencent. the nine healthcare service categories, used in this study, were derived from the objectives of the national healthcare service improvement initiative (2015-2017), which was dedicated to improving patient-centered healthcare and patient experience nationwide by the former national health and family planning commission of p.r. china (nhfpc) [29] . the initiative operated under the leadership of the bureau of medical administration of nhfpc [30] , which suggested that we used nine predefined categories to reflect the healthcare services in hospital (see table 2 ). table 2 . healthcare services categories and corresponding descriptions in the national healthcare service improvement initiative 2015-2017 (nhsii). objectives of nhsii optimize the layout of the facility and build a friendly service environment appointment-booking service promote utilization of clinical appointment services and guide patient flow service efficiency improve service efficiency and effectiveness by rational allocation of resources information technology take advantage of information technology to improve patient experience inpatient service promote inpatient service process reengineering and provide integrated healthcare service nursing service continuously improve quality of nursing care and enhance nursing workforce patient safety ensure patient safety by promoting adoption of standard operating procedures humanistic care strengthen humanistic care and provide medical social worker service doctor-patient relationship harmonize the doctor-patient relationship and reduce medical disputes in this study, we constructed a healthcare services corpus, in the chinese language from the social media data source, to enable further analyses. first, we constructed lexica of keywords and terms in accordance with the predefined service topics. for example, the lexicon for "information technology", used in this study indicate new information dissemination channels, based on information technology provided by hospital to improve patient experience of service information acquisition. and this lexicon contains six information technology service-related terms, namely, "weibo", "wechat", "website", as well as "self-service machine". second, we developed a set of searching strategy to extract the relevant data from the two sources based on the corresponding lexicon of topics. the entire list of search terms for each category and its corresponding searching strategy were provided in supplementary table s1 . finally, we applied the search strategies to the database of publicly posted materials to screen for posts related to the healthcare service categories to construct the corpus. the search and screening process were performed by qcloud. based on the healthcare services corpus, we classified the content to different healthcare services topics that predefined and measured the content volume of the topic. specifically, we used the open application programming interface (openapi) services provided by tencent nlp to analyze the retrieved contents. it is an open platform for chinese natural language processing (based on parallel computing and distributed crawling system) [31] . such services enable us to split reviews and blogs into sentences, and each sentence was filtered to classify whether it contained target service topic keywords and terms. if the sentences, containing certain keywords and terms, belonged to the corresponding topic of healthcare services categories as listed in table s1 , then they would be divided into a certain category. by counting the appearances of each service topic keywords in terms of the number of sentences in the corpus, we can aggregate the counts at the topic level and calculate the proportion of different topics from the social media corpus. for the sentiment analysis tool in chinese, we also select tencent nlp, as its algorithm was trained by hundreds of billions of entries of internet corpus data in chinese and with successful application in other tencent products (https://nlp.qq.com). openapi with function of chinese batch texts automatic summarization and sentiment analysis of tencent nlp enable us to categorize the sentences on certain topic in the social media corpus into a sentiment polarity classification (i.e., neutral, positive, and negative). finally, each sentence was tagged and classified into different sentiment polarity. the social media corpus contained approximately 29 million records from wechat and qzone, spanning the 9 pre-defined categories, related to hospital healthcare services. table 3 presents the content volume of each healthcare services topic by social media channel. among the social media content on healthcare services topics, patient safety was the most commonly encountered topic, both in wechat and qzone. the majority of the content related to patient safety issue, its approximately 8.73 million records and covered 30.1% of the entire corpus. the proportion of contents related to other topics varied in the corpus: information technology (22.2%), service efficiency (17.9%), service environment (10.3%), inpatient service (9.6%), appointment-booking service (3.4%), nursing service (2.5%), doctor-patient relationship (2.5%), and humanistic care (1.5%). the results of the sentiment analysis of contents from the corpus found that, in all nine healthcare services topics, 36.1% of the contents in the corpus have been recognized to reveal a positive disposition, 16 .4% neutral and 47.4% negative. we found that topic comprising most positive contents was service environment (59.6%), followed by patient safety (53.2%). with regard to the topics that contained more negative contents than positive, the most one was doctor-patient relationship (74.9%), followed by service efficiency (59.5%), and nursing service (53.0%). notably, over one third of contents in the appointment-booking service (30.4%) revealed a neutral disposition. additionally, in contrast to the content volume distribution for the nine topics, the sentiment disposition of contents in corresponding healthcare services topics shows differences. for instance, table 3 shows that the nursing service and doctor-patient relationship share an equal proportion (2.5%) of contents in the corpus, however, we observed the disposition of contents from social media users to the two topics varied in figure 2 . to our knowledge, this is the first study that has attempted to explore the public perceptions of healthcare services, using publicly posted materials, of two chinese social media platforms. our results showed that patient safety was the most significant topic for users of chinese social media platforms, followed by information technology and service efficiency. service environment was found to have the highest proportion of positive comments. the research assessed the application of content volume calculation and sentiment analyses on chinese social media data. the study is a crucial step to discovering the methodology on harnessing the social media data in china and an early attempt to track the perceptions of healthcare services in the public by analyzing a unique data source. this study found a large number of information technology and service efficiency, which might reflect the series of efforts made by both the government and the hospital in integrating information technology in healthcare services in china. several researchers have identified that health information technology services were used to enhance patient experience [32] [33] [34] , and as a potential solution to shorten the lengthy waiting time in china's public hospital [22, [35] [36] [37] . humanistic care was the least mentioned topic in the corpus complied by this study. it may suggest that chinese social media users are not very familiar with the idea of humanistic care. those who posted about it basically expressed a positive attitude. an alternative explanation might be this type of care has yet to reach the public only experienced by a few people. further empirical studies or controlled studies may be conducted to provide further insights. our research also explored the sentiment disposition of social media content on healthcare services: 47.4% provided negative feedback. although this was only the initial results, it could be quite alarming to healthcare administrations and policymakers. despite the fact that patient surveys generally had favorable results in china [9] , there was still a significant amount of negative comments to our knowledge, this is the first study that has attempted to explore the public perceptions of healthcare services, using publicly posted materials, of two chinese social media platforms. our results showed that patient safety was the most significant topic for users of chinese social media platforms, followed by information technology and service efficiency. service environment was found to have the highest proportion of positive comments. the research assessed the application of content volume calculation and sentiment analyses on chinese social media data. the study is a crucial step to discovering the methodology on harnessing the social media data in china and an early attempt to track the perceptions of healthcare services in the public by analyzing a unique data source. this study found a large number of information technology and service efficiency, which might reflect the series of efforts made by both the government and the hospital in integrating information technology in healthcare services in china. several researchers have identified that health information technology services were used to enhance patient experience [32] [33] [34] , and as a potential solution to shorten the lengthy waiting time in china's public hospital [22, [35] [36] [37] . humanistic care was the least mentioned topic in the corpus complied by this study. it may suggest that chinese social media users are not very familiar with the idea of humanistic care. those who posted about it basically expressed a positive attitude. an alternative explanation might be this type of care has yet to reach the public only experienced by a few people. further empirical studies or controlled studies may be conducted to provide further insights. our research also explored the sentiment disposition of social media content on healthcare services: 47.4% provided negative feedback. although this was only the initial results, it could be quite alarming to healthcare administrations and policymakers. despite the fact that patient surveys generally had favorable results in china [9] , there was still a significant amount of negative comments on the social media platforms. further and more detailed methodology is necessary to further understand the negative comments. in the 9 topics investigated in this study, we found huge variations in the negative feedback as well as content volumes across topics. for instance, the contents related to doctor-patient relationship only take percentage of 2.5% in the corpus, however 74.9% of the content revealed negative feedback. the varied sentiment polarity distribution of the topics may have important policy implications for healthcare reform in china. for example, 30.4% of the social media references to appointment-booking service reflected neutral feedback, which may suggest that the unsureness of the public on this novel service. patients have yet to be familiar with the services-even though it certainly aims to improve the convenience for patients as well as hospital efficiency. such feedback could be essential for hospitals to improve their service quality by enhancing patient education. further research might focus on what exactly were discussed in those negative posts so that targeted measures can be employed by the hospitals and responsible administrators to improve the services. in line with previous evidence [11, 12] , our results show that social media could be a useful tool for health research in china, as well as english, and could be used to capture the public's perspective of healthcare [23, 38] . however, it appeared that the most concerned issue of healthcare in social media is different from what has been found in patient surveys. findings from a recent qualitative study found that patients cared about the environment and facilities in hospital the most [39] , whereas in our study patient safety issues had the greatest volume. another research examined the online doctor reviews in china revealed that most posts expressed positive attitudes towards the physicians [21] . although the evidence on these issues are still not conclusive, it might suggest the perception difference between general public and patients. our research extends application of the natural language processing techniques to analysis of healthcare services related contents in china's social medial platforms and offers a new perspective of healthcare services in china's hospital. the results would be of benefit to healthcare providers and regulators benchmarking their performance on patient-centered healthcare delivery. this is important because the social media has been considered as a portal of health information acquisition for chinese netizens [40] , the perspective of social media would be supplementary in understanding how consumer views the healthcare services in hospital besides the results from traditional paper-based surveys. this study has the following limitations. first, because the raw material was user-generated data, selection bias may have affected the data. for example, it was observed that most social media users were born in the 80 s or 90 s [26], however we were unable to characterize the users social-demographic information in detail, since the user privacy policy of tencent currently prohibit such practice. moreover, considering the exploratory nature of the study, our study focused only on wechat and qzone as data sources, whereas other social media platforms in china may have the potential to conduct such analyses as well. second, since we derived the healthcare services categories and lexica based on the government document on nhsii and expert consultation, thus the corpus in this study may have failed to include certain amount of healthcare services related data. as a result, we may have underestimated the content volume of healthcare services from the two social media platforms. furthermore, although all the material in the databases are in chinese, and therefore most likely be generated by users from china, we are currently not able to determine whether the posts, containing the key terms on healthcare, were describing the chinese healthcare system or discussing foreign healthcare systems in chinese language. further research may strive to develop searching strategies that enable such distinction and increase the specificity of the results. third, although the consumer health vocabulary (chv) is the gold standard reference for retrieving the target data, it has been used in previous researches [13, 38] , such open source of vocabulary list and its corresponding lexica are not available in chinese language. the accuracy and credibility of the sentiment analysis of this study also await further validation; however, it would require an alternative method to conduct sentiment analyses for chinese language and the possibility to apply such methods on the tencent data, which were publicly posted material but still under strict terms of utilization. another limitation concerned that we have no ability to confirm that the data supplied by tencent completely represent all users' data as there could be undocumented keyword filter on the platforms. these would inflict potential bias and limit the generalizability of our findings. weibo is another popular chinese social media platform considered to be the counterpart of twitter in china. future research could consider extend the analysis process to contents from weibo, to further explore users, and their views, that have not been covered in this study. both the quantitative approach, as shown in our research, and the qualitative approach, such as the face-to-face individual interview method, would be useful to better understand consumer care in healthcare services. there is a scarcity of empirical research exploring the latter issue at present. it has been proposed to complement public perspectives on healthcare services [39] . furthermore, the popularity of consumers' unsolicited comments on healthcare providers in social media, prompts an important avenue for understanding patient experience, and has been demonstrated by previous researches [38, [41] [42] [43] [44] . future research for measuring patient experience based on social media data at hospital level would be help to better understand the landscape of healthcare quality in china. by analyzing shared information from wechat and qzone, this study showed that patient safety was the most concerned topic for users of chinese social media platform, followed by information technology and service efficiency, while the doctor-patient relationship was found to have the highest proportion of negative comments. this study explored the possibility of utilizing social media to monitor public perceptions on healthcare services. the findings provide an overview of public opinion on healthcare services, which could help regulators to set up the benchmark, on a national or regional level, to monitor the progress of healthcare improvements between comparator districts and services domains. it is also a necessary complement to the traditional paper-based consumer survey. the potential differences between social media perception and traditional consumer survey results would help regulators better understand the gap in quality of care services from various perspectives. further studies could also focus on extending the nlp method to a more content-based resource and to expand our understanding of mass opinion on healthcare services. the following are available online at http://www.mdpi.com/1660-4601/16/7/1273/s1, table s1 : list of keywords, terms, and text strings used for data searching. facing up to the threat in china violence against chinese health-care workers the danger of being a doctor in china the frequency of patient-initiated violence and its psychological impact on physicians in china: a cross-sectional study how to decrease violence against doctors in china? workplace violence against medical staff of chinese children's hospitals: a cross-sectional study media contribution to violence against health workers in china: a content analysis study of 124 online media reports changing of china's health policy and doctor-patient relationship consumer satisfaction with tertiary healthcare in china: findings from the 2015 china national patient survey patient-centred healthcare, social media and the internet: the perfect storm? instagram and whatsapp in health and healthcare: an overview twitter as a tool for health research: a systematic review using twitter to measure public discussion of diseases: a case study social big data analysis of information spread and perceived infection risk during the 2015 middle east respiratory syndrome outbreak in south korea characterizing depression issues on sina weibo sentiment analysis of breast cancer screening in the united states using twitter using social media to characterize public sentiment toward medical interventions commonly used for cancer screening: an observational study social media in health-what are the safety concerns for health consumers? utility of social media and crowd-sourced data for pharmacovigilance: a scoping review protocol systematic review of surveillance by social media platforms for illicit drug use the development of online doctor reviews in china: an analysis of the largest online doctor review website in china unhappy patients are not alike: content analysis of the negative comments from china's good doctor website capturing the patient's perspective: a review of advances in natural language processing of health-related text china internet network information center the 41st china statistical report on internet development national health and family planning commission announcement of implementing the healthcare services improvement initiative national health and family planning commission the implementation strategy of the healthcare services improvement initiative social media landscape of the tertiary referral hospitals in china: observational descriptive study a way to understand inpatients based on the electronic medical records in the big data environment what predicts patients' adoption intention toward mhealth services in china: empirical study patient experience with outpatient encounters at public hospitals in shanghai: examining different aspects of physician services and implications of overcrowding discrete event simulation models for ct examination queuing in west china hospital questionnaire survey about use of an online appointment booking system in one large tertiary public hospital outpatient service center in china collecting and analyzing patient experiences of health care from social media what do patients care most about in china's public hospitals? interviews with patients in jiangsu province how the public uses social media wechat to obtain health information in china: a survey study predicting hcahps scores from hospitals' social media pages: a sentiment analysis web-based textual analysis of free-text patient experience comments from a survey in primary care use of sentiment analysis for capturing patient experience from free-text comments posted online harnessing the cloud of patient experience: using social media to detect poor quality healthcare we would like to acknowledge dalu wang and hongda wu from tencent for their technical support in data analysis. the authors declare no conflict of interest. int. j. environ. res. public health 2019, 16, 1273 key: cord-253286-ieyqoxe6 authors: xu, judy; yang, yue title: traditional chinese medicine in the chinese health care system date: 2008-10-22 journal: health policy doi: 10.1016/j.healthpol.2008.09.003 sha: doc_id: 253286 cord_uid: ieyqoxe6 objectives: this study examines the role and value of traditional chinese medicine (tcm) in the current health care system in china. methods: based on literature review and publicly available data in china. results: the study shows that tcm is well integrated in the chinese health care system as one of the two mainstream medical practices. also, the chinese government is supportive of tcm development by increasing investment in tcm research and administration. however, there is downsizing of tcm utilization, a lack of tcm professionals with genuine tcm knowledge and skills, and limitations of and increasing public opinions on modernization and westernization. conclusions: tcm is still facing many challenges in playing critical roles in improving public health in china. these challenges can be explained from different perspectives. in addition to the unique characteristics of tcm, economic, cultural, and historical evolution in china may also be major determinants. tcm is based on the chinese philosophy of yin-yang and five elements. the oldest classic of tcm is huangdi neijing (inner canon of huangdi or the yellow emperor's medicine classic), which was written 2000-3000 years ago [1] . the basic theory of tcm includes five-zang organs and six-fu organs, qi (vital energy), blood, and meridians. tcm is based on the holistic principles and emphasizes harmony with the universe. it categorizes the causes of diseases into two groups: external causes and internal causes. it differentiates syndromes according to the eight principles (yin, yang, exterior, interior, cold, heat, deficiency (xu) and excess (shi)). although acupuncture and chinese massage have been well known and practiced in the west, clinical diagnosis and chinese herbology are very important components of tcm. the typical tcm diagnostic methods are inspection, auscultation/olfaction, inquiring and palpation. chinese herbal medicine not only includes plants, but also includes medicinal uses of animals and minerals. the herbal medicine preparation (pao zhi) and formulas (fang ji) are also very critical and unique. tcm has been carried over for thousands of years for a variety of clinical treatments of different kinds of diseases and symptoms in china. it also has experienced further development and modernization over time [2, 3] . in the 1950s, chairman mao zedong authorized an attempt to create an academic/formal/systematized medicine. one of the major changes in the medicine is it eliminated everything considered to be superstitious. one example of such a concept is "hun-po" 1 of which there was no mention in the texts of the 1960s and 1970s. in terms of acupuncture practice a certain standardization of the acupoints and needling techniques took place which was exported with the early teachers who came to the west and founded acupuncture schools on the tcm academic model. herbal medicine and zang fu syndrome differentiation were also standardized. thus, strictly speaking, the term tcm in the west should be referred as chinese medicine rather than tcm. during the qing dynasty, especially in the nineteenth century, western missionaries entered china and western medicine 2 started to dominate the market. currently, western medicine and tcm are the two mainstream medical practices in china. tcm/western integrated medicine, which attempts to combine the best practices of tcm and western medicine, and chinese medicine of minorities, such as mongolian medicine and tibetan medicine, are also formally practiced in the chinese health care system. 3 the chinese health prevention and delivery system is based on the three-tier system developed in the 1950s, which includes hospitals, health centers, and clinics. table 1 shows the number of health institutions in 2006. in general, hospitals have the best facilities and resources while health clinics/health service centers provide most of the health services, especially for treating patients with common illnesses and non-severe health conditions. currently, 99% of the health centers are in the rural areas and they are also very important for rural health delivery. before the economic reform in 1978, the central government was responsible for both health care financing and delivery. since 1978, a series of health care reforms were conducted to decentralize and privatize health care organizations. although most of the hospitals are still state-owned, many private clinics have opened in both urban and rural china. the government also dramatically reduced their financial investment in health care services, but still has tight price-control in the health sector [4] . the current chinese health care system is undergoing major reforms in order to increase health insurance coverage, improve quality of care, reduce health care costs, and minimize inequality of health care access between rural and urban areas. in the following, the paper describes the situation and changes of tcm in the health care system in the past decade. it also discusses the challenges and opportunities facing tcm in china. chinese herbal medicine is currently categorized into three groups in china: raw herbal medicine (zhong yao cai), sliced herbal medicine (zhong yao yin pian), 4 and patent medicine (zhong cheng yao). 5 in addition to 561 herbal resource centers in china that produce raw herbal medicine, there are over 1500 manufacturers producing sliced herbal medicine and 684 manufacturers producing patent medicine [5] . although herbal extracts are regarded as herbal medicine, strictly speaking, they are not chinese herbal medicine since they are not based on chinese herbology, but active ingredients or compounds extracted from herbs. they are listed as biomedicine in china. in addition to the drug administration law of the people's republic of china, chinese herbal medicine production, distribution, pricing, and utilization are under the regulations of different government agencies, such as the chinese state food and drug administration and the national development and reform commission. although the chinese government has implemented quality control systems on medical production, such as implementations of the good agricultural practice (gap), the good laboratory practice (glp), and the good manufacturing practice (gmp) for many years, there is still need to improve the quality control in the production of herbal medicine. due to the complexity of chinese herbal medicine, the critical component combinations and the appropriate standard component combinations are not quite clear. for example, since there is neither strict standards for controlling critical components in the patent medicine nor regulations on the process for sliced herbal medicine, some manufacturers are either using less effective components or cheap substitutes [6] . 4 sliced herbal medicine is the herbal medicine that has been processed. in addition to basic processes such as slicing, steaming, and drying, some raw herbal medicine is processed with ginger, honey, licorice, and sulfur. the major purpose of these processes is to reduce toxicity as well as to sanitize. 5 patent medicine is the herbal medicine formula that has been standardized rather than been "patented". tcm products have been exported to about 163 countries in the world. based on the report from the china chamber of commerce for import & export of medicines & health products (cccmhpie), the tcm herbal medicine export is almost us$ 1.2 billion in 2007, which increased 8% from 2006. depending on different definitions and calculation, chinese herbal medicine represents 20-50% of the herbal medicine market share worldwide. historically, tcm knowledge and skills were passed on only to family members or a couple of students through apprentice-master relationships. since the 1950s, tcm education has been formalized into an academic training. typically, tcm medical professionals are educated at medical schools or pharmacy schools with the same standards, admissions, and years of training as western medical professionals. students usually take 3-8 years' of training to get associates, bachelors, masters, or doctoral degrees from either tcm or other universities ( table 2) . among the 400,000 enrolled students, there are almost 4000 foreign students enrolled. 90% of them are from asia, followed by 4% from north america and 4% from europe. in addition to tcm theories and methodology, the fundamental tcm curriculum includes western medical science such as physiology and molecular biology. in 1959, tcm curriculum requires the course time ratio to be no less than 7:3 between tcm and western medicine. the current tcm training is much more westernized with the ratio of 6:4 or even 5:5, which causes concerns from tcm experts about the quality and time limitations in providing sufficient tcm knowledge and training [7] . tcm is also under the same registration and licensing procedures as is western medicine. in 1999, the chinese government implemented medical professional licensing requirements. after receiving regular degree training, both doctors and pharmacists 6 are required to do 1 to 3 years of residency in a medical institution before taking a national license examination to get their licenses [8] . since tcm is a practical study, which emphasizes the clinical experience as well as family lineage, those tcm practitioners who have studied traditional medicine under 6 in china, herbalists are called chinese medicine pharmacists (zhong yao shi). a teacher for at least three years or have really acquired specialized knowledge of medicine through many years' experience are also allowed to participate in the examination for the qualifications of medical practitioners. however, the complex process and certain requirements of the exam (e.g. some specific western medical science knowledge) prevent some tcm practitioners from getting their licenses. tcm professionals dramatically decreased from 800 thousand in 1911 to 500 thousand in 1949 due to the growing popularity of western medicine [9] . the number of tcm professionals also dropped further after the chinese government implemented medical professional licensing requirements in 1999. fig. 1 in health clinics, doctors who practice western medicine comprise 50.3% of the total doctors, followed by 32.3% of doctors who practice tcm/western integrated medicine, and 17.4% who only practice tcm [10] . currently, about 12% of the licensed doctors are tcm doctors and only 6% of pharmacists are licensed tcm herbalists. very few licensed tcm doctors or pharmacists work in township health centers or village clinics. tcm has been used for thousands of years in treating different types of diseases and symptoms, such as pulmonary, cardiovascular, gynecological, and pediatric, as well as mental illness [11] [12] [13] [14] [15] [16] [17] [18] . during the epidemic of severe acute respiratory syndrome (sars) in 2003, the sars death rate in china (6.5%) is less than the average international death rate (9.5%) [19] . among the 5326 sars patients treated, 3104 cases involved tcm treatment. this represents 58.3% of the total. specifically, in guangzhou, where the integration of tcm started the earliest, the death rate was only 4%. in beijing, the death rate decreased 80% after integrating tcm treatments. recently, the state administration of traditional chinese medicine of the people's republic of china, the chinese ministry of health, and the treasury department are collaborating on a program to provide free tcm however, along with other countries worldwide, the safety and efficacy issues of tcm are still major challenges in china. for example, tcm is more often used for chronic conditions than acute conditions. it is more complicated to evaluate its clinical effects. for example, some chinese herbal medicine is prescribed to treat diseases from the root cause rather than to decrease the symptoms immediately. so, it might take months or years for patients to recover, which is problematic for most of the clinical designs in order to evaluate long-term outcomes. currently, there are about 800,000 references and abstracts to literature on tcm in the traditional chinese medical literature analysis and retrieval system (tcmlars). however, very few of them are regarded as "rigorous" scientific evidence of efficacy and safety of tcm treatment based on western medical methodology, such as randomized clinical trials (rct). although both chinese and western experts realize that rct may not be appropriate to evaluate tcm since it requires individualized treatment based on the diagnosis of each patient, there is not any innovative evaluation design available [20] . to fill the gap between tcm and evidence based medicine (ebm), efforts have been put on conducting systematic reviews and clinical studies in china [21] . for example, as part of the international cochrane collaboration, the chinese ebm/cochrane center was established in china in 1999. it provides both clinical control trial studies and metaanalysis reviews on the available studies of tcm. many government agencies are also involved and increasing their investment on tcm research. in addition to tcm diagnosis, such as pulse diagnosis and tongue diagnosis, the common tcm treatments include herbal medicine, acupuncture/moxibustion, cupping, gua sha, 7 and chinese massage (tuina, an muo and qian yin). the total number of tcm out-patient visits is almost 1.3 billion per year, which is about one third of the total outpatient visits in china [10] . almost 40% of these tcm visits are delivered in village clinics/community health service centers, followed by 28% in tcm hospitals, 16% from health centers, 10% in other hospitals, and 7% from private clinics and others. table 1 shows that tcm hospitals represent 13.8% of all hospitals in china and tcm/western medicine integrated hospitals only represent 1.1%. in addition to the small proportion, the relative growth rate of tcm hospitals is much slower than general hospitals (fig. 2) . tcm hospital outpatient visits are only about 18% of the general hospital visits. the ratio of tcm hospitals to other hospitals and their visits does not provide us the whole picture of tcm practices in hospitals since tcm and western medical practices are mixed in both types of hospitals. first, about 90% of the general hospitals have tcm departments although the tcm department outpatient visits only represent 8% of the total outpatient visits in general hospitals [10] . second, in tcm/western integrated hospitals, tcm related treatment is about 40-45% of the total treatments given. third, almost all of the tcm hospitals are practicing western medicine as well as tcm [19] . in addition to using stethoscope and biomedical diagnostic tests, western surgeries for different kinds of diseases (e.g. liver, stomach, kidney, and breast cancer) are also common practice in tcm hospitals. as discussed earlier, the challenges of tcm clinical effectiveness may explain in some part the use of western medicine in the tcm hospitals. furthermore, due to the health reforms in the 1990s, most of the hospitals in china have to take care of themselves financially with less and less government investment [4] . in general, tcm practice is much cheaper and has a lower profit margin than western medicine. many tcm hospitals depend on government subsidies for survival [23] . it was reported that almost three quarters of the tcm prices are lower than their actual costs [24] . thus, most of the tcm hospitals implement western technology in diagnosis and treatment. since the government regulates and controls most of the utilization prices in hospitals, most of the hospital profits are from prescription drugs. this causes further overuse of western medication in many tcm hospitals as well as general hospitals. it was reported that 37% of outpatient medication revenue in tcm hospitals were from western medicine, followed by 35% from patent medicine and 28% from raw/sliced herbal medicine [25] . western medication utilization is even higher among in-patients in tcm hospitals. western medication revenue comprises almost 78% of the total medication revenue and 37.4% of the total revenue in tcm hospitals. chinese herbal medicine only represents 22% of the medication revenue and 8.1% of the total revenue in tcm hospitals. similar to hospitals, both tcm and western medicine are practiced alongside each other in health centers and health clinics. about 75% of health centers have a tcm department. including tcm/western integrated medicine treatment, the total tcm out-patient visits were 330 million, which was much higher than those visits in all tcm hospitals in 2001 [10] . in health centers, chinese herbal medicine revenue represented less than 15% of the total medication revenue. however, about one third of the total medical utilization in health clinics was from tcm, which was more than the tcm utilizations in tcm hospitals and health centers. although a majority of chinese believe in tcm, only a small portion of them prefer tcm treatment to western medical treatment when they are sick. in a survey conducted among 1161 out-patients, 19% of the respondents said they have never had any tcm treatment. 25% of the respondents said they have tcm treatment because they have chronic conditions while another 17% said they have tcm treatment because western medicine failed to cure them [26] . another larger household survey of 42,819 people in both urban and rural china also showed that 54% of the population prefers western medical treatment, 25% prefers tcm/western integrated treatment, 12% prefers tcm treatment only, 5% western medicine for acute conditions while tcm for chronic conditions, and 1% prefers western medicine for diagnosis while tcm for treatment [10] . for those people who prefer tcm treatment, the main reason to choose tcm is their belief in tcm (50.7%), followed by its good clinical outcome (21.5%), its treatment of the cause (11.2%), frequent adverse-reaction of western medicine (8.7%), and inexpensive price (6.8%). in general, age is positively related to people's choice of tcm treatment although after 65 the trend reverses. people with less than a grade school level of education and those with higher than college are more likely to use tcm. females, people who live in urban areas, and people with professional occupations are also more likely to use tcm. tcm is well integrated in the chinese health care system. however, tcm is still facing many challenges in playing critical roles in improving public health in china. these challenges can be explained from different perspectives. in addition to the unique characteristics of tcm, economic, cultural, and historical evolution in china may also be the major determinants. first, although the tcm philosophy is an important part of the chinese culture, tcm theories and methodologies are still not confirmed or measurable by modern science. for example, the mechanism of the different functions of the five-zang and six-fu organs is not clear. it is still hard to measure different kinds of qi, such as vital qi and wei qi. tcm diagnosis tools are less tangible and its clinical outcomes are less documented than western medicine. in addition, chinese herbal medicines are neither as easy to take nor as fast to reduce symptoms as western medications. these factors are important in explaining why western medicine is used more than tcm in china. second, due to the success of economic reform in the past 30 years, the concept of westernization and modernization are popular among the chinese people. some medical professionals and consumers regard tcm as far behind or less developed than western medicine [27] . although some chinese, especially those with a high level of education understand the side-effects and medical error problems of western medical treatment, very few studies or statistics are available on the issues in china. so, the knowledge and concerns about the adverse-effects of western medicine are much less than those in the us or in europe. currently, there are many highly regarded tcm programs and practitioners in china, such as beijing tcm university and shanghai tcm university. however, due to the difficulty in evaluation and regulation of tcm throughout history and adulterants of chinese herbal medicine and quack tcm doctors some negative opinions of herbal medicine and tcm professionals still exist. in rural china, the situation is worse since there is lack of health facilities and professionals. specifically, very few licensed tcm professionals are available there. these may not only explain why western medical treatment is more used than tcm in rural china, but also indicate the complex environment for public health services. third, due to the historical evolution and cultural changes, some of the traditional knowledge is lost in both the formal tcm practice and the education system. as discussed earlier, the lack of the genuine knowledge also causes problems in chinese herbal medicine production and regulation, which results in a negative impact on tcm clinical outcomes. experts argue that if chinese herbal medicine is prepared, prescribed, and used properly based on the tcm principles and chinese herbology (e.g. the principle of jun, chen, zuo, shi), they are very safe. most of the severe adverse-effects and toxicity occurred not due to high risks of chinese herbal medicine, but due to misuse or lack of genuine tcm knowledge [28] [29] [30] . similar to herbal extracts and intravenous (iv) formulae of herbal products, some of the new chinese patent medicines are not fully developed based on the tcm principles and chinese herbology [3] . although they are approved by the chinese state food and drug administration, the clinical outcomes of these products are not as remarkable as these traditional formulae. fourth, the limitations of hospital finance may also push the movement of western medicine in china. as discussed earlier, since chinese hospitals are expected to generate revenue to cover the majority of their expenses, they have incentives to use western medical devices and treatment due to the lower profit margin of tcm. the low profitability of tcm makes the tcm labor market less attractive. students also have less incentive to carry on the genuine tcm practice and tcm professionals have more incentive to practice western medicine. finally, there are also concerns on the integrated practice of tcm and western medicine since they are based on different philosophies and theories. as previously discussed, the integrated practices are found not only in those tcm/western medicine hospitals, but in all other type of medical institutions and with different forms. in addition to integrated treatment, some patients use western medicine for diagnosis and use tcm for treatment. some others use tcm for chronic conditions and use western medicine for acute conditions. although some studies have shown that integrated practice has the potential to improve clinical results [31] , there are also concerns that the traditional tcm characteristics are more likely to be ignored in the integrated practice. a study showed that only 30,000 tcm doctors in china are still prescribing raw/sliced herbal medicine based on tcm theory and chinese herbology [9] . the majority of tcm doctors only prescribe western medications. in response to these challenges, the chinese government is putting a lot of effort in protecting and expanding the roles of tcm in the health care system in the past decade. in addition to increasing investment in clinical research and regulation as discussed earlier, different government agencies are collaborating to develop a series of initiatives to promote tcm, such as studying the basic theory of tcm, identifying and supporting senior tcm experts to pass along the ancient knowledge, and training a group of tcm elites to inherit the experience [32] . the chinese government is also looking for ways to fit the traditional tcm care framework into the current health care system. for example, a trial study on permitting tcm doctors to treat and prescribe herbal medicine to patients in herbal medicine shops will be conducted in nine cities/counties in china from july 2007 to march 2008 [33] . since the chinese health care system is very centralized, the government's role is very critical for the future of tcm. with the on-going major health care system reforms to provide accessible, affordable, and equal health care, the chinese government should consider how to provide sufficient investment on tcm and allocate the limited resources rationally. specifically, government needs to build up its own infrastructure and provide regulations and public polices on tcm to facilitate consumers and health services providers. after developing a reasonable, simple, transparent and consistent tcm regulation system, more focus should be on how to effectively implement and enforce those regulations and initiatives. complete investigations should be conducted to evaluate whether these regulations and initiatives are cost effective from society's perspective. in addition to educating the public on tcm, the government should also educate the public on the risks of western medicine. in addition to investigating and releasing information on adverse-reaction and medical errors, the government can also provide knowledge and studies on the current development of traditional medicine and alternative and complementary medicine in western health systems. this knowledge will encourage the chinese people to open their minds and reconsider the value of tcm in the chinese health care system. under the current economic situation in china, further studies should also investigate the competitiveness of the tcm market and the behavior of consumers and health providers. it is critical to develop well-designed survey studies in order to further investigate the determinants of the tcm utilizations. for example, what is the impact of health insurance and other socio-economic factors? do historical factors, such as the adverse campaign on tcm during the cultural revolution result in some cohort differences in the tcm utilization? for example, what is the funding impact from pharmaceutical companies and medical device companies on western medicine usage and tcm medicine? do the pharmaceutical companies and herbal medicine manufacturers have different profitability, marketing strategies, social and political impact on health care policies and regulations, which directly or indirectly influence western medicine and tcm practices? better understanding of the pattern of tcm utilization can help government reform the health delivery and financing infrastructure. it can also guide government to provide specific policies, such as promoting tcm in specific geographic locations, for subgroups who may receive more benefit from tcm treatment, and to efficiently allocate tcm resources. knowledge, imagery in an ancient chinese medical text traditional chinese medicine could make 'health for one' true. world health organization the greatest benefit to mankind: a medical history of humanity privatization and its discontents-the evolving chinese health care system the problems and suggestions on traditional chinese patent medicine processing a couple of thoughts on how to train students with tcm thinking skills comparative analysis of jinxian dai licensing procedure and rules for tcm doctors the curative effect and prospect of tcm against aids demand and utilization of tcm services in china. hei long jiang scientific and technology publisher current situations of tcm treatment on coronary heart disease and angina review of tcm research on epilepsy effect of chinese herbs in treating hepatic fibrosis induced by chronic hepatitis b tcm treatment on refractory nephrotic syndrome (rns) the study about diagnosis and treatment of child attention deficit-hyperactivity disorder in chinese traditional medicine research progress on anti-diabetic chinese medicines current tcm development and administration reform committee on the use of complementary and alternative medicine by the american public. complementary and alternative medicine in the united states. institute of medicine. the national academies press study on application of evidence based medicine in internationalization of traditional chinese medicine. world science and technology/modernization of progress and prospects of research on information processing techniques for intelligent diagnosis of traditional chinese medicine health in china: traditional chinese medicine: one country, two systems major roles of western medicine in tcm hospitals. finance and economics daily decreasing tcm clinical utilization. health newspaper a study of tcm treatment choices among outpatients traditional medicine in china today: implications for indigenous health systems in a modern world tcm herbal drug toxicity analysis and prevention methods analysis of 169 cases of adverse reactions induced by puerarin injection causes for adverse reactions of traditional chinese medicine injections: a case study of the "houttuynia cordata injection event effect of integrated traditional chinese medicine and western medicine on the treatment of severe acute respiratory syndrome: a meta-analysis outlines on tcm innovation and development temporary regulation on tcm doctors' practice in herbal medicine shops we would like to give our thanks to mr. brian mckenna for his comments. key: cord-028566-avl980hg authors: palko, hannah catherine; xiang, wei-ning title: in fighting common threats, people’s deep commitment to taking collective action matters: examples from china’s covid-19 battle and her other combats date: 2020-07-06 journal: socio ecol pract res doi: 10.1007/s42532-020-00056-1 sha: doc_id: 28566 cord_uid: avl980hg in fighting against common threats to human survival and well-being, be they from natural disaster or human conflict, people’s commitment to taking collective action matters and can make a huge or even decisive difference. throughout human history, there is a myriad of powerful examples from around the world in which people’s deep commitment to taking collective action changed the course of combat against common threats. these examples are invaluable heritages that belong to the entire humanity. at this critical juncture in human history, they can help cultivate a greater sense of optimism among all the people in the world both in the present fight against the covid-19 pandemic and beyond. to this end, in this showcase article, we present examples of this kind from china’s ongoing covid-19 battle, and from two of her many historical combats. in february 2020, a team of 25 experts from 9 countries spent 9 days in china working on a world health organization's project entitled the who-china joint mission on coronavirus disease 2019 [the joint mission, thereafter]. 1 after a series of intensive field work across the country, including a two-day visit to the country's hardesthit city wuhan (fig. 1) , the joint mission team released its 40-page report on february 28, 2020 (the joint mission 2020). the team was most impressed with "the apparent efficacy" of a "bold" yet "science-based, risk informed and phased approach" to containing the covid-19 virus transmission (the joint mission 2020, p. 17, p. 18 : "a mild to severe respiratory illness that is caused by a coronavirus (severe acute respiratory syndrome coronavirus 2 of the genus betacoronavirus), is transmitted chiefly by contact with infectious material (such as respiratory droplets), and is characterized especially by fever, cough, and shortness of breath and may progress to pneumonia and respiratory failure. note: covid-19 was first identified in wuhan, china in december 2019." (merriam-webster 2020a) [2] about china's releasing of the covid-19 information to who after the virus was identified, the associate press published an article on june 2, 2020, entitled china delayed releasing coronavirus info, frustrating who (the associate press 2020). 2 in direct contrast to the idea underlying this approach is a bold, non-science-based, risk-laden idea. at the daily covid-19 briefing on april 23, 2020, the us president donald trump publicly suggested that medical doctors study the idea of people receiving injections of disinfectant to combat the coronavirus (smith and paul 2020) . the comment was denounced fiercely by medical doctors, health experts, and even disinfectant manufacturers as being not just ignorant but actively dangerous (brown and sink 2020; smith 2020) . the next day, president trump claimed that he was being "sarcastic." the claim is undermined by video of the april 23 briefing (smith and paul 2020) and stirred up a 900% surge in lookup for the words sar-china's bold (yet "science-based, risk informed and phased") approach … has changed the course of a rapidly escalating and deadly epidemic. a particularly compelling statistic is that on (february 10) the first day of the advance team's work there were 2478 newly confirmed cases of covid-19 reported in china. two weeks later, on the final day of this mission (february 24), china reported 409 newly confirmed cases. this decline in covid-19 cases across china is real (fig. 2 ). 3 the team was equally impressed with "the uncompromising rigor" the nation demonstrated in implementing such a casm and sarcastic on april 24 in merriam-webster.com dictionary (merriam-webster 2020b). footnote 2 (continued) 3 [1] on april 25, 2020, the authors of this article double checked the updated confirmed cases. who (https ://covid 19.who.int/): 2985 (february 10, 2020), 221 (february 24, 2020); worldometer (https :// www.world omete rs.info/coron aviru s/count ry/china /): 2467 (february 10, 2020), 508 (february 24, 2020); johns hopkins university (https://coronavirus.jhu.edu/map.html): 2525 (february 10, 2020), 219 (feb 24, 2020) . despite the discrepancies in numbers, data from these sources show the same declining trend during the two-week period and onward. [2] about "the first day of the advance team's work", the team provides the following information in annex b of the report (the joint mission 2020 p. 25; parenthesis by the authors of this article): "10-15 february 2020, beijing, advance team and who country team meetings with (chinese) national counterparts and institutions." it provides no information in the report about the nature and composition of the advance team. prudent public health approach (the joint mission 2020, p. 17): in the face of a previously unknown virus, china has rolled out perhaps the most ambitious, agile and aggressive disease containment effort in history (ibid., p. 16). … china's uncompromising and rigorous use of non-pharmaceutical measures (under its "sciencebased, risk informed and phased approach") to contain transmission of the covid-19 virus in multiple settings provides vital lessons for the global response (ibid., p. 19; parenthesis by the authors of this article). 4 the team attributes this significant advance on the battleground to, on top of other factors, the resolute, compassionate support from the people in china. 5 it praises (the joint mission 2020, p. 17; parentheses by the authors of this article): achieving china's exceptional coverage with and adherence to these containment measures has only been possible due to the deep commitment of the chinese people to collective action in the face of this common threat. at a community level this is reflected in the remarkable solidarity of provinces and cities in support of the most vulnerable populations and communities. despite ongoing outbreaks in their own areas, governors (of the provinces) and mayors have continued to send thousands of health care workers and tons of vital ppe (personal protective equipment) supplies into (the hardest-hit) hubei province and (its capital) wuhan city. 6 at the individual level, the chinese people have reacted to this outbreak with courage and conviction. they have accepted and adhered to the starkest of containment measures-whether the suspension of public gatherings, the month-long "stay at home" advisories or prohibitions on travel. 7 since then, china has shared her experiences with more than 150 countries and international organizations via 70 videoconferences; provided medical supplies to more than 125 countries and 4 international organizations, as well as sent medical teams to 16 countries (chik 2020; liu 2020) . 5 people's compassionate support can come in different forms (the dalai lama 2020; douglas 2020; hu 2020). "[a] compassionate or constructive act-whether working in hospitals or just observing social distancing-has the potential to help many." (dalai lama 2020). 6 "more than 42,000 medical workers around the country came to hubei (and its capital city wuhan) to work shoulder by shoulder with their local peers in battling covid-19. the last medical team left the province on wednesday (april 15, 2020) as the number of remaining covid-19 patients dropped below 150." (zou 2020, parentheses by the authors) on february 21, a group of volunteer photographers from beijing kicked off a massive project in wuhan to take a headshot photograph for each and every one of the 42,000-plus medical workers. in about a month, they wrapped up the project (ibid.). this is yet one of many examples for compassionate actions volunteers took during the covid-19 battle. 7 [1] wuhan city government announced the citywide lockdown on january 23, 2020, and ended it on april 8. its 76-day lockdown record is the highest among major chinese cities. [2] among newspaper articles on the efficacy of the stark lockdown strategy in china's covid-19 battle is a march 19, 2020, article in the guardian written by two reporters based in shanghai, china. it has a striking yet on february 29, 2020, the day after the joint mission team released its report, an international volunteer coalition endcoronavirus was formed. since then, a research team in the organization, led by american complex system scientist yaneer bar-yam, has been tracking and analyzing the global response to the covid-19 pandemic (endcoronavirus 2020). in the team's real-time, country-by-country assessment report, china, with her continuing progress after the joint mission team's visit, is listed among the 42 countries or regions that are "winning" the battle by "beating covid-19" (ibid.; as of may 15, 2020). 8 it is noteworthy that the high praise the joint mission team issued for the chinese people's deep commitment to collective action resonates an admiring remark the us president donald trump made 9 days before the team's visit to china. on february 7, reflecting on "a long and very good conversation (he "just had") by phone with president xi of china," president trump twitted, "great discipline ( a recent example is the battle against sars pandemic in 2003. 11 after a period of uncertainty and confusion in the (2020). 10 here we define "a common threat" as a danger, something or someone that can hurt or harm people, that might happen to every individual human being in a certain place. a common threat comes either from a natural disaster or human conflict to which no one in a certain place (e.g., the earth, a country, a region, a city, a village, a community, etc.) is immune. at the global scale, for example, the covid-19 pandemic exemplifies the former, and world war ii the latter; at a regional scale, one such example is the pernicious hardships of water shortage people in the linxian county, henan province, china had been enduring before the construction of the red flag canal (xiang 2019) . a broader definition of common threat that includes all the beings in a certain place is possible but not used in this article. 11 [1] severe acute respiratory syndrome (sars): "a severe respiratory illness that is caused by a coronavirus (species severe acute respiratory syndrome-related virus of the genus betacoronavirus), is transmitted especially by contact with infectious material (such as respiratory droplets or body fluids), and is characterized by fever, headache, body aches, a dry cough, hypoxia, and usually pneumonia." (merriam-webster 2020c) [2] for comprehensive reviews and critical assessments of the global response to the 2003 sars pandemic, readers will find the following publication informative and useful: learning from sars: preparing for the next disease outbreak-workshop summary (knobler et al. 2004) . [3] readers will particularly enjoy reading an article in the volume entitled the sars epidemic and its aftermath in china: a political perspective (huang 2004 ). in the article, chinese-american political scientist yanzhong huang provides a comprehensive, critical yet constructive review of the nationwide sars battle in china, its antecedents and aftermath. many of his insights shed light on the 2020 global response to the covid-19 pandemic, including the battle in china. early stage of the pandemic (huang 2004, pp. 117-123) , the chinese people collectively waged a "nationwide war on sars" the government declared on april 20, 2003, with the aim "to halt the epidemic" (mahmoud and lemon 2004, p. 14) . besides adhering to a series of large-scale quarantine measures, people partook in a mass "patriotic health campaign" (huang 2004, p. 125) , which was initiated by chairman mao zedong in 1952 when the country was plagued with epidemic diseases and shortages of medicine (china. org.cn 2020). in the hardest-hit guangdong province alone, for example, 80 million people were mobilized to clean houses and streets; in the countryside, virtually every village was on sars alert, with roadside booths installed to examine people who entered or left (huang 2004, p. 125) . with the widespread, steadfast support from the whole people, this government-led, nationwide "crusade against sars" (ibid., p. 117) triumphed on august 16, 2003 with the last two sars patients discharged from a hospital in beijing (ibid., p. 125). from 1939 to 1940 during the second sino-japanese war, 12 according to japanese historian yoshiaki yoshimi (吉見義 明), "japan not only expended more than ten billion yen and suffered more than one hundred thousand deaths in (its aggressive) battle (in china). it also absorbed several hundred thousand repatriated soldiers who had accumulated raw experiences of china and its battlefields" (yoshiaki 2015, p.87 ; parentheses by the authors). many brought back diaries in which they had recorded these experiences. some of the diaries were made public after the war ended in 1945 (mark 2015, p. 15 ). drawing largely on these diaries and other personal documents written during or shortly after the war (mark 2015, pp. 15-16) , yoshiaki yoshimi conducted a nuanced, critical yet compassionate examination of personal war experiences of these repatriated soldiers. he published his findings in 1987 [for the english editions of his works on this topic, see yoshimi (2012 yoshimi ( , 2015 ; for an intellectual biography of yoshiaki yoshimi, including an introduction of the research process he went through for this project, see mark (2015) ]. besides graphic descriptions of the soldiers' atrocious behaviors in implementing the notorious "three alls policy" ["kill all, loot all, and burn all"-fan (2016, p. 183) ], he found two common themes in these diaries. one is "a deepseated fear towards the total chinese popular resistance and the feeling that the war was not easy" (yoshiaki 2012, p. 125, p. 129) , and the other "a pointless, misplaced sense of superiority … in dealing with chinese people" (ibid., p. 112). he wrote (yoshiaki 2015; italics and parentheses by the authors), (these repatriated soldiers) had developed a deep fear of the chinese resistance that involved the country's entire people, … whose solidarity extended to the elderly, women, and children" (ibid., p. 87, p. 78 ). 13 "[t]he fierce, relentless war against the japanese (aggression) far surpassed (their) expectations … (and was) difficult (for them) to comprehend according to what had been japanese popular "common sense" (of their superiority over china and other asian nations) (ibid., p. 78). admittedly, being surprised and puzzled with the sheer tenacity of chinese resistance, these repatriated japanese soldiers were not alone-so were the americans who had long been sympathetic and eventually, in 1942, became an important ally fighting shoulder to shoulder with the chinese. 14 to many if not most of them, it was almost incomprehensible that the undergirding solidarity, defiance, and readiness for self-sacrifice could burst out of a people who had been labeled as "the sick man of east asia" ("东亚病夫") by the western powers since the late nineteenth century after the 12 the second sino-japanese war is a term used primarily by scholars outside china. it is also known as "the 14-year war of resistance against japanese aggression (1931) (1932) (1933) (1934) (1935) (1936) (1937) (1938) (1939) (1940) (1941) (1942) (1943) (1944) (1945) " by chinese historians (sun 2017; sino japanese wars 2018) . for perspicuous reviews of the war, see fan (2016, pp. 165-231) and mark (2015) . in china, the war had long been referred to as "the 8-year war of resistance against japanese aggression (1937) (1938) (1939) (1940) (1941) (1942) (1943) (1944) (1945) " until recently. in 2017, chinese historians reached a consensus that the resistance began in as early as 1931 in northeast china right after the september 18 incident (also known as manchurian incident among historians outside china); and that the resistance lasted 14 years till september 2, 1945 when japan's unconditional surrender was formally signed (sun 2017) . 13 such solidarity also extended to the foreigners in china who compassionately joined the resistance. among those who are well known and highly respected are canadian physician henry norman bethune [chinese name白求恩, (1890 [chinese name白求恩, ( -1939 ] and lebanese-american physician shafick george hatem [chinese name马海德, (1910 [chinese name马海德, ( -1988 ]. but there are many more. for example, in her 1997 best seller the rape of nanking: the forgotten holocaust of world war ii, chinese american author iris chang [张纯如, (1968-2004) ] tells the moving story of a group of foreigners during the 6-week nanking massacre (december, 1937 -january 1938 [nanking in wade-giles system is equivalent to nanjing in pinying system]. led by john rabe, a german businessman and, ironically, the leader of the nazi party in nanking, they created and guarded the international safety zone which saved almost 300,000 chinese lives (chang 1997, pp. 105-139) . nanking people regard them as heroes, and john rabe "the living buddha of nanking" (ibid, p. 109). iris chang praises john rabe as "the oskar schindler of china." (ibid.). 14 on december 8, 1941, the day after japan attacked pearl harbor, the united states congress declared war against japan. beginning in 1942, china and the usa formed a strong alliance against japan that dramatically changed the course of the war (fan 2016, p. 183 ). opium wars. 15 taking note of this was american sinologist owen lattimore , whose intellectual work and life experience "strongly shaped american public opinion toward china and central eurasia in the twentieth century" (perdue 2018) . 16 in our chinese ally, a 1944 pamphlet prepared for the united states armed forces institute (american historical association historical service board 1944), owen lattimore and his wife eleanor write (ibid., p. 57): china's heroic resistance to the modern military might of japan has caused many of us to wonder in astonishment how such a non-industrialized, loosely organized nation could carry on as it has. we have been inclined to accept the continued resistance of the chinese as an unexplainable miracle. throughout chinese history, it is indeed this sort of recurring "unexplainable miracle" in the eyes of admirers, or haunting "deep-seated fear" in the minds of enemies, that has saved the nation many times (fan 2016; makeham 2008) . suffice it to say, fighting common threats collectively, be they from natural disaster or human conflict, has been, and will continue to be, a signature hallmark of this oldest living civilization in the world. in asking this question, we share a similar curiosity with owen and eleanor lattimore who ask the intriguing question in their 1944 pamphlet: "what is there about the chinese that has enabled them to resist japan for seven years, almost with their bare hands?" (american historical association historical service board 1944, p. 1) 17 their answer: "[m]oral and spiritual forces"(ibid., p. 57)-"values of culture" that "have existed in china so long … (and) have soaked right through the whole people" (ibid., p. 21). they regard having these long-standing cultural values "a very real advantage" of the chinese people (ibid.). we concur. in fighting common threats to their survival and well-being, chinese people's deep commitment to taking collective action, in the forms of solidarity, participation, discipline, and readiness for self-sacrifice, as showcased briefly in this article, is simply a natural outgrowth, a manifestation, of a strong cultural belief in collectivism they hold for thousands of years. 18 best exemplifying this deep commitment and its undergirding, long-standing cultural belief in collectivism is the song march of the volunteers (the state council 2018). written and composed in 1935 by chinese playwriter tian han (田汉) and composer nie er (聂耳) during the 14-year war of resistance against japanese aggression (1931) (1932) (1933) (1934) (1935) (1936) (1937) (1938) (1939) (1940) (1941) (1942) (1943) (1944) (1945) , the song has ever since been inspirational to the chinese people from all walks of life, so much so that it was adopted as the national anthem in 1949 for the newly established people's republic of china (ibid.). below are the lyrics (ibid.; italics by the authors of this article to highlight expressions of both the collectivist 15 [1] the label became almost obsolete after the establishment of the people's republic of china in 1949, with chairman mao zedong's famous proclamation that"the chinese people have stood up" (lau 2008; mao 1949) . among rare posterior incidences is the case in which wall street journal's columnist walter russell mead used the label in an opinion piece on february 3, 2020 (mead 2020). the title china is the real sick man of asia: its financial markets may be even more dangerous than its wildlife markets was regarded by the chinese government as "a racially discriminatory title, triggering indignation and condemnation among the chinese people", and resulted in a strong diplomatic action by the chinese government (hjelmgaard 2020) . [2] "opium wars: two wars (1839-42; 1856-60) between china and britain resulting from the chinese refusal to allow the importation of opium from india. china ceded hong kong after the british victory in 1842. the british and french victory in the second war established free trade in chinese ports and the legalization of the opium trade." (collins online dictionary 2020). 16 for those who are interested in owen lattimore's life and work, american historian peter perdue provides a succinct and useful introduction (perdue 2018) . 17 [1] the official authorship of the pamphlet is american historical association historical service board, as printed on the pamphlet. but on american historical association's web page, it is indicated that the pamphlet is written "by owen and eleanor lattimore" (https :// www.histo rians .org/about -aha-and-membe rship /aha-histo ry-and-archi ves/gi-round table -serie s/pamph lets/em-42-our-chine se-ally-(1944) accessed april 24, 2020). following this fine-grain, official clarification, we acknowledge the two writers here. [2] the lattimores apparently follow the 8-year war convention (see footnote 12). 18 [1] collectivism is unquestionably among the perpetual cultural beliefs in china (hofstede 2001, p. 211; wong 2009, p. 152, p. 155; yau 1988 pp. 44-45) . in a 2009 essay for encyclopedia of positive psychology, chinese-canadian psychologist paul pt wong posits that six strong cultural beliefs and a concomitant set of signature virtues have enabled the chinese people to be culturally resilientprevail in the calamity and thrive in the aftermath-for more than 5000 years (wong 2009, p. 152, p. 155) . besides collectivism, these cultural beliefs are uncontrollability of the world, ubiquity of change, fatalism, dualism, and utility of efforts (ibid., pp. 152-154). virtues derived from collectivism include collaboration, altruism, and social capital (ibid., p. 155). [2] cultural beliefs are conceptions about the world and human life a group of people hold as true, important, and desirable for good life (edwards and jarrett 2009, p. 265; greif 1994, p. 915; wong 2009, p. 152) . cultural beliefs influence how people think, what they value, and how they behave and cope (fan 2000, p. 4; greif 1994, p. 915; wong 2009, p. 148 ). commitment in the face of a calamity and the cultural belief in collectivism; for audio track, go to http://engli sh.www. gov.cn/audio ). to conclude, it should be noted that taking collective action in fighting common threats is an innate human ability essential for survival and well-being. throughout human history, there is a myriad of powerful examples from around the world in which people's deep commitment to taking collective action made decisive difference in fighting common threats, be they from natural disaster or human conflict. examples of this kind, including those showcased above, are invaluable heritages that belong to the entire humanity. "there is nothing as inspirational as a good example" (xiang 2020, p. 126 )-by throwing sharp light on the power of taking collective action in fighting common threats, these examples help build a greater sense of optimism among all the people in the world both in the present fight against the covid-19 pandemic and beyond. https :// archi ve.org/detai ls/ourch inese ally/mode/2up (the whole book trump's comment on disinfectant prompts experts to warn against inhaling bleach to kill coronavirus these delivery drivers are risking their health to keep china running during the coronavirus epidemic the rape of nanking: the forgotten holocaust of world war ii. basicbooks, new york chen l, yuan x (2020) china's ongoing battle against the coronavirus: why did the lockdown strategy work well? socio-ecological practice research coronavirus: china wants to lead the fight against covid-19, but can it overcome the mistrust? south china morning post patriotic health campaign: chinese pioneering undertaking in health field opium wars. collins online dictionary covid-19 compassion in self-isolating old age: looking forward from family to regional and global concerns china wins: why trump's who funding cut is a gift to beijing cultural values. in: lopez sj (ed) encyclopedia of positive psychology some are winning: some are not: which countries do best in beating covid-19? a classification of chinese culture culture, institution, and development in china: the economics of national character cultural beliefs and the organization of society: a historical and theoretical reflection on collectivist and individualist societies china expels wall street journal reporters over "racist" headline on coronavirus. usa today culture's consequences: comparing values, behaviors, institutions, and organizations across nations, 2nd edn. sage, thousand oaks hu r (2020) reinventing community in covid-19: a case in canberra learning from sars: preparing for the next disease outbreak-workshop summary the chinese people have truly stood up. south china morning post learning from sars: preparing for the next disease outbreak-workshop summary china has valuable lessons for the world in how to fight covid-19: stigmatising the country only distracts from the global effort needed to beat the pandemic learning from sars: preparing for the next disease outbreak-workshop summary china: the world's oldest living civilization revealed the chinese people have stood up! in: marxist.org china is the real sick man of asia: its financial markets may be even more dangerous than its wildlife markets covid-19 sarcastic" lookups spiked 900% on owen lattimore: world historian helicon (ed.) the hutchinson unabridged encyclopedia with atlas and weather guide coronavirus: medical experts denounce trump's theory of "disinfectant injection debacle of trump's coronavirus disinfectant comments could be tipping point. the guardian 14-year war of resistance against japanese aggression a consensus among chinese historians. people's daily online china delayed releasing coronavirus info, frustrating who. https ://apnew s.com/3c061 79497 06610 42b18 d5aea aed9f ae the dalai lama on why we need to fight coronavirus with compassion the joint mission (2020) report of the who-china joint mission on coronavirus disease 2019 (covid-19) national anthem. the state council of the people's republic of china china's ongoing battle against the coronavirus: a scholar-practitioner's experiences and reflections chinese positive psychology the red flag canal: a socio-ecological practice miracle from serendipity, through impossibility, to reality from good practice for good practice we theorize; in small words for big circles we write chinese cultural values: their dimensions and marketing implications the second sino-japanese war and national mobilization: the issue of rallying soldiers and personal experiences of the battlefield grassroots fascism: the war experience of the japanese people. translated and annotated by ethan mark project shows faces behind the masks. chinadaily. com.cn | updated we are grateful to five anonymous reviewers for their constructive comments on an earlier version of the article; we thank erika boardman and patricia quinn (the atkin library, university of north carolina at charlotte, usa) for their valuable assistance during the preparation of this article. key: cord-268179-bmtfanax authors: fan, jingchun; gao, ya; zhao, na; dai, runjing; zhang, hailiang; feng, xiaoyan; shi, guoxiu; tian, jinhui; chen, che; hambly, brett d.; bao, shisan title: bibliometric analysis on covid-19: a comparison of research between english and chinese studies date: 2020-08-14 journal: front public health doi: 10.3389/fpubh.2020.00477 sha: doc_id: 268179 cord_uid: bmtfanax background: as an emerging infectious disease, covid-19 has garnered great research interest. we aimed to explore the differences between english language and chinese language medical/scientific journals publications, particularly aiming to explore the efficacy/contents of the literature published in english and chinese in relation to the outcomes of management and characterization of covid-19 during the early stage of covid-19 pandemic. methods: publications on covid-19 research were retrieved from both english and chinese databases. bibliometric analyses were performed using vosviewer 1.6.14, and citespace v software. network maps were generated to evaluate the collaborations between different authors, countries/provinces, and institutions. results: a total of 143 english and 721 chinese original research articles and reviews on covid-19 were included in our study. most of the authors and institutions of the papers were from china before march 1st, 2020, however, the distribution of authors and institutions were mainly in developed countries or more wealthy areas of china. the range of the keywords in english publications was more extensive than those in chinese. traditional chinese medicine was seen more frequently in chinese papers than in english. of the 143 articles published in english, 54 articles were published by chinese authors only and 21 articles were published jointly by chinese and other overseas authors. conclusions: the publications in english have enabled medical practitioners and scientists to share/exchange information, while on the other hand, the publications in the chinese language have provided complementary educational approaches for the local medical practitioners to understand the essential and key information to manage covid-19 in the relatively remote regions of china, for the general population with a general level of education. the seriousness of the rapid spread of the sars-cov-2 virus has caused people to panic around the world since december 2019 (1) . the tremendous danger of sars-cov-2, with a basic reproduction number (r 0 ) ranging from 2.30 to 3.58 (2) , resulting in a pandemic with the number of infections reaching 9,653,048 to date (3) . consequently, considerable attention has been focused on covid-19 from medical practitioners/scientists around the world to inhibit/stop the continuous transmission of sars-cov-2 and to develop guidelines for the effective treatment of severe cases. to fight sars-cov-2, authorities in many countries have enforced social isolation restrictions to control the epidemic of covid-19 throughout their countries, strategies utilized in china include wearing of facemasks in public areas, and minimizing outdoor, particularly mandating no public and/or private social gatherings (4, 5) . the internet classes has allowed schools to continue to educate without classroom (6) . consequently, newly identified local covid-19 cases have been reduced to near 0 in all of the provinces in china (7), mainly due to the active approaches outlined above, and strict limits to interstate/international travel. however, outside china, many countries now face escalating epidemics and are feeling overwhelmed due to the highly contagious nature of covid-19. as an emerging infectious disease, covid-19 has garnered great research interest. medical practitioners/scientists are studying the disease from various scientific and clinical areas, including specialists in infectious diseases, virology, microbiology. many uncertainties remain as to certain epidemiological, seroepidemiological, clinical and virological characteristics of the virus and associated clinical features. the key task is to explore how to enhance host defenses and/or destroy viral resistance (8) . many researchers have published their data within top international, peer-reviewed, highly reputable journals, including nejm, lancet, nature and science (9) . there are many studies that have been published in reputable chinese journals (10, 11) . bibliometrics used in the current study is to analysis quantitatively of citation scientific publications, based on constructing the citation graph, a network representing the citations of different documents. in addition, bibliometrics is also used for exploring comprehensively the impact of their field, a set of researchers, a particular paper within a specific field of research. furthermore, vosviewer software was used for constructing and visualizing bibliometric networks, whereas, citespace v software was utilized for visualizing cocitation networks. there are a few published papers, using bibliometric analysis of covid-19, to explore the activity (12) and trends (13, 14) of covid-19 research. we aimed to explore the differences between english language and chinese language medical/scientific journals publications, particularly aiming to explore the efficacy/contents of the literature published in english and chinese in relation to the outcomes of management and characterization of covid-19 during the early stage of covid-19 pandemic. we have undertaken a bibliometric comparison of research on covid-19 between english and chinese language journals. a comprehensive search was performed online using the english language databases embase (15) and scopus (16) in the present study, only original articles and reviews, published in the chinese or english languages were included. studies including the following were excluded: (1) articles or reviews published on preprint sites such as bioriov and medriox; (2) translated versions of articles or reviews; (3) comments, editorials, and letters; (4) eliminating duplicate literature. two reviewers independently performed study selection and data extraction. differences of opinion were settled by consensus or referral to a third review author. since some authors have the same short name, we added the affiliation behind the author names, if the same name's affiliation was different, it was considered as two different authors. for authors with more than one affiliation, we used the first one. for keywords with different expressions, we have processed them, leaving only one standardized keyword. we also reclassified publications from hong kong, macau and taiwan to china, and publications from england, scotland, northern ireland, and wales to the uk. publication characteristics were tabulated, including titles, authors, co-cited authors, journal sources, keywords, affiliations of authors and, for english journals, the continents, countries or regions to which the authors belong; whereas for chinese language journals, the provinces. co-cited authors means that the authors have been cited together. vosviewer (version 1.6.14) software was utilized to analyze the relationships among the most highly productive countries, research institutions, and frequently used keywords. we performed cluster analysis and generated social network maps (consist of nodes and links) for countries, institutions and keywords by vosviewer (16, 17) . cluster was also obtained by vosviewer via analyzing the frequency of the same keywords appearing within the different papers. we set either twice or four times as the minimum frequency of keywords occurrence in english or chinese publications, respectively, reflecting the number of included studies (143 or 721, respectively) and the consequent analysis results. thus, the main reason for the different settings between english and chinese is because there are more than double the number of keywords from the chinese vs. the english language papers. consequently, there would be too many clusters if the frequency of keywords were set as twice for the chinese publications. different nodes in a map represent elements including a country, institution, or keywords. the size of the nodes reflects the number of publications or frequency, the larger the node, the greater the number of publications or frequency (18) . the links between nodes represent relationships of collaboration, co-occurrence, or co-citations. the color of nodes and lines represents different clusters (19) . the parameters of vosviewer were as follows: counting method (fractional counting) and "ignore documents with a large number of authors" (maximum number of authors per document is 25). citespace is scientific software that reveals the trends and dynamics in scientific literature as well as identifies key points in a given research field (18, 20) . citespace was therefore used to design the social network. in the current study, citespace was used to identify co-occurrence maps of authors, keywords, institutions, countries or provinces and capture keywords. a total of 864 original research articles and reviews were included, of which, 143 were retrieved from embase and scope in english and 721 from sinomed, cnki, vip and wanfang in chinese. a total of 1,062 authors have been identified in the 143 articles published in 62 english journals. the top 10 authors and journals are listed ( table 1 ). the top 10 authors have contributed 46 (32.1%) of the papers. author li y has the highest number of published papers (7, 4.9%), followed by benvenuto d, eurosurveillance editorial team and leung gm (5, 3.5%), and angeletti s, gao gf, ran j, wei y, wu jt, and yang g (4, 2.8%). the top 10 english journals are responsible for the publication of 72 (50.3%) papers, of which, j med virol is the highest (18, 12.6%), followed by euro surveillance (16, 11 .2%) and lancet (13, 9. 1%) ( table 1) . meanwhile, 3,243 authors have been identified in the 721 articles published in 193 chinese journals. the top 10 authors have contributed 45 (6.2%) of the papers. authors wang yg and yang fw have published the highest number of papers (6, 0.8%), followed by wang yj (5, 6.9%). the top 10 chinese journals have published 193 (26.8%) of the papers, the highest is chinese general practice nursing (41, 5.7%), followed by j traditional chin med (23, 3.2%) and chin herb med (18, 2.5%) ( table 1) . for the analysis of the social relationships of authors (affiliated institutions) with more than three articles (figure 1) , it was found that of 38 authors who published english papers, seven clusters corresponding to seven categories were identified (a), and of 29 authors who published chinese papers, clustering identified eight categories (b). these categories demonstrate that the cooperation between the various authors is close. of a total of 143 english papers that were published, there were a total of 1,062 authors from 32 countries or areas, including china (75/143, 52%), usa (34/143, 24%), uk (11/143, 8%), canada (11/143, 8%), and italy (10/143, 7%). there are 252 institutions from 32 countries published covid-19 related english papers. the first five are from china, including wuhan university (15/252, 6%), university of hong kong (12/252, 5%), chinese academy of sciences (9/252, 4%), huazhong university of science and technology (8/252, 3%), and chinese cdc (6/252, 2%). for the analysis of the social relationships of countries with more than three articles (figure 2a) table 2) . for the analysis of the social relationships of provinces/areas with more than three articles, as can be seen from figure 2c , amongst 32 provinces/areas, 28 provinces/areas are clustered into seven categories; amongst 677 institutions, 56 are clustered into nine categories, and the cooperation between them is close with more than three articles ( figure 2d ). for the papers published in english, 471 english keywords are extracted from the 143 articles. a density map is generated for keywords with a co-occurrence greater than twice, including 54 keywords in the map ( figure 3a) . sars-cov-2 was the most frequently used keyword ( figure 3a) , with 93 (19.7%) co-occurrences, followed by covid-19 (44, 9 .3%), china (36, 7.6%), sars (22, 4.8%), and epidemic (17, 3.6%) ( table 3) . among the top 20 keywords, some are related to epidemiological characteristics, such as epidemic, adult, male, female, travel, others are related to a comparison with similar diseases, e.g., mers, sars. some are correlated to the structure of the virus, e.g., endogenous compound, amino acid, cladistics, and phylogeny. cluster analysis is performed on co-occurrence of english keywords with a frequency >2. there are 54 keywords clustered into five categories (supplementary figure 1b) . cluster 1 includes 22 a total of 1,234 chinese keywords are extracted from the 721 chinese-language articles. a density map is generated for keywords with a co-occurrence >4 times, resulting in the generation of five categories ( table 3) . as stated above, there are substantial more chinese keywords identified within the chinese journals. if thence-occurrence of three times or less is adopted for the analysis, the clusters would be too many to offer an objective outcome. covid-19 is the most frequently used keyword, with 543 (44.0%) co-occurrence (figure 3b) , followed by sars-cov-2 (381, 30.9%), tcm (153, 12.4%), prevention and control (141, 11.4%), epidemic (56, 4.5%), management (51, 4.1%), therapeutics (48, 3.9%), and computed tomography (ct) (35, 2.8%). among the selected top 30 keywords with frequency more than 10, there were five clusters generated with such information (figure 3b) . for more detailed clusters, these were as follows: the keywords from the cluster one included clinical symptoms, critical case, ct, diagnosis, nucleic acids, therapeutics, x-ray; the keywords from the cluster two included cancer patients, emergency, infection, management, medical care personnel, mental health, prevention and control; the keywords for the (figure 2a) . for the 21 english language articles jointly authored between chinese and international authors, the institutions involved in cooperation between china and other countries were found to be centered in hong kong, hubei province, beijing and shanghai within china, while the most frequent overseas institution involved in cooperation was the new york blood center from the usa (figure 2c) . this cooperation covered a range of scientific topics, mainly focusing on diagnosis, such as pcr testing in the laboratory, prevention and control, and the viral genome ( figure 3a ). the battle against covid-19 has been highly effective in china up to date, however, the pandemic of covid-19 is highly alarming in around the world with substantial morbidity and mortality (3). the most urgent task for medical doctors/scientists is to control covid-19, including the incorporation of aspects of the chinese approaches. many diverse studies addressing covid-19 have sprung up due to the urgent necessity of prevention and control. we have focused on english and chinese publications only for the comparison. most of the studies captured in this paper on covid-19 in english journals have been conducted by chinese scholars and institutions, which is highly likely to be due to the timing of the literature search for this study, march 1st 2020, at which point the predominantly affected locations were wuhan, and to a lesser extent the remainder of china. of the international publications, particularly from western countries, e.g., italy (21) and south korea (22) , these publications occurred during the latter part of the survey period, from 27 february 2020, which is likely to be attributed to the spread of the sars-cov-2 commencing within these other countries, both raising the index of concern within those other regions and directly making available to those regions affected local populations and biological materials on which studies could be conducted. more authors from hong kong published more english papers than papers in chinese, which may be due to the higher levels of advanced english literacy, reflecting the english-based educational system (23) . furthermore, the majority of the hong kong researchers have more opportunity to study/work and establish links overseas (24), in addition to their preference for english journals. although the impact of covid-19 in iran has been very severe (25) , there has been no studies published on the pandemic at all prior to march 1st, 2020. we speculate that the iranian government has experienced difficulties scaling up its response to combating the epidemic, due to the economic loss and supply issues associated with economic sanctions imposed (26) . similarly, the scholars who published studies on covid-19 in chinese journals are mainly from beijing, hubei, shanghai, guangdong and sichuan. a likely explanation is that most of the first-class medical universities are within these areas, corresponding to the top research institutional distribution in china. apart from wuhan, hubei province, sichuan university has published more papers than other areas, except for beijing, shanghai and guangdong, which are the three provinces with the highest gdp in china (27) . especially relevantly, as the capital of china, beijing is the nation's political, economic, cultural and educational center, and has the largest number of universities in the country. these data support the idea that advanced academic development needs financial support. certainly, less publications are from xinjiang uygur, qinghai, ningxia, and inner mongolia, all of which has fewer covid-19 cases, but also have lower gdp within remote northwest china (gdp rankings out of 31 regions 19, 23, 15, 9, respectively) (28). in the cluster of authors, we found that the cooperation between the various authors is close but there is not a hotspot amongst them, which is in line with the reality that the information sharing was lacking at the early stage. the studies in english related to covid-19 are published in international, highly reputable journals, including nature, science, cell, nejm, jama, and lancet. these publications enable medical practitioners/scientists to share/exchange information efficiently, providing essential background for some key policy decisions (29, 30) , e.g., mandatory wearing of face masks, minimizing social gathering [has been widely accepted, including australia (31), uk (32)], and the lockdown of interstate travel in many countries of the eu (33) . importantly, the ultra-rapid development of an effective vaccine, has been accelerated by the rapid sharing of scientific data, particularly the published sequences of the sars-cov-2 virus. thus, publications in english journals, particularly in well-recognized, top ranking international journals, results in rapid dissemination of key information for use of the data for practical applications. english is the well-accepted communication language of science around the world. our data demonstrated that substantial collaborative research has been undertaken from the very early period of the covid-19 outbreak (34, 35) , and that this research has become more frequent and deep following the declaration of a pandemic. such collaborations are certainly enhancing our understanding of the nature of the sars-cov-2 virus (36, 37) , have supported development of effective vaccines (38, 39) , and has provided vital data to assist clinical diagnosis at the international level (40) . these developments further support our conclusion that publications in english have enabled doctors/scientists to effectively share/exchange information at the international level. the cluster analysis of institutions at the international level demonstrated strong regional representation even at the international level, both within china and within international countries. interestingly, the cluster of cooperation for studies in china was thickest with the usa, suggesting the cooperation was mainly between china and usa, which is consistent with the publications retrieved from the database. the most likely explanation has been mentioned above, namely that the economic resources of each country is the likely most significant factor to impact both the disease and research into it. in contrast, there is a language barrier to the utilization of the information from the papers published in english journals for use by the general population in china. the publications in the chinese language are able to meet a complementary dissemination purpose for china-based medical practitioners to understand the essential key information concerning covid-19, especially for those in the remote areas of china, without proper access of english journals or sufficient language skills (41) . indeed, publications in chinese provide a more acceptable approach for chinese doctors to learn how to deal with covid-19 in the relatively remote regions of china, an outcome that is consistent with the large number of studies that have been published in chinese. the top 10 chinese journals that included covid-19-related papers are mostly from the chinese science citation database, representing the most authoritative and representative core of journals in all disciplines in china (42) . importantly, in this study there are a total of 721 papers that cover covid-19 from various scientific areas within the identified journals, often with a large number of authors, reflecting the chinese authority's intention to accelerate the control of covid-19 and the rapid dissemination of knowledge. there are a total 471 or 1,234 keywords in english or in chinese publications, respectively, used in the studies on covid-19 that we identified till march 1st, 2020. however, more than 78% of the keywords appeared once, only 3.9% of the english keywords have a frequency of >4, indicating the importance of a few keywords. in bibliometrics, a network graph of keyword co-occurrences reflects hot topics (18) . cluster analysis of co-occurrence keywords demonstrates that there are five clusters in this field. cluster 1 consists of 22 keywords, mainly relates to the epidemiological characteristics and clinical features, because these are the basis for understanding key aspects of the disease, such as treatment and control. at the present time, many scholars are focusing on the large proportion of covid-19 patients who exhibit mild symptoms or are asymptomatic carriers, reflecting the seriousness of the nature of viral transmission (43) . cluster 2 contains 11 keywords, mainly focuses on the virus detection and genome. some data demonstrate that bat cov and human sars-cov-2 might share the same ancestor (40) , and similar residues of the key receptor are observed in many species (44) . because of the importance of the original source of sars-cov-2, the evolution and genomics is a hot topic in this field. nine keywords are included in cluster 3, focusing on drug treatment and comparison with sars and mers, making comparisons to these fatal respiratory tract infections by coronaviridae, to explore any clues between the similarity and differentiation. for the papers published in chinese language journals, there are five clusters of keywords, including 2-6 keywords in each field. cluster 1 consists of six keywords, mainly relating to treatment and diagnosis, because these activities are the basis for understanding key aspects of the disease, such as treatment and control. at the present time, many scholars are focusing on the large proportion of covid-19 patients who exhibit mild symptoms or are asymptomatic carriers, reflecting the seriousness of the nature of viral transmission (43) . cluster 2, contains 6 keywords, mainly focusing on emergency, infection, management, medical carers, prevention and control, which are supported by the others, demonstrating the critically importance of covid-19 in such outbreak (45) , transmission (46) and disease control and management (47) . cluster 3 is focusing on tcm or chinese and western treatment for covid-19, mainly to explore the benefit of the combination of tcm and classical western management approaches, especially aiming to provide the guidelines for relatively remote/rural regions of china. the advantage of this particular cluster is its usefulness in the outskirts of metropolitan or rural areas, where there is a relative lack of advanced or first line anti-viral medications (48) . cluster 4 is an extension of the current existing treatment to the cardiovascular system (49) , as well as, using the previous experience in mers (50) , and also places emphasis on antiviral drugs and herbs (51) . interestingly, cluster 5 includes pregnancy and nursing, which is a very venerable population at high risk, either due to compromised immunity during pregnancy (52) or the lack of sufficient data to adequately understand the severity of the potential risk of covid-19 in pregnancy and the need to guard against covid-19 infection in pregnancy (53) . part of the reason for the chinese scholars focus on tcm when publishing in chinese medical journals is the difficulty chinese scholars have to disseminate their findings using modern scientific terminology/theory, compared to rather ancient theory of tcm, e.g., balance of ying and yang. actually, we believe that balance of ying and yang is equivalent to the modern theory of anti-vs. pro-inflammatory responses in the micro-environment, i.e., imbalance of anti-vs. pro-inflammatory responses contributes to autoimmune diseases (54) . thus, from the point of view of the management of covid-19, the efforts should be focused on the suppression of the sars-cov-2 virus, disregarding the backgrounds, theories, and approaches of modern vs. traditional scientific ideology. consequently, analysis of the dissemination of the critical information from english and chinese languages could facilitate such a purpose appropriately. these covid-19 related english language papers, especially at the top end, e.g., nejm (55), lancet (7, 26) , science (8), nature (36) , provide the most critical information in the development of effective vaccinations (31) . on the other hand, for many primary health carers at the front line in the relatively remote regions in china, obtaining the most up dated information of covid-19 particularly, regarding prevention and/or controlling has been from the chinese language. in addition, the local government at the county levels are also heavily dependent on such key information in chinese, in detail, e.g., keep social distance, no public gathering, and lockdown of manufacture and so on (56) . there are some limitations in the current study. first, our study is focusing only on english and chinese journals, which inevitably could miss some important information from other languages. we will further analyze such points by collaborating with researchers from the different regions/countries. second, our study has been undertaken at the vortex of the epidemic before march, 2020, which may miss the most updated information. third, the total number of included studies is relatively small, and the study duration of just more than 2 months from when the first covid-19 patient is identified till march 1st, 2020, is a short cutoff time for data retrieval. the publications related to covid-19 research has been rapidly growing since the disease emerged. more studies have been published in chinese journals than in english, due to the epicenter being located in wuhan, china before march 1st 2020. the publications in english have enabled doctors/scientists to share/exchange information at the international level; the publications in the chinese language provides complementary educational approaches for the local doctors to understand the essential and key information to manage covid-19 in the relatively remote regions of china for the general population. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. jf and sb conceived of the presented idea. jf and yg developed the theory and performed the computations. yg and jt verified the analytical methods. nz, rd, hz, xf, and gs collected and synthesized the data. cc and bh encouraged jf and yg to investigate and supervised the findings of this work. all authors discussed the results and contributed to the final manuscript. the supplementary material for this article can be 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zhen, yu; wang, zhu-jun; mu, jing-xi; zhu, min; ouyang, qin; zhang, hu title: chinese research into severe ulcerative colitis has increased in quantity and complexity date: 2018-03-16 journal: world j clin cases doi: 10.12998/wjcc.v6.i3.35 sha: doc_id: 2918 cord_uid: jmjtr1pb aim: to investigate the current state of research output from chinese studies into severe ulcerative colitis (suc) using a bibliometric analysis of publications. methods: the contents of the chinese periodical databases wanfang, vip, and china national knowledge infrastructure were searched for all papers regarding uc or suc published in last the 15 years (from 2001 to 2015). the number of publications in each year was recorded to assess the temporal trends of research output. all suc related publications were downloaded and the complexity of this research was evaluated with methods described previously. the number of patients with suc reported each year was recorded and their clinical characteristics were analyzed using information available in the relevant papers. results: there were 13499 publications regarding uc published in chinese medical journals between 2001 and 2015, of which 201 focused on suc. the number of publications increased rapidly with more than half of all papers being published in the most recent 5-year period. there was a significant increase in analytical studies and clinical trials over the study period (p < 0.01), with research into the management of suc, included pharmacotherapy, nutrition support as well as surgery, predominating. almost half (46.2%) of the observational analytical studies and clinical trials focused on traditional chinese medicine, with little research on the efficacy of cyclosporin and infliximab in disease management. about 6222 patients with suc were reported in the 201 suc relevant papers, with a ratio of male/female of 1.38. the number of patients reported in each 5-year period significantly increased. the colectomy rate and short-term mortality rate were 7.7% and 0.8% respectively. the most commonly employed operation was total proctocolectomy with ileal pouch-anal anastomosis. conclusion: the output and complexity of research related to suc in china increased significantly over the previous 15 years, however few of these studies focused on salvage therapy. luo cx et al . chinese research into severe ulcerative colitis studies and clinical trials over the study period (p < 0.01), with research into the management of suc, included pharmacotherapy, nutrition support as well as surgery, predominating. almost half (46.2%) of the observational analytical studies and clinical trials focused on traditional chinese medicine, with little research on the efficacy of cyclosporin and infliximab in disease management. about 6222 patients with suc were reported in the 201 suc relevant papers, with a ratio of male/female of 1.38. the number of patients reported in each 5-year period significantly increased. the colectomy rate and short-term mortality rate were 7.7% and 0.8% respectively. the most commonly employed operation was total proctocolectomy with ileal pouch-anal anastomosis. ulcerative colitis (uc) is a chronic idiopathic inflammatory disease characterized by relapsing and remitting mucosal inflammation in the colon [1] . about 15%-25% of all uc patients experience at least one severe exacerbation requiring hospitalization [2] . severe uc (suc) is a potentially life-threatening condition which is defined as six or more bloody stools per day plus at least one of the following of truelove and witts' criteria: fever (temperature > 37.8 ℃); tachycardia (pulse rate > 90 bpm); anemia (hemoglobin ≤ 75% of normal); and elevated erythrocyte sedimentation rate (esr > 30 mm/h) [2, 3] . intravenous corticosteroid remains the first-line therapy for suc, having been reported to reduce the mortality rate from 24% to 7% [4, 5] . however, 30%-40% of patients have disease which is steroidrefractory, requiring more invasive treatment [6, 7] . the overall colectomy rate in suc patients is higher than 30%, according to a cohort study [8] . however, in cases that fail to response to steroid therapy [stool frequency >8 stools/d, or 3-8 stools/d together with a c-reactive protein (crp) > 45 mg/l on day 3], the colectomy rate is 85% [9] . salvage therapy with either infliximab or cyclosporin appears to improve clinical outcomes for cases of steroid therapy failure in randomized controlled trials [10] . patients who do not respond to intensive medical therapy or with severe complications including toxic megacolon, perforation and severe hemorrhage should be considered for timely surgery. delayed surgery is associated with increased mortality and a higher risk of postoperative complications [11, 12] . therefore it is of paramount importance to assess the response to therapy regularly, using standardized criteria, and to initiate optimal therapy options promptly. above all, effective management of suc remains a great challenge. china and other asian countries are experiencing an increasing incidence and prevalence of uc [13] . a longterm follow-up study from hong kong reported a sixfold increase in the incidence of uc (from 0.3 per 100000 in 1986-1988 to 1.8 per 100000 in 2004-2006) [14] . wang et al [15] analyzed 3100 uc patients hospitalized in 23 hospitals in mainland china from 1990-2003, and noted a steady increase in the number of cases. 21.7% of these patients (654/3100) were identified as severe. bibliometric analyses and literature reviews of scholarly publications in chinese periodical databases provide more epidemiological information. for example, a comprehensive search of the chinese biomedical literature database retrieved 3384 articles relating to inflammatory bowel disease (ibd) published in chinese medical journals between 1989 and 2013, in which 140114 cases of uc were reported with the number of reported cases steadily increasing annually [16] . according to jiang et al [17] , there were 1560 chinese papers regarding uc published from 1981 to 2000 where 10218 patients with uc were reported. given this dramatic increase in uc, further database surveys and publication analyses are required to collate the available information about the recent epidemiology and treatment efficacy of uc and suc in china. in addition to epidemiological information, bibliometric analyses provide a perspective of research hotspots. for example, according to ouyang et al [18] , articles of basic research on ibd in china rapidly increased and predominantly focused on immunological mechanisms. moreover, bibliometric analysis of indicators including publication output and research complexity is widely used to assess the performance of the research programs of institutions and/or countries [19, 20] . as mentioned above, china has witnessed an increasing incidence and prevalence of uc. furthermore, china's population accounts for 20% of the total world population. a comprehensive study of the quantity and quality of sucrelated chinese publications is desperately needed. this study aims to perform a bibliometric analysis to determine the temporal trends in the number of chinese publications on uc and suc between 2001 and 2015, and to assess the suc research performance. this study also aims to provide a review of the data on treatment type and efficacy in suc patients that has been reported in chinese medical journals. in addition, such a study can more broadly provide insight into improving uc and suc treatment worldwide. we conducted searches of the chinese periodical databases wanfang, vip, and china national knowledge infrastructure (cnki) on august 1, 2016 using the search terms "ulcerative colitis" or "severe ulcerative colitis" in the article title or keywords. results were limited to those published in the years from 2001 to 2015. publications from 2016 were excluded since only partial data was available for this year. the number of uc related publications in each year as defined by the wanfang database was recorded, however only the suc related publications were downloaded to obtain information about publication year, type, topic, study design, and sample size. all suc publications were retrieved and reviewed. publications were classified as original research articles, case reports and case series, reviews and others (conference papers, graduation theses and papers published in journals on nursing practice). the topic of each paper was recorded and only those that were clinical in nature were included in the assessment of the complexity of suc research. according to the methods described by scott et al [20] , the study design of clinical papers was grouped into one of three categories: descriptive studies (case reports, cases series and cross sectional studies), observational analytical studies (case-control and cohort studies) and clinical trials. the proportion of the total within each group was compared in every 5-year period from 2001 to 2015. the characteristics of the patient treatment and disease activity reported in all suc related publications were recorded in excel for further analysis. all statistical analyses were performed using spss statistics 22.0. spearman's rank correlation coefficient was calculated to study trends over time. the statistical significance of differences between proportions was compared with chi-squared test. a p-value of < 0.05 was considered as statistically significant. to determine if the same temporal changes occurred in suc publications, we repeated the search process in the wanfang, vip and cnki databases with the search terms "severe ulcerative colitis" in the article title or keywords. about 510 papers were retrieved from these three databases when the publication year was limited to the most recent 15 years the 201 publications in chinese journals on suc compromised 96 original research articles (47.8%), 29 case reports and case series (14.4%), 18 reviews (9%), 25 conference papers, 7 graduation thesis and 26 papers that were published in journals of nursing. of the 96 original articles, 65 (67.8%) have reported the adopted diagnostic criteria for suc, which are diagnostic criteria in "consensus on the diagnosis and management of inflammatory bowel disease" that were developed and revised by chinese society of gastroenterology in 1978, 1993, 2000, 2007, or 2012 . in these consensuses, suc is diagnosed according to truelove and witts' criteria (six or more bloody stools per day plus at least one of the following: temperature > 37.8 ℃; pulse rate > 90 bpm; hemoglobin ≤ 75% of normal; esr > 30 mm/h). above all, the severity of uc was judged according to truelove and witts' criteria in these chinese hospitals, consistent with the criteria applied in western countries. we included original research articles and case reports/case series in our analyses of the complexity of suc research in each 5-year period, as described by scott et al [20] . articles on basic research were excluded to ensure that all articles included in our study were clinical in nature. the resulting 125 papers were classified into three groups (descriptive studies, observational analytical studies, and clinical trials). there was a significant increase in observational analytical studies and clinical trials, especially in the most recent 5 year period (p < 0.05) ( there were 6222 patients with suc reported in the total of 201 papers on suc (the number of patients reported in each 5-year period is presented in figure 5 ) to roughly estimate the incidence of serious complications in patients with suc, the number of cases with toxic megacolon, intestinal perforation, severe hemorrhage, intestinal obstruction, colorectal cancer was luo cx et al . chinese research into severe ulcerative colitis recorded to be 40 (0.64%), 30 (0.48%), 25 (0.40%), 10 (0.16%), and 8 (0.13%) respectively. the colectomy rate in the 6222 suc patients was 7.7% (480 cases of colectomy were reported in 201 papers); while the mortality rate calculated with our data was 0.8%, since 50 deaths were reported from a total 6222 patients. management is the prime focus of suc related clinical research. sixteen of the 21 observational analytical studies and all of the 36 clinical trials focused on the medical management of suc (median sample size of 64). treatment types included traditional chinese medicine (46.2%), corticosteroid therapy (17.3%), enteral or parenteral nutrition support (11.5%), immunosuppressive drugs (7.7%), biological agents (3.8%), probiotics (5.7%) and others (7.7%) ( figure 6 ). adjunctive therapy with traditional chinese medicine was studied in 55.6% (20/36) of clinical trials with the effective rates ranging from 73% to 97%, with 12 articles reporting an effective rate of more than 90%. the most commonly used herbs were radix pulsatillae, radix scutellariae, rhizoma coptidis, radix paeoniae rubra, and radix puerariae and the most commonly used formulation was a modified pulsatilla decoction. intravenous corticosteroids treatment remains the first-line therapy; however, the assessment of response to therapy remains a great challenge. predictors and predictive indices for the failure of steroid therapy and the subsequent need for colectomy have been widely studied. nine of the 96 original research articles focused on corticosteroid treatment, in which 800 patients with suc received corticosteroids as the principal therapy. three of these 9 articles reported both outcome and predictors of therapy failure, while 6 only reported outcomes. the effective rate of steroid treatment ranged from 58.3% to 90%, with a pooled effective rate of 67.3%. previous severe attack and onset with stool frequency ≥ 10/d are associated with increased rates of steroids failure. further predictors of steroid treatment failure include: a stool frequency ≥ 6/d, obvious bloody stool, severe hypoalbuminemia, and an elevated platelet count after 3 d of intravenous steroids. we found few publications on research into salvage therapy. no clinical trials for cyclosporin were available and only 2 retrospective studies were retrieved, including 29 and 7 cyclosporin treatment cases respectively. side effects were reported for 15 of these cases (8 cases of hypertension, 4 hepatic dysfunction, 2 hypertrichosis, and 1 hyperlipidemia). there were only 2 studies on the treatment efficacy of biological agents (1 casecontrol study and 1 randomized controlled trial), in which 33 suc patients received infliximab as salvage therapy, resulting in 4 cases of nonresponse, 4 cases of transfusion reaction, 2 upper respiratory tract infections. the disease response rates were found to be 82.3% and 87.5% respectively, with the rates of adverse effects being 17.6% and 25.0%. our publication search retrieved 8 original research articles focused on surgical management in suc patients, in which 200 suc patients who received surgical intervention were studied. two articles investigated the predictors for the need for colectomy, using the oxford index, swedish index, edinburgh index, and seo index [21] . the oxford index, also known as the travis index, was developed in 1996 and has been validated in cohort studies. according to this index, patients with a stool frequency of more than 8 per day, or 3-8 stools per day plus an elevated crp (> 45 mg/l) at day 3 of corticosteroid therapy, have a 85% chance of colectomy. the swedish index is calculated using the algorithm: "number of stools per day + 0.14 x crp (mg/l)", with scores > 8 indicating a high risk of requiring colectomy. the edinburgh index is also known as the ho score, in which scores for stool frequency (1-4 points), hypoalbuminemia < 3 mg/dl (1 point) and radiological evidence of colonic dilation (4 points) are summed, and scores greater than 4 are predictive for failure of corticosteroid therapy and subsequent need for colectomy. the seo index is calculated using the mathematical formula: "60 x frequency of bloody stool + 13 x bowel movements + 0.5 x esr (mm/h) -4 x hemoglobin (g/dl) -15 x albumin (g/dl) + 200"; where scores greater than 200 predicting the need for colectomy. these 2 articles reported that the either the oxford and swedish indices are superior to the edinburgh and seo indices in predicting medical failure and the subsequent need for surgical intervention. only one of these 8 articles reported the rate of colectomy. according to pan et al [22] , there were 412 patients with uc admitted to the west china hospital (sichuan, china) from 1996 to 2008, of which 162 patients (39.3%) were identified as having severe disease with the colectomy rate in these patients being luo cx et al . chinese research into severe ulcerative colitis 17.9% (29/162). five articles reported the indications for surgery, which included medically refractory disease and severe complications (toxic megacolon, colonic perforation, massive hemorrhage and colorectal carcinoma). six of these articles reported the specific operative approaches adopted to treat these cases. the most commonly employed operations were total proctocolectomy with ileal pouch-anal anastomosis (ipaa) (45%), total proctocolectomy with ileostomy (19%), total proctocolectomy with ileoanal anastomosis (iaa) (15%), and total colectomy with ileorectal anastomosis (ira) (14%). the most common late complication of ipaa was pouchitis with an incidence of ranging from 7.7% to 50%, as reported in 4 articles [23] . two articles reported a high frequency of postsurgical bowel movements in patients that underwent iaa, between 20-30 per day in the first month and decreasing to 6-10 per day in the third month. among the 21 patients who underwent ira following total colectomy, 67% experienced disease recurrence in the rectum, however no cases of rectal dysplasia and/or cancer was reported after a median 3-year follow-up. bibliometric analysis is widely used to assess the performance of the research programs of institutions and/or countries. research productivity and research influence are important bibliometric indicators that can be measured by the number of publications and subsequent citations [24] . we performed a bibliometric analysis of chinese suc research using both quantitative and qualitative approaches. the number of publications about uc and suc both experienced a significant increase over the 15 year study period. this temporal change is similar to the trends in ibd publications archived in pubmed between 1993 and 2011, as reported by weintraub et al [25] . this may be attributable to the increased prevalence of uc, improved diagnostic methods, physician awareness of the disease, increased interest, and the spread of internet access [26, 27] . accompanied with the increasing output of suc research, we also observed a significant increase in the number of analytical studies and clinical trials, which are more complex in study designs and are stronger in terms of the strength of evidence than descriptive studies [20] . above all, this study has demonstrated that there has been a significant increase in publication output and research complexity on suc in chinese scholarly journals. this implied that there was a correlated increased in the prevalence of uc and suc disease resulting in a subsequent increase in uc/suc associated research in china. there was a more than tenfold increase in the number of suc patients reported in chinese medical journals over the most recent 15 years. a male predominance in suc incidence was observed in our data, with a male to female ratio of 1.38, similar to the value of 1.34 reported by a multi-centre study in china [15] . however, male and female patients were reported to be equally affected in 10218 uc patients reported in chinese medical literature from 1981 to 2000, with a male to female ratio of 1.09 [17] . a similar gender distribution for disease has also been noted in other asian and western countries [26] . one hypothesis for this observation is that male patients with uc may have a more severe disease course since male gender has been reported as a risk factor for colectomy [8, 28] . further, more detailed, population-based studies are required to validate these data. these data also indicate that management is the prime focus of suc research in china, since almost all analytical studies and clinical trials were found to focus on management regimes, including pharmacotherapy, nutrition support and surgery. while intravenous corticosteroid treatment remains the first-line therapy for suc, the low rate of efficacy, 67.3% reported in our pooled analysis is consistent with the high refractory rate of 31%-35% reported by seah et al [2] . prompt and objective assessment of the failure of steroid therapy plays an important role in the management of suc [29] . however, only 3 of the 201 articles reported predictive factors for steroids failure, consequently it is hard to obtain a unified index with high sensitivity and specificity. further studies are required to establish homogenous predictors and unified methods for predicting steroid treatment failure and the subsequent requirement for salvage therapy or surgery. cyclosporine and infliximab are commonly used as salvage therapy in patients that fail to enter remission after corticosteroid treatment. cyclosporine treatment has improved the outcome of steroids-refractory disease in suc patients and achieved an immediate response rate of 64%-82% [2] . there is a lack of randomized controlled trials and long-term follow-up studies focused on cyclosporine treatment in china, two retrospective studies with small sample size have reported a high rate of side effects. treatment with infliximab was also reported to reduce the colectomy rate in suc patients, but our search determined that publications on infliximab therapy in chinese suc patients did not appear until 2013. the 2 studies regarding infliximab treatment both reported a response rate greater than 80%, with rates of adverse effects of 17.6% and 25%. more evidence is required to evaluate the benefit and safety of both cyclosporine and infliximab treatment in chinese suc patients. traditional chinese medicine is one of the most developed complementary and alternative medicine approaches used in the treatment of ibd [30] . extracts or decoctions of herbs are administrated by oral intake or retention enema combined with 5-aminosalicylic acid or corticosteroid therapy as treatment for severe or refractory uc. the underlying mechanisms involve anti-oxidation, anti-inflammation, and alteration of gut microbiota [30, 31] . in our study, more than half of the analytical studies and clinical trials related to suc focused on traditional chinese medicine, with most reporting an efficacy rate greater than 90%. the most commonly used formulation was found to be a modified luo cx et al . chinese research into severe ulcerative colitis pulsatilla decoction, which has been proven to attenuate experimental colitis in mice by inhibiting the activation of nuclear factor-κb signal pathway, reducing the production of pro-inflammatory cytokines, and repairing the colonic epithelial barrier [32] . a review of chinese articles regarding ibd therapy also reported a higher proportion of articles (60.9%) that focus on traditional chinese medicine and less use of immunosuppressants and biological agents [18] . although the popularity of traditional chinese medicine has increased both in china and some western countries, further studies are required to validate its efficacy and safety. the colectomy rate in our study was found to be 7.7%, while the colectomy rate in hospitalized suc patients reported by the west china hospital is 17.9%, both are lower than the 20%-40% reported in united kingdom [8] . it is assumed that the indications of surgery are more conservative in china than in western countries such as the united kingdom [22] . lower colectomy rates were also reported in uc cohorts in other asian countries like japan and korea [26, 28] . the most commonly employed operation was total proctocolectomy with ipaa since it avoids the requirement for a permanent stoma, has a lower risk of disease recurrence and/or rectal carcinoma, and has excellent long-term functional results with good quality of life [33] . however, almost 20% of patients experienced pouch failure due to pouchitis or pouch dysfunction after ipaa [33] . the incidence of pouchitis ranged from 7.7% to 50% as reviewed in this study. according to our data, the short-term mortality rate of suc is 0.8%, lower than the 1.2% reported in western countries [15, 28] . these results are consistent with that reported by wang et al [16] , who observed a relatively milder clinical course and lower rate of complications in chinese uc patients. uc is associated with an increased risk of colorectal cancer. the severity of histological inflammation correlates with colorectal cancer risk [34] . the incidence of colorectal cancer among suc patients is 0.13% in our study, lower than the values of 0.4% and 3%-5% reported by wang et al [15] and in western studies respectively. further studies are required to confirm the hypothesis that asian uc patients have a milder disease course and a lower risk of colectomy, colorectal cancer, and mortality. there are some limitations about this study. firstly, we only included literature published from 2001 to 2015 and performed the bibliometric analysis in each 5-year period. publications since 2016 were not included since only partial data of these publications were available online when the database search was performed. as it is well known that the mode of treatment is continuously changing day by day, here we repeated the database search with published year limited to 2016 and 2017. we retrieved 33 publications, included 23 original articles, 6 case reports, 2 reviews, and 2 papers published in journals of nursing. in these 23 original articles, 21 were focused on the management of suc, including traditional chinese medicine (17.4%), corticosteroid therapy (8.7%), immunosuppressive drugs (4.3%), biological agents (26.1%), and probiotics (17.4%). there is an increase in articles about biological agents than before. secondly, biological agents have been widely suggested and used in developed countries, but in our study, it's found that biological agents had been prescribed for patients in 3.8% publications regarding suc from 2001 to 2015. this might be due to the fact that biological agents such as infliximab was approved just a few years ago in china, and this kind of medication is so expensive that some patients who met the indications could not afford it. this situation may be changed with the passage of time and the development of economy. as discussed above, biological agents have been prescribed more frequently in the last two years than before. thirdly, we only reviewed the 201 papers with a prime focus of suc, the patients with suc that reported in articles regarding inflammatory bowel disease might be omitted. we also failed to calculate the incidence of suc since this study is not an epidemiological study, and furthermore, the total number of patients with uc is unavailable. in conclusion, our study documents that significant progress has occurred in suc research within the chinese medical research community, as reflected by the increased output and complexity of publications. although traditional chinese medicine has been widely used as a complementary therapy for suc, rigorous experiments and careful analysis of the resulting experimental data are required to validate the benefit and safety of this type of treatment. the relatively few publications into salvage therapy suggest that more research into the efficacy of treatment with cyclosporin or infliximab in chinese suc patients is required. we reported a male predominance in suc incidence and a lower colectomy rate in chinese suc patients compared to western countries based on literature review. data of clinical characteristics obtained from our literature review should be verified and extended by further welldesigned and detailed population-based studies. severe ulcerative colitis (suc) is a potentially life-threatening condition and its effective management remains a great challenge. china is experiencing an increasing incidence and prevalence of uc. however, data about the state of suc related research outputs are unavailable and thus, a comprehensive study on the suc-related chinese publications is desperately needed. a bibliometric analysis and literature review of the suc-related publications in chinese periodical databases would provide more epidemiological information and provide a perspective of research hotspots. the suc research performance in china can be evaluated by the number of publications and the complexity of research designs presented with these manuscripts. bibliometric analysis will provide information about the temporal trends of the number of publications and the change in complexity of the research described. further, a literature review will provide information about the number of patients reported each year, the clinical characteristics, and the state of the management of suc patients. such a study can provide information luo cx et al . chinese research into severe ulcerative colitis useful for the design of new treatment programs for suc patients worldwide. the aim of this study is to perform a bibliometric analysis to determine the temporal trends in the number of chinese publications on uc and suc (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) , to assess the overall suc research performance; to provide a review of the data on treatment type and efficacy in suc patients that has been reported in chinese medical journals. such a study can provide an understanding of the current state of research output from chinese studies into suc, a perspective of research hotspots, and provide information for suc patient treatment worldwide. we retrieved the chinese publications related to suc published between 2001 to 2015 in the chinese periodical databases (wanfang, vip, and china national knowledge infrastructure). the number of publications for each year was recorded after the duplicates were removed. the topic of each paper was recorded and only those that were clinical in nature were included in the assessment of the complexity of suc research. the complexity of suc research was evaluated according to the methods described by scott et al. the proportion of the total within each group was compared in every 5-year period (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) . the statistical significance of the differences between proportions was compared using a chi-squared test where a p-value of < 0.05 was considered as statistically significant. the number of suc patients reported in each year, the clinical characteristics of these patients, the treatment and efficacy reported were recorded and analyzed. there were 201 publications regarding suc published in chinese medical journals between 2001 and 2015. the number of publications increased rapidly. significant increase was found in analytical studies and clinical trials over the study period, with research into the management of suc, included pharmacotherapy, nutrition support as well as surgery, predominating. about 46.2% of the observational analytical studies and clinical trials focused on traditional chinese medicine, with little research on the efficacy of cyclosporin and infliximab in the disease management. about 6222 suc patients were reported in 201 relevant papers (ratio of male/female patients: 1.38). the number of patients reported in each 5-year period significantly increased. the colectomy rate and short-term mortality rate were 7.7% and 0.8% respectively. total proctocolectomy with ileal pouch-anal anastomosis was the most commonly employed operation. this study documents that significant progress has occurred in chinese suc research, as reflected by the increased output and complexity of publications available in research databases. the complexity of publications was evaluated with the new methods described by scott et al. the number of patients reported significantly increased. the information on the clinical characteristics of suc in chinese patients obtained from our literature review should be verified and extended by further well-designed and detailed population-based studies. although traditional chinese medicine has been widely used as a complementary therapy for suc, rigorous experiments and careful analysis of the resulting experimental data are required to validate the benefit and safety of this type of treatment. more research into the efficacy of treatment with cyclosporin or infliximab in chinese suc patients is required. ulcerative colitis review article: the practical management of acute severe ulcerative colitis cortisone in ulcerative colitis; final report on a therapeutic trial management of acute severe colitis management of acute severe ulcerative colitis response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression improved outcome of acute severe ulcerative colitis while using early predictors of corticosteroid failure and rescue therapies the pattern and outcome of acute severe colitis predicting outcome in severe ulcerative colitis lémann m; groupe d' etudes thérapeutiques des affections inflammatoires digestives. ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial outcome following emergency surgery for refractory severe ulcerative colitis in a tertiary care centre in india delayed surgery for acute severe colitis is associated with increased risk of postoperative complications the emergence of inflammatory bowel disease in the asian pacific region long-term follow-up of ulcerative colitis in the chinese population ulcerative colitis in china: retrospective analysis of 3100 hospitalized patients progression of inflammatory bowel disease in china an analysis of 10218 ulcerative colitis cases in china inflammatory bowel disease in the 21(st) century in china: turning challenges into opportunities a bibliometric analysis of pubmed literature on middle east respiratory syndrome increasing complexity of clinical research in gastroenterology: implications for the training of clinician-scientists predicting outcomes in acute severe ulcerative colitis advances in the surgical management of inflammatory bowel disease macular disease research in the united kingdom 2011-2014: a bibliometric analysis of outputs, performance and coverage temporal trends in inflammatory bowel disease publications over a 19-years period an update on the epidemiology of inflammatory bowel disease in asia temporal and geographic trends in celiac disease publications: a bibliometric analysis epidemiology and natural history task force of the international organization of the study of inflammatory bowel disease. a review of mortality and surgery in ulcerative colitis: milestones of the seriousness of the disease severe ulcerative colitis: at what point should we define resistance to steroids? chinese herbal medicines in the treatment of ibd and colorectal cancer: a review favorable results from the use of herbal and plant products in inflammatory bowel disease: evidence from experimental animal studies modified pulsatilla decoction attenuates oxazolone-induced colitis in mice through suppression of inflammation and epithelial barrier disruption surgical treatment of ulcerative colitis: ileorectal vs ileal pouch-anal anastomosis inflammatory colonic carcinogenesis: a review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis chinese research into severe ulcerative colitis bpgoffice@wjgnet.com help desk chinese research into severe ulcerative colitis has increased in quantity and complexity according to our bibliometric analysis. the methods previously described by scott et al could be used to evaluate the complexity of publications for suc and other diseases. we also reported an increase in the number of suc patients, a male predominance in suc incidence, and a lower risk of colectomy for chinese patients compared with suc outcomes worldwide. further well-designed population-based studies are required to validate these results. in addition, more research into the efficacy of treatment with cyclosporin or infliximab in chinese suc patients is required. key: cord-278117-hypyxzk2 authors: gao, wayne; sanna, mattia; wen, chi pang title: geo temporal distribution of 1,688 chinese healthcare workers infected with covid-19 in severe conditions, a secondary data analysis date: 2020-03-23 journal: nan doi: 10.1101/2020.03.19.20032532 sha: doc_id: 278117 cord_uid: hypyxzk2 introduction the covid 19 outbreak is posing an unprecedented challenge to healthcare workers. this study analyzes the geo temporal effects on disease severity for the 1,688 chinese healthcare workers infected with covid 19. method using the descriptive results recently reported by the chinese cdc, we compare the percentage of infected healthcare workers in severe conditions over time and across three areas in china, and the fatality rate of infected healthcare workers with all the infected individuals in china aged 22 to 59 years. results among the infected chinese healthcare workers whose symptoms onset appeared during the same ten day period, the percentage of those in severe conditions decreased statistical significantly from 19.7% (jan 11 to 20) to 14.4% (jan 21 to 31) to 8.7% (feb 1 to 11). across the country, there was also a significant difference in the disease severity among patients symptoms onset during the same period, with wuhan being the most severe (17%), followed by hubei province (10.4%), and the rest of china (7.0%). the case fatality rate for the 1,688 infected chinese healthcare workers was significantly lower than that for the 29,798 infected patients aged 20 to 59 years 0.3% (5/1,688) vs. 0.65% (193/29,798), respectively. conclusion the disease severity improved considerably over a short period of time in china. the more severe conditions in wuhan compared to the rest of the country may be attributable to the draconian lockdown. the clinical outcomes of infected chinese healthcare workers may represent a more accurate estimation of the severity of covid 19 for those who have access to quality healthcare. the covid-19 outbreak is posing an unprecedented challenge to healthcare workers. this study analyzes the geo-temporal effects on disease severity for the 1,688 chinese healthcare workers infected with covid-19. using the descriptive results recently reported by the chinese cdc, we compare the percentage of infected healthcare workers in severe conditions over time and across three areas in china, and the fatality rate of infected healthcare workers with all the infected individuals in china aged 22-59 years. among the infected chinese healthcare workers whose symptoms onset appeared during the same ten-day period, the percentage of those in severe conditions decreased statistical significantly from 19.7% (jan 11 -20) to 14.4% (jan 21 -31) to 8.7% (feb 1 -11). across the country, there was also a significant difference in the disease severity among patients symptoms onset during the same period, with wuhan being the most severe (17%), followed by hubei province (10.4%), and the rest of china (7.0%). the case fatality rate for the 1,688 infected chinese healthcare workers was significantly lower than that for the 29,798 infected patients aged 20-59 years-0.3% (5/1,688) vs. 0.65% (193/29,798), respectively. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the disease severity improved considerably over a short period of time in china. the more severe conditions in wuhan compared to the rest of the country may be attributable to the draconian lockdown. the clinical outcomes of infected chinese healthcare workers may represent a more accurate estimation of the severity of covid-19 for those who have access to quality healthcare. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the first cluster of novel coronavirus disease 2019 (covid-19) originated in wuhan, china on december 31, 2019 1 . by february 27, 2020, 82,170 cases of covid-19, including 2,804 deaths, had been confirmed, mainly in china and more than 40 countries and areas 2 . severity and transmissibility of the covid-19 have been the most important issues researchers and public health authorities have been urgently trying to tackle since the start of the outbreak. the first studies reporting single-center case series of hospitalized patients of covid-19 showed high rates of admission to intensive care (32%), high mortality (15%) 3 , and case fatality rates (cfr) of 4.3% (6/138) 4 and 11% (11/99) 5 in wuhan, while lower figures were reported outside the city 6 . however, the high cfrs observed in wuhan are likely to be overestimated, as the cited studies have mainly considered patients with severe symptoms who were hospitalized, excluding mild and asymptomatic patients who are less likely to be admitted to the hospital 7 . the most recent estimation of an overall 2.3% cfr reported by china cdc 8,9 is thus tentative, and more specific figures will remain undetermined until a later point. frontline healthcare workers are significantly more likely than general public to come into contact with the infected individuals. knowing the clinical outcomes of all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march 23, 2020. . https://doi.org/10.1101/2020.03.19.20032532 doi: medrxiv preprint healthcare workers who have been infected may provide critical information on both risk and disease severity, especially when proper healthcare services are available. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the cfr for the 1,688 infected chinese medical workers was significantly lower than the cfr for the 29,798 infected patients aged 20-59 years-0.3% (5/1,688) vs. 0.65% (193/29,798), respectively. as shown in table 1 , for infected healthcare workers, the percentage of those in severe conditions decreased significantly, from 19.7% (jan 11 -20) to 14.4% (jan 21 -31) to 8.7% (feb 1 -11) . considering only patients whose symptom onset appeared during the same 10-day period, the percentage of those in severe conditions exhibits a distinctive geographic distribution centered around the lockdown epicenter of the outbreak -wuhan being the most severe (17%), followed by hubei province excluding wuhan (10.4%), and by of china excluding hubei (7.0%) (figure 1 ). of the 149 chinese health workers who were infected with covid-19 outside of wuhan city after february 1, only 4% were in severe condition (6/149) and there were no deaths. preventing nosocomial transmission is a top priority during an epidemic. the consistent higher percentage of covid-19 infected healthcare workers in severe conditions in wuhan may be related to the draconian city lockdown and the established of massive quarantines camps, since viral factors such as mutation or adaptation are unlikely to be responsible for the difference observed for the three all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march 23, 2020. . https://doi.org/10.1101/2020.03.19.20032532 doi: medrxiv preprint 10-day periods (as they occur over longer periods) and across the three locations taken into account. the transmission control was improper and co-infections were common during the initial period of the outbreak in wuhan. one recent study found a correlation between the higher cfr in wuhan with the higher healthcare burden compared with other provinces in china 10 . it is unthinkable that sickening citizens, infected or not, and family members were confined in a city lockdown with an overwhelmed medical system and that they were forbidden from going to other provinces to seek for better care to save their lives. this also inevitably created logistical as well as psychological impact on healthcare workers operating in those harsh environments, described in a call for international assistance by chinese medical workers, as "nurses' mouths are covered in blisters and some nurses have fainted due to hypoglycaemia and hypoxia 11 . sixty-three percent of the infected healthcare workers have been in wuhan, including the 5 who died as a result of the infection 9 . however, the 0.3% cfr for the 1,688 medical workers (who were mainly aged less than 60 years as indicated in the report 8 ), may represent a proper estimation of the severity of covid-19 in this age group in countries with universal access to quality medical services. our study has a few limitations: there may be infected healthcare workers who still have not completed their natural progression of the disease with definite outcomes. however, as of february 28, no additional deaths of all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march 23, 2020. . https://doi.org/10.1101/2020.03.19.20032532 doi: medrxiv preprint healthcare workers were reported. second, our data analysis is based on a governmental investigation of the outbreak, thus the validity of the descriptive results in the report inevitably determines the accuracy of our secondary analysis. the spectrum of clinical severity of a novel communicable disease is critical in knowing the potential impact of an ongoing epidemic. our finding that the spectrum of covid-19 severity decreases eccentrically from the epicenter as well as over short periods of time, will help to avoid drastic, costly, and fear-driven measures that impede not only daily activities, but also a proper containment of the epidemic. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march 23, 2020. . https://doi.org/10.1101/2020.03.19.20032532 doi: medrxiv preprint world health organization an interactive web-based dashboard to track covid-19 in real time clinical features of patients infected with 2019 novel coronavirus in wuhan clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical findings in a group of patients infected with the 2019 novel coronavirus (sars-cov-2) outside of wuhan, china: retrospective case series full spectrum of covid-19 severity still being depicted. the lancet all rights reserved. no reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this preprint this version posted march 23, 2020. . https://doi.org/10.1101/2020.03.19.20032532 doi: medrxiv preprint key: cord-025246-zah72cd6 authors: lai, daniel w. l.; ruan, yongxin title: revisiting social work with older people in chinese contexts from a community development lens: when east meets west date: 2020-03-13 journal: community practice and social development in social work doi: 10.1007/978-981-13-6969-8_13 sha: doc_id: 25246 cord_uid: zah72cd6 community development is an empowering and comprehensive method for social workers to address individual and societal challenges facing chinese older people. this chapter explores the different meanings of community development in chinese contexts, including communities in mainland china and chinese immigrant communities. when actualizing community development, social workers require theories to guide their actions, and this chapter proposes three interrelated theoretical bases: ecological system theory, empowerment theory, and anti-oppressive theory. based on these theoretical bases, three practice directions are suggested to guide community development at different levels: “aging in place,” “age-friendly community,” and “gray power.” in particular, social workers need to adapt community development approaches to chinese cultural contexts. case examples are discussed to illustrate how to implement community development projects with older people in chinese contexts and the roles of social workers in such projects. improvements in healthcare and standards of living have resulted in an increase in longevity and in the size of the aging population. with at least one or two decades of life span after official retirement age, many older people are faced with more choices and opportunities to further enhance their own aspirations and enrich their purpose in life. thus, working with older people should not only focus on remedial interventions that deal with problems and challenges but also on supporting these new aspirations and opportunities. social work with older people involves different approaches within different sociocultural contexts. from a community development perspective, social work with older adults can take many forms. while some may address problems such as health concerns or social inequity issues, others have focused on empowerment and addressing personal development among aging populations. this chapter will discuss the conceptual bases of community development approaches that are used for working with older people in the community. focusing on the experience of older people in different chinese contexts, including chinese older adults in chinese societies and older chinese migrants residing in non-chinese societies, this chapter will discuss the alignment of community development and its application in social work practice with older people, with attention to the influence of sociocultural context. as they age, people experience various challenges, on both individual and societal levels. while chinese older adults in chinese societies and older chinese migrants residing in non-chinese societies face particular challenges associated with their different contexts, they also face some similar challenges. at the individual level, older people, including chinese older people, face physical, social, and psychological challenges associated with increased age. they may experience declining cognition and mobility along with increased likelihood of illness and disabilities (coyle and dugan 2012; lai et al. 2016) . their social network may decrease due to the loss of spouses and friends (coyle and dugan 2012) , and they may be more likely to experience negative emotions, anxiety, and depression due to physical decline, life transitions, and a decrease in social networks (parker 2013) . additionally, when older people reflect on their life, they may experience a sense of despair associated with perceived failures and regrets (parker 2013) . at the societal level, challenges facing older people, including chinese older people, may be associated with environment, infrastructure, and wider social network dynamics. community-dwelling older people may rely heavily on facilities provided by housing estates (chan et al. 2016) , and social environments that are not sufficiently age-friendly can hinder social interaction . for example, limited access to transportation can decrease participation in social activities among older people . additionally, older people may experience ageism, which refers to stereotypes and discriminations against older people (harris et al. 2018) . societies convey ageism in various ways, such as media representations of older people as expensive burdens or as vulnerable (hastings and rogowski 2014) . for example, in mainland china, though the chinese tradition emphasizes respect for older people and attaches importance to their contributions, this value is changing (bai et al. 2016) . there is an increasing emphasis on productivity (bai et al. 2016) , which means that the social status of older people is decreasing as they are no longer "productive" after retirement. additionally, in the context of mainland china, as a result of the "one-child" policy, the younger generation faces difficulty in providing sufficient filial support for older people, as expected in chinese tradition. hence, older people may be viewed as a burden for the family, and when older people internalize this view of being a burden to society and family, they experience a greater risk of depression (bai et al. 2016) . some older people experience greater challenges and vulnerability associated with aspects of status, such as being an ethnic minority. this experience, known as "multiple jeopardy," also affects groups of older chinese adults who are immigrants in societies where chinese are the ethno-cultural minority population (chow 2010) . older chinese immigrants not only face challenges common to older people in general but also experience particular physical, psychological, and social challenges associated with their status as ethnic minorities and immigrants in their new communities. owing to language differences, cultural conflicts, and racial or ethnic discrimination, older chinese immigrants may be at greater risk of physical illness (chow 2010) and feelings of marginalization and other psychological distress, such as depression (chow 2010; park 2016) . moreover, worries about being accepted by the majority society can reduce involvement in social life (park 2016) . healthcare and social services may not be user-friendly, due to a lack of culturally sensitive providers as well as language barriers in organizations (chow 2010) , meaning that older chinese immigrants may be prevented from using needed services. the challenges facing older chinese adults, both for those in china and for immigrants, at both individual and societal levels illustrate the need for interventions and supports that address the broader systems and structures that cause these issues. community development, focusing on empowerment and addressing personal development among aging populations, can be effective in addressing physical, psychological, and social challenges. to understand the meaning of community development, it is first important to examine the meaning of "community," given that different definitions of "community" lead to different interpretations of community development. two main definitions can be identified. the first is a "place-based" perspective, which views "community" as a geographic place with physical boundaries, comprised of residents, resources on which residents subsist, and processes through which residents distribute and exchange those resources to address their needs (matarrita-cascante and brennan 2012). the second is a "non-place-based" perspective, which focuses on the connections that people share, such as using the same language or having other shared interests (human resource development canada [hrdc] 1999; twelvetrees 2017) , shaped by boundaries of moral proximity (green 2016) . people may experience both place-based and non-place-based forms of community. for example, older people may be connected with both peers and other age groups within the same neighborhood, as a result of sharing a particular place, while also being connected to other older people in other geographical locations due to commonalities such as challenges, characteristics (including cultural background or migration status), or interests. these two perspectives inform different conceptualizations of community development. scholars adopting a place-based perspective focus on the management of resources in that geographic community (green 2016) , as communities need to rely on resources to subsist and progress (matarrita-cascante and brennan 2012). for example, matarrita-cascante and brennan (2012, p. 297) define community development as a process that "provides vision, planning, direction, and coordinated action towards desired goals associated with the promotion of efforts aimed at improving the conditions in which local resources operate," involving efforts to "harness local economic, human and physical resources to secure daily requirement and respond to changing needs and conditions." scholars following a non-placebased perspective focus on joint efforts by community members to improve their life circumstance. for example, meade et al. (2016) define community development as a process through which "ordinary people" make an impact on their living conditions through collective action, while human resource development canada (1999) interprets community development as a process through which community members take action and propose solutions together to address common challenges. regardless of the perspective adopted, different community development actors will use different approaches, which can be broadly synthesized into three forms of community development (matarrita-cascante and brennan 2012). the first is an "imposed" form of community development, which involves the improvement of community through physical and economic development and is usually promoted by private industry and government actors. the second is a "directed" form of community development, which refers to structural improvement to a community promoted by nongovernmental organizations (ngos) or government, in which community members are invited to participate. the third is a "self-help" form of community development, which implies community members' own efforts to carry out programs or activities (matarrita-cascante and brennan 2012). community development is an important component of social work practice. community development in social work concentrates on empowering various sections of society, such as creating employment opportunity and promoting gender equality (dhavaleshwar 2016) . scholars have discussed different roles for social workers in community development, focusing on advocacy and empowerment. for example, das et al. (2018, p. 389) suggest that social work "has the potential to be mutually supportive to address gaps, design interventions and lobby more influentially for the use of empowering community-based approaches." similarly, gilbert (2014) suggests that through community development, social workers can promote problem-solving in human relationships as well as social change, empowerment, and liberation in order to enhance well-being. effective community development has been described as having the following characteristics: (1) it is long-term, (2) it is well-planned, (3) it is inclusive and equitable, (4) it is holistic and integrated into the bigger picture, and (5) it is initiated and supported by community members (hrdc 1999) . therefore, social workers should pay attention to these characteristics when planning and promoting community development. yet, while the conceptualization of community development is mostly situated in "western" cultural contexts, it is also important to address how community development could be realized as part of social work practice in chinese contexts, which represent the range of different sociocultural and political values emerging among chinese people residing in different juridical contexts. in the context of this chapter, this includes both chinese older adults in chinese societies and older chinese migrants residing in non-chinese societies. given that social, cultural, and other dynamics in chinese community contexts are different from those in "western" countries, community development will involve different approaches and focuses in chinese contexts. even within chinese contexts, community development may be understood differently when working with chinese older adults residing in a chinese jurisdiction such as mainland china as compared to chinese immigrants in other countries such as canada. even within these groups, identities, challenges, and experiences may differ widely. for example, social, political, and economic contexts affecting aging differ across chinese jurisdictions, such as in the cases hong kong and mainland china. similarly, the experiences of older adults in chinese immigrant communities are shaped by factors such as region, community, and language of origin; social, political, and economic contexts in countries and communities of residence; immigration and settlement policies; ethno-cultural community presence; and so on. the following paragraphs further explore meanings of community development among these diverse groups. when working with chinese immigrants, practitioners may adopt a non-place-based perspective on community, focusing on immigrants with chinese nationalities (yeung and ng 2011; yuen 2013) , who may live in different geographic locations. practitioners may have to adapt community development strategies to chinese cultures, which value social harmony, social relationship, and collective good (yeung and ng 2011; yuen 2013) . yeung and ng (2011) suggest that concepts such as empowerment, social change, and equality, which are often identified as elements of community development, may not be easily be adopted by chinese immigrant communities, who may not have been frequently exposed to these western values. although it has been argued that actions focusing on collective good and collective responsibility may be more acceptable (yeung and ng 2011) , social workers can play important roles in facilitating mobilization and socialization with immigrants from chinese cultural contexts, in order to achieve the desire for change as well as processes of individual as well as collective empowerment. for example, yuen (2013) describes a community development project in canada in which chinese immigrants volunteer in building a low-income senior and new immigrant residence and community center. participants enjoyed the socialization aspects of this project, which strengthened their social relationships and contributed to solidarity within the community. family-like connections among chinese immigrations in turn provided sources of support that serve to strengthen social relationships (yuen 2013) . therefore, it is believed that empowerment and equity could also be achieved via focusing on collective efforts and collective goods, reflecting a broader conception of "empowerment" (beyond only individual dimensions). when working with chinese residents in china, the contemporary political situation and structures means that "community" is generally interpreted as a geographic place administrated by a residents' committee and street office (bray 2006) . there are three characteristics of this understanding of community: (1) each community has a territorial space, (2) the nature and functions of the community are determined by the government, and (3) the community performs administrative roles (bray 2006) . this specific definition of "community" means that community development has its own meanings in china, shaped by political, economic, and historical dynamics. since the breakdown of the work unit system (a system intended to facilitate social regulation and provide social welfare in the early developmental stage of modern china (he and lv 2007) ), the community has had to take on functions that were originally performed by the work unit system (li 2013) . additionally, with the increasing number of rural migrant workers in urban centers (bray 2006) , a process of "community building" has been proposed, adapted from the concept of community development (li 2013) . therefore, community development in china often refers to community building, in which the community takes care of various issues (e.g., welfare services, environment, education, grassroots democracy) in order to "promote social development, raise living standards, expand grassroots democracy and maintain urban stability" (see bray 2006, p. 536) . in this sense, community building is, in a way, an imposed form of community development because it is the administrative offices that take on responsibilities to improve the environment in communities, focusing not only on the physical and economic environment but also welfare service provision and cultivation of grassroots organizations in community building. some grassroots organizations have also been initiated and governed by community members in china. for example, the owners' committee was set up by residents, through which they deal mainly with issues in their living areas with their own efforts (li 2013) , reflecting to some extent a "self-help" approach to community development. however, the owners' committee is supervised by the residents' committee (state council of the people's republic of china 2016). therefore, community development in china is mainly promoted by administrative offices in each community, focusing on physical and social environment improvement. when approaching community development work with older people, theories provide the frameworks to enable practitioners to understand events and generate strategies for practice (phillips and pittman 2014). the following sections examine three main frameworks that inform understandings of and approaches to community development with older people as part of social work practice: ecological system theory, empowerment theory, and anti-oppressive practice. ecological system theory provides a framework for understanding the interaction between different levels of systems that comprise both the environment and people (menec et al. 2011 ). the first level is the microsystem, which refers to a person's immediate surroundings, such as family. the next is the mesosystem, which involves the connections between two or more microsystems, such as the interaction between peers and family. this is followed by the exosystem, referring to the social settings that have indirect effects on individuals, such as workplaces, and then by the macrosystem, which consists of larger contexts such as social values and cultural beliefs. the broadest level is the chronosystem, which refers to a person's life transitions or historical events in society. systems in all levels interact with each other (paat 2013) . as community development deals with aspects of the environment, ecological system theory provides a way to comprehensively examine the influence of environments (at different scales) on older people and serves as a guideline to improve these environments. for example, ecological system theory has been used to understand how environmental factors influence the participation of older people in community activities (greenfield and mauldin 2017) . empowerment refers to a process of "letting client, group or community have as much control as possible over the change processes they are involved in" (see vongchavalitkul 2015, p. 14) . empowerment theory emphasizes the participation of community members in the change process, to ensure that they have the power to control this process. as a result of structural challenges, older people, especially those experiencing "multiple jeopardy," may be marginalized from gaining resources and opportunities, which can lead to a sense of powerlessness. therefore, empowerment theory can provide a framework for social workers to facilitate the involvement of older people in community change projects, through which these older people can enhance their resources and address their own needs (irving 2015) . anti-oppressive practice is an approach to work with people who are oppressed by structural inequalities such as poverty and racism, and creating changes to correct the oppressive status is important (dominelli 1998) . this is closely related to empowerment theory, as both pay attention to addressing inequalities resulting from power differences in relationships. therefore, anti-oppressive practice is often used alongside empowerment-focused approaches. societal stereotypes regarding older people mean that they often face oppression. for example, people with dementia might be deprived the right to make their own decisions by carers because they are viewed as people with poor cognitive functions (martin and younger 2000) . therefore, it is important for practitioners to support the establishment of anti-oppressive environments for older people. these three interrelated theories highlight principles of community development such as empowerment, social justice, participation, and so on. together, they can serve to guide the design and operation of community development projects for older people. for example, ecological system theory could be used to raise awareness among older people to examine the influences of their environments (e.g., barriers that lead to inequality, comprising a key element of anti-oppressive practice) or used as a guideline to improve aspects of these environments. as part of community development processes, empowerment can serve as a framework to facilitate the participation of older people and enhance their abilities to cope with and address community issues. it should be noted that when applying these three theories, the different meanings of community development in chinese contexts should be considered, based on the specific experiences and challenges of older adults in chinese jurisdictions as well as older chinese immigrants in other places. for example, the concept of empowerment and anti-oppression could be adapted to emphasize the principle of collective good in community development with chinese older people. in these ways, social workers can "normalize" community issues and raise awareness among older people about how they, as a group, are disadvantaged by the environments in which they live and potential strategies for change. the following paragraphs introduce three broad practice directions for operationalizing community development in working with older peopleaging in place, age-friendly communities, and "gray power"with a focus on their implementation within the general chinese cultural context. aging in place (aip) refers to "the ability of older adults to live in their homes or communities as long as possible" (see lehning et al. 2017, p. 235) . aip aims to enable older people to maintain their social relationships and daily lifestyle in an environment with which they are familiar, which also facilitates independence and a sense of control over their lives (iecovich 2014) . several theories support the concept of aip and guide its operationalization. the "theory of insideness" focuses on people's attachment to place along three dimensions: physical (sense of environmental control), social (social relationships), and autobiographical (attachment to place, developed from memories that shape self-identity) (iecovich 2014) . older people develop strong ties to a place along these three dimensions (iecovich 2014) and have a high willingness to age in their communities. empowerment theory focuses on helping older people age in place by promoting participation and autonomy (mcdonough and davitt 2011) . person-in-environment theory supports the realization of aip by focusing on mutual interactions between individual and environment: individuals are influenced by their environment but can influence the environment at the same time (weiss-gal 2008) . practitioners can assist older people to adapt to their environment (aging in place) by realizing their potentials and mobilizing the community to support adaptation. scholars have described a "village" model to realize the concept of aip, referring to grassroots organizations that are formed, governed, and served by residents in the community (such as community-dwelling older people) (mcdonough and davitt 2011; scharlach et al. 2012) . those nonprofit organizations provide services for older people in the community through volunteers, generally focused on nonprofessional services such as housekeeping, transportation, etc. (mcdonough and davitt 2011) . social workers can play several roles in promoting aip (scharlach et al. 2012) . as community organizers, social workers can help to foster a sense of commitment to the community and mobilize and support residents to provide assistance for older people in the community. as assessors, social workers not only help community members to understand their challenges and make plans but also help them to evaluate the strengths and resources they have and to use their abilities to support older people. as brokers, social workers connect community members with resources to assist them (scharlach et al. 2012 ). the village model reveals a key concept of aip: mobilizing community members to help community-dwelling older people adapting to place. the process of building, mobilizing, and utilizing capacity of community members to assist older people in the community aligns with chinese cultural and political situations, illustrating its applicability in chinese contexts. first, it reflects an emphasis on the collective good. second, as the community shoulders the responsibility for development, this requires joint efforts from residents (yan 2011) . in china, for example, administrative offices encourage self-help from residents to reduce the burden of solving problems in communities, including by cultivating grassroots organizations, which relies on mobilizing, building, and utilizing the capacity of community members. one way to do this is by promoting volunteering, as volunteers acquire knowledge and skills as well as utilizing their abilities in this process (akingbola et al. 2013) . social workers can improve the commitment of community members to be volunteers, by mobilizing them, assessing their existing strengths, and enriching their knowledge and skills through training (guo 2018) . scholars and practitioners in china have emphasized the importance of recruiting volunteers to assist communitydwelling older people, such as a project in which the "young-old" assist the "old-old," which involves cultivating "young-old" volunteer teams who are trained to apply their knowledge and skills to assist "old-old" people with daily living (e.g., meal delivery) and mental health (e.g., reducing loneliness through home visits) (hong 2012 ). age-friendly communities (afcs) focus more on the influence of the environment, referring to "policies, services, settings and structures support and enable people to age actively" (world health organization [who] 2007) . this involves a focus on both the physical and social environment in the community (including issues such as safety, accessibility, and stereotypes) across eight interacting domains: transportation, housing, outdoor spaces and buildings, social participation and interactions, respect and social inclusion, civic participation and employment, communication and information, and community support and health services (who 2007) . two theories can be used to interpret and support afc. first, the personenvironment fit perspective assumes that people are likely to be maladapted if there is a low level of fit between their needs and environment (park et al. 2017) , indicating that environment plays a crucial role in individual's adaptation. therefore, "even those who have limited resources and capability can age optimally if environmental characteristics support them in a way that compensates for their limitations or lack of resources" (see park et al. 2017 park et al. , p. 1328 . in this sense, an age-friendly environment is helpful for vulnerable older people to age well because, for example, it compensates for personal limitations such as disability by building lifts to increase mobility. second, ecological system theory reveals interactions between people and various systems in the environment (menec et al. 2011) , which is highlighted in afc efforts. for example, social participation influences social inclusion, but social participation depends on the accessibility of outdoor spaces (who 2007) . the achievement of afcs relies on addressing issues such as commitment, capacity, collaboration, and consumer involvement (scharlach and lehning 2016) , in which social workers can play a role. first, it is important to improve commitment of relevant stakeholders to facilitate change in a community, and social workers can help to reduce ageism and enhance awareness of the importance of building afcs. second, social workers can serve as educators to enhance community capacity for developing and implementing afc change processes. third, since change processes require joint efforts from various stakeholders, social workers can be mediators to facilitate stakeholder collaboration. creating afcs relies on interdisciplinary collaboration between various stakeholders. however, this is not easy to create and sustain, and social workers require skills and knowledge (and thus training) to lead collaboration (garcia et al. 2010) . finally, social workers can facilitate the involvement of older people in developing afcs, which is important because it can support greater responsiveness to community needs, capacity building, and empowerment, as well as enhanced use of existing and new programs and services (scharlach and lehning 2016) . as rémillard-boilard et al. (2017) note, the inclusion and participation of older people in developing an age-friendly community is important to achieve age-friendliness. for example, in an age-friendly project in guangzhou, china (lai et al. 2017) , older people in different communities were invited to take part in sharing views and generating ideas about how to make their community more age-friendly. however, chinese older people may have different perspectives on community participation. for example, older people in china do not have strong sense of citizenship and may have limited understanding of the importance of community participation and thus may have low willingness to participate in community initiatives (zhao and huo 2018) . older chinese immigrants, who value social relationships where trust is developed, may not be willing to participate in activities that do not include people they trust (yeung and ng 2011) . therefore, social workers should explore and address potential barriers to the participation of chinese older people as part of afc initiatives. "gray power" "gray power" (gp) is a term mentioned frequently in policy and refers to the political power that older people have (davidson 2012) . as the number of older people is increasing and the new generation of older people has higher awareness of improving public services through political actions, their influence on policy is increasing (davidson 2012) . in response to structural barriers such as ageism, older people can use their "gray power" to improve their community and society. two theories support the idea of gp and provide insights into its operationalization. anti-oppressive practice considers how people are deprived of power due to structural inequalities (dominelli 1998) , and this perspective can assist older people to aware of the oppressions they are facing and understand how their powers are restricted. empowerment theory includes three levels, micro, mezzo, and macro, and macro-level empowerment focuses on influencing resource distribution through collective action (kruger 2000) , revealing a process through which older people can use their power to fight for more resources. social workers can play important roles in assisting older people to exert their power. first, social workers can be educators to raise awareness of how structure barriers lead to particular challenges and problems (mchugh 2012) and can support and strengthen older people's abilities to access information and take action (inaba 2016) . second, social workers can serve as facilitators to bring older people together and support them to generate solutions and seek policy changes (inaba 2016) . for some older chinese adults in mainland china, some moderate strategies to address community issues may be preferred, due to their sociocultural and political upbringing. for instance, one approach used by community workers and researchers is photovoice and may be considered. this is a qualitative research method that enables people to record (through photographs) and reflect on strengths and concerns in their communities, promotes critical thinking about the influence of environment on individuals through discussion of photographs, and reaches who can make changes such as policy makers through the exhibition of photographs (sitter 2017) . when discussing their photographs, participants reflect on how they relate to their lives; the reasons for which a problem, concern, or strength exists; and what can be done about it (sitter 2017) . individuals are empowered by voicing their concerns and raising awareness of concerns in the community and among policy makers (sitter 2017) , which can lead to policy changes. chui et al. (2019) describe a photovoice project to raise civic awareness among older people in hong kong. older people received training on skills such as theme identification and presentation, and a public photo exhibition was launched to raise public awareness. this enhanced participants' ability and willingness to participate in community and civic affairs. in this way, social workers can support and facilitate the empowerment of older people and maintain an equal position with participants throughout the process (sitter 2017) . these three practice directions are interrelated and show a progressive relationship. aip focuses more on individuals' adaptation to the environment, at the micro level, while afc emphasizes improving physical and social environment in the community for older people, at the mezzo level. lastly, gp focuses on policy and political changes, at the macro level. through engagement with these three practice directions, social workers can support community development processes with older people in a comprehensive way. chinese older people encounter various challenges, from individual to societal levels, illustrating the need for comprehensive responses beyond the individual level. social workers can apply the practice of community development in working with chinese older people, representing an approach to intervention and support that addresses broader systems and structures and focus on empowerment and personal development among aging populations. this chapter has explored definitions of community development and its meanings, with a focus on diverse chinese contexts, including those of chinese older adults in mainland china and chinese immigrants in non-chinese societies. three interrelated practice directions, including aging in place, age-friendly communities, and "gray power," provide insight into how social workers can engage in community development processes with older people, including in chinese contexts. the following describes two cases of community development projects with older chinese immigrants, which integrate the concepts of empowerment theory and antioppressive practice. the two cases reveal how social workers can apply these two concepts in community development with chinese older people and the roles they can take on in such projects. one particular challenge that older chinese immigrants may experience concerns elder abuse when living with adult children and their families. they may tend to hide abuse due to a fear that their children would desert them and the cultural belief of not disclosing family matters to outsiders. as a result, there may be little awareness of this issue among community members. in a community development project in canada (lai and luk 2012) , raising awareness of elder abuse among chinese older people and their children was the goal. some chinese older people were invited to talk about incidences of elder abuse and then were involved in group discussions to generate solutions for educating community members about this issue. they decided to design a comic book to present the problem of elder abuse, as they thought that pictures would be easier to comprehend than words and would be readable for older people with low literacy capacities. social workers invited some experts to design the comic book with the older participants, and the comic books were distributed to various elderly centers. this case integrates the concept of empowerment. social workers empowered chinese older people by raising their awareness of an important community issue and supporting those older people to take action to tackle this issue. throughout the project, chinese older people were responsible for discussing the issue, generating solutions, and implementing those solutions. social workers acted as facilitators and brokers (linking participants to resources). the most challenging part was raising awareness of elder abuse among older chinese immigrantsan important step in the empowerment processbecause it contrasted with chinese cultural concerns. therefore, social workers needed to normalize the issue and ensure that chinese older people were aware that this issue influenced their wellbeing. the second case involves a project to involve chinese older people in calgary, canada, into combatting discrimination. in 2003, there was a sars (severe acute respiratory syndrome) outbreak in calgary, and some members of the public thought that chinese people had brought the virus to their city. older chinese immigrants not only experienced public discrimination, but also worried about their vulnerability to sars. in this case, workers at a chinese senior center brought the chinese older people together to discuss the issue and later launched a public meeting with representatives of government health officials and local politicians to discuss how to reduce public stereotypes toward sars and the chinese community. in this case, social workers applied the concept of empowerment and antioppressive practice. chinese older people were supported to take collective action and expressed their perspectives in order to reduce public stereotypes. through this process, their capacity to express and present opinions and discussion skills were improved, and their social networks were strengthened or extended. social workers serve as mediators in discussions between chinese older people, health authority officers, and legislative counselors. social workers also took on roles as facilitators and brokers to support chinese older people to take collective action and provide necessary resources. these two cases illustrate that when social workers carry out community development projects with chinese older people, they can serve as facilitators to raise awareness of community issues and as brokers to link older people with resources such as networks with other professionals, in order to support chinese older people to deliver collective action. however, given the increasing educational level of chinese older people, their awareness of their rights and possibilities to mobilize through community development may be stronger, and social workers may work less in the facilitator role and more as brokers to support those older people to improve their well-being through their own collective action. learning and knowledge transfer in volunteering: exploring the experience of red cross volunteers ageism and depression: perceptions of older people as a burden in china building 'community': new strategies of governance in urban china an age-friendly living environment as seen by chinese older adults: a "photovoice" study growing old in canada: physical and psychological well-being among elderly chinese immigrants fostering civic awareness and participation among older adults in hong kong: an empowerment-based participatory photo-voice training model social isolation, loneliness and health among older adults re-engaging with community work as a method of 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practice: a route to the empowerment of people with dementia through communication and choice conceptualizing community development in the twentyfirst century it takes a village: community practice, social work, and aging-inplace aging, agency, and activism: older women as social change agents politics, power and community development conceptualizing age-friendly communities working with immigrant children and their families: an application of bronfenbrenner's ecological systems theory ageing in anomie: later life migration and its implications for anti-anomic social work practice aging in place of vulnerable older adults: personenvironment fit perspective the relationship between ego integrity and death attitudes in older adults an introduction to community development involving older residents in age-friendly developments: from information to coproduction mechanisms the "village" model: a consumer-driven approach for aging in place taking a closer look at photovoice as a participatory action research method the state council of the people's republic of china (2016) the regulation of property in the people's republic of china community development, social action and social planning using empowerment theory in health promotion guided development the home for the elderly in nakhon ratchasima, thailand the person-in-environment approach: professional ideology and practice of social workers in israel global age-friendly cities: a guide how to take part in community management in beijing engaging service users and carers in health and social care education: challenges and opportunities in the chinese community building juniper: chinese canadian motivations for volunteering and experiences of community development the situation and improvement of the community participation of the elderly in the middle and small cities key: cord-285268-39c7pqr3 authors: niu, baozhuang; li, qiyang; liu, yaoqi title: conflict management in a multinational firm's production shifting decisions date: 2020-08-18 journal: int j prod econ doi: 10.1016/j.ijpe.2020.107880 sha: doc_id: 285268 cord_uid: 39c7pqr3 in recent years, many apparel multinational firms (mnfs) have shifted their production from traditional manufacturing bases (e.g., china) to the emerging ones located in southeast asia (e.g., vietnam and bengal). the interactions among market sizes, mnf's competition with local rival and the global tax rules play key roles in the mnf's decisions. in this paper, we study the preferences of a mnf and its contract manufacturer (cm) over two manufacturing outsourcing structures and investigate whether their objective conflicts can be reconciled. the mnf relies on the cm for production and sells goods in both chinese and southeast asian markets. it is optional for the mnf to use a cm located in china, but has to suffer from the cm's differential prices because of china's partial value-added tax (vat) refund policy. it is also optional for the mnf to use a cm located in southeast asia, resulting in uniform production fee for the goods sold in two markets. the former is traditional outsourcing structure (ts), and the latter is shifted outsourcing structure (ss). interestingly, we find that, the mnf may first prefer ss, then prefer ts, and back to prefer ss, as the relative market potential between the southeast asian market and the chinese market increases. the cm's preferences may switch twice, too. we identify the opportunities where the preferences of the mnf and the cm are aligned, which are driven by china's partial vat refund policy. it is common practice for the multinational firms (mnfs) to outsource their manufacturing to contract manufacturers (cms), which is particularly prominent in the apparel industry (sodhi and tang, 2013; xu et al., 2018) . traditionally, because of china's low labor cost and huge market potential, many apparel mnfs have outsourced manufacturing to chinese cms. a typical example is uniqlo, which relies on chinese cms such as shenzhou group as its long-term manufacturing partners (shenzhou group, 2006) . next insight reports that, uniqlo's products manufactured in shenzhou group's factories are of large volume because they are for both chinese and southeast asian markets (zhang, 2009 ). however, it is witnessed that many apparel mnfs have shifted their production to southeast asian countries such as bengal and vietnam, because of the increasing labor cost in china (fibre2fashion, 2012) . according to an industrial report in 2019, the percent of southeast asian countries' cms in the world has accounted for 37.67% in , 39.13% in 2018 and 42.15% in 2019 (fast retailing, 2019 . many popular fashion brands such as uniqlo, steve madden, coach, and deckers are shifting their production to southeast asian countries (pino, 2018) , which motivates their chinese cms to close the factories in china and open new ones in southeast asian. for example, shenzhou group, the biggest apparel cm in china, has built factories in vietnam to continue providing contract manufacturing services for uniqlo (china daily, 2015) . what are the driving forces behind the decisions of the apparel mnfs and their cms to shift production out of china? many discussions have been conducted. we summarize the key points as follows. (1) if the cms are located in china, they will follow china's partial value-add tax (vat) refund policy when exporting products to southeast asian. in recent studies such as hsu and zhu (2011) and xu et al. (2018) , this specific vat policy will significantly affect mnfs' supply chain decisions, when the products are made in china and sold in both chinese and southeast asian markets. that is, if a firm uses inputs sourced in china to produce an exported product, it will receive a partial refund of the paid input vat, resulting in a tax burden (the details of "partial vat refund policy" can be found in section 3: model settings). therefore, chinese cms have the incentives to price differentially for the products sold in chinese and southeast asian markets, so as to mitigate the profit loss because of partial vat refund policy (xu et al., 2018) . (2) from the j o u r n a l p r e -p r o o f 3 perspective of the mnfs, they have to suffer from the impact of price discrimination from the cms, and the cms' pricing flexibility helps themselves better squeeze profits from the mnfs. (3) on the contrary, if the cms are located in southeast asian, the mnfs benefit from the low labor costs, and there are no partial vat refunds policies 1 . the cms have no reasons to charge two manufacturing prices for the goods sold in chinese and southeast asia markets. this eventually benefits the mnfs. it seems that the mnfs always prefer production shifting to southeast asian, but the cms do not. this induces objective conflicts between these two supply chain parties. several natural questions arise: will apparel mnfs really benefit from production shifting? whether the chinese cms have incentives to shift production too? how to manage the objective conflicts between the mnfs and their cms? to answer the aforementioned research questions, we build a stylized model comprising a cm, a mnf and a chinese local competitor of the mnf. the mnf sells goods in both chinese and southeast asian markets and competes with the local competitor in the chinese market. the mnf can either outsource manufacturing to the cm located in china, referred to as traditional outsourcing structure (ts), or outsource manufacturing to the cm located in southeast asian, referred to as shifted outsourcing structure (ss) . our focus is the mnf and the cm's preferences over two outsourcing structures and whether the objective conflict can be reconciled. the main findings are as follows. first, the mnf's preference over ts and ss depends on the relative market potential between the southeast asian market and the chinese market. that is, the mnf is better off under ss when the relative market potential is either low or high, while it is better off under ts when the relative market potential is in a moderate range. the driving force for the mnf to prefer ss is that, under ss, the cm can only set a uniform manufacturing price and hence lose the pricing flexibility. this benefits the mnf. it is interesting to find that the mnf may benefit from ts even though it 1 southeast asian countries also have export tax refund policies, but they return all the vat (in china, it is partial refund vat). taking vietnam as an example. according to the guidance document (circular no. second, interestingly, the cm's preference over ts and ss shows an opposite trend to the mnf's. the cm benefits from ss when the relative market potential is in a moderate range, which is contrary to the intuition that the cm always benefits from ts. the key is still china's partial vat refund policy. the tax burden under ts becomes heavier as the relative market potential increases, resulting in the deviation from ts for the cm. we then investigate the incentive alignment opportunities of the mnf and the cm, finding that win-win solutions can be achieved where both of them benefit from ts or ss. the rest of this paper is organized as follows. in section 2, the related literature is reviewed. section 3 presents the model settings and notations. in section 4, we first analyze the preferences of the mnf and the cm over ss and ts. section 5 provides two extensions considering the impact of the cm's non-negative manufacturing cost under ts and the local competition the mnf faces in southeast asian. section 6 concludes this paper. all the proofs are in the appendix. our work is closely related to the studies on conflict management. there are mainly three sub-streams of literature. the first one is on channel conflicts because of upstream companies' direct sales, which results in competition with their existing retail partners. some studies demonstrate that, the retailer might benefit from channel conflict because the double marginalization effect can be weakened (chiang et al., 2003; kumar and ruan 2006; arya et al., 2007) . some other studies try to find ways to mitigate channel conflicts by designing coordination mechanisms using sales effort, pricing scheme, linear quantity discount contract, subsidy, markup pricing strategies et al. see tsay and agrawal (2004) , cai et al. (2009) , david and adida (2015) , yoon (2016) and wang et al. (2017) for the details. the second sub-stream of literature is on system conflicts because supply chain parties' decisions usually do not align with the system optimal one. how to design supply chain contracts hence become the research focus. for example, cachon and lariviere (2005) design revenuesharing contracts to coordinate the supply chain and compare the coordination effect with the j o u r n a l p r e -p r o o f 5 other contracts (e.g., buy-back contracts (pasternack, 1985) , quantity flexibility contracts (tsay, 1999) and sales-rebate contracts (taylor, 2002) . see cachon (2003) for an excellent review of this sub-stream of literature. we note that, there is a growing body of literature that investigates how to maximize a mnf's after-tax profit and balance the conflicts between the mnf and its retail division (liu et al., 2015; shunko et al., 2017; kim et al., 2018; niu et al., 2019a) . our paper is related to these studies but our focus is the objective conflict between the cm and the mnf on production shifting, which is important in today's global operations. we investigate the role of china's partial vat refund policy in aligning the preferences of the mnf and the cm, which appears new in the literature. the third sub-stream of literature is on objective conflicts, especially on that between profit objective and social responsibility objective. in terms of corporate social responsibility, previous studies mostly concern environmental sustainability ( shen and li 2015; dong et al., 2016; lam et al., 2016; yang et al., 2019) . however, their studies do not study how to achieve the coordination of "economic sustainability" and "environmental sustainability" (choi and chiu, 2012) . this motivates scholars to identify ways to coordinate these two objectives. see krass et al. (2013) and tax-planning that helps a mnf obtain more after-tax profits, so their concern is the corporate income tax. there is a line of research that considers china's import-export tax rules such as hsu and zhu (2011) and xu et al. (2018) . specifically, hsu and zhu (2011) demonstrate that china's import-export tax rules will affect the logistics strategies of a mnf, which serves both overseas and domestic markets. xu et al. (2018) consider the impact of china's import-export tax rules on a mnf's procurement outsourcing decisions who sells goods in china confronting local competition but is monopolist in the overseas market. different from their studies, we study how china's import-export tax rules affect the mnf and cm's preferences of production shifting decisions and the opportunities where their objective conflicts can be solved. we build j o u r n a l p r e -p r o o f 6 competition models in both chinese and overseas markets, which is different from xu et al. (2018) . the third stream of related literature is on global manufacturing decisions. on the one hand, early literature, such as kogut and kulatilaka (1994) , colotla et al. (2003) , kouvelis and su (2005) , vereecke et al. (2006) , lu and mieghem (2009) and sodhi and tang (2013) , focuses on the optimization of global manufacturing network. on the other hand, more recent studies focus on the production location issues, for example, wu and zhang (2014) study the tradeoffs between responsive sourcing and efficient sourcing strategies, based on demand variance and competitors' information correlations. chen and hu (2017) investigate a manufacturer's offshoring-reshoring decisions by formulating its offshore supply dependence and the impact of tariffs. our work is mostly related to shao et al. (2019) and niu et al. (2019c) . the former investigates a sourcing game of competing firms that considers cost difference and cost uncertainty issues between the traditional manufacturing country (e.g., china) and the emerging manufacturing countries (e.g., southeast asian countries). the latter studies a mnf's two global manufacturing strategies called "overseas-production-local-sales" (opls) and "local-production-local-sales" (lpls). they focus on the tradeoff between producing in emerging markets for tax concessions and producing overseas for factory establishment cost avoidance. differently, we study the incentive alignment issues for a mnf and its cm when factories can be shifted from china to southeast asian countries. we formulate china's specific partial vat refund policy, which is absent in the other countries/regions. we also study the impact of import tariff when the goods are produced in china (southeast asian countries) and then sold in southeast asian countries (china). we consider a supply chain comprising a mnf, a competitor located in the chinese market and a cm manufacturing for the mnf. the mnf establishes two divisions that are responsible for the sales in the chinese market (the retail price is ) and the southeast asian market (the retail price is ), respectively. in terms of the chinese competitor, it only sells products that are partially substitutable for the mnf's (the retail price is ). we use the subscripts c, m, o and cm to denote the competitor, mnf's supply to the chinese market, mnf's supply to the southeast j o u r n a l p r e -p r o o f 7 asian market and the cm, respectively. we study two outsourcing structures that are defined as follows. in this structure, the mnf outsources its manufacturing to the cm located in china. the cm charges two different manufacturing prices for the products sold in chinese and southeast asian markets, because of china's partial vat refund policies. in this structure, the mnf outsources its manufacturing to the cm located in southeast asian. the mnf pay a uniform manufacturing price to the cm. we here briefly illustrate how china's partial refund policy works. consider firm c that purchases one unit input in china at a price 10$(exclusive of vat). the total payment by firm c to its supplier is 10 1 + $, where (fixed at 13% in china (china daily, 2019)) is the standard vat rate. then, firm c has two options in sales. suppose firm c sells one unit product to firm d in china at price 100$ (exclusive of vat). firm c will receive a total payment of 100 1 + $ from firm d, where 100 $ is firm c's output vat. thus, firm c has to remit 90 $ to the tax authority as its vat, and acquires after-tax profit of 100 1 + − 10 1 + − 90 = 90$. suppose firm c exports one unit product to an overseas buyer at price 100$. in this case, it cannot collect output vat and will receive a partial refund of its input vat. firm c's vat payment to the tax authority = output vat for domestic salesinput vat paid + nondeductible vat, where nondeductible vat = (total export sales -cif costs of bonded imported inputs) × − . ≤ is the vat refund rate (hsu and zhu, 2011) . clearly, the vat for domestic sales = 0$, input vat paid = 10 $ and nondeductible vat = 100 − $. therefore, firm c's vat payment to the tax authority = 0 − 10 + 100 − $. thus, firm c can obtain after-tax profit 100 − 10 1 + − 0 − 10 + 100 − = 100 1 − − 10 $ , where we see from the above illustrative examples that the firm's domestic profits are unaffected by vat, but the unit profit for its export business is affected by the partial vat refund policy in the 2 when firm c produces goods in southeast asian countries and exports them to china, there is no nondeductible vat. therefore, firm c's vat payment to the tax authority = output vat for domestic salesinput vat paid. and firm c's after-tax profit is 100 − 10 1 + − 0 − 10 = 90$, which is unaffected by the vat. j o u r n a l p r e -p r o o f 8 form of 1 − − . thus, a firm selling its product to both overseas and domestic markets legally prices the exported and domestic products differently (even to the same buyer), in order to mitigate the negative effect of the partial vat refund policies (see page 255 of xu et al. (2018) ). back to our case of the cm located in china. clearly, the profits from the chinese market is unaffected by vat, but the profit from the southeast asian market is affected by the partial vat refund policy. therefore, the marginal profits of the cm located in china charges manufacturing prices and 1 − for the goods sold in the chinese and southeast asian markets, respectively. we assume the manufacturing cost of the cm is zero, and the case of non-zero cost is discussed in section 5.1. indicates that the southeast asian market's potential is smaller (bigger) than the chinese market's potential. " and " are the sales quantities of the local competitor and mnf in the chinese market, and " is the sales quantities of mnf in the southeast asian market. # ∈ 0,1 represents the product substitutability between the local competitor's product and mnf's product in the chinese market. we present the objective functions of the decision makers as follows. for ease of analyzing, we assume .+ to ensure positive outputs. the sequence of events is presented in figure 2 . in ss (ts), at the first stage, the cm sets the uniform (different) unit manufacturing price ( and ) to the mnf. at the second stage, the mnf and the competitor decide the sales quantities. we use backward induction to solve the games (see appendix a.1 for more solution details). the equilibrium outcomes are summarized in lemma 1 and 2. lemma 1. under ts, the equilibrium wholesale prices, order quantities, and profits are: in this section, we first present the comparison results of wholesale prices and sales quantities between two structures. then, we show the mnf and the cm's preferences over two structures and discuss the incentive alignment opportunities. define % = )+ , we summarize the comparison results in proposition 1. proposition 1. when % < % , we have 0 < 7 < 0 ; otherwise, we have 0 < 7 < 0 . proposition 1 indicates that, the order of three wholesale prices is determined by the relative market potential %. lemma 3 indicates that, the absolute difference between 0 and 7 , and that between 0 and 7 are both first decreasing and then increasing in %. when % is small, the two wholesale prices under ts both become closer to the uniform wholesale price under ss, as % increases. however, when % exceeds a threshold, the two wholesale prices under ts both deviate from the uniform wholesale price under ss, as % increases. we define | 0 − 7 | and | 0 − 7 | as the index of wholesale price effect. note that, under ts, according to china's partial vat refund policy, the cm can charge two wholesale prices based on whether the goods are sold to chinese or southeast asian market. the cm has the pricing flexibility which benefits itself while hurts the mnf. therefore, the wholesale price effect is always a negative (positive) force that makes the mnf (cm) prefer ts. moreover, as the relative market potential increases, the wholesale price j o u r n a l p r e -p r o o f 12 effect is first weakened and then enhanced. it is especially pronounced when % is either small or large. we then investigate how the market potential influences the sales quantities of two firms. see proposition 2 for the comparison results. proposition 2. when % < % , we have " 0 > " 7 , " 0 < " 7 , " 0 > " 7 and " 0 + " 0 < " 7 + " 7 . when the relative market potential is small. as such, for a small %, ss can boost mnf's chinese division's sales quantity for the lowered wholesale price. as a result, the total sales quantity in the chinese market is large (i.e. " 0 + " 0 < " 7 + " 7 ), leading to more intense downstream competition. one might intuitively expect that the intense competition hurts the mnf's profit. on the contrary, regardless of the intense competition, we observe that the mnf can occupy a larger chinese market share under ss than ts (i.e. lemma 4 implies that, the increase of relative market potential first weakens and then enhances the competition effect. it seems that % has the similar impact on the competition effect and the wholesale price effect. however, different from the wholesale price effect, which is always j o u r n a l p r e -p r o o f 13 a negative force for the mnf to prefer ts, the competition effect appears as a positive or negative force, depending on the value of %. as % increase, a larger % makes the mnf benefit more under ts, from the competition effect. next, we investigate the mnf's preference over two structures by comparing the equilibrium profits. define % = 2 -)+ , .+ )+ , , we have proposition 3. proposition 3. the mnf prefers ts when % < % < % . otherwise, it prefers ss (i.e. / 0 > / 7 ghh % < % < % ). proposition 3 indicates that, the mnf prefers ss when the relative market potential is either small or large, while prefers ts when the relative market potential is in a moderate range (see figure 3 for illustration). we use the abovementioned effects to explain the mnf's preference change. when % is small (i.e. % < % ), the southeast asian market is negligible, the mnf cares more about the profit from the chinese market for its huge market potential. the uniform wholesale price under ss is much lower than that for the mnf's chinese division under ts, resulting in a heavy wholesale price effect. in addition, compared to ts, the low procurement cost under ss boosts the mnf's chinese division's order quantity and hence, leading to a heavy competition effect. clearly, given a small %, the wholesale price effect and the competition effect both act as negative forces that make the mnf prefer ss. as % increases, the two negative effects are both weakened, reducing the mnf's incentives to prefer ss. when % is in a moderate range (i.e. % < % < % ), the southeast asian market is considerable and the mnf faces two equivalent profit sources. the wholesale prices for the mnf's two divisions under ts are close to the uniform wholesale price under ss, resulting in weak wholesale price effect. however, since the wholesale price for the mnf's chinese division under ts is lower than that under ss, the competition effect changes from a negative force to positive force, inducing the mnf to prefer ts. in this interval, the benefit from the competition effect offsets the loss from the wholesale price effect, resulting in mnf's preference over ts. when % is sufficiently large (i.e. % > % ), the relative market potential is huge and becomes more appealing for the mnf because of the lack of competition. due to the heavy wholesale price j o u r n a l p r e -p r o o f 14 effect, the mnf benefits from ss for its lower uniform wholesale price, compared to ts. under this condition, even though the competition effect brings the mnf into an inferior position in the chinese market competition, the mnf prefers ss because the benefit from the southeast asian (monopolistic) market is far greater than the competition loss from the chinese market. next, we analyze the cm's preference over two structures. define % 5 = )+ i )j 6)+ , 5k 2) 6)+ , 5 and % 5 = )+ i .j 6)+ , 5k 2) 6)+ , 5 , where % 5 < % 5 . proposition 4. the cm is better off under ss when % 5 < % < % 5 (i.e. / 7 > / 0 ghh % 5 < % < % 5 ). interestingly, similar to the mnf, the cm's preference changes twice as the relative market potential increases. intuitively, the cm may always prefer ts because it has the pricing flexibility and can use this pricing weapon to squeeze the mnf's profits. why does the cm benefit from ss, even though it loses the pricing flexibility? the key reason is china's partial vat refund policy. note that the cm actually cannot receive the wholesale price it charged for the mnf's southeast asian division. instead, it can only receive a part of the manufacturing price (i.e. 1 − ) because of china's partial vat refund policy. we define as the index of the tax refund effect. the tax refund effect acts as a negative force for the cm to prefer ts and is enhanced as % increases. when % is small (i.e. < % 5 ), the cm cares more about the chinese market because it can receive large orders from the mnf's chinese division. the orders from the mnf's southeast asian division are so inappreciable that the cm doesn't have to worry about the negative effect of tax refund. under ts, the benefit from pricing flexibility overcomes the loss from tax refund, resulting in cm's preference over ts. as % increases, the orders from the southeast asian market increase and hence, the negative effect of tax refund is magnified. recall that, when % is small, the wholesale price effect is weakened while the tax refund effect is enhanced as % increases. the benefit from pricing flexibility decreases while the loss from tax refund increases. as a result, when % is moderate (i.e. % 5 < % < % 5 ), the negative effect dominates the positive effect. the j o u r n a l p r e -p r o o f 15 cm is better off under ss. in contrast, when % is sufficiently large (i. e. % > % 5 ), even though the orders from southeast asian market is large, the cm may undertake a huge loss from tax refund. we find that the cm prefers ts for the more powerful pricing weapon. to better understand how to manage the conflicts between these two supply chain parties, we analyze their incentive alignment opportunities. (1) the mnf and the cm both prefer ss if one of the following conditions holds: , # < # < 1 and % ∈ % 5 , % . (2) the mnf and the cm both prefer ts if and only if 0 < < o 2:: , # < # < 1 and % ∈ % 5 , % . here, # ∈ 0,1 uniquely satisfies 576 − 192 # + −8 + 16 # 2 + # -= 0. proposition 5 indicates that, there exist several win-win zones for the mnf and the cm (see figure 3 for an illustration). interestingly, the mnf and the cm may engage in incentive alignment under both ss and ts, depending on the difference between the vat rate and the tax refund rate (i.e. ) , and the chinese market's competition intensity (i.e. #). as proposition 5 (1) shows, when % 5 < % < % , the mnf and the cm both benefit from ss. considering the wholesale price effect, one may conjecture that the mnf and the cm's preferences over ss and ts are opposite. however, we note that the wholesale price effect and the competition effect both act as positive forces for the mnf to prefer ss, while the tax refund effect acts as a negative force for the cm to prefer ts. as a result, the cm changes its preference earlier than the mnf as % increases, resulting in a win-win situation for the mnf and the cm. when % goes on increasing, another win-win zone arises, where the mnf and the cm's common preference depends on # and . note that, higher # and represent stronger competition effect and tax refund effect, respectively. when is high (i.e. > in this subsection, we explore the impact of the cm's non-zero manufacturing cost (including the labor cost) by assuming the cm's cost is when it is located in china and 0 when it is located in southeast asian countries. can be viewed as the cost difference. therefore, the profit functions of the cm, the mnf and the chinese competitor remain unchanged under ss, but those under ts are as follows. we use ts 1 to denote this case. we solve the game by backward induction and derive the equilibrium outcomes in appendix , the mnf will not prefer ts 1 . observation 1 and 2 show that, given a sufficiently small manufacturing cost, the mnf will prefer ss when the relative market potential is either small or large. that is, the cm's small j o u r n a l p r e -p r o o f 18 manufacturing cost will not affect the mnf's preferences qualitatively (see in figure 4 (a)). however, given a large manufacturing cost, the mnf is more willing to prefer ss, especially when the cm's manufacturing cost exceeds an upper bound (see in figure 4 (a) and (b)). the reason is that, a large manufacturing cost in china results in a high manufacturing price for the mnf. therefore, ts 1 becomes less attractive for the mnf. in the basic model, we assume that the mnf is a monopolist in the southeast asian market. in this subsection, we consider the mnf has a rival in the southeast asian market. we assume the degree of competition intensities in the chinese and southeast asian markets are heterogeneous, which are noted as # ] ∈ 0,1 and #^∈ 0,1 , respectively. we denote the southeast asian competitor's sales quantity as " . therefore observation 3: when the competition intensity in the chinese market is equal to that in the southeast asian market, the mnf has no incentive to choose ts 2 (i.e. |# ] − #^| = 0). when there is a difference in competition intensity between the chinese market and southeast asian market, the mnf's preferences will switch twice from ss 2 to ts 2 and back to ss 2 (i.e. |# ] − #^| > 0). 20 from observation 4, we know that the mnf prefers ss 2 when the relative market potential % is small or large if there exists a difference in competition intensity between the chinese market and southeast asian market (i.e. |# ] − #^| > 0 ). that is, the difference in the competition intensity between the chinese market and the southeast asian market will not fundamentally change the mnf's preference over ss 2 (in our basic model # ] > #^= 0). however, from the perspective of competition, if there is no different between the chinese market and the southeast asian market (i.e. |# ] − #^| = 0), the mnf will absolutely prefer ss 2 because the southeast asian market is more attractive. therefore, when the competition intensities in both chinese and southeast asian markets are higher, the mnf's preference over ss 2 fall into a larger range (see the blue line in figure 5 (a)~(c)). in this subsection, we investigate the mnf's incentives to find two heterogamous cms located in different markets. we denote the manufacturing prices of the cms located in chinese and southeast asian markets as f and 7 , respectively. this hybrid outsourcing structure is referred to as hs. see an illustration in figure 6 . we solve the game by backward induction and derive the equilibrium outcomes in appendix a.4. the proofs for the following outcomes are similar to those of proposition 1 and 3, thus we omit the details. comparing the equilibrium outcomes under ts and hs, we find that the mnf's preferences under ts and hs are identical (i.e. / 0 = / g (the proof for this outcome is similar to that of proposition 3)). this is easy to understand. although the cm located in the chinese market needs to bear the tax burden because of partial vat under ts, its manufacturing price will not be directly affected. therefore, we have 0 = f g (the proof for this outcome is similar to that of proposition 1), and the mnf's profits and preferences are unchanged. in this subsection, we explore the influence of import tariff on the mnfs' preferences over ss and ts. note that, the chinese and southeast asian markets (e.g., vietnam) have different tariff rates, namely, h and h . it implies that if the mnf's southeast asian retail division purchases each unit of product from china, the import tariff is h , while that for the imported products to china is h . thus, the profit functions of the mnf, the competitor, and the cm under ts and ss are as follows. we use ts 3 and ss 3 to denote this case. indicating the mnf has more incentives to prefer ts 3 to avoid high import tariff cost. observation 6: in terms of the cm's preferences, the most interesting observation is shown in in this paper, we study objective conflict management between an mnf and its cm towards production shifting china to southeast asian countries such as thailand and vietnam. the competition, the cm's pricing power and china's partial vat refund policy play important roles in the mnf and their cm's incentives of production shifting. we first study the wholesale pricing and quantity decisions under two outsourcing structures. we identify the wholesale price effect, which acts as a positive (negative) force for the mnf (cm) to prefer ss (ts), and the competition effect, which acts as a positive or negative force for the mnf to prefer ss. the interaction of these two effects affects the mnf's preferences over outsourcing structures, making it first prefer ss, then ts, and finally back to ss. we then investigate the mnf and the cm's preferences over ts and ss. we find that, the two firms' preferences show an opposite trend and both change twice as the relative market potential of the southeast asian market to the chinese market increases. the mnf (cm) prefers ss (ts) when either the relative market potential is small or large. we identify several win-win zones where both the mnf and the cm prefer the same structure. our main findings are insightful for the mnfs (e.g., uniqlo) and cms (e.g., shengzhou group) who are considering to shift their factories to southeast asian countries. for the chinese government and southeast asian governments, our main findings, especially those in proposition their sales quantities " , " and " , respectively. j!k b c ,b l / = ! − " − #" − " + !% − " − " ; we have the best response functions " " , = 1)+b d )= > , " = 13)= , and " " = therefore, x% − y% + { is a quadratic function with positive coefficients, which suggests we have / 7 > / 0 when x% − y% + { > 0. solving the quadratic function, we obtain two roots as follows comparing % , and % (the lower bound of %), we have % − % = − 6)+ , -)+ , .+ )+ , < 0, that is, % < %. thus, there are two feasible solutions % and % within % ∈ t%, %u, which incur / 7 > / 0 if % ∈ t%, % u ∪ t% , %u. otherwise, / 7 < / 0 if % ∈ % , % . proof of proposition 4. proposition 4 can be derived by comparing the cms' profits under ts and ss. the difference between / 7 and / 0 is / 7 − / 0 = − 1 , 2)65.+ , 5 3 , ) 6)2+ 3. )+ , 6 6)+ , we have x = 4 − 8 + # > 0 for any feasible # ∈ 0,1 and ∈ 0,0.13 ; j o u r n a l p r e -p r o o f 34 y = 8 − 4# > 0 for any feasible # ∈ 0,1 ; { = 2 − # > 0 for any feasible # ∈ 0,1 ; − 1 , 6 6)+ , < 0 for any feasible # ∈ 0,1 . therefore, x % − y % + { is a quadratic function with positive coefficients, which suggests we have / 7 > / 0 when x % − y % + { < 0. solving the quadratic function, we have two roots > 0 for any feasible # ∈ 0,1 and ∈ 0,0.13 . as % 5 − % is increasing in for any feasible ∈ 0,0.13 . so the minimum of % 5 − % is % 5 − %s 5•: = y − )+ , z = )+ 6)+ , )+ , > 0 for any feasible # ∈ 0,1 . therefore, we have % 5 > % for any feasible # ∈ 0,1 and ∈ 0,0.13 . similarly, comparing % 5 , and % (the lower bound of %), we have .+ < 0, that is, % 5 < %. taking the foc of % 5 − % with respect to , we have ; 3~,) 3 ;5 = − )+ j 6)+ , 5i2[ .j 6)+ , 5\. 6)+ , 5k 5 2. 6)+ , 5 , < 0. it means that % 5 − % is decreasing in for any feasible ∈ 0,0.13 . so the maximum of .+ < 0 for any feasible # ∈ 0,1 . therefore, we have % 5 < % for any feasible # ∈ 0,1 and ∈ 0,0.13 . thus, there are two feasible solutions % 5 and % 5 within % ∈ t%, %u, which incur / 7 > / 0 if % ∈ % 5 , % 5 . otherwise, / 7 < / 0 if % ∈ t%, % 5 u ∪ t% 5 , %u. proof of proposition 5. proposition 5 can be derived by comparing % , % 5 , % and % 5 . the difference between % − % 5 and % − % 5 is % − % 5 = )+ i j 6)+ , 5) 6)+ , 5k 2) 6)+ , 5 > 0. then, solving % − % 5 = 0, we have = + w 6)+ , --)+ , , . throughout this paper, = − represents the difference between vat rate and tax refund rate, where (fixed at 13% in china (china daily, 2019)) is the standard vat rate and (0 ≤ ≤ ) is the vat refund rate (hsu and zhu, 2011) . therefore, the difference = − ranges from 0 to 13% and the maximum of is 13%. in the proof of proposition 5, we substitute the maximum value of the nondeductible vat rate = 0.13 to derive the up bound of the feasible condition. comparing = + w 6)+ , --)+ , , and = 0.13, we have two conditions that make % < % 5 under ts and ss. the difference between "… 7 and "… 0 is "… 7 − "… 0 = x f " 7 + k" 7 + k" 7 − x f " 0 + k" 0 + k" 0 = 1+ ) .+. 3 † ‡ 2 6)+ , q > 0, ghh % > )+ < 0, ghh % < )+ ; thus, proposition 6 is immediate. equilibrium outcomes in structure ts 1 : the bright side of supplier encroachment sustainable supply management: an empirical study ningbo's shenzhou int expands abroad premier calling for greater tax reduction direct marketing, indirect profits: a strategic analysis of dual-channel supply-chain design game theoretical perspectives on dual-channel supply chain competition with price discounts and pricing 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capacity decisions with demand uncertainty and tax cross-crediting the impacts of markets and tax on a multinational firm's procurement strategy in china supplier encroachment and investment spillovers efficacy of china's strategic environmental management in its institutional environment shenzhou int'l: largest oem supplier for uniqlo, nike in china rethinking the role of partnerships in global supply chains: a riskbased perspective the authors are grateful to the editor and reviewers for their helpful comments. this work was supported by nsfc excellent young scientists fund (no. 71822202), nsfc (no. 71571194), chang jiang scholars program (niu baozhuang 2017), gdups (niu baozhuang 2017). the corresponding author is yaoqi liu. therefore, if % < )+ , the focs of | 0 − 7 | and | 0 − 7 | with respect to % are j o u r n a l p r e -p r o o f key: cord-287135-m73nepej authors: pham, tien duc; nghiem, son; dwyer, larry title: the determinants of chinese visitors to australia: a dynamic demand analysis date: 2017-07-01 journal: tour manag doi: 10.1016/j.tourman.2017.06.015 sha: doc_id: 287135 cord_uid: m73nepej although china has progressively become an important inbound tourism market for australia, its demand elasticities have been little studied to date. this study examines the determinants of chinese visitors to australia using a dynamic time-series estimator. interesting findings include a high income elasticity as a source of the continuous doubledigit growth rates in chinese arrivals that australia has experienced over the past two decades, together with relatively high total trip price elasticities for both short run and long run. a trend of chinese outbound to australia is also identified. from a policy perspective, the results confirm that keeping a low cost of visiting australia, both ground and travel costs, is a good strategy to secure greater numbers of chinese tourists. the strong economic growth in china has raised the middleincome class of the country significantly and stimulated substantial growth in outbound tourism to many countries around the world, including australia. the income effects on tourism demand from the middle-income class of china were well observed and documented in literature. earlier, when hong kong was first granted approved destination status, chinese tourists were described as locusts who ravaged hong kong's economic landscape, leaving nothing behind (liu & mckercher, 2014) . to some extent, adverse impacts of price increases in the destinations on tourism demand from china did not seem to materialise. as its economy has grown, tourism demand from china has impacted on most countries. china has become one of the key inbound markets for australia and has played an increasingly important role in boosting the australian tourism sector. the growth of this market still has much more to offer in the coming years, stemming from the pulse of the middle-income class amongst a large size of the chinese population. despite its increasing importance for many destinations worldwide, very little is known about the sensitivity of chinese demand for tourism to changes in key economic variables, except for destination hong kong (li, song, cao, & wu, 2013) . the determinants of the chinese market in other destinations have not been examined clearly and specifically. it is imperative for australia's policy makers and the australian tourism industry to understand the determinants of chinese tourists accurately in planning and policy development. in particular, the extent to which chinese visitors are sensitive to price changes is a crucial factor informing tourism policies in australia. if chinese visitors are indeed price inelastic, policy makers could take advantage of this and set the price in favour of the australian tourism industry. in contrast, if they are price sensitive, an increase in prices could result in a substantial loss of tourism revenue from chinese tourists. this paper fills an important gap in the literature to help formulate tourism policies to nurture the growing momentum of the australian tourism industry. it provides timely information, and raises awareness, to better manage an important market. a dynamic demand analysis is undertaken to determine the important factors underpinning inbound tourism to australia from china. the paper begins with a brief overview of important features of the australian tourism industry together with a review of previous australian studies on tourism demand. it then outlines the adopted approach, provides a description of the study methodology and data, and interpretation of the results. the paper concludes with a discussion of the importance of the findings for tourism stakeholders in australia and elsewhere. although set in the china-australia context, the findings in this paper should be of interest and value to those directly involved with the marketing and management of chinese tourists in many other countries. for several decades, tourism has been a key industry contributing to the australian economy through its export capacity. more recently, macro-economic conditions have been conducive for tourism growth, particularly the inbound sector, given the depreciation of the australian dollar, the release of employment from the downturn of the mining boom, and the reduced demands for aeroplane seats by the fly-in fly-out (fifo) workers associated with mining (pham, jago, spurr, & marshall, 2015) . tourism shares of gross domestic product (gdp) for both domestic and inbound tourism sectors peaked in 2000e01 (fig. 1) , and have settled at slightly lower levels at approximately 2.1 per cent and 0.8 per cent, respectively, over the last three years. however, it appears that the tourism sector has not been able to accelerate to its full extent to take advantage of the macro-conditions. in 2014e15, tourism contributed $47.5 billion to gdp, with $34.2 billion from the domestic tourism sector and $13.3 billion from the inbound sector (the australian bureau of statistics, or abs, 2016) . of the inbound sector, latest data from tourism research australia (tra) for the past decade show china and india to be the two fastest growing markets (table 1) . arrivals from both markets have sustained double-digit growth over an extended period. chinese arrivals growth reached 22 per cent in 2014e15, slightly more than two percentage points above that of india (19.6 per cent). however, from a low base, in 2014e15 the indian market share reached approximately three per cent of total inbound tourism expenditure, about the same level as that of singapore, malaysia, south korea and hong kong ( table 2 ). the indian market still has much potential in the years ahead, given the rapid development and large population of the indian economy. for china, the expenditure share had expanded from 7 per cent in 2005e06 to 21 per cent in 2014e15, putting china at the top among all inbound markets in australia, driving the australian tourism industry on its trajectory toward the tourism 2020 target (tourism australia, 2016) . given the rapid increase of chinese arrivals in australia, one might have thought australia would be one of the favourite destinations that chinese tourists would go. latest data from the united nations world tourism organisation (unwto, 2016) in table 3 show the mix of destinations that chinese visitors have travelled. australia was not among the top ten destinations of chinese tourists in 2014. while it is not surprising to see countries in proximity to china such as hong kong, macao, korea, thailand, taiwan and japan on top of the list, it is interesting to see countries including the united states of america, france and russia ranking above australia. this observation highlights a need for australia to formulate tourism policies carefully in such a way to penetrate the chinese market more effectively. thus, it is crucial to understand the determinants of the chinese tourist arrivals to australia. as summarised in lim (1997) , crouch (1992) , song and li (2008) , and peng, song, crouch, and witt (2014) , previous studies on modelling tourism demand and forecasting have typically been based upon fundamental economic theory capturing the effects of income, own-price, cross-price and occasionally some other specific factors included as dummy variables. the determinants reflect the interaction of drivers between the country of origin and the destination country. thus, both sides of 'a trip' can have an influence on the number of arrivals at a destination. from the country of origin e tourism generating region e income is predominantly applied in most of previous tourism demand studies; it is a fundamental concept of the economic demand theory. income is often proxied by gross domestic product (gdp), personal (disposable) income or national income. studies over the past three decades undertaken for many countries reveal that the purchasing power of individuals is an important influence on their decision to travel. an increase in real income provides consumers with greater spending power, resulting in the increased discretionary consumption of many types of products including tourism (crouch, 1992; peng et al., 2014) . at the destination country, depending on the study purposes, prices applied in previous studies range from a highly disaggregated commodity level (divisekera, 2006; wu, li, & song, 2010) to the national aggregate level (lim & mcaleer, 2001) . thus, the actual form of prices varies between studies. however, the lack of a tourism price index per se was, and still is, a real challenge in modelling tourism arrivals. individual researchers have adopted various proxies as a result. the most common ones are price-adjusted exchange rates (i.e., real exchange rates), consumer price indexes of destinations and transportation costs. in some cases, cpi and exchange rates have been used in a comprehensive combination to derive own-price and competing prices song, wong, & chon, 2003) . the use of cpi as a proxy for tourism prices is rather controversial. o' hagan and minnock (1983) argue against the practice, in contrast to the supporting findings in morley (1994) that, since non-fare tourism prices and cpi are highly correlated, the cpi could be used as a proxy for a tourism price index. in such situations, interpretation of the estimated coefficient is problematic, as implicitly visitors were assumed to be in the country already regardless whether or not they could afford to pay for the airfares. for comparing with cpi, morley (1994) derived tourism price indexes directly by combining the individual price indexes of goods that are associated with tourism consumption and the corresponding expenditure shares. this approach coincided with the tourism satellite account (tsa) framework that was introduced by the unwto (2008, 2010) . this approach has inspired and orientated our thinking in this paper. an important observation here is that most studies have applied prices to reflect the cost of living for tourists at the destination (such as cpi or real exchange rate) to measure the own-price effects, with some also adding transportation costs (airfare) to measure the response from tourists when transportation costs change. while table 1 historical annual growth rates of arrivals of australia's top ten international markets (per cent). this separate treatment of transportation cost may be appropriate in some situations (e.g., where countries of origin and destination are close together and particularly where transport substitution is possible (martin & witt, 1987) ), it may not be practical for the case of australia where airfare can determine whether or not a trip takes place. a bundle approach (i.e., total costs including airfare) to measuring price effects for travelling to australia is probably more realistic (divisekera, 1995) , since high airfares that require a larger budget to come to australia could deter some visitors, even though they are willing to pay for costs of living while in australia. in that case, the non-airfare spending will never eventuate. alternatively, cheaper airfares during promotion periods, or an introduction of new low-cost carriers, may not suffice to attract additional visitation expenditure in australia if an expensive destination reduces "length of stay". in that case, the airfare spending will also not eventuate. what matters here is the required total budget for travelling, including the cost of travelling (airfares) and the cost of living (accommodation, food and drinks) that simultaneously make a trip affordable and worthwhile for visitors to travel. regarding inbound tourism demand to australia, kulendran (1996) , kulendran and king (1997) , lim and mcaleer (2001) , divisekera (1995 divisekera ( , 2003 , lim, mcaleer, and min (2009) , examined the international short-term tourist flows to australia from japan, new zealand, singapore, the uk, and the us. visitors from those countries of origin were found to be very responsive to changes in tourism prices in australia and changes in their income, indicating that international tourism is a luxury product. seetaram (2010 seetaram ( , 2012 , and seetaram and dwyer (2009) used the dynamic panel data technique to model international arrivals to australia from ten markets, 1 including china, over the period 1991 to 2007. seetaram (2012) and seetaram and dwyer (2009) also estimated the relationship between immigration and induced inbound tourism demand. with the panel data, elasticities obtained from seetaram (2010 seetaram ( , 2012 take the form of the aggregate response of the inbound tourism sector across all ten markets. given the fact australia was granted approved destination status in 1999, and china's economic growth has been much faster than any of those selected countries, using the aggregate income and price elasticities from a group of ten markets as a proxy for the chinese market is very likely to under-estimate the response from chinese visitors notwithstanding the fact that the aggregate elasticity estimates are valuable for the policy making process at the aggregate level. to the best of our knowledge, to date there is no published study on tourism demand elasticities for chinese visitors to australia as a destination. this study will fill the gap by estimating those demand elasticities and determinants of chinese tourists to australia. given the available time-series data and our interest in estimating the elasticities of chinese visitors to australia, we specify a dynamic demand relationship in equation (1). the number of chinese arrivals is chosen as the dependent variable. the independent variables include three main groups of variables: income factor (proxied by gdp per capita), price factor (proxied by the weighted price), and other factors representing changes in the operating environment of tourism as well as migration flows from china to australia. these choices are broadly consistent with most other tourism demand studies over the past five decades as pointed out in crouch (1992) , lim (1997) , dwyer (2009), seetaram (2012) , dwyer, seetaram, forsyth, and king (2014) , and peng et al. (2014) . all variables in equation (1), except the dummy variables, are implemented in the annual growth form 2 to mitigate effects of possible heteroscedasticity. the advantage of using growth rates is that the marginal effects (i.e., coefficient parameters) can interpreted as elasticities, which is similar to the doublelog form that has been commonly used in previous studies. as the same for the double log form, the elasticities derived from equation (1) are not changing over time, they are the average elasticities over the whole study period. with the lagged dependent variable incorporated in the model, we argue that chinese visitors could either return to visit australia after the first visit, the kind of habit persistence or stable behaviour patterns as applied in martin and witt (1987) and , or they could promote and convince their neighbours, friends and relatives to visit australia after they return home from their trips. we explicitly emphasise the role of this factor as a determinant of tourism demand. if it is in the form of word of mouth, then this "advertising" should be taken seriously, as in a way it is free publicity. furthermore, it is essential to know how australia is perceived by chinese visitors by the inclusion of this variable, which could be either positive or negative, depending on their experience while they are in australia. from a technical point of view, the lagged dependent variable allows us to examine the effect in the short-run and the long-run explicitly. this study adopted the real gdp per capita as an income measure to explain the movements of chinese visitors. the bundle approach combines the costs of domestic and international travels in a weighted average sum to estimate the price index variable. in particular, we make a slight variation to morley's approach to deriving tourism price index for chinese visitors using the two tourism price indexes published by the australian bureau of statistics (abs), one for domestic and one for international travelling. both contain price movements of airfares and accommodation. the domestic price index is dominated by a large accommodation share. it is what both domestic and foreign visitors face when travelling within australia e the cost of living for tourists at the destination from the perspective of the chinese visitors. the international price index is predominantly represented by the longhaul airfares for the australian outbound. as the international competition will force airfares of all international carriers to move broadly in line with each other, the abs 0 international price index would be the same with the price index that inbound foreign visitors to australia would also have to face e the cost of travel to the destination (martin & witt, 1987; witt & witt, 1995) . to combine both airfares and cost of living, the australian tourism satellite account data for inbound tourism expenditure abs (2016) indicate that the long distance transportation cost dominates, accounting for nearly 70 per cent the total. using this ratio (7:3), a tourism price index for chinese visitors was derived using 70 per cent of international price index (airfare) and 30 per cent of the domestic price index (cost of living). this approach is similar to that in kulendran (1995) , in which the ratio of 6:4 for transport to accommodation costs was applied for the japanese visitors. the reason for a low accommodation share in tourism expenditure for chinese visitors is probably because the chinese community in australia now is much larger than the japanese community of the 1990s; the free accommodation offered by families and friends could reduce the accommodation expenses for the chinese visitors. the chosen specification presented as equation (1) does not include the bilateral exchange rate between china and australia, as the exchange rate was found to be statistically insignificant during the model testing. the rationale for not using the exchange rate is that the yuan has been heavily influenced by trade policies to promote exports from china, and is tightly controlled by the chinese government. analysis from fxcm market insights pointed out that the "yuan has not been made fully convertible" (fxcm 2016). furthermore, the practice of two rates, offshore (cnh) through the bank of china in hong kong, and onshore (cny) in the mainland (desloires, 2015) , helps to de-associate the link between exchange rate changes and outbound tourism by the chinese. in term of cross-price effects, we share the view of crouch, schultz, and valerio (1992) that since australia is rather distant from all other major destinations, price substitution or price complementary are not influential. in addition, the consistency of price indexes in the bundle approach across all possible countries is a real challenge. thus, the inference of the estimates would not be very accurate if other destinations were to be incorporated as substitutes. hence, equation (1) does not include cross-price elasticity. the group other factors includes migration flow from china and four dummy variables capturing events that happened during the study period 1991e2014 (24 observations), namely the breakout of the severe acute respiratory syndrome (sars) in late 2002, shocks in the domestic travel supply caused by the australian mining boom; the global financial crisis (gfc) 2008; and a trend in tourism demand for travel by the chinese. chinese migration is expected to have positive effects on tourism via visiting friends and relatives (dwyer, pham, jago, bailey, & marshall, 2016) . other mechanisms through which migration can affect tourism include: making the destination country more tourism attractive with diverse culture; business networks that connect the destination and an origin country, stimulating business travel (seetaram & dwyer, 2009) . when sars broke out in guangdong province of china in november 2002, it effectively reduced the number of travellers significantly across many countries, particularly for visitors from china. the event was modelled as an intercept change for 2003. it is expected that sars has a negative effect on tourism (dwyer, forsyth and spurr, 2006) . in 2005, the mining boom in australia began to absorb a substantial amount of hotel rooms and air transport capacity to facilitate the needs of the fifo mining workers pham et al., 2015) . the fifo activity imposed a severe constraint on the supply side of the australian tourism sector, at least over the period from 2005 to 2007, during which aviation and accommodation services could not be expanded quickly to satisfy the demands from both mining and tourism industries. in this context, the supply constraint is incorporated as a dummy variable for the period 2005e2007. we expect that this variable has a negative sign due to the supply constraint for both transport and accommodation. the global financial crisis (gfc), starting in 2007, reduced household consumption and created a loss in consumer confidence across many countries. while the gfc effects still linger for many countries, its exact time span for china is not clear-cut, since the economy grew at 9 per cent in 2008, well above the economic growth rates of many other developed and developing countries. however, comparing the performance of the chinese economy before and after the gfc, it is clear that the chinese economy was building growth momentum, rising upward from 10 per cent in 2003 to 14 per in 2007, but from 2008, it has actually been trending downward from 9 per cent to just slightly above 6 per cent growth in recent years (the world bank, 2016; imf 2016) . for this reason, the gfc dummy variable is adopted for the period from 2008 onwards. it is expected that the gfc has a negative effect on tourism via its affects to the budget constraint of travellers (li, blake, & cooper, 2010) . although the chinese economy has slowed down, the strong long-run growth path of the economy throughout the period since 1991 has certainly changed consumer behaviour over the course of time. it is well documented in economic theory that, when growth is continuously strong over a long period, income increases become more permanent and consumer behaviour will move toward the purchase of more luxury goods. tourism is generally perceived as a luxury consumption item (crouch, 1992) and people might use it to state their social-economic status among friends and relatives. as such, in developing countries like china, demand for travel might be added to the household consumption bundle of the wealthier residents. that this trend is likely to apply to the chinese population is justification for our assumption to include the trend variable. because the trend reflects aspects of economic growth (i.e., increase travel budget) and technological progress (i.e., lower travel costs), we expect that the trend variable has a positive sign. in summary, expected signs for the coefficients are as follows. all data in this study are presented in yearly percentage change format and cover the period of 1991e2014. due to the yearly data format, we do not need to examine the nature of seasonality in the time series. however, this issue will be examined in the future if monthly or quarterly data sets become available. the time series plot of the main variables in the form of annual growth used in equation (1) shows no abnormality in the trend and pattern (see fig. 2 ). there is a sharp decline (by 7.3 per cent) of tourism arrivals at the outbreak of the sars pandemic in 2003 while the global financial crisis only produced a minor fall of 0.8 per cent. however, the reductions in these two periods were followed by strong bounce-back corrections, resulting in an average annual growth rate of 19.3 per cent in the whole period, which is much faster than the average annual growth rate of gdp per capita (9.3 per cent) and price index (0.5 per cent). to check for stationarity of main variables, we use the augmented dickey-fuller test with the null hypothesis that the series have a unit root. the test results rejected the null hypothesis for tourist arrivals (p-value â¼ 0.001), lag of tourist arrival (p-value: 0.002), cost index (p-value â¼ 0.000), and migration flows (pvalue â¼ 0.004) but failed to reject the null hypothesis for gdp per capita (p-value â¼ 0.272). despite one of the regressors having a unit root, we can still proceed with the analysis if all regressors are not cointegrated. the johansen trace test for cointegration failed to reject the null hypothesis that the rank of the cointegration matrix is zero (test statistics: 63.55; critical value at 5%: 47.21). thus, we are confident that these variables can be used to estimate the determinants of chinese arrivals in australia as specified in equation (1). because the lagged dependent variable is included, the error term in equation (1) may have serial correlation. 3 to mitigate this issue, we firstly applied the prais-winsten regression to take into account possible heteroscedasticity and serial correlation in the error terms. the diagnosis tests show that the regression residuals meet the required criteria. in particular, the durbin h test failed to reject the null hypothesis that the regression residuals do not have autocorrelation (p-value: 0.393) while the portmanteau test failed to reject the null hypothesis that the residuals are white noise (pvalue: 0.622). to check for the robustness of results, we then conducted the cochrane-orcutt regression, which is an alternative approach to control for serial autocorrelation in equation (1). although results from both techniques are similar, the cochrane-orcutt estimator is better for model selection criteria (i.e., akaike information criterion e aic, and bayesian information criterion e bic) are lower (see table 4 ). thus, it is a preferred model in this paper. we now focus on discussing results of the cochrane-orcutt estimator. overall, all coefficients in table 4 have the expected signs. the results confirm a lag effect of the arrivals from the previous year e every one percentage point increase in the number of arrivals in a year is associated with about 0.30 percentage points increase in arrivals in the following year. the positive sign for the lagged dependent variable indicates that chinese visitors have a positive perception of australia as a tourist destination. the result is strongly consistent with tra's unpublished data for the period from 2010/11 to 2014/15 which show approximately 50 per cent of chinese arrivals are repeat visitors (data provided to authors). while the lagged variable indicates an immediate effect between two consecutive years, the historical data simply recorded the return visitors in general, not specifically referring to those coming back immediately after their visits in the previous year. results show a trend of 2.8 per cent growth per year in arrivals to australia from china. by itself, it appears to be rather a strong trend. however, putting this value in the context of the arrival (2016) growth rates with an average of 19.3 per cent per annum over two decades (and at times the rates went up to 30 per cent and 44 per cent), the value of the trend coefficient is realistic. understanding the causes of this trend is beyond the scope of this paper. this remains a critical area for further research to explain how the australian marketing agencies can influence such a perception among chinese travellers. also, an important question for future research would be how large are the outbound trends from china to other countries, as compared to the results for australia. results for sars, mining-boom-induced supply constraints and gfc are highly statistically significant. adverse impacts of these events on the number of the chinese arrivals to australia appear to be larger than the changes in the observed historical data. the reason is that, while the observed changes are the net simultaneous results of various factors, the regression parameters isolate and represent the effects of each factor individually without the interactions of the others (i.e. parameters are measured with the "ceteris paribus" or "all else remain constant" assumption). however, when considering all factors together, the net effects of parameters are close to the observed data. for example, the predicted mean effects of all factors in 2003 apart from sars is 55.8 per cent; hence, the effective impact of sars is only 8 per cent (55.8e47.8), which is close to the observed change of the 7 per cent reduction in 2003. the growth rate of chinese arrivals to australia has generally increased faster than the gdp per capita growth rate in china. this results in a short-run income elasticity of 3.8 per cent, implying a long-run income elasticity of 5.5 4 per cent. the value of the longrun income elasticity is slightly higher than that of japanese tourists (4.45%) that kulendran (1995) estimated earlier when japanese tourists were prominent in australia. as demand for necessities will not grow faster than, or even proportional to, income increases, a value greater than unity of the income elasticity in this case reflects the luxury consumption nature of a tourism experience in australia among the chinese. this high income elasticity explains clearly the source of the continuous double-digit growth rates in chinese arrivals that australia has experienced over the past two decades. indeed, in any years without major events, sars for example, the income effect has predominantly driven the total chinese arrivals. with low population growth rates in china (approximately 0.5 per cent per annum), the gdp per capita growth rates of the country are nearly the same as the gdp growth rates; this implies the economic impact of china's gdp growth on tourism demand will not be discounted on the per capita basis (gdp divided by the size of the population). even at the projected gdp growth at the low end of 6 per cent for china in the next few years (imf, 2016) , this high income elasticity will continue to sustain a significant tourism demand for australia. the value of the income elasticity is strongly reinforced, independently, by the projection of the chinese arrivals growth rate of 23.3 per cent for 2015e16 by tra (2016) given a forecast of 6.3 per cent growth for china's gdp. it is important to note that the price elasticity in this paper is on the basis of the total trip costs, including the costs of living and costs of airfares (also referred to as travel or transportation in previous studies). thus, a one per cent increase in the price index for chinese visitors used in this paper is equivalent to a combined uniform increase of one per cent for both the costs of living and the airfares simultaneously in other studies which have two separate price components. the estimated short-run price elasticity for chinese visitors is ã�4.4% (table 4) , with a long-term price elasticity of ã�6.4%. this long-run price elasticity is larger than those individual long-run price elasticities for the cost of living (ã�3.5%) and the cost of transportation (ã�3.6%) that divisekera (1995) estimated earlier for japanese tourists. however, on an equivalent basis, the impacts of 1 per cent increase in the tourism price index in this paper should be compared to the sum of both individual price elasticities, ã�3.5 plus ã�3.6, per cent for japanese tourists. thus, in comparison, japanese tourists back then were even more price responsive than chinese visitors currently, ã�7.1 per cent as opposed to ã�6.4 per cent. however, compared to the aggregated long-run elasticities in seetaram (2010) for all inbound markets in australia, the elasticities in this paper for the chinese visitors are higher, at the upper end of the range. again, the long-run price elasticity of ã�6.4 per cent in this paper should be compared with the sum of both price and airfare elasticities in seetaram (2010) , ã�2.54 and ã�2.08 per cent respectively. this difference is expected, as compared to all other regions in seetaram's study, china is the fastest growing economy; thus, the response to price changes are much stronger. it may well be the case that chinese tourists to australia are more price sensitive than other key markets given the large proportion of first time travellers. a study of tourism to malaysia (habibi & rahim, 2009 ) estimated a price elasticity of demand for visitors from china of ã�8.09, the highest price sensitivity of the ten inbound markets studied. overall, estimated elasticities in this paper are within the range of elasticities estimated in previous studies. together with the income price elasticity, the absolute value greater than one for the price elasticity reinforces the fact that tourism is indeed a luxury consumption for the chinese. the high value of the price elasticity is simply because australia is far from china, airfares are relatively expensive, and in addition to the costs of living in australia, the cost for a trip to australia can take up a large proportion of an average chinese household income. any price changes can lead to changes in the travel decision of chinese visitors. thus, the bundle price elasticity is an important determinant for policy makers in australia to keep in mind when considering policies directly related to the cost of trips as a whole. the effect of migration is significant but with a modest magnitude of 0.1 in the short run and 0.14 in the long run. our estimated parameter is higher than that of seetaram (2012) with an estimated immigration elasticity of 0.028 for the short run and 0.009 for the long-run for 15 main tourist markets in the 1980e2008 period. the higher magnitude of migration elasticity in the long run of this study is in line with the finding of dwyer et al. (2014) who found that the elasticity of migration for tourism in 2006 was 0.59 compared to 0.33 in 1991. ideally, the bundle price index could have been estimated using all individual price series associated with chinese tourists' consumption and the expenditure shares that chinese tourists spend in the consumption bundle. unfortunately, the expenditure series of the international visitor survey (ivs) data are only available for the period from 2004 to 05 to 2014e15 (tourism research australia, 2016) , which severely constrains the number of observations available for this study. technically, data for ivs prior to 2004e05 could be "backcasted" but results are not guaranteed to produce consistent time series data as the survey methodology has been revised several times. as a result, the direct approach, as outlined in morley (1994) , was not able to be undertaken. the movements of airfares for chinese visitors are then based on the domestic and international holiday travel and accommodation price series (abs, 2016) . in particular, the airfare price index for chinese visitors is proxied by the australian outbound series as the exact airfare price index for chinese visitors would require the shares of airlines that chinese visitors used and the corresponding average airfares. such information was not available. thus the ratio 7:3 was used. this ratio can change over time, as consumption patterns can change over time, resulting in changes in the value of the price elasticity of tourism demand. an important caveat also attaches to the significant economic growth path of china. the size of the chinese economy has grown nearly eight times in real terms from 1992 to 2014 (the world bank, 2016), and now is the world's largest economy on a purchasingpower-parity basis (international monetary fund, 2016) . in such an environment, consumer behaviour is changing so rapidly that longer time series data than the sample size currently available to this study may be required. china's economic growth has become a significant stimulus to many countries, including australia. the sources of stimulus apply across a whole range of industries of australia. the chinese economy is shifting toward more sustainable growth based on consumption and services. thus, growth in chinese outbound tourism demand has played an important role in the australian tourism industry, and is expected to continue to grow in the coming years. tourism is rapidly developing as a luxury consumption item for chinese households. as such, demand for tourism is likely to continue to grow ahead of the chinese gdp growth. on average over the study period, china's gdp per capita grew by 9 per cent, a strong positive influence on the visitor number to australia. gdp growth of china is the main driver for the chinese arrivals in australia. although china's economy has slowed in recent years, the economic growth of the country still generates double-digit growth in its tourist arrivals to australia. chinese visitors are also very responsive to price signals. hence, it is important to keep prices in australia to a minimal level, as the impacts of price increases will be detrimental to the level of inbound demand from china. the australian government has implemented a raft of tourism reforms in recent years including more direct flights between australia and selected markets (china included), simplifying tourist visa applications offering online options for a wide range of countries, granting multiple entry options to key markets (including china), widening criteria for the working holiday maker visas, and adding more occupations to the skilled occupational list (tourism australia, 2016) . these reforms effectively open up market access for the australian tourism sector, and certainly this is the right direction to boost inbound tourism revenue. the keys to achieving maximum revenue from china tourists are to (a) ensure more convenience for travelling to australia and (b) maintain cost effectiveness so that the high income demand elasticity for travelling to australia of chinese visitors will bring more visitors to australia from china. the present study has major policy implications for destination management. the findings advance our knowledge of the elasticities of demand for tourism arrivals from china, a neglected area of tourism research. as such, they have implications for forecasting tourism arrivals from china as well as policies to maintain high growth from this market. for australia, the combination of high income elasticity with high price elasticity associated with chinese visitors represents a potentially explosive cocktail. a proposal under consideration is to charge a cheaper multiple entry visa fee for tourists from china (pham, son and dwyer, forthcoming) . the potential loss of visa fee revenue will certainly be over-compensated by a large increase in expenditure brought by chinese arrivals. as the chinese economy experiences its expected slowdown into the future, the growth rate of visitors to australia is likely to slow also. in this context, since australia is already a high price destination ranked 138 from 141 countries in world economic forum (2016), any increase in costs could exacerbate this decline. policies to reduce costs or at least to keep it in check, should continue to support healthy tourism flows from china. australian national accounts: tourism satellite accounts effect of income and price on international tourism marketing international tourism to australian -a regression analysis dirty float': how china manages its currency. the sydney morning herald an econometric model of international visitor flows to australia a model of demand for international tourism domestic demand for australian tourism: an almost ieal demand system effects of sars crisis on the economic contribution of tourism to australia modeling the impact of australias mining boom on tourism: a classic case of dutch disease is 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cost of living the use of cpi for tourism prices in demand modelling the economic significance of tourism within the european community a meta-analysis of international tourism demand elasticities the economic impacts of a higher visa fee for chinese tourists to australia (under review) the dutch disease effects on tourism e the case of australia. tourism management use of dynamic panel cointegration approach to model international arrivals to australia immigration and international inbound tourism: empirical evidence from australia immigration and tourism demand in australia: a panel data analysis tourism demand modelling and forecastingda review of recent research tourism demand modeling: a time-varying parameter approach modelling and forecasting the demand for hong kong tourism tourism 2020 tourism forecasts international visitor survey results jointly presented by the united nations statistics division (unsd), the statistical office of the european communities (eurostat), the organisation for international recommendations for tourism statistics data on outbound tourism forecasting tourism demand: a review of empirical research analyzing tourist consumption: a dynamic system-of-equations approach the authors would like to thank associate professor jaume rossell o at universitat de les illes balears and dr jen-je su at griffith business school for their comments and feedback to the paper. key: cord-277446-0e6akcjf authors: liu, peilong; guo, yan; qian, xu; tang, shenglan; li, zhihui; chen, lincoln title: china's distinctive engagement in global health date: 2014-08-28 journal: lancet doi: 10.1016/s0140-6736(14)60725-x sha: doc_id: 277446 cord_uid: 0e6akcjf china has made rapid progress in four key domains of global health. china's health aid deploys medical teams, constructs facilities, donates drugs and equipment, trains personnel, and supports malaria control mainly in africa and asia. prompted by the severe acute respiratory syndrome (sars) outbreak in 2003, china has prioritised the control of cross-border transmission of infectious diseases and other health-related risks. in governance, china has joined un and related international bodies and has begun to contribute to pooled multilateral funds. china is both a knowledge producer and sharer, offering lessons based on its health accomplishments, traditional chinese medicine, and research and development investment in drug discovery. global health capacity is being developed in medical universities in china, which also train foreign medical students. china's approach to global health is distinctive; different from other countries; and based on its unique history, comparative strength, and policies driven by several governmental ministries. the scope and depth of china's global engagement are likely to grow and reshape the contours of global health. in only three decades, china's global engagement has accelerated from closed autarky to open engagement; from relative isolation to integration into the world system; from a low-income to a middle-income country; and from an aid recipient to an aid donor. as a global demographic and economic giant, china's prominence in global health should not be surprising. with 18% of the world's population, china weighs heavily in all global health metrics, such as life expectancy, disease burden, and health systems. as the world's largest trading nation, its movement of goods and services is associated with transfer of health technologies, diseases, and risk factors. in health knowledge and strategies, china has a rich history of traditional medicine and has pioneered many health-care innovations. china's ascendency has generated many questions and some concerns. a common assumption is that china uses foreign aid to secure energy and natural resources and to expand export markets. 1,2 china's claim of aid with "no strings attached", is considered by some to encourage corruption, weaken accountability, or ignore human rights. 3 the international press has reported delayed and muddled notifi cation of infectious outbreaks, and much news of exported contaminated chinese manufactured products. china is sometimes perceived as working alone and insuffi ciently cooperating with other countries. in this review, we attempt to address the following questions: what is china's role in global health? is china's engagement distinctive or similar to other countries? what does the evidence illuminate of china's global health engagement? china, similar to most countries, has no single offi cial source of data for global health because of the multiplicity of governmental stakeholders, the absence of a national strategy on global health, and the unclear borderline between aid and trade investments. 4 a study 5 by nyu's wagner school has estimated china's foreign aid to africa, latin america, and southeast asia from 2002 to 2007. strange and coauthors 6 estimated all previous estimates of chinese development fi nance to africa. the state council of the chinese government, the highest body of state administration, published white papers summ arising china's overall foreign aid in 2011 and 2014. none of the above estimations disaggregated or separately reported health aid. 7, 8 we thus have resorted to an extensive search of data from multiple chinese sources-the state council, the ministries of health, commerce, education, foreign aff airs, and science and technology. reports from provincial governments, chinese embassies abroad, and the press were searched. altogether, we obtained data from 529 sources-425 from various websites, 70 from statistical yearbooks, 23 from regular reports, and 15 from newspapers. data sourced came from 15 groups of organisations, including 227 sources from the ministry of commerce, 35 from the health ministry (national health and family planning commission), and 15 from ministry of education. the overwhelming proportion of these data sources are in chinese (95%), with less than 5% in english. all data sources are shown in the appendix. interviews were done with dozens of former offi cials, medical team members, and key provincial authorities to collect fi rst-hand information. not surprisingly, the data quality is mixed, often incomplete, and the fragments need to be matched and fi tted together. the chinese government is essentially the only source of information, without other sources of independent verifi cation. reports of classifi cation and nomenclature often do not follow international standards. a common limitation is the mixing of stock data versus fl ow data. our compiled data, nevertheless, generate what we believe to be the most robust estimation possible. matching and piecing together the fragments allows inconsistencies to be double checked for consistency. most inconsistencies relate to exact numbers, but estimation of the general order of magnitude is believed to be reasonably robust. all data sources for this review are shown in the appendix in both original chinese and translated english. after introducing a framework, we present sections on china's work in health aid, health security, health governance, and knowledge exchange. china's participation in global health has deep historical roots, not only just in recent years. in the fi rst millennium, knowledge of medical cures were transmitted by the silk road that facilitated exchange between china, india, the middle east, and europe. 9 in the 20th century, some chinese health crises such as the manchurian plague epidemic captured the attention of neighbouring countries of the international community. 10 china has historically been the origin of many infectious epidemics and a source of key health innovations of breakthroughs such as the barefoot doctor (a term that emerged in the 1960s and 1970s, which refers to farmers who received minimal basic medical and paramedical training and worked in rural china to promote basic hygiene, preventive health care, family planning, and treat common illnesses. the name comes from southern farmers, who would often work barefoot in the rice paddies), and artemisinin, an eff ective antimalaria drug developed from plant-based chinese traditional medicine. 11, 12 because there is no universal consensus for the defi nition of global health, some approaches focus on transnational health risks, which lie beyond the reach of national governments, whereas other approaches stress the global commitment and responsibility to address health inequities and to support health. 13 we have adopted a framework of global health as characterised by health and related transnational fl ows of diseases, people, money, knowledge, technologies, and ethical values. [14] [15] [16] four domains capture these globalisation processes (fi gure 1). first, health aid aims to advance global health equity. it is the traditional area of offi cial development assistance (oda) coordinated by organisation for economic cooperation and development (oecd) countries. second, global health security should be ensured by management of interdependence in global health and mutual protection against shared and transferred risks, such as epidemic diseases. third, health governance is needed for global stewardship to set ground rules as mediated by health diplomacy. fourth, knowledge exchange is needed, which includes the sharing of lessons and knowledge production, ownership, and application worldwide. knowledge centrally aff ects all four pillars of global health, and global health governance is recognised to be central to all four domains (fi gure 1). on the basis of this framework, china's modern timeline might be demarcated by fi ve landmarks. first, in 1963, china sent its fi rst overseas medical team to algeria, followed 6 years later by the donation of its fi rst hospital in tanzania. 17 the explicitly articulated purpose of china's health aid was to further political solidarity as part of china's foreign policy. second was china's economic openings after 1978, which launched the dramatic transformation of china from a low-income to a middle-income country, leading to china qualifying as an aid recipient followed by increasingly becoming an aid donor. 17 third, starting from 2000, china has hosted a series of forums on china-africa cooperation, with each forum announcing yet another major aid pledge-eg, hospital construction, malaria control, and high education scholarships (2007-09); training of health workers and artemisinin drug donation (2010-12); and brightness action (eye care) campaign (2013-15). 18, 19 fourth, global engagement greatly accelerated after 2001 when china entered the world trade organization (wto), an event that marked china's joining almost all international bodies. finally, and perhaps most dramatically, the 2003 severe acute repiratory syndrome (sars) epidemic underscored both china's neglect of its health sector and the reality that china's global trade cannot be done without mutual health protection. 20 in recent years, the state council has published two white papers in april, 2011, and july, 2014, summarising china's foreign aid by volume and type. the 2011 white paper reports foreign aid of us$37·6 billion accumulated up to and including 2009 in three categories: grants of $15·6 billion; concessional loans of $10·8 billion; and interest-free loans of $11·2 billion. this amount is fairly close to another estimate of china's foreign aid at $40·5 billion cumulative from 1950 to 2010, reaching $3·9 billion annually by 2010. 21, 22 the aid increased signifi cantly during the period of 2010-12, reaching an average of $4·8 billion per year, of which the grants accounted for 36·2%. 8 figure 2 shows that african countries received 46% of all aid, with asia receiving about a third (33%) and latin america receiving around 13%, before the end of 2009. the share for african countries increased to 51·8% during the past 3 years, whereas latin america received relatively less. 8 another estimate computed china aid to africa in 2008, at $1·2 billion in comparison with japan at $1·6 billion and usa at $7·2 billion. 22 chinese aid in health is provided in fi ve categories: medical teams, construction of hospitals, donation of drugs and equipment, training of health personnel, and malaria control. the largest share of health aid is spent on medical teams and donated facilities. the fi nancial value of chinese in-kind health aid is diffi cult to estimate. crudely, from 2007 to 2011, we estimated the value of chinese medical teams in africa to be about $60 million annually, with donated facilities at a similar amount. total health aid to africa annually has been estimated at about $150 million. understanding of the type of health support off ered rather than the precise volume of funding might be more important. diff erent from most oecd donors, china does not off er general sectoral support, albeit small cash grants given to several countries in recent years. its health aid uses a project approach. 7 the in-kind provision in the fi ve categories is based on chinese competencies. health seems to constitute only a small proportion of the total chinese aid. health aid is mainly in donation form, whereas most of china's overall foreign aid is off ered as either concessional or interest-free loans. since 1963, under the protocol on the dispatch of medical teams signed between the government of china and the recipient countries, about 23 000 chinese medical workers have been sent to about 66 countries to provide services to an estimated 270 million people. at the end of 2013, 1171 chinese medical workers were working in 113 medical centres in 49 countries. 42 of the countries are in africa, and the remaining seven are mainly small countries-four in asia, one in europe, one in south america, and one in oceania. 23 the table shows african countries in 2013 according to medical teams, aided facilities, and malaria control programmes, along with the chinese provinces twinned to each country. figure 3 shows china health aid to africa with countries shaded according to density of medical team coverage and demarcated by aided facilities and malaria control. the distribution shows wide coverage of nearly all african countries with a higher density of medical teams in western and eastern africa regions. the largest and most powerful african countries such as south africa, nigeria, and kenya do not have chinese medical teams. chinese selection of hosting countries is based on country request and the joint decision by china's ministries of health, foreign aff airs, and fi nance. the medical teams are overseen by the chinese embassy economic and commercial counsellor's offi ces. medical teams are fi nanced by the health aid budget in the health ministry (except the basic salaries), which is responsible for dispatching medical teams. selected countries are twinned to specifi c chinese provinces with public hospitals and local medical schools responsible for staffi ng, supervising, and partially funding the medical teams. 24 some practical criteria such as willingness and workload are used to match chinese provinces and recipient countries in the twinning arrangement. the number of members in medical teams ranges from a half dozen people to nearly 100, usually working out of chinese donated hospitals and clinics. most workers are clinicians, and most teams include a leader and a translator. public health skills are usually not included. medical teams mainly provide clinical services, especially for specialties in short supply-eg, surgery, gynaecology, and obstetrics. the average duration of an overseas assignment is 2 years, with team members receiving housing and food plus enhanced salaries. over the period of 2010-12, these medical teams working in 54 countries had provided about 7 million medical consultations and treatments. 8 panel 1 describes some of these medical teams in southern sudan and the democratic republic of the congo. since 1970, china has constructed more than a hundred health facilities overseas with its health aid. china accelerated its assistance in the construction of hospitals and clinics-from 2010 to 2012, china has supported about 80 construction projects of health facilities. 8 most of these facilities are donated, and only a few are built as part of large infrastructure projects funded by chinese loans. african countries were the recipients of more than three-quarters of the donated facilities. although most countries have received at least one facility, some have received up to 6. these facilities are mostly so-called turnkey operations, for which chinese construction fi rms build the facility for transfer to local authorities. malaria control has recently been prioritised. control programmes are undertaken through 30 anti-malaria centres, featuring artemisinin based on chinese traditional medicine. panel 2 describes an ambitious chinese programme of malaria eradication with mass drug administration with artemisinin on the comoros islands. the question of whether health aid is mainly driven by china's commercial interest is not easy to investigate. much depends upon interpretation of underlying motivation. for example, chinese aid to africa might be viewed as either helping the world's poorest countries or building friendship with the origin of much of the world's energy and natural resources and potential export markets. a comprehensive analysis of this question would need access to data not currently available. as a preliminary fi rst step, we attempted to examine correlations between health aid and commercial economic indicators. regression analysis of african countries with variables of health aid (medical teams, donated facilities, malaria control) and economic interests (petroleum imports, china's foreign investment, and china's imports and exports) yielded no signifi cant pattern. figure 4 shows four scatter-plots of china health aid and african trade. in the four diagrams, individual african countries are plotted according to health and commercial indicators. the scatter-plots did not show any association between medical aid and economic interests. spearman's rank correlation and t test analysis for the period of 2002-11 showed no signifi cant fi ndings of correlations. these preliminary analyses should not be interpreted as conclusive. a core component of global health is mutual health protection against international transfer of health risks, which shows health interdependence. transborder movement of infectious diseases, contaminated goods and products, air pollution, and globally pooled co 2 are prime examples. for china, the 2003 sars epidemic was a crisis with serious economic and political consequences. both disease control and international cooperation were delayed. chinese errors made in the early stage of sars have been acknowledged and have generated strong corrective measures, both domestically and internationally. 28 domestic measures include major re-investment in the public health system via the chinese center for disease control and prevention (cdc), including development of the world's largest real-time electronic surveillance system. 29 international eff orts include active participation and leadership in many international forums that foster cooperation in compliance of disease reporting and control, as shown by the initiation of the un resolution on enhancement of capacity-building in global public health in 2003, and the joint international pledging conference on avian and human pandemic infl uenza with china, the european commission, and the world bank held in beijing in 2006. [30] [31] [32] subsequent management of infectious outbreaks such as avian infl uenza a h7n9 virus shows that china recognises the importance of strict adherence to the international health regulations. in the 2003 sars outbreak, china needed 87 days between fi rst case detection and report to who and another 46 days for joint teams to investigate the outbreak. for h7n9 one decade later, less than half the days lapsed between fi rst case and report to who and the initiation of joint investigations. [33] [34] [35] infections can move in several directions. china has been the destination of cross-border infectious transmissions. in 2011, a polio epidemic was imported from pakistan into china's xinjiang province. 36 after making arduous eff orts and expending large resources. 37 similarly, china has been threatened by the import of dengue fever, malaria, and several other transmissible diseases. 38, 39 cross-border risks can also accompany the import and export of commodities. as the world's largest exporter of manufactured products, china, of course, transfers health risk overseas. news reports have been plentiful of contamination in chinese exports of toothpaste, lead paint, milk products, and heparin. [40] [41] [42] [43] these safety concerns are not limited to exporters. china has also been a destination in the dumping of contaminated chemicals from richer to poorer countries; 44 these safety hazards are of equal concern to the chinese public. these concerns might be why china has upgraded its state food and drug administration (sfda) to the status of a ministry with larger budget, increased staff , and stronger regulatory powers. 45 environmental pollution also moves across national boundaries. air pollutants in china have been cited as causing acid rain damage to forests in korea and japan. 46, 47 china is today the world's largest emitter of carbon dioxide, contributing substantially to global climate change. 48 to tackle air pollution, china's state council released an action plan setting a 5-year road map for air pollution control. 49 its implementation deserves tracking for monitoring and evaluation of control eff ect. health governance sets ground rules for global stewardship of diverse activities. across the board, china has become an active member of the world system, opening with china's economic reform and accelerating after its entry into the wto in every aspect-eg, political (un), fi nancial (world bank, international monetary fund), economic (wto), and military (arm control and data underscore the participation of china in global governance. china's receipt of net offi cial development assistance and offi cial aid peaked at about $1800 million in 2005, had steadily decreased to a third of that amount by 2010, and is already disappearing as china increasingly becomes an aid donor rather than an aid recipient. 50 from 1998 to 1999, china's receipt and contribution to who were equal at about $5 million. by 2012-13, china's assessed contribution to who had increased to $30 million, while who funding to china had remained at baseline. 51 in parallel with this increase in funding, the number of chinese staff members in who has expanded. whereas in 1999, there were only 12 chinese offi cials working in who, that number had tripled to 34 by 2012, although chinese staff in who are still under-represented. 52 additionally, based on the newly released white paper, china allocated $280 million to support the global fund and other international organisations in 2010-12. 8 global health participation by china has been mainly governmental. in non-governmental stakeholders, growth in the international participation of some academic universities, business, and industry has occurred. china has very few non-governmental organisations (ngos) and thus the chinese are mostly absent from global civil society forums. a few international ngos work in china, but few have achieved offi cial registration from the chinese government. it will take substantial time, if ever, before china's civil society becomes active in global health. knowledge is both local and global, and its production, ownership, exchange, and application have global dimensions. china has much to share with and much to learn from the rest of the world. in medicine, strategy, and implementation, china has had some spectacular accomplishments, worthy contributions to the world's knowledge pool. chinese traditional medicine off ers many health-enhancing technologies-ranging from ephedrine to acu puncture. [53] [54] [55] in the 1930s, village health workers were fi eld tested, and later re-engineered as the barefoot doctor. 11 china's three-tier rural health system was established soon after the founding of the people's republic. 56 the alma ata movement for primary health care took great encouragement from china in showing what barefoot doctors could do at the community level. the three decades after the founding of the people's republic in 1949 witnessed some of the steepest advances of mortality control in human history. 57 china's management of common infectious diseases, maternal-child health, tropical disease control, malaria and schistosomiasis containment, mass social hygiene campaigns, and recent achievement of near-universal health coverage are worthy of documentation as valuable lessons. 29 physicians, two nurses, two chefs, two translators, and one medical engineer from shaanxi province constituted china's 30th medical team to sudan in 2007-09. the 15th chinese team from hebei province to the democratic republic of the congo arrived in 2012, consisting of a team leader, 13 physicians (including one in chinese traditional medicine), two nurses, one french translator, and one chef. for both teams, their primary role was to provide clinical care to patients. an ancillary function was to mentor, train, and improve the skill of local health workers. medical teams were self-suffi cient, bringing all their own supplies, equipment, and medicines. in response to questionnaires, team members commented positively on their experiences. higher salaries, fi nancial subsidies, and allowances from both central government and employers (about a six-fold increase) operated as important incentives. reported constraints included language barriers, unaccustomed disease profi les, poor facilities and equipment, unstable water and electricity supply, and homesickness. if the opportunity were off ered, nearly all would be willing to serve again. 25, 26 panel 2: traditional chinese medicine to eradicate malaria? malaria eradication in some countries had been successful with dichlorodiphenyltrichloroethane, and hopes have focused on new vaccines. but a professor of chinese traditional medicine from guangzhou university of chinese medicine is leading an unprecedented eff ort to eradicate malaria on the comoros islands with traditional chinese medicine. starting in 2007 on moheli island where 23% of the 36 000 residents were carriers of plasmodium falciparum, disease prevalence has dropped to 0·3% in 4 months with mass administration of artemisinin and piperaquine, donated by china's ministry of commerce. 5 years later, the chinese team extended this programme to anjouan, an island of 350 000, reducing the prevalence of p falciparum carriers from 19% to 0·5%. last year, the eff orts were expanded to the 420 000 residents of grande comore, the country's largest island. the project goal is malaria eradication in the 900 000 people of the comoros by 2016. 27 panel 3 describes an innovative grant by uk government's department for international develop ment (dfid) to foster research by, and capacity building for chinese universities and other institutions to disseminate and share chinese lessons with other countries. for the future, china aspires to be a worldwide knowledge leader and it has fast growing research and development investments in biomedicine. chakma 60 reported china's biomedical research and development at $8·4 billion in 2012, in comparison with usa ($119 billion), europe ($82 billion), and japan ($37 billion). the absolute size of these fi gures might undervalue chinese investments because the lower salaries, cost of infrastructure, and cost of operations in china might not be captured fully by purchasing power parity-adjusted values. strikingly, china's investments since 2007 have increased annually at 33% in comparison, for example, to −2% for the usa. 60 china, moreover, houses laboratories for most of the major pharmaceutical companies. it has advanced genetic research capacity as shown by its genetic sequencing of the h7n9 virus within 7 days of isolation and identifi cation. 34 china is also a growing producer and exporter of generic products. china aspires to be a powerhouse in the discovery and production of new drugs and vaccines in global health. china's medical universities are increasingly undertaking research and education in global health. in the past year, several new multidisciplinary centres of china supports government offi cials, technical professionals, and young people from developing countries to participate in training and education programmes in china. in 2010-12, the government provided 76 845 scholarships for such programmes, of which many were health related. 8 china's medical universities also train foreign medical students. according to the data from the china education yearbook, in 1999-2011, china trained 240 123 foreign medical students, who constitute 13% of all foreign students in 2011. for that year, the ministry of education reported almost 27 000 foreign medical students studying modern medicine and 12 000 studying traditional chinese medicine. 64, 65 by 2013, china had extended authorisation to 52 medical schools to admit foreign students who will study medicine in english. 66 figure 5 shows the rapid increase of foreign medical students and scholarships in china in 2002-11. although foreign interest in traditional medicine is high, most foreign students register for modern medicine. about 10% of the foreign medical students receive chinese government scholarships that might be regarded as part of china's foreign health aid. chinese medical schools charge foreign students higher than chinese tuition fees, 67 and the schools acknowledge foreign students as a source of school revenue. in 2011, many of the students came from neighbouring asian countries, such as india, japan, pakistan, south korea, and southeast asia. our most salient fi nding is china's distinctive mode of engagement in global health. china's health aid volume is small, but the mode is distinctive, driven by china's health capabilities and national experiences. unlike many other traditional donors, china's in-kind aid focuses more on some important aspects of the health system. china's overall global engagement follows a very diff erent path from developed countries partly because it has no colonial experience nor did it participate in shaping the american-led post-world war 2 world order. china was inward-looking until it expanded into the global economy in 1978. over the ensuing three decades, china has had large shifts from a low-income to a middle-income country, and from aid recipient increasingly to aid donor. the spread of its foreign aid throughout the breadth of africa presumably refl ects both eff orts to solidify friendship politically, promote mutually benefi cial economic gains, and compete with taiwan for political friendship. 68 china's health aid is embedded in the dynamic shifting of foreign and economic policies. the opening in 1978 marked a shift from economic development serving foreign policy to foreign policy serving economic development because china's association, for example, with africa, has developed from a political one in the 1970s to a broader economic-based and trade-based engagement. 69, 70 these are all defi ning characteristics of china's engagement in global health. china's global health work, unfortunately, does not seem to rank highly in government agencies. health has been assigned a lower position than political and commercial aff airs. taking advantage of both domestic and international resources and accessing both domestic and international markets is china's explicit national development strategy. 71 these powerful economic motives drive much of china's global engagement, including its engagement in africa, to the point where the dividing line between trade and aid become blurred and hard to demarcate. 70 health aid is only a very small adjunct to these much larger and more powerful forces. china's overseas forces include several government agencies. as a result, improved interministerial coordination is a necessary development for the evolution of a coherent overall engagement in global health. formulation of a china global health strategy could help bring coherent policy and harmonised action, because it would compel the articulation of specifi c health and humanitarian objectives in chinese governmental policies. an explicit china global health strategy would provide a stronger context for ngos and private sector overseas participation. china's bilateral approach diff ers substantially from its multilateral approach. although china's bilateralism takes an independent approach, china's multilateral strategy is full participation, joining as a regular member and complying with its responsibilities and privileges in un bodies such as who. the records show that china respects and complies with rules governing multilateral institutions in all aff airs-health, trade, migration, environment, and other aspects of global governance. china has increased its contribution to multilateral funding pools, such as the global fund from $2 million per year in 2003, to $5 million per year in 2012. how important china will become as a major donor to these pooled funds is uncertain. some see the early actions as symbolic gestures of cofunding, whereas others hope that the size of the chinese economy will propel it to become a fi nancial leader of multilateral funds. the new development bank being established by brics countries aims to compete with the world bank and international monetary fund, which is one example of how china has debatably played a leadership role. 72 most important is the avoidance of over-simplifi cation. no country's international engagement is free from political or economic motives-eg, europe colonialism, us millennium development accounts, or sweden-vietnam partnership during the american war. 73 and no single modality of foreign aid has proven to be more eff ective or more sustainable. 74,75 although china's health aid is generally appreciated by recipient offi cial statements, there are indeed complaints about the scale of china's intrusion, access to natural resources, and the trade market in africa. but energy resource-based trade structure with africa does not occur only in china; it occurs with all major african trading partners. the most fundamental improvement is to increase the capacity for independent development, to which all partners in africa should contribute. china's global health engagement is diffi cult to attribute to one motivation factor. chinese driving forces are undoubtedly several and complex-political, economic, social, and humanitarian. china's approach has been characterised as pragmatic that "combines the utilitarian logic of reaping material benefi t, the realist objective of expanding its global power and infl uence, the neo-liberalist interest in pursuing absolute gains from international cooperation, and the constructivist attempt to become a responsible stakeholder in the system". 76 china's global health engagement will probably grow substantially with expanding budgets, more projects, and more staff sent abroad. china will pursue its own distinctive approach, not copying the developed world model; chinese government policy and indigenous professional capacity will be key. the fi rst generation of chinese professionals with experience and foreign language fl uency is emerging along with stronger global health institutions. given this trajectory, one should assume global health will likely be re-shaped by china's participation, with its structures and processes increasingly accommodating chinese characteristics. pl led and coordinated the authors' group. all authors participated in study design, data collection, analysis, interpretation, and paper writing and editing. lc and zl produced the fi rst draft. we declare no competing interests. emory global health institute. case study: can global sanitation 2020 contribute to china's prosperity? atlanta, e-mory global health institute china's global hunt for energy council on foreign relations 6 will china change international development as we know it? china's foreign aid activities in africa, latin america, and southeast asia china's development fi nance to africa: a media-based approach to data collection information offi ce of the state council white paper on china's foreign aid, the people's republic of china passage to china the great manchurian plague of 1910-1911: the geopolitics of an epidemic disease the barefoot doctors of the people's republic of china artemisinin (qinghaosu): a new type of antimalarial drug making sense of global health governance: a policy perspective towards a common defi nition of global health health professionals for a new century global health governance at a crossroads chinese medical cooperation in africa aid within the wider china-africa partnership: a view from the beijing summit the fi fth ministerial conference of the forum on china-africa cooperation beijing action plan china's engagement with global health diplomacy: was sars a watershed? shifting paradigm: how the brics are reshaping global health and development chinese development aid in africa: what, where, why, and how much? china to strengthen cooperation with africa on health key players in global health: how brazil, russia, india, china, and south africa are infl uencing the game characteristics of china-africa health collaboration: the case of democratic republic of congo the experience of chinese physicians in the national health diplomacy programme deployed to sudan fighting malaria china engages global health governance: processes and dilemmas china information system for disease control and prevention (cisdcp) permanent mission of the people's republic of china to the un. statement by chinese permanent representative wang guangya at the 58th session of the un introducing a draft resolution entitled "enhancing capacity building in global public health who. international pledging conference on avian and human pandemic infl uenza china's health diplomacy: sharing experience and expertise infl uenza a virus subtype h7n9 joint mission on human infection with avian infl uenza a (h7n9) virus timeline: sars virus controlling the polio outbreak in china xinjiang remains polio-free china tightens quarantine for malaria, dengue china regions on alert for malaria, dengue fever elements of a sustainable trade strategy for china made in china melamine in milk products in china: examining the factors that led to deliberate use of the contaminant contaminated heparin seized by fda toxic exports: the transfer of hazardous wastes from rich to poor countries china upgrades drug safety agency-people's congress: move aims to raise quality of food and drug supply trend of acid rain and neutralization by yellow sand in east asia-a numerical study air pollution from china reaches japan, other parts of asia world carbon dioxide emissions data by country: china speeds ahead of the rest ministry of environmental protection, the people's republic of china. the state council issues action plan on prevention and control of air pollution introducing ten measures to improve air quality data: net offi cial development assistance and offi cial aid received (current us$) who. financial and auditing reports from world health assembly, from wha51 to wha66 who. human resources: annual report chinese materia medica: chemistry, pharmacology and applications chinese acupuncture and moxibustion asian medicine. the new face of traditional chinese medicine health service delivery in china: a literature review mortality in china global health support programme supports shared international development objectives uk global health support programme (ghsp) asia's ascent-global trends in biomedical r&d expenditures duke kunshan university, and the leading chinese universities launch new global health consortium liberal education meets chinese tradition china consortium of universities for global health established in beijing ministry of education of people's republic of china. china education yearbook . beijing: people's education press ministry of education of people's republic of china. brief statistics of international students in china new list of chinese medical institutions admitting international students for academic year ministry of education of people's republic of china. interim provisions to control the quality of foreign students' undergraduate education (english class) in china beyond borders: potential gaps in the international system of public health surveillance china: foreign policy serves domestic development china's priorities in africa: enhancing engagements collection of important documents since third plenary session emerging economics to launch development five metaphors about global-health policy development assistance for health: critiques and proposals for change the great escape: health, wealth, and the origins of inequality china and global health governance we thank haomin yang, yang li, and jing bai for their work on data collection, data analysis, and research assistance. key: cord-019040-lj1r8ptb authors: xiao, ren title: human security in practice: the chinese experience date: 2018-12-07 journal: human security norms in east asia doi: 10.1007/978-3-319-97247-3_3 sha: doc_id: 19040 cord_uid: lj1r8ptb this chapter elaborates on how the idea of human security is defined and understood by the government and various actors in china. as one of the permanent members of the united nations (un) security council, china, has been supportive of international norms advocated by the un, and even though the term human security has not been frequently used, in effect it has been vigorously practiced. for both the government and the academic community in china, human security and national security are not necessarily in confrontation but rather can complement and strengthen one another. the purpose is to improve the quality of people’s everyday life and the government is expected to contribute to this end. chinese people expect the government to extend a parental roof over the people. are perceived as pressing human security issues in china. the chapter concludes with a discussion of the overall human security practices and shows that, based on current indicators, china is heading in a healthy direction in terms of promoting human security. the understanding of human security in china in china, the government is often wary of new academic terms and tends to avoid using them directly. however, the findings from our previous study (ren and li 2013) clearly showed that the country is following a trajectory of increasingly attaching more importance to human (both individual and collective) security. much greater attention has been paid to mitigating threats to human security, and practical measures are being taken to fulfill the mandate. we emphasized the convergence of the human security idea and china's practices (ren and li 2013) . our findings disprove the following statement: "the very notion of 'human security' has so far not appeared in the chinese language in any possible translation, and the people's republic of china (prc) has not even accepted or adopted the concept of human security in either domestic development papers or foreign policy guidelines…" (wu 2013, 1) . our examination suggests otherwise. though the chinese government has only used the term "human security" on a few occasions, china is definitely engaged in the enterprise of enhancing human security. the fact that china is becoming more open and receptive to human security is strongly related to its experience within the un system. as one of the five permanent members of the un security council, china has long been supportive of the un, the most important international organization in today's world, and the country has played a proactive role in various un activities such as peacebuilding, development, and global governance (breslin and ren 2018) . over the years, the un has been subjected to criticisms and it is widely believed that reforms are needed, which china supports. nevertheless, beijing continues to show a belief that the un plays an irreplaceable role in global governance, and china has endeavored to support this by encouraging the un to play its role well (kim 1999) . this has remained an unchanged priority in china's foreign policy agenda. china's steady backing has boosted the status of the un in world affairs, at a time when the world is faced with growing global challenges in the first decades of the twenty-first century. meanwhile, the un has taken the lead in advocating and/or spreading norms and principles, and this has affected and helped to shape china's ideas (kent 2014) . usually, un initiatives or proposals attract china's attention, and prompt beijing to have a closer look at them before taking actions to adapt to the new norms or principles (morton 2009, 75-76) . for example, china was involved in the deliberations and adoption of the un world summit outcome document in 2005. although it is not the same thing as the "responsibility to protect" idea proposed by the international commission on intervention and state sovereignty (iciss 2001) , to some extent the outcome document is consistent with this idea in terms of thinking on protection. the outcome document attempts to strike a balance between the need to protect innocent people around the world from being harmed while avoiding the abuse of external intervention or selfish behavior in the name of protection. for this, the outcome document imposes limitations by listing four specific crimes against which the international community should act to prevent people's lives from being jeopardized: genocide, war crimes, ethnic cleansing, and crimes against humanity. in this way, the outcome document has become a new international legal document. china was involved in this process and made its own contribution. thus, involvement in global or regional institutions has pushed china to clarify or develop its own thinking on human security. against the backdrop of the great earthquake and tsunami that devastated japan's tohoku region, the ministerial millennium development goals follow-up meeting was held under the un framework in june 2011 in tokyo, japan. china sent vice foreign minister cui tiankai to attend the meeting. in the speech he delivered, cui, as the representative of the government of china, stated: to discuss the mdgs from the angle of human security offers a thoughtprovoking perspective. we believe that the mdgs and human security are interrelated and should be mutually reinforcing. the mdgs embody so many aspects of human security, while the realization of mdgs aims at greater wellbeing and security of more people in the first place. (t. cui 2011) cui pointed to the fact that the general picture of global security remains disturbing: "civilians in north africa and the middle east continue to bear the brunt of turmoil, and innocent women and children are still being displaced or killed in armed conflicts in various parts of the world." cui concluded that: these give rise to the call for a new concept on security and an international political order where the united nations should play a central role. we strongly believe that the purposes and principles of the un charter should be upheld, and security council resolutions should be implemented in a faithful manner. …in a word, if human security in the larger sense of the term is still so much threatened, there is little hope for better individual security. (t. cui 2011) this is an illuminating example of how china has clearly and definitively adopted and used both the idea of and the actual term "human security" in the context of a formal un meeting. although it was an event on mdgs and not specifically on human security, the term "human security" was explicitly employed to express china's opinion and position. this discourse was reinforced by further developments. in february 2014, ms. fu ying, chairperson of the national people's congress foreign affairs committee, was invited to and spoke at the munich security conference. she argued that the security necessary for people to survive and develop is fundamental to any security. the core of the chinese dream of the revival of the chinese nation proposed by president xi jinping is to have the 1.3 billion chinese people live a happy life. in other words, all ordinary people have the right and are entitled to live with dignity in a secure environment. this is the attraction of china's success story to the world, as well as the charm of the chinese dream. 1 this line of thinking has many elements in common with the widely shared "human security" idea. for instance, both place emphasis on individuals and their happiness, and this must be fulfilled together with national development. ends and means should be consistent, and the persistent value is that people themselves are the end and they should not be sacrificed for arbitrary national goals. the key point here is that china's security concept is undergoing a profound transformation. a new consensus has emerged that assumes security does not equal military security, and security should not only be comprehensive but also people-centered (yi renmin wei zhongxin): "national security" now has new connotations. during the landmark third plenum, which was held in november 2013, a major resolution to comprehensively deepen china's reform was deliberated and passed. the long reformist document has 16 parts and 60 items. the decision to create a new national security commission (nsc) was announced as a component of the 13th part on the new social governance system. the purpose of the nsc is to improve the relevant institutions and strategy to better safeguard china's national security. according to the explanatory speech president xi jinping gave, reform and development are conditional on national security and social stability, without which reform and development cannot be advanced further. 3 at present, china is faced with the dual pressure of safeguarding national sovereignty, security, and development interests externally, and maintaining political security and social stability internally (xi 2017, 411) . all kinds of risks that can or cannot be foreseen are clearly increasing, while the country's institutions and security mechanisms are insufficient to adequately meet the need of maintaining national security. this has resulted in demands to set up a powerful and capable platform to coordinate all work on national security. the responsibilities of the nsc include formulating and implementing national security strategies, advancing the construction of national security rule of law, deciding national security guidelines and policies, and studying and addressing major issues in the national security work. 4 quite understandably, this major decision drew considerable attention both at home and abroad. in april 2014, the first meeting of the new nsc was held. according to the speech president xi jinping delivered, the security of the people must be its core purpose. state security should in every sense serve the people and rely on the people. the mass foundation of state security must be laid and consolidated. 5 this means that state security and human security are not confrontational but rather that the two can and should coexist. internally, china is undergoing a modernization process and the number of contradictions is growing. in this time of rapid economic and social development, a series of social problems have been accumulating that have not been "digested" well. for some chinese observers, "group incidents" resulting from unbalanced distribution of interests frequently break out, negatively affecting social stability. externally, as china continues to grow, some powers and neighboring countries have been hedging against china, and as a result, contradictions or frictions in china's neighborhood have been increasing. moreover, challenges to social stability and security, from home and abroad, have been affecting each other, and they are interlinked. coping with them is becoming a more difficult job. in the current era, the concept of national security is becoming richer in depth and wider in breadth, involving a range of issues in a variety of areas. increasingly complex problems cannot be dealt separately by foreign affairs, national defense, and security departments but rather are demanding that more agencies, social organizations, and even the whole society work together (hu and wang 2013) . since the initiative to create china's nsc appears in the "social governance system" section of the november 2013 resolution, its domestic and internal security dimension is self-evident. in the meantime, the commission's work involves two dimensions (both external and internal) rather than just one. thus the "security" the initiative refers to is of a comprehensive nature. it is not difficult to come to that conclusion if we simply recall the july 5, 2009, incident in xinjiang, the riots in tibet and tibet-related self-immolations in its neighboring provinces, and the horrible killing at the kunming railway station on march 1, 2014. during all these incidents, innocent people were killed or injured, and some of the incidents resulted from the actions by hostile external forces. that is why it was widely believed that internal security would be the dominant concern for china's nsc, at least in its early stage. when ordinary people can be unexpectedly harmed by violent terrorist attacks in any situation and without warning, a sense of insecurity arises, and this can be frightening. thus, even though freedom from want is no longer a problem in today's china, ordinary people should also be able to live their lives free from fear. a broad concept of security of this kind logically became the goal for china's nsc. in fact, as cui shunji of zhejiang university points out, since the initiation of reform, at the highest levels, attention has been placed on poverty reduction, the pursuit of a sustainable development model, and china's proposals for constructing a "harmonious society" and a "harmonious world." these goals indicate that china regards the guaranteeing of basic human needs, social justice, and harmony as well as sustainable development as important parts of a continuum of national security (s. cui 2014, 68-69) . "letting people live a happier life with more dignity" has become the goal of national development, which indicates that china's recognition of human security has been elevated to the political level. putting people first and "governing for the people" have become the new thinking for governing the country. as a reflection of the foreign policy changes, handling foreign affairs for the state is shifting to handling foreign affairs for the people (s. cui 2014). this was reinforced at the 19th party congress, held in october 2017, which emphasized the need to regard people's interests as paramount and let the achievements of reform and development benefit everybody more and fairly. in china's research community, "human security" is often discussed in terms of the discourse on "non-traditional security." for years, chinese researchers have utilized the term "non-traditional security" to distinguish the so-called non-traditional matters from more traditional matters. traditional security usually refers to military security, namely, assuring national security through boosting military power. however, after the end of the cold war, threats to security have increasingly come from nonmilitary domains in the form of unconventional or non-traditional security threats. such issues include financial crises, terrorism, transnational crime, environmental degradation, the spread of hiv/aids, scarcity of water resources, food insecurity, and so forth. according to the summation by a leading chinese researcher, nontraditional security is broad-based, complex, and multi-dimensional. examining each in turn, while traditional security falls into military, political, and diplomatic areas, and its supreme value is the pursuit of peace and the elimination of war or the possibility of war, a broad-based non-traditional security is more about economic, social, cultural, and environmental threats as well as the emerging cyber security and space issues. in addition to peace, non-traditional security relates more to risk, crisis, emergency, and daily threats to life. it relates more to natural disasters, accidents, emerging public health incidents, and major public security events. second, non-traditional security is complex. threats to non-traditional security are mainly the threats to "societal security" and "human security." society and people are the chief referent objects of non-traditional security, and a "safe china" has societal and human dimensions. for individuals, safety means that the security of people is guaranteed: namely, individuals enjoy a state of existence in which a person's body is not injured, their mind is not harmed, they are not deprived of their property, and their living environment is not undermined. third, non-traditional security is multi-dimensional. according to the place and origin of non-traditional security events, threats to nontraditional security facing a country can be divided into four categories: (1) exogenous non-traditional security threats which take place abroad and chiefly require diplomatic negotiations; (2) endogenous nontraditional security threats which take place at home and chiefly require domestic interventions; (3) "bi-dogenous" (双源性) non-traditional security threats which take place in peripheral areas, necessitating both domestic and international management; and (4) "multi-dogenous" (多源性) non-traditional security threats that involve both traditional and nontraditional security issues requiring the involvement of the military in addition to other organizations (yu 2013, 3-6) . throughout the above process of ideational transition, a few landmark crises have affected china deeply, including the 1997 asian financial crisis that highlighted the importance of financial security, the 2003 sars crisis that highlighted public health security, and the march 1, 2014, terrorist attacks at the railway station in kunming, the capital of yunnan province. the horrible march 1 violence against innocent people especially highlighted the serious security threat that ordinary people could encounter in their daily lives. this genuine risk could give rise to a widespread sense of fear. as noted, earlier conceptions of security in china were mainly focused on state security, the importance of which remained unquestioned. now that human security has been put forward, and given its undeniable value orientation, support for the concept is gaining momentum. in fact, chinese scholars speak highly of human security and argue that it goes beyond the limits of state-centric traditional security research and is the least traditional theory among the non-traditional security domains (yu 2014, 18) . human security research explicitly sees people as a collectivity and individuals as the referent object of security. this transcends the dilemma of more traditional security theory, since the state can bring about insecurity to its citizens. such a possibility raises questions concerning the relationship between state security and human security. in general, chinese researchers do not endorse the view that human security overrides state security or that the two are confrontational, but rather affirm the reasonableness and value of state security at the same time. for example, shi bin, a professor at nanjing university, asserts that the human security idea is a focal embodiment of non-traditional security and new security concepts, and yet the relationship between human security and state security is much more complicated (shi 2014, 97-100) . shi argues that both state security and human security, in terms of their security concerns and value pursuits, have legitimate claims. however, there is no reason for either of them to become totally dominant. human security is of course the fundamental goal and ultimate value of human development. the value orientation of putting people first, with human security at the center, provides it with the moral high ground and legitimacy. however, a person has both individuality and sociality, and individuals are often weak and helpless. resisting foreign military invasion and safeguarding national sovereignty and territorial integrity are therefore in the nation's common interest. nonetheless, the traditional state-centric security idea and strategy indeed ignores the security needs of many non-state or sub-national entities and cannot adequately deal with external nonmilitary threats such as environmental degradation and pandemic disease. second, shi bin articulates that, although there is a tension between "human security" and "state security" and the two may conflict in practice, they can still be mutually accommodating and complementary if handled and balanced well. therefore, this can provide a favorable opportunity for upgrading the overall security level of all entities. people's security and welfare, and the improvement of their living conditions and quality of life, are an important base for national identity, social stability, and political legitimacy. in this sense, human security and state security are not necessarily contradictory. for shi, the human security discourse has a tangible western value orientation bearing liberal colors; consequently, in practice, it tends to override the security interests of the sovereign state. the acclaimed paradigm shift from the state to individuals excessively downgrades the positive role of the state in dealing with various security challenges. for zhang yunling of the chinese academy of social sciences, the rise of non-traditional security issues does not mean that traditional security is no longer important. the appearance of non-traditional security on the agenda and the fact that it is stressed imply that it has been included in the category of security, and therefore the formation of a "comprehensive security" concept includes both traditional and non-traditional security as well as the corresponding security policies (y. zhang 2012) . taken together, with "non-traditional security" increasingly becoming part of the mainstream discourse in china, researchers tend not to deny the value of state security but rather see human and state security as being mutually accommodating. nevertheless, the theoretical shortcomings of non-traditional security, as guoguang wu rightly points out, are obvious, when it is narrowly framed as oppositional to traditional security, without any positive and substantive defining of the contents and nature of new "securities" (wu 2013, 5) . the relationship between state security and personal security is not a zero-sum one though. more state security does not mean less personal security, and vice versa. the goal should be a calibrated balance between the two. moreover, the increasing tendency to securitize many issues and aspects of life may not be entirely beneficial. an overemphasis on discussions of security may imply a growth of insecurity. for example, in china food safety was previously not discussed often but was later widely talked about. this indicated that food safety was not formerly an issue, but it became such an issue. the deterioration of food safety was a negative development that involved the need for moral reconstruction in the society. as shown above, the chinese research community has attached increasing importance to the issue of human security. meanwhile, they are not just following in others' footsteps, but rather have developed their own analyses and views. some researchers have stressed that individuals are both the starting point and the ultimate purpose of any society. the emancipation of human beings should be the fundamental goal of any social emancipation. it is people who are the final objective of the concept of human security, and this is the core value any security is supposed to protect, while the state provides the means or temporary purpose (j. li 2013, 74-75) . the establishment of "people are the purpose" as a value grew to have great significance for chinese society after the community had drawn lessons from the history of the people's republic since 1949. during the cultural revolution period, many innocent people were attacked, detained, or persecuted illegally and immorally; rights were ignored, and people were harmed. after a disastrous decade, many people reflected on their painful experiences and thought about the phenomenon of imposing horrible acts on innocent individuals, something that should never recur. in the early reform period, there emerged a movement in china's intellectual community that began to discuss the issues of humanism (rendao zhuyi) and alienation (yihua). during this time, many intellectuals affirmed the significance of humanism and argued for the promotion of human values. some of them cautiously adopted the term "marxist humanism" or "socialist humanism" to distinguish from the so-called capitalist doctrine. not long after, the debate abruptly came to a halt due to a political intervention. however, along with further economic reform and considerable social development, the awareness of the value of the individual human being in china was reawakened and the value of people confirmed. the initiative for humanism in the 1980s was in fact later accepted by the whole of chinese society. this was also reflected in the discussions and research on human security, since it was made clear that guaranteeing human security is the value base for maintaining non-traditional security. the protection of people and human development should be set as the ultimate goals of any security course. obviously, this progress is precious for chinese society and deserves appreciation by the outside world. the paradigm of human security opposes the harming of the human freedoms and rights to promote economic growth or social stability. nor does it favor the pursuit of economic benefits and communitarian policies at the expense of sacrificing the security and dignity of the individuals or the nation. the fundamental reason for this lies in enhancing the value of people, which is the key and ultimate goal, and there is no higher goal than this. the previous practices of both "collective security" and "common security," yu xiaofeng, a leading scholar in human security, argues, could not have avoided the limitations of regarding the state as the chief actor (yu 2014, 33) . by contrast, "shared security," which he has proposed, regards the human community as occupying the central position of security, the protection of human life as the value base of security, social safety and prosperity as the priority goals of security, and harmony and cooperation as the supreme principles for security interactions between the states (yu 2014, 33-34) . this moves the discussion beyond the traditional security discourses and has the potential for further theoretical development. according to the human security now report (chs 2003) and the october 2012 resolution adopted by the un general assembly as a follow-up to paragraph 143 on human security of the 2005 world summit outcome, as well as the definition and design of this book, human security has two dimensions: protection and empowerment. in china, the dimension of protection has drawn much attention, epitomized in the doctrines of "putting people first" (yiren weiben) and "diplomacy serving the people" (waijiao weimin), which i discussed in a detailed way in an earlier study (ren and li 2013) . the findings from this earlier study have been reinforced by recent evidence. for example, a chinese newspaper correspondent wrote of his impressions when reporting from the national people's congress (npc) sessions. he was deeply impressed by the attention the npc delegates paid to the concrete issues concerning people's daily lives, including social insurance, income distribution, rights of peasant workers, food safety, unreasonably high drug prices, and protection of stakeholder interests. in his view, those kinds of issues had never before been so meticulously discussed at the npc (yuan 2005) . the changes the correspondent detected indicate ongoing healthy trends in human security terms. a harmonious society is one that puts people first, which means people's everyday life is a priority for the society. a government that puts people first is a government that represents people's interests. economic and social development should put human development at the center, and human development is the ultimate value judgment for social progress (yuan 2005) . meanwhile, the achievement of human security is a cooperative venture between the individual, society, and the state (bedeski 2013, 29) . government as a "necessary evil" is very much a western invention and is not a chinese idea. traditionally, people in china often have wishes for their government, and they want it to do good things for them. compared to western political culture, they have less vigilance but higher expectations of the government. one revealing example is the use of the term "parent officials" (fumu guan) to refer to government officials, with people expecting them to play a paternalistic role. without cooperative ventures, human security cannot be achieved. on the protection side, while people-oriented ideals might be considered noble ones, challenges come from the process of implementation. not surprisingly, many problems are persistent. one prominent example is the matter of government land appropriation and relocation of residents. sometimes the failure to protect the rights and interests of the ordinary people has led to acute standoffs and conflicts, and in some cases even extreme acts of protest. when property development businessmen and arbitrary power coalesce, together they can undermine the interests of the ordinary people who are affected. protecting people's legitimate interests has become an outstanding issue in china's human security amid the drastic social changes and urbanization of recent decades. moreover, the chinese leadership came into office with a promise to narrow the widening gap between rich and poor, and to shift to a more environmentally and economically sustainable growth model. since gross domestic product (gdp) became the brand of accomplishment for many government officials, "gdp worship" has prevailed. local officials tended to initiate projects that show their "achievements" and promote their image to the public. when poorly planned, such projects led to unexpected outcomes and environmental damage. when this became obvious, a strategic shift had to be undertaken. "no gdp growth at the expense of the environment" is becoming a new norm and "ecological civilization" the new banner, which was again stressed in the 19th party congress report of october 2017. the reform era has been characterized by remarkable success in terms of rapid economic growth and the improvement of living standards. after three decades of successful economic development, the country is standing at a new starting point. if the ruling party's historical promise to "let some people get rich first and eventually arrive at common prosperity" was a prerequisite for the reforms to unfold, and if four decades later this historical task has been basically fulfilled, what the reform enterprise must accomplish now is the other half: namely, to realize a common prosperity. this is a goal that will justify and inform further reforms. the reaffirmation of realizing common prosperity in line with the principles of governing for the people and building a comprehensive and balanced well-off society will guide future reform with a clear direction. 6 to fulfill its pledge to narrow the gap between rich and poor and to "unwaveringly pursue common prosperity," the leaders have to place the people in their hearts and take their needs seriously in order to realize the goal of the "chinese dream." after the 18th party congress in 2012, the new general secretary xi jinping expressed his view that "to fulfill the people's desire for better lives is what we shall strive for." 7 this statement sounded dear and close to the ordinary chinese people. on the empowerment side, there have also been several measures. only when a person has the capability for survival and development can he or she enjoy real freedom. the capacity for development is what empowers an individual. thus, a modernized china should not only accept empowerment through protection but also appreciate its importance in realizing human freedom and guaranteeing human security. education as a right is the fundamental and most significant form of empowerment, as the human experience has repeatedly revealed. thus, educational development is a significant way to empower people, especially compulsory education. china has reason to be proud in this regard. it has a tradition that puts significant emphasis on education, in which parents always try their best to pave the way for their children to receive a good education, and often they are willing to make sacrifices. in china, nine-year compulsory education has been in force for years. in 1989, project hope was set up as an educational support supplement, which later became well known throughout chinese society. it was initiated by the central youth league and the china juvenile development foundation as a philanthropic enterprise to help less developed areas to establish primary schools, to financially support children who have dropped out of school in the poorer regions to return to school, and to improve education in rural areas. the project received society-wide attention and support. implemented successfully, the project has positively changed the fate of hundreds of thousands of children of poor families and has also beefed up the whole society's awareness of the importance of education, thereby improving china's fundamental education. as a major initiative for the future, the third plenum set the aim of modernizing china's governance system and governing capability, a longterm goal for china. an important part of it is to reshape a new social governance system. during the 2014 national people's congress session, president xi joined the shanghai delegation for a deliberation of the government's work. for him, the key to future social governance is institutional innovation, and its core lies in people. only when people are living harmoniously can society be operating in a stable and orderly manner. for han zheng, the party secretary of shanghai, social governance was up to everybody, and the governing process should serve the all-round development of people. rule of law is the foundation of social governance, without which there can be no base for long-standing good governance and robust stability. 8 for that matter, among other things, it is necessary for grass-root cadres to regard people's concerns as their own matters, while always trying to understand their feelings and demands. again, the key challenge is to make this happen in real life. fortunately, in china there have been local autonomous grassroots organizations that play an intermediate role and serve to help in addressing problems at the grassroots level. they assist ordinary people who encounter difficulty, and they also, for example, mobilize donations to help people in the regions that have been struck by earthquakes or other natural disasters. the work of these local self-help organizations has proved to be useful and reassuring in terms of social governance. since 'human security' is central to non-traditional security, it is concerned with all kinds of factors that directly threaten human security" (zhou 2012, 255-256) . in today's china, prominent direct threats include air pollution, food safety, and cyber security. this section examines each of these in turn. the seriousness of the problem of air pollution first became apparent right all across china in 2013. heavy smog emerged not only in north and northeast china but also was reported in other regions. many people were alarmed by the situation, including concerns expressed by china's neighbors, japan and south korea. the spread of the smog made it obvious that the environment in which people were living was deteriorating, a red-light signal providing a warning on the existing pattern of economic growth, which was consuming a great amount of energy and yielding considerable waste. while many people were already aware of the issue, the shocking reality of the situation in 2013 and its related risks served to awaken people as never before. with many people walking in the streets wearing masks, the sense of insecurity was palpable and imminent. in this context, the specific threat of air pollution became the number one threat to people's security. to cope with this threat, in june 2013, china's state council laid out ten measures to prevent and combat air pollution. as a follow-up, in september, china released an action plan to implement this, which was a blueprint to fight against air pollution by 2017. since then, further work has been undertaken. in his government work report delivered in march 2014, premier li keqiang swore to "fight pollution like fighting poverty." when he was looking around the city of beijing, president xi emphasized that the sprawling pattern of urban development had to be contained and steps should be taken to deal with smog pollution and improve air quality. among the five requests xi made, one was logically to reinforce the measures to rein in air pollution. the top priority to combat air pollution and improve air quality was to control pm2.5, with major steps that included reducing the burning of coal, strictly limiting growth in the number of cars, adjusting industries, tightening management, and executing joint prevention and control. 9 xi's move clearly sent a signal that the government was committed to taking measures for better air quality. the chinese leadership had previously pledged to launch a revolution in energy production and consumption and said that urbanization must be balanced with ecological security (hook 2012, 1) . however, pollution was worsening and was posing a serious threat to human health and social stability. to reduce air pollution and carbon emissions, beijing (population 20 million) is attempting to phase out coal-fired power plants within the city's urban core, replacing them with cleaner-burning natural gas power plants. these measures are also basically valid for other cities. after all, fighting pollution is relevant to everybody's security, a point that has attracted a high-degree of consensus within chinese society. similarly, china's energy sector had a watershed year in 2013. reforms that could have a profound impact on china's environment and energy policy were floated. with concerns over air pollution mounting throughout the year, the country is poised to shift away from its reliance on coal and toward use of cleaner forms of energy, including natural gas. shale gas exploration is making progress in the country. driven by crises, a true transformation is under way but surely will take time to complete. the second human security concern among the chinese people is that of food safety. in recent years, a series of food contamination incidents occurred throughout the country, causing serious concern. a 2010 poll by xiaokang (小康 [moderately well off]) magazine and tsinghua university conducted in 12 chinese cities found that food safety ranked number one of all social concerns among those surveyed, reflecting mounting anxiety after the 2008 melamine crisis (z. zhang 2010; wishnick 2013, 256) . within this context of growing concern over food safety, the government has not been unaware or insensitive. appearing at a press conference, premier li keqiang responded by stressing that "food safety is of utmost importance." 10 answering a different question concerning the missing mh370 aircraft, he stressed that "any case involving human life has to be treated with the utmost care" (renming guantian). as with the issue of air pollution, the 2014 government work report promised to adopt the strictest surveillance, the most severe punishment, and the most serious accountability measures to resolutely govern pollution at the meal table and reassure people of "security on the tongue tip" (k. li 2014). in fact, there is a widely shared consensus in china on the need to make efforts to ensure food safety. specialists distinguish between two separate food-related issues: the first is related to food security or ensuring sufficiency in the quantity of food; the other concerns food safety, which refers to the quality of food. while the former involves the question of whether there is sufficient overall provision of food, an area in which china has vowed to "hold the bowl firmly in our own hands," the latter involves the question of whether people can be assured that the food they eat every day is safe. formerly, the issue of food scarcity trumped food safety. but today the main problem in china lies in food safety, with people alarmed by reports of different kinds of contamination. in recent years, this has even spilled over into china's foreign relations, and was epitomized in the spoiled jiaozi (dumpling) incident between china and japan. the incident originated in hebei province. an employee in the tianyang food factory was resentful over his low income. in revenge, he deliberately poisoned jiaozi, and the contaminated products were exported and sold in japan. some customers bought and ate them, becoming ill. on investigation, pesticides found in the frozen dumplings were traced back to china. this was a single case of a crime that resulted in grave consequences. the reputation of china's food products was seriously damaged, and the sino-japanese relationship was also somewhat affected. this incident once again highlighted the close links between domestic and international affairs. in the final analysis, the root cause lies with individuals, and the issue of "moral collapse" has been used to refer to this situation. to what extent this is true can be debated. there was a belief that overuse of fertilizers and pesticides was rampant, and that growers distinguish between what they themselves eat and what is sold in the market, even if they know the latter is not suitable to be eaten. again, how widespread the phenomenon is can be discussed, yet reports on these kinds of practices result in people feeling that the food they eat may be unsafe. as a result, in china there was an obvious lack of public trust in food safety. tighter regulations must be implemented. greater transparency helps to build public trust, including more official data and statistics about the improvement (or deterioration) in food safety, increased freedom for media and civil society to verify the official data, more effective actions from the government in handling the corruption and malfeasance involved in food safety issues, stronger protection for whistle blowers who uncover production of unsafe food and, more importantly, removal of the corrupt officials involved. further measures must be taken to improve china's food safety regulations, consumer education levels, and supply chain traceability and sustainability. the third and final issue is that of cyber security. the use of the internet has increasingly become a part of everyday life in china. by 2013, there were over 600 million internet users in the country, and mobile internet users reached 461 million, making the community of chinese "netizens" (wang min) the world's largest. with this growth, cyber security has become a prominent issue. in fact, china is one of the major victims of cyber-attacks. the covert activities revealed by edward snowden highlighted the vulnerability of nations and individuals who are monitored illegally and immorally (meng 2014) . at the government level, a central small leading group on cyber security was created, which held its first meeting in february 2014. it was emphasized that cyber security involved national security and development, as well as the careers and everyday lives of a vast number of ordinary people. it was therefore a major strategic issue. 11 the breakdown and vulnerability of the internet can have a widespread impact on people and their lives. this chapter has addressed the three research questions the research project raised by elaborating on how the idea of human security is understood or defined by the government and social actors, the ways in which the distinctions between the "protection" and "empowerment" aspects of human security are understood and accepted, and what downside risks are perceived as pressing human security issues in china. the major ones discussed here included air pollution, food security, and cyber security. as has been indicated in this chapter, although human security as a term is not frequently used, there have been various human security practices in china. the idea of human security has been firmly established and threats to human security have been detected. such problems result from china's still unfinished process of industrialization, urbanization, and drastic social change. the good news is that progress is being made, and theoretically, globally accepted values often exist at the individual level. with this comes occupancy of the moral high ground. china has gone far beyond the lip service level of cheaply talking about people's interests. this deeper approach can be fully integrated into human security in its holistic sense. threats to human security can be domestic risks, yet they often are transnational ones such as air pollution and sand storms. they require different sectors of the society and neighboring countries to work together. over 20 years ago, the commission on global governance drafted a report that emphasized the distinction between the security of states and the security of peoples (cgg 1995) . twenty plus years later, the security of peoples has gained momentum. this is also true in china, the most populous country in the world. china's practices have considerably reinforced the overall trends of affirming the value of people, protecting their lives, ensuring their legitimate interests and dignity, and empowering them not only to survive but also to live a respectful life. what is happening in china is indicating a healthy trend in this direction. each year the communist party of china central committee holds an annual plenum to deliberate what it believes to be the most important issues for the full text of the resolution and xi's explanation, see renmin ribao ershiyi shiji jingji baodao xi's remarks at the closing of the 18th party congress li's remarks at the 2013 national people's congress press conference anthropocentric theory of human security china and global governance our global neighborhood: the report of the commission on global governance chs (commission on human security). 2003. human security now. new york: commission on human security from commitment to concerted action. remarks by vice foreign minister cui tiankai of china at the ministerial follow-up meeting ren de fazhan yu ren de zunyan: zaisi ren de anquan gainian battle to balance urbanization with ecological sustainability ruhe kandai sheli guojia anquan weiyuanhui iciss (international commission on intervention and state sovereignty). 2001. the responsibility to protect. ottawa: the international development research centre china's participation in international organizations china and the united nations ren de anquan: fei chuantong anquan nengli jianshe de xinshijiao zhongguo fei chuantong anquan nengli jianshe zhengfu gongzuo baogao wangluo anquan: guojiazhanlue yu guoji zhili [cyber security: national strategy and international governance). dangdai shijie china and the global environment: learning from the past, anticipating the future. sydney: lowy institute for international policy a return to people: china's approach to human security ren de anquan' yu guojia anquan resolution 66/290. follow-up to paragraph 143 on human security of the 2005 world summit outcome food security and food safety in china's foreign policy human security challenges with china the governance of china ii fei chuantong anquan zhili yu 'hemei zhongguo' [nontraditional security governance and a 'safe china beijing: shehui kexue wenxian chubanshe ren' de daxie food security tops people's concern in survey. china daily preface zhongguo shipin anquan wenti yu qushi report on china's non-traditional security studies key: cord-034118-zwlugvlk authors: whitten, gregory; dai, xiaoyi; fan, simon; pang, yu title: do political relations affect international trade? evidence from china’s twelve trading partners date: 2020-10-22 journal: j doi: 10.1186/s41072-020-00076-w sha: doc_id: 34118 cord_uid: zwlugvlk china’s growing influence on the world has generated profound effects on the political and economic decisions of her partner nations. recent conflict escalation between china and western countries gives rise to widespread concern over the possibility of delinking china from global trade and supply chain. by drawing on utility theory, we suggest that the political relationship is a key determinant of collective emotions of consumers and trading companies and consequently the interactions between importers and exporters. we hypothesize that warmer relations lead to larger increases (or smaller decreases) in trade while cooler relations have the opposite effect. based on monthly data of china and her twelve trading partners from 1981 to 2019, our study provides an empirical investigation into the association between political relationship and bilateral trade flows. our results show that shocks to relations are highly persistent and frequently cause changes in trade. however, relations themselves are little influenced by changes in trade, changes that show little persistence. we also address the us-china trade war and the observation that innovations to china’s exports to the us improve china’s relations with the us while shocks to american exports to china worsen relations from china’s perspective. globalization and economic integration is a salient feature of the modern world. in particular, the increasing division of labor and fragmentation of supply chains have led to the globalization of production and shipping of many commodities and services, which has enhanced international economic cooperation. greater trade flows provide supportive evidence of this cooperation (see krugman, obstfeld, and melitz 2014) . against this trend of globalization, however, international politics is not necessarily becoming more cooperative, an idea that had been promoted in the popular press and academia (friedman 2000 , mandelbaum 2003 , witt 2019 . political tensions may considerably hinder all aspects of economic integration such as trade, investment, supply chain, and transport logistics. china presents herself as an interesting case for considering the link between international conflict and international trade. since 1949, china has experienced relations both excellent and tense with other countries, often switching quickly. while worsening relations have led to severe armed conflicts in certain cases (e.g., the sino-indian war of the 1960s, the sino-vietnamese war of the 1970s), most cases of tense international relations between china and other countries have not led to explicit military aggression. over the past four decades, china has substantially increased its exports and imports of manufactures and services and has emerged in the global marketplace with greater economic significance and more prominent political influence (lukin 2019) . meanwhile, china has often been the target of criticism in some western media for not strictly following international norms. these criticisms tend to generate a heated reply from the chinese mainstream media. one may wonder if outright military aggression or a general worsening of diplomatic relations hinders international trade. investigating the links between china's political and economic influences emerges as a reasonable line of inquiry. this paper is motivated by the recent association of falling trade and political conflicts between the us and china. in the context of escalating tensions over aggressive rhetoric concerning the south china sea and accusations of espionage and intellectual property theft, the trump administration released the new national security strategy in 2017, which described china as a revisionist power aiming to "shape a world antithetical to (the us) interests and values." 1 poor diplomatic relations have emerged in tandem with greater calls to limit trade activities (cheng, whitten, and hua 2020) . the covid-19 pandemic outbreak in 2020 seems to have pushed bilateral relations to the breaking point. many american companies are shifting their supply chains to other asian countries, and china's exports to the us are decreasing sharply (bown 2019). both the general public and political leaders have expressed their fears of decoupling of sino-us economic ties given their increasing deterioration of political relations: 2 nowadays, it is common to hear arguments warning of a split of the global economy into mutually exclusive american and chinese spheres of influence... [i]f indeed we arrive at a fully 'decoupled world' , it would herald the return of an 'iron curtain' between the east and the west, and "the beginning of a new conventional and nuclear arms race with all its attendant strategic instability and risk. " motivated by these anecdotal observations, this paper aims to conduct an empirical study addressing how does china's political relation with a foreign country affect their bilateral trade. although the above discussion emphasizes the causality of politics on trade, recent history shows the potential for causality to go the other way. trade has historically served as a lighting rod of political disputes (hiscox 2002) . it is expected that closer economic integration helps to reduce international conflicts. for instance, china's relations with the west soured after the 1989 tiananmen square incident, prompting a fall in international trade and investment (brantstetter and lardy 2008) . then-candidate bill clinton promised to exclude china from the to-be-formed world trade organization (wto) owing to displeasure with china's human rights record. unexpectedly, president clinton changed his mind, believing that greater trade could improve sino-us relations as well as chinese relations with the world generally (martin and roberts 2017) . this paper adds to empirical studies on the interactions between international political relations and trade. due to scarcity of data on political relations, the existing empirical research remains scanty, with most qualitative analyses being in the literature of political science (e.g., pollins 1989, schneider, barbieri, and gleditsch 2003) . this literature essentially investigates how institutions affect trade. in the economics literature, moenius and berkowitz (2011) present a more general analysis about how institutions influence international trade. taylor (2002), che, du, lu, and tao (2015) , and he, nielsson, and wang (2017) are three empirical studies that are particularly related to this paper. based on the gravity model of trade, glick and taylor (2002) demonstrate that over the period 1870-1997, the wars between two countries have substantial and persistent impacts on their trade. che, du, lu, and tao (2015) show that in china, regions that suffered more civilian casualties during the japanese invasion from 1937 to 1945 tend to trade less with japan in recent decades, ceteris paribus. he, nielsson, and wang (2017) find that non-violent events harming the cross-strait relations adversely affect stock prices of pro-independence taiwanese firms that are economically exposed to mainland china via either investments or exports. in this paper, we focus on international conflicts generally, which are mainly emotional in nature and do not involve the potential destruction of factors of production, rather than wars exclusively. we examine the impacts of the change of political relations between china and twelve trading partners, namely, australia, germany, france, india, indonesia, japan, korea (south), pakistan, russia, the united kingdom, the united states, and vietnam. our results from pair-by-pair analyses (e.g., china and one of the preceding countries) show that trade, political relations, and gross domestic product (gdp) all exist in a long-run stable relationship as evidence by the finding of at least one cointegrating vector for the aforementioned variables. we present impulse response functions, showing that the largest effect of a positive to shock to each our three variables of interest (political relations, china's exports to a partner, a partner's exports to china) is nearly always on the corresponding variable. yet the persistence of these effects differs. shocks to political relations are notably persistent while shocks to exports (be it from china or from a partner) dissipate often within a year. a positive shock to relations usually leads to greater trade flows between china and the economies (especially for australia, france, germany, indonesia, pakistan, the uk) though trade declines in a few cases (india and vietnam). a positive shock to partner exports to china results in better relations for six countries (australia, france, germany, india, japan, vietnam); interestingly, the same shock leads to slightly or significantly worse relations (from china's perspective) for the remaining 6 country pairs (australia, indonesia, korea, russia, the uk, the us). a positive shock to china's exports to a partner boosts china's relations with that partner for a few countries (indonesia, korea, the uk, the us) and lowers relations for a few others (india, japan, vietnam). moreover, our granger causality tests show that relations frequently granger-cause trade in both directions while trade granger-causes less frequently. our analysis sheds some light on the ongoing shifts in trade flows and global sourcing in response to the changing political and diplomatic climate. a var model that incorporates 11 of the 12 country pairs shows that china's trade with any country rarely depends on china's political relations with a third country. the structure of this paper is as follows. "theoretical background" section provides the theoretical underpinnings to our conjecture. "methodology" section describes our statistical methodology. "data" section discusses the data used. "results" section presents estimation result. "conclusion and further discussion" section concludes. the potential effect of political conflicts on international trade can be rationalized by the utility theory, which is developed to study multiple dimensions that determine people's decision-making. in economics, the concept of utility can be interpreted as an index of happiness and satisfaction. conventional wisdom holds that an individual can obtain utility from several sources such as product quantity, diversity, brand, and perceived quality based on their preferences. elster (1998) and glaeser (2005) provide surveys on the literature that incorporates emotions in economic theories, and explores the impacts of emotional factors on social and business behaviors. they postulate that an individual's utility sources from not only material consumption but also emotions. in psychology literature, collective emotions are defined as emotions that are shared by a large fraction of individuals in a certain society, are evident in social gatherings, and are an important feature of nationalism (e.g., bar-tal, halperin, and de rivera 2007, von scheve and ismer 2007) . collective emotions are usually contagious in the sense that one's emotions and behaviors directly cause similar emotions and behaviors in other people. glaeser (2005) develops a model of rational public choice, in which hatred is fostered by interactions between some politicians' supply of hate-creating stories and voters' willingness to listen. by this logic, a change in home country's political relation with a foreign country can be a significant trigger of domestic citizens' collective emotions toward from that country, and consequently, emotions enter into these utility-maximizing decisions of stakeholders at every level, including consumers, exporters, and importers (pollins 1989) . in the absence of international conflicts, nationalist emotions are at a low ebb. consequently, consumers tend to focus only on conventional dimensions such as quantity and quality. however, in the presence of an exogenous international conflict, nationalism may suddenly flare up from sensational media coverage. many people may refuse to purchase commodities and services produced by the "enemy" country. for instance, the 2012 conflict between china and japan over a group of islands known in chinese as diaoyu and in japanese as senkaku led to boycotts by each nation of the other nation's products 3 . in contrast, a more harmonious international relationship will foster globalization and incur fewer boycotts. finally, trade barriers, both tariff-based and non-tariff-based, are detrimental to economic efficiency. for example, the literature of supply chain management addresses the capacity and efficiency of transport logistics in promoting foreign trade (hausman 2004 , lai, ngai, and cheng 2004 , lai and cheng 2009 , munim and schramm 2018 . poor port infrastructure and backward shipping and communication technologies constitute a nontariff barrier for many firms in the evolution of international trade (nordås, pinali, and grosso 2006, lai, pang, wong, lun, and ng 2012) . similarly, poor political relationship can be regarded as an effective non-tariff trade barrier. racial hatred, mutual distrust, unresolved historical tensions, and longstanding political disagreement drive two countries apart, thereby presenting a hidden transaction cost or even an insurmountable obstacle for them to build economic interconnections. in contrast, warm relationship or similar ideology helps to enhance friendly feelings between two peoples, which in turn facilitates the development of closer business ties, as manifested in their increasing trade, shipping, and economic cooperation. a model such as a gravity equation is used traditionally to explain bilateral trade for all pairs of countries in a given set of countries where trade between countries i and j depends on i-specific variables, j-specific variables, and i, j -specific variables (head and mayer 2014) . the question of interest for this paper (the importance of political relationships in explaining chinese trade) makes a gravity equation unfeasible owing to the lack of data quantifying political relationships between non-chinese countries. for example, a gravity model of bilateral trade for all pairs of a set of countries with a political relations variable as a control would require observations on the political relations between any and all pairs, i, j , of countries (e.g., the us and japan). as we have measure of bilateral political relations only for pairs of countries where china is one of the members (i.e., no data on changes in political relations between the us and japan), the gravity framework is not directly applicable. the lack of political relations data for country pairs not involving china also limits our ability to control for 3 rd -country effects on china?s political relations and trade. one salient example is that former us senator sam nunn claimed that stability on the korean peninsula was an important motivation for accepting china into the wto, which leads to greater us-chinese trade (martin and roberts 2017) . in the absence of a particular functional form to follow for our estimating equation, we use a general functional form informed by gravity (as it includes gdp as a key determinant for trade). head and mayer (2014) detail a long literature of gravity models that explain bilateral trade as depending contemporaneously on the gdp of the exporting and importing economies. the literature study bilateral trade over time with repeated cross-sections of the simple gravity model rose 2002, 2016) or dynamically with lagged levels of gdp (olivero and yotov 2012). the gravity literature provides strong justification to model trade, gdp, and political relations with dynamic models, namely vector autoregression (var) and vector error correction models (vecm). var modeling captures the linear interdependencies among multiple time series, allowing for more than one evolving variable. vecm modeling allows for the possibility that the variables in question exist in a long-run equilibrium where exogenous deviations in any one variable lead to the restoration of the long-run equilibrium via changes in the other variables; the magnitude of the deviation determines the magnitude of the adjustment speed in pursuit of restoring the long-run relationship. we first adopt a simple five-equation model to study each of the country pairs (china, i, and a corresponding nation, j). let x ijt denote the real value of aggregate exports from i to j at time t and let political ijt denote the political relation score between i and j at time t. our model to study an individual country pair is of the following form: where is the lag length of the system, all α, β, γ , δ, and ξ are coefficients to be estimated, and is the error term. note that this specification does not address the possibility for trade or political relations between china and country j to affect trade or relations between china and country k for j = k. to take into account the 3rd-country effect, we later adopt a richer model where we try to include all country pairs in our var model. brantstetter and lardy (2008) document, among others, the tremendous growth of china's international trade, particularly after the ascendance of deng xiaoping in the late 1970s and china's adherence to the wto in 2001, and the importance of this growth for china's economic output. the near-unceasing growth in china's trade (especially exports but also imports) all but guarantees that recorded values of trade and gdp lack mean-reverting behavior. china's relations with other countries (e.g., australia, germany, pakistan, south korea) also demonstrate strong, upward-growing behavior without any mean reversion. to avoid estimates potentially biased by dynamic behavior in the data, we adopt the following approach based on berkowitz, dejong, and husted (1998) and whitten (2018) in order to discover a meaningful relationship between international political relations and trade. first, we use stata's varsoc command in order to find an appropriate number of lags (as determined by the number of lags that minimizes the schwarz bayes information criterion or sbic) for a var model in question. second, we use the vecrank command to apply johansen's test for the presence of cointegrating vectors based on a var with the number of lags identified in the first step. in the event that we find at least one cointegrating vector, the third step is to estimate a vector error correction model (vecm) in stata using the lag length identified by varsoc and the number of cointegrating vectors identified by vecrank and to estimate impulse response functions (irfs). since we do not have an a priori model to justify a particular cholefsky decomposition of the variance-covariance matrix (i.e., imposing restrictions on certain error terms), we estimate ordinary irfs, not orthogonalized irfs. the presence of a least one cointegrating vector from the third step demonstrates that a long-run, stable relationship exists among the five variables. such a long-run relationship implies that we can conduct granger causality tests on the levels of the variables, which is our final step. if the second step yields no cointegrating vectors, then we estimate a var on the variables in differences and conduct granger causality tests based on those results. to perform the regression analysis, we use monthly data on trade, political relations, gdp, and price indices. we create real trade data denominated in us dollars by deflating nominal values of export in domestic currency (converted with exchange rate data) by a price index, where export data are from the imf's direction of trade statistics and data on price index and exchange rate are from the imf's international financial statistics. there are four available price indices, namely consumer price index (cpi) with all items, harmonized cpi, cpi of retail prices, and producer price index (ppi). not all countries have all price indices available for on a monthly basis, but all price indices are highly correlated. we therefore average the available values across all indices to impute an inflation measure for a particular country in a particular month. gdp data are taken from the imf's international financial statistics. note that some data such as price indices and gdp require interpolation from quarterly data (or in the case of pakistan and vietnam, from yearly data) to create monthly series. the observations cover the period 1981-2019, with different trading partners varying in timespan due to data availability. political relations data come from the relationship between china and major nations database compiled by the institute of international relations of tsinghua university 4 . let us briefly summarize the construction and interpretation of this dataset as follows. on a monthly basis, tsinghua researchers evaluate each influential event concerning china's foreign relations reported by people's daily and china's ministry of foreign affairs and then calculate a score for each relationship. in other words, the relations are all evaluated from china's perspective. the scores range from −9 to 9, with 0.1 being the smallest increment. a higher score means a better bilateral relationship. as the numbers reported in the political relations data come without specific units of measurement, the question of interpreting these numbers as cardinal as opposed arises. the technical documentation provided by tsinghua demonstrates that their methodology for constructing the index yields a cardinal measure of relations and that all measures can be comparable across country pairs and over time. consider the following three examples: 5 example 1: given that the sino-us relation score in march 2004 is 1.2, the sino-us relation score in april 2004 can be calculated in the following five steps. 1. collect information on the relevant news occurring between april 1st to 30th. 2. the positive news in this month, which, according to tsinghua's evaluation, has a impact of 2.6. meanwhile, negative news generates a impact of −1.9. 3. apply the formula developed of the research team to compute the positive factor equals (9 − 1.2)/9 × 2.6 = 2.3 and the negative factor equals (9 + 1.2)/9 × (−1.9) = −2.2. therefore, the net value is 2.3 + (−2.2) = 0.1. 4. all events occurring in april improve the relation by 0.1/5 = 0.02, where 5 is a constant according to the formula. since 0.02 is smaller than 0.1 (the smallest increment), the score is rounded down. 5. calculate the score for april 2004 as 1.2 + 0 = 1.2, example 2: from may to june 1989, the sino-us relation score falls from 2.6 to 0.4, decreasing by 2.2. from april to may 1999, the sino-us relation score falls from 1.9 to −0.3, decreasing by 2.2. it can be inferred that the change rate in may-june 1989 is the same as that in april-may 1999. example 3: if the china-russia relation score and the china-vietnam relation score are both 3 in any given month, then china's relation with russia is equally good as her relation with vietnam. in may 1989, the sino-us relation is rated as 2.6, while the sino-japan relation is rated as 4.3. the difference is 1.7. another concern might arise as the possibility of endogeneity in the event that the news cited in the above excerpts includes announcements about international trade negotiations. we argue based on the evidence provided in the document that endogeneity is not a concern owing to the focus in the construction of the index on issues that are almost exclusively political or military in nature. the technical document does not state explicitly the types of events that it uses but the examples provided to describe its process include war, military conflict, the establishment of diplomatic relations, state visits, multilateral summits among leaders, the tiananmen square incident, conflits over historical issues, maritime rights, united nations (un) reforms, nuclear energy and weapon issues, and human right issues. the document mentions international trade once on its page 7: take the sino-japanese relation in 2005 as an example. economic ties between the two countries have continued to develop, and their trade volume has increased by 9.9%; however, they have great controversies on historical issues, maritime rights issues, and un reforms. in the bilateral relations, security and political relations are high-level politics, while economic and cultural relations are low-level politics. therefore, the sino-japanese relation in 2005 is assessed as being disharmony 6 . therefore, we contend that endoegeneity is not a problem when using the political relations data to study china's international trade or vice versa. let us proceed to discuss the scores for developing countries. the relation measure between china and indonesia mostly increased through the 1950s and early 1960s and fell dramatically, coinciding with a failed communist coup in indonesia and the indonesian government's decision to sever relations with china. the restoration of these relations in the late 1980s is indicated by a sharp increase in the relation score (ku 2002). the sino-indian war in the 1960s and india's nuclear tests in the late 1990s correspond to decreasing relation scores (maxwell 1972) 10 . the sino-vietnamese war leads to the slump in the chinese-vietnamese relation score, reversed only by the normalization of relations in the early 1990s (womack 2006) . the results from the vecm yield at least 1 (and sometimes more than 1) cointegrating vector for all of our country pairs (see appendix 1). these results imply that political relationships, bilateral trade, and the gdp of the partner countries have a long-run, stable relationship. the johansen method to test for cointegration will impose coefficients of 1 or 0 on certain variables when calculating the cointegrating vector. consequently, these coefficients have no standard errors. however, the coefficients for remaining variables are generally significant. exceptions include the cointegrating vectors for germany and indonesia. the coefficients for a given cointegrating vector (including the constant term) are a mixture of positive and negative numbers, as is to be expected. since the trade and gdp variables generally grow over time and the relation variables (with some exceptions) have positive trends, a vector of coefficients whose dot product with the dynamicallyincreasing variables that yield a constant number over time must contain some negative numbers. as cointegration exists for all country pairs, we compute irfs for them based on the vecm results. since the cointegrating vectors lack standard errors for some variables, we cannot compute confidence intervals for the irfs. consequently, our analysis is limited to the point estimate of the irfs. figure 2 provides a visual presentation of irfs for political relations. a common feature is that the effects are quite persistent and lead to point estimates that are generally persistently higher than are the effects on international trade. a positive shock to relations usually has a larger effect on china's exports to partner than on the partner's exports to china (the case for australia, germany, indonesia, russia, and the uk). a shock to chinese-australian relations leads to persistently higher relations and persistently higher trade. chinese exports to australia are more responsive than are australian exports to china. a positive shock to chinese-german relations leads to a slight improvement after the first month during which chinese exports to germany fall slightly but german exports to china rise slightly. yet, by the next month, all 3 variables change direction: relations fall steadily, chinese exports to germany increase steadily, and german exports to china fall before rising again (but not as much as do chinese exports to germany). chinese-indonesian relations and trade achieve persistently high levels as a result of a positive shock. chinese exports to indonesia respond more strongly than do exports from indonesia to china. a shock to chinese-russian relations fades steadily after the first month though relations remain improved even after 2 years. chinese exports to russia grow as a result while russian exports to china fall and recover gradually. the effect of in four out of twelve cases, the effect of a positive political shock is almost equally negligible for both types of trade (india, japan, korea, the us). a positive shock leads to much better relations between china and india though exports between the economies both shrink over time and remain low for up to 2 years. a similar pattern holds for china and japan though the decline in trade is less pronounced. an improvement to chinese-korean relations falls steadily after 1 month while bilateral trade fluctuates slightly in the first 3 months before achieving a slightly higher level than previously. improved chinese-american relations are quite persistent but have little effect on trade. if anything, chinese exports to the us fall initially and recover only gradually. american exports to china show little response to a shock to relations. we finally discuss the cases for vietnam, france, and pakistan. a positive shock to chinese-vietnamese relations oddly causes those relations to fluctuate slightly around the new, higher level, then decline gradually. contemporaneously, trade between the two economies falls noticeably and then rise. however, while vietnamese exports to china continue to grow (if slowly), chinese exports to vietnam continue to fall (if slowly) in response to the shock to relations. a positive shock to chinese-french relations leads to persistently higher relations for the next 2 years while trade between the economies also increases. yet, while the change in political relations is largely monotonic, the trade response to a political shock is more complicated. french exports to china display initially some cyclical behavior (growing, falling, growing) before reaching a steady and higher level about 10 months after the shock to political relations. chinese exports to france demonstrate similar if more muted behavior. a positive shock to chinese-pakistani relations creates a persistent improvement while pakistani exports to china expand tremendously. chinese exports to pakistan also grow (after some initial fluctuations) and remain elevated for the 2 year period. overall, the shocks to relations are persistent showing little evidence of fading even after 2 years (germany, korea, and russia are exceptions to this pattern). the response of chinese exports to the partner country is noticeably larger than is the response of partner exports to china for 5 of the 12 pairs. in fig. 3 , we plot the irfs for a shock on partner exports to china. they generally have the longest-lived effects on partner exports to china, though the magnitude of this effect falls quickly after the innovation. in a slight majority of cases, the next largest effect is on china's exports to the partner followed by the effect on relations. this pattern holds for the us, for example, where china's exports to the us fall briefly following a positive shock to american exports to china before rising. interestingly, the positive shock to american exports to china leads to a persistent decline in us-china relations. similar to the us case, a positive shock to korean exports to china leads to a worsening of chinese-korean relations. chinese exports barely change while korean exports to china decline after experiencing a shock and return to their original level after 2 years. russian exports to china increase and then decline steadily after they experience a positive shock. any positive effect disappears within a year, and exports fall below their previous level. similarly, relations between the 2 countries worsen and chinese exports to russia decline noticeably. a positive shock to vietnamese exports to china is generally short-lived and leads to oscillating behavior for the first 7 months before declining steadily over the remainder of 2 years. however, this shock leads to a steady increase in vietnamese-chinese relations and a steady if smaller increase in chinese exports to vietnam. a positive shock to japanese exports to china is also transient but converges more quickly to a persistently higher level. chinese exports to japan as well as relations improve to a persistently higher level rather quickly (after 6-7 months). the australian case resembles the japanese case though relations deteriorates following a positive innovation to australian exports to china. the innovation to british exports to china is also short-lived though chinese exports to britain do rise. relations worsen slightly before reversing that trend. pakistani exports to china decline quite quickly after a positive shock though they converge to a slightly higher level than previously. relations and chinese exports to pakistan change very slightly (the former improve while the latter worsen). a similar pattern happens for indonesia. the chinese-indian relation to a positive shock to indian exports to china resembles the chinese pakistani case. the positive shock falls steadily and converges to a slightly higher level after 9 months. chinese exports to india remain improved for the duration of 2 years after a slight fall. relations improve steadily and remain so after around 6-7 months. german exports to china also decline quickly after a positive shock but remain elevated over the 2-year period. both relations and chinese exports improve steadily. a positive shock to french exports to china dissipates quickly and somewhat noisily, leading to a slightly higher level after 6-7 months. relations improve slightly while chinese exports to france show little movement. figure 4 plots the irfs for exports from china to her trading partners. the strongest response to a positive shock to chinese exports to a partner economy generally manifests itself on chinese exports to a partner economy. the next-strongest effect is on relations for half of the pairs and on partner exports to china for the remaining half. as is the case with innovations to partner exports to china, the effect of the innovation on its own series declines quickly before reaching a persistent level that may or may not be the initial level before the shock. an innovation to chinese exports to the us oscillates for up to a year before evening out. relations and american exports to china also oscillate for 5 to 11 months before they all reach higher-than-initial levels, though the effect on relations is modest. similarly, the positive shock to chinese exports to vietnam also decline quickly, rebound, then decline again before dissipating after a year. both relations and vietnamese exports to china decline and remain below their initial levels for the 2-year period. an innovation to chinese exports to japan uniformly leads to persistently lower levels of bilateral trade as well as relations, though the long-run effect on chinese exports to japan is only slightly lower than is the initial level. the china-korea case stands out uniquely from all others in the sense that a positive shock to chinese exports to korea produces much stronger relations while having a modest effect on trade in both directions (after some initial fluctuations). the innovation to chinese exports to russia declines immediately if gradually after it occurs and reaches a new, persistent level within 10 months. russian exports to china decline slightly before growing gradually. relations improve then decline slightly. the innovation to chinese exports to india declines quickly but to a persistently higher level than initially. indian exports to chinese decrease sharply after 1 month but grow and surpass their initial level. interestingly, relations between the two economies decline gradually and remain below initial levels. chinese-british relations improve modestly if persistently after a positive shock to chinese exports to the uk while bilateral trade declines slightly, more so for british exports than for chinese exports. the china-australia relation demonstrates similar behavior though relations also remain lower than previously. chinese exports to france remain persistently higher after an innovation while french exports to china remain mostly lower than before. relations exhibit few changes. this pattern also describes the china-germany case though chinese exports to germany fall by a larger magnitude than do chinese exports to france. a positive shock on chinese exports to pakistan produces almost no effect on any other variables except chinese exports to pakistan. this effect disappears quickly and even leads to a persistent decline within 4 months. the china-indonesia case is similar. given that all country pairs that we examine contain at least 1 cointegrating relationship, we perform granger causality tests following a var on the levels of the variables. see tables 1, 2 and 3 for a summary of the results. a "y" indicates that we can reject the null hypothesis of no causality between row-variable (or variables for "all") and the variable indicated in the table title. overall, political relations appear to granger cause trade in either direction. five countries demonstrate causality from their relations with china to their exports to china. six countries demonstrate causality from relations to china's exports to the countries. however, trade seems not to granger cause changes in political relations. even the results for the null hypothesis that all other variables in the var fail to granger cause political relations are rejected for, at most, 6 of the 12 pairs. chinese-korean relations appear to be the relations most easily-explained by our model's variables. in contrast, bilateral trade is easily explained by relations and previous bilateral trade. as we stated in "model specification" section, our previous estimating framework could not address the possibility for trade or political relations between china and country j to affect trade or relations between china and country k for j = k (as would have been possible in a gravity model). this section analyzes results for a var where we include 11 of the 12 country pairs that we study to account for the possibility that relations between china and country j might affect trade or relations between china and country k for j = k. we exclude india as data for india are not available for enough months contemporaneously with all other countries. our main finding is no cointegrating vector for the 11 country pairs. consequently, we estimate a var model in differences with 1 lag (as indicated by results from the sbic). tables 4, 5 and 6 summarize the fully multilateral var results (see the full results in appendix 2). the results show some instances where 3 rd country effects can influence china's trade and political relations with a particular country. generally speaking, china's foreign trade (especially exports from china) with country j have at least one statistically significant relationship with the lag of china's trade with country k = j. trade between china and country j rarely depends on relations between china and country k = j. in contrast, there are fewer instances where political relations between china and some country j have a statistically significant association with some country k = j. a few patterns emerge from the result. chinese-indonesian political relations and trade flows are the least influenced by 3 rd parties while trade between china and each of vietnam, japan, and korea are seemingly the most responsive to china's links with other countries. the importance of these three countries may be a consequence of long-standing political, economic, and cultural links. interestingly, a few patterns emerge when examining regressors across equations rather than individual equations. australian-chinese trade frequently appears as a positive determinant for chinese trade in both directions with other economies (7 equations each for exports to and from china). japanese exports to china are a positive determinant for exports from china to 8 different economies while korean exports to china are a positive determinant for exports from china to 6 countries. these patterns may emerge from production chains where raw materials (harvested in australia) and/or intermediate goods (produced in japan and korea) are key inputs in china's exports to the rest of the world. conventional wisdom dictates that with a greater volume of international trade and a greater degree of international economic dependence, countries tend to be more restrained in international conflicts. in turn, under a more peaceful and harmonious environment, consumers and businesses tend to have less "home bias" in their purchases of goods and services. while proponents of greater international economic integration have cited such conventional wisdom to ensure global stability, recent events (e.g., brexit, covid-19 pandemic) have caused people to think otherwise. our paper provides an empirical test of the conjecture that the warming and cooling of political ties between two countries is accompanied by expansion and contraction of their trade activities with each other. to perform the empirical investigation of the interdependence between economic and political spheres, we employ data of political relations and trade flows between china and table. a non-empty cell in the table denotes a statistically-significant (p-value ≤0.05) finding between a variable involving china and a country other than the country indicated by the entry in the lefthand side column of the row in question. the nature of the variable is indicated by the contents of the cell ("to china" means exports to china, "from china" means imports from china, "relations" means the political relations). the country with which china has this particular relation is stated at the top of the column of the cell in question her twelve large trading partners during the period of 1981-2019. we find that political, relations, and gdp exist in a steady-long run relationship as evidenced by the existence of cointegrating vectors among the variables. we find that shocks to political relations variables are persistent while shocks to export variables are less persistent. granger causality tests indicate that relations granger cause trade more often than do trade flows granger cause relations. while trade and political relationships usually demonstrate a positive relationship (as indicated by the irfs), several cases of a negative relationship between the variables do exist. owing to recent political tension at the time of this paper's writing, a closer examination into the us-chinese case is instructive. the irf for us-chinese political relations shows a high level of persistence: when relations improve, they stay improved for a long time. the counterpart, of course, is that if relations worsen, then they stay worsened for a long time. trade, however, demonstrates little reaction in response to a change in relations. a positive shock to trade, however, yields different results depending on the type of trade flow. a positive shock to china's exports to the us leads to persistently higher levels of exports to the us, us exports to china, and relations (measured from china's perspective). yet, a positive shock to america's exports to china leads to persistently worse relations with china while trade in both directions increases slightly. if these responses implied by the irfs indicate common patterns based on years of data, then it stands to reason that chinese officials genuinely do feel that china's relations with the us worsen when the us increases its exports to china. only one other country, south korea, exhibits a worsening in relations with china, similar in magnitude to that of relations with the us, following growth in exports to china. a logical consequence of worsening relations would be that chinese officials would undertake measures to reduce us exports to china. consequently, claims made by us officials that the chinese government seeks to limit non-chinese (or at least american) exports into china may have some merit 11 . the managerial implication of our study is that although intergovernmental or interstate amity and enmity are usually out of control of businesses, companies still need to prepare for instability caused by changing political and diplomatic climate. given that political relationship can lead to intended and unintended consequences for manufacturers and trading companies, operations leaders have a responsibility to put their companies in a position to capitalize on new opportunities for business creation and growth while avert the damages caused by potential political risks. importers should enhance their adaptive capabilities into their supply chain strategies and shipping management, and exporters should better align demand and supply and develop viable response plans when adjusting their marketing strategies. since the induced changes in international trade may further cause a shift in global supply chain, logistics and shipping companies, which usually tend to pay much more attention on cost, time and reliability of delivery than on political factors that shape the external business environment, should be aware of international political relationship that may lead to the evolution of shipping networks. while our paper tests the effect of china's foreign relations on its trade activities, the conjecture can be applied to other contexts. in 2012, nobel peace prize was awarded to the european union (eu) "for over six decades contributed to the advancement of peace and reconciliation, democracy and human rights in europe." 12 the eu's main practical function has been promoting international trade among its member countries. the eu's achievements belong to a larger set of greater international, political and economic integration witnessed in the post-world war ii era, which provides evidence that better political relations and a greater volume of international trade go hand-in-hand. in contrast, there are numerous events that adversely affect interstate political relations in the eu. recent examples include political disagreement between the united kingdom and other member states of the european union over immigration and refugee policy. despite the deep economic links created by trade between the united kingdom and other eu members, this disagreement led to the brexit in january 2020 and an anticipated decline in uk-european trade. collective emotions in conflict situations: societal implications quantifying price liberalization in russia 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reinforcing? some empirical evidences from asean countries the us-china trade war and china's strategic future the ideas that conquered the world: peace, democracy, and free markets in the twenty-first century cokie roberts answers your questions about presidents and trade policy india's china war. anchor books, garden city moenius j, berkowitz d (2011) law, trade, and development the impacts of port infrastructure and logistics performance on economic growth: the mediating role of seaborne trade joint communiqué of the government of japan and the government of the people's republic of china dynamic gravity: endogenous country size and asset accumulation conflict, cooperation, and commerce: the effect of international political interactions on bilateral trade flows globalization and armed conflict. rowman & littlefield scheve v, christian, sven i (2013) towards a theory of collective emotions price-level co-movements within currency unions: an alternative integration metric de-globalization: theories, predictions, and opportunities for international business research china and vietnam: the politics of asymmetry springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations this paper supersedes an early version titled "the effect of china's political relations on her international trade", which was presented at the 2016 biennial conference of hong kong economic association. we thank two anonymous reviewers for valuable comments, yifan zhang for some extensive discussions, and baosi meng for research assistance. gw is in charge of detailed econometric methods and empirical analyses; xd collects the data and does empirical estimations. sf proposes the original research idea and conducts theoretical analyses. yp conducts data analyses, which helps reshape the econometric method. gw, sf, and yp conduct literature review. the authors read and approved the final manuscript. the direct allocation grant of lingnan university (ds14a4) is gratefully acknowledged. the datasets used and/or analysed during the current study and the two appendices are available upon request. the authors declare that they have no competing interests. key: cord-022161-quns9b84 authors: cui, shunji title: china in the fight against the ebola crisis: human security perspectives date: 2018-09-02 journal: human security and cross-border cooperation in east asia doi: 10.1007/978-3-319-95240-6_8 sha: doc_id: 22161 cord_uid: quns9b84 the outbreak of the ebola virus disease (evd) in west africa became one of the worst disease-driven humanitarian crises in modern history. the crisis turned the global securitization of health issues into unprecedented levels, at the same time, aligned closely with human security frameworks and thus has significant impacts on national foreign and aid policies. china has played a significant role in the global fight against ebola, indicating important changes in its foreign policy orientations. based on the lessons drawn from china’s operation in africa, it is argued that states must transcend their narrow national interest and seriously consider the dignity and well-being of vulnerable people. in september 2014, when the crisis was at its peak, the number of weekly cases reached almost 1,000. by january 14, 2016, when the world health organization (who) officially declared the epidemic to be over, the crisis had lasted nearly two years, during which time more than 28,600 people were infected with the virus and more than 11,300 lives were lost, mostly in guinea, liberia and sierra leone (who 2016b; cbs 2016) . faced with such a devastating humanitarian crisis, the entire international community has shown great courage in fighting the disease. after the august/september 2014 announcement by the who that ebola was a 'public health emergency of international concern' and the united nations security council (unsc) declaration that ebola was a 'threat to international peace and security,' many countries as well as international organizations, non-governmental organizations, companies and individuals participated in the fight against this unprecedented challenge to humanity. china played a significant role in the international efforts to halt the spread of the ebola disease. through four rounds of emergency aid supplied in april, august, september and october 2014, a total of 750 million yuan (about usd 123 million) was contributed to west african countries by china. in addition to financial and material assistance, china also sent more than 1,000 medical personnel to the region to help with local epidemic prevention and control work (nhfpc 2015a; undp 2014a) . this was unprecedented in the history of chinese foreign assistance. in fact, china has often been considered as lacking a philanthropic culture, and its international aid and financing models are frequently criticized as resource-backed and tied to aid in a way that simply serves the business interests of the country. thus, the chinese case raises intriguing questions, especially in terms of human security: what are the main motives and driving forces behind these efforts, and how effective are they? this chapter aims to answer these questions through the lens of human security rather than from a general foreign policy perspective. for this purpose, it begins by laying out the criteria and framework for the analysis. this is followed by an examination of china's efforts to fight the crisis. the chapter then goes on to evaluate these policies with a focus on effectiveness, empowerment and motives. based on china's experiences in africa, the concluding section draws some lessons for future human security-oriented foreign policies. when the un security council adopted resolution 2177 on september 18, 2014, declaring the outbreak of ebola in africa to be 'a threat to international peace and security,' the ebola crisis was no longer a mere health issue but an international security crisis (unsc 2014) . of course, it was not the first time that the security council had acknowledged the link between health and security. in 2000, the council had recognized the hiv/aids pandemic in resolution 1308 (unsc 2000, 1) , and declared it to be 'a risk to security and stability,' although its main concern was on the 'regional effects' in africa (deloffre 2014a) . resolution 1308 is important in terms of human security because the council clearly focused not only on issues such as preventing wars and control of the proliferation of weapons of mass destruction but also dealt with matters concerning human security such as disease (poku 2013, 529) . therefore, resolution 1308 constitutes a clear securitization of public health issues within the un system. following the ebola crisis, resolution 2177 and the creation of the united nations mission for ebola emergency response (unmeer) in 2014 pushed the scale and depth of securitization to an unprecedented level, while at the same time brought the securitization processes into close alignment with human security frameworks (snyder 2014) . the question to be asked in this context is, therefore: what is meant by human security, and what counts as appropriate foreign and aid policies toward human security threats? since its introduction in 1994 (undp 1994) , the concept of human security has increasingly been reflected in global governance and in the foreign and aid policies of many countries. yet the kind of definition one adopts, narrow or broad, will have very different operational and policy implications. in keeping with the approach to human security taken by jica and many east asian countries (see chapter 2 in this book ; tanaka 2015; jica 2010) , this chapter takes a broader concept as its working definition and uses this to identify the three features of human security. first, the causes and effects of human security can be far-reaching and multifaceted, and if we underestimate the complexity of such threats, we can never have adequate policies toward human security practices. secondly, human security and human development are so closely related that, even though we can conceptually separate them, we must be aware of the interconnectedness between the two at the operational level (cui 2014) . amartya sen made the point comprehensively. he argued that on the one hand, human security demands both 'protection' of people from a variety of dangers, and 'empowerment' of people so that they can cope with, and when possible overcome, these hazards. on the other hand, human development is concerned with 'removing the various hindrances that restrain and restrict human lives and prevent its blossoming,' and hence goes beyond 'overarching concentration on the growth of inanimate objects of convenience' (chs 2003, 8-9) . such a comprehensive understanding is at the heart of his conceptualization of 'development as freedom,' in which poverty, one of the central concerns of human security, is no longer premised solely on income, but seen as a non-fulfillment of basic human rights (sen 1999) . thirdly, when human security is threatened by conflict situations, natural disasters or pandemics, it is often the case that the most vulnerable people in society are the ones who are most threatened. given these features of human security, what kinds of policy tools are to be considered as most appropriate and effective? tanaka (2015, 15-20) distinguishes between two types of human security instruments: 'fundamental measures' that affect the underlying causes of human security, and 'defensive measures' that affect consequences. this is very similar to johan galtung's (1969) distinction between 'positive peace' and 'negative peace,' because fundamental measures may bring positive peace, while defensive measures are more likely to bring negative peace. for galtung, peace can be defined in a negative way, meaning the absence of violence (both direct and structural). yet more importantly, peace can also be defined positively, that is, the construction of an appropriate environment for lasting peace. in other words, the conditions for positive peace may be built through a process analogous to the 'building of a healthy body capable of resisting diseases, relying on its own health forces or health sources' (galtung 1985, 145-46) . drawing on these ideas, this chapter is framed around three measures by which human security policies can be assessed. the first measure is effectiveness. once human security threats have occurred, how should we respond to the problem more effectively? the issue here is how swiftly and decisively can a country reduce the negative impacts of disease and human suffering. this is in line with tanaka's defensive measure or galtung's negative peace. effectiveness means more than speed, scale and comprehensiveness; it also refers to the ability to cooperate with a variety of actors to tackle human security threats. speed and scale are extremely important; however, if they are pursued singlehandedly, their impact remains limited. cooperation is imperative when trying to effectively handle deadlier challenges. the ebola crisis is a good demonstration of how a problem goes beyond the capacity of a single state. unmeer was created specially to coordinate a variety of actors to fight the crisis more effectively. thus, both comprehensiveness and cooperation are required if human security policies are to be effective. the second measure is empowerment. if human security practices are only prepared to tackle problems once they emerge, only negative peace can be achieved. taking individual health as an example, although a person may be cured of a disease, if they do not build up their bodily conditions, illness will reoccur. empowerment is more closely related to dealing with structural violence as the underlying cause, building capacities, and creating a more secure environment, so that the occurrence of human security threats can be prevented or the likelihood of them occurring be reduced (cui 2012) . in this way, even if threats occur, people have the ability, or at least an increase in the ability, to address those threats on their own. thus, if the first evaluate of effectiveness is used to assess more short-term defensive approaches, empowerment is used to evaluate longer-term fundamental approaches to human security. thirdly, in addition to the above measures, motives or moral imperatives are important in assessing human security policies. traditionally, theorists, particularly realists, emphasized national interests when measuring national foreign policies. hans morgenthau (2005 morgenthau ( , 1950 argued explicitly that a 'foreign policy derived from the national interest is in fact morally superior to a foreign policy inspired by universal moral principles.' of course, morgenthau did not deny political morality and prudence, or the need for a logic of consequences to save policy makers from both moral excess and political folly. however, because most human security-related governance activities do not directly relate to national interests in the narrow realist sense, the notion of raison d'état provides poor guidance and does not fully explain the current global efforts to achieve human security. thus, the practice of human security requires a certain degree of consideration of those people who are socially vulnerable, and concern should be given to the possibility of their dignity being exposed to existential threats. the ebola virus disease (evd) in west africa broke out in december 2013 and the who put out its first alert in march 2014. what followed was the largest, longest, and most severe and complex outbreak of the virus since it was discovered in 1976 (who 2016a). although at the initial stage the impact of the outbreak was underestimated, following the declaration of emergency and threat by the who and the unsc in august and september 2014, the international community has made great efforts and shown solidarity in the fight against the deadly disease. among the countries fighting evd, traditional donors, such as the usa and the uk, played a leading role. by october 2014, the us government was ranked as the largest donor having contributed around usd 750 million in aid, with the uk coming in second with about usd 330 million (who 2014a). yet, the crisis also saw intense media attention given to some non-traditional donors, like china. by october 2014, china had contributed close to usd 123 million in financial aid. although this was much lower than that of the usa, it was still above the contribution of traditional donor countries such as france, japan and canada (undp 2014a; see also fig. 8 .1). 2 accordingly, china's role and its impact on human security merit more detailed examination. china's participation in fighting the ebola epidemic is regarded as being historic, marking the first time it offered such aid to help combat a foreign health crisis (tiezzi 2015) . the chinese government also admits that it was the largest medical aid program to be implemented by china at the time (nhfpc 2015b). china's role in fighting ebola was particularly important in the early stages and was in stark contrast to the delayed response of the rest of the international community. for instance, even though the who was first alerted to the outbreak on march 23, 2014, it was not until april that médecins sans frontières (msf) first warned that ebola was getting out of control. by june, the spread and scale of the epidemic was obvious to many experts, yet it was not until august 8 that the who declared that it was a public health emergency. as a result, the international response generated criticism as being both too small and too slow (dearden 2014; grépin 2015) . in comparison, china's response was swift. there are two reasons for this swift response: first, given china's long-term medical cooperation with african countries, many doctors and medical staff were already present in african countries when the outbreak began. for example, when the epidemic first emerged in guinea, a chinese medical team of nineteen people from beijing's anzhen hospital was working at the china-guinea friendship hospital in conakry, the capital of guinea. during this time, one infected patient was treated in the hospital without anyone realizing it was ebola and was thus faced with the risk of death. secondly, the chinese experience with sars in 2003 and its struggle to stop its spread, coupled with an awareness of the weaknesses in the medical system in west africa, made chinese officials and medical experts particularly alert to pandemics in west africa. 3 in fact, the weak healthcare systems in all three countries were emphasized by many medical experts after ebola broke out. as marie-paule kieny (2014) notes, ebola became epidemic in guinea, liberia and sierra leone in large part due to their weak healthcare systems. indeed, all these countries lack adequate numbers of qualified health workers, particularly in rural areas. other limitations included weak or absent rapid response systems, and a lack of electricity and running water in some health facilities (kieny 2014; who 2014c) . in march 2014, when the outbreak of ebola in africa began to be reported, the news placed policy makers and medical experts in china on high alert. immediately, high-level meetings were held with the ministry of health calling for discussions on the ebola virus and how to help africa deal with it. among those involved in the meetings was the deputy director of the center for disease control and prevention (cdc) in beijing, he xiong, who was a frontline veteran of china's battle with sars. 4 in april 2014, the chinese government announced its first emergency assistance plan, under which it would send disease prevention and control materials worth 4 million yuan (about usd 600,000) to guinea, liberia, sierra leone and guinea-bissau; by may 2014, the assistance had arrived (china daily, october 20, 2014; nhfpc 2015a) . by june 17, 2014, the ebola situation had become even more urgent as it had reached the liberian capital, monrovia. six days later, the death toll had risen to 350 and it had officially become the worst ebola outbreak on record (nhfpc 2014). in august, the epidemic accelerated as the total number of cases reached almost 2,000, with more than 1,000 deaths in guinea, liberia and sierra leone alone. cases of infections among american, british and spanish citizens were also reported. on august 8, 2014, the who declared that the epidemic had gone from being an african problem to an 'emergency of international concern' (who 2014b). this situation alerted the top chinese leaders. on august 7, 2014, beijing announced its second round of assistance, whereby it would provide emergency anti-epidemic supplies worth 30 million yuan (about usd 4.86 million) to the three most affected countries. the supplies were mainly medical protective clothing, sterilization equipment, drugs and other much-needed medical equipment and supplies. due to the urgency of the situation, china even used chartered planes to deliver medical supplies, which arrived on august 13, just one week after the announcement. the initial aid was followed by another three chinese medical teams dispatched across west africa to help with prevention and treatment. by this stage, more than 170 medical workers had been dispatched (china daily, september 26, 2014) . the situation further developed and reached a devastating level. by september 16, the total number of infected cases had reached 4985, including 2461 deaths (medical express, september 16, 2014) . two days later, the unsc declared the outbreak of ebola to be a 'threat to international peace and security' (unsc 2014). on september 19, the unmeer, the first-ever un emergency health mission, was formed. this mission was led by a full range of un actors, who utilized their expertise under the leadership of a special representative of the secretary general. it was in such crisis atmosphere that many countries pledged more aid and manpower to help. on september 16, us president barack obama announced 'major increases' in the us response to fighting ebola in africa including up to 3000 troops, material to build field hospitals, additional healthcare workers, community care kits and badly needed medical supplies (new york times, september 16, 2014) . in a speech to the un high-level meeting on the response to the evd outbreak on september 25, 2014, japanese prime minister shinzo abe also promised that japan would provide 500,000 sets of protective gear for medical personnel working to combat ebola in africa. in october, japan used civilian aircraft to deliver 20,000 sets of protective gear to liberia and sierra leone (asahi shimbun, february 18, 2015) . in september, as its third phase of assistance, china increased its contribution significantly by opening a biosafety lab and providing protective treatment supplies and food assistance. additionally, to help sierra leone improve lab testing, china sent a laboratory team of 59 (thirty doctors and twenty-nine laboratory technicians) to work at the sierra leone-china friendship hospital (china daily, september 17, 2014). on october 24, china announced its fourth round of emergency aid worth 500 million yuan (usd 82 million), which would mainly be used to finance the construction of a 100-bed treatment center in liberia, where the epidemic was most serious. as the chinese foreign ministry explained, the treatment center, which was completed on november 25, would be managed and operated by a medical team from the people's liberation army (pla) (xinhua, november 4, 2014 ). the treatment center was able to accept patients for observation and testing from december 5, 2014 (nhfpc 2015b). the aid package also included sending medical equipment and materials, such as 60 ambulances, 100 motorcycles, 10,000 healthcare kits, 150,000 pieces of personal protection equipment, and other materials (larson 2014) . china continued its commitment to fighting ebola after these four phases of contributions, as lin songtian, director of the foreign ministry's african affairs department, stated, 'china's assistance will not stop as long as the ebola epidemic continues in west africa' (xinhua, october 31, 2014) . thus, in early november, the nhfpc announced that china planned to send 1000 medical workers and experts to west africa over the months that followed (xinhua, november 5, 2014) . in february, china handed over a p3-level biolab to sierra leone as part of its continued contribution to fighting ebola; it also delivered a consignment of 1500 metric tons of food assistance for distribution to ebola patients at various treatment units across the country. evaluating china's role: an emerging human security-oriented foreign policy? from the above discussion, it is not difficult to see how china actively participated in the global efforts to address the ebola outbreak. how then should china's role be assessed through the specific lens of human security? what lessons can be drawn for future human security-oriented foreign policies? the following section will analyze china's role in terms of effectiveness, empowerment and motives. as previously argued, effectiveness comprises both comprehensiveness and the ability to enhance multiple-level cooperation. first, china's assistance is considered as comprehensive and wide-reaching. its contribution of personnel is particularly highlighted compared with many other countries, especially asian countries. at a news conference in seoul on november 4, 2014, the world bank group president, jim yong kim, lamented the fact that although they may have the capacity, many asian countries were not doing enough to help. he called upon asian leaders to send trained health professionals to west african countries (aljazeera, november 4, 2014) . the lack of assistance by asian countries is true to some extent. japan, for example, while making significant financial and material contributions lagged behind many other countries in terms of the provision of personnel. by the end of 2014, japan had sent a total of twenty japanese experts to participate in who missions to liberia and sierra leone, two self-defense force (sdf) personnel to the headquarters of the us africa command (africom) in germany to support liaison activities, and one to unmeer as a senior advisor (government of japan 2015). there were suggestions from japan's defense ministry that a ground sdf unit would be dispatched to join the fight in sierra leone. the plan was submitted to the prime minister's office on february 18, 2015, and called for 400 gsdf personnel to begin operations in april, with a possible maritime sdf contingent to serve as the base of operations. however, for many reasons japan did not go ahead with the plan. this decision generated some criticism because although prime minister abe promotes a vision of 'proactive pacifism,' he chose to put japanese lives and his government's own political interests ahead of global well-being (pollmann 2015; the japan times, february 24, 2015) . south korea made a large step in its contribution to international personnel at this time. in addition to the usd 12.6 million of assistance it had already provided, between december 2014 and april 2015, seoul sent three emergency relief teams (a total number of thirty people), comprising mostly skilled military and civilian healthcare workers, to west african countries to carry out medical activities (the korea times, october 17, 2014; china news, april 3, 2015) . this represented the first time that the south korean government had sent an emergency relief team to fight the outbreak of an epidemic overseas. in comparison, china's participation was much swifter and of greater weight. the un secretary general ban ki-moon acknowledged 'the speed and breadth' of china's response and emphasized the commitment and dedication made by chinese medical staff to fighting ebola (china daily, february 15, 2015) . but, there were also other countries who made significant contributions, including personnel, to this global effort to fight ebola. since mid-september 2014, the usa had shown renewed engagement and significantly enhanced the global scale of the fight against ebola. over the course of the epidemic, the usa deployed more than 3500 personnel to the affected region 5 ; as a superpower and as a longstanding traditional donor country, the usa did play a leading role in this humanitarian effort. nevertheless, as a rising great power and as a non-traditional donor country, china's growing role in international aid and global governance is commendable for its willingness and comprehensiveness. secondly, in terms of cooperation, china's role is, however, less straight-forward. the complexity and devastation of the ebola crisis again demonstrated the value and necessity of cooperation among a variety of actors. of course, in the process of engaging in the global effort to fight ebola, china did cooperate with many countries and international and regional organizations by providing financial support to the un, the who and the au, and assisting them in playing leading and coordinating roles. china also made many bilateral and trilateral agreements to combat the unprecedented spread of ebola, including with the usa, france and the uk (focac 2014). the health ministers of china, japan and south korea also agreed to boost information-sharing on the ebola epidemic and countermeasures against other types of diseases, such as pandemic influenza (the japan times, november 24, 2014). however, in comparison with many traditional donor countries, china had less experience of coordinating with non-governmental actors, and the ebola crisis, in a sense, highlighted the shortcomings of china's private sector participation and its philanthropic shortfalls (rajagopalan 2014) . even though at the government level china contributed over usd 120 million to fight ebola, at the private sector level it donated little to the cause. many firms and business people in china still assume that the chinese government should take the lead on international assistance. 6 in a deeper sense, this philanthropic shortfall is the result of china's international aid tradition, which has been predominantly bilateral and government-to-government. this is clearly revealed in china-africa relations. since china began its assistance to africa in the 1950s, it has been the government that has initiated the sending of medical practitioners and the building of roads and railways (chan 2011, 95-122) . even at present, this tendency has not changed very much; hence, the aid commitment under the multilateral mechanism of the forum on china-africa cooperation (focac) is also realized mainly through a bilateral mechanism (xu 2012) . with global multilateral cooperation frameworks growing in sophistication, china faces the challenges of how to better integrate itself into the multilateral development framework. to what extent has china's approach to the ebola crisis contributed to empowerment rather than just protection? as argued earlier in this chapter, empowerment refers to a longer-term positive/fundamental approach to human security that looks at the underlying causes of human security threats and should ultimately lead to an improved capacity to overcome threats. strictly speaking, capacity building and empowerment may not be entirely identical, as the former is more related to organizational capabilities, while the latter is more concerned with people. yet, the two are closely related to each other, and building organizational capabilities such as proper health systems can directly and indirectly enhance individual health resilience in the long term. thus, this chapter examines the following two aspects in detail: china's effort in offering help to build public healthcare systems and its active engagement in african economic and social reconstruction. first, in fighting the ebola crisis, china has not only devoted itself to tackling the deadly disease but has also offered valuable help to african countries to improve their capacity to respond to public health emergencies. if china's four major rounds of assistance between april and october 2014 were dedicated mainly to stopping the spread of the ebola epidemic, since then china has focused more on long-term capacity building (embassy of the prc 2014). in november 2014, china sent its public health training team to sierra leone to study the ways they could carry out training for public health professionals in west africa. the team was to smooth the way for large-scale training programs in the future. by august 2015, chinese public health training teams had trained more than 10,000 residents, including medical staff, community healthcare workers, government officials and volunteers. using china's fight against sars as a way of sharing their experiences, the training teams were able to deliver useful prevention and control knowledge and skills to the participants (nhfpc 2015a; embassy of prc 2015). indeed, empowerment through improving regional health systems has become an important part of the china-africa health cooperation. at the second ministerial forum of china-africa health development in early october 2015, ministers emphasized the importance of african people being able to access quality essential health commodities, medicines, vaccines and medical services (nhfpc 2015c). to that end, china pledged to send 1500 medical workers to africa in the next three years, and it encouraged ten of its large pharmaceutical and medical equipment enterprises to cooperate with various african counterparts, through measures such as technology transfers in the production, maintenance and distribution of quality pharmaceutical products (china daily, october 8, 2015) . secondly, along with establishing and improving public health systems, poverty reduction and economic and social reconstruction have become china's key goals in its efforts to address the ebola epidemic. the chinese foreign minister wang yi emphasized this point while on a visit to the three countries worst hit by ebola, by saying that 'poverty was the root cause' of the ebola outbreak (xinhua, august 10, 2015) . from china's perspective, the fundamental solution to preventing the reoccurrence of ebola and other epidemics of this kind is to find effective paths to eliminate poverty and achieve development as soon as possible. for this purpose, china's cooperation would prioritize areas such as infrastructure building, resumption of trade and export, food security and other areas to enhance their resilience to crises (xinhua, august 8, 2015; august 10, 2015) . of course, rebuilding the fragile health system and enhancing socio-economic reconstruction in these countries will not be easy and will require a much longer time-period and persistent efforts. in this sense, whether wang yi's visit to the african continent will lead to more substantial engagement from china, or whether it will bear positive fruits, remains to be seen. however, china's commitment to african development and to the recovery of the three countries was demonstrated at the 2015 forum on china-africa cooperation (focac). indeed, in the past three focac meetings, china has consistently doubled its financing commitment to africa-from usd 5 billion in 2006 to usd 10 billion in 2009 and usd 20 billion in 2012 (sun 2015) . additionally, at the 2015 forum, china pledged usd 60 billion worth of assistance and loans for african development. it also specified ten areas of cooperation and assistance, including agriculture modernization, public health and poverty reduction that it would engage in. 7 in the declaration, china promised it would transfer agricultural technology to africa; cancel outstanding debt for some of the poorest african countries; help build an african center for disease control; and back cooperation between twenty chinese and african hospitals. china also hoped to explore the possibility of linking china's belt and road initiative and africa's economic integration. if these efforts can be materialized, they would certainly have a positive impact on africa. finally, why did china participate so actively in the global efforts to contain ebola? as discussed, realist notions of raison d'état cannot provide sufficient answers about the international efforts for human security purposes. the question is this: to what extent can china's role transcend this notion of national interests? of course, one cannot deny that china's national interests are growing in africa, including in the three most affected countries. when evd emerged, there were approximately 20,000 chinese nationals living in the three afflicted countries (beijing youth daily, august 8, 2014) . moreover, when chinese foreign minister wang yi visited the three countries in august 2015 to prepare for the post-ebola reconstruction, he promised more funding and joint projects including infrastructure building, and resumption of trade and export (xinhua, august 11, 2015) ; this was an indication of china's growing economic interests in these countries. however, national economic interests alone cannot explain china's proactive engagement in the global fight against ebola, given that these countries are the least developed countries in africa. if china was purely seeking economic interests in the area, it should have invested in countries that had a greater chance of return. therefore, we should examine the ways in which human security as a fundamental value has an increasing impact on national foreign policy and strategic choices. china's active participation in and significant contributions to the global fight against ebola indicates its 'growing position within the international community as a global actor in humanitarian aid' (undp 2014a, 2) . it also reflects some important changes in its foreign policy orientations, particularly in foreign aid strategy. this is clear in china's second white paper on foreign aid (wp ii) (state council of china 2014). in 2011, china published its first-ever foreign aid white paper (wp i), which was already indicative of its effort and strategy to become a responsible great power in international society. by moving its focus from its own development to the provision of assistance to other developing countries, china is 'fulfilling its due international obligations' (state council of china 2011, 1), and is enhancing its image as a responsible great power (liu and huang 2013) . in wp i, the underpinning principles for china's foreign aid were clearly put forward: the 'five principles of peaceful coexistence' and the 'eight principles' for economic aid and technical assistance to other countries. 8 china often defended its role as being 'an alternative to western donors who impose more conditions on recipients' (state council of china 2011, 4-5) . by comparison, there are some noticeable modifications contained in the wp ii, which sets out the following two areas-'helping improve people's livelihood' (改善民生) and 'promoting economic and social development'-as its major foreign aid objectives (state council of china 2014, 8-22) . of course, this does not mean that china has abandoned the principles of non-conditionality, non-interference, and respect for sovereignty, which continue to underpin the basic principles of china's foreign and aid policies. however, the growing emphasis on poverty reduction (减少贫困) and improvement of people's livelihood (改善民生) means that these are increasingly attuned to those values of human security which have been endorsed and promoted by the un and the international community (state council of china 2014; undp 2014b). the shift also reflects some important changes in the way china assesses global security threats and identifies its national interests; this is increasingly in line with the broader definition of human security. as china's foreign aid specialist wang xiaolin argues, the trend of china's foreign assistance has changed significantly from being driven by ideology and only aiding socialist countries to being based on its assessment of global security challenges. china sees the global security agenda, such as poverty reduction and tackling climate change, as being part of its foreign aid agenda, and hence its foreign assistance is more consistent with the millennium development goals (now the sustainable development goals) (wang 2014) . importantly, as the global security agenda expands, human security norms such as poverty reduction and environmental responsibility have emerged and been institutionalized as important norms and institutions in international society (kozyrev 2016; kopra 2017) . the global adoption of mdgs (2001) and sdgs (2016) has hugely contributed to the institutionalization of a human security norm in international society. building on the success of the mdgs, the sdgs with 17 goals and 169 targets are particularly determined to eradicate poverty and hunger in all their forms, which are the core elements of human security. moreover, the sdgs are also truly global in nature and universally applicable, and all countries have a shared responsibility to achieve them (unga 2015) . in this way, human security norms have become an important and legitimate basis for moral claims within international society and even have an impact on 'the criteria for rightful membership' of international society (falkner and buzan 2017, 31) . given that china is so eager to build its global image as a responsible 'great power,' it cannot ignore these changes. thus, the argument can be made that china may not entirely abandon its national interests and would not promote its foreign aid purely out of altruistic aspirations; however, it does indicate the ways in which china assumes and identifies its national interests in the changing international environment of the twenty-first century. in other words, china is increasingly seeing its national interests and security in terms of the interests and security of international society as a whole; in so doing, china is showing a growing sense of raison de système in global international society, in which human security considerations are becoming an important part of its foreign policy projection. china's participation in the global effort to address the ebola outbreak provides us with several important lessons as to how human security-oriented foreign and aid policies should be conducted, especially in an environment of emerging and complex human security challenges. the destructive nature of the ebola crisis and the devastation it brought with it again demonstrated the changing nature of global security threats. as ginsburg vividly illustrates: 'it is shocking to realize that a tiny virus with just a handful of genes can fracture families, shred communities, destroy national economies and destabilize whole regions in just a matter of months. but this is what we are witnessing with ebola.' (guardian, october 3, 2014). diseases like ebola can become as serious and deadly as the threats caused by conflicts and even wars. moreover, as viruses know no borders, once a breakout occurs, it can easily affect people across countries, regions and worldwide. as is often the case, it is always the most vulnerable individuals and groups who are the most affected. given the complexity and potential destructiveness of infectious diseases, future health security governance should be prepared with greater care. first, it is imperative that early warning systems for future health crises should be developed at the national, regional and global levels, especially in low-and middle-income countries. one of the important lessons that was drawn from the ebola crisis was the weak (or even lack of) healthcare systems in the three most affected countries. according to anthony fauci, a health expert based in bethesda, usa: 'if there was a system to have recognized and stopped the outbreak that began with the child in guinea in december 2013, we might have avoided the explosive outbreaks in sierra leone and liberia' (kupferschmidt 2016) . it is in this sense that the un secretary general ban ki-moon stressed 'the need to strengthen early identification systems and early action' (snyder 2014) . the east asian region has also been faced with many health and security challenges, for instance, the outbreaks of sars in 2003 and h5n1 bird flu in 2005-2006, both of which had the potential to turn into pandemics (fidler 2013) . the sars outbreak did indeed spark regional health security initiatives (caballero-anthony and amul 2015, 39). yet, to prepare for complex challenges in the future, more enhanced and sophisticated regional public health systems are required. secondly, the ebola crisis strongly demonstrated the value of cooperation between actors at various levels, including both state and nonstate actors (nsas). particularly, cooperation between external militaries and ngos is a notable development. both china and the usa deployed many troops to help control the epidemic. importantly, some ngos, such as msf, which had previously refused to work with national militaries, 9 are now calling for military intervention as part of outbreak responses. in fact, it has been proven that with their adaptability, discipline, ability to operate in challenging environments and logistical capabilities, the military can be a particularly valuable resource during large-scale public health crises (edelstein et al. 2015) . however, it should be emphasized that in this situation the operationalization of the role of states and their militaries cannot be properly understood in the traditional sense of state centrism. importantly, as the most powerful state in the world, the usa acknowledges that global health security is a 'shared responsibility' that cannot be achieved by a single actor or sector of government (white house, september 26, 2014) . thus, in any future health security governance, ngos and other nsas should become important partners, and through state-ngo or public-private partnerships (ppp), they should achieve their common objectives through collaboration. in addition to public-private partnerships, future health security governance should also pay sufficient attention to the idea of 'local ownership,' which values cooperation between international actors and local actors. exploring the concept of 'local ownership' in the field of conflict resolution and peacebuilding, shinoda (2012, 66) argues that unless it is solidly rooted in local society, conflict resolution and peacebuilding would end up becoming 'superficial' and 'short-sighted.' this is true with international development cooperation, because the ultimate aim of such cooperation should empower stakeholders of a local society to enable them to take responsibility for dealing with the situation. finally, the close link between health security and poverty is another case in point. indeed, the fact that 'poverty and infectious diseases interact in subtle and complex ways' has long been recognized by scholars through various case studies (alsan et al. 2011 ). the ebola case further supported the argument that human security and human development cannot be treated in isolation. poverty can and has often been the root cause of many human security threats. in this sense, future human security governance must combine proper defensive measures with more fundamental measures so that human security can be achieved and sustained not only through protection, but more importantly, through empowerment. in all these cases, should future human security-oriented foreign policies be truly realized, states must transcend their narrow national interest and seriously consider the dignity and well-being of the most vulnerable people in society. china's foreign policy. the 'eight principles' were announced by premier zhou enlai in 1963 during a visit to africa. the principles 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the responsibility of the security council in the maintenance of international peace and security: hiv/aids and international peace-keeping operations, sc/6890 with spread of ebola outpacing response, security council adopts resolution 2177 (2014) urging immediate action, end to isolation of affected states, sc/11566 remarks by the president at global health security agenda summit who (world health organization). 2014a. ebola situation summary. geneva: world health organization 2014b. statement on the 1st meeting of the ihr emergency committee on the 2014 ebola outbreak in west africa 2014c. high level meeting on building resilient systems for health in ebola-affected countries, meeting report. december 10-11 ebola virus disease latest ebola outbreak over in liberia; west africa is at zero, but new flare-ups are likely to occur china pledges continuous aid to africa in anti-ebola efforts china uses anti-sars experience to fight ebola in w china plans 1,000 more staff to fight ebola in africa china's anti-ebola efforts further enhance china-africa community of common destiny wang yi: xifei sanguo zhansheng aibola zui genben de shi yao fazhan qilai wang yi tan xifei sanguo xing forum on china-africa cooperation: creating a more mature and efficient platform key: cord-258792-4lakgpxp authors: yoon, sung‐won title: sovereign dignity, nationalism and the health of a nation: a study of china's response in combat of epidemics date: 2008-04-08 journal: stud ethn natl doi: 10.1111/j.1754-9469.2008.00009.x sha: doc_id: 258792 cord_uid: 4lakgpxp this paper seeks to understand the role of nationalism in china's policy towards the combat of emerging infectious diseases. by locating nationalism as a factor which facilitates or impedes global governance and international collaboration, this paper explores how nationalism influences china's political decision‐making. given her historical experience, china has in its national psyche an impulse never to become ‘the sick man of the east’ again. today, china's willingness to co‐operate with international bodies emanates out of reputational concerns rather than technical‐medical considerations. this was clearly manifested in her handling of two epidemics in recent years: the severe acute respiratory syndrome (sars) and hiv/aids episodes. this paper concludes that china's nationalism plays an inhibiting role in china's attempts to further incorporate herself into the architecture of global health governance in the long run. as well as a regulatory approach to a new disease outbreak. sars demonstrated that simple divisions between national and global health policy do not work in practice. during the outbreak, governments had to realise that a disease in any one part of the world is a threat to the rest of the world. however, ironically governments were in general reluctant to acknowledge the existence of the outbreak. most notably, the chinese government's response to sars was critical to the functioning of global governance in infectious disease control. it is a classic textbook example and a fundamental test case of how nationalism can impede or facilitate global governance and international collaboration. china had initially covered up the outbreak, but later reversed its stance to fully co-operate with the world health organization (who). scholars viewed china's initial response to sars within the context of china's poor public health infrastructure, ineffective and fragmented bureaucratic system, and political transition in leadership at the time of the outbreak. at the same time, china's remarkable u-turn towards international collaboration was demonstrated in the framework of the tremendous power of international organisation (i.e. who) in facilitating china's submission and the changing nature of international politics where sovereignty has been curtailed (eckholm 2006: 28) . some scholars have even gone further to argue that china's sars episode demonstrated the governance transition from westphalian to post-westphalian strategies (fidler 2004; ). yet, despite some scholars' claims based on china's initial reluctance and subsequent acquiescence to international forces, there is no evidence that china's sovereignty has been curtailed or that china has been integrated into global health governance. while the existing literature has focused on china's stunning reversal during the sars outbreak, less attention has been paid to the extent to which this turnaround has continued during the aftermath of sars. indeed, in light of the chinese leadership's attitude and commitment towards other infectious diseases such as hiv/aids and the recent cases of avian influenza, china's newfound openness did not seem to be genuine. this leads to the following questions: what were the factors that inhibited and then facilitated the collaboration during the outbreak? what eventually brought china back to 'business as usual' after the outbreak? what ultimately motivates the government's agenda and actions towards infectious diseases? this paper argues that nationalism in the form of national pride and security consciousness in china are enduring driving forces that have studies in ethnicity and nationalism: vol. 8, no. 1, 2008 shaped chinese policy towards emerging infectious diseases. by locating nationalism as a factor which facilitates or impedes international collaboration, this paper explores how the chinese leadership has exhibited ways in which nationalism affected much of their political decision-making in their quest to restore national pride and to secure china's developmental goals and national interests. it is argued that more often than not, nationalism hindered the formulation and implementation of health policy at both the provincial and national levels. maintaining a positive image of china in the international arena and securing the interests of the regime were key driving forces that affected policy-making. more specifically, this usually revolves around the ruling elites' competency in the handling of a national crisis and in its foreign policy. given the historical experiences of china, it has in its national psyche an impulse never to become the 'sick man of asia' again. the reaction of the chinese authorities at both the central and provincial levels towards unknown health threats is often to deny and cover up the disease's existence. this could be in part to avoid the stigma of being a 'sick' nation as well as to buy time in order to search for an indigenous solution to the problem. this sort of mentality belies a negotiated basis of existence behind the modern chinese nation -as if to say that there are no problems that modern china cannot handle or solve. yet it is also the same desire to appear 'healthy', 'confident' and a 'responsible' member of the international community that often swings chinese response to disclosure and collaboration. however, the latter only happens when the disease in question and china's handling of it is put under international scrutiny and often criticism. in short, china's compulsion to co-operate with international bodies emanates out of reputational concerns rather than medical considerations. nationalism can then be rapidly conjured up as a force which legitimises the draconian measures taken in the name of the nation to defend its sovereignty. one of the most immediate effects is that public health threats are often securitised and political-security solutions are sought rather than technical-medical ones. this means that any information pertaining to the outbreak is treated as classified, and is revealed on a 'need to know' basis, and collaboration is discouraged. it also means that the development of treatments is often seen as an opportunity to showcase the work of indigenous scientists who are 'able' to come up with a cure. an interrelated point pertains to the prospect of china's integration into global health governance. unless and until the chinese leadership examines the nationalistic element embedded in their approach towards growing disease sung-won yoon: sovereign dignity, nationalism and the health of a nation epidemics and globalising health challenges, china's ascendance to great power status will actually be harmed rather than helped. history is replete with examples of nationalist wars, where historical enemies and entire cities were wiped out, territories annexed and glory won, often at an exorbitant cost. history is equally manifested with examples where massive genocide has taken place in the name of the nation to realise some deranged nationalist blueprint, such as hitler's efforts to achieve a pure and superior aryan race or pol pot's infamous year zero project to restart civilisation in pursuit of a communist utopia. yet, such apocalyptic devastation is not always wrought by genocides or wars, but often through inaction, ineptness or impotence by national leaders who fail to defend the nation against aggression, man-made disasters, and pandemics. just as the great athenian statesman pericles learnt from the athenian plague in the fifth century bc and the roman emperor marcus aurelius from the outbreak of smallpox, epidemics could besiege large segments of any given population with quick and lethal consequences on a scale far greater than imperialistic wars or disastrous famines. the primitive state of medical science, limited understanding of hygiene, poor sanitary conditions, and widespread poverty often enable plagues and epidemics to thrive and spread with ease. the plague of justinian (sixth century ad), the black death (fourteenth and fifteenth centuries ad), and the bubonic plague (1665-1666) stand in testimony throughout the ages to remind the world of the imagery of the four horsemen of the apocalypse described in revelation 6:8: 'and i looked, and behold, a pale horse; and his name that sat on him was death, and hell had followed him'. it was not until the advent of modern advances in science and technology that the verse was more associated with nuclear weapons than with epidemics. since the peloponnesian war in 430 bc, when a plague that originated in ethiopia spread to the persian empire and to athens, the world has seen nation-states combat these epidemics at a localised and, at most, a national level (hays 1998: 39; porter 1999; watts 1997) . health policy on disease epidemics was a matter of sovereign discretion and exclusively dependent on the concerned nation's capabilities. when the black death (bubonic plague) in the fourteenth century spread through international travel and trading routes afflicted europe and north america, quarantine measures aimed exclusively at preventing disease threats from entering a nation from outside its borders were taken in major european nations. as in defence or foreign policy, health policy is most certainly an exclusive jurisdiction of the national government or ruling regime, and on numerous occasions, great rulers who have built their empires on military conquests have seen their legitimacy to rule crumble very quickly with the unbridled spread of pandemics in their nations. religion, as opposed to science, became the salvation from diseases and epidemics until the eighteenth century. nonetheless, the combat of plagues and epidemics has always invariably been seen and recognised as a national 'problem' for leaders, even though pathogens, bacteria and epidemics in general have no respect for political borders or sovereign rights over territory or people. however, as the rapid growth of populations and intensified human interactions in the sixteenth century and the process of industrialisation from the eighteenth century offered many communicable diseases opportunities to spread more widely, nations began to contemplate types of global response. one dimension of this response was a nascent form of international conferences. these early conferences were widely supported by the economic and political elites, as they believed that the spread of epidemic diseases would hamper the expansion of trade and the development of commerce. therefore, in retrospect, most nations' responses to epidemics were not born out of historically nationalistic gestures underpinned by a statist discourse to protect and defend against westphalian notions of sovereign dignity. instead, the nations' responses were traditionally based on more rationalistic and interest-based considerations. elites regard the protection of the nation's health to be of paramount importance, sometimes not so much to defend the citizen's right to life or liberty, but out of a less altruistic desire to ensure that the state's interests are maintained (e.g. keeping the economy vibrant, harvesting crops, maintaining troop levels, and rendering services and goods). as norman howard-jones observed, the very first international health conferences in the nineteenth century were not motivated by a wish for the general enhancement of the world's health, but by the desire to protect certain favoured (european) nations from contamination by their less favoured (eastern european) counterparts (howard-jones 1975: 10-32) . therefore, earlier forms of collaborative action illuminated these politicians' concerns about the impact of outbreaks on their nationals and, in particular, the rationale that underpinned the sense of nationalism behind the ruling elite's orientation towards healthy policy. one of the fundamental pillars of understanding in the westphalian notion of sovereignty in the modern fraternity of nation-states is the very fact that sung-won yoon: sovereign dignity, nationalism and the health of a nation all nation-states are sovereign entities, with their own jurisdiction over territories and peoples. extrapolating from this, all nations are therefore born 'equal' in this fraternity of nations, as enshrined in article 2 of the charter of the united nations that membership in the un is 'based on the principle of the sovereign equality'. the stark reality is that the members in this community of nations can hardly be equal. we hear of 'great powers' all the time, as much as we hear of the influence of the 'bi-polar' or the 'uni-polar' world. the logic that drives and motivates nations in this fraternity today is the quest to become 'great', and this desire for nationalism underpins most nationalist thinking and discourse within any given state. while there is no definite statistical evidence for this, it would not be an exaggeration to say that most nations wished that they could at least play in the finals of the world cup. for that matter, americans beam with pride as the us is consistently regarded as the only superpower left in the world, just as a significant number of russians look back nostalgically with pride to a glorious past. the french are convinced that they are the most superior civilisation and culture left in the world, and point to the vibrancy and the romance of their capital, paris, and the french dominance in luxury and designer goods industry. it is also quite clear that the chinese are extremely proud of their economic rise and perceive the hosting of the 2008 olympic games as a sign that it has made it in the world. in short, nations thrive on pride and sovereign dignity. most nations regard themselves as 'strong', founded on science, rationality, and progress. this vocabulary is found not only in discourse pertaining to health but also politics and economics. a healthy nation is strong, resilient, and able to withstand any political, economic, or health crisis. in 1832, the french medical community thought that the disease creating havoc in the eastern mediterranean would never affect france, expecting that it be confined to weaker and less civilised populations experiencing a poor and unhealthy climate. the cholera killed 15,000 people in four days in paris (delaporte 1986) , thus confounding most of the elites. today when political leaders speak of a healthy nation, they more often use 'health' as an analogy to draw comparisons, alluding to their aspirations for the country to be strong in all dimensions. the 'health' of a nation is therefore founded on both symbolic and substantive terms, and they are often intertwined in reality. in symbolic terms, a 'sick' nation is one that is weak. tsar nicholas i described the crumbling ottoman empire as the 'sick man of europe', just as russia has been tagged with the same label in the last two decades after the demise of the soviet union. in asia, one saw the japanese labelling the decaying qing china the 'sick man of east asia'. qing china was not only weak economically, militarily, and politically, but was also plagued by internal stifle, unrest, and opium addiction. the most potent symbol of this 'sick man of east asia' was the imagery of chinese men hooked on opium, a drug introduced by the british to reduce its trade deficit as its demand for chinese tea, silk, and porcelain increased. this imagery has underpinned various versions of chinese nationalism ever since. william a. callahan (2004) eloquently discusses the role of shame in chinese nationalism. as callahan argues, nationalism in china very often commemorates its weaknesses rather than celebrating the glories of chinese civilisation (2004: 202) . the official narrative of modern china is generally a tragic tale of its fall from being the 'centre of the universe' beginning with the opium wars, to the incursion of western powers into imperial china, to the grand finale of the invasion of china by the japanese. this is intricately linked with the rise of the communist party of china (cpc) and the founding of the people's republic of china (prc), and provides the very basis of the legitimacy with which the cpc stakes its political right to reign. it is this deeply seeded shame that motivates the modern chinese state never to fall behind again -whether in economic or political terms -as modern china seeks to erase the 'shame and humiliation' today. this quest for greatness is a significant impetus for china's economic rise. in essence, 'achievement' is used as a remedy to get rid of the shame that china has written into much of its official discourse over the past developmental trajectory. one need not look far for evidence. china's national anthem written in 1932 (translated below), one year after the japanese invasion of china, poignantly documents the sense of shame behind the 'sick' nation: arise, ye who refuse to be slaves! with our very flesh and blood, let us build our new great wall! the peoples of china are in the most critical time, everybody must roar his defiance. arise! arise! arise! millions of hearts with one mind, brave the enemy's gunfire, march on! brave the enemy's gunfire, march on! march on! march on! sung-won yoon: sovereign dignity, nationalism and the health of a nation numerous scholars have documented how the obsession with 'humiliation' and the goal of turning 'grief' to 'strength' have significantly influenced china's foreign and security policy towards the united states and japan (dittmer and kim 1993; gries 2004; shambaugh 1991: 81-93) . one of the most important dimensions is china's obsession with sovereignty or perceived infringements of her sovereignty or pride. this has made china hypersensitive to any sort of international criticism, it as an infringement of her sovereignty or meddling in her internal affairs. obviously one could argue that this is a political strategy of the cpc to deflect any sort of political challenge, but given the rise of nationalism within china over the last decade, one cannot help but realise that these sentiments might be more widespread than conceived. while china maintains a discourse of equality and camaraderie of friendship with other nations of the world, its actions and its policies often belie china's real intention of ascendance and greatness. as such, china is not only concerned with building capabilities associated with a great power, it is also extremely concerned with portraying an image that it is one. most interestingly, china's obsession with sovereign dignity and pride and its place in chinese nationalism is clearly manifested in its handling of two health-related issues: china's approach towards the handling of the aids epidemic and its response to the sars epidemic in 2002-2003. the impulse for china's reticence on sars perhaps the most pertinent question discussed in this paper is why the chinese leadership tried to cover up the extent of sars and later took decisive action. answering this entails an understanding of a number of factors, but it is argued that nationalism and sovereign dignity played a part in china's response to sars. despite all the changes that the country has undergone, the traditional so-called 'face-saving' approach seemed to be as intact as ever and even deeply engrained in the mentality of the chinese leadership. therefore, when there is an event that could damage national pride, it is highly embarrassing for them to admit. the best way to resolve the troublesome event is to actively avoid or deny. thus the mode of dealing with national calamity is to identify a problem before the outside world discovers it, take measures to address it, and only afterwards report the improved situation. these mechanics have been generally at the heart of the chinese leadership's crisis management, particularly with regard to emerging infectious diseases. this was evident in china's response to sars. the crucial feature of the sars outbreak in china from early january 2003 through early february 2003 was that the provincial authorities kept the lid on the situation. the cpc has tended to suppress negative news such as diseases and disasters out of fear that such information would disrupt national stability. cover-ups are usually started by local officials who want to avoid embarrassment in front of their superiors due to their incapability to control the situation themselves. therefore, there is no incentive for local officials to pass the information up the chain of command. when early cases occurred in guangdong province, the local authority was at least aware of the situation. anxious to avoid criticism for their mishandling of earlier outbreaks and in an effort to maintain guangdong as a location of commercial dynamism and economic growth, the provincial leaders concealed the gravity of the disease. later, provincial party secretary zhang dejiang, the highest-ranking official in guangdong, stated: 'if we made a contrary decision, it would have been impossible to achieve a gdp growth rate of 12.2 per cent' (cctv interview, 9 june 2003) . this denotes the fact that the guangdong leadership feared the impact of the disease's outbreak on national development. the potential 'loss of face' also contributed to provincial leaders' concealment, as the disastrous public health problem would eventually contribute to the negative effects on the cpc's legitimacy. sars was considered something that needed to be defeated before it became embarrassing. therefore, the suppression of information at the provincial level was not only motivated by development goals for the nation but was also prompted by the desire to save face and maintain reputation. once the virus spread internationally, the nature of the problem and the possibilities for resolution broadened significantly. when the chinese government failed to address the growing epidemic, the health problem in china became a political issue and an embarrassment for the central government. however, the central government's long-overdue response to growing infectious diseases was not reversed abruptly. beijing's initial reaction to the epidemic was silence and an unwillingness to co-operate. until early april 2003, an international team of experts was not permitted to investigate hospitals in beijing. china's health minister zhang wenkang declared at a press conference that there were twelve sars cases in beijing but claimed that the disease had not spread to other parts of china (abraham 2005: 45) . the discourse that sars was under control was also backed by hong tao, the esteemed chinese microbiologist, who asserted that the cause of the disease was chlamydia and that the outbreak was dying down. due to sung-won yoon: sovereign dignity, nationalism and the health of a nation systematic problems in the chinese scientific community -a lack of coordination; stifling political influence; hesitation to challenge authorities; and isolation from the rest of the world -the chlamydia hypothesis was firmly established in china (enserink 2003: 294) . when the world-leading scientific labs confirmed that the causative agent was a coronavirus that had never before been seen in humans, china's persistent assertion had to be withdrawn. it was another national embarrassment that the emerging power was short of a scientific solution. there was a major turning point on 20 april 2003. faced with widespread international criticism of china's unresponsiveness, president hu jintao and premier wen jiabao finally declared a war against sars, calling for accurate and timely information about the disease to be provided and shared amongst units and international partners. this announcement was widely reported by chinese newspapers and television. shortly after the declaration, health minister zhang wenkang and beijing mayor meng xuenong were dismissed, ostensibly for their inadequate response to sars. premier wen went on to attend the asean-china leaders meeting in bangkok on 29 april and stated that 'the chinese government is here in a spirit of candour, responsibility, trust and cooperation' (macan-markar 2003) . in hindsight, as the country's reputation suffered abroad, the leadership needed to re-establish itself as a responsible member of the international community in the eyes of its international counterparts. having exposed the emerging power's incapability of handling a disease crisis, the only way of restoring national pride was to show the world that the great china had the capacity to deal with the national threat efficiently and effectively in a short period of time. the chinese leadership made a lot of effort to inform the general public of the dangers of sars and to mobilise society in the name of the 'national' spirit. depicting the combat against sars as a 'baptism of fire' for the entire nation and urging the public to unite around the communist leadership to defeat the national crisis, the chinese government set up the 'sars control and prevention headquarters of the state council' headed by vice premier wu yi. the government created a fund for new building projects and the provision of more healthcare services (balasegaram and schnur, 2006: 80) . amazingly, the government was able to build a dedicated hospital for the treatment of sars within a week. apart from government initiatives, the propaganda department made an effort to 'nationalise' a regional outbreak into a national crisis and, in doing so, mobilised an entire nation into the battle against sars virus. the people's daily (15 may 2003) used traditional maoist revolutionary rhetoric, such as calling for the people to 'build out a new great wall -on the great spirit of the fight against sars' (ren zhongping, 2003) . the propaganda department worked towards alerting the people about the disease and instilling in every individual a sense of patriotism and national duty to rally around the cpc. in guangxi province, minority groups sang songs about sars; in inner mongolia, murals were painted to depict the sars experience; and in beijing, banners spurred comrades on, harkening back to mao's campaigns during the cultural revolution (balasegaram and schnur 2006: 81-82) . having decided to be transparent, the media sprung into full action with reports of 'whitecoated warriors' and 'angels in white coats', describing heroic stories of doctors and nurses working for love of their nation and its people. community leadership also re-introduced the traditional neighbourhood committee by revitalising the grassroots party structure. this committee, mainly consisting of elderly residents, barred outsiders and checked for sars symptoms in their neighbourhood. these committees created groups of ten households and appointed one volunteer. the volunteers were in turn grouped in tens and reported to a higher authority. this structure continued upwards until it meshed seamlessly with the communist party system that ruled the country (south china morning post 2003) . yet, what is important to note here is that this nationalism extends beyond making sars an immediate enemy of the nation. the image of a china being 'sick', the inability of chinese scientists and people to eradicate the virus independently, the ineptness of the chinese health system to effectively contain the outbreak were all smudges on the chinese image that the leadership wanted erased. by encouraging the national spirit and mobilising the energy of the entire population, the government was able to show the international community that china in fact had the capacity to deal with the national crisis, thereby restoring the national pride and dignity that was commensurate with china's international reputation and image as a rising great power. the success of this reversal did ameliorate the damage done to china's image by its previous bungling. china's handling of the sars crisis, unfortunately, does not represent its approach to epidemics in general. scrutinising the prc's approach to the hiv/aids epidemic in the country, china's reticent approach to international co-operation is clear. compared to the recent sars episode, the aids epidemic has been around for more than two decades. although its sung-won yoon: sovereign dignity, nationalism and the health of a nation effects are less 'visible' than the sars outbreak, in reality, the aids epidemic is probably more devastating and has had a much higher death toll than sars. aids, however, did not receive much attention from the central authorities until very recently. however, the actual number of aids carriers is believed to be much greater. the inaccuracy of the estimate is due to the fact that there is massive underreporting of the disease, especially the rural areas. there are many reasons for underreporting, but a shortage of adequate resources and a lack of openness in confronting the epidemic at many levels of government (provincial and local levels) are some of the major factors that contribute to china's slow response. exact figures are difficult to gauge because the government at the local level is very reticent to report on actual cases (human rights watch 2003). when aids was first reported in beijing in 1985, the initial cases were treated with disdain and the disease was labelled as 'foreign'. the government warned that young women having sexual relations with foreigners could be in danger, and that 'foreigners' would facilitate aids becoming an epidemic in the prc. the government also tightened immigration controls and required all foreign students entering china to present a certificate from their country of origin testifying that they were not infected with aids. during the 1990s, although aids began to spread from yunnan province to other parts of country, the chinese government officially denied that it had an hiv/aids problem. this was exposed as a lie by a few whistleblowers, at least one of whom was imprisoned for revealing 'state secrets' (watts 2006: 804) . therefore, the real extent of hiv/aids cases remains unknown as the government's long-standing position towards this epidemic has always been that aids is a 'foreign' disease requiring surveillance and border control, as well as action against social undesirables such as prostitutes, drug users, and blood brokers. the chinese government's response to aids was initially persistent silence and a refusal to acknowledge that the issue was serious. a major factor behind the government's recent change in its attitude towards the aids epidemic seemed to be the outbreak of sars in china in studies in ethnicity and nationalism: vol. 8, no. 1, 2008 2003, which exposed the dangers of not reacting to emerging infectious diseases. yet, it took almost two decades and a lot of pressure, internationally and domestically, before the chinese government decided to institute measures to 'contain' the aids epidemic. despite some candidness surrounding the discussion of aids in china, the scale of the problem is still being played down, mainly due to the government's tight control on media and infected aids patients not coming forward for fear of discrimination. thus the true extent of the problem remains unclear. yet, the chinese government was actually forced to address the aids epidemic for reasons very similar to those that led to the disclosure of the sars epidemic. it was sparked by the revelation of the very controversial case of an entire aids village in henan province, where thousands of poor farmers were infected by hiv while selling blood to the health authorities. initially the villagers were isolated and ostracised, and local authorities acted in the name of the national interest and the public good to cover up this outrageous negligence on the part of the health authorities. due to the mounting weight of evidence that china is in the grip of a major epidemic, the chinese government came under tremendous international criticism for their inaction over aids. the government seems to have increased efforts to fight aids by reversing some policies. despite enhanced intervention measures and infrastructure, stigmatisation, fear, and hidden infection constitute a vicious circle that fuels the aids epidemic in china. the prevalent societal attitude in china towards aids was and still is very prejudiced. aids is regarded as a 'foreign' disease and is associated with promiscuity, perversion, and homosexuality. hiv carriers are shunned by society as social outcasts and are seen as 'deserving' the disease because of their 'morally' decadent lifestyles. according to a survey conducted in china, seventy-five per cent of respondents said they would sung-won yoon: sovereign dignity, nationalism and the health of a nation avoid hiv/aids carriers and forty-five per cent responded that the disease was a consequence of moral degeneration (the un theme group on hiv/ aids in china 2002). the dominant narrative in china of these unknown diseases is characterised by a lack of understanding and education, and is 'nationalistic' in the sense that biological threats and diseases are still perceived by the majority of people to be 'foreign', even though germs do not respect political boundaries. it is very unlikely that health policy towards epidemics will be reconfigured overnight without a corresponding change in societal attitudes and government perceptions. there are other factors at work that have prevented the chinese state from addressing the aids issue openly and candidly. chinese nationalism has often compelled the chinese state to securitise any issue it perceives to be damaging to its national interests. the literature on aids has long highlighted that it is a significant security threat. significantly, other than the direct impact of aids on the constituent population, aids has grave consequences for the 'affected' nation. aids heightens the prospect of wars internally and externally and hollows out military and state capacities, weakening both to the point of failure as this is a disease that targets the most economically active and demographically most reproductive segment of any nation's populace (singer 2002) . moreover, aids will also have a tremendous and significant impact on the demographics of the population, as the disease has demonstrably killed off the most productive and strongest segment of the population first, rather than the infirm and weak segments. aids will dramatically increase health costs per capita within a relatively short period of time. it could possibly affect prospects for inward investment and long-term economic development. the chinese state realises that the aids epidemic might well have more disastrous and far-reaching consequences than previously thought. yet, at the same time, the chinese government realises that the inability to handle and contain any epidemics would have repercussions for their legitimacy to govern internally and china's reputation externally. given china's historical experiences, china has an obsession with sovereign dignity which has been rigidly built into her strategic and political culture. china therefore has a propensity to construe issues critical to china's interests as a zero-sum game, as the chinese outlook is very much influenced by neorealist thinking. this has rendered china hypersensitive to any threats and often to frame its responses to any challenges to its well-being by securitising these challenges. as such, china's initial reaction to the infectious diseases is most distinctly characterised by securitising the disease, as opposed to taking a biomedical and technical approach. china's incomplete turnabout on aids is in large part due to her reticence and inability to adjust her approach to perceive aids as something beyond a security issue. this is also significantly highlighted in the sars episode. right from the beginning of the sars outbreak, information about the disease was deemed to be a state secret. divulging data regarding infectious disease outbreaks could make one a defendant in a treason case (saich 2006: 77) . therefore, there was no reason to go public regarding a curious incident or with rumours of a new disease. despite recent changes, china is still characterised by its obsession with the notion of security and much information remains confidential, including information about infectious diseases. the scope of classified information is wide and can be flexibly applied to anything considered related to national security (human rights watch/asia and human rights in china 1997: 21-25) . while a 2001 regulation had amended a 1996 regulation that classified high-level infectious diseases as highly secret with the secrecy extending from the first occurrence of the disease until the day it was announced, infectious diseases still remained national security matters. when a report on earlier cases of sars was produced in january 2003 in guangdong, the report was labelled neibu or 'top secret', which meant that information about the situation must be kept among only the highest national officials (human rights watch/asia and human rights in china 1997: 25). the classification of sars as a secret may have been motivated not only by the post-cold war legacy (i.e. their obsession with security), but also the leadership's desire to hide from other nations vulnerable issues which could be regarded as national threats. in order to deal with the national secret, the top officials needed to close the lid tight. an array of actions and policies demonstrated this. for example, the ministry of health explicitly ordered the heads of beijing hospitals to report sars only through channels upward on a confidential basis but not to any media. according to one ministry of health official, they had been told by higher levels that the outbreak was a closed matter: 'this came from quite high up in our ministry. . . . we did not have that information and once we were told that the outbreak was officially closed, we could not secure cooperation' (greenfeld 2006: 87) . hiv/aids has been securitised in much the same way as sars. aids activists in china have been either detained or arrested by the chinese officials for 'harming the state security' or 'revealing state secrets' sung-won yoon: sovereign dignity, nationalism and the health of a nation (benjamin kang lim 2007) . with regard to releasing official figures on aids patients, the government withheld information from the public while they checked political matters and prepared for immediate economic repercussions. national interests and security maintained precedence over transparency. this sort of 'secrecy' with regard to national security issues is typical of post-communist regimes and of most countries. it also characterises what might be a first response for any country that is sensitive to the judgement of international opinion. interviews with the chinese scientists involved in the aftermath of sars revealed that many of them felt that it was a great shame that the virus was not first identified by chinese scientists, since the virus outbreak occurred primarily in china and the majority of the victims were chinese (ensernik 2003: 294-296) . in fact, many of the scientists were frustrated by the way information was 'partitioned' and the epidemic 'securitised'. yet, it is not only that securitisation of this epidemic that would pose a problem. a more important problem is how the prc elites could possibly believe that there could be a response other than a bio-medical solution to a health threat. this situation may be slowly changing as the chinese government becomes more amenable to outside co-operation as long as their regime and defined national interests are not compromised. there seems to be an inverse correlation between china's propensity to cooperate internationally and her desire to protect her core national interest and national aspiration i.e. reunification with taiwan. this aspiration is intricately linked to the regime's legitimacy and political survival and if threatened would lead the chinese government to become more hardline and nationalistic, and less willing to discuss any form of cross-border cooperation. the sars episode saw the regime's legitimacy challenged by the fact that the authorities appeared to be quite inept at handling the crisis, but more importantly the sars episode was also politicised as a reunification and a security issue. chinese nationalism complicated the handling of this medical crisis across the taiwan straits. preventing taiwanese independence has been a foremost chinese national priority. in that respect, china has consistently exerted tremendous political and diplomatic pressure to prevent taiwan from gaining membership in any international organisation. taiwan has made seven efforts to join the who. china insists that taiwan is an 'inalienable' part of china and should therefore not be recognised as an individual entity. when sars cases mounted in taiwan, the taiwanese government asked the who for assistance. in response to this, zhang wenkang, china's minister of health, stated: 'we hope that the leaders of taiwan authority no longer spread rumours with ulterior motives, or even use the disease as an excuse and in the name of human rights to try to enter the who, which is only opened to sovereign nations' (mirsky 2003) . this symbolised china's long-standing position towards taiwan, which denies taiwan's place in the international system. but it also reflected how chinese leaders regarded sovereignty issues over other impending issues such as the immediate crisis of the epidemic. for china's leadership, the health crisis was no longer a health issue but a political one. there is no guessing how the ruling elites would choose when deciding between political survival and enhancing international co-operation. the process of globalisation significantly impacts the socio-political context of health. emerging infectious diseases, in particular, have triggered the political aspect of public health because the threat of the trans-border spread of disease challenges the traditional state-centric approach to infectious disease policy. the pathogenic threats highlight the inability of states to act alone to prevent the spread of infectious diseases amid globalisation. as a consequence, emerging infectious diseases have forced a reconceptualisation of public health governance both nationally and globally, leading to an increase in the process of global collaboration. the concept of global health governance has therefore emerged in this context, characterised by the relative decline in the salience of states alone and the increased involvement of new ways of norm setting and compliance processes. the question that this article considers is whether nations and national dignity have been virtually impacted and eventually weakened by the new health governance mechanism which is able to set and control the rules of health at a global level. it is argued that global health governance may influence the nation's response to the threats posed by emerging infectious diseases such as sars or aids as a mode of building political compromises but does not considerably alter the nation's behaviour, at least for china. it is argued that in case of china, sovereign dignity and nationalism outweighed the global values in the response to infectious diseases. the chinese government's initial silence on sars and aids, and its lack of co-operation despite its awareness of the extent of the epidemic, demonstrated the nature of national pride inherent in china's response to national crisis. in pursuit of national prosperity through foreign investment and international trade, any discourse or narrrative on potential disasters such the sars or aids epidemics would naturally be suppressed at the first instance. in addition, the chinese leadership's obsession with issues of national security further allowed the sars virus to spread across the world. no one could disclose information about the epidemic unless they had security clearance, because sharing information pertaining to or even acknowledging the existence of any infectious disease is regarded as a crime by revealing 'state secrets'. if anything, the sars and aids episodes have shown that the existence of epidemics cannot be contained by censorship, regulation or legislation alone. however, once the information about the sars outbreak was divulged, the growing epidemic was beyond the national public health capacity, and to make matters worse, other nations began to criticise china's unresponsiveness, the chinese government had to institute 'damage control' measures by denying that it had any role in intentionally concealing the disease's existence. this would undoubtedly further damage china's national pride and dignity by announcing to the world that china was not able to deal with domestic public health problems. by the same token, the chinese government therefore had to show the international community that as an emerging power, it could still address the public health crisis, this time through mobilising the nation to participate in international efforts to stem the epidemic. with the help of international health expertise, china was able to successfully curb the sars epidemic in a very short period and with remarkable efficiency. its successful efforts somewhat ameliorated the embarrassment it caused itself by the bungled handling of the disease outbreak, and to a certain extent restored some of its lost national pride and international reputation. in the aftermath of the incident, china's successful story of controlling sars was a sign that china was incorporated into the global health governance where international health problems are resolved for the greater global public good. it seems, however, that china's leadership was only prepared for limited and selective openness. in light of china's response to recent cases of avian influenza, the need to preserve an infallible national image still takes precedence over public health concerns in the minds of china's leaders (cyranoski 2005a: 542-543; cyranoski 2005b cyranoski : 1009 . indeed, the incidents surrounding reporting of avian influenza in china clearly demonstrate how the chinese government has hindered progress towards halting the epidemic, denied the presence of an outbreak, prevented the exchange of information on the flu virus, and allegedly promoted widespread misuse of antiviral vaccination in chickens. scientists were often faced by less than cooperative local and central officials, whose primary concern was how health problems would negatively impact on national development goals. therefore, china's long tradition of avoiding sensitive questions and denying negative developments has yet to change. rather, it appears that national pride in a great china invariably contributes to the national response to emerging infectious diseases. in an era of rapid globalisation, it remains uncertain to what extent the chinese leadership's concern with nationalism and sovereign pride would modify itself to fit into the global governance if a more serious threat posed by a new transnational but more lethal disease than sars emerges. clearly, china's national pride and security would do little to further the achievement of china's incorporation into global health governance, not to mention the health of the population of an emerging world power. twenty-first century plague: the story of sars china: from denial to mass mobilization', in world health organization, western pacific region, sars: how a global epidemic was stopped china rejects internet claims of human cases national insecurities: humiliation, salvation, and chinese nationalism flu in wild birds sparks fears of mutating virus china's chicken farmers under first for antiviral abuse' disease and civilization: the cholera in paris, 1832 china's quest for national identity nationalism and the health of a nation eckholm, erik china's missed chance sars, governance and the globalization of disease from international sanitary conventions to global health security: the new international health regulations china syndrome: the true story of the 21st century's first great epidemic china's new nationalism: pride, politics and diplomacy the burdens of disease: epidemics and human response in western history the scientific background of the international sanitary conferences locked doors: the human rights of people living with hiv/aids in china sars strengthens china-asean ties joint united nations programme on hiv/aids, and world health organization containing sars: the scandal over taiwan', international herald tribune health, civilisation and the state: a history of public health from ancient to modern times building our new geat wall -on the great spirit of resisting and attacking sars', people's daily, 15 may is sars china's chernobyl or much ado about nothing? beautiful imperialist: china perceives america neighbourhood watchers join sars battle hiv/aids: china's titanic peril aids in china: new legislation, old doubts epidemics and history: disease, power, and imperialism summary of probable sars cases with onset of illness from 1 sung-won yoon is a phd candidate at the who collaborating centre on global change and health, london school of hygiene and tropical medicine (lshtm). prior to coming to lshtm, she completed her graduate studies at seoul national university and ewha womans university in korea. sung-won has worked as a policy researcher for various korean universities, think-tanks and the parliament of the republic of korea for several years, principally researching on social and health care issues. she was awarded a fully funded research fellowship by the korean government to undertake research work at london school of economics and political science before she embarked on her work at lshtm. key: cord-271853-wexe9gq0 authors: lu, quan; cai, zehao; chen, bin; liu, tao title: social policy responses to the covid-19 crisis in china in 2020 date: 2020-08-14 journal: int j environ res public health doi: 10.3390/ijerph17165896 sha: doc_id: 271853 cord_uid: wexe9gq0 the 2020 coronavirus pandemic has catapulted china into a serious social and political crisis. this article focuses upon how chinese social policy has responded to the covid-19 crisis. it reveals that the chinese welfare state has woven a comprehensive social safety net to mitigate the social suffering of chinese society in the midand post-crisis periods. different types of social policy programs have been combined and synthesized, including social insurance, social assistance, and social welfare arrangements. facing the challenges of the new risks caused by the pandemic, the collaboration of the chinese state and intermediary social welfare organizations has played a crucial role in providing both cash benefits and social services (benefits in kind). for the first time, social policy in china has acted as a major player for coping with the negative outcomes of a pandemic. this article concludes that the pandemic-related crisis has justified an interventionist approach and logic, driven by the state’s welfare system, which favors a model of “big government”. however, this model also requires justification and legitimation. the covid-19 pandemic represents the most serious public health crisis in china since the founding of the people's republic of china (prc), with the fastest spread and the widest infection range, challenging the country's socioeconomic development and people's daily life. facing these challenges, chinese governments have established strong command-and-control mechanisms, reminiscent of war times, to respond to this crisis and control the virus [1] . these measures appear to have worked sufficiently, and the pandemic in china seems to have been brought under control. the central government has played a proactive role by issuing a number of key policies in the field of social security, effectively relieving the anxiety of patients infected with covid-19 and their families from the financial burden of medical treatment, and also fully mobilizing social resources to effectively support the resumption of work and production. china has witnessed a rapid expansion of social security programs over the past decades, especially since 2000, and has established the world's largest comprehensive social protection network [2] . currently, the social security system in china consists mainly of three types of social programs: contributory social insurance, non-contributory social assistance, and tax-financed social welfare. employment injury insurance, and maternity insurance, and all of these programs are extended to urban employees. at the same time, it also includes basic pension insurance and basic medical insurance for urban and rural residents who do not fall under the category of urban employees. according to a report released by the ministry of human resources and social security, the total number of persons covered by pension insurance is 943 million (419 million are urban employees and 524 million are urban and rural residents). the total number covered by medical insurance is 1.344 billion (317 million are urban employees and 897 million are urban and rural residents). more than 95 percent of chinese citizens are covered through this program. medical expenses in conformity with the drug catalogue, diagnosis and treatment items and medical care service facility standards for medical insurance and medical expenses for emergency treatment or rescue are paid from this program. the current reimbursement rate is around 60 percent of the total expenses for insured urban employees and about 50 percent for insured urban and rural residents. further, at the end of 2018, 196 million employees had been covered by unemployment insurance, 239 million employees had been covered by work accident insurance and 204 million employees had been covered by maternity insurance. for china's social assistance system, the most important program is the minimum living standard scheme (mlss, known as dibao), which covers residents whose per capita income/annual net income falls under the threshold of the local minimum living standard in both urban and rural areas. according to the statistical report on the development of civil affairs issued by the ministry of civil affairs in 2019, 10 .07 and 35.02 million people received benefits from the mlss in urban and rural areas, respectively. in addition, medical assistance, educational assistance, housing support, legal assistance, and a relief system after natural disasters are also important ingredients of china's social assistance system. the country's social welfare program provides funds and social care services to ensure the livelihood of the elderly, children, and persons with disabilities who experience extraordinary difficulties [3] (see figure 1 ). however, interventions through social protection policy and questions that must be reconsidered in relation to disease-related crises have been largely neglected in academic research. therefore, this article will specifically analyze how different types of current social security programs have responded to the outbreak and the outcome of the pandemic-related crisis and highlight the however, interventions through social protection policy and questions that must be reconsidered in relation to disease-related crises have been largely neglected in academic research. therefore, this article will specifically analyze how different types of current social security programs have responded to the outbreak and the outcome of the pandemic-related crisis and highlight the shortcomings of these measures. the remainder of this article is organized as follows. section 2 constructs an analytical framework for the study. section 3 presents the research findings, including reflections on policies in areas such as unemployment insurance, welfare institutions, social insurance, and social assistance. section 4 offers a discussion and concludes the paper. within modern capitalist welfare systems, social policy is considered an institutional response to the negative effects of free-market competition and the rising and contingent risks that occur during market fluctuation [4] [5] [6] . in particular, state-organized social protection programs have corrected the primary distribution mechanism, mitigating social problems in the capitalist market economy. social policy dovetails with the long-term institutional policy intervention by welfare states in the field of production and reproduction [7] , having been established in the continuing transformation of the capitalist economy from a laissez-faire model to a market economy increasingly regulated by welfare states [8] . although the formation of modern state-organized social policy represents a long-range transitionary process, it is necessary to take another aspect of social policy into consideration-the social policy and social protection adopted and stimulated by short-term events and shocks. in particular, special attention should be paid to social crises and socially and economically anomic developments that deviate from the state of social normality, challenging and jeopardizing regular and consistent socioeconomic development within a short-term or medium-term period [9, 10] . social crises often alter the "normal" state of a society, creating a critical juncture posing an acute threat to the status quo of the current social and political system. the nexus between crises and social policy has not been investigated sufficiently in academia. commonly, crises have been regarded as negative events that can overshadow the regular functioning of welfare states, causing dysfunctionality and disruption of the existing social order. moreover, historically, social crises are closely related to welfare state retrenchment. for instance, the oil crisis in the 1970s and the subsequent stagflation in the western world had precipitated the end of the golden age of capitalism and the postwar economic boom, resulting in the reduction of social expenditures during the reagan and thatcher administrations [11, 12] . however, the intuitive assumptions concerning the nexus between crisis and welfare retrenchment have been upended by empirical developments in various welfare states and welfare regimes. usually, social crises have increased the suffering and the poverty gap in a society and precipitated social protests and social turmoil, challenging the current social political order and endangering the legitimacy of governments. against this backdrop, many state administrations have been inclined to expand public revenues and state social investments to circumvent social disorder and sharply increasing social and economic problems. in some cases, crises have fostered new opportunities for the extension of welfare state intervention and the expansion of social protection programs. conflict theories have generally verified that social conflicts such as social protests, social movements, and struggles among different social classes for resources have benefited and accelerated social policy expansion in welfare states [6, 13] . social crises represent a special type of social conflict. during the outbreak of crises, social conflicts usually intensify, social grievances are raised, and the battle among different social classes for subsistence and resources escalates. all this tremendously jeopardizes social cohesion; thus, social and political responses are urgent for the survival of governments. if governments do not act in time, social discontent may transform into destructive protest. for instance, the roosevelt-administration initiated welfare state arrangements in the united states in the 1930s after the shocking (after-) effects of the great depression began to unfold [14] . hort and kuhnle have verified empirically that after the asian financial crisis of 1997-1998, social expenditures in the region of east and southeast asia were not reduced as usually assumed; on the contrary, in nearly all of the 10 selected examples in this region, social protection programs remarkably expanded, during and even after the crisis [15] . these counterexamples demonstrate that crises do not always cause austerity and the state's retreat from public investment. under certain conditions, crises and the subsequent pressure imposed upon governments may unintentionally become driving forces for elite groups to change and respond to critical demands from society. in other words, the suffering during periods of crises can be transformed into positive assets for welfare state extension and expansion. this paradoxical development concerning welfare expansion during economic crises has also been traced in the developmental trajectory of the korean welfare state [16] . historical examples, along with the current pandemic crisis in 2020, have unveiled a trend in which state administrations from various countries are inclined to expand their capacities and intensify state intervention in society to lessen social tensions and calm the social discontent and public anger emerging from the outbreak of crises. in major global crises, such as the great depression, the global financial crisis of 2007-2008, as well as the covid-19 crisis, "big government" represents a model for coping with social problems and social conflicts [17] ; accordingly, the myths of market omnipotence and neoliberal ideology have been substantially diluted [18] . counter to assumptions concerning the retreat of welfare states, these substantial crises have strengthened the power of the state, disenchanting the "laissez-faire model". facing a crisis of acute existential survival, ordinary working populations and residents, as well as enterprises short on liquidity must seek assistance and bailouts from the state. in turn, the state must devote considerable resources to society to ensure a threshold of existence. otherwise, widespread malnutrition or famine, or the demise of many small-and medium-sized enterprises, would very likely endanger the state's basic functioning, causing enormous loss of human resources and financial drain, and leading to danger and risk for the survival of the state itself. crises have provided stimuli for governments to assume the role of the ultimate guarantor and provider of public goods for their citizens. thus, crises are somehow related to "big government" and an active interventionist state. in the chinese case, the pervasive model of "big government" may shift rapidly into a quasi-war state to respond to crisis. however, many emergency measures and acts need special justification and legitimation, since personal freedoms and right of free mobility may be constrained, as they have been during the pandemic-related lockdowns and curfews. the social security system has been designed and built to cope with risks. however, the covid-19 pandemic is a sudden public health event, which by itself is a risk of a new type. it therefore brings substantial challenges to the existing social security system. during the covid-19 pandemic, china's social security system has largely functioned well in many aspects, but some serious problems have also been exposed that call for further improvement. this study applies the method of event analysis with a special focus on social and political responses to this special crisis event. the trajectory and chronological development of covid-19 from february through june of 2020 has been intensively observed and consequently integrated into our analysis of the social policy responsiveness to this crisis-related event. the pandemic-related crisis has been divided into three primary stages-the pre-crisis, during crisis, and post-crisis periods. regular social policy arrangements before the outbreak of covid-19 have previously been introduced. some hallmark subevents in the arena of chinese social protection during the outbreak of the pandemic and in the post-crisis period have been identified and analytically discussed and reflected, including policy measures and strategies adopted in the areas of health insurance, unemployment insurance, social assistance, and social welfare, among others. to complement our event-centered policy analysis, we have collected different kinds of secondary data such as policy documents and data published by the state administration, including the ministry of human resources and social security (mhrss) and the ministry of civil affairs (mca), which characterize the coping strategies of the chinese state and society in relation to covid-19. secondary documents issued by different state administration and public media have uncovered the urgency and exigency created by pandemic and presented an assemblage of emergency measures, formal and institutional policies implemented during the crisis. through the process tracing crisis-related events, using various data sources, we reconstruct the panorama of social policy responses to the critical juncture that chinese society experienced amid the pandemic. the impact of the covid-19 pandemic on employment might be short-term, but it is more serious and complicated than the situation of sars in 2003 [19] . therefore, helping enterprises to overcome difficulties is still an important measure to stabilize employment and the economy. governmental departments have formulated various policies for different regions and different types of enterprises to reduce social insurance contributions. for example, in hubei province, where the pandemic has been most severe, the government has exempted certain employers (except for the public sectors) from paying social insurance fees for no more than five months. for other regions, the social insurance contributions of large enterprises may be halved for a period of no more than 3 months, not exceeding 5 months for small-and medium-sized enterprises. finally, enterprises with difficulties in production and operation may apply for deferred payment of social insurance premiums for no more than 6 months. (the above contributions refer to the portion paid by the employer; payments by individuals must be made on time. it is noteworthy that none of the above policy adjustments affect personal entitlements.) using unemployment insurance to help employers and reduce the unemployment rate is another important measure. specifically, for small-and medium-sized enterprises, if the unemployment rate is not higher than that in the national survey of the previous year, part of the unemployment insurance benefits may be refunded to stabilize employment. meanwhile, enterprises were encouraged to implement training programs for those affected by the pandemic, which could be subsidized if they organized employees to participate in offline or online vocational training during the shutdown period. according to a spokesperson from the ministry of human resources and social security, the pension insurance, unemployment insurance, and employment injury insurance contributions reduced in february reached 123.9 billion yuan ($17.5 billion). the total amount of deductions in contributions from february to june was estimated to be more than 500 billion yuan ($70.6 billion), effectively supporting the resumption of work and production. at the same time, 1.46 million enterprises received unemployment insurance refunds, amounting to 22.2 billion yuan ($3.1 billion), benefiting 49.51 million employees [20] . notwithstanding the achievements outlined above, some problems have also been exposed with regard to supporting enterprises by fully utilizing unemployment insurance policy. the functions of the unemployment insurance system are twofold: one is to maintain the basic livelihood of the unemployed and their families, and the other is to actively create conditions for their reemployment through professional training, job referrals, and other means. at present, the main function of this system in china is to maintain the livelihood of the unemployed; however, the promoting and preventing functions have not been fulfilled. it is mandated that employees shall participate in unemployment insurance, and the premiums should be jointly paid by employers and employees; however, statistics reveal that the number of people participating in this insurance program stands at 196 million, accounting for only 45 percent of urban workers. this is the lowest insured rate among all types of social insurance, because a large number of migrant workers and informal employees are not included in this program. at the same time, the cumulative balance of unemployment insurance funds reached 581.7 billion yuan ($82.1 billion), 6.4 times of its expenditure of 91.5 billion yuan ($12.9 billion) in 2018 [21] . in other words, even if unemployment insurance fees are no longer collected, the funds can still be used for more than 6 years, suggesting that the amount of cash benefits paid out is low, and other unemployment benefit programs should be added. it is worth noting that, in this pandemic, some companies in china have adopted innovative forms of employment such as "shared employees", with individuals working in multiple companies at the same time, to reduce their own expenditure burden by lowering wages and/or not paying social security fees; however, the government has also required these companies to reduce the layoff rate and pay basic wages. therefore, a responsibility-sharing mechanism should be established to finance the expenditures. in this sense, the unemployment insurance funds can shoulder the task by paying a portion of the wages for workers who have not returned to work, and thereby reducing the burden on the enterprise. these measures will better allow the enterprises to weather the storm. the practice of the unemployment insurance system has exposed another problem: according to current regulations, insured persons will not be qualified to receive unemployment insurance benefits after being laid off, unless they have contributed to the system for no less than one year. in the pandemic, a new special policy has been introduced to provide unemployment subsidies for laid-off employees who have contributed for less than one year. however, this subsidy is lower than the usual unemployment insurance benefits. we believe that the special policy should become part of the formal unemployment insurance system and be incorporated into the current regulations. welfare organizations, such as nursing houses for people in need, tend to be higher-risk areas in terms of emergency management, as these are places where elderly people, dependent children, people with disabilities, etc., live in close quarters. in the event of emergencies (including the covid-19 pandemic), high-density living spaces and collective actions cause a chain reaction of infection, making residents even more vulnerable [22] . indeed, specific demographic groups living in welfare organizations are susceptible to covid-19 because of their underlying health conditions, making special protection policies during the pandemic more significant and urgent than ever. in the early stages of the areas with high incidence of covid-19 in china, there were clustered cases within nursing homes. on 21 february 2020, according to the notice of the wuhan civil affairs bureau, as of february 19, social welfare agencies in wuhan had a total of 12 confirmed cases; 11 were elderly residents (including one deceased) and one employee [23] . in response to this, the relevant departments implemented three measures: (1) several anti-pandemic guidelines were issued for different types of welfare agencies based on the risk level of the region, followed by stricter closed management for these agencies to accommodate the elderly, persons with disabilities, and their service staff. (2) cross-regional caregivers were arranged to provide necessary support. there were more than 20,000 elderly residents in the old-age care agencies in wuhan, but only 3000 local care staff. in addition, some of these caregivers were infected or self-isolated, so there was a shortage of care staff in general. thus, the ministry of civil affairs of the central government coordinated cross-regional care and nursing staff to offer support to wuhan [24] . (3) care services for stay-at-home elderly residents whose families were isolated and/or sick were provided. daily life became more complicated for elderly residents living alone due to the pandemic, and their routine caregivers were not always available to serve in a timely manner. moreover, some caregivers were being treated or medically isolated because of the pandemic, which forced vulnerable groups to stay at home. to address this situation, welfare agencies would provide door-to-door services or arrange for these residents to be cared for in-house. however, the protection for some caregivers and volunteers in this case was, to some extent, less focused. in the process of prevention and control of the covid-19 pandemic, in addition to medical workers, some volunteers were infected or even passed away at work, but technically, volunteers cannot be identified as beneficiaries of work-related accident benefits; similar cases also applied to caregivers as informal workers without work-related accident insurance. therefore, establishing a social compensation system is necessary. social compensation refers to the compensation by the state and society for the loss of interests (physical disability or a sharp decrease in income, and so on) of relevant stakeholders, when is caused by uncontrollable risks (such as natural, societal, or policy-related events). germany and the taiwan region have built relatively complete social compensation legal systems, but mainland china has not yet established such a system. unlike the civil compensation caused by torts, the administrative compensation brought by wrong administrative acts and state compensation brought by judicial misconduct, social compensation is mainly to pay for losses caused by wars, natural disasters, and other uncontrollable social risks. this includes not only compensation for the direct victims of such disasters, but also praise for the staff and volunteers involved in disaster relief. in china, the social insurance system is primarily composed of five sub-programs: medical insurance, employment injury insurance, unemployment insurance, pension insurance, and maternity insurance. the first three in particular have played a major role in providing economic support for the insured during the covid-19 pandemic. 3.3.1. medical insurance and related policies: programs that bear the brunt as mentioned above, there are two kinds of medical insurance system in china: one for urban employees, and the other for urban and rural residents other than urban workers. the former is paid by employers and employees (6 percent and 2 percent of wages, respectively), and the latter is paid by residents and subsidized by the government (in 2020, the individual contributions are 280 yuan, and the central and local financial subsidies are not less than 270 yuan). the medical insurance fund is principally used for in-hospital and substantial medical expenses of the insured, and the current average reimbursement rate is more than 70 percent of the total expense for urban employees, and around 60 percent for urban and rural residents who participate in the scheme. effective medical security measures, mainly medical social insurance, were taken in a timely manner during the covid-19 crisis in china, so that patients and their families are relieved from worrying about treatment costs, specifically: (1) shortly after the outbreak, the state issued a policy to include drugs and medical services for the treatment of the new coronavirus as part of the payment range for the medical insurance fund. (2) furthermore, the personal medical burden is borne by fiscal resources of the government, thus achieving free treatment for patients with covid-19. the policy was initially limited to confirmed cases, but was later expanded to suspected ones. (3) simultaneously, when people seek medical treatment within one's coordinated areas of the social medical insurance fund, it is mandated that treatment must be provided first, with the fee to be settled later. (4) for medical institutions admitting a large number of patients, social medical insurance would prepay funds to ensure that the effectiveness of treatment from hospitals is not impaired due to payment policies. the above policies may be summarized as "two guarantees", first to ensure that no patient is rejected or treated in an untimely manner due to medical expenditure or cost problems, and, second, to guarantee that no designated medical institution is impaired from treating patients due to budget management regulations from the medical insurance fund. for foreign patients, if they have participated in china's basic medical insurance or any commercial insurance, their fee will be paid by the corresponding insurance funds; alternatively, they must bear the cost themselves. however, whether insured or not, medical institutions will treat first and charge later to ensure that everyone can receive medical treatment in time. the total cost of confirmed and suspected covid-19 cases in china was about 1.486 billion yuan ($0.21 billion) as of 6 april 2020. the per-capita medical cost of diagnosed inpatients reached 21,500 yuan ($3035), and of the severe ones, more than 150,000 yuan ($21,176). the medical insurance fund paid 990 million yuan ($139.8 million), accounting for 66.6 percent of the total medical cost. the total cost of diagnosed inpatients involved was 1.118 billion yuan ($0.16 billion), 746 million yuan ($105.3 million) of which was paid by the medical insurance fund, accounting for 66.7 percent. the total cost of the suspected patients was 368 million yuan ($52 million), with the medical insurance fund paying 66.6 percent of it (245 million yuan) [25] . overall, the medical insurance fund paid about two thirds of the total cost, and the remaining one third was borne by fiscal funds at various levels. however, these medical security measures were not without constraints. many of the medical security policies issued during the covid-19 pandemic were interim measures, which made them difficult for some local medical funds to implement in an orderly fashion [26] . one question yet to be clarified concerns the ultimate responsibility for payment: between public finance and the medical security fund, which one should eventually bear the medical expenses, or how they should be shared on the basis of specific principles? that is, in this pandemic, the medical security funds and fiscal funds work together to provide free medical care to patients. however, according to the social insurance law (the third paragraph of article 30), the basic medical insurance funds should not pay expenses that should be borne by public health funds. therefore, it is necessary to rethink the relationship between public finance and medical security funds in major pandemics like covid-19. to address this problem, the first step is to take the perspective of the comprehensive process of public health emergency management. according to china's emergency response law, the emergency management process includes four phases: prevention and preparation; monitoring and early warning; rescue and disposal; and rehabilitation and recovery. on the one hand, the beneficiaries of the public health funds include the entire population, so these funds should be mainly used in the prevention and preparation phase, for vaccination, tracking, and service provision for people who test with underlying health conditions. on the other hand, medical insurance helps diversify risks among insured persons, so it should mainly target the medical expenses of patients. furthermore, the impact of major public health events on different regions is often disproportional. according to the latest information, among 84,614 confirmed cases recorded nationwide, 68,135 were diagnosed in hubei province, accounting for more than 80 percent of the total cases. however, at present, the overall planning level of medical insurance funds in china is only at the municipal level, inevitably resulting in a larger burden of medical expenses in areas with severe pandemics, which cannot be shared on a larger scale. faced with such a contradiction, limited by the reality of the situation, medical insurance cannot achieve national pooling in a short period of time; it is still necessary to establish a sharing mechanism between the medical insurance and the public finance for medical expenses, especially in areas with severe pandemics. the responsibility-sharing mechanism between public finance and the medical insurance system also concerns the issue of due beneficiaries, or more specifically, foreigners in china and chinese students overseas. for foreigners in china, as long as they have participated in medical insurance, they are entitled to benefits; and if they also fulfill their tax obligations, they should also benefit from public financial subsidies. for overseas students, in the context of the global spread of the covid-19 pandemic, a large number of students want to return to china. in response, the chinese government has issued a policy stating that if they return, they will be responsible for their accommodation and boarding expenses during the period of quarantine. whether their medical expenses will be paid depends on whether they have participated in medical insurance. this practice is in line with the basic principles of medical insurance. however, if the medical expenses are mainly to be borne by public finance at the national level, these students should enjoy free treatment, regardless of whether they are insured or not, paying taxes or not. other insurance sub-programs have also contributed to the battle against the covid-19 crisis. as far as unemployment insurance and work-related injury insurance are concerned, although the contribution rates have continued to decline over the past five years, and the scope and level of expenditures have increased, the accumulated balances have continued to rise [27] . (there may be many factors contributing to the increasing accumulated balance. first, and likely foremost, more workers have participated in the social insurance system. according to the ministry of human resources and social security, the number of participants in the unemployment insurance system increased from 170.43 million in 2014 to 196.43 million in 2018. second, on the expenditure side, the total number of beneficiaries has remained stable, fluctuating around just above 2 million people during 2014-2018, despite the relatively higher level of benefits and larger scope of compensation projects for qualified insured persons. moreover, the level of overall planning in the unemployment insurance system has been low, reducing the efficiency of unemployment insurance funding, which also helps explain the situation. relatively developed regions usually enjoy more advantages in the labor market such as more local and immigrant workers, and thus more contributions to the unemployment insurance program, while unemployment rates are relatively low, in contrast to underdeveloped regions. these developed regions have contributed the most to the accumulated balance on a national scale, but this surplus cannot be properly shared by other regions if they are not in the same overall planning area.) this has provided a solid foundation for expanding expenditures related to the pandemic. employment injury insurance was adjusted in time to recognize and thus protect caregivers on the front line. to begin with, it was made clear that medical care staff and other related staff, who were infected with covid-19 or died from it in the course of their work to prevent and control the pandemic, would be recognized as work-related injuries cases, and their legitimate entitlements and interests would be protected. given that the covid-19 outbreak in china was mainly concentrated in wuhan, the central government mobilized medical care staff from other administrative areas to support wuhan city. from 24 january (a traditional chinese holiday, the eve of the spring festival) to 8 march, approximately 42,600 staff members from 346 medical teams across the country arrived in wuhan and hubei province to participate in medical treatment. however, as of 11 february, 1716 medical care staff, accounting for 3.8 percent of the national confirmed cases, had been confirmed as infected with covid-19 nationwide [28] . in addition, as of 8 march, 53 community workers perished in the line of duty during the epidemic prevention and control [24] . in order to ensure the basic entitlements for these employees, the relevant authorities opened a "green channel" to simplify the procedure for identifying work-related injuries. at the same time, if the requirements are met, deceased medical care staff and other pandemic prevention workers are eligible to be recognized as martyrs. according to the regulation on honoring martyrs, the state has established a reward system for martyrs. the reward standard is 30 times the per capita disposable income of urban residents in the previous year. meanwhile, the state grants preferential treatment to the survivors of martyrs to ensure that their quality of life is not lower than the average living standards of local residents, and the state will also provide support for their children's education and parents' pension. furthermore, the unemployment insurance system, by nature, works counter-cyclically in the sense of economics. as the pandemic caused a large number of enterprises to fail in resuming a timely production schedule, workers were thus unable to return to work, which adversely affected both the employers and employees. as a policy response, a series of regulations have been issued by various governmental departments to broaden the scope of beneficiaries. for insured persons who lost their jobs due to the pandemic in hubei and other pandemic-stricken areas, if they do not meet the basic requirements for receiving unemployment insurance (e.g., participating in and contributing to the insurance fund for no less than one year), they will be offered an unemployment subsidy. the standard is no higher than 80 percent of the local unemployment insurance premium, and it is only paid for six months. for those who had not contributed to unemployment insurance, the unemployment assistance benefit would be paid, in an amount equivalent to 120 to 150 percent of the social relief amount prescribed by the local civil affairs department, and the specific amount is determined by the provincial government. in most countries, social assistance acts as a bedrock and functions as a last resort of social protection, which aims to contribute to the prevention and alleviation of poverty. china issued the interim measures for social assistance (imsa) in 2014, which initially established a social assistance system consisting of the minimum subsistence security system and eight specific social assistance programs. (the eight specific social assistance programs include the minimum living standard scheme, the relief and support system for people living in dire poverty, medical assistance, educational assistance, housing support, legal assistance, a relief system after natural disasters and the temporary-assistance scheme.) with the target of "precise poverty alleviation" to be achieved in 2020, the goal of the social assistance system will shift from eliminating absolute poverty to alleviating relative poverty [29] . following the outbreak of the covid-19 pandemic, a range of social assistance measures were taken to guarantee a basic livelihood for the poor. during the period of epidemic prevention and control, vulnerable groups, such as families receiving subsistence allowances (i.e., the dibao households), low-income groups, vagrants, beggars, and workers who could not return to their workplace, encountered many difficulties as a result of regional closures, self-isolation, or quarantine. to address this situation, chinese civil affairs departments adopted a series of measures: (1) for the dibao households, the family means test could be carried out remotely, and the means test and dynamic adjustments could be suspended in areas with severe pandemics. (2) the amount of cash benefits for the impoverished increased. for instance, hubei province stipulated that 500 yuan ($70.6) should be added to the amount received by people in need in urban areas, and 300 yuan ($42.4) in rural areas. (3) temporary assistance would be given to those who have difficulty in life due to self-isolation, quarantine, or infection. (4) in principle, china's social assistance is mainly for people with local household registration (hukou). however, during the covid-19 outbreak, temporary accommodation, food, clothing, and other help was provided to non-local residents in need. despite the success in constraining the covid-19 pandemic, at present, one of the major problems with social assistance in china is that each specific sub-program is based on the minimum subsistence security system. in many regions, only those households with low-income are qualified to apply for benefits from other specific assistance programs. during the covid-19 pandemic, there were many laborers who could not return to their hometowns in time for the new year's holiday. urban residents' incomes dropped, and they experienced temporary difficulties due to their employers failing to resume work in time. these fragile groups are undergoing hardship and need temporary assistance. however, according to china's imsa, the objectives and standards of temporary assistance are not clear. in practice, it is mainly aimed at the homeless. but it should be also targeted at fragile groups whose lives have been severely constrained during major crisis events like the covid-19 pandemic. since china's social assistance is tied to local household registration, workers and residents from other administrative areas cannot apply, which may be reasonable under normal circumstances, but in the context of major emergencies, household registration restrictions should be softened. this scenario represents another problem in the existing social assistance system that has been exposed during the covid-19 pandemic. many people in need of social assistance benefits might not be living in their local household registration location, and thus cannot possibly apply in a timely manner. thus, it is crucial to reflect on the current social assistance system in china and extend social assistance benefits to all residents in the face of sudden public health events. furthermore, the current social assistance system operates mainly by providing cash benefits. however, in this pandemic, most communities have adopted the strategy of closed management, and cash benefits alone might not enable the beneficiaries to purchase goods or services in time. therefore, during the covid-19 pandemic, social assistance must provide in-kind benefits and services and ensure the basic livelihood of chinese residents. at the same time, special emphasis should be placed on employment assistance, as it helps people who have temporarily lost their jobs due to the pandemic become more employable as soon as possible and become self-reliant workers again. in modern society, social security systems represent an important institutional arrangement in responding to individual risks through collective organization. with the proper utilization of techniques and digitalization in public services, the efficiency and effectiveness of the social security can be substantially enhanced. first of all, a number of charitable organizations actively carry out various fundraising activities to make up for the shortage of public resources. during the pandemic prevention and control periods, charitable organizations fully utilized their advantages in terms of fundraising, social services, and mental health interventions. various foundations mobilized social donations and purchased pandemic materials for prevention, effectively making up for the lack of materials in some significant areas in the early stages of the crisis. as of 24:00 on 8 march, charitable organizations and the red cross system at all levels across the country had received about 29.29 billion yuan ($4.14 billion) in donations and donated about 522 million items [24] . among them, the wuhan red cross society (rcs) received more than 1.697 billion yuan ($0.24 billion) by 24:00 on 3 april, according to the announcement on its official website [30] . in addition, the closed management of residential areas in many regions brought great inconvenience into the daily lives of residents. many charitable organizations have launched services such as centralized purchase of daily necessities for residents and the provision of mental health counseling to help residents survive the pandemic period. in addition, efforts to promote and practice online activities not only improved the efficiency of the services, but also reduced the risk of pandemic spread. after the pandemic occurred, various social security agencies actively promoted online processing. business that previously was undertaken on a face-to-face basis could be moved online, thus reducing the crowding of people, the chances of infection for various fund-contributing companies, charitable organizations, etc. moreover, the efficiency and quality of such services were also improved. for example, the departments of human resources and social security announced an online application platform for claiming unemployment insurance benefits, notifying each recipient about their benefits online. it is believed that after the pandemic, more beneficiaries of social insurance will be accustomed to handling social security procedures or formalities online. nevertheless, looking back at the performance improvement of the social security system reveals some urgent and necessary adjustments. the larger and broader the impact of the public health emergency, the more actors are involved in the response, and more effective cooperation between different parties is required [31] . among them, the most important is the cooperation between the government and charitable organizations. as the third sector, charitable organizations can provide more precise, differentiated, and high-quality services. over the course of the pandemic prevention and control, charitable organizations not only demonstrated a strong capacity to draw resources, but also exposed problems such as insufficient credibility, untimely information disclosure, and unfair resource distribution. for example, the wuhan rcs did not distribute donated materials to hospitals in time, there was unfairness in the process of distribution, and the information about donated and distributed materials was not disclosed in time, all of which led to a wave of questioning by the public. charitable organizations in china are largely still immature; therefore, to strengthen their capacity, china should focus on the following three aspects: (1) strengthen the role of hub-type charitable organizations such as the charity federation, the rcs, etc., at all levels, and utilize them as a link between governments and charitable organizations to coordinate social resources in response to major public crises. (2) acknowledge the shift in charitable organizations' functions from financing to service provision. charitable organizations in china are currently divided into social groups, foundations, and private non-enterprise units. among them, foundations can both raise funds and provide social services; private non-enterprises can only provide social services and are unable to raise funds. in accordance with the principle of the social division of labor, it is recommended to establish a new pattern, with funds raised by foundations, professional services provided by social service agencies, and a connection between these two types of organizations through a bidding mechanism. (3) information disclosure should be well implemented. in the event of a major crisis, in particular, charitable organizations should promptly release information about fundraising and material distribution through various channels and accept public supervision. only in this way can public maintain confidence in charitable organizations. the unexpected and sudden outbreak of covid-19 in wuhan and its prompt spread nationwide have created a special situation and state of exigency and urgency, challenging the status quo of the socio-economic order within and outside hubei province. the crisis precipitated by the pandemic has quickly led to a critical juncture at which the chinese administration must quickly and effectively respond. the negative effects of the crisis have created strong pressure and an incentive for a quick administrative response and effective action in the part of the chinese state. the explosiveness and severity of the pandemic crisis and its unpredictable as well as astronomical social costs have strengthened the model of "big government" in the chinese case [32] , with massive state intervention in society and the economy. besides the usual intervention methods such as lockdowns, curfews, travel bans, the use of big data for tracing and breaking infection chains, the creation of health-related codes via smartphones, and nationwide mobilization of medical assistance for wuhan and hubei province, social policy intervention has also become especially relevant. in both the mid-crisis and post-crisis periods, we have observed an increase in social welfare and social protection programs. however, this topic has been largely neglected, both in academic research and public perception. social policy intervention is deeply connected with the social fact that modern society is a risk society [33] , and some social risks, such as environmental pollution and global warming, have evolved into global risks that challenge all nation states. social policy must circumvent new global risks like global pandemics, and the social protection programs of nation states must find an effective way to mitigate the social risks and hazards caused by newly emerging infectious diseases such as covid-19. these programs are not only targeted at national citizens, but also at international migrants such as tourists, foreign visitors, guest workers, etc. how modern social policy responds to pandemics has become a new and urgent research question for all nation states. the adopted social protection programs in china include a wide range of policy areas, such as health insurance, unemployment insurance, and accident insurance, among others. from the perspective of system types, we can differentiate social protection programs amid the covid-19 crisis into social insurance, social assistance, social welfare, and enterprise-related special subsidies and policy measures. existing social insurance programs, the mlss, and some special temporary policy arrangements have been combined to circumvent the sharp increase in social suffering. within the portfolio of different benefits, we have noted: (1) cash payments such as unemployment allowances and unemployment subsidies, benefits from the chinese social assistance program (mlss), ensuring the material security of millions of people and employees who have suffered from temporary layoffs, shortened work hours, or mandatory breaks imposed by employers; (2) benefits in kind, including service programs like testing, diagnosis, and therapy for covid-19 patients, free of charge, either financed by health insurance programs or subsidized by state revenues. also included are special social protection and social services for elderly people in nursing homes and social welfare units who constitute one of the highly vulnerable groups exposed to the virus; (3) favorable policy measures, such as the alleviation of income tax burdens and the granting of special loans for small-and medium-sized enterprises who face challenges in existential survival owing to a lack of liquidity because of the drastic freeze in economic and commercial activities. with regard to targeted welfare clients, we can also distinguish two types of program-individual-related and collective-related benefits. the first includes benefits that target individual demands, delivered to each citizen in case of need. the second is delivered to collective units such as households and enterprises. in sum, different interventionist forms, including monetary intervention, service-related intervention, policy-related intervention, and legal intervention have been combined and synthesized to help residents and social and economic units to traverse the "valley of tears" [34] amid the covid-19 crisis. the unprecedented covid-19 crisis has indeed stimulated rigorous state intervention in the areas of livelihood, welfare, and wellbeing for millions of people who have suffered directly and indirectly from its negative effects. as with various historical examples, the crisis derived from the coronavirus has stimulated public expenditures and a model of "big government". it has further legitimated hyper-normal and, in some cases, nationwide and large-scale extralegal intervention policy to lessen the intensity and severity of soaring social problems and escalating social conflicts. however, this kind of special intervention within and beyond the regular legal and institutional framework has also reached its limits, leaving many problems unresolved, such as the question of who should take responsibility for the medical treatment of residents that have dropped out from the regular health insurance system and who should finance diagnosis and therapy for overseas chinese and foreigners returning to chinese territory, and to what extent. the tacit problems of coverage loopholes in the chinese social security system have become explicit during the development of the crisis. even in cases of monetary compensation and intervention, impoverished residents or the unemployed who have received cash benefits, either from social assistance or from unemployment insurance, have been unable to purchase enough daily necessities and basic commodities due to the lockdown and curfew that has constrained the normal functioning of physical stores and brick-and-mortar businesses. charitable organizations have played a vital role in providing benefits in kind for individuals and families in need. ensuring material security and social safety encompasses more than one single area of social policy and requires much more coordinated policy intervention from different arenas, including economic policy, employment policy, fiscal policy, and social policy. coproducing responses to covid-19 with community-based organizations: lessons from zhejiang province the social protection system in ageing china china's social assistance: in need of closer coordination citizenship and social class and other essays vom armenhaus zum wohlfahrtsstaat: analysen zur entwicklung der sozialversicherung in westeuropa; campus: frankfurt am main the three worlds of welfare capitalism herausforderungen des sozialstaates; campus: frankfurt am main the political economy of the welfare state a grounded theory of construction crisis management fractal crises-a new path for crisis theory and management ending welfare as we know it (again): welfare state retrenchment dismantling the welfare state? reagan, thatcher and the politics of retrenchment toward a theory of social conflict america's welfare state: from roosevelt to reagan the coming of east and south-east asian welfare states the korean welfare state: a paradox of expansion in an era of globalisation and economic crisis global financial crisis and government intervention: a case for effective regulatory governance the financial and economic crisis of 2008: a systemic crisis of neoliberal capitalism impact of covid-19 on china's employment protection and social security system accelerate the implementation of periodic tax and fee reduction to stabilize employment how to revive 600 billion unemployment insurance funds with the benefit rate has been declining for ten years? available online evolution mechanism of safety accidents and rule of law path of risk management and control in old-age care institutions 12 confirmed covid-19 and 1 death in wuhan social welfare home. the beijing news epidemic prevention and control and livelihood security in civil affairs. china news the per-capita medical cost of patients with severe covid-19 exceeds 150000 yuan, being reimbursed in accordance with regulations reform and high-quality development of the medical security system with chinese characteristics social security fee reduction from the perspective of "tax wedge": fighting the epidemic and long-term reform national health commission. care for the health of medical staff and improve working conditions theoretical and policy focus of relative poverty: establishing a governance system for relative poverty in china innovation and development of national emergency management institution and mechanism in the new era bring back big government from industrial society to the risk society: questions of survival, social structure and ecological enlightenment crossing the valley of tears in east european reform . special thanks to two anonymous referees for their insightful, valuable, and very helpful comments, which contributed to improving the text significantly. the authors declare no conflict of interest. key: cord-016120-pz2q62i7 authors: zhang, jie title: chai jing: the power of vulnerability date: 2019-02-16 journal: female celebrities in contemporary chinese society doi: 10.1007/978-981-13-5980-4_3 sha: doc_id: 16120 cord_uid: pz2q62i7 in the past seventeen years chai jing has risen from china’s official media to become a recognized investigative journalist, public intellectual, author, and more recently, an independent filmmaker and environmental activist. her experience and work reflect how china’s news apparatus has reformed to adapt to the drastic societal changes with emotion being used to open up new ways of news communication. her documentary under the dome further shows how the internet has transformed the ecology of media and provided innovative platforms for social engagement. chai’s embracing her own feelings of vulnerability, which dominated the beginning of her career, and using it to channel public feelings and drive news reporting has made her a distinctively controversial media personality. her leaving the cctv can be viewed as a self-marginalization that helps her sustain that vulnerability, through which she gains resilience and critical power. the use of maternal voice in under the dome exemplifies her use of the power of vulnerability in its most mature form. the controversiality about that voice signals that post-socialist china remains a space where environmental and gender discourses are contested and negotiated. . courtesy of guangxi normal university press some of china's best-known media people, further made chai known as an influential writer. in 2015, chai released under the dome (qiongding zhixia 穹嵿之下), an independently produced, 103-minute documentary that brought environmental issues to the frontline of china's public debate again. chai declared the film "a personal war against the smog" and its release energized china's burgeoning environmental movement. the film received 300 million online clicks from 28 february to 7 march 2015, after which the government banned it. chai's engagement with the nuanced transition of china's official media, the rise of investigative journalism, and the development of environmental discourses have made it essential to examine her media and literary work within these correlated contexts. this chapter continues existing inquiries about chai's roles in these contexts, with a special focus on how gender plays an indispensable part in forging her news reporting and commentating style on television, her self-positioning in insight, and her "ecofeminist" voice in under the dome. the unapologetically maternal voice that has caused much controversality in the reception of the film is not a radical shift from her established career; instead, femininity is a constant in chai's self-awareness and it has taken different forms in different stages of her career, sometimes making possible her agency and breakthroughs, while at other times making her subject to reckless critiques that mark the limitations of china's gender equality. when chai started working at the news probe department at cctv in 2001, she was a twenty-four-year-old "literary and artistic youth" (wenyi qingnian 文藝青年) whose inspiration predominantly came from "romance fiction and popular songs," as she would reflect more than a decade later. "literary and artistic youth" in the chinese context refers to people in their twenties to forties who love literature, travel, photography, and arts and who speak sentimentally and tend to lose touch with reality. 1 chai admitted self-mockingly that these qualities made her sail through her earlier job at a hunan radio station, where she read listeners' letters on the air for an evening program called "gentle night" (yese wenrou 夜色溫柔). throughout chai's career, she has never hesitated to self-criticize this unpractical aspect of her identity, underlining how it clashes with her journalistic mission of exposing some of the most hidden and complex realities in china. however, noticeably chai has never lost her sentimentality, neither have her audiences and readers failed to recognize it. when chai's insight came out in 2013, some of her disapproving readers denominated her chai huiyin 柴徽因, alluding to lin huiyin 林徽因 (1904 -1955 , one of china's celebrity intellectuals known for her literary talent and romantic relations with several high-achieving men. the denomination poignantly recognizes chai's literary talent while also reprehends her self-promotion in the book's much publicized press release. some other audiences and readers have also faulted chai for her connections with powerful men. "why are your friends all old men?" asked one of chai "friendlier" audiences in the book release conference. hinting unfairly that chai's success had to do with gender-based favoritism rather than her capability, such questionings nevertheless drive home the fact that china's news corresponding had been male-dominated when chai started her career at cctv. chen meng 陳虻 (1961-2008), chai's recruiter to cctv, was a widely respected reformer in china's news apparatus, radically envisioning and implementing many groundbreaking changes in the cctv news since the early 1990s. similarly, chai's partner bai yansong 白岩松 (b. 1968 ) was then a newly established media personality appreciated for his candid, sharp, and thoughtful approach to news reporting. bai created, produced, and anchored "horizon connection," through which chai had her cctv debut. chai described in the first chapter of insight the many mistakes she made at this onset of her cctv career, highlighting, not without literary dramatization, how her colleagues' challenges and mentoring made possible her professional growth. significantly, all of these nineteen colleague-mentors were men. although chai also mentioned two additional women colleagues in passing, they did not contribute to her professional development. a woman called sister lei 雷姐 attempted to be a matchmaker, arranging chai with another colleague. chai also heard that some cctv executive remarked that she looked like jing yidan 敬一丹 (b. 1955), an award-winning hostess of economy-related programs. chai's colleagues interpreted this remark as the executive's approval of chai's hire. the deep irony here is that to some of her seniors and her colleagues alike chai's look seemed to matter more than her quality. chai's lack of female role models was further complicated by the unprecedented changes in the cctv news itself. since the early 1990s, a new documentary movement had begun shaping in china. filmmakers and television professionals took advantage of the spread of video technology and hoped to "open up new public spaces for discussion of social problems and dilemmas in the post-socialist era" (berry et al. 10) . consciously distancing themselves from the official propagandistic news and culture production mode, filmmakers and media professionals both inside and outside the state-owned film studios and television stations started experimenting with "a more spontaneous mode of documentary" (berry et al. 5 ) that focused on the experiences of people marginalized by china's modernization. they used hand-held cameras to record unrehearsed and unscripted pieces of realities-"my camera doesn't lie" was one of their slogans 2 -and later went as far as completely democratizing video making itself and letting the voiceless record themselves. 3 in news reporting, oriental horizon (dongfang shikong 東方時空, est. 1993) combined investigative journalism and news-documentary realism and quickly became a hit. chai's seniors chen and bai were both deeply involved in the formation of oriental horizon. bai anchored the news magazine and became its spokesperson. chen famously verbalized the catchphrase-"telling the common folks' own stories" (jiangshu laobaixing ziji de gushi 講述老百姓自己的故事)-for life space (shenghuo kongjian 生活空間), the hallmark segment of oriental horizon. the path-breaking nature of the news programs that chai joined meant that she had no models to follow and must come to an understanding of what news meant to her and her audiences through both soul searching and hand-on experiences. all these uncertainties made chai feel unprepared and vulnerable. apparently, she felt like an impersonator, a syndrome many professional women share in an unsupportive working environment. as she wrote in insight, she kept dreaming about days of her cheating in a vision test in fourth grade by memorizing the last line on the test poster. she also tried to hide herself in the crowd when the station anchors gathered for a group photo. when simultaneously interviewing three guests on the phone from the newsroom-with images of the guests to be edited in later due to technological restrictions-chai felt disconnected and instead became highly conscious of her own gestures. she was too anxious to breathe and had to deep breathe in the restroom. she also found herself resorting to clichéd phrases such as "let's hope for the prompt arrival of a democratic and law-governing society" to safely conclude some of her news corresponding so that she could run away from it. naturally she found strength through withdrawing to literature, where she felt most at home. clarice starling, the twenty-four-year-old f.b.i. trainee in thomas harris's novel the silence of the lambs, became her alter ego. in the novel, starling starts with the need to prove herself in the male-dominated bureau but eventually transforms into a confident agent resolved to serve nobody but the silent women victims of cannibalism. it was the single thought that "nothing can make starling afraid" which kept chai sitting at her newsroom in spite of the perceived failures at the beginning of her cctv career, as she confessed with hindsight in insight. rising from disaster reporting when chai was interviewed for her cctv position, she was asked, "what concerns you the most when you do news?" she answered, "the human in the news." it was this constant concern for the human when suddenly confronting disastrously inhuman situations in 2003, which helped chai breakthrough from her earlier frustration and develop her own news reporting and commentating style. within the two months from february to april 2003, chai found herself doing on-the-spot reporting from two of china's most distinctive locations, the remote uygur area devastated by a 6.8 magnitude earthquake that caused more than two hundred deaths, and the political and cultural capital beijing plagued by an outbreak of severe acute respiratory syndrome (sars) epidemic, with more than nine hundred confirmed cases and more than two thousand probable cases by mid and late april. chai would later call these experiences a turning point of her career. "all started with uncertainty. you don't have time to deliberate on what questions you want to ask. only from uncertainty can one forget all about oneself. it was in this situation that i found what i really wanted" (li) . as disasters are unpredictable and destructive, disaster reporting involves a larger extent of on-the-spot improvisation and spontaneity. this gave chai much-needed agency to explore her media persona. in what follows, i analyze chai's sars coverage from four angles, focusing on how her disaster reporting credited her as a journalist. disaster reporting is innately one of the most dramatic genres of the news discourse. disasters are unnegotiable and the stakes are high, with humans stuck in liminality and caught in intensive emotion. this sets up a great background for great storytelling, the core of great news reporting. as a cctv reporter, chai had privileged access to this stage. she was on her way to uygur half an hour after the earthquake and was able to get to its center by taking a military transporter (chai 16) . her prompt first-hand experience filled in the need for the latest information to keep her audiences updated and to facilitate coordinated disaster-relief. because the transmission of this information itself can mean the difference between life and death for victims, as media visibility may expedite relief action, this type of reports generally tends to be treated as more valuable. moreover, in an age when social media did not yet exist, television news were the predominant means by which people were informed about the disasters. all these factors made it possible for chai's coverage to get the immediate attention of the largest possible number of audiences. chai's sars report was well-received also because it was perceived to be a significant step toward promoting governmental transparency and civilians' "right of knowing" (zhiqingquan 知情權). precisely because disasters have great potential of causing social instability, the chinese government tended to execute strict control of disaster news release and sometimes opted for a cover-up. just months before the sars outbreak, western media warned how china's "catastrophic mismanagement of its aids crisis" (kristof) , which was largely caused by illegal blood collecting in henan province, will result in unprecedented deaths if the official cover-up continued. the sars outbreak seemed to have been treated in a similar fashion in the beginning, with the chinese media instructed to propagandize that the situation was under control and there was no need to be "panic" (konghuang 恐慌). but an unexpected turn-around took place on 20 april 2003, when china's health minister zhang wenkang 張文康 (b. 1940) and beijing mayor meng xuenong 孟學農 (b. 1949) were fired for "mishandling the matter." the firing may have been necessitated by the governmental need to fully publicize the seriousness of the epidemic in order to discourage mass travels anticipated for each may. it created the impression that government officials were held accountable and the people's "right of knowing" was reinstated. chai's reporting on sars, which began three days before the firing and aired several days thereafter, coincidentally provided a timely outlet for people to exercise this newly vindicated "right of knowing." more than 70 million people watched the 35-minute special report in which chai, covered by white insulating clothing and gauze masks, entered the quarantined sections of beijing hospitals where sars patients were treated and, for the first time since the outbreak, interviewed. chai became the face of sars reporting not only because of her strong work ethics-"if i were to have a child in the future and he asked me, 'mom, what were you doing when sars broke out?' i cannot just say, 'i was watching tv.' i really cannot just say that!" chai reflected later (chai 21)-but also because that the ways that she conducted the interviews pioneered a profound transformation of chinese reporters from a detached information transmitter into an empathetic individual capable of co-experiencing what the interviewees were experiencing. amid the life-threatening public health crisis, everyone was equally vulnerable; some of the first causalities of the epidemic were health professionals. chai's awareness of her own vulnerability and her refusal to succumb to it made her not only a credible reporter but also a relatable and likable individual. the high risk that she took highlighted the worthiness of the "right of knowing," and the idea of a slender and young woman confronting deadly viruses for the sake of public understanding was immediately heart-warming and guilt-provoking. in fact, in the first interview when chai's team had to let her enter the quarantined area alone with a hidden audio recorder-the cameramen were banned because there was no way to insulate and sanitize their heavy equipment-the left-behind camera lingered on her back and the glass door that she entered through for an extended time. this camera's gaze is meta-narratorial in its recognition of its own limits and its concern for chai. that chai did not stop at where the camera had to stop helped construct her as a credible reporter seeking nothing but truth, truth that she deemed more important than her life. in this process, chai has also transformed from the insecure girl disconnected with the news that she was commentating into a dedicated reporter fully immersed in the news in its making. at the same time, her own sense of insecurity has also been subliminally transcended. the epidemic reveals that being vulnerable is an integral and universal part of human experience and embracing it rather than denying it is the only way to survive or to thrive. through the sars reporting, chai developed her own distinctive style of news probing. in the succeeding hospital visits, she treated her interviewees as fellow human beings and encouraged them to share their feelings. when talking to a patient, she said, "understandably there are currently a lot of fear about the disease. can you tell us from the perspective of a patient what it feels like to have this disease?" by discussing fear with the patient, the target of the fear, chai was including rather than excluding the patient in the construction of sars discourses and also insisting that the humanity of the patient rather than the virality of the patient should be emphasized. the patient's subsequent description, which highlighted that this disease was not so different from other more common diseases in its identifiable pattern of development, serves to demystify the virus. in fact, this patient was so comfortable with sharing her feelings with chai that she expressed that she felt for the nurses and doctors who took care of her. she said, "they wore thirty layers of gauzed masks but they still got infected. they take care of us but then they cannot go home. this is really hard on them!" that a patient infected with a deadly virus can feel empathy for her caregivers only shows how humans are deeply connected when facing their vulnerability. throughout the report, chai effortlessly created contexts for her interviewees to talk about their feelings. "can you go home after work?" she asked a nurse this seemingly obvious question. as the interview went on, the audience learned what going home actually meant for the nurse: she and her fiancé had to postpone their wedding ceremony and had not seen each other for more than a month. this episode reminded people how life had been interrupted by the epidemic but it also emphasized how the epidemic had made people care even more for others. in another occasion, chai asked a doctor, "you knew the risk of working here, but why did you volunteer to stay?" visibly getting emotional in spite of the cover of insulating clothes and masks, the doctor recognized her own vulnerability but insisted that the virus only makes humans more connected. "i could be one of them," she said plainly. this message about shared burden is all the more powerful because it comes from a quarantined hospital room, a space designated to separate people. at the end of the report, chai asked a patient who almost died of the infection but was on her way to recovery, "have you ever thought what you want to do the most when you are discharged?" the patient seemed shocked to face this question and stuttered, "ai-ya…i've thought too much [about this]…life is really, really…i have a new understanding of life now." chai's ability to arouse feelings made her sars report a heart-warming piece about humanity, community, and connectivity. she also exemplified how a reporter's personality can memorably shape the ways that stories unfold. chai's success in reporting the sars epidemic helped consolidate a change in china's news production, which shifted from a scriptwriterand director-centered model to a reporter-centered model. such a shift in the early 2000s reflected the nuancedly transformed relationship between the state and the media apparatus. while the chinese media remained an integral part of state propaganda, since the 1990s the state had cautiously allowed some reform so that the media can be less financially dependent upon the government. this meant that the media, while still subject to top-down censorship, must also take its mass appeal more seriously than ever. in other words, while political correctness remained a central concern, creative storytelling and audience rating (shoushilű 收視率) also became essential. at the same time, the new documentary movement had provided an effective narrative model to engage audiences, through focusing on the underprivileged and using hand-held camera, long shots and long takes, and voiceover, etc. both of these changes made possible a democratic shift in their emphasis on the agency of the conventionally neglected majority. both also pushed for a similar democratic shift in news reporting, from script-based, newsroomsituated monologues to reporter-anchored, on-site heteroglossia that oftentimes resist mainstream outlooks. this shift necessarily gives reporters new importance as the very process of news discovery rather than the official interpretation of the events has become the focal point of news stories. in september 2003, cctv's "news probe" pioneered the reportercentered model, giving reporters unprecedented power to veto a proposed topic and to direct the actual on-site shooting of the news. "the more central a reporter becomes, the more appealing the news becomes," "news probe" director zhang jie 張洁 stated, admitting that chai's success had given him the confidence to implement this overdue reform (li) . the reform gave chai and her peers much agency in exploring their own media person and eventually made it possible for them to become public intellectuals who relentlessly unpack the complexity of post-socialist china and engage audiences in public debates. on 8 november 2003, china's fourth journalists' day, eight journalists including chai were selected to be that year's "journalists of the time" (zhongguo jizhe fengyun renwu 中國記者風雲人物). collectively, their reports covered police violence, monopolized taxi market, controversial private rights, fatal side effects of traditional chinese medicine, a cover-up of a coalmining disaster, a scandal of a drug rehabilitation center, and the iraq war, showing how journalists have become increasingly recognized as a force to push for pluralistic discourses about social transparency and justice. 4 chai's remarkable capability of co-experiencing with her intervieweesvillagers whose lands were taken, abused women who killed their husbands, left-behind children, voiceless gays, earthquake survivors, mentally disabled women forced into prostitution, et al.-have made her news reports pivotal to raise awareness about neglected and misunderstood social-political-cultural issues. through her interview of "crazy english" (fengkuang yingyu 瘋狂英語) founder li yang 李阳 (b. 1969) and his wife kim lee 李金 (m. 2005-2013), chai revealed not only the excruciating pain that the wife experienced as a result of her husband's domestic violence but also how his inability to love and connect (a result of his own problematic childhood) and his over-emphasis on his professional success (a way to escape the fear to connect with his own family through running into "a crowd of strangers," as his wife puts it) have made him insensitive to his family's needs and feelings . through her interview of gays, activists, and their families, chai demystified gay people and normalized their sexuality and their feelings, calling for a more accepting environment. in her report on teen suicides in a northeastern town, she traced how a girl's suicide tipped into a chain of five teen suicides, with each revealing how the confusion of individual boundaries, the anxiety of growing up, and the lack of meaningful contact with parents and teachers have intensified the stress of coming-of-age and made suicide a contagious outlet. these reports have earned chai the reputation of a rising public intellectual (gongzhi 公知) decisively contributing to newly emerging and rapidly shifting public discourses about the underrepresented in the chinese society. 5 chai's approach has also caused much controversiality due to the centrality of emotionality in it. when interviewing the cousin of the girl who committed suicide, chai asked, "have you talked to her [since her death]?" the boy, having felt very close to the girl, answered firmly, "yes." "what did you say to her?" chai pursued. breaking into tears, the boy muttered, "… how are you?" in a moment of heart-felt empathy, chai raised one of her hands to wipe the tears on the boy's face. this moment was eventually aired and became extremely controversial. some of chai's colleagues, embracing the idea that "a female reporter should never be aware of her gender except when she uses the restroom," pointed out that this style of what they called "crying interview" (qisheng caifang 泣声采访) could make her unqualified to pursue "hardcore news" (ying xinwen 硬新闻) (chai 61). in fact, one of her colleagues confronted her, "why did you wipe his tears?" "what would you have done?" chai countered. "nothing! that is what makes me a reporter!" the colleague hollered (chai 53) . some audiences also challenged chai's ingenuity, wondering whether she cared more about her own image than the news itself and calling her style "performative news anchoring" (biaoyan xing zhuchi 表演性主持) (chai 53). still, others questioned whether she was manipulative in triggering these vulnerable moments of her interviewees, making their emotion the selling points (maidian 卖点) of her own news storytelling. this uneasiness with emotion, which is perceived to be opposite to journalistic objectivity, as well as the questioning of chai's sincerity, which is an innate paradox of the new documentary movement itself (some questioned whether the filmmakers are using the stories of the marginalized people for their own identity politics), provides a lens into the media consumption habits of the chinese public in the first two decades of the twenty-first century. for decades prior to these, the emotions allowed on television news were mostly orchestrated, ranging from patriotic pride to nationalistic anger. it was rare for individual emotions to erupt on the screen; any occasion when such moments occurred could be interpreted as a subtler way of propaganda, due to audiences' consensual distrust in the media in general. in fact, since cctv's talk show artistic life (yishu rensheng 艺术人生) first began in 2000, its host zhu jun 朱军 (b. 1966) has also been heavily criticized for "arousing and manipulating feelings" (shanqing 煽情) among his interviewees. 6 paradoxically, chai's news reporting diversified the emotional dimensions of china's television news, but the more people felt the new possibility of connection the more they felt the need to be reassured about the authenticity of that connection, particularly given the prevalence of artificially mediated feelings on television before this. chai recognized that excessive sentimentality can harm the discovery of truth, but she also believed that emotional affect can be an advantage rather than a liability for truth finding. in 2003, cctv news reformed to focus more on "revealing what is behind the scenes" (kaijue neimu 开掘内幕), leaning heavily toward investigative journalism. chai's reports began to involve more confrontational situations. she covered some of china's darkest sides: bribery in a village election, shady deals in real estates, fraud in international trade, money laundering, and antique trafficking. chai and her partners found themselves having to use hidden cameras, face threats and bribery, cultivate informants, and outsmart deceiving interviewees more frequently than ever. but her deep understanding of humanity quickly made her an example of investigative journalism. chai's interviews are characterized by their persistent demand of truth, and she particularly excelled in belying the hyperbolism and illogicality of political formula that many of her deeply flawed interviewees used for their self-defense. when investigating why an entrepreneur was sentenced to three years in prison just because he refused to obey the mayor, chai asked the judge why the essential piece of evidence was a photocopy. she dispelled the judge's excuse one after another and eventually cornered him to admit that his sentencing was purely based on the photocopy. when the judge, obviously exasperated, cried out "i still believe he is guilty," resorting to his personal belief and thus betraying his lack of legal proof, and threatened chai, "don't you become other people's tool!" chai calmly pursued his hypocrisy further, "in the court debate, the defendant's lawyer stated that the law should not become the government's tool. what do you think of this?" (chai 60-71). chai's ability to feel for the vulnerable goes hand in hand with her perseverance to question how the system works and whether it is fair. from 2006 to 2009, chai covered the annual "two conferences" (lianghui 兩會), or the combined national people's congress (zhonghua renmin gongheguo quanguo renmin daibiao dahui 中華人民共和國全國人民 代表大會) and the chinese people's political consultative conference (zhongguo renmin zhengzhi xieshang huiyi 中國人民政治協商會議), and pushed for capturing the heated discussion of topics essential for people's livelihood, such as governmental control of business, environmental pollution caused by economic development, skyrocketing medical expenses, and the lack of senior care, etc. chai's coverage subverted the conventional "two conferences" reports that tended to feature highly scripted and heavily edited discussion among the representatives in order to deliver a unified voice. "what others experience, i must experience," she wrote after an earlier interview of abused women. this insistence on co-experiencing has made chai's demand for truth almost personal and her commitment to truth all the more earnest, urgent, and powerful. chai's understanding of how a reporter should handle emotions has evolved throughout her cctv career, reflecting how china's news discourses have incorporated emotions in the first two decades of the twentyfirst century. earlier on, the news advocated for the right, particularly of those who were marginalized, for feelings, feelings that challenge ways that things have always been done. these expressions of feelings served to dramatize the news storytelling, drive home the social issues being explored, and call for resolutions. at the same time, because feelings are universal, they also served as an equalizer-wrongdoers are also entitled to express their feelings-and as a result news coverages became more inquisitive and comprehensive. a prominent example of this use of emotion was chai's interview of a woman who stomped a cat to death and a man who videotaped this scene for an online platform. the woman used this abusive action to vent out her frustration as a single mother and the man recorded it to compensate on his financial woes. in her report, chai suspended her own judgments, refrained from anchoring the interviewees' feelings, and instead retreated to quietly observe as the complexity of humanity emerged. as chai matured as a reporter, she began to be more self-reflexive of the constructed nature of emotion. she reflected how the limited scope of her own experience can make her own feelings biased, uninspiring, and even dangerously propagandistic. she also pondered how feelings can be performative and manipulated to resist deeper inquiries of the truth. she reminded herself that she must not be overwhelmed or "hijacked" (xiepo 脅迫) by anything, including the feelings of the majority (minyi 民意) (chai 189). as a result she attempted to be more attentive to unsmooth and paradoxical elements in stories that resist a holistic interpretation. she also became more willing to leave her stories open-ended, allowing her audiences to experience and reach their own conclusion. "a society that does not care about truth is hopeless and immoral" (chai 249) , she wrote in 2013, clarifying that a reporter's job is "not to express, but to serve" (要服務,不要表達) (chai 228) . chai left the cctv in 2014 and returned to the public sphere in 2015 with her documentary under the dome, which uses a ted talk format to combine personal testimonials, graphs and data, animation, and interviews to investigate the causes of china's air pollution. because the film was taken down from online shortly after its release, many assumed an antagonistic relation between chai and the official censorship. but such an assumption is reductive and unhelpful in explaining chai's dynamic engagement with authorities. just as chai had used the cctv as a platform for her investigative journalism, she had also used the network and resources developed from her cctv career to gather insiders' information and win interview opportunities for this film. many also assumed that chai had left cctv to develop an independent voice-chai's fans often asked how she could have, for so long, "held fast to" (jianshou 堅守) her ideals while in cctv-but i would like to argue that it was the ongoing changes in cctv that made possible and sustained chai's rise. chai's book insight clearly shows how her career is about negotiating with media conventions and creatively testing the boundaries of governmental control. "many things exist only because there were people who believed in them," chai wrote in 2013, showing how she perceived her work to be a force to push for the realization of ideals through navigating through the system, rather than a force to attack and invalidate the system itself . the production and circulation of under the dome demonstrates that chai has been consistent with her active negotiation with powers rather than suddenly shifting her selfpositioning to subvert those powers. chai's purpose was to develop a niche to discuss china's smog hazard in the hope to propel an effective solution. earlier on, she had covered environmental topics such as sandstorms, polluted rivers, and problems caused by trash burning and coking plants, during her cctv career. the beginning of under the dome particularly referenced her earlier coverage of how the coal mining and coking plants in her hometown shanxi province 山西 had become a public health hazard. one of the most memorable moments of this segment was when a six-year-old local girl confessed that she had seen neither a blue sky nor a piece of white cloud in her whole life. inspired by al gore's inconvenient truth, chai aimed to unpack the information that she discovered and made them accessible and memorable. 7 throughout the documentary, she kept reassuring her audiences that she, just as everyone else, was also ignorant of the concepts, data, graphs, and discourses on the smog. the film is simultaneously a piece of scientific popularization (kepu 科普) and public relation (gongguan 公關), intending to dispel myth about the smog and call for some collective pressure upon the government for reform. specifically, the timing of the documentary's online release (28 february 2015) corresponded with the annual "two conferences" (3 and 5 march 2015) , which chai had earlier reported, in a particularly important year when discussions at the conferences were anticipated to shape china's key policymaking in the many years to come. clearly chai knew how the system works and attempted to expand what an insider-turned-independent journalist can do within the limitation of that system. chai adopted a maternal voice to engage her audiences emotionally from the very beginning. her use of the ted talk format, the best examples of which all summon emotion powerfully (gallo) , allows her to reference her own personal experience, focusing on the emotional turmoil she felt when she found out that her newborn daughter had a lung tumor. she then engaged her audiences visually, another powerful tool of ted talks (gallo) , showing a picture of her toddler confined at home peeking at the heavy smog outside the window (image 3.2). "i panic when my daughter smiles to me [because of the smog she is breathing in]," chai stated, turning a mother-daughter bonding moment into a nightmarish battle that she has no way to win. chai embraced her vulnerability in the most resolutely desperate form here: she was a helpless mother that did not know who her enemy was and how she could fight back. notably chai is drawing on a biological discourse (her being a mother) to justify her exploration of the environmental discourse, making it possible to interpret the documentary through the lens of ecofeminism. 8 for instance, earlier ecofeminists defended animal rights as a biological calling, indicating that women have more compassion for animals (ropers-huilman ix). the maternal voice intended to address the universal ground-that is, parental concern for their children-of the environmental awareness that chai hoped to instill; however, it has proven to be a "soft spot easily challenged by both discursive rhetoric and the virtual internet" image 3.2 chai presenting her daughter, who was confined at home and gazing at the smog through a window, in under the dome (2015, produced by chai) (cui 32) . considering reason and nature as being separated and incompatible, some audiences stated that chai lacked scientific proof to link her baby's tumor to the smog. one of china's most rebellious artists, ai weiwei 艾未未 (b. 1957), went as far as calling chai a "brain-damaged mother" and further insulted that "those who comprehend the notion of smog only through chai's womb must be brain-damaged, too" (cui 32) . it is ironic that the iconic artist eagerly volunteered to defend scientific data, only betraying that however politically idiosyncratic he may appear, his gendered biases remain deeply entrenched. ai's criticism of chai is based on the belief that the brain and the womb are antagonistic to each other and a woman's thoughts and feelings all have to do with her womb. ai's reductive reception of the documentary, however, demonstrates how gendered biases can drive people to criticize chai's work based on their own deeply flawed perceptions unhelpful to understand the work itself. chai may have used the maternal voice to mitigate potential offenses to the chinese government-she hoped to propel a policy level change after all-but her being attacked for embracing that voice becomes a lens into how gendered biases remain fully charged in the social and cultural norms that she attempted to change. in fact, chai's self-funded film represents the most comprehensive and in-depth investigation of the causes of china's air quality problems and fills in an urgent information gap through remarkably engaging storytelling and solid reasoning. chai reveals how china's excessive coal consumptions, ineffectively regulated automobile emission, inferior oil quality, flawed policymaking dominated by petroleum companies, and powerless environmental agency have collectively contributed to the smog hazard. she not only explored what caused the problems but also explained how they caused the problems, situating the environmental problems into larger historical contexts. for instance, she revealed how china's energy industries have inherited policymaking privileges from the state-regulated economy era and conveniently translated this political status quo into economic gains in the market-driven economy. she also revealed many gray areas in automobile and industrial emission controls, showing how state and local environmental agencies have been marginalized by recent state-level policies that heavily prioritize economic development. chai also referenced the lessons of london and los angeles in their tough recovery from air pollution, driving home her points about the worrying long-term damages caused by short-term economic gains. chai's interviewees are all insiders of the government, the law reinforcements, the industries, and the academia. each of them is not only dissatisfied with the situation but also remarkably critical of the existing systems. chai provided a platform for them to candidly express themselves and to contradict each other's claims, shedding light on how unclearly defined governmental functions, intertwined with prevalent self-interests and lack in transparency, have collectively led to non-action and dangerous numbness to the urgency of this problem. chai did not claim originality for these information, but she firmly pushed the publicity of these information in a systematic manner so that reform could become possible. the banning of under the dome should be situated in the context of how the chinese government has become increasingly responsive to public discourses. when facing environmental issues, the state actually also has a high stake. environmental issues pose a challenge to the sustainability of china's economic model and can potentially mobilize people and escalate into a threat to the "harmonious society" (hexie shehui 和諧社會) that the chinese government hopes to build. the government therefore must take them seriously. in this context, chai's film could be useful for the state to vent out people's frustration and to test the possibility of reform. with frequent, unprecedented changes happening in all aspects of chinese society within a short period of time, it is not uncommon for practices to precede regulation in post-socialist china, as new changes demand new regulations. the rise and fall of chai's documentary apparently follows a familiar pattern: as something independently produced, the documnentary rose from the margin of china's media apparatus, suddenly became viral and mainstream (the documentary received 117 million views within 24 hours), and eventually faced state's regulation because of its popularity. in this case, the state stepped in to shut down the online circulation of under the dome in order to contain potential damages, for the film could make people interpret the smog as a "human-caused catastrophe" and finger point at the state, whose legitimacy has largely depended on aggressive economic development that devastated the environment. but pulling the documentary offline does not mean that chai's work does not have any meaningful impact upon the government. notably the chinese government finally began incorporating environmental factors into the evaluation of state and local officials' work in 2016. the various attacks of under the dome provide a useful lens into how the construction of environmental discourses in china is radically contested and unavoidably linked to political and economic discourses. firstly, some audiences criticized chai for prioritizing environmental issues over economic development. they further claimed that this tension reflected the conflicted interests between the "well-off middle-class elites," to whom chai belongs, and the poor who presumably could benefit from aggressive economic development. when there are many people struggling with basic food and housing issues, they declared, it is insensitive and pretentious for chai to discuss clean air as a human right. this criticism of chai is driven by an anxiety about modernization, which the state has effectively used to justify its economic ambition, and will be a continuous burden of china's environmental movement. secondly, some specifically attacked chai's elitist status, showing how the chinese society has been stratified and how the tensions among different social classes have intensified as a result of china's uneven development. that chai's daughter was born in america seemed to fuel this criticism, triggering heated debate about whether she was hypocritical to give birth to an american citizen while also claiming she deeply cared about china. some, justifiably concerned about the urban and rural gap, also argued that chai's campaign against smog may divert limited sources from more serious environmental issues, such as polluted lands and water in the countryside, that have plagued powerless farmers. thirdly, chai's film has also suffered nationalistic interpretations fueled by conspiracy theory. critics stated that chai's self-declared "personal war against the smog" was actually a western smear of china's economic miracle. presumably the film received funding from western powers-while in reality chai used the royalty of her book to self-produce the film-in order to sabotage china's economic development through portraying the smog as a negative result of that development. under the dome triggered an intensive, renewed interest in chai's 2005 interview of ding zhongli 丁仲禮 (b. 1957), a geologist and fellow of the chinese academy of science. clearly, the interview demonstrates how chai's neoliberal perspectiveshe emphasized universal standards, co-existence, and shared environmental burden across the world-clashes with ding's china-centered perspective. ding articulated with powerful elocution that the right for emission (paifangquan 排放權) equals the right for economic development (fazhanquan 發展權) and that each chinese people should be allowed to have a fairly calculated amount of emission when compared to their western counterpart. ding's openly admitted patriotism gave the impression that chai lacked it in her emphasis on the shared burden of the international community and her insistence that environmental issues transcend international politics, making under the dome even more politically suspicious for some of its chinese audiences. in the past seventeen years, chai jing has risen from china's official media to become a recognized investigative journalist, public intellectual, author, and more recently, an independent filmmaker and environmental activist. her experience and work reflect how china's news apparatus has reformed to adapt to the drastic societal changes with emotion being used to open up new ways of news communication. her documentary under the dome further shows how the internet has transformed the ecology of media and provided innovative platforms for social engagement. chai's embracing her own feelings of vulnerability, which dominated the beginning of her career, and using it to channel public feelings and drive news reporting has made her a distinctively controversial media personality. her leaving the cctv can be viewed as a self-marginalization that helps her sustain that vulnerability, through which she gains resilience and critical power. the use of maternal voice in under the dome exemplifies her use of the power of vulnerability in its most mature form. the controversiality about that voice signals that post-socialist china remains a space where environmental and gender discourses are contested and negotiated. notes 1. the abbreviation is "wenqing" 文青. some also translated the term as "the cultured youth." the use of the term has a clearly negative undertone. when one uses this to refer to oneself it often intends to humorously self-disparage. a stereotypical female wenqing usually wears cotton clothes and shoes, reads literary works by eileen chang 張愛玲 and haruki murakami (b. 1949) , watches arthouse movies, listens to non-mainstream music, carries professional cameras, drinks coffee, and loves to travel. she also embraces romantic fantasies and indulges in sentimental self-reflection. a stereotypical male wenqing tends to be quiet and mature, capable of commanding language and echoing others' feelings, and leans toward spirituality and perfectionism. whose independent documentary bumming in beijing: the last dreamers 流浪北京 (liulang beijing, 1990) was widely considered the inaugurating piece of new documentary movement in china to commemorate the 63th anniversary of china youth news reporters' association (zhongguo qingnian xinwen jizhe xiehui 中國青年新聞記 者協會, est. 1937, renamed all-china journalists association 中華全國 新聞工作者協會 in 1957) according to goldman (661-662), there were no laws to protect public intellectuals in chinese history and some of the intellectuals that mao persecuted and that were later rehabilitated in the 1980s were the earliest public intellectuals in post-mao china. although contemporary chinese public intellectuals have been silenced or purged continuously, they have been able to spread their ideas through private publishing, the internet, and working out contracts with hong kong and foreign media since the reform he became a target of vehement criticism after cui yongyuan 崔永元 (b. 1963), one of china's best known media people, mentioned in an interview that one of his cctv colleagues had some very disrespectful comments on the crying interviewees' of a talk show; many linked cui's remarks to zhu's show and accused zhu of this presumed wrongdoing at the end of an eight-minute interview about whether gore intended to run the 2004 president race. chai noted that stahl's question intended to expose how a politician cannot provide a straight answer even to the simplest question. chai concluded her own interview of an official who tried to brush away the pollution issue by asking him cui shuqin was the first critic to propose an ecofeminist reading of chai's documentary introduction the power of vulnerability guilin: guangxi shifan daxue chubanshe chai jing's under the dome: a multimedia documentary in the digital age what i learned watching 150 hours of ted talks repression of china's public intellectuals in the post-mao era dir. my camera doesn't lie china's deadly cover-up chai jing: a protagonist of news drama editorial introduction: ecofeminism translated by cathryn clayton comparative study on the appraisal resources of china daily's disaster news the urban generation: chinese cinema and society at the turn of the twenty-first century key: cord-261971-rt6uo9pw authors: jaworsky, bernadette nadya; qiaoan, runya title: the politics of blaming: the narrative battle between china and the us over covid-19 date: 2020-09-01 journal: j chin polit sci doi: 10.1007/s11366-020-09690-8 sha: doc_id: 261971 cord_uid: rt6uo9pw during the covid-19 pandemic, we are witnessing a surge of nationalism throughout an ostensibly globalized world. in this article, we focus on the “narrative battle” over covid-19 that has escalated between two competing major powers – china and the us. guided by a cultural sociological approach, we reveal the meaning-making processes behind the narrative battle through in-depth, hermeneutical reconstruction of the “reactive performance” of each country, as articulated in political speeches and mass media. we point out that, in the chinese narrative, the country emerges from a “century of humiliation,” becoming a major world power that will no longer be subject to the “bullying” of the west. in the us narrative, even though trump initially highlights the country’s “very good” relationship with china, as the storyline unfolds, china is blamed for the global pandemic, assuming again the role of a dangerous actor on the world stage. our research shows that the current reactive communicative mechanism is not only unsustainable, but also dangerous in times of crisis. we suggest that recognition of the narrative battle and acknowledgement of its performative function in the public sphere is the first step toward mutual understanding and meaningful dialogue between these two world powers. suggest that accelerated de-globalization [24] is not imminent. looking at the five facets of globalization stressed by contemporary social theoristsdeterritorialization, social interconnectedness, speed or velocity of social activity, its character as a longterm process, as well as a multi-pronged process [38] it is difficult to imagine a substantive reversal in these processes. whether or not the "global village" [31] will ultimately transform, one thing that seems clear is that a resurgence of nationalism has overtaken many nation-states. conflict and crisis tend to bring up nationalist sentiments, especially if the nation appears under threat ( [21] : 46) . in the case of covid-19, some have noted the emergence of "vaccine nationalism," a race among individual states to be the first on the market, reminiscent of the situation in 2009 with the swine flu [47] . the us president stokes national sentiments by referring to the "foreign virus" or the "chinese virus," 2 while china engages in what zhang [53] calls "disaster nationalism," in which the focus is on the "heroic sacrifices of individuals as well as the cohesion of the national community. state media also celebrates the contribution of ordinary citizens more than usual, indicating a more human-centred and participatory approach." zhang notes the people's daily hashtag, "thank you, every ordinary chinese citizen," which garnered more than 570 million views on weibo by the end of april. nationalistic sentiments are not new, of course; but during the pandemic they have been reinforced and/or transformed. in china, anti-imperialist nationalism was already popular during the mao era. even though the "reform and opening up" in the 1980s weakened such anti-western sentiment, this type of nationalism, which "pitted an exploitative foreign imperialism against a courageous chinese people" ( [15] :67), has regained its popularity thanks to official propaganda and popular writings since the tiananmen square incident [48] . official nationalism is crystalized in the rhetoric of "patriotism" (aiguozhuyi), in which western antagonism in the past and present plays a significant role in shaping national pride and solidarity. populist nationalism is more radical, upholding an explicit anti-imperialism ideology of china vs. the west, accusing western (mainly us) policies for confronting and containing china. for these nationalists, any conflicts between china and the west, such as the trade war or the narrative battle over covid-19, can be interpreted as new rounds of western attempts to contain and bully china. the glorious memory of imperial china and the bitter memory of a "century of humiliation" serve as unifying factors for these nationalists and motivate them to exert pressure on chinese foreign policy [51] . such pressure from nationalists has become one of the major reasons china has difficulties adopting more moderate foreign policy, especially in its interaction with the us. nationalism's many faces in the us have touched china at several historical junctures. in the late nineteenth century, fears about chinese immigrants and their impact on the us labor market led to an exclusion movement, which lasted nearly one hundred years [40] . the chinese exclusion act of 1882 (cea), a "watershed event in the context of race, nation, and the law," eventually led to a complete ban on chinese entering the us, creating a framework of "danger" posed against the "purity" of whiteness and nation ( [26] : 663). the themes of danger would continue throughout the cold war, notwithstanding nixon's "path-breaking journey" to china in 1972 ( [9] : 25) , and the fact that the two countries often stood together in opposing the soviet union. us historian gordon chang argues that the communist takeover in 1949 represented the moment that "china became a sensitive domestic political issue," and views on the country have remained contentious between democrats and republicans in the us (quoted in [5] ). nevertheless, in an overarching sense, china stands in the us geopolitical imagination as a "dangerous" state "that cannot be counted on to act in accordance with the norms of civilized international relations" ( [28] : 145). this characterization has had lasting effects; some argue that "[a]lthough the specific language and target of racist nativism has changed over time, similar themes still reverberate in the contemporary anti-immigrant discourse in the usa as it did during the cea" ( [40] : 675). indeed, anti-asian sentiments seem to have increased during the covd-19 pandemic, with conservative elites labeling it the "chinese flu" or the "wuhan virus" [36] . to be sure, these nationalist sentiments from both sides have further strained already competitive sino-us relations. while the us-china relationship was more "complementary and cooperative in nature from 2001 to 2008," having reached symbiosis in the late 1990s ( [46] : 54) and especially after china's accession to the wto in 2001, the global financial crisis transformed cooperation into competitiveness, which only accelerated in the trump-xi era. [46] : 57) attribute the shifts to various factors, including "china's domestic economic reforms and growing ambition in global economic governance," as well as a change in the us stance toward china at the end of 2017 (ibid, p. 66). as a "rising power," china is also looked upon as potentially taking a leadership role in global health governance [30] . even though the future is unpredictable or unknowable, we posit that the covd-19 crisis and what we call the "narrative battle" between the two countries have led to an escalation of the binary thinking that sees the pandemic as a "power game of winners and losers" [53] . our analysis departs from typical approaches in international relations and nationalism studies, however, and follows the cultural turn in the social sciences. first and foremost, nations are symbolic constructions. as stuart hall asserts: "[a] nation is not only a political entity but something which produces meanings-a system of cultural representation" ( [20] : 612). regardless of how rationalized national politics may seem, modern nationalism is not removed from cultural meanings and the meaning-making process [37] . following alexander and smith's "strong program" [4] , we conceive of culture as an independent causal factor: meanings in modern societies are relatively autonomous…. the internal structure of meaning must be established before such beliefs can ever be related to noncultural factors. to see culture as cause rather than product is to move from the older "sociology of culture" to contemporary "cultural sociology." ( [3] : 693, italics ours). of course, more material structural factors, such as political and economic conflicts, play a role and direct the development of nationalistic sentiments. but culture nevertheless forms and informs all of these realms; as alexander puts it, culture is a "thread that runs through, one that can be teased out of, every conceivable social form" ([4]: 7). cultural sociology is complementary to some of the most cited views on nations and nationalism. for example, anderson's [7] idea of the nation as an "imagined community" in which members, who can hardly know all the others personally, have faith in the fact that they are part of a larger collective, functions as a "cultural structure," or repository of meaning. the strong program's hermeneutical reconstruction of cultural structures, or "structural hermeneutics," is thus a fitting methodology to reveal the cultural mechanisms underlying the narrative battle over covid-19 between two of the world's most powerful imagined communities. brittingham's [11] constructivist approach to developing a "reactive model" of nationalism and conflict also dovetails with the strong program in cultural sociology. she argues that "nationalism is a social role that becomes active when a state seeks to defend its national identity from perceived threats from another state i.e., nationalism is inherently reactive," demonstrating how chinese nationalism results from the "ideational threat from its most significant otherthe united states" (ibid: 149). in this iterative process, social actors, such as political leaders, call upon available cultural resources/structures. although not explicitly cultural, turcsányi's [43] study of china's assertive policies in the south china sea reveals a similar concept: "reactive assertiveness." in 4 out of the 5 policy cases he examines, the immediate trigger for acting (inappropriately) boldly and assertively comes from the actions of an external actor (ibid: 173-174). we bring the cultural turn into conversation with these reactive models by conceptualizing a theoretical framework in which performance is paramount. as alexander [3] asserts, "defining the nation is a performative accomplishment." using cultural sociology, we aim to provide a granular view on this process, focusing not only on the "how" but also the "why" of the sino-us narrative battle over covid-19. our theoretical framework is adapted from the "cultural pragmatic" theory of social performance within the strong program in cultural sociology [1, 2] . in particular, alexander defines a cultural performance as "the social process by which actors, individually or in concert, display for others the meaning of their social situation" ([2]: 32). in the framework of "reactive performance," we pragmatically extricate and translate four elements from alexander's cultural pragmatics, which are background representations, scripts, actors, and audiences. actors are the flesh-and-blood performers who project meanings in a social interaction. audiences are the observers who take in the projected meanings and potentially influence actors through their (re)actions. background representations are the general symbolic systems the actors and audiences draw upon, the "universe of basic narratives and codes and the cookbook of rhetorical configurations from which every performance draws" ([1]:550). scripts provide the text for what actors do and say in front of audiences, informed by the background representations. alexander [2] claims that in a successful performance, there is an "electric charge" between the texts and the actors, and if the actors can project this electric charge to the audience, which enables "psychological identification" and "cultural extension" from audiences to actors, then this performance is coherent or "re-fused." however, this mechanism of re-fusion downplays the role of the audience [8] , because re-fusion is more about actors' social "actions" than the social "interactions" between actors and audiences (author 2018). to capture the process of "interaction," we use the word "resonance" to highlight the participation of both sides. resonance, put simply, is when actors' performances (actions or, more often, speeches) "ring a bell" with audiences (ibid). likewise, because resonance depends on interaction, audience responses in their roles as citizen-listeners may influence actors' discourses. as illustrated in fig. 1 , in the drama of the sino-us battle over covid-19, the actors are the politicians of each side involved in the conflict. these actors perform their scripts via press conferences/briefings, twitter posts and other public statements. in the process, the actors consciously or unconsciously draw on background representations, or the dominant narratives floating in each society, such as the cultural trauma of "a century of humiliation" on the chinese side and the identity as the "beacon of the free world" on the us side. it is thus a "narrative battle," in which each side has its version of a story, with a coherent structure (beginning, middle and end), a compelling plot, and characters [16, 39] . narratives not only guide the actors, but also influence audiences, the general public in each country taking in the performances of both their own leaders and the leaders of the other side. whether a performance is successful or not is reflected in audience reactions, namely, the level of resonance. a successful performance occurs when audiences identify with the actors, insofar as they have skillfully incorporated the dominant codes of the background representations. in the process of the sino-us narrative battle over covid-19, the performances in the two countries occur reactively. that is to say, the response of one country seems to be triggered by that of the otheran assertive move from one side results in a more assertive move from the other sideand this back-and-forth escalation resembles the "reactive nationalism" ( [11] ; cf. [43] ) discussed above. in fig. 1 , we present a "reactive performance" model that captures the reactive interaction between the two countries on the national level. guided by the framework of "reactive performance," in this section, we analyze the battle between the united states and china over covid-19 from the beginning of february 2020 until the end of may. firstly, we present a chronological analysis of the key scripts from actors on both sides of the narrative battle, highlighting the "reactiveness" and the nationalistic tones of the performances. we then elaborate the dominant story-line emerging from these scripts and discuss how they correspond to background representations, namely, the narratives, symbols, and codes floating in these societies. the background representations can be understood as the long-term ethos that the public endorses; thus, to achieve resonance, actors must incorporate the narratives, symbols, and codes from background representations into their scripts, which is precisely what chinese and us political elites did during their narrative battle. in a globalized context, the general public is not only exposed to the performance of its own leaders, but also that of other nations. therefore, to maintain resonance, the performance of political elites is inevitably reactive, subject to the performance of its counterparts. we have situated the beginning of the narrative battle at the publication of a symbolically titled article. on february 3, the wall street journal (wsj) published an opinion piece commenting on the chinese government's mismanagement of the covid-19 epidemic and the possible global consequences of a chinese economic meltdown. the headline -"china is the real sick man of asia" 3immediately aroused public anger in china. the chinese ministry of foreign affairs (mfa) reacted quickly and condemned the author for his "arrogance, prejudice and ignorance," 4 accusing the wsj of being "racially discriminatory" and demanding a public apology. 5 receiving no apology, on february 18, a major chinese media outlet, global times, published an opinion piece that ridiculed the wsj for lacking the courage to even say it was sorry. 6 on the same day, the u.s. state department designated five chinese media outlets as official government entities under the foreign missions act, which meant their journalists would be subject to the same constraints as the prc government's diplomatic outposts. 7 within hours, beijing 3 mead, walter russell. 2020. china is the real sick man of asia. wall street journal, february 3. retrieved from https://www.wsj.com/articles/china-is-the-real-sick-man-of-asia-11580773677. accessed 10 july 2020. 4 ministry of foreign affairs of the peoples republic of china. 2020. foreign ministry spokesperson hua chunying's daily briefing online on february 6, 2020. february 6. retrieved from https://www.fmprc.gov. cn/mfa_eng/xwfw_665399/s2510_665401/2511_665403/t1741546.shtml accessed 10 july 2020. 5 ministry of foreign affairs of the peoples republic of china. 2020. foreign ministry spokesperson geng shuang's daily briefing online on february 10, 2020. february 10. retrieved from https://www.fmprc.gov. cn/mfa_eng/xwfw_665399/s2510_665401/2511_665403/t1743009.shtmlaccessed 10 july 2020. 6 ling, shengli(凌胜利). 2020. the wall street journal does not even have the courage to say sorry? (华尔街日 报》连道歉的勇气都没有?) global times (环球时报-球网), february 18. retrieved from https://world.huanqiu. com/article/9cakrnkprw2. accessed 13 july 2020. 7 fifield, anna, carol morello, and emily rauhala. 2020. u.s. designates major chinese media outlets as government entities. washington post, february 18. retrieved from https://www.washingtonpost. com/world/asia_pacific/us-designates-5-major-chinese-media-outlets-as-government-entities/2020/02/18/d82 b3ece-5210-11ea-80ce-37a8d4266c09_story.html. accessed 10 july 2020. retaliatedthree wsj journalists were given five-day notices to leave the country, and the mfa asserted that "the chinese people do not welcome media that speak racially discriminatory language and maliciously slander and attack china." 8 the next day, us secretary of state mike pompeo condemned china's expulsion of the foreign correspondents, saying: "mature, responsible countries understand that a free press reports facts and expresses opinions. the correct response is to present counter arguments, not restrict speech." pompeo ended his statement by wishing the chinese people could "enjoy the same access to accurate information and freedom of speech that americans enjoy." 9 two weeks later, the trump administration announced further restrictions on chinese journalists in the us, claiming such restrictions were aimed at upholding "reciprocity" in us-china relations. 10 responding to this, chinese mfa spokesperson, hua chunying, posted on her twitter account: "reciprocity? 29 us media agencies in china vs 9 chinese ones in the us. multiple-entry to china vs single-entry to the us. 21 chinese journalists denied visas since last year. now the us kicked off the game, let's play." 11 but this "game" was not limited to the "reciprocity" of journalist visas. in march, the battle shifted to conspiracy theories about the origin of the virus. on march 4, the chinese mfa spokesperson, zhao lijian, said at a press conference and also tweeted: "confirmed cases of #covid19 were first found in china, but its origin is not necessarily in china," 12 implicitly promoting the widespread conspiracy that the virus might have originated in a military lab in the us, brought in by the us army to wuhan during the 2019 military world games in october. trump fired back within days, retweeting a message containing the term "china virus," 13 invoking the popular conspiracy that the virus was leaked from a high-security biochemical lab in wuhan, suggested already by us senator tom cotton publicly in february. 14 on the same day, the centers for disease control and prevention (cdc) director robert redfield criticized the term "china virus" as "absolutely wrong and inappropriate." 15 8 ministry of foreign affairs of the peoples republic of china. 2020. foreign ministry spokesperson geng shuang's daily briefing online on february 19, 2020. february 19. retrieved from https://www.fmprc.gov. cn/mfa_eng/xwfw_665399/s2510_665401/2511_665403/t1746893.shtmlaccessed 10 july 2020. 9 pompeo, michael r. 2020. chinese action against journalists. us department of state, february 19. retrieved from https://www.state.gov/chinese-action-against-journalists/. accessed 10 july 2020. 10 [5] . u.s. places new restrictions on chinese journalists. axios, march 2. retrieved from https://www.axios. com/us-restrictions-chinese-journalist-wsj-china-trump-f4074630-9280-4251-b927-004688380575.html. accessed 10 july 2020. 11 hua chunying 华春莹. 2020. @spokespersonchn, march 3. retrieved from https://twitter. com/spokespersonchn/status/1234734030907555840?lang=en. accessed 10 july 2020. 12 spokesperson发言人办公室. 2020. @mfa_china, march 4. retrieved from https://twitter.com/mfa_ china/status/1235160704677642240?lang=en. accessed 10 july 2020. 13 trump, donald j. 2020. @realdonaldtrump, march 10. retrieved from https://twitter. com/realdonaldtrump/status/1237334397172490240. accessed 10 july 2020. 14 stevenson, alexandra. 2020. senator tom cotton repeats fringe theory of coronavirus origins. new york times, february 17. retrieved from https://nyti.ms/2wlqnpb. accessed 10 july 2020. 15 itkowitz, colby. 2020. cdc director rejects label "chinese virus" after trump, mccarthy tweets. washington post, march 10. retrieved from https://www.washingtonpost.com/politics/cdc-director-rejects-labelchinese-virus-after-trump-mccarthy-tweets/2020/03/10/58bd086c-62e5-11ea-b3fc-7841686c5c57_story.html. accessed 10 july 2020. this gesture seemed to be appreciated by the chinese side, when mfa spokesperson hua chunying tweeted a link to redfield's testimony on march 12. 16 meanwhile, however, another mfa spokesperson, zhao lijian, tweeted on the same day, "it might be us army who brought the epidemic to wuhan." 17 on march 16, trump again referred to the "chinese virus," 18 and during a white house press briefing on the 17th, he defended his use of the term: "i didn't appreciate the fact that china was saying that our military gave it to them." 19 he also rejected the idea that such a term creates a stigma: "i don't think so. i think saying that our military gave it to them creates a stigma." 20 on march 18, trump similarly claimed that he used the term because china had blamed the virus on us soldiers. 21 a day later the chinese state media outlet, cgtn, reinforced the idea that us soldiers had brough the virus to wuhan, publishing "10 questions for the u.s.: where did the novel coronavirus come from?" 22 toward the end of march, the two sides showed signs of rhetorical de-escalation of the battle. on march 22, china's ambassador to the us, cui tiankai, said during an interview that he thinks it is "crazy" to spread rumors about the coronavirus originating from an us lab. 23 mfa spokesperson, zhao lijian, tweeted "#covid19 epidemic once again proves that mankind is a community with a shared future […] we should unite to deal with the epidemic and carry out international cooperation to save more lives." 24 in response, trump seemed to back off from using the phrase "chinese virus," stating that he would not use it again: "i don't have to say it," if the chinese "feel so strongly about it." 25 on march 26, trump made a phone call to chinese president xi jinping, and afterward tweeted amicably about their "very good conversation." 26 however, the deterioration of the situation in the us reignited the flames. on april 1, us intelligence officials submitted a report to the white house relaying their doubts about china's numbers on covid-19 cases and deaths, 27 reflecting the mistrust and hostility that still haunts sino-us relations. pushing back, the people's daily published an article entitled, "us covid-19 statistics challenged by multiple research: lethal virus is far more widespread in the country than previously thought." 28 meanwhile, in washington, trump claimed on april 23 that he has evidence that gives him "high level confidence" that the virus came from the wuhan institute of virology in china. 29 at the same time, u.s. secretary of state mike pompeo claimed in an interview that there is "enormous evidence" that the coronavirus originated from a lab in wuhan. 30 in response, beijing returned to the conspiracy theories that covid-19 originated in the us. the mfa spokesperson twitter account posted on april 27, "when did the first infection occur in the u.s.? is the u.s. government hiding something? why they opt to blame others?" 31 three days later, chinese state media outlet xinhua released a remarkable video animated by lego blocks and named, "once upon a virus," which outspokenly mocked the us coronavirus response. 32 in this video, china is represented by a terracotta warrior and the us by the statue of liberty. the exchange depicts the events in january 2020, with the warrior announcing: warrior: "we discovered a new virus." statue: "so what?" warrior: "it's dangerous." statue: "it's only a flu." criticisms by western media on chinese efforts to contain the virus follow: warrior: "stay at home." statue: "it's violating human rights." warrior: "build temporary hospitals." statue: "it's a concentration camp." 27 wadhams, nick and jennifer jacobs. 2020. china concealed extent of virus outbreak, u.s. intelligence says. bloomberg, april 1. retrieved from https://www.bloomberg.com/news/articles/2020-04-01/chinaconcealed-extent-of-virus-outbreak-u-s-intelligence-says. accessed 10 july 2020. 28 people's daily online. 2020. us covid-19 statistics challenged by multiple research: lethal virus is far more widespread in the country than previously thought. april 21. retrieved from http://en.people.cn/n3/2020 /0421/c90000-9682363.html. accessed 10 july 2020. 29 aljazeera. 2020. trump "confident" coronavirus may have originated in chinese lab. may 1. retrieved from https://www.aljazeera.com/news/2020/05/trump-confident-coronavirus-originated-chinese-lab-200501003915123.html. accessed 10 july 2020. 30 us department of state. 2020. secretary michael r. pompeo with martha raddatz of abc's this week with george stephanopoulos. may 3. retrieved from https://www.state.gov/secretary-michael-r-pompeowith-martha-raddatz-of-abcs-this-week-with-george-stephanopoulos/. accessed 10 july 2020. 31 spokesperson发言人办公室. 2020. @mfa_china, april 27. retrieved from https://twitter.com/mfa_ china/status/1254757672282275845. accessed 10 july 2020. 32 shelton, tracy and iris zhao. 2020. chinese state media releases animated propaganda video mocking us coronavirus response. abc news, may 1. retrieved from https://www.abc.net.au/news/2020-05-01/chinastate-media-propaganda-video-mock-us-coronavirus/12204836. accessed 10 july 2020. warrior: "[hospital] built in 10 days." statue: "show off!" warrior: "time to lockdown." statue: "how barbaric!" the mockery of china continues in february, but by mid-march, the stature of liberty is shown receiving an intravenous drip with a face red from fury, contrasted to an everstrong mask-wearing warrior followed by an army of fully equipped medical doctors. the dialogue continues: statue: "you didn't warn us." warrior: "we said it was dangerous." statue: "you lied!" the dialogue then underscores how the us continues to contradict itself in april. the statue of liberty insists: "you gave false data. why didn't you warn us? [...] the virus is not dangerous, but millions of chinese are dead, even though the virus is not dangerous. we are correct, even though we contradict ourselves." the video ends with the warrior questioning the statue: "are you listening to yourselves?" the statue replies, "we are always correct, even though we contradict ourselves," the warrior concludes cynically: "that's what i love best about you americans. your consistency." on may 1, people's daily published 10 questions on covid-19 that must be answered by us politicians. 33 how many of the over 20,000 deaths from the last seasonal flu in the united states in september 2019 were the "novel coronavirus undetected"? why was the bioweapons lab in fort detrick, the largest bioweapons research base of the u.s. military suddenly shut down last july? the article explicitly links the closure of this lab with mysterious pneumonia cases, the h1n1 seasonal flu, a pandemic exercise called event 201, and the first case of covid-19 in wuhan. meanwhile, across the ocean, trump threatened to bring back tariffs if china would not fulfill all of its promises from the phase one trade deal. 34 journalist visa issues also re-entered the battleground. on may 8, the u.s. department of homeland security announced new restrictions on visas for prc passport holders working for non-us outlets, reducing their visas from open-ended, single-entry stays to a limited 90-day work visa. 35 unlike the previous strike on visas, this policy targeted all chinese journalists, regardless of the (foreign) news agency they worked for. on may 11, 33 people's daily online. 2020. 10 questions on covid-19 that must be answered by u.s. politicians. 2020. may 1. retrieved from http://en.people.cn/n3/2020/0501/c90000-9686382.html. accessed 10 july 2020. 34 klein, jodi ju. 2020. 10 questions on covid-19 that must be answered by u.s. politicians. south china morning post, may 4. retrieved from https://www.scmp.com/news/china/diplomacy/article/3082687/trumpthreatens-phase-one-trade-deal-if-china-us200. accessed 10 july 2020. 35 wang, vivian and edward wong. 2020. u.s. hits back at china with new visa restrictions on journalists. new york times, may 9. retrieved from https://www.nytimes.com/2020/05/09/us/politics/china-journalistsus-visa-crackdown.html. accessed 10 july 2020. beijing threatened "countermeasures" if washington does not "immediately correct its mistakes." 36 rather than "correcting its mistakes," the fbi and cisa issued a joint warning about chinese attempts to steal u.s. covid-19 research. 37 people's daily responded to this allegation with an article entitled, "china leads vaccine r&d, no need to steal." 38 and in a may 13 tweet, trump called covid-19 the "plague from china," 39 showing no sign of backing down. this three-month interactive performance is summarized in fig. 2 . the story from the chinese side as presented above, in the drama of the sino-us battle over covid-19, the "actors"politicians and government officialsperform their "scripts" via press conferences and briefings, twitter posts, and other public statements. in the process, they consciously or unconsciously draw on "background representations." on the chinese side, the dominant narrative concerns how an increasingly strong china will not tolerate bullying from the imperialist west any longer. this narrative symbolically opens with the opinion piece entitled "china is the real sick man of asia," which reminds the chinese of the longstanding cultural trauma of "a century of humiliation," starting when a glorious middle kingdom was invaded and divided by colonial powers. this cultural trauma has been a unifying factor in "anti-imperialist nationalism" [48] and "populist nationalism" [51] . it is also central to the concept of the "china/chinese dream (zhongguomeng)"to achieve "the great rejuvenation of the chinese nation" (fuxing) promoted by chinese president xi jinping [6] . therefore, it is unsurprising that the mfa took a strong stand against this opinion piece and insisted on an apology from the wsj, signaling that today's china is not the weakened nation of late 19th and early twentieth century. moreover, when washington took assertive steps against chinese journalists, beijing also retaliated without much hesitation, emphasizing the "countermeasures" that today's china is able to take, as mfa spokesperson hua chunying put it: "now the us kicked off the game, let's play." this playful statement implies 1) the u.s. is the offender, and china is the defender, just like 150 years ago; but 2) china is now in an equal position to "play" the game with the west. the offensive language used by top us officials, such as the term "china/chinese virus," and the bullying attitude of the trump administration, threatening to bring back tariffs, were instantly interpreted as a western attack to undermine china again. meanwhile, many chinese genuinely believe that the virus was (intentionally) brought in by the us soldiers to wuhan, which further intensified their anti-imperialist nationalism. the chinese public's anti-imperialist nationalism developed with the conflict, best seen through the "fang fang incident" in april, which represents a peak in the antiimperialist narration. fang fang is a 65-year-old writer based in wuhan. during the lockdown, she had chronicled the situation in her city since late january, posting online daily. her diaries had gained wide popularity among chinese readers initially, yet the public's perception changed dramatically after they saw the english and german versions of her book on amazon in april. fang fang was then accused of "handing foreigners a dagger" to attack china by offering "(false) evidence" through her diary, 40 and even her previous supporters felt betrayed. 41 fang fang, one of "us," speaking for the sick and the voiceless in wuhan during the pandemic, suddenly became a member of "them," those who intended to attack and weaken china. while chinese officials remained silent regarding this matter, the public quickly jumped into the mode of the cultural revolution, denouncing the "pro-western petty bourgeoisie writer." 42 such participatory nationalism online clearly reflects the anti-imperialist ethos seeded by and rooted in collective memory and reignited by the trump administration's strikes against china. public opinion has been shown to have an impact on chinese foreign policy [35, 51] . therefore, the mfa and official state media drew upon background representations their audiences could identify with, using well-chosen symbolic codes to narrate a story that could achieve "resonance" with the public. to start, they expelled us journalists when the wsj named china "the sick man of asia" and the us restricted 40 jiangxiaozhang (蒋校长). 2020. the female chinese writer who sends "ammunition" to the us (那个向美国 输送"弹药"的中国女作家). ucas2004 (国科环宇), april 11. retrieved from https://mp.weixin.qq.com/s/ssmu-9obmirlynpbnh4t_a. accessed 1 june 2020. 41 woshishiyijun (我是拾遗君). 2020. fang fang disappointed those who supported her (方方有点对不起支持她的 人). shiyi201633 (拾遗), april 9. retrieved from https://mp.weixin.qq.com/s/u79icgouj4zgjiobwrkzkq. accessed 23 may 2020. 42 ibid. chinese journalists. 43 as the conflict proceeded, they promoted a counter conspiracy when the united states suggested its version of a chinese conspiracy, 44 and when washington questioned chinese numbers, china responded in kind. 45 towards the end of the period we analyzed, the chinese story featured the lego animation created by xinhua ridiculing, "that's what i love best about you americans, your consistency," which corresponds to popular chinese public discourse about the inconsistent, hypocritical, and double-standard west [12] . meanwhile, the people's daily article "china leads vaccine r&d, no need to steal" signals that china is already a scientifically and technologically advanced country, overtaking traditional world powers. therefore, in this narrationas in previous narrations about the sino-us trade war, for example -china has achieved its transformationfrom a weak "sick man" to a strong leading world power that will not tolerate bullying by the hypocritical and declining west. the us background representations on china have historically painted the country, and the chinese communist party in particular, as a dangerous juggernaut [9, 26, 28] . this sentiment is reflected in the wsj opinion piece about china as the "real sick man of asia" that opens the covid-19 narrative battle we portray. 46 the author warns: "[a] world that has grown accustomed to contemplating china's inexorable rise was reminded that nothing, not even beijing's power, can be taken for granted" (italics ours). the wuhan government is characterized as "secretive and self-serving," and the national authorities responded "ineffectively." not only is the response to the virus suspect, but the country's economic power is something to fear: "china's financial markets are probably more dangerous in the long run than china's wildlife markets." as the battle continues, china's danger to the "free world" is highlighted. a florida representative tells the immensely popular fox news channel that china, much like the soviet union in the twentieth century, is the "most existential threat to the united states, to liberty around the world, to a free world order that we've ever faced." 47 us secretary of state mike pompeo brings it back to the coronavirus, tweeting that china has "a history of infecting the world," through their "substandard laboratories." 48 while in 2005, a plurality of us respondents (43%) had expressed favorable views of china, by the early-mid 2010s, the majority had shifted to an unfavorable position. as the covid-19 crisis escalated in march, fully two-thirds were now unfavorable, and 62% felt china's "power and influence" was a "major threat." 49 interestingly, president trump's narrative on china throughout the covid-19 battle, opens rather differently. it is reflective of the utmost diplomacy, even at the same time that a travel ban from china has taken effect since january 31. a script performed at the end of february even praises the country's response to covid-19: "and i want to say that china seems to be making tremendous progress. their numbers are way down." 50 the president almost seems cosmopolitan: we're all in this together. it's something that nobody expected. it came out of china, and it's one of those things that happened. it's nobody's fault. we allwe all will solve this problem; we'll solve it well. 51 the performance shifts dramatically, however, in mid-march, when trump apparently used a black sharpie pen to cross out "coronavirus" in a speech, replacing it with the "chinese virus." 52 vigorously defending the use of the term, he slips a reactive response into his script: "china tried to say at one pointmaybe they stopped now that it was caused by american soldiers. that can't happen. it's not going to happen not as long as i'm president. it comes from china." 53 this shift is well illustrated by our model: after the wall street journal article, which escalated the narrative battle and strengthened negative perceptions of china in the us, trump reacted in kind. now, the president's scripts for the middle of the narrative are in lock step with the public and other politicians. while trump is referring to the "chinese virus," pompeo calls it the "wuhan virus"notably, six times in one press briefing. 54 by early may, pompeo cites "enormous evidence" that the virus originated in a chinese lab, and accuses the communist regime of lack of transparency, among other dangerous characteristics: "this is an enormous crisis created by the fact that the chinese communist party reverted to form, reverted to the kinds of disinformation, the kinds of concealment, that authoritarian regimes do." 55 again, the idea of china as dangerous to the world resonates with us audiences. a plurality (47%) of the respondents to an economist/yougov poll taken in mid-may believes it is definitely or probably true that "a laboratory in china was the origin of the virus responsible for covid-19." the public is quick to engage in a politics of blame: a solid majority (64%) asserts that "china's handling of the covid-19 outbreak led to the worldwide pandemic." 56 the end of the us narrative in this reactive performance is clear. the us will be the rescuer, as it has always been. trump declares: "as history has proven time and time again, americans always rise to the challenge and overcome adversity." 57 pompeo notes in a tweet that "the u.s. government is now providing more than $1 billion to the global response on behalf of the generous american people -the world's greatest humanitarians." 58 the us must respond because china presents a clear danger to the nation. already in march, an email and a website post by the trump-pence 2020 campaign had declared, "america is under attacknot just by an invisible virus, but by the chinese." 59 and the public believes the us should step in; a plurality (41%) thinks the u.s. should "take some action for the express purpose of punishing china for the covid-19 pandemic." 60 it is notable that throughout the narrative battle between the two countries, the us public itself engages in reactive nationalism: an astounding 91% feel that it is "better for the world if the us is [the] world's leading power. 61 looking toward the future: "distress rejuvenates a nation"? in this article, we have employed in-depth hermeneutical analysis and thick description to elaborate an emergent culture structure, namely, the narrative battle between china and the us over covid-19. utilizing a model of "reactive performance," we demonstrate the ways in which social "actors" perform reactive nationalism ( [11] ; cf. [43] ) by calling upon "background representations" to fill their "scripts" with meaningful references, narratives, symbols and codes that will "resonate" with their "audiences" ([1, 2]; author 2018). politicians and government officials in each of these imagined communities ( [7] [1983]) narrate a story informed by long-standing cultural representations. in the chinese narrative, the country rises from being the "sick man of asia," weary from a "century of humiliation," to a strong world power that no longer needs to suffer the bullying of a hypocritical west full of double standards. the us narrative seems to fulfill this characterization of a nation of contradictions. while historically, the us has seen china as a dangerous actor on the world stage, to which its people stand in contrast as the "world's greatest humanitarians," at the beginning of the covid-19 crisis, trump proudly touts the country's "very good" relationship with china. but he boldly moves on to denigrate the country, blaming it for the global pandemic, and noting it is "well-known" for its "pattern of misconduct." 62 from an analytical and theoretical perspective, the careful reconstruction of meanings and culture structures help reveal the nuances of contemporary sociological phenomena such as the international conflict over the covid-19 crisis. while interactions between nation states are often examined through the lens of political science and international relations, this research shows that a cultural-sociological approach, which shifts the focus from sovereign states to the identities, memories and narrations of individuals and collectives in those states can yield fruitful outcomes. a cultural-sociological perspective like the one employed for this analysis complements existing perspectives on foreign policy and international relations by stressing the meaning-making processes underlying social action. it is through unpacking such meaning-making processes that we have reconstructed not only how the battle unfolded but also touched upon why, on the level of a social psychoanalysis, the battle proceeded as it did. even as the social scientific results of our analysis help enhance how we conceptualize and understand social life, they point to important political implications on a global scale. as we noted in our introduction to this article, we clearly see a "shrinking" of the public sphere in which evidence-based rational discussions are cornered by radical opinions. the conspiracy theories that have appeared in both china and the us and the promotion of such theories by high-level officials serve as good examples of such radicalization. does the narrative battle imply the resurgence of what the economist posits as a "new scold war," threatening the world by "tearing it apart"? 63 the author warns that "relations between america and china have plunged into an abyss from which they will struggle to escape." an article penned by the magazine on the same day heralds, "there is less trust between washington and beijing than at any point since 1979." 64 the resurgent nationalism certainly paints a bleak picture for foreign policy. our research shows that behind this "scold war" and the bleak reality are competing narratives embedded in the collective memories and cultural identities of the two nations. reconstructing such historical and cultural webs of meaning may not automatically move the relationship in a better direction, but it offers a road map to better understand oneself and the other side. 62 whitehousse.gov. 2020. remarks by president trump on actions against china. may 30. retrieved from https://www.whitehouse.gov/briefings-statements/remarks-president-trump-actions-china/. accessed 10 july 2020. 63 the economist. 2020. the new scold war: the pandemic is driving america and china further apart. may 9. retrieved from https://www.economist.com/leaders/2020/05/09/the-pandemic-is-driving-america-andchina-further-apart. accessed 10 july 2020. 64 the economist. 2020. superpowered insults: there is less trust between washington and beijing than at any point since 1979. may 9. retrieved from https://www.economist.com/united-states/2020/05/09/there-isless-trust-between-washington-and-beijing-than-at-any-point-since-1979. accessed 10 july 2020. former chinese premier wen jiabao wrote four characters on a school blackboard in beichuan, the epicenter of the 2008 sichuan earthquake: "distress rejuvenates a nation (多难兴邦)." the chinese believe that "a nation can be successful only after experiencing some hardships and difficulties, as a disaster can also open new opportunities and bring new changes" ( [45] : 160). can we apply this maxim to the global level? some scholars are optimistic, stressing that the covid-19 crisis will eventually have a positive impact on globalization through the recognition that we share a "common fate" [50] . lampton [27] has suggested that leaders in both the us and china should "rethink the us-china bilateral dialogue mechanism" to improve cooperation and avoid major conflicts between the two super powers. our research shows that the current reactive communicative mechanism is not only unsustainable, but also dangerous in times of crisis. we suggest that recognition of the narrative battle and acknowledgement of its performative function in the public sphere is the first step toward mutual understanding and meaningful dialogue between these two world powers. hua chunying 华春莹. 2020. @spokespersonchn chinese diplomat promotes conspiracy theory that us military brought coronavirus to wuhan remarks by president trump, vice president pence, and members of the coronavirus task force in press briefing remarks by president trump, vice president pence, and members of the coronavirus task force in press briefing where did the novel coronavirus come from? cgtn top chinese official disowns u.s. military lab coronavirus conspiracy trump strikes conciliatory tone with china's xi on coronavirus call. nbc news foreign ministry spokesperson zhao lijian's regular press conference on people's republic of china (prc) targeting of covid-19 research organizations china leads vaccine r&d, no need to steal. global times referring to our analytical model, these scripts feed into public attitudes toward china, clearly resonating for us audiences and escalating the reactive performance foreign ministry spokesperson geng shuang's daily briefing online on chinese diplomat promotes conspiracy theory that us military brought coronavirus to wuhan us covid-19 statistics challenged by multiple research: lethal virus is far more widespread in the country than previously thought china is the real sick man of asia waltz: china's rise "the most existential threat" to the 2020. u.s. views of china increasingly negative amid coronavirus outbreak remarks by president trump, vice president pence, and members of the coronavirus task force in press conference remarks by president trump, vice president pence, and members of the coronavirus task force in press conference coronavirus drives the u.s. and china deeper into global power struggle remarks by president trump, vice president pence, and members of the coronavirus task force in press conference. 2020. whitehouse.gov secretary michael r. pompeo's remarks to the press the economist/yougov poll remarks by president trump in address to the nation 2020 @secpompeo joe biden defends china and parrots communist party propaganda the economist/yougov poll 2020. u.s. views of china increasingly negative amid coronavirus outbreak cultural pragmatics: social performance between ritual and strategy cultural pragmatics: social performance between ritual and strategy the strong program in cultural sociology: elements of a structural hermeneutics democrats and republicans have argued about china for 150 years china dream: still coming true? imagined communities: reflections on the origins and spread of nationalism the drama of politics: jeffrey 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following the rise of china and the future of the west: can the liberal system survive? foreign affair telling the china story well: a discursive approach to the analysis of chinese foreign policy in the "belt and road" initiative deglobalization: the rise of disembedded unilateralism the assertive china narrative: why it is wrong and how so many still bought into it fearing yellow, imagining white: media analysis of the chinese exclusion act of 1882 a new type of major-power relationship: seeking a durable foundation for us-china ties china in the contemporary american geopolitical imagination racing toward tragedy? china's rise, military competition in the asia pacific, and the security dilemma rethinking global health governance in a changing world order for achieving sustainable development: the role and potential of the "rising powers the medium is the massage: an inventory of effects the gathering storm: china's challenge to us power in asia a time for positive-sum power sampling strategies in qualitative research strong society, smart state: the rise of public opinion in china's japan policy 2020. xenophobia in the time of pandemic: othering, anti-asian attitudes, and covid-19 how nationalism can be a force for good in the struggle against covid-19 globalization. the stanford encyclopedia of philosophy (winter) why war? the cultural logic of iraq, the gulf war, and suez us-china relations: perilous past, uncertain present theory construction in qualitative research: from grounded theory to abductive analysis power, equality, nationalism: how the pandemic will reshape the world. the guardian chinese assertiveness in the south china sea: power sources, domestic politics, and reactive foreign policy how the world will look after the coronavirus pandemic never forget national humiliation: historical memory in chinese politics and foreign relations from economic cooperation to strategic competition: understanding the us-china trade disputes through the transformed relations the danger of vaccine nationalism chinese populist nationalism: its intellectual politics and moral dilemma escalated policy space conflict: tracing institutional contestations between china and the united states would covid-19 be the turning point in history for the globalization era? the short-term and long-term impact of covid-19 on globalization glorious memories of imperial china and the rise of chinese populist nationalism constructing a "new type of great power relations covid-19 in china: from "chernobyl moment" to impetus for nationalism her two most recent articles, featuring the cultural sociological analysis of media coverage on refugees entering the united states and canada, have been published in 2019 in nations and nationalism and journal of immigrant & refugee studies runya's research focuses on civil society, social governance, and international relations through cultural sociological lenses. her recent publications include an essay on the symbolic meaning of face masks during covid-19 in social anthropology, a paper on chinese state-society relations under the new "graduated control 2.0" model published in china information, and an article with jessica c. teets reviewing the responsiveness of hu and xi administrations acknowledgements this research was financially supported by the european regional development fund through the project 'sinophone borderlands -interaction at the edges' (no. cz.02.1.01/0.0/0.0/16_019/ 0000791) and the student research project "migration and contemporary societies: cultural sociological perspectives," project num. muni/a/1157/2019. we would like to thank the two anonymous reviewers for their comments and special thanks goes to dr. richard q. turcsanyi for his suggestions on the literature. key: cord-260565-cdthfl5f authors: burkle, frederick m. title: declining public health protections within autocratic regimes: impact on global public health security, infectious disease outbreaks, epidemics, and pandemics date: 2020-04-02 journal: prehospital and disaster medicine doi: 10.1017/s1049023x20000424 sha: doc_id: 260565 cord_uid: cdthfl5f public health emergencies of international concern, in the form of infectious disease outbreaks, epidemics, and pandemics, represent an increasing risk to the worldʼs population. management requires coordinated responses, across many disciplines and nations, and the capacity to muster proper national and global public health education, infrastructure, and prevention measures. unfortunately, increasing numbers of nations are ruled by autocratic regimes which have characteristically failed to adopt investments in public health infrastructure, education, and prevention measures to keep pace with population growth and density. autocratic leaders have a direct impact on health security, a direct negative impact on health, and create adverse political and economic conditions that only complicate the crisis further. this is most evident in autocratic regimes where health protections have been seriously and purposely curtailed. all autocratic regimes define public health along economic and political imperatives that are similar across borders and cultures. autocratic regimes are seriously handicapped by sociopathic narcissistic leaders who are incapable of understanding the health consequences of infectious diseases or the impact on their population. a cross section of autocratic nations currently experiencing the impact of covid-19 (coronavirus disease 2019) are reviewed to demonstrate the manner where self-serving regimes fail to manage health crises and place the rest of the world at increasing risk. it is time to re-address the pre-sars (severe acute respiratory syndrome) global agendas calling for stronger strategic capacity, legal authority, support, and institutional status under world health organization (who) leadership granted by an international health regulations treaty. treaties remain the most successful means the world has in preventing, preparing for, and controlling epidemics in an increasingly globalized world. “honesty is worth a lot more than hope…” the economist, february 17, 2020. infrastructure, prevention, and preparedness, yet these protections remain far from being globally understood, available, practiced uniformly, or free of political control. what is increasingly common since the last one-third of the 20 th century is the thread of public health emergencies permeating, and often dominating, the consequences brought on by wars, conflicts, and large-scale disasters. 2 few are aware that wartime public health crises cause more deaths than weapons. 3, 4 consistently in war, the public health protective threshold is destroyed and not recovered or maintained. 5 recovery is purposely ignored, resulting in increasing post-crisis mortality and morbidity indices that are characteristically ignored or denied, especially if they negatively impact political, ethnic, or religious groups whose views are contrary to the newly installed autocratic regime. ruger reminds us that authoritarian regimes suppress political competition and tend to have an interest in preventing human development, because improved health, education, and economic security mobilizes citizens to advocate for greater participation and more resources. 6 public health protections are literally invisible to populations; they are often taken for granted and applauded as great successes serving as propaganda ploys in public speeches. 7 although there has been scant investment in public health infrastructure and protections in all parts of the world, those countries suffer the most under autocratic regimes, especially where they have failed to keep pace with population growth and density. 8 currently, both the urban and rural environment of the 21 st century are being defined by deficient dwellings, aged and inadequate infrastructure, and insufficient capacity to respond to crises, especially in ensuring access to safe water, food, sanitation, and energy. public health surveillance, the "continuous, systematic collection, and analysis of health-related data serve as an early warning system for impending public health emergencies, but compliance differs remarkably from one country to another." 6, 8 indeed, the direct and indirect mortality and morbidity resulting from these tragedies are the responsibility of the government in power, but are often the first to be ignored. ecological and environmental protections and preservations, such as the continuous surveillance mandated by the world health organization (who; geneva, switzerland) of wet markets in china that launched sars (severe acute respiratory syndrome) in 2008, is an example of a critical monitor that was ended prematurely. only the reporting of three diseases (yellow fever, plague, and cholera) are currently binding under the international health regulations, and then some countries are unwilling to notify who fearing economic and political consequences. 9 stable and unstable political systems the processes of political development, primarily as they apply to stable and unstable political systems and change, have always been dynamic, especially in crisis situations such as outbreaks of infectious diseases in less-developed countries. crisis situations test the stability of political systems in revealing ways, placing extraordinary demands on the political leadership and the existing public health structure and processes of the country. in the absence of early and effective preparedness, societies may experience social and economic disruption, threats to the continuity of essential services, reduced production, distribution difficulties, and shortages of essential commodities. the who emphasizes a "whole-ofsociety" approach that emphasizes significant roles not only for the health sector, but also by all other sectors, individuals, families, and communities, in mitigating the effects of a pandemic. 10 developing such capacities is at the heart of preparing the whole of society for a pandemic. i assert that it is the loss of the whole of society's concept, thinking, and participation that is systematically destroyed in autocratic regimes that contributes to why these political systems fail. they fail when citizens have no defined ownership, channels of communication, or are allowed to participate in any aspect of the disaster cycle (prevention, preparedness, response, recovery, or rehabilitation). they fail when citizens are not allowed a voice in the implementation of acceptable policies when the political system ceases to be viewed as responsive by individuals and groups making demands on it, and by what is considered inappropriate political behavior. infectious disease outbreaks have the uncanny capacity to question the status quo, catalyze smoldering unrest, and most importantly, reveal population-based public health imperfections. 11 the "whole of society" which depends on a form of collaborative governance, which complements public policy, disappears and is seen only as the dictate of one person. indeed, the negative influence on society, what i refer to a "societal mental health," is out of proportion to their representation in society. 12 the 2019 democracy index, compiled by the united kingdom's economist intelligence unit (london, uk) and published annually in the economist, ranks countries according to political and civic freedom using five criteria: whether elections are free and fair, whether governments have checks and balances, whether citizens are included in politics, the level of support for the government, and whether people have freedom of expression. nations are divided into "full democracies, flawed democracies, hybrid regimes [which include those exhibiting regular electoral frauds], and authoritarian regimes" where "political pluralism has vanished or is extremely limited." 13 the 2019 edition is considered as having the "worst average global score since the index was introduced in 2006, driven primarily by regressions in latin america and sub-saharan africa. 14 globally, this is the first time in the modern era where we have the fewest democracies. by ranking on how functional their political systems are, less than five percent of the world's population live in a "full democracy." 15 fewer countries can claim free and fair elections, checks, balances, and participation in their governments. fewer nations offer freedom of expression or political participation in established political cultures. rapidly established and increasingly prosperous autocratic regimes, many first drawn in by populist claims that enticed the masses of working-class and poor, are now firmly established by an economy ruled by dictators and oligarchs with unfettered political influence. the united states is now categorized as a "flawed democracy," experiencing both undeniable presidential claims for more authoritarian rule, a population that increasingly claims loss of traditional liberties, and low esteem in which us voters hold their government, elected representatives, and political parties. 15 characteristics of autocratic regime leadership autocratic leaders demonstrate personality and behavioral characteristics that are remarkably consistent across borders and cultures. 16 in great part, this is due to a common fault line from their adolescent development which becomes arrested cognitively and emotionally. while they may, at first glance, seems smart, they are not bright or capable of attaining abstract reasoning. 17 this type of reasoning is required to formulate theories and understand multiple meanings crucial for reasoning. it demands generalizations, ideas, the ability to identify the relationship between verbal and nonverbal ideas, and to understand the multiple meanings that underlie an event, statement, or object; an example often cited is: "the liberty bell is not just a piece of american history, but is a symbol of freedom." 18 concrete thinkers misinterpret many concepts like this and are compelled to reinterpret them in their own concrete manner in political speeches and legislative decisions. abstract thinking refers to a cognitive concept involving higherorder, or complex thoughts. to be able to think in an abstract manner implies that one is able to draw conclusions or illustrate relationships among concepts in a manner beyond what is obvious. 19 often the terms "abstract thought" and "concept formation" are used interchangeably. in the past, the term "fluid intelligence" has been used to refer to the ability to reason. the generation of concepts, or abstract ideas, indicates an ability to progress beyond concrete thinking. the concrete interpretation of a concept involves a focus on the salient, obvious characteristics. progressing beyond the tangible characteristics in order to conceptualize theoretical relationships between items or processes involves abstract thought. deeper meanings such as "freedom," "equality," "charity," "love," and "democracy" express ideas, concepts, or qualities that cannot be seen or experienced. 20 they are considered only in the concrete sense as it applies to autocratic thinkers. the us constitution would not be understood in the manner it was originally written as it is an example of a document that requires abstract thought and is either not read, understood, or interpreted concretely by a leadership that is completely self-serving. concepts such as freedom and equal rights interpreted concretely become self-serving. studies demonstrate that "persons with different value preferences apply different neurobiological strategies when facing a decision" and can help explain the fixed values that decisions are made that are independent of an actual situation. 21 this stubbornness of thought and action is reflected in shared personality disorders of autocratic despots. brain areas beyond those activated in actual moral dilemma situations were found to be involved. they are psychologically fixed, as illustrated by muammar gaddafi when he was being beaten to death by his own people, claiming up to the last minute: "but the people love me!" some of the well-known behaviors include cover-ups, exaggeration, and fabrication; fraud, omission, half-truth, perjury, and lies that come in various types, conveyed to exaggerate one's credentials or get the attention that reflects their universal narcissistic disposition and constant needs. in great part, these behaviors are witnessed between all despots of the world. despite the bad press lies get, and that many press agencies tally the daily lie numbers, most are ignored by political supporters in every country, particularly the ones that have spoken to avoid conflict, and as a show of collective support. operationalization of narcissism is "dispositional" which accompany a "grandiose sense of selfimportance, exhibitionism, entitlement, interpersonal exploitativeness, and a total lack of empathy." 22 autocratic leaders: [r]etain all power, authority, and control, and reserve the right to make all decisions; distrust their subordinate's abilities, closely supervise and control people under them; rarely delegate or empower subordinates; adopt one-way communication, do not consult with subordinates or consider their opinions; create a system of rewards and punishments; use threats and punishments and evoke fear; rarely concern themselves with developmental activities; and take credit for all the accomplishments. 23 in truth, once in positions of power, only the most emotionally healthy and resilient can avoid the slide into psychopathology. for those with some of the personality attributes of sociopathy or psychopathy, the descent into deeper pathology may be beyond their ability to resist. even their followers can become pathologically dependent. democracies characterized by individual freedom and liberty are rare. throughout history, autocratic governments and tyranny have been the rule. their lack of conscience and an inability to feel remorse are the underlying factors that are often viewed initially as charming, but soon reveal uncanny skills as master manipulators, skillful at lying and cheating. they have no capacity to feel guilt. despite an incidence rate of three percent to five percent within the general population, and 25% of prison populations, it sometimes seems that they already rule the most despotic and populated areas of the world. 24 part ii: pandemic status of countries under autocratic rule as of february 20, 2020, 26 nations have who-confirmed cases of covid-19 (coronavirus disease 2019) outside china. the global surveillance covid-19 database centralizes all covid-19 cases reported from outside china and is maintained at the who headquarters in geneva. their data analysis is conducted daily to: "follow the transmission of the disease between countries; describe the characteristics of human-to-human transmission within clusters of cases; describe the characteristics of affected persons and their exposure history; and support the evaluation of public health measures implemented in response to the epidemic." 25 this study focuses only on countries under autocratic rule and describes the current status of public health preparedness and current responses. this review includes all countries run by one person or party with absolute power. autocracy is a system of governance headed by a single ruler called an autocrat. decisions made by the autocrat are not subject to legal restraints and the autocrat exercised unlimited and undisputed power. 26 as of 2018, 50 nations are ruled by a dictator or authoritarian regime. admittedly, democracy remains unsure in many countries, especially africa, where dictators rising to power are increasingly likely. the study adds that: "europe is home to one dictatorship, while three of them can be found in latin america and south america. there are eight dictatorships in asia, seven in the eurasian region of the world, and twelve span territory from the northern parts of africa to the middle east." 26 china i cut my humanitarian teeth in china in the 1970s and 1980s when an unprecedented 83% of the population was suffering from poverty and malnutrition, one of the highest in the world. i was one of the few foreign physicians continually invited back under mao's repressive regime. this allowed me an unprecedented view of china's attempt to re-define what is the anthesis to the established global who requirements that guaranteed population-based public health protections. i taught basic public health management and reforms and helped establish emergency services to many hospitals. i was engaged in these activities while the government emphasized unprecedented industrial and economic development that contributed to rapid and "remarkable achievements" in the overall social and economic health of the population. the incidence of poverty in china in 1981 declined from 85% to 27% in 2004, a reduction of slightly more than 600 million people, primarily accomplished through targeting rapid industrialization and village-based poverty. 27 it also caused "twists and turns on the development of china's public health" requirements, which lagged vastly behind industrialization. public health was never given the same priority and failed to catch up with changes that required timely updating and adjustment of services. 28 while it took time to recognize that china was on a path to also politically and economically redefine public health protections, infrastructure, and development, warnings directed at china's new regional centers for disease control (cdc; beijing, china) fell on deaf ears. that same lack of coordination and collaboration remains evident today, placing china under a different microscope, one of greater scrutiny and judgment from the global community who sees their many poor health outcomes. many of these poor outcomes are especially related to air pollution in re-defining hazardous air by who standards as "acceptable," and prompting many in china and the world to ask "at what price?" 29 in 2010, there was water scarcity in two-thirds of china's 600 cities, 80% had no sewage treatment facilities, the food security program was unsustainable, 90% of groundwater was polluted, and major rivers had their downstream microorganism ecology altered by chemicals and fertilizers dumped by industry and cities into the water. this resulted in new and re-emerging diseases. 30 after identifying sars origin from a wet market civet source in august of 2016, president xi's economic address, tied to security concerns, called for "full protection of people's health, stressing that public health should be given priority in the country's development strategy." 31 an independent survey of the chinese citizenry two months later revealed that while the chinese public agreed with xi's need to promote china's more influential role in the world, they raised grave concerns about environmental safety, numerous high-profile scandals regarding unsafe medical and food products, and water and air pollution. 32 china's story mirrors that of other developing countries in asia, the fastest-growing region in the world, in that government spending on public health is inadequate and not focused on those who need it the most. studies in 2018-2019 confirm that 90 % of china's groundwater is contaminated; tap water is not safe due to water contamination by the continued dumping of toxic human and industrial waste, because oxygen levels have obliterated normal organisms in all major rivers and only algae continue to flourish. air quality remains "very unhealthy" and continues to have a major toll on public health, resulting in 350,000 to 400,000 premature deaths. 33, 34 it remains unclear whether china will ever meet its air pollution goals, let alone participate in global climate commitments to reduce carbon emissions. 34 no one in global public health was surprised to learn that once again a wet market animal, not suited for human consumption, was probably responsible for this year's covid-19 pandemic. however, chinese researchers now stress that the virus did not originate in the wet market, but was transferred from elsewhere, on december 8th and again on january 6th. 35 transmission could have begun in early december or late november, admitting the world-wide spread could have been limited had the earlier alerts been implemented. after sars in 2002, external pressure has also impacted on the development of china's public health. 36 during the sars outbreak, the who directly told the chinese government in its mission report in april 2003 that "[t]here was an urgent need to improve surveillance and infection control" in the country. 37 two years later, in a joint report issued by state development research center (beijing, china) and who, the chinese government officially admitted its health care system was failing, and it needed to improve its disease surveillance system at the local wet market levels if they were to be seen as a "responsible state." 38 in december of 2019, the first cases of covid-19 were diagnosed in wuhan, the capital of hubei province, and rapidly expanded. for two weeks, the existence of a novel rapidly expanding virus was known to president xi. unconscionably, china arrested, jailed, and punished physicians and journalists who defied government attempts to silence the truth of the virus. moreover, the government ceased to enforce the timely flow of crucial public health information, delaying both critical medical care, its obligations to the who, and the sacred paradigm of human interaction with a disease that collectively defines "freedom of speech." 39 andrew price-smith put the same point succinctly post-sars, stating that "while the sars epidemic may have generated moderate institutional change at the domestic level, it resulted in only ephemeral change at the level of global governance." 40 in other words, national sovereignty is still of paramount importance for the chinese leadership. because of its sensitivity to foreign interference into its internal affairs, the chinese government has not yet formally or officially endorsed the notion of "human security." 40 while china has embraced multilateral cooperation in a wide array of global health issues, its engagement remains "state-centric." 37, 38 the sars event not only exposed a fundamental shortcoming of china's public health surveillance system, as well as its singleminded pursuit of economic growth since the late 1970s, but also forced china to realize that, in the era of globalization, public health is no longer a domestic, social issue that can be isolated from foreign-policy concern. 37 having no tolerance in ceding its supreme authority, the central government has adopted a multifaceted attitude towards its civil society organizations. while beijing shows its willingness to cooperate with a wide array of actors inside china, it refuses to let its domestic nongovernmental organizations (ngos) and activists establish direct links with their counterparts overseas. 37, 41 china was openly accused of a cover-up with sars, and few professionals are confident that anything has changed. 42 chan maintains that while "it is still uncertain whether this sovereign concern will trump the provision of global public good for health. nevertheless, in a highly globalizing world, infectious diseases know no border. while china is seeking to adhere as much as possible to the underlying norms and rules of global institutions," reemphasizing that china after sars "perhaps [needs] to reframe health as a global public good that is available to each and every individual of the world, rather than merely as an issue of concern to nation-states." 37 in a rare openness, rarely seen before, the normally secretive xi admitted at a meeting to coordinate the fight against the virus that china must learn from "obvious shortcomings exposed during its response." yet given the second-guessing that always surfaces in these tragedies, "it cannot be denied that the chinese government tried to control the narrative, another sign of irrational hubris, and as a result, the contagion was allowed to spread, contributing to equally irrational fear." a china researcher for human rights watch (new york usa) noted: "authorities are as equally, if not more, concerned with silencing criticism as with containing the spread of the coronavirus. : : : repeating a pattern seen in past public health emergencies." 43 although less clumsy than with sars, the government kept all non-party groups that could have helped prevent the spread of the virus out of the loop. 44, 45 china's religious groups who "reflect the country's decades-long revival and feeling among many chinese that faith-based groups provide an alternative to the corruption that has plagued the government" are being ignored. 46 will this just be a temporary stay as it was post-sars, or is china capable of adopting, without conditions, the who public health requirements they have ignored to date? north korea, the most sealed-off country in the world, has literally shut down all borders and communications on covid-19, denying, according to their propaganda channels, the existence of any cases or deaths. this is unusual as it sits between china and south korea, which have recorded the largest numbers of cases. researchers state it is "unlikely that north korea is free of covid-19." south korean media reported that kim jong un, the north korean leader, had an official executed for violating the quarantine after the official returned from a trip to china. this may or may not be true since such reports have proved dubious in the past. north korea press outlets claim that "not one novel coronavirus has emerged;" yet south korea's unification ministry (seoul, south korea), in charge of inter-korean relations, reported to the who that north korea had tested 141 suspected cases of coronavirus and all came up negative. 47 nevertheless, south korean media, relying on anonymous sources, report cases of covid-19 in north korea, some of them fatal, according to john linton, head of the international health care center at severance hospital in seoul: "through private sources, they're asking for disposable gowns, gloves, and hazmat suits, which are undoubtedly lacking," he says. "so something is going on, otherwise they wouldn't be asking for this." 47 north korea relies on china for more than 90% of its trade. researchers admit that while health indicators have improved in the two decades since the country's 1990s famine, during which hundreds of thousands of people starved to death, 48 but there are still major problems. in the 1990s, amnesty international (london, uk) detailed a crumbling health care system in north korea, a nation unable to feed its population, and, in violation of international law. north korea refused to cooperate with the international community to receive food. levels of malnutrition, maternal health, and tuberculosis (tb) are chronic problems, but a lack of accurate data on hiv/aids and hepatitis b present cause for alarm. health indicators have improved in the two decades since the country's 1990s famine, but major problems still exist. whereas communicable diseases account for a large proportion of the disease burden, there are very few opportunities to better understand and control them. 49 while health infrastructure has improved, capacity is low and the health system is chronically under-resourced. north korea has allowed for united nation (un) interventions, primarily focused on sustainable development, but this has been on north korea's terms, a demand not unusual for autocratic regimes. 50 in 2014, the report of the un commission of inquiry on human rights in the democratic people's republic of korea (dprk) concluded that: "20 years after humanitarian agencies began their work in the dprk, humanitarian workers still face unacceptable constraints impeding their access to populations in dire need." 51 the report found that the dprk has "imposed movement and contact restrictions on humanitarian actors that unduly impede their access." the dprk has "deliberately failed to provide aid organizations with access to reliable data, which, if provided, would have greatly enhanced the effectiveness of the humanitarian response and saved many lives." the north korean government "continually obstructed effective monitoring of humanitarian assistance, presumably to hide the diversion of some of the aid to the military, elite, or other favored groups, as well as to markets." in summary, the report stated: in this tightly controlled political climate, international humanitarian staff often have to make compromises. some point out privately that it is unrealistic to try to uphold humanitarian standards in an environment as difficult as north korea's. they try hard to come up with ways to make their aid sustainable for the north korean people, but their plans are not always accepted. 51 although the knowledge of public health has improved in recent years, 18 million people are dependent on a public distribution system of food rations and more than 10 million are undernourished. 52, 53 iran early in the coivid-19 crisis, iran introduced containment measures that china had instituted placing tens of millions of people under lockdown. yet, iran has confirmed 43 infections and eight deaths, and appears to have entered the epidemic phase of the disease. pakistan and turkey announced the closure of land crossings with iran, while afghanistan said it was suspending travel to the country. four new covid-19 cases surfaced in tehran, seven in the holy city of qom, two in gilan, and one each in markazi and tonekabon. as of this writing, several reports from the cities in the south, west, center, and north of iran indicate cases testing positive for covid-19. the iranian minister of health stated that the origin of the virus was in qom, where infected chinese nationals and iranians who traveled to china during its pandemic were diagnosed. reports suggest that a minimum number of cases is between 1,000 to 1,500, with additional unofficial reports of deaths from hamedan, saveh, tonekabon, and tehran, suggesting that the government under-reports the number of positive cases. 53 the health ministry ordered the closure of schools, universities, and cultural centers across 14 provinces. all sport and cultural events were shut down for two weeks and all educational public exams were postponed. unfortunately, many health workers and physicians are among newly infected cases, including the deputy health minister. 53 the country suffers a lack of basic equipment such as masks and disinfecting materials, even in health care centers. people are in a panic due to a lack of access to protective materials and angry over the government cover-up. 54, 55 personal contacts in iran, unfortunately, report that: "there is a major concern of misinformation because people do not trust the governmental information, opening the doors for rumors and more misinformation." paul hunter, professor of medicine at britain's university of east anglia (norwich, england), said the situation in iran has "major implications" for the middle east. "it is unlikely that iran will have the resources and facilities to adequately identify cases and adequately manage them if case numbers are large." 56 as of this writing, turkey has not reported any covid-19 infections. the government has closed its border with iran, introduced health checks from iran, and are turning back travelers. yet travel from turkey to iran continues. turkey is strategic in its geographic position. it is bordered by eight countries, is the intersection point of asia, europe, and africa, making it one of the most strategic countries in the world. with its geopolitical position, turkey is a unique bridge between eastern and western civilizations and between all religions. 57,58 i bring up turkey because that nation also has one of the most autocratic regimes in the world, which has mastered control over the population and media. the government has a pattern of undercutting critic's claims, accusing the opposition of having ulterior motives, and systematically undercutting the independence of the rule of law. 57 recep tayyip erdogan's one-man rule-control all executive, legislative, and judicial functions by imprisoning critical journalists and destroying what was left of the free media. he has arrested teachers, police, and government workers. erdogan must be in control of the narrative on all issues, including health. 59 after the lessoned learned in china with one non-medical voice controlling all news on covid-19, a similar false narrative, seen with all dictators, may again occur. health differences with their northern european union (eu) neighbors were a concern that delayed accession talks for full membership in the eu in 2005. one-half the population is made up of secular and liberal turks who wish to restrain erdogan and his abuse of power. 59 african nations autocratic or authoritarian regimes-dictatorships-have been a dominant form of governance in africa for many years. in the second decade of the 21st century, one concern is that they may hinder the attainment of one of the un's crucial sustainable development goals. in the last three years, analysts say that african countries have registered an overall decline in the quality of political participation and rule of law. the british broadcasting corporation (bbc; london, uk) recently reported that "more and more elections are being held in africa." however, analysts dismiss many as being "lawful but illegitimate." although studies show a majority of africans still want to live in democracies, an increasing number are looking to alternative, autocratic models. 60 african countries, in the last three years, have registered an overall decline in the quality of political participation and rule of law; analysts say: "today there are almost the same number of defective democracies (15) as there are hardline autocracies (16) , among the continent's 54 states," nic cheeseman, professor of democracy at birmingham university (birmingham, england), concludes from his analysis of the last three years. 60 nigeria is among those listed as a "defective democracy," which underscores the importance of recognizing fragile political parties in africa. recent elections in nigeria illustrates this. 60 nigeria is seen as an emerging democracy often found in newly emerging states, and established democratic regimes existing in states with long traditions of uninterrupted sovereignty. 60 most critically, many autocratic african countries have been thrown into an inescapable political mix with china because of china's close economic ties with multiple african countries. this economic dependence on china has grown so fast that it has critical future implications. the rapidity in which china has launched its massive continent-wide initiatives has been lost on many. the covid-19 pandemic has awakened scholars to revisit its impact on africa, where the world's most powerful autocratic regimes exist. 61 as of 2012, the african continent was home to more than 1.1 million chinese immigrants. 62 from 2001 to 2017, china's africa strategy began to solve overpopulation, pollution, and the poor economy in africa and other developing countries. china offered sizeable loans to finance infrastructure projects, which incurred major debts for many third world nations, but especially africa. these loans have changed the cultural and ethnic landscape of many struggling nations. 63 the building of african ports, highways, and railways, all with chinese money, have primarily corporate-level intentions, not the daily welfare of the populations. on the surface, these sound infrastructure projects are what africa legitimately sees as necessary for progressing out of poverty. but on closer examination, they serve china's ambitions to write the rules of the next stage of what they define as "globalization." 64 of major concern is that these african countries are now defaulting on the loans, primarily funded by countries other than china, for daily external assistance and survival. the very predictable failures of the african countries to pay back the loans have entrapped african nations even further: "china, as the only major creditor in africa, won't be far away from taking hold of virtually every industry in africa." 65 according to the agreements set up by china, the african nations can repay loans with natural resources such as oil. yet, the defaulted loans made for constructing ports that were not productive are already owned by china. china's massive "belt & raid initiative" was designed to link up to 70 countries, all tied to china's multiple infrastructure contracts and investments. overland routes for roads and rail transportation guarantee that most countries involved will never be able to fully pay the loans and will remain dependent on china for their trade economies in the coming years. this receives very little attention in the western press. in 2017, forbes reported that china now owns international port holdings in greece, myanmar, israel, djibouti, morocco, spain, italy, belgium, cote d'ivoire, egypt, and about a dozen other countries. 66 in 2018, china took control of kenya's largest port after that nation defaulted on its unpaid chinese loans. china wants everything from africa-its strategic location, its rare earth metals, and its fish. this leaves african nations forever indebted to beijing. over one million chinese now work in africa, with one author citing that africa is "china's second continent," 67 but the actual long-term impact of these many transient workers on african's future is mixed. one author summarized that "on closer examination, china's ambition is to write the rules of the next stage of globalization. this suggests that beijing will not accept anything less than being the dominant landlord, one that is autocratic and mimicking the current authoritarian regime in china. china wants africa's resources and its maritime roads for beijing's large military presence." this is evident from the fact that chinese troops and weapons outnumber all other countries, especially the us, which is decreasing its military footprint. china formally launched its first overseas military base in djibouti, where it constructed strategic ports, an electric railway, logistics, and intelligence facilities. 68 but in all their projects, they focus on highways, ports, dams, and public networks, such as electric grids, not public health infrastructure. military might is their priority, a model taken from the us over the past two decades. while the us today is trimming down its military presence in africa, china is increasing theirs. from the outset, china and heads of state from 53 african countries met to implement eight major initiatives to strengthen the cooperation between china and africa. some of the initiatives included industrial, trade, and cultural promotion, with public health ranking as a top priority for the china-africa health cooperation plans. in 2017, there were 1,050 health professionals from china working in all 53 african countries, focusing on public health training and disease-control programs centered on emerging infectious diseases, malaria, hiv/aids, and health informatics, in collaboration with africa cdc (addis ababa, ethiopia), us cdc (atlanta, georgia usa), and other global partners. 69 what remains a contradiction is the strong health priorities of the china-african cooperation, which emphasizes many health initiatives that mainland china currently lacks. but china looks to the future and its survival. as they say in their next phase of "globalization," african economic dominance will be necessary for africa's survival. 69 what political regime will rule at that time is questionable, but will probably be autocratic across china, africa, and other countries that currently face a potential military takeover by china, such as cambodia and myanmar. in the meantime, who and other regional and country public health experts are concerned the "fragile" health systems in most african countries will not be able to cope if coronavirus takes hold on the continent. even china, with its larger pool of technical and financial resources, appears to be struggling to contain the virus. 70, 71 russia for all the advances in weaponry, including the first hypersonic missile, the poor-quality of public health directly "undermines the country's economic development." their aging population and declining birth rates contribute to the low overall health status and low life expectancy. more than two million russian men are considered to be hiv positive and extremely high multi-drug resistant tb persists. the direct connection between the public health crisis and russia's economic potential is clear. it is generally accepted that the highly productive educated soviets leave the country largely for reasons having to do with the deteriorating political freedoms in the country. failure to tackle russia's huge public health problems is likely to exacerbate the brain drain already underway. it is estimated that up to 2010, more than 1.25 million russians emigrated. that represents an even greater number than those who left after the collapse of the soviet union. 72, 73 russia reported its first two cases of covid-19 and said the infected people were chinese citizens who have since recovered. the first three russian citizens have also been infected with covid-19 onboard a quarantined cruise ship in japan. around 2,500 people arriving from china have been ordered/placed under quarantine for covid-19 and monitored by the russian capital's facial-recognition technology. 74 their quarantine measures have mimicked other nations and appear robust, but remain challenging to the economy and sustainability. the one achilles heel in russia's public health is the abominable rise of infectious diseases such as tb and aids. public measures for their control in russia are insufficient, mainly because of the lack of funding for treatment, vaccine prophylaxis, and health education. tuberculosis has become an epidemic in a country where it was once a rarity. immunity is down because of poverty, too little food, and difficult access to health care. russian doctors are worried that the tb epidemic could lead to epidemics of another disease. today, tb is endemic in russia, and there is a rising incidence of multi-drug-resistant strains of tb. 75 like other autocratic regimes, russia's "political model" of globalization that feeds transnational research and treatment of infectious diseases is seriously flawed and must take responsibility for the prevention of the spread of infectious disease beyond their borders accelerated by enhanced migration. 76 what this reveals are cautious doubts about whether russia, combined with shortages of medical supplies and inadequate standards that further highlights a number of public health challenges for the country, has the public health and political capacity to manage a serious covid-19 epidemic. the borgen project, which addresses poverty and hunger, focuses on the leaders of the most powerful nations addressing the need to deal with poverty as a consequence of their dictatorial rule. it is repeated here as it serves as an objective measure of the consequences of a despotic rule, as well as an indication of the physical and emotional state of populations that might not survive the additional insult of an infectious disease: 76 the united states, now designated a "flawed democracy," is showing increasing authoritarian rule and threats to basic health protections, especially in combatting communicable diseases. most concerning is the president's embrace of authoritarian leaders and the real possibility of major pandemic prevention funding, including the emergency reserve fund, which is designed to be "quickly deployed to respond to pandemic outbreaks." president trump has mimicked other autocratic leaders' positions in managing any serious outbreak. he has praised president xi's rulings and failed to comment on the chinese ruler's decision to punish physicians for grossly delaying international warnings and calling attention to the public health threat for which xi was totally responsible. trump's narcissistic personality will force him to be defensive and again lie to save face. peter navarro, trump's senior trade advisor, is quoted: "this delay allowed the virus to proliferate much faster than it otherwise would have and reach other countries that it might otherwise have not." 77 trump does not possess the knowledge base or intellectual capacity to be the spokesperson for any north american outbreak. most critically, trump has set up a narrative that will impair the us's ability to manage any serious outbreak. he has argued for cutting spending for the cdc, national institutes of health (nih; bethesda, maryland usa), and medicare directly related to communicable diseases and will directly hinder any public health response. he is oblivious to the current status of emergency medicine departments in all hospitals, rural and urban, which are currently overloaded and have no beds for influenza patients. patients must remain in emergency rooms until critical care beds open somewhere in the system, and that may take days. in no manner is our current health system capable of handling a serious outbreak, and the failure to begin a dialogue with practicing medical professionals is being ignored. lipsitch predicts that some 40%-70% of the world's population will be infected this year. 78 despite political claims, a vaccine is more likely seen within a year or two at best. 79 it is no longer realistic to expect the management of these gaps in infectious disease outbreaks, especially those that threaten to be epidemics and pandemics, are to be capably managed in their present state of willful denial and offenses by many countries, especially those that are ruled by authoritarian regimes. 80 despite resistance to globalization's health benefits that would markedly benefit the global community during these crises by authoritarian regimes, in 2015, i called for a new who leadership granted by the international health regulations treaty that has consequences if violated. i stated: the intent of a legally binding treaty to improve the capacity of all countries to detect, assess, notify, and respond to public health threats are being ignored. while there is a current rush to admonish globalization in favor of populism, epidemic and pandemics deserve better than decisions being made by incapable autocrats. during ebola, a rush by the global health security agenda partners to fill critical gaps in administrative and operational areas was crucial in the short term, but questions remain as to the real priorities of the global leadership as time elapses and critical gaps in public health protections and infrastructure take precedence over the economic and security needs of the developed world. the response from the global outbreak alert and response network and foreign medical teams to ebola proved indispensable to global health security, but both deserve stronger strategic capacity support and institutional status under the who leadership granted by the [international health regulations] treaty. treaties are the most successful means the world has in preventing, preparing for, and controlling epidemics in an increasingly globalized world. other options are not sustainable. given the gravity of on-going failed treaty management, the slow and incomplete process of reform, the magnitude and complexity of infectious disease outbreaks, and the rising severity of public health emergencies, a recommitment must be made to complete and restore the original mandates as a collaborative and coordinated global network responsibility, not one left to the actions of individual countries. the bottom line is that the global community can no longer tolerate an ineffectual and passive international response system. as such, this treaty has the potential to become one of the most effective treaties for crisis response and risk reduction world-wide. practitioners and health decision-makers world-wide must break their silence and advocate for a stronger treaty and a return of who authority. health practitioners and health decision-makers world-wide must break their silence and advocate for a stronger treaty and a return of who's undisputed global authority. 81 will china's unilateral decisions just be a temporary stay as it was post-sars, or is china capable of adopting, without conditions, the who public health requirements they have so far ignored? autocratic leaders in history have a direct impact on health security. dictatorships, with direct knowledge of the negative impact on health, create adverse political and economic conditions that only complicate the problem further. this is more evident in autocratic regimes where health protections have been seriously and purposely curtailed. this summary acknowledges that autocratic regimes are seriously handicapped by sociopathic narcissistic leaders who are incapable of understanding the health consequences of infectious diseases or their impact on their population. they will universally accelerate defenses indigenous to their personality traits when faced with contrary facts, double down against or deny accurate science to the contrary, delay timely precautions, and fail to meet health expectations required of nations under existing international health regulations, laws, and epidemic control surveillance. 82 kavanaugh's lancet editorial initially praised chinese tactics that reflected a level of control only available to authoritarian regimes. as days and weeks passed, it revealed a government that inherently became victims of their own propaganda based on "need to avoid sharing bad news." he concluded that authoritarian politics inhibited an effective response, and that openness and competitive politics favor a strategically fair public health strategy. 83 democratic nations in comparison to autocratic regimes recognize that public health fundamentally depends on public trust. 84 the who's china joint mission on coronavirus disease report has applauded china's eventual response capability and capacity with strict measures to interrupt or minimize transmission chains with extremely proactive surveillance, rapid diagnosis, isolation tracking, quarantine, and population acceptance of these measures, to implement the measures to contain covid-19 within the country. 85 it must not be forgotten that china's authoritarian rule "put secrecy and order ahead of openly confronting the growing crisis and risking alarm or political embarrassment," 86 arrested and compelled dr. li wenliang to sign a statement that his warning constituted "illegal behavior," all of which delayed a concerted public health offensive that led to his death. 86 this was an "issue of inaction" that would have contained covid-19 within china and remains a potent symbol of china's failures. 86 there is no evidence that the authoritarian regime has or will change to prevent this from happening again. 87 i suspect china's sophisticated censorship and propaganda systems will outlast any public health improvements. world health organization research priorities in emergency preparedness and response for public health systems: a letter report wartime public health crises cause more deaths than weapons, so why don't we pay more attention? new security beat civilian mortality after the 2003 invasion of iraq interference, intimidation, and measuring mortality in war democracy and health democracy matters for health care report on global surveillance of epidemic prone infectious diseases: types of surveillance roles and responsibilities in preparedness and response development and change in political systems whole of society and whole of government approach. health and healthcare in transition: dilemmas of governance the economist intelligence unit the 30 most authoritarian regimes in the world. business insider these are the best democracies in the world: and the us barely makes the list character disorders among autocratic world leaders and the impact on health security, human rights, and humanitarian care antisocial personality disorder and pathological narcissism in prolonged conflicts and wars of the 21st century comparing governments (13a): american government encyclopedia of aging and public health what is the point of equality? moral concepts set decision strategies to abstract values the profile of narcissistic dispositions: development and validation a critique of the autocratic leadership style. bright hub project management: resource management sociopaths: statistics: the nature of a sociopath covid-19) situation report-31. world health organization dictatorship countries china poverty reduction. the world bank the development and reform of public health in china from 1949 to 2019 beijing smog prompts new concerns. borgen magazine china's deadly water problem. comment/opinion. south china morning post chinese public sees more powerful role in world, names us as top threat china's top 6 environmental concerns. live science seeing through the smog: understanding the limits of chinese air pollution reporting. feature article. china environment series wuhan seafood market may not be source of novel virus spreading globally research: virus did not originate at wuhan market china's engagement with global health diplomacy: was sars a watershed the sars epidemic and its aftermath in china: a political perspective disappearing the coronavirus truth tellers sars was a watershed for china public health domestically but not globally negotiating and navigating global health: case studies in global health diplomacy the guardian weekly. staff and agencies. china is accused of sars cover up coronavirus "rumor" crackdown continues with censorship, detentions. china digital times another citizen journalist covering the coronavirus has gone missing in wuhan the coronavirus outbreak exposes the truth about socialism with chinese characteristics religious groups in china step into the coronavirus crisis. the new york times north korea claims zero coronavirus cases, but experts are skeptical north korea isn't ready for coronavirus devastation the crumbling sate of health care in north korea humanitarian engagement with north korea sanctions hurt but are not the main impediment to humanitarian operations in north korea public health in democratic people's republic of korea why is iran's reported mortality rate for coronavirus higher than in other countries? nbo news now coronavirus: iran's deputy health minister tests positive as outbreak worsens world is approaching coronavirus tipping point, experts say. the guardian xi says china facing "big test" with virus, global impact spreads healthcare in overview of turkey how dictatorships take root in the 21 st century a comparative analysis of the european union's and turkey's health status: how health-care services might affect turkey's accession to the eu is africa going backwards on democracy? bbc news june 12 is now democracy day in nigeria. why it matters chinese immigration to africa: an essay countries jumped tenfold in the last five years what china wants from africa? everything how large chinese loans are entrapping african nations china's seaport shopping spree: what china is winning by one million chinese in africa perspectives china says it will increase its military presence in africa public health priorities for china-africa cooperation africa prepares for coronavirus some african countries at risk for the new coronavirus aren't prepared. the verge: science/health public health challenges facing russia today cripple its potential for tomorrow. the globalist: rethinking globalization the sickness of a nation. the yale global health review coronavirus in russia: the latest news. the moscow times top diseases in russia 8 current dictators as of 2018. the borgen project the coronavirus outbreak could bring out the worst in trump. virology isn't politics harvard scientist: coronavirus pandemic likely will infect 40%-70% of world this year johns hopkins bloomberg school of public health usa: the international bank for reconstruction and development/the world bank global health security demands a strong international health regulations treaty and leadership from a highly resourced world health organization theme papers on global public health and international law authoritarianism, outbreaks, and information politics china's harsh response to the coronavirus has influential admirers, but western nations recognize that public health fundamentally depends on public trust report of the who-china joint mission on coronavirus disease as new coronavirus spread, china's old habits delayed fight. the new york times coronavirus weakens china's powerful propaganda machine. the new york times key: cord-278083-ut2ssdbz authors: li, juan; zhu, yuhang; feng, jianing; meng, weijing; begma, kseniia; zhu, gaopei; wang, xiaoxuan; wu, di; shi, fuyan; wang, suzhen title: a comparative study of international and chinese public health emergency management from the perspective of knowledge domains mapping date: 2020-10-02 journal: environ health prev med doi: 10.1186/s12199-020-00896-z sha: doc_id: 278083 cord_uid: ut2ssdbz background: at the end of 2019, the outbreak of coronavirus disease 2019 (covid-19) severely damaged and endangered people’s lives. the public health emergency management system in china has played an essential role in handling the response to the outbreak, which has been appreciated by the world health organization and some countries. hence, it is necessary to conduct an overall analysis of the development of the health emergency management system in china. this can provide a reference for scholars to aid in understanding the current situation and to reveal new research topics. methods: we collected 2247 international articles from the web of science database and 959 chinese articles from the china national knowledge infrastructure database. bibliometric and mapping knowledge domain analysis methods were used in this study for temporal distribution analysis, cooperation network analysis, and co-word network analysis. results: the first international article in this field was published in 1991, while the first chinese article was published in 2005. the research institutions producing these studies mainly existed in universities and health organizations. developed countries and european countries published the most articles overall, while eastern china published the most articles within china. there were 52 burst words for international articles published from 1999–2018 and 18 burst words for chinese articles published from 2003–2018. international top-ranked articles according to the number of citations appeared in 2005, 2007, 2009, 2014, 2015, and 2016, while the corresponding chinese articles appeared in 2003, 2004, 2009, and 2011. conclusions: there are differences in the regional and economic distribution of international and chinese cooperation networks. international research is often related to timely issues mainly by focusing on emergency preparedness and monitoring of public health events, while china has focused on public health emergencies and their disposition. international research began on terrorism and bioterrorism, followed by disaster planning and emergency preparedness, epidemics, and infectious diseases. china considered severe acute respiratory syndrome as the starting research background and the legal system construction as the research starting point, which was followed by the mechanism, structure, system, and training abroad for public health emergency management. public health emergencies have increased in recent years and have shown a trend of causing considerable damage [1] . according to the emergency events database (em-dat), the most widely used and influential disaster database in the world, the average number of deaths per major public health event was more than 10,000 [2] . population growth, urban development, migration, and other issues brought about by globalization have sped up the incidence of public health events, such as epidemics [3, 4] . public health events also propelled the process of emergency management, giving top priority to changes in emergency operations. the outbreak of coronavirus disease 2019 in china spread rapidly throughout the world in a short time, which illustrated the need to build a resilient health emergency system that can withstand epidemics [5] . public health emergency management (phem) is a relatively new field that draws on specific sets of knowledge, techniques, and organizing principles found in emergency management [6] . specifically, it includes public health emergency planning, organization, leadership, coordination, control, evaluation, prevention, preparation, and response [7] . for covid-19, china's phem system quickly took the following measures: emergency mobilization measures within the government, lockdown of cities and communities, nationwide medical mobilization, provision of financial support, preferential policies for the medical community and pharmaceutical industry, and the categorical comprehensive publicity to spread prevention and treatment knowledge [8] . these measures effectively reduced the spread of the disease. thus, current recommendations are mostly derived from the reported chinese experience [9] . given the weaknesses and deficiencies exposed by the covid-19 outbreak, people have recognized the need to improve the national phem system [10, 11] . a growing body of research has studied phem from different perspectives, mainly those of institutions, funds, technologies, and laws. the public health emergency was a severe challenge to health institutions such as hospitals, the centers for disease control and prevention (cdc), and governments [7, 12] . the solutions to these challenges were characterized by sustainability, redundancy, and flexibility [13] . monetary and technology resources can merge the roles and responsibilities of public health preparedness and emergency management [14] . severe deficiencies in legal preparedness can undermine effective responses to public health emergencies [15, 16] . these were the essential factors in dealing with public health emergencies. additionally, many countries took corresponding measures to strengthen the emergency management of public health. for example, the usa established phem operations centers either independently in health departments or as a part of the overall command system in the government [17] . china established the phem system from the national level to the local level to be responsible for emergency preparedness and response in 2004 [17] . in march 2018, the ministry of emergency management of the people's republic of china was established, which was an integral part of the state council. thus, we can see that phem is still a timely topic for scholars and governments [18, 19] . however, there are still some problems that need to be solved. to the best of our knowledge, there is little evidence about the differences that occurred between international and chinese phem. moreover, what are the hotspots and trends of phem? what are the main research forces of phem? it is necessary to sort out the characteristics of the development of phem and explore the hotspots of phem research. additionally, we compared international and chinese research on phem. based on this situation, we reviewed the articles on phem that were published over the past nearly 30 years in international and chinese journals. then, we used the knowledge map method to reveal the research strengths, frontiers, and development trends in this field. study conclusions are helpful to draw people's attention to public health emergencies, provide a reference for scholars to understand the current situation and trends of phem, and for government departments to formulate guidance strategies. data were divided into two categories: international and chinese data. according to the relevant authoritative research [20] , the database of bibliometric methods should contain complete documents. a considerable amount of literature has shown that the web of science (wos) is the largest comprehensive academic information resource, covering peer-reviewed journals with high impact factors [21] [22] [23] [24] . accordingly, the international data used for our study were collected from the wos core collection, including science citation index expanded (sci-e), science citation index expanded (ssci), and arts & humanities citation index (a&hci) databases. chinese data were downloaded from the china national knowledge infrastructure (cnki), which had the largest chinese journal full-text database, including the vast majority of chinese journals relating to public health management. more importantly, it has become one of the critical basic data sources for bibliometric research in china [25] . data obtained by inappropriate literature information retrieval strategies could not accurately reflect the content of the research [26] . emergency management is a common term in china that focuses on the occurrence, development, and evolution of emergencies and finding effective ways of responding to them [27] . however, it was not certified internationally. after consulting the experts from the chinese cdc who once worked for the world health organization (who), we learned that the management was refined by preparedness, operation, response, and recovery for an international public health emergency. additionally, this has been mentioned in articles [5, 28] . based on the above points, the international data retrieval strategies were set as: ((ts = public health) and (ts = preparedness or ts = operation or ts = response or ts = recovery) and ts = (emergency)) and language: (english) and document types: (article) indexes = sci-expanded, ssci, a&hci, timespan = 1988-2018. when retrieving chinese data, we choose "public health" and "emergency management" as the theme words, timespan = 1988-2018. we ran the search query of wos and cnki on february 19, 2019. a total of 2759 articles from 1991 to 2018 were retained from wos, while 999 articles from 2003 to 2018 were retained from cnki. after discussing the results with the team members, we further selected the articles based on inclusion and exclusion criteria to ensure that all of the data were closely aligned to the study targets. the inclusion criteria were as follows: (1) occurrence, development, and evolution of phem; (2) prevention, preparedness, response, operation, and recovery of the phem system; (3) planning, organization, leadership, coordination, and control of public health emergencies; and (4) practice and method of phem. the exclusion criteria were as follows: (1) health care, medical record management, or disease treatment; (2) guidelines on the action, proceedings paper or book chapter, interviews, summaries of conferences, and patent abstracts. finally, 2247 international articles and 959 chinese articles were accepted for the analysis after data filtering and removing duplications. the international articles were downloaded in "plain text" format with a full record and cited references for classification and statistical analysis. the chinese articles were downloaded in the "refworks" format. those downloaded data contained the list of authors, the title of the publication, the abstract, keywords, and so on. accordingly, we obtained the data for this study. figure 1 shows the specific search steps. we used citespace 5.5. r2 and microsoft excel 2016 for the data analysis. citespace was a free java-based application found by chaomei chen to analyze the potential knowledge contained in the scientific literature. it has been widely adopted for scientometric analysis in various scientific fields [29] , and has achieved excellent results [30, 31] . the parameters of citespace for this study were set as follows: time slicing (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) (2016) (2017) (2018) , respectively), years per slice (1), term source (all selection), node type (author, institution, keyword, for chinese and international data; country for international data), selection criteria (top 50), and visualization (cluster viewstatic, show merged network). the corresponding other settings were selected according to different study questions. microsoft excel 2016 was used for temporal distribution and polynomial prediction of the number of articles. it should be noted that the results of the cnki database made by citespace were presented in chinese. to make it easier to read, we translated the chinese results into english. this study involved using bibliometric and mapping knowledge domain analysis methods. bibliometric methods provided an approach to identify the development trends or future research orientations by combining different tools and methods to analyze the articles [32, 33] . it allowed researchers to generate information from historical data and indicators, such as keywords, authors, institutes, and countries [34] . we were mainly engaged in cooperation network analysis (including the network analysis of the authors, institutions, and countries) and co-word network analysis (including keyword co-occurrence network and burst detection analysis) in the mapping knowledge domain analysis. first, we performed a statistical analysis of the temporal distribution of relevant articles. then, we made a polynomial prediction of the number of articles, fitted the trend line of international and chinese study, and predicted it for the next 3 years. cooperation network analysis was used to analyze the contribution to different authors, institutions, and countries in one field. it was obvious that the more an author, a country, or an institution publishes its research findings, the more contributions it will make [35] . betweenness centrality is an index to measure the importance of nodes in the network. the purple circle represents documents with betweenness centrality not less than 0.1, which means that the authors, institutions, or countries occupied an essential position in this field [20, 36] . co-word analysis was a content analysis technique that was effective for mapping co-occurrence relationships and the strength of the relationship between a pair of items existing in the same text, revealing the inner construction of a research field [24] . analysis of the keyword co-occurrence network was meaningful and valuable for exploring timely topics in a specific knowledge domain [37, 38] . in addition, keyword burst detection analysis can clearly grasp articles that receive particular attention from related scientific communities in a certain period. therefore, the frontiers founded by burst detection analysis can provide researchers with upto-date information [39, 40] . the analysis of the highly cited articles in the field can reflect the development of the discipline in a period, examine timely topics, and supplement the above results to provide a reference for topic selection by scientific researchers [41] . temporal distribution analysis countries, yet a large number of chinese scholars participated in this study at the beginning. after the descriptive analysis of the data, we conducted a polynomial prediction analysis of the number of articles and predicted it for the next 3 years. the trend of chronological distribution of articles related to phem in international data can be expressed as follows: y = 0.2790x 2 + 0.7688x−7.7708 (r 2 = 0.9577), while chinese data was y = −0.0345x 3 + 1.5079x 2 −14.142x + 27.273 (r 2 = 0.9251). y indicates the number of articles, and x indicates the years. r 2 > 0.9, indicating a good degree of fit. the chronological distribution of international articles showed a trend of increasing year by year. in 2019-2021, the annual number of articles will exceed that of previous years. at the same time, the trend line of chinese articles, such as a wave line, and the number of articles will continue to decrease over the next 3 years. in addition, as time goes on, the gap in the number of articles in chinese and international journals will be gradually increasing. figure 3 , which shows the international co-author network, shows that there have been many authors writing . however, all three items' centrality was less than 0.1. in fig. 4 , the top-ranked item for chinese scholars by citation count was qunhong wu with a citation count of 22. she was followed by yanhua hao (17), feng han (11), ning (10), yadong wang (10), zheng kang (8), ying liu (6), jincheng ma (6), mingli jiao (5), and libo liang (5) . most of them were teachers at harbin medical university. the top-ranked items by centrality were yanhua hao and ning, with a centrality of 0.02. the third one was qunhong wu, with a centrality of 0.01. their nodes' centrality is also less than 0.1. in terms of the quantity and quality of articles, qunhong wu and yanhua hao were the leaders of phem in china. from the co-author network, we can see that many authors internationally and table s1, table s2 , and figure s1 ). similar to the co-author situation, many institutions have studied phem (figs. 5 and 6). the top-ranked item by international citation count was the centers for disease control and prevention (ctr dis control & prevent.), with citation counts of 255, which means that the institution publishes the largest number of articles in this field. the second one was johns hopkins university (johns hopkins univ.), with citation counts of 92, which means that johns hopkins university had the largest number of articles published among the universities in this field. johns hopkins was followed by harvard university (harvard univ.), columbia university (columbia univ.), and so on. the above analysis showed that the cdc and universities were the leading institutions to study international phem. the centrality ranked item was cdc (0.50). then, johns hopkins university (0.21), harvard university (0.16), university of washington (univ washington., 0.13), university of toronto (univ toronto., 0.10), university of pittsburgh (univ pittsburgh, 0.10), and boston university (boston univ., 0.10) followed. the centrality of all these nodes was no less than 0.1 with the purple circle, which meant that they were the institutions with higher publication quality and the leading institutions in this field. the top-ranked item by citation count in the chinese database was the school of health management, harbin medical university, with a citation count of 20, followed by shanghai publishing and printing college (9) table s3 , table s4 , and figure s2 ). [42] , these were all high-income countries except china. geographically, half of them are centralized in europe. among these countries, the usa was the most productive, far ahead of the rest in this field, and its centrality was the largest. this showed that in the field of phem, the usa carries out the most studies, and their studies were more advanced. although china ranks fifth on this list, its centrality was only 0.03. therefore, these results indicate that chinese scholars could publish some internationally recognized articles in the field, which would offer an advantage in quantity; however, they need to improve their article quality. it is worth noting that although the number of articles from switzerland (44) and sweden (34) was much lower than that of the usa, the articles' centrality of these two countries was more than 0.10, which showed that the quality of the articles was still high. generally, keywords represent the research hotspots, which represent topics of wide concern for researchers in this field. figure 7 shows that the top 10 keywords ranked by citation count for the international database were public health (297), preparedness (215), emergency preparedness ( preparedness and monitoring for public health events, while chinese research mainly focuses on analysis and disposition (additional file 1: table s5, table s6 , and figure s3 ). figure s4 ). to further explain the above research hotspots, the top 8 cited articles are shown in tables 2 and 3 article elevated blood lead levels in children associated with the flint drinking water crisis: a spatial analysis of risk and public health response was the most cited (372) international article [43] followed by the 2006 california heat wave: impacts on hospitalizations and emergency department visits [44] . in terms of the time distribution, the research on international bioterrorism started first [45] , followed by recommendations for health emergency response teams and health incident management [46, 47] . in recent years, the causes and disposal of public health events have been the hotspots of international attention [43, [48] [49] [50] . this was basically consistent with the analysis results of the above research keywords. the top 8 chinese cited articles of phem appeared in 2003, 2004, 2009, and 2011 . table 3 shows us that the most frequently cited chinese article was emergency logistics [51] , written by zhongwen ou, huiyun wang, and dali jiang et al. with a frequency of an astonishing 473. this was followed by kaibin zhong's article review and prospect: construction of emergency management system in china [52] . the next three articles, legislative situation and characteristics of china's emergency international research on phem occurred earlier than the chinese research, and it has been growing over time. this means that international scholars have paid increasing attention to phem. in 1991, the first article on phem was written by richard l. siegel and was titled code 9: a systematic approach for responding to medical emergencies occurring in and around a hospital [56] . it mentioned the need for an organized system to respond to such emergencies involving patients, visitors, local community residents, and hospital employees, both inside the hospital and on the grounds surrounding the building. he recommended the establishment of a systematic emergency response system in all health care institutions. since then, academia has begun to pay attention to emergency management of public health incidents. the number of international articles is increasing gradually, reaching the maximum in 2017, and it is expected to continue to grow in the next 3 years. the development of phem in china shows a fluctuating pattern. the occurrence of public health emergencies in the 10 years from 2006 to 2016 showed a general trend of first rising and then slowly declining. it is likely related to the number of significant events that occur in each year [57] . the severe acute respiratory syndrome (sars) epidemic in 2003 resulted in significant increases in both the amount of research and articles on emergency management [7] . the number of articles reached a small climax in 2008. events such as the wenchuan earthquake and the southern snow disaster occurred in that year. the maximum was in 2013, with human infection from h7n9, the ya'an earthquake, and death from a hepatitis b vaccine occurring that year. moreover, 10 years after the sars outbreak, some authors compared the development of phem in china over the 10-year period. the first chinese article on phem was written by tiewu jia and was titled capacity-building for public health emergency response to disasters (2003) [58] . this article was published during the epidemic of sars. in 2003, china did not establish a network and echelon phem system. the author combined the development of emergency management, reform of health and epidemic prevention institutions, and discussed the capacity building of public health emergency response. it is helpful for the social function orientation of the disease control center and the improvement of disease prevention ability. although the number of chinese articles decreased in the following years, it remained above 48. in summary, the above analysis shows that phem is still a timely topic. from the perspective of cooperative networks, we find that there is more cooperation among chinese authors but less cooperation among authors from different institutions. the cooperation between different research institutions is believed to be highly effective in facilitating high-level and fruitful research, which can also help develop the research field into a more established area [59] . therefore, chinese scholars should strengthen cooperation between different institutions. the research institution focus on phem mainly comes from universities and health institutions, while chinese institutions have regional differences. reasons include the following: the western region had poor fiscal capacity, a limited personnel size, and an inadequate stockpile in terms of working budget, timely reserves, and prompt delivery [60] . as a leader in international phem, the cdc has begun to help other entities strengthen their capacity, recognition, and technical expertise to strengthen their phem capacity [61] . additionally, some other health institutions, such as the who, have promoted development in this field. in 2005, the 58th world health assembly (wha) adopted the revised international health regulations, which instructed the who member states to collaboratively confront public health emergencies of global significance [5, 17, 62] . universities have undertaken the scientific task of phem, and they have conducted in-depth research on it in china. the chinese cdc has carried out more disease prevention and control services, but its scientific research ability is weak. the country network analysis shows obvious differences in regional and economic development levels for phem. those countries with more developed health emergency management systems are the most high-income ones. geographically, most of these countries are concentrated in europe, where the numbers of publications and citations are also significantly higher [60] . the usa, the uk, japan, and other countries have constantly built and improved their phem systems, which have become a comprehensive management network. co-word analysis of phem international research is more complex, extensive, and multidimensional. it reflects some of the major ideas of this research. based on these ideas, scholars mainly focused on emergency preparedness and monitoring of public health events. from the perspective of chinese phem development, it has gone through a process from theory to preparation, disposition, response, evaluation, organization, and discussion. that is, the main contents of china's health emergency management include the prevention and preparation of health emergencies as well as the key links of disposition, evaluation, and management, system construction, personnel training, and so on. the development of the whole discipline is therefore systematic and clear. the keywords with the strongest citation burst for international research on phem started with terrorism and bioterrorism [63] , followed by disaster planning and emergency preparedness. in recent years, epidemics and infectious diseases have become the new research frontier. from the perspective of the whole development context, international research on phem has been related to current affairs hotspots, such as terrorism, which may have originated from the 911 incident, and epidemics, which may be related to the epidemic of infectious diseases caused by viruses and bacteria such as the ebola virus. the study of phem in china is a process from theory formation to practice discussion, involving many links of management. during 2003-2008, chinese scholars focused on health emergency response and disposition. after that, chinese scholars began to learn more about foreign phem models. some new methods have gradually been applied to chinese phem in recent years. the top-ranked articles by citation for the international knowledge domain of phem appeared in 2005, 2007, 2009, 2014, 2015, and 2016 . in 2005, lawrence m. wein [45] developed a mathematical model of a cow-toconsumer supply chain to reduce bioterrorism events. once again, it shows that international emergency management research is based on terrorism and bioterrorism. in 2007, nathalie embriaco focused on the working condition of emergency management personnel [46] . kim knowlton [44] and salim s. abdool karim [47] mentioned the emergency department. the above three articles are all about the factors involved in health emergency management. the remaining articles analyze the specific events involving the mechanism, response, and recovery [43, [48] [49] [50] . from the above analysis, it can be seen that terrorism, emergency response and health incident management, and the disposition of public health events are the hotspots of international attention. legislative situation and characteristics of china's emergency law [53] , legal construction of public emergency response in china: legal construction task proposed by sars crisis management practice [54] , and the realistic subject of administrative rule of law in public emergency management [55] were published in 2003. all three articles discussed the problems existing in the construction of the administrative legal system under the background of sars. after that, three articles were published in 2004, mainly studying the mechanism and structure of phem in china. this research proposed the need to establish the emergency response mechanism for phem and establish emergency structure construction as soon as possible. in 2009, kaibin zhong wrote the article review and prospect: construction of emergency management system in china [52] . he elaborated on the core contents of chinese phem construction, including emergency plans, emergency structures, emergency mechanisms, and legal systems. china's phem integrates emergency systems, emergency mechanisms, and legal systems in an all-round way, which is characterized by comprehensiveness, institutionalization, openness, and guarantees. in 2011, the status quo of emergency management system for sudden public health events in america and japan and its enlightenment [64] was published, showing that china has been learning the theory and experience of phem from some advanced countries. from the above analysis, it can be seen that the legal system, mechanism, and structure, system, and learning from abroad are the theoretical guidance for chinese phem in the past 30 years. admittedly, there are some limitations to this study. first, the conclusions drawn from this study were based on only two large literature retrieval libraries. other databases, such as embase and springer link, were not studied. not being able to search all the literature in this field may lead to incomplete retrieval results. second, citespace has some shortcomings in processing the results of the chinese database; it cannot translate the result from chinese into english directly. third, there is a 1-year or longer time lag between our paper submission and its publication. the database articles may change during this time. fourth, we conducted a comparison between chinese and international databases similar to that performed in many other studies. it should be acknowledged that the two databases had different acceptance ratios, and this difference in data sources might lead to bias in the study results. in addition, we categorized english articles focusing on china as being part of the international database and did not analyze them alone. although only a small part of the total, this may have created some deficiencies. this limitation may constitute an object of future studies, namely, those analyzing the differences between english papers focusing on china vs. chinese papers. in summary, we selected two large retrieval library documents to define the phem domain and detected the research status and the trends related to it from 1991 to 2018. according to the analyses, the conclusions are as follows. in the next 3 years, the number of international phem articles will continue to increase, while the number of chinese articles will decline. chinese scholars show less cooperation among different organizations. there are differences in regional and economic distribution between international and chinese cooperation networks. china focuses on the east regionally, while developed countries and european countries have a more international focus. international research often relates to timely issues, mainly by focusing on emergency preparedness and monitoring of public health events, while china focuses on public health emergencies and their resolution. the international research on phem begins with terrorism and bioterrorism, followed by disaster planning and emergency preparedness, and emerging infectious diseases. china uses sars as the research background and the legal system construction as the research starting point, which is followed by the mechanism and structure, system, and training abroad. oscar: a framework to integrate spatial computing ability and data aggregation for emergency management of public health. geoinformatica the international disasters database complex emergencies of covid-19: management and experience in zhuhai, china robert koch institute: towards digital epidemiology the public health emergency management system in china: trends from the evolution of public health emergency management as a field of practice hospital emergency management research in china: trends and challenges how did chinese government implement unconventional measures against covid-19 pneumonia rapid response in the covid-19 pandemic: a delphi study from the european pediatric dialysis working group beijing: ministry of national defense of the prc hazardous materials emergency incidents: public health considerations and implications cdc support for global public health emergency management can merging the roles of public health preparedness and emergency management increase the efficiency and effectiveness of emergency planning and response? the role of law in public health preparedness: opportunities and challenges promoting public health legal preparedness for emergencies: review of current trends and their relevance in light of the ebola crisis analysis of good practice of public health emergency operations centers from sars to h7n9: the mechanism of responding to emerging communicable diseases has made great progress in china progress and challenges of disaster health management in china: a scoping review citespace ii: detecting and visualizing emerging trends and transient 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response california heat wave: impacts on hospitalizations and emergency department visits analyzing a bioterror attack on the food supply: the case of botulinum toxin in milk high level of burnout in intensivists: prevalence and associated factors hiv infection and tuberculosis in south africa: an urgent need to escalate the public health response cross-reactivity, and function of antibodies elicited by zika virus infection social capital and community resilience hiv infection linked to injection use of oxymorphone in indiana emergency logistics review and prospect: construction of emergency management system in china legislative situation and characteristics of china's emergency law legal construction of public emergency response in china: legal construction task proposed by sars crisis management practice the realistic subject of administrative rule of law in public emergency management code 9: a systematic approach for responding to medical emergencies occurring in and around a hospital analysis of knowledge bases and research hotspots of coronavirus from the perspective of mapping knowledge domain capacity-building for public health emergency response to disasters a bibliometric analysis of emergency management using information systems emergency capability construction of institution of disease prevention and control cdc fact sheet public health emergency operations center -a critical component of mass gatherings management infrastructure the nature of disaster: general characteristics and public health effects the status quo of emergency management system for sudden public health events in america and japan and its enlightenment supplementary information accompanies this paper at https://doi.org/10. 1186/s12199-020-00896-z.additional file 1: table s1 . top 10 authors in the published volume and centrality of international database. table s2 . top 10 authors in the published volume and centrality of chinese database. table s3 . top 10 institutions in the published volume and centrality of international database. table s4 . top 10 institutions in the published volume and centrality of chinese database. table s5 . top 10 keywords ranked by citation counts and centrality of international database. table s6 . top 10 keywords ranked by citation counts and centrality of chinese database. figure s1 . co-author network of chinese database. figure s2 . coinstitution network of chinese database. figure s3 . keyword cooccurrence network of chinese database. figure s4 . keywords with the strongest citation bursts of chinese database. authors' contributions jl conceived and designed the study and wrote the manuscript. yz adjusted the retrieval strategy and edited the manuscript. jf collected the international data. wm collected the chinese data. gz and xw performed data processing. kb and dw reviewed the writing problem. fs and sw work orientation and secured funding for this study. all authors discussed the results and reviewed the manuscript. the authors read and approved the final manuscript. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-022316-mh4pslnv authors: breda, zélia; costa, carlos title: safety and security issues affecting inbound tourism in the people's republic of china date: 2009-11-16 journal: tourism, security and safety doi: 10.1016/b978-0-7506-7898-8.50017-5 sha: doc_id: 22316 cord_uid: mh4pslnv nan over the past few years, the tourism industry has been seriously undermined by the growing lack of safety and security. this factor has been identified as one of the five forces causing changes in the tourism sector in the new millennium. crime, terrorism, food safety, health issues, and natural disasters are the main areas of concern. however, these issues only started to gain more visibility after the september 11 events. terrorist attacks have also been experienced in other parts of the world and they are pushing the travel industry to deal with a major travel paradigm shift, which is based on the fact that tourism security is now a key concern for travelers. it is now widely accepted by the international community that the success of the tourist industry in a particular country or region is directly linked to its ability to offer tourists a safe and pleasant visit. governments, travel agents, and news media periodically issue warnings about the risks associated with international tourism. tourists are urged to buy guidebooks and obtain vaccinations as precautions against such risks. for quite a long time the influence of safety and security for tourism had been ignored in the literature, particularly the issue of safety in the destination country as a determinant of tourism demand. tourism literature is now turning its attention to matters of safety and security, which were classified among the ten most important world tourism issues for 2004. previous research has pointed out four major risk factors: crime (de albuquerque and mcelroy, 1999; alleyne and boxill, 2003; barker, page, and meyer, 2002; barker, page, and meyer, 2003; brunt, mawby, and hambly, 2000; dimanche and lepetic, 1999; george, 2003; lepp and gibson, 2003; levantis and gani, 2000; lindqvist and björk, 2000; mawby, 2000; roehl and fesenmaker, 1992) ; health-related risks (cartwright, 2000; maclaurin, 2001; maclaurin, maclaurin, and loi, 2000) ; terrorism (coshall, 2003; kuto and groves, 2004; leslie, 1999; pizam and fleischer, 2002; pizam and smith, 2000; sönmez, 1998; sönmez, apostolopoulos, and tarlow, 1999; sönmez and graefe, 1998; tarlow, 2003) ; and war and political instability (ioannides and apostolopoulos, 1999; neumayer, 2004; richter, 1999; weaver, 2000) . concern for crime and safety, whether real or perceived, has been clearly identified as adversely affecting tourism behavior, influencing destination choice and experience satisfaction. political instability and war can increase the perception of risk at a destination. similarly, terrorism can cause a profound impact on destination image. health hazards are also regarded as potential issues that can undermine tourism development. all disasters can divert tourism flows away from affected destinations, but war, terrorism, or political instability have a much greater negative psychological effect on potential tourists when planning their vacations (cavlek, 2002) . this applies not only to the time of crisis, but also to the period following it. although there is no evidence of a threat from global terrorism in the people's republic of china (prc) and the country's image is seen as generally safe, there are some issues related to political instability, health, safety and security concerns that have caused disruptions in growth rates. since safety and security directly influence decisions in international travel, this chapter researches the consequences of relevant events that have caused major disturbances in inbound tourism in the prc, namely the tiananmen square incident and the outbreak of severe acute respiratory syndrome (sars). in addition to these two main issues, which until now were the only ones capable of deterring china's booming domestic and international tourism industry, other important issues will be discussed. other epidemic diseases (such as hiv/aids, avian influenza, and mosquito-borne diseases); crime directed at foreigners in major cities and tourist areas; road and air safety; natural disasters (earthquakes, flooding, and typhoons); crossstrait relations; and restrictions on public demonstrations, political, and religious activities constitute important considerations that will be also addressed throughout the chapter. tourism security and safety: from theory to practice a useful way to study the evolution of the traveler safety situation in china is through guidebooks. although these do not constitute scholarly works, they convey the impressions of professional travel observers and are widely disseminated among prospective travelers, playing a large part in the creation of a destination image. although nowadays there is no lack of travel guides, the present work has focused on lonely planet because it is one of the best-selling english-language guidebooks, and it was the first to be published on china (the next guide to be published on china-the rough guide-wasn't published until 13 years later). lonely planet's first edition was issued in october 1984, six years after the country's opening up to international tourism, targeting primarily budget and independent english-speaking travelers, particularly young people. the comparison between lonely planet's first edition (hereafter referred to interchangeably as the first edition or the 1984 edition) and the latest edition (the 8th, published in august 2002) is very useful to identify the consumer image of china's safety and security evolution over the past 18 years. the 1984 edition's section on health sounded a bit alarming, starting with the notification that cholera and yellow fever vaccinations were required for travelers going to certain areas. malaria and hepatitis were identified as serious infectious diseases in china. tetanus, diarrhea, and drinking water problems also received special attention. the 8th edition expanded on the health risks section, but was more reassuring. it noted that although china had particular health hazards and that some problems can be encountered in isolated areas, it is a healthier place to travel to compared to other parts of the world. sexually transmitted diseases, with special attention given to hiv/aids, were pointed out as something that foreigners should be cautious about, due to the fact that they are becoming more widespread in china. regarding physical safety, the first edition presented china as not exactly a crime-free country, but not especially dangerous. however, the authors devoted several paragraphs to the unsettling nature of the chinese justice. the edition of 2002 identified economic crimes as the most common offenses committed against international travelers. foreigners were pointed out as natural targets for pickpockets and thieves, with certain cities, like guangzhou, guiyang, and xi'an, as the most notorious examples of this type of crime. high-risk places were mainly train and bus stations. nevertheless, some more violent crimes, with foreigners being attacked or even killed for their valuables, were reported in more rural locations, thereby stressing that individual traveling to those areas should be regarded as at high risk. terrorism activities were also reported, although it was highlighted that foreign travelers were not specific targets. racism in china is not a real problem. its existence is not recognized by the chinese people; however, racial (ethnic) purity is still the desired norm. the isolationist position imposed by the communist leaders over more than three decades, coupled with a millenary self-centered vision of the world, did really have a lasting effect on chinese people (huyton and ingold, 1997) . although it is unusual to encounter direct racism in the form of insults or to be refused services in china, tourism safety and security in the prc especially directed at white people coming from prosperous nations, africans or people of african ancestry and travelers from other asian nations can face discrimination. the old dual-pricing system for foreigners was identified in the 2002 edition as fundamentally racist. this discriminatory pricing was exemplified in the 1984 edition, referring several times to the higher costs charged to foreigners. the cost of hotel rooms depends on what you are. if you have a white face and a big nose then you pay the most. the chinese also attempt to plug you into the most expensive of the tourist hotels, and to give you the most expensive rooms. they do this for two reasons; they want the money, but also they think you're spectacularly wealthy, and that you'll want to do things in spectacular style . . . they're not trying to rip you off, they're just trying to please you. (samalgaski and buckley, 1984, p. 186) prices and services showed racial disparities, regardless of the person's willingness to pay. overseas chinese (holders of a chinese passport who reside outside china in countries or regions other than taiwan, macao, and hong kong) or compatriots (visitors from taiwan, macao, and hong kong) were frequently refused service, or given poor service (anyway the quality was generally low, as employees had very little knowledge of international standards), just because they paid less than foreign visitors. foreign visitors, on the other hand, often felt embarrassed and annoyed by their preferential treatment (zhang, 1995) . this special treatment took place not long after the end of the cultural revolution. the hard-line communist leaders' way of thinking that characterized the cultural revolution period had fostered anti-foreign sentiments, resulting in foreigners in china being insulted and badly treated. under the new government's kowtowing policy foreigners received special treatment, while the government relegated its citizens to an inferior condition (richter, 1983) . the campaign against "spiritual pollution" from the west was launched in china in the mid-1980s, but it did not affect tourism, as the attack on spiritual pollution was deliberately kept as a low key internal affair, and most tourists were quite unaware of it (lynn, 1993) . nonetheless, the ambivalent chinese attitude toward foreigners has naturally affected how they handle tourists. as a 1930s writer once said, "throughout the ages, chinese have had only two ways of looking at foreigners, up to them as superior beings or down on them as wild animals. they have never been able to treat them as friends, to consider them as people like themselves" (quoted in richter, 1989, p. 32 ). travel warnings and advice issued by governments of the main outbound tourist markets to china were analyzed in an attempt to verify major concerns regarding the safety and security of their citizens while traveling in china. with the aim of acquiring a broad picture of the nature of those concerns, research was conducted in order to identify what type of information had been released to travelers to china in each world region. government organizations, as well as some international agencies, were the main source of information regarding potential disruptions to tourism in china. although nine countries were firstly considered as significant to analyze (japan, usa, uk, canada, malaysia, korea, germany, russia, and australia), it was soon realized that only english-speaking countries, with the exception of japan, had such information available to their citizens on the tourism security and safety: from theory to practice internet, which is a useful and rapid way to disseminate information. as tourists tend to be better informed about destinations prior to their trip, travel advisories issued by competent entities are of crucial significance. the facts presented below are thus based on the information collected from travel advisories issued by governmental agencies (the content of those warnings was found to be very similar), thus permitting the construction of an image of china's safety and security situation, and how it is regarded by its main tourist-generating markets. (see table 1 .) because of the economic damage that can be inflicted on a country's tourism industry, its visibility, and the leverage it may have on governments, some terrorist and organized crime groups have targeted tourism directly. the fact that in the september 11 terrorist attacks, passenger airplanes, which are a key part of the tourism system, were used as weapons, has had a damaging psychological effect. these attacks strikingly impacted the tourism sector worldwide, being more dramatic than any other crisis in recent years (wto, 2001) . in asia, the situation has deteriorated as a result of regional terrorism, especially the october 2002 bali bombings, which exacerbated people's reactions regarding asia as a tourist destination. there is no evidence of global terrorism in china, although a small number of bomb-related actions and incidents of unrest do occur. over the past 10 years there has been an increase in bombing events throughout the country. however, this does not constitute a serious threat to tourists, since foreigners are not specific targets. nonetheless, there is always the risk of indiscriminate attacks against civilian targets in public places, including tourist sites. these bombings are often the result of commercial disputes among chinese. it is true that terrorist attacks are also common, many of which have been linked to the eastern turkistan islamic movement (etim), also known as the xinjiang-uyghur separatist movement. etim was designated a terrorist organization by the united nations in 2002 and is currently active in the xinjiang autonomous region. xinjiang is largely constituted by muslim turkic-speaking minorities (uygurs, kazakhas, kirghizs, and uzbeks) and there has been ethnic tension between these four groups and the han people for quite a long time. these conflicts have promoted the upsurge of a movement calling for the turkic-speaking people to unite and form an east turkistan state tourism safety and security in the prc under islam. since the 1990s, various factions of the etim have engaged in a series of violent incidents (supported and funded by al qaeda), both inside and outside china, which were responsible for a total of 166 deaths and more than 440 injuries, and for a serious negative impact on social stability in china and in neighboring countries (wang, 2003) . crimes against tourists result in bad publicity for destinations and create a negative image in the minds of prospective visitors. tour operators tend to avoid destinations that have the reputation for crimes against tourists (goeldner and ritchie, 2002) . they also play a very important role in creating the image of a destination and can significantly influence international tourism flow toward a country hit by safety and security risks (cavlek, 2002) . overall, china is a safe country, with a low but increasing crime rate. serious crimes against foreigners are rare. nevertheless, crime does occur both in chinese cities and in the countryside. crime directed at foreigners is becoming more frequent in major cities and at tourist sites, which attract thieves and pickpockets. robberies and attacks on foreigners in popular expatriate bar and nightclub areas in beijing and shanghai, and in the shopping district of shenzhen, are common. minor thefts and sexual harassment on overnight trains and buses tend also to occur. the most remote areas of china are poorly policed and there is the risk of attack from armed bandits. in yunnan, drug smuggling and related crimes are increasing. money exchange on the black market at better rates is frequent in china. foreigners tempted to exchange money this way, besides breaking the law and possibly having to incur charges, face the risk of shortchanging, rip-offs, and receiving counterfeit currency, which is a problem in china. since china started its economic reforms, social institutions (which molded thought and behavior, rewarded compliance, and punished deviance) have been seriously weakened. the loosening of formal and informal controls as a result of the changes in social structure that have accompanied economic reform, alongside the unequal distribution of wealth, has led to a significant increase in crime (deng and cordilia, 1999; xiang, 1999) . one of the most notable trends is the dramatic rise in serious economic crimes; it seems that getting rich is becoming an obsession. indeed, since the official slogan proclaimed that "to get rich is glorious," materialism became the dominant ethos of the reform era. juvenile delinquency has also drastically increased, becoming more serious and violent in nature; the criminal motivation is mainly money (xiang, 1999) . some of the responses adopted by the chinese government aiming to maintain social order and to reduce crime consist of intensification of programs of legal education that teach people about the law and its requirements. the revival of traditional confucian values to increase people's awareness of the appropriate balance between individualism and collective responsibilities, and the revitalization of informal social controls programs, can also be felt (deng and cordilia, 1999; xiang, 1999) . indeed, social control has always been successfully attained through informal organizations and indigenous institutions, which regulate much of social life. the empowerment of the masses to take control of their community's welfare (mass-policing) is one of the best ways to engage people in fighting crime. tourism security and safety: from theory to practice people are normally more susceptible to health hazards while traveling. these can range from minor upsets to infections caused by serious diseases. the world health organization (who) reported that the following diseases can occur in china: cholera, hepatitis a, malaria, tuberculosis, and typhoid fever. mosquitoborne diseases, such as dengue fever and encephalitis b (endemic in rural areas of southern china from june to august) can also be encountered, although they do not pose a serious risk to travelers. rabies infection is also frequent; china has 1,000 human rabies cases every year. travelers planning to visit regions where these diseases are common are advised to take medication against them. the use of mosquito repellent is also recommended. western-style medical facilities with international staff are available in large cities in china. however, in rural areas, medical personnel are often poorly trained and have little medical equipment or availability of medications. air pollution is also a problem throughout china; seasonal smog and heavy particulate pollution are an issue for travelers, especially for those with respiratory problems. avian influenza epidemics of avian influenza (bird flu) were reported in the beginning of 2004 in parts of asia and 34 human cases were confirmed in vietnam and thailand, with a total of 23 deaths. although an outbreak of bird flu was confirmed in china, no human cases were reported, but even if travelers were unlikely to be affected, they were warned to avoid bird markets, farms, and places where they might come in contact with live poultry. a second wave of avian influenza infection was reported in late june 2004, when new fatal cases among poultry were communicated to the who, and subsequently there were more fatal human cases in vietnam and thailand. in july 2004, china was affected by this new outbreak, and one month later it was discovered that pigs had been infected with the strain of avian influenza. although findings on the possible spread of the infection among pigs (and its transmission to people) are still preliminary, human infection with avian influenza viruses still remains a public health hazard. travel precautions are being issued in order to provide information to travelers, but no recommendation to avoid the affected areas has been made. although two thirds of the world's population infected with hiv is located in sub-saharan africa, the preponderance of new infections is likely to shift to asia in the coming decades (burgess, watkins, and williams, 2001) , being already well established in the region. recent social and economic changes in china greatly increased the potential for a substantial hiv/aids epidemic, which is already causing great concern, given the growth rates observed in the past decade. ignorance about the disease, poor sterilization practices, and unsafe blood transfusions contribute to hiv/aids transmission, as well as transmission of hepatitis. china is one of the world's great reservoirs of hepatitis b infection. in 2003, china ranked thirteenth in the world, with 840,000 people infected with hiv/aids; the number of deaths reached 44,000. it presented an adult prevalence rate (estimated number of adults living with hiv/aids) of 0.1%. hiv is currently concentrated in the southwestern province of yunnan, near the golden triangle. the increasing use of drugs, the rapid expansion of open commercial sex activity tourism safety and security in the prc (prostitution has become a massive industry in china over the past decade, most noticeable in zhuhai, shenzhen, and macao), and a more liberal sexual climate (the emergence of the homosexual "underground") may support an expanding epidemic throughout the country. some experts speculate that china will have 10 million cases of hiv by 2010 (harper et al., 2002) . in august 2004, china revised its law on the prevention of infectious diseases to include the first reference in the legal code to aids, which reflects a shift in the government's aids policy. the new law, which contains specific clauses on blood donation, stipulates that governments of various levels should strengthen prevention and control of aids and take measures to prevent the spread of the disease. it also specifies punishments for anyone concealing the spread of a disease, clearly showing a reaction to failed attempts to cover up the extent of the sars problem. severe acute respiratory syndrome (sars) sars was first recognized as a new disease in asia in mid-february 2003. however, it had already started to spread to other parts of the country and to the world since the first case was reported in november 2002 in guangdong province. according to the who, between november 2002 and july 2003, more than 8,000 cases were reported, causing 774 deaths, from 29 countries and regions on the five continents. the most affected country by this new epidemic was china, with more than 75% of the cases. in face of this unknown disease, and as a measure of precaution, the who decided to issue travel advisories to areas that reported the most sars cases. travel advisories are intended to limit further international spread of sars by restricting and reducing travel to high-risk areas. it was the first time in more than a decade that the who had advised travelers to avoid a particular area. figure 1 shows a chronology of travel recommendations to china issued by the who. in april 2004, the chinese ministry of health reported a total of nine new cases of sars (including one death) in china. these were the first cases of severe illness and secondary spread of sars after the 2003 outbreak. however, no further cases in china or anywhere else in the world have been reported since april 29, 2004. on may 18, the who reported that the outbreak in china appeared to have been contained with relatively limited secondary transmission. nonetheless, within a relatively short period of time the sars epidemic had already caused major damage to china's economy, particularly affecting its tourism industry. the impact of the sars outbreak on tourism will be expanded upon in the next section. while in china, foreigners may encounter substantial differences in traveling conditions compared to those in their home countries. in general, many accidents occur, some of them serious, resulting from the poor quality of roads, the often chaotic traffic, and the generally low driving standards (although driving etiquette in china is progressing). safety standards in public transportation differ from those in the west as well; child safety seats and seat belts are not widely available. pedestrians and cyclists, if not cautious, are also at risk while near traffic. they are frequently involved in collisions or encounter unexpected road hazards. in fact, it is not unusual to see a pedestrian or a cyclist on a sidewalk being hit by a car or bus driving in the wrong lane. air accidents have been reported on internal flights, mainly in routes to the north and east of beijing. nonetheless, the us federal aviation administration (faa) has assessed the chinese civil aviation authority as category 1, which means that it complies with international aviation safety standards for overseeing china's air carrier operations. similarly, there have been several incidents of overcrowded ferries sinking, resulting in the loss of lives. attacks of piracy in the south china sea should also be regarded as a threat to yachting safety. china has been greatly affected by natural disasters. the country is located in an active seismic zone and is subject to earthquakes, notably in inner mongolia, yunnan, and xinjiang. the most recent earthquakes occurred in october 2003 in gansu province, measuring 6.1 and 5.8 on the richter scale. typhoons can occur along the southern and eastern coasts, affecting hainan, guangdong, fujian, and zhejiang provinces during the summer rainy season. travelers are advised that prior to departing to affected areas they should monitor weather reports. from april to october there are also many severe rainstorms that can cause flooding and landslides. in 1998, floods along the yangtze river devastated parts of central china, killing more than 3,600 people, destroying 5.6 million houses, and swamping 64 million acres of land (lang, 2002) . this situation is not new, and is part of the list of environmental problems that china is facing as a consequence of its rapid economic growth. loss of forest cover as a result of massive tree clear-cutting over the years (especially during the great leap forward, when huge areas were logged to provide fuel for backyard furnaces in a disastrous campaign to make steel) led to an increasing severity in the flooding. reforestation and a ban on logging china's natural forests in the upper reaches of the yellow and yangtze rivers, along with the completion of the three gorges dam project, are some of the measures of the chinese government to help control flooding. a study using the data envelopment analysis (dea)-based model for the analysis of vulnerability to natural disasters in china from 1989 to 2000 (wei, fan, lu, tourism safety and security in the prc and tsai, 2004) concluded that, in general, the western region was affected more severely. some provinces in central china were also badly affected, with hunan, guizhou, and jianxi provinces being the worst-hit areas. there are restrictions on undertaking certain religious activities, including preaching and distributing religious materials. foreigners are also under strictly enforced regulations against any public demonstrations that do not have prior approval from the authorities. travelers from australia have been specifically advised to avoid large public gatherings or demonstrations, particularly of a political nature. the most well-known case of severe measures taken by the chinese authorities upon religious activities is the ban of the falungong movement and the imprisonment of some of its followers. nonetheless, it was not the falungong movement, but the spread of a christian-inspired group called the "shouters" that initiated the "fight for investigation and the banning of heretical teachings campaign, launched by the chinese leadership" (kupfer, 2004) . the elimination of groups that are perceived as a potential danger to underpinning political unrest, posing an ideological and organizational threat to the chinese state, is still the guiding principle of the communist regime. tiananmen square incident the june 4, 1989, incident in tiananmen square showed that the way in which china approaches and solves its domestic economic and political problems will no doubt be reflected in the extent to which foreign tourism is encouraged or constrained. the government's declaration of martial law and the subsequent crackdown on the student democracy movement by the people's liberation army (pla) led to the death of hundreds of protesters. the reaction of the international community to those events and how this new political environment in china has affected tourism will be further developed later in this chapter. since the 1949 military confrontations, political relations between taiwan and the mainland did not begin to improve until the 1980s. after almost 40 years of strict restrictions on travel between the two divided states, the ban on travel via a third country was finally lifted in 1987, allowing taiwan residents to enter mainland china for the purpose of visiting families. leisure and recreational travel was, however, still prohibited. notwithstanding the 1987 change in policy, many obstacles still remain in the development of tourism and travel between taiwan and the mainland, being highly dependent on the political relations between the two governments. nevertheless, as a result of the policy change, the flow of taiwan visitors to china increased rapidly. yet, the increased travel activities did suffer a severe setback in 1994, as a result of the global economic recession in the first half of the year. the china airlines plane crash at nagoya airport in central japan, which resulted in the deaths of 87 taiwanese passengers; and the qiandao lake incident, where 24 taiwanese visitors were murdered while on a sightseeing tour on a boat on qiandao lake in zhejiang province, were also instrumental in exacerbating this setback (huang, yung, and huang, 1996) . the chinese authorities' initial dismissal of the lake tragedy, and its attempt to cover up the case, renewed the political tension tourism security and safety: from theory to practice between the two governments. it also led a large number of people in taiwan to reassess their position and shift in favor of taiwanese independence. following the incident, the taiwanese government temporarily halted group travel to china, as well as other types of cultural exchanges and business activities with the mainland. as a result, tourist arrivals from taiwan decreased by 9% in 1994. however, this political tension did not last long, and travel activities were soon reinstated, restoring the normal development of tourist arrivals from taiwan. in 1995, taiwan tourists accounted for 3.3% of the country's total arrivals and contributed 19% of china's total tourist receipts. taiwan tourism has since then become a major component of china's tourism industry. despite this rapid recovery, the qiandao lake tragedy might have caused a long-term impact, similar to the one tiananmen square massacre had on the people of hong kong, which deeply affected the perception of mainland china, thus strengthening general feelings for independence. the independence of taiwan is still in debate. however, it is something that mainland china will never accept, thus posing the question as to whether a clash between the two states will be unavoidable. according to sheng (2002) a war across the taiwan strait is neither inevitable nor imminent, and is less likely in the future since china is rather confident in the face of taiwan's current political and economic deterioration. this situation gives beijing the opportunity to exploit, weaken, and paralyze any demand of independence. the pla has boosted its military pressure over taiwan by modernizing its warfare capacity. by doing so, china also intends to deter us intervention in the taiwan strait, placing emphasis on its strike capability, rather than on its power-projection capability (sheng, 2002) . however, china's claim of sovereignty over taiwan and its threat to attack the island if it formally declares independence have led security analysts to see the taiwan strait as the most dangerous flashpoint in asia. tensions between china and taiwan have been escalating since the march reelection of president chen shuibian, who is a keen independence supporter. the strain was aggravated by the recent announcement of taiwan's intention to buy weapons in order to help to maintain a balance of power with china, thus permitting it to make a counterstrike to hit shanghai (china's financial center) if the pla attacks taipei. international tourism in china started to develop after 1978 as a result of the "opendoor" policy. since the chinese government's decision to open the country to the outside world and to promote tourism as a vital economic force to earn foreign exchange earnings to help finance its modernization program, there has been a dramatic increase in tourist arrivals. tourist arrivals rose from 1.8 million in 1978 up to 91.7 million in 2003, representing a 50-fold increase, with an average annual growth rate of 17%. although the growth trend of china's international tourism industry has been quite consistent over the last decade (excluding the year 2003), growth rates were not stable during the initial development period, with fluctuations occurring, and even experiencing a major decline in 1989 (the students' demonstration in tiananmen square was the cause of a decline of 22.7%). figure 2 shows the annual percentage variation of international tourist arrivals in china for the period 1978-2003. over the period as a whole, the average annual growth rate of tourist arrivals showed a downward trend. problems with accommodation, service, and transport are indicated as possible reasons for this slowdown in the growth of arrivals of overseas visitors. however, richter (1983) contends that deng xiaoping's theories about china's socialist economy might have been considered too controversial, or may have been only temporary policies designed to get deng xiaoping into power, and were not necessarily created to be an ongoing program. the worldwide recession of the early 1980s apparently had an impact on china's tourism industry, as tour cancellations increased from 30% in previous years to 50% in 1982 (lew, 1987) . overseas visitor arrivals grew only by 2%. to offset the slowdown in tourism, china instituted a number of new policies. foreign tour operators were allowed to open offices in china, and the "open city" program was introduced, giving more freedom of movement to foreign travelers. this program achieved great popularity, and the number of cities and regions opened to tourists has grown ever since. the 1989 incident in tiananmen square resulted in a severe decline in arrivals from all market segments, with the exception of taiwanese. however, even before the events of 1989, there was a slowdown of the growth rate in international visitor numbers. declining interest in china as a destination, as a consequence of overseas perception of poor management, service problems, and congested transport infrastructure, could also have contributed to the low growth rates (choy, dong, and wen, 1986) . the figures of total annual visitor arrivals indicate that tourism in china began to pick up shortly after 1989. in the mid-1990s, china again experienced sluggish growth rates, motivated by a slowdown in the overseas chinese and the compatriots' segments, partly due to the 1994 incident in zhejiang province. again in the 1990s, china's tourism withstood severe tests-the impact of the asian financial crisis in 1997 (which was felt mainly in the overseas chinese market segment) and the devastating floods occurring in the tourist season along the yangtze river. in may 1999, demonstrations mostly aimed at the united states were held in the major chinese cities, due to the north atlantic treaty organization's bombing of the chinese embassy in belgrade. as the demonstrations turned violent, the governments of the united states and the united kingdom issued travel advisories, causing thousands of cancellations from potential visitors (breda, 2002) . but the explosion of 1 9 8 1 1 9 8 3 1 9 8 5 1 9 8 7 1 9 8 9 1 9 9 1 1 9 9 3 1 9 9 5 1 9 9 7 1 9 9 9 2 0 0 1 2 0 0 3 annual growth rate (%) figure 2 annual percentage variation of international tourist arrivals in china, 1978 xenophobia that hit china during this period had a limited impact on tourism. after a sharp drop in bookings, airlines and hotels reported a return to normality. the lifting of travel advisories from foreign governments also helped the industry bounce back. however, these events did not have a long-lasting negative impact in the chinese tourism industry; to prove it, in that year, china ranked fifth in the world. the september 11 terrorist attacks had a severe impact on long-haul tourism, leading to a shift towards intraregional travel, partly compensating the loss of american and european inbound traffic. intraregional travel is the major kind of travel in the east asia and the pacific region, accounting for nearly 80% of total arrivals, and was a major factor in offsetting the impact felt in the travel and tourism industry. china was the best performing destination within this region (with a more than 6% increase compared to the year 2000), partly because of the close proximity to its main generating markets. for example, the japanese outbound market, one of the world leaders in the field, replaced destinations in america by china, thailand, and australia (wto, 2001) . despite the fact that china showed a robust increase in tourist arrivals over those in 2000, these events contributed to slow down china's growth rates. in 2003, china again faced a severe test. until the sars epidemic became public, china was one of the few countries that did not experience a decline in tourism, even during the recent war in iraq. despite the good results in the beginning of the year, figures had been significantly impacted as a result of the who's travel advisory for sars affected areas in china (ap, 2003) , resulting in a 7.1 decline in total arrivals over 2002. this was the most damaging event for the chinese tourism industry since the tiananmen square incident in 1989. since the traveler must physically be in the destination country to consume the tourist product that it has to offer, any event that persuades the potential traveler to either stay at home or travel elsewhere directly impacts that destination's exports earnings (roehl, 1990) . there is no doubt the tiananmen square conflict severely damaged the international tourism industry of the prc, at least in the short term, mostly because of the economic sanctions imposed by the world community. "tour cancellations and a drop in foreign business activity sent hotel occupancy rates in the prc to the lowest point since the country opened its doors to tourists in 1978" (gartner and shen, 1992, p. 47) . political events of this nature clearly influence tourist demand. the low occupancy rates reflected many hotels' reliance on business travelers. business visits were affected by both perceptions of stability, which influenced business confidence, and also by the formal and informal sanctions that were imposed on corporations conducting business in china (hall, 1994) . the political unrest of 1989 has led to considerable difficulties for planning and investing within the chinese tourism industry and posed substantial problems for improving the image of china as a tourist destination. "the conflict in tiananmen square was carried out by major news networks throughout the world and, owing to the nature of the conflict, did not portray the prc in a light favorable to improve its tourist image" (gartner and shen, 1992, p. 49) . "many people in western nations demonstrated moral sup-port for the democracy-loving chinese students by not traveling to china" (yu, 1992, p. 10) . in a study targeting the mature travel market in the united states, before and after the conflict (gartner and shen, 1992) , the extent of the damage to china's tourism image was analyzed. it was concluded that its overall image was still favorable and positive. the hospitality component appeared to be directly affected by the conflict, much more than the image of the attractions of its tourist sites. "safety and security, pleasant attitudes of service personnel, receptiveness of local people to tourists, and cleanliness of environment were all down significantly, indicating that respondents felt the prc was less likely, after tiananmen square, to provide the hospitality needed for an enjoyable visit" (gartner and shen, 1992, p. 51) . not all countries of origin responded to the tiananmen square incident in the same way. while almost all tourist-generating markets for china registered recessions in 1989, taiwan and the soviet union became the top generating markets for china's international tourism industry, at the time when tourists from western democratic countries declined. the decline of tourists from the western democratic countries immediately after the tiananmen incident is logical and understandable. the perception of china as an international destination held both by the tourists and the travel industry in the west was dramatically altered by the anti-democratic actions of the chinese government in 1989. as moral support for the democratic demonstrators in china, tourists cancelled their already scheduled trips or put off their travel plans to a later date. (yu, 1992, p. 11) the drastic decline in the number of tourists was evident at beijing's joint-venture hotels, where all hotels reduced both their chinese and expatriate staffs, and most remaining employees were working at some 65% of their normal wage package (breda, 2002) . it was also estimated that 620,000 tourism workers underwent compulsory political indoctrination aiming "to cleanse their socialist minds, deepen their love of the communist party, and, alarmingly, to cultivate their suspicions of foreigners" (hall, 1994, p. 123) . the crackdown on the students' demonstration in beijing definitely created a new environment for chinese tourism, which affected both the chinese and global travel industries. there was an immediate drop in the number of incoming visitors, a total decrease of 23%, and a 17% decrease in terms of international tourism receipts. visitation from japan and the united states, china's two largest markets and sources of high-expenditure visitors, showed even larger declines. roehl (1995) estimated that the impact of the tiananmen square incident on arrivals was greater than previously estimated. overall, his study suggests that the impact of the events led to a decrease of 11 million compatriot arrivals than might otherwise have occurred. likewise, foreign visitors registered more than 560,000 fewer arrivals. the incident also affected foreign investment in china, particularly in the hotel industry, which had serious consequences for both investors and lending institutions. a breakdown of the quarter-by-quarter tourist arrivals in 1989 is shown in figure 3 . although political events greatly affect the tourism industry, it seemed that the situation in china in 1989 only had a short-term impact. the crisis was between the government and its internal critics; there was no violence directed towards international visitors. china's tourism industry responded to this event rather well as it only experienced a 17% decline in receipts in 1989 and was fully recovered 2 years tourism security and safety: from theory to practice later. this quick recovery can be attributed especially to the "continued government's commitment to reform and open-door policies; the rapid growth of the chinese economy; and the industry's successful responding strategies in terms of product development, market positioning, and overseas promotion" (jenkins and liu, 1997, p. 105) . after the tiananmen incident, the government attempted to rebuild its international tourism industry by improving the country's tourist image. a press release from the cnta in june 1989 stated: the cnta solemnly proclaims that the safety of overseas tourists who come to china has never been affected and can be guaranteed. tourists may carry on their visits and tours as planned. they are welcome to visit china and do not need to change their scheduled travel plans. (quoted in wei, crompton, and reid, 1989, p. 322) china's booming domestic and international tourism industry has recently suffered losses in tourism and related service industries as a result of the sars epidemic. in light of the events concerning the disease, the who advised international travelers to avoid visiting some areas in china that had the most sars cases. china was the worst affected country. the outbreak of sars in china led to a sharp decline in inbound and domestic travel, with social and economic impact, but also had a disproportionately large psychological influence on the public, considering the relatively low morbidity and mortality of the disease. the pronounced psychological impact of sars can be attributed to a combination of two aspects regarding information about the illness percentage variation in china's arrivals, by quarter, from its major inbound tourist markets in 1989. source: china national bureau of statistics. (breda, 2004) . first, there was a rapid transmission of information about the number of people infected by sars, as a result of modern media and highly developed networks of communication. second, there was insufficient medical information on sars and great uncertainty over the nature of the disease. the lack of accurate, timely, and transparent provision of information on the nature and extent of sars increased the public's fears, caused second-guessing, and naturally led to an exaggerated perception about the danger of the disease. concealing health information from tourists, as well as not taking adequate measures to prevent the outbreak of communicable diseases, can be almost as lethal for tourism as the disease itself. tourism was thus especially affected by the sars-induced panic (mckercher and chon, 2004) . even some destinations that had not recorded any cases of infection suffered almost as much as the areas actually affected. the rapid and wide geographical spread of the disease by travelers, cases of transmission during hotel stays, in restaurants, places of entertainment, or even during airplane trips, made sars a phenomenon that was perceived to be linked with tourism itself. the intraregional tourism market is an important source of visitors to china. as the sars epidemic started to spread into other countries within the asia-pacific region, china suffered a major decline in tourist arrivals. some airlines that offer service to china cancelled regularly scheduled flights due to insufficient bookings. governments from some foreign countries advised their citizens not to visit china, thus causing the cancellation of a significant number of package tours (chien and law, 2003; overby, rayburn, hammond, and wyld, 2004) . china's inbound travel suffered seriously, but had a somewhat lower accumulated loss of 11.7% in the first two quarters of the year, due to the positive results in the first months of 2003. the worst period recorded was during the months of april and may, both for foreign and compatriot arrivals, registering decreases of 61.8 and 25.1, respectively. with the sars outbreak over in june, decrease rates started to become less and less accentuated, showing that recovery was under way. foreign arrivals suffered greater losses and took a little longer to recover. at the beginning of 2004, arrivals from both markets already showed positive growth rates. figure according to the international labour organization (ilo), countries or areas directly affected by sars were estimated to lose more than 30% of their travel and tourism employment. the world travel and tourism council (wttc) estimated that china was expected to lose more than 2.8 million jobs. however, if also taking into consideration the indirect impact of sars, its real impact would be even greater. china was expected to suffer, directly and indirectly, a sars related loss of 6.8 million jobs and 20.4 billion us$ worth of gdp (wttc, 2003) . although the sars outbreak significantly slowed the development of chinese tourism, it also facilitated the reorganization of chinese tourist agencies. many hotels, restaurants, and other attractions remained closed while the public continued to avoid such frequented locations; however they seized the opportunity to undertake renovation projects and to introduce unprecedented hygiene measures, in an attempt to build consumer confidence (breda, 2004) . this slow growth period was thus used to perform renovations and employee training, representing a means of improving china's service industry. during the post-sars period, the tourist industry of various parts of china, driven by new changes and new market demands, has been absorbing new ideas and approaches to future strategies. these positive developments and improved public health measures have added weight to arguments that sars, although serious, contributed to the improvement of sanitary conditions and caused only a temporary shock to economic growth. the industry players designed aggressive revitalization campaigns in an attempt to accelerate recovery; and a series of high-profile special events have been organized, beginning with the asean tourism ministers meeting in august 2003, the wto general assembly in october, and the travel fair in kunming in november, all part of the "seeing is believing" campaign (wto, 2003) . the women's world cup in 2007, combined with the olympics in beijing in 2008 and the international world's fair and exposition to be held in shanghai in 2010, which is considered the world's third largest event after the olympics and the world cup, will contribute to boosting the image of the country. there was hardly any international tourism in china before the chinese government's decision to open the country to the outside world, and to promote tourism as a vital economic force to earn foreign exchange to help finance its modernization program. with the introduction of reform and the open-door policy since 1978, china entered the international tourist market. in recent decades, tourism has been a boom industry in china, and has come to play an extremely significant role in economic and regional development, as well as in international relations. it has become one of the most important tourist destinations in the world. in 2002, it ranked fifth in the world, showing a substantial increase over the total international tourist arrivals achieved during the initial stage of tourism development. the spectacular boom experienced during this period was partly due to the fact that initial policies affecting tourism were directed toward maximizing growth rates of visitor arrivals, especially foreign travelers. however, unlike the domestic and compatriot tourism industry, which is conditioned largely by location and access, the foreign tourism market is competitive and risky; it is highly dependent upon fashion trends and political, economic, and social stability. experience and tourism security and safety: from theory to practice studies have shown that the special character of the tourism industry makes it more liable to independent events than other sectors. it is vulnerable to variations in politics and economics, as well as any major change in policy or ideology, and these changes can significantly modify its development process. however, until now there is no evidence that china might want to change its reform and open-door policy; on the contrary, major policies within the tourism sector show a greater openness to the outside world. the increased dependence on tourism as a source of economic growth also shows that it would be extremely difficult for china to halt tourism development. the wto estimates that china will receive 130 million foreign tourists by 2020, making china the world's number one tourist destination. terrorism use of premeditated violence (or threat of violence) by organized groups, against civilians or unarmed military personnel, in order to attain political, religious, or ideological goals. crime any act punishable by law, motivated by economic, political, racial, or religious reasons. it can range from petty offenses to violent crimes. health hazard any source of danger that can be harmful to people's physical condition, ranging from minor upsets to infections caused by serious diseases. natural disaster a phenomenon not caused by humans, involving the structure or composition of the earth, ranging from eruptions, avalanches, or earthquakes to landslides, floods, hurricanes, or typhoons. political instability disturbances motivated by political, racial, ethnic, or religious conflicts, which can lead to social disorder and instability. 1. what are the main factors regarding safety and security affecting the tourism industry? what might be the implications of those issues for destinations? 2. how do the main tourist markets see the safety and security situation in china, and how do they perceive it as a tourist destination? 3. the growth trend of china's international tourism industry has not been consistent over the years. what factors have caused disruptions in tourism growth? 4. explain the major implications of the tiananmen square incident to china's tourism industry. 5. why did the sars outbreak have such a repercussion on china's tourism sector? the impact of crime on tourist arrivals in jamaica encountering sars: a perspective from an infected area. e-review of tourism research (ertr visitor safety in urban tourism environments: the case of auckland modeling tourism crime: the urban visitor perceptions of safety during a special event tourism in the people's republic of china: policies and economic development the impact of severe acute respiratory syndrome (sars) on china's tourism sector tourist victimisation and the fear of crime on holiday hiv in china reducing the health risks associated with travel tour operators and destination safety the impact of the severe acute respiratory 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exploratory war-distorted destination life cycle cultural conflicts: experiences of us visitors to china the assessment of vulnerability to natural disasters in china by using the dea method special report number 18-tourism after special report number 25-fifth meeting of the tourism recovery committee. madrid: wto world travel and tourism council (wttc) delinquency and its prevention in china emerging markets for china's tourism industry china's tourism development since 1978: policies, experiences and lessons learned key: cord-275171-uokqn2u8 authors: zhang, li; hua, ning; sun, shan title: wildlife trade, consumption and conservation awareness in southwest china date: 2008-03-21 journal: biodivers conserv doi: 10.1007/s10531-008-9358-8 sha: doc_id: 275171 cord_uid: uokqn2u8 commercial trade in wildlife is the major cause of species endangerment and a main threat to animal welfare in china and its neighboring countries. driven by consumptive use for food and traditional medicine, the large volume of both legal and illegal trade in wildlife has caused great destruction to ecosystems and pushed many species to the brink of extinction. data gathered from trading hubs at ports, boundary markets, city markets and stores, indicates the large amount of wildlife traded in the region of guangxi, yunnan and qinghai provinces, a direct result of the numerous wildlife markets available. in a survey distributed in various trading places, while about half of the respondents agreed that wildlife should be protected, 60% of them had consumed wildlife at some point in the last 2 years. the results also indicated that law and regulation on wildlife trade control is insufficient. wildlife trade controls are very limited because of bias on the utilization of wildlife as a natural resource to be exploited by the government agencies. the survey also shows that the current situation of wildlife consumption in key cities in china is serious, especially the consumption for food. the main consumption groups in china are male and young people with high education levels and good incomes. the key in public awareness publicity and education is to give them more information on the negative impacts of wildlife consumption and knowledge of protection. the concept of modern wild animal protection was introduced to the chinese from abroad. china's trade of edible and medicinal wildlife dates back thousands of years. ''the skin can be worn, feathers can be used, meat is edible, and organs can be used for drugs''-throughout chinese history, wild animals have been viewed as an important source of food and income. from a traditional chinese perspective, as the same as many other countries, wild animals are a resource to be exploited, not something to be protected for their intrinsic value. in recent years, with the development of a consumer economy, people's demand for wild animal products has grown substantially. the markets for consumption are increasing, and using wild animals as pets, for medicine and health care, and as food has become a status symbol and a fashionable lifestyle pursued by many (zhou 1997; morgan 2000; wang et al. 2001a; nooren and claridge 2001) . this robust market demand means lucrative profits for traders, providing a strong incentive for more people to join the trade. as a result, wild animal trade has expanded quickly, and illegal wild animal trafficking has increased sharply. trafficking, which involves excessive capture and non-sustainable utilization of wild species, poses a severe threat to many endangered species (li et al. 1996; li and li 1997) . large quantities of wild animals are now on the verge of extinction as a result of commercial development, such as chinese pangolin (manis pentadactyla) and tiger (panthera tigris) (traffic southeast asia 2004; s. wu 2007, private communication; dinerstein et al. 2007) . as a conservative estimate, tens of millions of wild animals are shipped each year regionally and internationally destined to southern china for food or east and southeast asia for use in traditional medicine (wwf 2001) . according to the third annual report released by the biodiversity working group of the china council for international cooperation on environment and development (bwg/cciced), nearly 70% of mammal species in china are endangered because of hunting and habitat destruction, with the primary threat being excessive hunting (bwg/cciced 1999) . in the report entitled ''wildlife trade in southern china'' released in 1995, the bwg pointed out that the increase in wildlife trade on mainland china in recent years could be attributed to four main of causes: (i) china's reform and economic growth has resulted in an increasingly prosperous population in the region who can afford expensive wild animals, increasing the incentive to trap animals. (ii) the improved infrastructure within china results in the availability of much sought after 'rarities' from distant or remote areas. (iii) the recent opening up of borders between china and its neighbors in southeast asia (e.g. vietnam and laos) has provided a new source of wild animals for the trade. (iv) the growing popularity of keeping reptiles and amphibians as pets in western countries, and more recently in japan, hong kong and taiwan, constitutes a substantial market outside china's mainland. thus reptiles and amphibians are imported to hong kong for re-export and, to a lesser extent, for local sale. wild animal trafficking worldwide is estimated to be worth more than us$8 billion a year globally, second only to the trade in illegal drugs, with profit margins which are more attractive than illegal arms dealing (sain-ley-berry 2000) . adding to the problem, wild animal trade monitoring is very weak in china, making it difficult to assess the impact on wild animals domestically; relevant data obtained from consumers are also very scarce. meanwhile, the coexistence of legal trade and illegal trade makes it very difficult to monitor wild animal trade and distinguish which products are entering the market legally and which are being smuggled in illegally (li and zhang 2003) . identifying animal species traded at the sales terminals, estimating trading frequency, identifying species under protection or rare species, and assembling data on the countries and routes involved in trafficking are complex tasks that require support from a wide variety of sources (mill et al. 1995; zhou 1997; xie 1999; wan 2004) . challenges faced by organizations and government agencies working to combat illegal wildlife trade are vast: few key provinces house systematic wildlife trade management systems; enforcement authorities lack legal enforcement power; not enough data are available to sustain local biodiversity conservation; and a scientific monitoring and evaluation system has not yet been established to support conservation efforts (lee et al. 2004 ). in addition, limited data on wildlife trade are not efficiently shared and utilized between relevant protection and decision-making departments. another alarming trend is that the cross border trade in mammals, birds and reptiles between china and neighboring countries has reached a level previously unmatched in history, substantially affecting wildlife populations (li et al. 1996; yang et al. 2000; nooren and claridge 2001; wang et al. 2001a, b; lee et al. 2004) . as a result, we are working to establish a database and monitoring platform on wildlife trade which can be used to enhance the communication among government administrative departments, decision-making departments and related organizations, improve monitoring and evaluation methods, strengthen law enforcement, and advance management and control on wildlife trade. the aim of this project is to eliminate commercial exploitation of animals by creating a sound public and democratic environment for the public to voice their opinions on wildlife consumption and protection issues. over-exploitation and cross-border wildlife trade are directly related to the fast growing chinese market which has inflated the price of wildlife products, making it more profitable to engage in the trade. many species of plants and animals are now in danger of becoming extinct because of over-exploitation, like liquorices (glycyrriza uralensis) in gansu and some other provinces in west china, birds and arethusa (dendrobium spp.) in guangxi and yunnan, matsutake (tricholoma matsutake) and other wildlife population in sichuan and yunnan. such threats may influence the administrations and individuals in some key departments of forestry, environment protection, agriculture, tourism and livestock farming into taking action. other stakeholders include local residents who depend on these natural resources, pharmaceutical manufacturers who want a sustainable medicine supply, and decision-makers who deal with local and global economies. the border area where yunnan and guangxi connect to vietnam, laos and burma is of particular concern. forests growing in the border area support 70% of wildlife population (li et al. 1996; yang et al. 2000) . problems exist in this area for all parties seeking to control illegal wildlife trade; transportation is inconvenient, the economy is undeveloped, law enforcement is weak, and wildlife management staff are few. traditionally, hunting was a main source of income for local residents. with the border trade opening and more frequent cross border trade, illegal wildlife trade is increasing, posing a serious threat to the species which can easily be transported across the international boundary (lau et al. 1995; li and li 1997) . poaching and smuggling in qinghai and tibet is also a serious problem. local residents heavily depend on natural resources for their livelihood, but lack awareness of the need to protect these resources. local government authorities lack efficient wildlife management and law enforcement capacity and are in need of training (wan 2004; lee et al. 2004) . over recent years, people's demand for wildlife has grown in some of china's developed cities, especially coastal cities along the border. as in other regions of china, eating wildlife has become a fashionable lifestyle and symbol of elite status. regions and routes (see fig. 1 (4) a public poll on wildlife consumption and protection awareness was carried out in shanghai, guangzhou, beijing, chengdu and kunming. (1) interview the study used a structured questionnaire and face-to-face interviews in beijing, shanghai, guangzhou, chengdu and kunming, with at least 250 successful samples per city. interviewees included local self-identified animal lovers, former hunters, high school biology teachers, rangers, herb collectors, field research staff, nature reserve and forestry center staff and urban residents. questions focused on the change in numbers and species of wildlife, as well as threats (special emphasis was given to the situation facing key species like tiger, bear, snakes and turtles etc.). the total valid sample size of the interview is 1,352 individuals. (2) field and market investigation the investigation was carried out by: observing the animals and their tracks, including footprints, footprint traces, lying traces, feathers, hairs, feces and other marks; investigating the living condition and threats wildlife are facing; recording the quantities and species of the animals; visiting markets and talking to the dealers; and recording the species and volumes of endangered and rare wildlife in trade. (3) information gathering information was gathered by visiting customs and entry-exit inspection and quarantine bureaus, referring to case records, collecting historical data, and investigating the historical situation of wildlife and changes in quantity by talking to local residents and specialty shops. posing as interested customers or dealers, we also collected information on overall trade, the source of wildlife for the trade and transportation routes. (4) sampling in this survey, we used multi-phase random sampling methodology, and followed the order of ''overall neighborhood committees-neighborhood committee samplehousehold sample-individual'' to randomly filter the households. if this sampling method resulted in selection of an unqualified respondent in the target household, another qualified respondent was substituted. if there was more than one qualified respondent in a household, only one was interviewed, in accordance with the kish sampling method. (1) urban residents (2) shopping centers, restaurants, open markets, customs, ports, forestry bureaus, forest police, bureaus of foreign trade and border trade, administrations for industry and commerce, administrations for wildlife entry-exit inspection and quarantine etc. beijing, shanghai, guangzhou, kunming and chengdu are five representative chinese cities with high population density and high wildlife consumption levels. we requested a consulting company to conduct research by using a questionnaire to address the following issues: 1. the current attitude of chinese urban residents towards wildlife consumption, the kinds of wildlife people think can legally be consumed, and factors influence on the consumer's attitude. 2. the current situation includes four types of consumer behavior among chinese urban residents: using wild animals as food, using medicine or tonic products containing wildlife ingredients, wearing ornaments and garments made from wildlife, and keeping wildlife as pets. in understanding behavior, it is essential to consider level of consumption, consumption channels, species and motives so that we can understand the wildlife consumption better and find ways to improve the law enforcement, as well as public awareness and education. 3. characteristics of wildlife consumer groups among chinese urban residents. 4. chinese urban residents' awareness of wild animal protection, the attention they pay to wildlife protection efforts and their willingness to participate in conservation. by conducting the survey on public awareness of wildlife consumption, we hoped to be able to provide government authorities and ngos with useful information to enhance the management of the unregulated market and help combat illegal wildlife trade. we also hoped that it would assist the government in adopting methods to educate the public, promoting wildlife conservation awareness, establishing the concept of protection, and ultimately reducing and eliminating illegal commercial exploitation and trade. current situation of wildlife trade in key regions 1. trading sites. the main sites for wildlife trade are ports, border markets, and markets and stores in cities. there are 11 ports of entry in yunnan, among which 7 are road ports (foreigners are allowed to go through ruili, mohan and hekou ports by railway), 2 are air ports (foreign flights are allowed to land in kunming international airport and xishuangbanna international airport), and 2 are water based (foreign ships are permitted to go through jinghong and simao ports). in addition, there are 90 border channels and 103 border markets, including, along the border with burma, dehong prefecture with 3 road ports (houqiao, ruili and wanding), 2 provincial ports in longchuanzhangfeng and yingjiang, and 28 ferries and 64 roads and channels with 22 border markets. along the border with laos, there are 3 ports (of which honghe county of honghe prefecture is the largest), 2 provincial ports, over 10 ferries and numerous informal channels. in guangxi 8 counties share a border with vietnam, with 12 border ports of entry, among which dongxing, pingxiang, youyiguan, shuikou and longbang are national ports. along the border with vietnam, 25 border markets are connected by road to these ports and other trading points. dongxing, puzhai and nongrao-nonghai are the three most important border trade ports. nanning, as the capital of guangxi, is one of the largest international wildlife trading hubs in china, also acting as a market for trade in domestic wildlife resources illegally harvested from within the province and yunnan. qinghai does not share a border with any of china's neighbors, but the province itself is rich with wildlife resources and trade evident in the numerous markets, drug stores, specialty stores and breeding farms within the cities in qinghai. xining is the biggest city within qinghai for trade transactions and consumption of wildlife resources. geermu is also a major trading spot for species traded within the province or coming from tibet and xinjiang autonomous region, especially for the skin of tibetan antelope. huangzhong county draws tourists, both foreign and domestic, and is also a major hub for trading wild animal skins and crafts. 2. traded species. the six taxonomic groups found in this study to be affected by trade in china include (species totals are in parentheses, 102 in total): insects (2), fish (2), reptiles (3), amphibians (33), birds (21) and mammals (41). reptiles and mammals are the most prevalent species in wildlife trade ( confiscated over 10,000 wild animals, 3,400 kg of wildlife products and 528 wildlife skins. at a pet market in kunming, investigators found more than 600 turtles and birds as well as 1,200 pieces of wildlife products waiting for sale. in guangxi province, most wildlife trade takes place along the border area. for example, the number of specimens found in pingxiang city included 20,000-30,000 tokay geckos, 500-1,000 asian water monitors, 1,000-2,000 pangolins, 30-50 tons of snakes, 10-20 tons of frogs, 20-30 tons of turtles, 5-10 tons of soft-shelled turtles, and 1-3 tons of birds of prey each year. in dongxing city, wildlife trade each year amounts to 10,000-24,000 snakes, 12,000-24,000 tons of frogs, 3,600-6,000 turtles, 480-1,200 raptors, and 2,400-6,000 tokay geckos. in addition, investigators found 600 frogs, 1,100 turtles, 550 soft-shelled turtles, 1,360 snakes, 177 asian water monitors, 100 raptors, over 60 small mammals, 3,680 wild birds and 180 reptiles in the pet markets in nanning. in qinghai province, a wildlife trade survey was carried out in xining city, germu city and huangzhong county while customs' data would indicate that wildlife smuggling is gradually decreasing, the government's data on confiscated wildlife indicates otherwise, signaling that the majority of smuggling is occurring in underground and black markets. 4. trading purposes. wildlife trade is driven by a multitude of markets including: â�¢ food, such as snake and monkey, most of which can be found in the market as live animals or animal parts; â�¢ medicine and tonic products, such as tiger bone, bear bile, or deer horn, most of which can be found as animal parts in the drug store or supermarket; â�¢ crafts and souvenirs, such as ivory and antelope skull, most of which can be found as animal parts in the craft store, gift shop or open market; â�¢ garments and decoration, such as tiger skin, crocodile skin, and tibetan antelope wool, most of which can be found as animal skins in the market or port; and â�¢ pets, like turtles, lizards, and blue peacocks, most of which can be found as live animals in the market. (1) sources wildlife is mainly coming in from border markets such as vietnam, laos and myanmar. some animals coming through this route include the hieremys annandalii, cuora amboinensis, indotestudo elongata, aspideretes hurum, varanus salvator, enhydris bocourti, manis javanica. from other provinces within china, such as yunnan, guizhou, sichuan and guangdong, species traded include elaphe taeniura, ptyas korros, erinaceus europaeus, passer montanus, and many species of pheasants, hawks and owls. wildlife traded mainly in local markets includes cervus elaphus (qinghai), trimeresures stejnegeri, rana guentheri, gallicrex cinerea, and lepus capensis (guangxi). breeding facilities also exist, the largest being in baoshan. species commonly found in farms include pavo cristatus (yunnan-for domestic sale) and pelodiscus sinensis. wild caught nycticebus intermedous, naja naja and manis javanica are also smuggled from vietnam into yunnan but declared as captive bred animals. (2) routes ruili city of dehong prefecture is the largest trading port of entry between china and myanmar, and it represents more than half of the total import and export trade volume in yunnan. unlike guangdong, yunnan has more convenient road transportation and longer shared borders with neighboring countries. this means that many smugglers prefer to trade along the borders, instead of through customs, making it even harder to regulate and monitor the illegal trade. legal wildlife trade in yunnan mainly comes from river ports in eastern yunnan. guangxi benefits immensely from wildlife trade. as wildlife in guangdong is expensive in comparison to other regions, most of the imported wildlife in guangxi (about 85%) is traded to guangdong and the rest goes to nanning, then liuzhou. qinghai is rich in wildlife resources, so most of the wildlife traded there is sold locally or to nearby provinces (fig. 2 ). 6. government trade control agencies. government agencies with a role in wildlife trade management include customs, the state forestry administration, the bureau of (1) customs customs is responsible for inspecting imported and exported goods, managing and monitoring wildlife trade, overseeing wildlife smuggling cases, within the customs inspection area and the coastal area near customs, and confiscating wildlife during smuggling and illegal importation. (2) state forestry administration in terms of import and export control, the forestry bureau has the right to monitor the implementation of the law of the people's republic of china on the protection of wildlife and other related regulations. according to the ''specific permit law,'' the forestry bureau can authorize or submit import and export applications to higher level authorities for authorization, and the bureau has the right to handle cases involving forging, cheating, or transferring import or export permits. the convention on international trade of endangered species of flora and fauna (cites) is enforced by offices around the country under the management of the china national management authority (cnma) and the forestry bureau. they are responsible for the monitoring of cites implementation on wildlife trade, authorizing permits and certificates, assisting relevant law enforcement bodies in illegal importing or exporting cases, rescuing and resettling confiscated live wild animals, charging wildlife import and export management fees based on relevant regulations, and organizing the training or publicity on cites and the related domestic laws. this ministry is responsible for the registration and management of import and export companies, foreign investment, international economic and technical cooperation, and port development and management. (4) ministry of police the police bureau, particularly the administration of forestry police, is responsible for managing state protected wildlife trafficking occurring outside of customs inspection areas and coastal area near customs. the armed police bureau and the police bureau inspect people going through customs to check whether they are carrying prohibited goods. if prohibited wildlife is found, offenders are transferred to forestry police and customs for further legal procedures. this administration is responsible for the management of domestic markets, protection of wildlife species, monitoring the market selling of livestock, marine animals, flowers, medicine and wildlife, and jointly working with the forestry bureau to regulate the market. confiscated wildlife or smuggling cases identified by this administration are handed over to the police bureau. (6) bureau of fisheries under the ministry of agriculture the bureau is responsible for the implementation of state laws and regulations on oceans and fishery management, as well as for related international conventions. this means they control the overall management of china's ocean space, including ocean environmental monitoring, aquatic animal conservation, fishery industry administration, the fishery industry business permit system, and other fishing activities, such as processing and distribution. current situation of wildlife consumption in the market ''should wild animal consumption be allowed?'' ''what kind of wild animals can be used for consumption?'' through urban chinese residents' answers to these questions, we can assess general attitudes towards wildlife consumption that the first group is explicitly opposed to wildlife consumption, and they hold ''pure protection'' (pp) viewpoint; the second, third and fifth groups are subject to the influence and inducement of various kinds of factors, and thus they may be divided into an interest-driven group-the ''conditional utilization''(cu); without misgivings about wildlife consumption, the fourth group holds the ''pure utilization'' (pu); those who are not sure about their attitude belong to the ''vague'' cognition group (see table 1 ). attitudes regarding wildlife consumption. thus, our analysis reveals that at present 43.3% of urban residents agree with the cu cognition, compared to 43.2% with pp cognition; pu group and vague group account for 6.9% and 6.6% respectively. attitudes towards wildlife consumption varied between cities ( table 2 ). the result showed that 54.9% of residents in guangzhou agreed with the cu cognition, together with the pu group (11.4%), the percentage of wildlife utilization group was significantly higher than that of the other four cities. consumption levels. we divided the wildlife consumers into three groups: light consumption group (2 times or below per year), medium consumption group (3-9 times per year) and heavy consumption group (10 times and more per year). there is distinct difference among cities in the level of consumption of wildlife. heavy consumption is by far higher in beijing (27.1%), guangzhou (25.8%) and shanghai (24%), than in chengdu (8.7%) and kunming (7%). medium consumption is much higher in shanghai (44%) and guangzhou (34.8%) than in other cities. among 1,352 respondents 78.8% did not eat any of the species listed. animals that were consumed by more than 5% of respondents in the past year include quail (8.2%), ring-necked pheasants (6.7%), hares (6.7%), frogs (6.5%) and snakes (6%). where is wildlife consumed. among the places where wild animals are consumed by chinese urban residents, common and high-grade restaurants and hotels account for 41% and 34% respectively. the purchasing of wild animals at vegetable/non-staple/flea markets (32.8%) and supermarkets (24%) is also high. why do people consume wildlife. more than 50% of wildlife consumers said they consume wildlife because they find the taste delicious. those who tried wild animals because they felt they were rare represent 23.3% of the surveyed, while 20.9% of people indicated they tried wildlife out of curiosity. those who tried wild animals for nutritional and nourishment purposes accounted for 19.3%. about 5.1% of respondents said they eat wild animals at dinner parties. about 13.6% of consumers ate wild animals because they were served to them by others. geographical differences on wildlife consumption. there is a marked difference between consumers from different cities in the degree of wild animal consumption. the ''heavy consumption'' group is higher in beijing (33.3%) than in other cities; the ''medium consumption'' is higher in chengdu (50%) and guangzhou (41.7%) than in other cities; and the ''light consumption'' is highest in kunming (65.5%). major wildlife products in consumption. the 21 wildlife breeds or products selected in this survey consist of 14 species of wild animal and seven breeds of wild plants. among the 1,352 respondents: â�¢ 85.8% said they had not eaten any of the breeds mentioned on the list in the past year. â�¢ sinkgo (4.9%), snake gall (4.6%), cordyceps sinensis (3.9%), musk (moschus spp.) (3.3%), snow saussurea (saussurea spp.) (2.3%) and snake oil (2.2%) were all heavily consumed in the past year. â�¢ of the people who purchased medicine or health products containing wildlife ingredients: -67.3% of consumers purchased them at pharmacies, -26.3% purchased from supermarkets, and -12.3% purchased from general stores -24.7% used wildlife medicine or health products given to them by others (higher than the percentage of those who ate wild animals as food given by others (13.6%)) -48.8% think medicine and health products containing wildlife ingredients promote health by increasing nutrition and nourishment, 44.5% think such medicine and health products have special curative effects, and 26.7% say that they have no other choice because the medicine they need contains these ingredients. in this survey, we listed 11 wildlife products for respondents to identify. according to the results, 40%, or 3%, of the total respondents had articles made from wildlife (see table 3 ). thirteen respondents said they were not sure about or refused to answer their consumption frequency. on average, the wildlife product owned had been made within the last 2 years (27 respondents). ninety seven percent of the respondents did not own any of the 11 articles made from wild animals on the list in the past 2 years. among the 40 people who had articles, the percentage of the ownership of ivory and marten products were highest. in the survey, of those with wildlife products, 47.9% of the ornaments and readymade products owned by the respondents were given to them by others, 19.4% were purchased from leather and wool product stores, 24% were purchased from stores, 18.8% were purchased at general ornament stores, 13.8% at tourist stores or markets, and 10% were purchase in flea markets. in the survey, 67.3% of the respondents believed that ornaments and ready-made clothes made from wildlife were beautiful. those who owned these products out of curiosity account for 34.1%; those who regard it as a fashionable lifestyle make up 25.5%, and those who think it shows their distinctive taste and status account for 6.4%. on the survey, we also listed 18 species of wild animals that can be raised in captivity, a total of 107 respondents have raised the wild animals on the list, accounting for 7.9% in the total (see table 4 ). in terms of the average number of wild animals raised by residents in the cities, beijing ranks first, and shanghai comes second. among 1,352 total respondents, those who did not raise any of the species listed account for 92.1%. however, tortoises, mynah, parrot, sparrow and thrush are the most common species raised by people. respondents who purchased wild animals from pet markets account for 49.1%, those who adopted wild animals or accepted wild animals given by others account for 27.1%. a percentage of 63.6% of the respondents raise wild animals because they have fun in doing so, and over 75% raise wild animals for aesthetic purposes. what drove respondents to start wild animal consumption? among the 420 respondents who have consumed wild animals, 25.5% purchased wild animals or products recommended by their relatives and friends, 24.9% consumed wild animals given to them by others, 17.4% purchased wild animals after watching advertisements on the products or publicity materials on the species, 10.3% purchased wildlife products recommended by professionals (like traditional medicine practitioner), and 11.5% were unsure of how they started wild animal consumption. among those who have consumed wild animals, 36.9% do not know whether they have consumed captive bred or wild animals, 23% know the animal they consumed was captive bred, 19.2% know that they consumed both captive-bred wild animals and real wild animals, and 7.7% know that what they consumed are real wild animals. among 420 respondents who have consumed wild animals, 36.9% prefer real wild animals, 20.2% prefer captive-bred wild animals and 28.4% do not have a preference. preference varies by city: the percentage of consumers in guangzhou who prefer wild animals (44.2%) is slightly higher than that in other cities, followed by the percentage in kunming (40.6%) and shanghai (37.5%); the percentage of consumers who prefer captive-bred wild animals is the highest in beijing (33.3%), and the percentage in chengdu (26.5%) comes second. from this survey, 932 of the 1,352 respondents had never consumed wild animals. among them, those who regard wild animal consumption as uncivilized behavior account for 37.5%; 37.4% think it is unhealthy and may cause infection of diseases; 33.7% believe wild animals should be conserved and they are not for consumption; 33.3% think it will destroy the ecological environment and it is not conducive to environmental protection; 26.8% have no particular preference for wild animals; 5.1% have not consumed wild animals because they could not afford it, and 0.6% have not because they had no opportunity for consumption. the survey findings show that at present, 61.7% of chinese urban residents believe ''all wild animals should be protected'' (protection group), 15.5% think ''some wild animals should not be conserved because they carry viruses or bacteria that human beings are susceptible to and they may communicate the diseases to human beings'' (middle group 1), 11.5% think ''it is not necessary to protect wildlife, which is a kind of resource and valuable to human beings, and has strong ability to reproduce and survive'' (utilization group), and 3.4% think ''wild animals that pose a threat to human beings' safety, like jackals and wolves, should not be protected'' (middle group 2). those who are not sure about this issue account for 7.1%, and 12 respondents refused to answer this question, taking up 0.9% in the total number of respondents. interestingly, the distribution of the four groups varies significantly from one city to another. the protection group represents the majority of respondents in kunming (68.8%), beijing (69.1%) and shanghai (67.2%). the middle group 1 and 2 takes up a higher percentage in guangzhou (31.5%) and chengdu (23.6%). the utilization group accounts for a higher percentage in chengdu (21%) than in the other four cities. in this study, we listed 20 species of heavily consumed wild animals under priority protection in china for respondents to identify. the results show that for the majority of the 20 species, the protection group rate is below 50% among chinese urban residents (table 5) . again, there is a marked difference in cognition levels of residents living in different cities. residents in kunming have the highest cognitive level regarding protected wildlife, beijing is second, shanghai and chengdu rank third, and the lowest is in guangzhou. how do the chinese regard the relationship between wild animals and human beings? in this survey, 57.3% of the respondents see wild animals as serving a companion role for human beings, 52.6% think wild animals are equal to human beings and both deserve protection and respect, 30% regard wild animals as good resources and believe the purpose of wild animal conservation is to allow better utilization by human beings, 13.6% think wild animals and human beings belong to two different worlds, 9.1% see no relationship between wild animals and human beings and think they are lower than human beings, and 6.5% think wild animals pose a threat to human lives. at present, animal welfare is a popular topic in china. when asked about this issue, nearly 60% of urban respondents think improved animal welfare is related to societal development and 21.8% say there is a close relation. meanwhile, 12.1% of the respondents say they are not sure about this issue, and 6.1% see no relation between the two. how many and why chinese people are concerned with wild animal protection work now will affect what methods are used for future intervention. more than 50% of chinese urban residents are supportive of wildlife conservation; those holding a negative attitude account for 19.5%. residents of beijing are most supportive of conservation efforts (67.1%), followed by shanghai and guangzhou. among 209 respondents who explicitly noted that they were not concerned about wildlife conservation, 36.7% say they have no personal connection to wildlife, 17.9% believe conservation should only be through the government, 16.1% believe any effort they make will have little impact, 12.7% feel there are too few people involved in conservation for it to make a difference, 4.2% of them regard the work a waste of time and money, 0.7% of them think it unnecessary to protect wildlife, and 10.6% indicated no specific reason for not being concerned with conservation. most urban residents have an accurate understanding of the severe situation faced by wildlife in china. in this survey, 83.1% of the respondents are positive about the issue and believe that wildlife could avoid extinction through conservation measures, and 10.6% of them are negative about this issue, believing that, considering the current situation, species extinction is unavoidable. in 1988, china promulgated the law on wild animal protection, which stipulates a list of wild animals under priority protection in china. the list contains about 100 species of wild animals under first-level state protection and more than 200 species under second-level state protection (http://www.sepa.gov.cn/natu/swdyx/swwzzybh/200211/t20021118_83384.htm). as its supporting statute, the implementation rules on the protection of land wild animals of the p.r.c., promulgated in 1992, claims that the legal system for wild animal protection with the law on wild animal protection has been firmly established. yet, in this survey, as many as 46.7% of the respondents are unaware of the two statutes, 30.4% know about the law on wild animal protection, and 15.1% know about the implementation rules on the protection of land wild animals. at present, despite these legal provisions, unlawful consumption of wild animals still exists in china. in this survey, 41.6% of respondents impute it due to poor enforcement, 39.5% think the law itself is lack of details on regulating the wildlife consumption that results in rampant unlawful consumption, and 37.5% hold that the sanctions imposed by law are not stern enough, which is why the law does not truly play its role of prohibiting unlawful behavior. meanwhile, 35% believe that many people do not know the existence of relevant statutes, due to inadequate efforts made toward publicity of the statutes, 32.9% think that money is more powerful than law, and that the rich can access any product they desire despite illegality, and 22.8% maintain that traditional notions in the chinese society have significant influence on people's behavior, and it is difficult to change in a short time. at present, respondents indicated the following actions as urgently needing to be taken: â�¢ publicity efforts to heighten public awareness of wild animal protection (50%), â�¢ relevant statutes formulated and the legal system improved (33.2%), â�¢ punishment on the persecution of wild animals should be increased (27.6%), â�¢ cultivate public awareness of environmental protection (25.7%), â�¢ tighten regulation and control over wild animal trade and transportation (25.4%), â�¢ strengthen education on wild animal protection among children and adolescents (21%), â�¢ devote additional funds to wild animal protection (17.7%), â�¢ improve the professional quality of foresters and law enforcement personnel in the market (17.5%), â�¢ support more wild animal protection organizations (14.1%). of information chinese urban residents have been exposed to in the last 6 months, the top three types are wild animals in trade (30.4%), photographs of wild animal hunting (29.6%) and documentaries on wild animals' lives (28%). in additional, people also indicated learning about wildlife conservation (22.7%) and the spread of diseases from wild animals to human beings (22.6%). dissemination of information most commonly comes through tv and rarely through publicity activities or other community programs. for information on wild animals, the percentage of those who pay attention to visual information is much higher among heavy consumers than among light and medium consumers. a high percentage of medium consumers pay attention to non-visual information. among the various types of public benefit activities concerning wild animals, people are most willing to take part in publicity activities on wild animal protection (45.7%), and a high percentage of people are interested in ecotourism (31.6%). regarding consumer behavior, the respondents explicitly noted that they would abstain from purchasing wild animals (38%), using medicine or health products containing wildlife ingredients (20%), or acquiring cosmetics containing wildlife ingredients (17%). less than a quarter of respondents would be willing to provide monetary support for improving conditions of zoo animals or supporting wildlife conservation organizations. in this study, 932 respondents noted that they had no consumption experiences involving wild animals in the past 2 years, accounting for 68.9% in the total number of respondents (1,352). among the 420 respondents who had wild animal consumption experiences, three respondents consumed wild animals other than the species we listed in this survey; 91 respondents consumed the species listed but were not sure about their consumption frequency; 326 respondents consumed the species listed and were clear about their consumption frequency. among the 326 respondents who have had wild animal consumption experiences, light consumers account for 59.8%, medium consumers 28.7%, and heavy consumers 11.5%. among the five cities, the percentage of light consumers is the highest in kunming and chengdu, and the percentage of heavy consumers is the highest in beijing and guangzhou. the percentage of medium consumers is higher in beijing than in other cities. further analysis reveals some difference between these consumer groups in sex, age, income and occupations. the heavy consumption group (392 samples in total) consists largely of young men (222 individuals) who were under 35 year old, many of whom are physical workers, students, self-employed and freelancers, with relatively good education and high monthly household income. the majority of them have a monthly household income of above rmb 3,001. there is significant variability between different consumer groups in understanding the scope of wildlife under protection. the percentage of consumers with the pure protection cognition type is higher among light consumers and medium consumers than among heavy consumers; the percentage of those holding the conditional utilization cognition is the highest among heavy consumers. in summary, people's knowledge about state-protected wildlife does not directly influence their consumer behavior. consumption level is proportional to cognitive levels. the percentage of those with high cognitive level is the highest among heavy consumers. among residents with high cognitive level, the percentage of those who have consumed wild animals is equal to the percentage who has never consumed wild animals. a higher percentage of residents with low cognitive level have not consumed wildlife. the majority of light consumers began consuming animals on their own accord, while the majority of medium and heavy consumers involuntarily began consuming animals (e.g. pressure from family, coworkers or items given as gifts). heavy consumers are more concerned about the place of origin of wild animals compared to the other consumers. they generally know whether they have consumed wild or captive bred animals, and have a stronger preference towards wild animals than the other consumer groups. wildlife trade in key regions continues to be very active because of a continuous supply of wildlife resources and large market demand for wildlife goods. our survey statistics show that as time passes, however, there is a gradual trend toward a reduction in total wildlife trade for the following reasons: (1) due to heavy cross-border poaching, wildlife resources have been greatly reduced, with some species even facing extinction. (2) in recent years, the government has strengthened law enforcement and the wildlife trade control system. as a result, illegal trading is riskier, causing some traders to leave the trade. (3) after sars in 2003 and bird flu in early 2004, previously legal wildlife was banned for import, and the general public began becoming aware of the negative impact wildlife could have on their health. though smuggling still exists, the trade amount was reduced. recommendations: 1. establish a wildlife trade control & monitoring network. it is difficult to identify the numerous wildlife species and their products in daily trade control and legal procedures, and, due to language barriers and politics, it is hard to compile evidence for foreign crimes. the handling of confiscated live wild animals is also a problem. enforcement officers often release confiscated animals anywhere, without any consultation from wildlife experts. this improper release can directly affect the life of local people and the ability of the animals to survive. stringent measures must be taken to ensure that an effective trade control system is established to prevent the deficiencies in management of wildlife trade and ensure adequate enforcement so illegally traded animals cannot enter the market. the cites management authority should work with customs and the forestry bureau to set up a joint network and obtain greater support from international organizations to conduct long-term wildlife trade control and monitoring in the border regions, develop a wildlife import and export database, and give feedback on natural resource utilization. 2. enforcement capacity building. most of the villagers in the border regions are minority groups with their own customs and culture. there are very few wildlife conservation publicity events or education materials (such as video or audio) in their villages. there are no regulations for wildlife import and export control. limited by the slow economic development and the limited amount of education received, local governmental decision makers often feel there is no alternative but to consume the natural resources. it is necessary to educate the public on the relationship between global environmental conservation and country and local economic development, as well as short and long term potential economic benefits associated with wildlife protection. the improvement of statutes and law enforcement should not be neglected. the survey shows that people regard lax enforcement, poor operability of statutes and too lenient sanctions on violations as the main causes for the rampant unlawful wild animal consumption. even heavy consumers of wildlife recognize that improvement and enforcement of statutes and punitive measures would have great influence on their practices and reduce demand for wildlife consumption. for improvements to be made, it is essential that cites training and education programs focusing on techniques for trade control, cites regulations and species identification are delivered to law enforcers, including those from forestry bureau, forestry police bureau, customs, and administration of industry and commerce. in addition, government agencies and international ngos can work jointly to promote information exchange and cooperation between border countries. as was found in this investigation, local networks, government agencies and ngos have been established to mitigate trade but enforcement is lacking. considering the current heavy wild animal consumption, it is difficult to be too optimistic in this survey, we found that 31.1% of residents had consumed wild animals. considering that people may conceal their actual consumption behaviors when answering our questions, we adopted aversion techniques in designing the questionnaire. however, techniques can only reduce the intervention of subjective factors to some extent. therefore, the percentage of wild animal consumers in real life is assumed to be higher than the data suggest. even thought the data likely underestimate the problem, the actual figures obtained still reveal a desired approach to wild animal consumption among chinese urban residents. those who consume wildlife regularly are the largest group, accounting for 31.1% of the total. what is more worrying is that 57.5% of residents who consume wildlife voluntarily started to buy wild animals due to word of mouth, media or the influence of professionals. in the analysis of different groups' attitudes towards wild animal consumption, we find that a high percentage of those who have never consumed wild animals hold the ''utilization value theory,'' and the percentage of those holding ''vague cognition'' is even higher among those who have never consumed wild animals than among wild animal consumers. given that chinese urban residents' wild animal consumption is affected to a great extent by community views and pressure, in the future it is possible that more people will begin wild animal consumption due to societal influences. considering the current situation, intervening now, before more people become wild animal consumers, is very important, as changing consumer behavior once it has begun is much more difficult. less than 50% of chinese urban residents hold the correct attitude toward wild animal consumption. consumer attitude is subject to various factors, and cognitive level does not play a decisive role people's attitudes influence their behavior. in this survey, we found that only 42.7% of chinese urban residents think no wild animals should be consumed. consumer attitude is subject to various factors, and cognitive level does not play a decisive role. first we examined people's views regarding the scope of wild animals that should be protected. those who hold the view that ''all wild animals should be protected,'' were more likely to not be supportive of animal consumption. this would indicate that to some extent people's attitude toward wild animal consumption is directly proportional to their cognitive level. second, through a comparative study on consumer attitude of groups with different demographic background, we find that well educated groups have high cognitive level of wild animal protection. yet people's attitude towards wild animal consumption is not directly proportional to their educational level. among groups with different educational background, the percentage of those who could correctly identify the listed protected species is the highest among two-year college graduates, followed by high school and junior high school graduates. however, those who are not necessarily in disagreement with wildlife consumption are more likely to hold at least a bachelor's degree, and likewise the percentage of those following the ''utilization value theory'' is higher among those with bachelor's degree or above (55.8%) than among those with less formal education. among groups with different income levels, the percentage of those holding the ''utilization value theory'' is higher among those with monthly household income above 3,001 yuan than among other groups. this indicates that, to a certain degree, financial strength increases people's propensity to consume wild animals. third, there is marked difference between groups with different consumption levels and their motives for consumption. for example, the behavior of eating wild animals: a greater proportion of heavy consumers (58.7%) eat wild animals because they find them delicious. the percentage of those holding the utilization value theory is much higher among heavy consumers than among the other two groups. on the other hand, a higher percentage of light consumers tried wild animals out of curiosity. due to traditional notions, heavy consumers hold the ''utilization theory,'' and they also have fixed consumption behavior because of the preference for wild animals. this poses a considerable obstacle to intervention efforts. wild animal consumption has distinct regional differences and group features (1) regional differences. when looking at consumer behavior, consumption degrees, consumption channels and consumption motives, different cities have different consumption features. for example, the behavior associated with eating wild animals: a high percentage of residents in shanghai and guangzhou eat wild animals at popular restaurants and purchase wild animals from markets to cook at home, and the percentage of heavy and medium consumers in guangzhou is higher among residents in these two cities than in other cities (the percentage of heavy consumers in guangzhou is second only to that in beijing). for consumption motives, taste and nourishment are the two primary motives for eating wild animals among residents in shanghai and guangzhou. this indicates that eating wild animals has become a habitual consumption behavior among residents in shanghai and guangzhou. among the five cities, the percentage of residents in beijing who eat wild animals at high-end restaurants and hotels is highest, as is the percentage of heavy consumer and light consumer residents. most people consume wild animals out of curiosity, with the idea that wild animals are rare. for initial consumption motives, a major percentage of people involuntarily started wild animal consumption (i.e. it was given to them by friends, family, or colleagues). this indicates that wild animal consumption has become part of the lifestyle of some high-income people in beijing; it also indicates the influence of peers and group pressure on consumer behavior and consumption methods. it is possible that without effective control and intervention, many consumers will become medium and heavy consumers. according to the current trend, beijing is likely to become a swing consumer city. (2) group features. we divided the 326 consumers into groups depending on their consumption degree. in terms of consumer attitude, the percentage of those with the correct attitude toward wild animal consumption is lower among heavy consumers than among light consumers and medium consumers. with regard to the viewpoint regarding the relationship between human beings and wild animals, the percentage of those holding the ''utilization view,'' ''unrelated view'' and ''threat view'' is higher among heavy consumers than among light and medium consumers. interestingly, we find that although the percentage of those with the correct cognition is higher among light consumers and medium consumers than among heavy consumers, heavy consumers' cognitive level of state-protected wild animals is the highest among the three groups. this indicates that in terms of intervention efforts, strengthening education among heavy consumers is not necessarily effective. for consumption preference, the percentage of those who know they have consumed wild animals (as opposed to farmed) and the percentage of those who prefer wild animals are higher among heavy consumers than among other groups. this indicates that the group has very high awareness of their consumer behavior. regarding wild animal protection work, the percentage of those not supportive is much higher among heavy consumers than among the other two groups. meanwhile, the percentage of those regarding conservation as the government's responsibility and the percentage of those who think few people are concerned about this issue are much higher among heavy consumers than among the other two groups. the percentage of those who do not know about the two statutes on wild animal protection is higher among heavy consumers than among light and medium consumers. the percentage of those who know about the two statutes is the highest among light consumers. for information on wild animals, the percentage of those who pay attention to visual information is much higher among heavy consumers than among light and medium consumers. with regard to the willingness to participate in public benefit activities for wild animal protection, a high percentage of heavy consumers are willing to take part in ecological tourism and provide monetary support, but the percentage of those willing to change their consumption behavior is lower than the other two groups. a high percentage of medium consumers are willing to take part in publicity activities, and a high percentage of light consumers are willing to abstain from wild animals in food, medicine or health products containing wildlife ingredients. this further indicates the importance in intervening in consumer behavior before it become habitual, as in the case of heavy consumers. merely underscoring the threat posed by wild animals to human beings' health (taking sars for example) does not help. it is necessary to use both hard and soft tactics in behavior intervention since the outbreak of sars in 2003, there has been greater focus on human health in the discussion of eating wild animals. animal medical experts point out that wild animals such as primates, rodents and ungulates share more than 100 diseases with human beings (karesh et al. 2005) . even with warnings from various consumer associations and animal protection organizations, diseases continue to spread. recent studies have identified the chinese horseshoe bat as the natural reservoir of the coronaviruses from which the sars viruses that infected humans and civets likely emerged (lau et al. 2005; li et al. 2005) . in july 2003, 22 academics from the chinese academy of sciences jointly called for efforts to be stepped up for resources supporting wildlife conservation, improving statutes on wildlife protection, and establishing healthy diet views. sudden threats of disasters like a widespread disease certainly affect people's lifestyle and behaviors quickly, but it is not feasible to expect such temporary impact to fundamentally change the deep-rooted motives and notions formed by long-term social customs and traditions. in this study, we find that merely educating people on the threat posed to their health by wild animal consumption cannot fundamentally change people's attitude towards wild animal consumption. it can only heighten, to a certain extent, people's hostility toward wild animals, and cannot engender a conservation-oriented view towards wild animals. in comparing residents in different cities in terms of their understanding of wild animal protection, we find that the percentage of guangzhou residents, who were the first to receive the impact of sars, hold the ''threat theory'' at the highest; while their cognitive level about protected wild animals is the lowest. among the four groups divided by the viewpoints regarding the scope of wild animals that should be protected, the percentage of those holding the ''utilization value theory'' of consumption is comparable to those holding the ''threat theory'' and the ''utilization value theory.'' in other words, the view that wild animals may spread diseases to human beings or pose a threat to their lives does not reduce peoples' propensity to utilize or consume wild animals. therefore, in conducting behavior intervention we not only need to consider differences between consumer groups in cognition, attitude and behavioral features, but, more importantly, various measures should be taken to produce changes in human behavior. the key to publicity and education should be increasing knowledge. in this survey, we find that currently a high percentage of chinese urban residents is still not clear about what wild animals are protected. undoubtedly, this poses a major obstacle to regulating consumer behavior. due to the pertinence of people's cognitive level and their attitude toward wild animal consumption, it is a crucial task to cultivate the correct cognition among general residents through publicity and education. for widespread change, it will be necessary to combine the strategies of publicity and education. through the analysis of the cognition of the scope of wild animal protection and consumer attitude, a high percentage of the ''threat theory'' and ''utilization theory'' groups adopt the consumption attitude of ''utilization value.'' meanwhile, the percentage of those with the incorrect attitude toward wild animal consumption is highest among the ''utilization theory'' group. this indicates the strong influence the utilization theory has on people's behavior. therefore, publicity and education should be aimed at changing this mentality and making it clear that all wild animals should be protected, which will certainly take a long time. we may also utilize other publicity strategies suited for specific stages/groups of consumption. for example, in analyzing reasons for not consuming wild animals, we find that a high percentage of people have never consumed wild animals because they regard the behavior unhealthy or they do not like it. different groups have different reasons. the percentage of those who regard it as unhealthy is higher among people aged 46-55 than among other age groups. a high percentage of people aged 56-60 and 18-25 do not like it. the percentage of those who think it is not right to consume wild animals is far lower among people with primary school education and below than among other groups. a high percentage of junior high school and high school graduates think it unhealthy, while a high percentage of those with bachelor's degree or above do not like to consume wild animals for different reasons. this indicates that we may guide the audiences by cultivating healthy consumption notions using various approaches in a short time. for example, we may educate young people not to eat wild animals and encourage them to abstain from wild animals early on. meanwhile, we may imbue middle-aged people and those with low education with the view that wild animal consumption is not healthy. of course, as stated earlier, even if we guide the audiences with the ''unhealthy'' view, it is also necessary to popularize correct knowledge and conduct education. recommendations: 1. one major strategy should be to prevent wildlife from reaching the markets. through this survey, it was found that villages along the border act as temporary stops for smugglers. if paid, villagers will often help the smugglers to escape, which strongly increases the difficulty in seizing criminals. a program needs to be implemented that targets key villages and simultaneously provides community development and biodiversity education projects to arouse their environment protection awareness, develop the local economy and convince villagers of the value of working together to stop smuggling. 2. as demonstrated by the survey results, heavy wildlife consumers are often those who are young, well-educated, and have a high income. without correct knowledge and understanding of wildlife consumption and protection, university students, as the next potential consumers, are the main target to be educated. schools are good places for knowledge input. as a starting point, education programs should be developed for university students and then move forward from there. biodiversity working group of china council for international cooperation on environment and development, bwg/cciced (1999) the 3rd annual report to china council for international cooperation on environment and development the fate of wild tiger wildlife trade and global disease emergence severe acute respiratory syndrome coronavirus-like virus in chinese horseshoe bats wild animal trade monitoring at selected markets in guangzhou and shenzhen, south china guide book on wildlife import and export management a survey on wildlife trade in guangxi and guangdong bats are natural reservoirs of sars-like coronaviruses the bear facts: the east asian market for bear gall bladder. trafffic, cambridge morgan d (2000) chinese medicine raising wildlife concerns unpublished report on wildlife trade and enforcement in qinghai province sain-ley-berry c (2000) new campaign launched to fight illegal wildlife trade wildlife trade management and enforcement. china forestry publishing house status of live wildlife trade in yunnan border area souvenir alert highlights deadly trade in endangered species breeding techniques for turtles trade of wild animals and plants in china-laos border areas: status and suggestion for effective management captive breeding of economic wildlife acknowledgements we are grateful for the grant from critical ecosystem partnership fund (cepf) to support this project. we thank the support of cites management authority of china, and its kunming, guangxi and sichuan branch offices. we are grateful to chun li, fang zhou, and all participants in the field trade survey, and the horizonkey information and consulting co., ltd. who conducted and implemented the public awareness survey for this project. we are also grateful for xue wang, stacy vynne, clare sierawski and chantal elkin for reviewing the english language of the manuscript. key: cord-264675-w8ptpg0b authors: bai, chengke; yang, jingjing; cao, bo; xue, ying; gao, pufan; liang, hui; li, guishuang title: growth years and post-harvest processing methods have critical roles on the contents of medicinal active ingredients of scutellaria baicalensis date: 2020-12-15 journal: ind crops prod doi: 10.1016/j.indcrop.2020.112985 sha: doc_id: 264675 cord_uid: w8ptpg0b optimizing the processing technology is an effective way to improve the yield of active ingredients for the industrial production of medicinal crops. baikal skullcap (scutellaria baicalensis georgi) is a perennial herb in the lamiaceae family and its dried root is used as a famous traditional chinese medicine (tcm). modern pharmacological studies have shown that the active ingredients of s. baicalensis have important pharmacological effects including anti-oxidation, anti-bacterial, anti-viral, anti-tumor, and anti-inflammation. specifically, it is recently found that s. baicalensis has significant curative effects on the treatment of corona virus disease 2019 (covid-19). in recent years, the market demand for the medicinal products of s. baicalensis is increasing because of its great medicinal values. however, the annual yield of active ingredients originated from the root of s. baicalensis is limited due to that little progress has been made on the traditional processing technology used in the extraction process. a pressing issue faced by both herbalists and scientists is how to improve the processing efficiency, thereby obtaining the maximum yield of products for s. baicalensis. in this study, a systematic analysis on the effects of growth years and post-harvest processing on the contents of medicinal active ingredients of s. baicalensis was conducted. the contents of eight active ingredients (baicalin, wogonoside, baicalein, wogonin, scutellarin, scutellarein, apigenin, and chrysin) in roots of s. baicalensis of different growth years (ranging from 1 year to 15 years) were estimated using high performance liquid chromatography (hplc) and further analyzed to determine the optimal harvest period. in particular, the contents of six active ingredients in different parts (cortex and stele) of the root of s. baicalensis were estimated and compared. meanwhile, the dynamic changes of the contents of active ingredients in fresh-crush and fresh-cut roots of s. baicalensis at room temperature were compared and analyzed to reveal the influence of post-harvest treatment on the contents of active ingredients. in addition, the effects of six different post-harvest treatments on the contents of active ingredients were systematically designed and compared to determine the best primary processing technology. the results showed that the best harvesting period for s. baicalensis should be determined as 2–3 years based on comprehensive evaluation of active ingredient content, annual yield increment, and land use efficiency. the contents of active ingredients including baicalin, wogonoside, baicalein, and wogonin in cortex were significantly higher than those in stele (p ≤ 0.05). the contents of baicalin, wogonoside, and scutellarin in fresh roots of s. baicalensis significantly reduced as the storage time increased, but the reduction of fresh-cutting was significantly lower than that of fresh-crushing. for the effects of different processing treatments, the contents of four main active ingredients (baicalin, wogonoside, baicalein, and wogonin) under drying (d) and cutting-drying (c–d) treatments were significantly higher than those of the other four treatments (p ≤ 0.05). collectively, the above results will not only provide novel processing methods that will improve the yield of active ingredients for s. baicalensis, but also shed light on the optimization of processing technology for the industrial production of medicinal crops. medicinal plants with effective pharmacological activities, low side effects as well as high economic values have long been used as raw materials and reservoirs of new drugs in pharmaceutical industry (tschofen et al., 2016; wurtzel and kutchan, 2016; tu, 2011; balandrin et al., 1985) . as an important part of the traditional chinese medicine (tcm) system, medicinal plants have shown great therapeutic potentials in severe and acute diseases including malaria, diabetes, cancer, etc. (chukwuma et al., 2019; feachem et al., 2019; manukumar et al., 2017; miller and su, 2011) . specifically, in the recent pandemic of corona virus disease 2019 , tcm preparation and drugs showed effective anti-viral and anti-inflammatory activities against the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) (chan et al., 2020; li et al., 2020a; liu et al., 2020; luo et al., 2020; ren et al., 2020; su et al., 2020; yang et al., 2020) . exploring the potential pharmacological functions and promoting the introduction and development of tcm will bring benefits to human health globally. currently, the primary aim of studies in tcm cultivation and production is how to improve the yield and quality of medicinal crops (specifically the active ingredients with high medicinal values). in recent years, the market demand of raw materials originated from medicinal crops is increasing with the development of pharmaceutical industry (barata et al., 2016; chen et al., 2016) . nevertheless, the yield of medicinal crops with high quality is decreasing due to growing human activities and habitat loss (cao et al., 2020; he, 2018; zhang et al., 2018; chi et al., 2017) . a pressing challenge faced by scientists is how to obtain the maximum yield of active ingredients in medicinal crops. improving the yield of active ingredients by optimizing the processing methods is a good way to achieve the above goals (mishra et al., 2020; nabet et al., 2019; wang et al., 2018a) . typically, the active ingredients in medicinal plants are secondary metabolites that are closely related to cultivation methods, field management, harvest time, primary processing in the producing area, deep processing, storage, and transportation, etc. (kessler and kalske, 2018; zhao et al., 2012; xiao et al., 2009; canter et al., 2005) . specifically, the processing methods including removing impurities, stacking, steaming, slicing, and drying have significant effects on the contents of active ingredients of chinese medicinal materials (nozad et al., 2016; guo et al., 2015; azizi, 2008) . the primary processing in the producing area is the first key step for the quality formation of chinese medicinal materials. previous studies have demonstrated that primary processing in the producing area have a great influence on the yield, quality, and efficacy of the medicinal materials (chen et al., 2015; duan et al., 2009 ). in the traditional technology of primary processing, it is specified that post-harvest treatment and processing of medicinal materials in the producing area should follow the natural rules of the formation of active ingredients. meanwhile, the specific characteristics of raw materials during the process of storage and transportation should be carefully considered to ensure the quality of medicinal materials (wang et al., 2013; zhao et al., 2012) . nevertheless, most of the active ingredients (e.g., alkaloid salts, inorganic salts, etc.) of tcm have different affinity degrees with water jin et al., 2016; yang et al., 2016) . improper processing treatments (long-term exposure to water, water flushing, immersion, etc.) will cause considerable loss of active ingredients (gao et al., 2011) . in addition, the contents of active ingredients in medicinal materials are closely related to the enzyme activity of plant tissues kotwal et al., 2019; yang et al., 2019; liu et al., 2017) . for medicinal crops that are rich in alkaloids and polysaccharides, the contents of active ingredients as well as the quality of medicinal materials will rapidly decline, due to the absence of high-temperature treatment that can inactivate enzyme activity in tissues and organs after harvest. for example, for the important medicinal crop tall gastrodia tuber (gastrodia elata bl.), high-temperature steam is firstly used to inactivate enzyme activity in the root after harvesting, and then the steamed roots are dried. as an alternative, it can also inactivate enzyme activity by boiling the root in water. however, the boiling process will significantly reduce the content of gastrodin, which will further reduce the quality of medicinal materials (xiao, 2017) . accordingly, it is necessary to investigate the effects of processing methods on the quality formation of different active ingredients in medicinal crops, thereby providing optimum processing methods that will obtain the maximum yield of products for the industrial production of traditional chinese medicinal materials. baikal skullcap (scutellaria baicalensis georgi) is a perennial herb in the lamiaceae family and its dried root is used as a famous traditional chinese medicine, which was first recorded in the shen-nong-ben-cao-jing (the classic of herbal medicine) for the treatment of diarrhea, dysentery, hypertension, hemorrhaging, insomnia, inflammation, and respiratory infection (zhao et al., 2016a; fig. 1) . as one of the most commonly used chinese medicinal materials in china, it has been used as medicinal materials for more than 2000 years since being recorded in the ancient medical books. up to date, it has been included in over 90 % tcm formulas for treating cold (national pharmacopoeia committee, 2015) . modern pharmacological studies show that the active ingredients of s. baicalensis have important pharmacological effects such as anti-oxidation, anti-bacterial, anti-viral, anti-tumor, and anti-inflammation (ma et al., 2018; wu et al., 2018a wu et al., , 2018b park et al., 2011; zhao et al., 2007; gao et al., 1999) . specifically, it is recently found that s. baicalensis has significant curative effects on the treatment of covid-19 su et al., 2020) . the main pharmaceutical active ingredients are flavonoids, of which the glycosides (e.g., wogonoside) and the aglycones (e.g., baicalein, wogonin) have the strongest medicinal activities (fig. 2) . among them, the content of baicalin is determined as the main evaluation index and quality control of s. baicalensis by the pharmacopoeia (national pharmacopoeia committee, 2015) . due to its great medicinal values, there is a huge market demand for s. baicalensis every year and it is becoming one of the top ten sales of chinese medicinal materials in china (zhao et al., 2016a) . before the 1990s, the products of s. baicalensis are mainly originated from wild resources. since the 21 st century, the decreasing wild resources of s. baicalensis were far from meeting the rapidly increasing market demand of pharmaceutical use. accordingly, the market share of cultivated varieties has been increasing after extensive cultivation of s. baicalensis (su et al., 2008) . for the industrial production of s. baicalensis, the harvesting time and processing in producing areas are considered as the key factors for the quality formation of medicinal materials . since s. baicalensis is a perennial herb, its stele of the root gradually decays from the base after growing for about 4 years (known as "hollow roots") ( fig. 1) . although it has been recorded in the classical prescriptions and the medical classics that the hollow roots of s. baicalensis has the best curative effect in tcm, the theoretical basis of this statement remains unclear. meanwhile, the factor of harvesting time is very important for the quality and yield of medicinal materials as well as the income of farmers during the cultivation process. at present, the farmers and herbalists believe that harvesting time at two and a half years or three years can ensure the best quality, the highest yield, and the highest land use efficiency for s. baicalensis. however, there is no clear evidence to show whether the contents of medicinal active ingredients of s. baicalensis harvested at such time have the highest levels. in addition, the primary processing in producing areas (removing impurities, drying, slicing, etc.) is considered as another key factor that affects the contents of medicinal active ingredients. previous studies have shown that the contents of medicinal active ingredients in s. baicalensis after harvesting are closely related to enzyme activities in roots zhao et al., 2016b) . the active ingredients such as baicalin and wogonoside in fresh roots are easily reduced in enzyme solution under humid environment or washing and soaking in water (liu, 2015) . nevertheless, there is a lack of systematic research on the effects of post-harvest treatment and processing technology on the contents of medicinal active ingredients to reveal such mechanisms. taken together, it is of great theoretical significance and practical prospect to reveal the effects of different processing technology on the medicinal active ingredients under the background of increasing market demand for s. baicalensis. on the basis of our previous research in s. baicalensis over the past 15 years bai et al., 2018; guo et al., 2016; zhang et al., 2016; bai et al., 2013) , in this study we conducted a comprehensive study from the following aspects by taking eight medicinal active ingredients from the root of s. baicalensis as indicators: (1) the contents of active ingredients in roots of s. baicalensis from growing 1-15 years were compared and analyzed to determine the optimal harvest time; (2) six medicinal active ingredients in the parts of stele and cortex in roots of 2-year and 15-year old s. baicalensis were compared and analyzed to reveal the differences of active ingredients in different growth years; (3) the dynamic changes of the contents of active ingredients in fresh-crush and fresh-cut roots of s. baicalensis at room temperature were compared and analyzed to reveal the influence of post-harvest treatment on the contents of active ingredients; (4) the effects of six different post-harvest treatment on the contents of active ingredients were systematically designed and compared to determine the best primary processing technology. collectively, the above results will provide a theoretical basis for the scientific harvest and the primary processing in the producing area of s. baicalensis, and provide a reference for the selection of optimal processing technology of medicinal materials for the industrial production of medicinal crops. in this study, the germplasms of s. baicalensis from singe genetic source (originated from the main producing area in shaanxi province) were planted from 2004 to present in the germplasm resources garden for medicinal plants in shaanxi normal university (n34 • 09 ′ , e108 • 54 ′ ), xi'an, china. to determine the age of s. baicalensis for further experiments, the germplasms with different growth years were planted separately in the garden. for experiments regarding different ages, the root samples were collected from three plants of s. baicalensis with similar phenotypic and physiological characters of each age group (planted in 2004, 2007, 2010, 2012, 2014, 2015, 2016, 2017, and 2018) (table s1) . for experiments regarding different storage time and different processing methods, the root samples were collected from three plants of s. baicalensis with similar phenotypic and physiological characters planted in 2017. for experiments regarding different parts, the samples of cortex and stele were collected from three plants of s. baicalensis with similar phenotypic and physiological characters planted in 2017. all the plant samples of s. baicalensis were harvested in september 2019. after removing sediment and impurities, the samples were prepared for further experiments. to obtain the maximum yield of active ingredients, six different postharvest processing methods were designed based on traditional technology in this study. the six treatments for processing the roots of s. baicalensis were listed as following (d for drying, s for steaming, and c for slicing, respectively): d treatment: fresh whole roots were dried at 80 • c in oven (101-2a, taisite, tianjin, china) to constant weight, and then crushed and filtered through a 60-mesh sieve; d-s-c-d treatment: fresh whole roots were dried at 80 • c in oven to constant weight, softened by steam for 20 min, then sliced and dried, and finally crushed and filtered through a 60-mesh sieve; d-s-c treatment: fresh whole roots were dried at 80 • c in oven to constant weight, softened by steam for 20 min, then crushed directly after slicing, and finally filtered through a 60-mesh sieve; c-s-d treatment: fresh whole roots were cut into slices, softened by steam for 20 min after slicing, dried to constant weight at 80 • c in oven, and finally crushed and filtered through a 60-mesh sieve; s-c-d treatment: fresh whole roots were softened by steam for 20 min, cut into slices, dried to constant weight at 80 • c in oven, and finally crushed and filtered through a 60-mesh sieve; c-d treatment: fresh whole roots were cut into slices, dried to constant weight at 80 • c in oven, and finally crushed and filtered through a 60-mesh sieve. after collecting the fresh roots of s. baicalensis, the soil was removed and the surface moisture of roots were dried. the dried roots were then sliced quickly and mixed thoroughly. the fresh slices were divided into two parts. one was crushed directly and another was left untreated. the two groups of samples were placed in a petri dish, sealed with plastic wrap to retain water, and then stored at room temperature for 0 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 8 h, 11 h, 22 h, 23 h, 24 h, and 25 h, respectively. finally, these samples were immediately placed in a 10 ml centrifuge tube, quick-frozen with liquid nitrogen, and stored at -80 • c. after completely frozen, these samples were freezedried at -80 • c for 6 h using freeze dryer (gold-sim, newark, usa), and then crushed and filtered through a 60-mesh sieve. the extraction and measurement of eight active ingredients (baicalin, scutellarin, chrysin, scutellarein, wogonoside, apigenin, wogonin, and baicalein) were conducted using our previous protocol . first, 0.5 g dried sample was accurately weighed and placed in a centrifuge tube. then the sample was added with 20 ml 70 % ethanol. after 30 min of ultrasonic treatment (500 w, 80 khz), the sample was cooled to room temperature, and then filtered and the filtrate was collected. next, 20 ml 70 % ethanol was added to the residue followed by sonicating for 30 min under the same condition. after filtration, the two filtrates were combined into a 50 ml volumetric flask and 70 % ethanol was added to the scale line. then the sample was filtered through a 0.22 μm filter after thoroughly mixing to obtain the sample solution. the eight medicinal active ingredients of samples were extracted using high-performance liquid chromatograph (hplc) (thermo fisher scientific, new york, usa) (fig. 3) . the determination condition was as below. mobile phase: acetonitrile to 0.1 % formic acid. gradient elution: 0 ~ 10 min, 10 % ~ 15 % acetonitrile; 10 ~ 20 min, 15 % ~ 20 % acetonitrile; 20 ~ 30 min, 20 % ~ 25 % acetonitrile; 30 ~ 60 min, 25 % ~ 45 % acetonitrile; 60 ~ 65 min, 45 % ~ 10 % acetonitrile. flow rate: 1.0 ml/min. detection wavelength: 274 nm. column temperature: 30 • c. sample size: 10 μl. for the generation of standard curves, the standards of the eight active ingredients were prepared with a concentration of 5 × 10 − 4 mg/ μl. the eight standards were then injected with volumes of 1, 2, 4, 6, 8, 10, 12, 14, 16, and 20 μl, respectively, and were detected at wavelength of 274 nm. the peak area values of each standard were recorded. the linear regression equations were then calculated using the sample volume of standards as abscissa (x) and the peak areas as ordinate (y) (fig. 4) . for the quantity evaluation of estimated samples, the peak values of each active ingredient were substituted to the linear regression equations to obtain the sample sizes. then the content of each active ingredient of 10 μl was calculated by multiplying by the concentration of standards (5 × 10 − 4 mg/μl). finally, the contents of the eight active ingredients of samples (mg/g) were calculated by multiplying by the dilution ratio. the data of this study were analyzed using ibm spss statistics (version 22.0). for the analysis of the contents of eight active ingredients of different growth years, the analysis of variance (anova) was conducted. the growth years were chosen as dependent list, and the content of each active ingredients was chosen as factor. the lsd pattern was used as equal variances assumed. the options of "descriptive" and "homogeneity of variance test" were selected. for the comparisons of the contents of active ingredients among different part, different storage time, and different processing methods, the nonparametric tests for each group of data was first conducted. the differences of data were then analyzed using student's t-test. p ≤ 0.05 indicates statistically significance. to investigate the effects of growth years on the contents of active ingredients in s. baicalensis, the roots with different growth years (ranging from 1-15) were collected and then dried at 80 • c in oven after removing sediment and impurities. the contents of eight medicinal active ingredients were further estimated ( table 1 ). the results showed that the contents of baicalin in roots of s. baicalensis in different growth years were all higher than 12 % (corresponding to 120 mg/g), which met the minimum requirement of the pharmacopoeia (2015 version; 9%, corresponding to 90 mg/g) and could be used as medicinal materials (national pharmacopoeia committee, 2015) . further anova analysis showed that the content of baicalin exhibited a "v" trend changing with growth years (table 1) . it is relatively high at both ends (2 years old and older than 7 years old) but low at the middle period (3-5 years old). in general, the total amount of the four main active ingredients (baicalin, wogonoside, baicalein, and wogonin) (13.5 %, corresponding to 135 mg/g; national pharmacopoeia committee, 2020) in roots of s. baicalensis showed the following trend: 15 years > 9 years > 2 years > 7 years > 12 years > 3 years > 5 years > 4 years >=1 year. among them, the total content of the four main active ingredients in 15-year-old roots was as high as 190 mg/g, followed by that of 9-year-old roots (185.57 mg/g). the content of 2-year-old roots reached 180 mg/g, which was significantly higher than that of 1-year-old roots (149.73 mg/g) (p ≤ 0.05). for the other four active ingredients (scutellarin, scutellarein, chrysin, and apigenin) with lower contents, they also showed significant differences among different growth years ( table 1 ). the contents of scutellarein and scutellarin were significantly lower than those of all the four main active ingredients (p < 0.001). for the former, its content continued to increase in the first three years and remained basically stable after the fourth year. while for the latter, its content continued to decrease with growth years, and reached the lowest level (0.03 %) in 15-year-old roots. conversely, for chrysin which is the precursor of baicalin, wogonoside, baicalein, and wogonin in the flavonoid synthesis pathway, its content reached the highest level (about 0.08 %) in 15-year-old roots. to further reveal the mechanism regarding the "v" trend of the contents of the four main active ingredients, we next investigated the disparity of active ingredients in different parts (cortex and stele). for s. baicalensis, as the growth period increases, the part of stele in the whole root gradually decays, and the proportion of cortex increases rapidly. our results showed that the contents of active ingredients including baicalin, wogonoside, baicalein, and wogonin in cortex were significantly higher than those in stele (p ≤ 0.05, fig. 5) . thus, the contents of older roots (rotten stele, older than 4 years) were significantly higher than those of younger roots (non-rotten-stele, not older the contents of six active ingredients (from a to e: baicalin, wogonoside, scutellarin, baicalein, wogonin, and scutellarein) in whole root, cortex and stele of 2-yearold and 15-year-old s. baicalensis were estimated and compared. data were presented as mean ± sd. *p ≤ 0.05, **p ≤ 0.01 (student's t test). than 4 years). the proportion of stele and cortex in the root of 2-yearsold s. baicalensis was balanced, so the content of four active components retained high levels. however, for 3-to 5-year-old s. baicalensis, the enlargement of roots was mainly due to the rapid growth of stele. therefore, the contents of active ingredients were relatively low. when s. baicalensis grows for more than three years, the part of stele in the whole roots begin to rot and the proportion of cortex increases year by year. meanwhile, the contents of six main active ingredients in 15-yearold roots of s. baicalensis were significantly higher than those in 2-yearold roots (fig. 5) . further comparative analysis of the contents of six active ingredients in cortex and stele revealed that the contents of five medicinal active ingredients (baicalin, wogonoside, scutellarin, baicalein, wogonin) in the cortex of 2-year-old and 15-year-old s. baicalensis were all significantly higher than those of the stele (p ≤ 0.05) except for scutellarein. however, the contents of baicalin, wogonoside, scutellarein in the stele of the roots of 2-year-old s. baicalensis were all significantly higher than those of the cortex. the contents of baicalein and wogoninin in the stele of 15-year-old s. baicalensis were all significantly higher than those of 2-year-old s. baicalensis. the above results indicated that the contents of active ingredients in s. baicalensis tended to decrease with the increase of growth years (more than 3 years). since the stele began to rot after several years, the proportion of cortex in roots increased year by year. due to the great difference of the contents of active ingredients in cortex and stele, the contents of six medicinal active ingredients in the whole root of 2-year-old s. baicalensis was lower than that of 15-year-old s. baicalensis, but it was higher than that of 3-to 5-year-old s. baicalensis. collectively, these results will give reasonable interpretations why s. baicalensis with rotten stele is taken as top-quality products in tcm, thereby providing theoretical basis for determining the best harvesting time as 2 or 2.5 years. in general, the plant of s. baicalensis needs to be dried after harvesting in the primary processing process. during the subsequent extracting process, it will be softened with water or steam, and then sliced, and finally dried for extraction. thus, it is of great importance to investigate how the storage time before extraction affects the contents of active ingredients in the industrial production of s. baicalensis. in this study, the fresh roots of s. baicalensis were directly crushed after removing sediments. the samples were then stored for different times at room temperature to reveal the trend of the contents of eight active ingredients changing with storage time. the results showed that the contents of chrysin, baicalein, wogonin and scutellarein in the freshcrushed roots of s. baicalensis increased from 0 h to 25 h at room temperature (fig. 6) . among them, the contents of chrysin and wogonin showed similar trend, and then they reached the highest level at 25 h (dry weight: 1.97 mg/g and 13.94 mg/g, respectively), which were 6.0 % and 10.9 % higher than those in the beginning time (0 h). the content of baicalein increased slowly, reaching a stable level at about 38.84 mg/ g after 2 h. on the contrary, the contents of baicalin and wogonoside continued to decline with the extension of storage time, and tended to be stable at around 22 h. the two active ingredients decreased from 95.67 mg/g and 17.89 mg/g (0 h storage) to 5.04 mg/g and 1.13 mg/g (22 h storage), with decreases of 94.7 % and 93.7 %, respectively. in particular, the contents of baicalin and wogonoside decreased significantly from 0 h to 1 h. the content of apigenin showed a generally downward trend with the extension of storage time, and it rebounded at 3 h-4 h with a peak of 0.03 mg/g, and then continued to decline after 4 h. collectively, the above results showed that the storage time at room temperature had a significant effect on the eight active ingredients in fresh-crushed roots of s. baicalensis. according to the trends of active ingredients to be extracted, specific extraction process should be developed for the industrial production of s. baicalensis. in traditional processing methods, the roots of s. baicalensis are dried after harvesting, and then softened by steam or boiling water, which is convenient for further cutting. however, this process takes a long time and consumes energy. moreover, the contents of effective active ingredients in the slices will decrease once the dried roots are softened with steam or boiling water. it is not clear how the active ingredients change after the fresh roots of s. baicalensis were cut to slices and then placed at room temperature for different times. in this study, the fresh slices of roots of s. baicalensis were stored for different times at room temperature, and then the contents of active ingredients were determined after drying and comminuting. the results showed that the contents of baicalein (fig. 7a) , wogonin (fig. 7b) , and chrysin (fig. 7e) gradually increased with the extension of storage time at room temperature, reaching the maximum of 0.39 mg/g, 12.67 mg/g and 1.67 mg/g, respectively at about 25 h. compared with those at 0 h, the contents of baicalin (fig. 7a) , wogonoside (fig. 7b) , and scutellarin ( fig. 7c ) all decreased significantly with the extension of storage time, but were observed with a repeated fluctuation at different storage time. comparatively, the two active ingredients apigenin (fig. 7d ) and scutellarein (fig. 7c) had relatively low contents with a gradually increasing trend, reaching a maximum of 0.053 mg/g and 0.091 mg/g, respectively, at storage time of 25 h. the above results indicated that the contents of baicalin, wogonoside, and scutellarin in the slices of fresh roots of s. baicalensis will significantly reduce as the storage time increases, but the reduction of fresh-cutting was significantly lower than that of fresh-crushing. the above results demonstrated that the eight medicinal active ingredients exhibited increasing or decreasing trends changing with storage time after crushing the fresh roots of s. baicalensis at room temperature. to investigate whether there exist correlations among the changes of active ingredients, we further conducted correlation analysis on the contents of different active ingredients. the results showed that there was significant negative correlations between the contents of baicalin and baicalein (correlation coefficient: -0.815, p < 0.0001, fig. 8a ), as well as the contents of wogonoside and wogonin (correlation coefficient: -0.998, p < 0.0001, fig. 8b ), indicating that there exists mutual conversion between baicalin and baicalein, and between wogonoside and wogonin. the contents of baicalein and wogonin increase significantly with the extension of storage time, while the contents of baicalin and wogonoside decrease significantly. on the contrary, the contents of scutellarin and scutellarein (fig. 8c ) have a very significant positive correlation with correlation coefficient as high as 0.95 (p < 0.0001). the contents of several other ingredients were relatively low, and the correlations among them were not significant (p > 0.05). these results suggested that the secondary metabolism in fresh roots of s. baicalensis had not been stopped after crushing, and there were still mutual transformations among different components. in recent years, the market demand for the raw medicinal materials of s. baicalensis is growing, with the development of pharmacological studies (yuan et al., 2010) . specifically, pharmaceutical enterprises mainly focus on how to obtain the maximum contents of active ingredients in medicinal materials. in this study, six different post-harvest treatments were designed and used to systematically reveal the effects of different processing treatments on the contents of eight medicinal active ingredients ( table 2 ). the results showed that the contents of four main active ingredients (baicalin, wogonoside, baicalein, and wogonin) under d and c-d treatments were significantly higher than those of the other four treatments (p ≤ 0.05), indicating that the active ingredients in roots of s. baicalensis lost considerably after softening treatment by steam. the contents of the other four medicinal active ingredients were all lower than 0.06 % (corresponding to 0.6 mg/g), which were significantly lower than those of the four main active components in roots (p ≤ 0.05). among the six different treatments, the contents of baicalin were all higher than 10 %, which was in accordance with the standard of the pharmacopoeia. the highest content was observed in d treatment (134.54 mg/g), followed by c-d treatment (129.48 mg/g). the contents of baicalin and wogonoside of d-s-c treatment were the lowest (104.09 mg/g and 18.27 mg/g, respectively). collectively, the above results suggested that pharmaceutical companies should adopt appropriate processing treatments according to the characteristics of medicinal materials, since the active ingredients were significantly influenced by processing methods. for instance, the crushing process after direct drying (c-d treatment) is very suitable for improving the yield of active ingredients. in addition to the d-s-c treatment (cutting after drying and softening), the c-s-d treatment (killing enzyme by steam after cutting, and then drying the slices) is a potential processing method for the industrial production of s. baicalensis. recent studies have revealed that there exists conversion among different active ingredients in plants, and only one active ingredient is difficult to reflect the quality and stability of medicinal materials (li et al., 2020b) . accordingly, in the latest release of chinese pharmacopoeia, it is stipulated that the total content of baicalin, wogonoside, baicalein, and wogonin should not less than 13.5 % for s. baicalensis (national pharmacopoeia committee, 2020) . in this study, the total content of four main active ingredients in the root of s. baicalensis treated with six different processing treatments was further analyzed (fig. 9) . the results showed that the total content of the four main active ingredients of s. baicalensis roots under d treatment was the highest (166.47 mg/g), followed by that of c-d treatment (163.15 mg/g), which was much higher than the standard of 13.5 % (corresponding to 135 mg/g) stipulated in the chinese pharmacopoeia (2020) (national pharmacopoeia committee, 2020). for s. baicalensis roots under d-s-c treatment, the total content of the four main active ingredients decreased to 125.33 mg/g, which was below the minimum requirement of 13.5 % by the pharmacopoeia. the total contents of the four main active ingredients under d-s-c-d, c-s-d, and s-c-d treatments were 153.88 mg/g, 155.64 mg/g, and 151.29 mg/g, respectively, which were all lower than those of d treatment (16.6 %) and c-d treatment (16.32 %), but were higher than the minimum requirement of 13.5 %. collectively, the above results indicated that different post-harvest processing treatments had significant effects on the total contents of medicinal active ingredients of s. baicalensis. specifically, the d-s-c-d treatment can be adopted for the medicinal materials used in traditional formulations of chinese medicine, while the d and c-d treatments can be used in industrial production since neither of the two treatments significantly reduce the total content of four main active ingredients in medicinal materials. compared with d and c-d treatments, the total content of the four main active ingredients under c-s-d treatment significantly decreased. nevertheless, the traditional processing treatment (d-s-c-d) requires four steps including drying, softening, cutting, and drying treatment, which is considered to high consumption of energy and time. in contrast, the c-s-d treatment with energy conservation and high efficiency is a potential processing technology to be further studied in the future. the contradictions between harvesting years and contents of active ingredients have long been the primary issue for the industrial production of medicinal crops (saha and basak, 2020; wang et al., 2017) . at present, the medicinal materials of s. baicalensis used in pharmaceutical industry are mostly collected from cultivation resources. according to our field investigation as of may 2020, the cultivated area of s. baicalensis is more than 26,000 ha in china, with an annual production of about 60,000 tons for raw materials. however, an emerging challenge faced by herbalists and pharmaceutical enterprises is how to obtain the maximum yield of active ingredients from limited medicinal materials. for s. baicalensis, its root gradually grows thicker, and the production of medicinal materials increases with cultivation years. however, the yield of active ingredients showed different regular patterns changing with growth years . in this study, the contents of four main medicinal active ingredients (baicalin, wogonoside, baicalein, and wogonin) showed a changing trend of "v" type from 1-year-old to 15-year-old s. baicalensis, indicating that the contents of 2 or 3 growth years and 15 growth years were higher than those of 4 or 5 growth years. the main reason is mostly due to the age of plant tissues. as the growth year increases, the phenotypic, biochemical, and physiological characters (e.g. leaf area, chlorophyll content) of plants change gradually. previous studies have found that leaf area as well as chlorophyll content have critical effects on the contents of primary and secondary metabolites of crops (munz et al., 2018; senger et al., 2014; hudina and š tampar, 2002) . for s. baicalensis, its capacity of sugar biosynthesis increases with growing leaf area and chlorophyll content, thereby increasing the contents of secondary metabolites (e.g. the four main active ingredients). however, the increasing leaf area will also lead to more consumptions of organic matters through cellular respiration. thus, there exists a trade-off between accumulation of secondary metabolites and consumption of organic matters. this is rational to explain the "v" type trend of active ingredients of 1-year-old to 15-year-old s. baicalensis. in addition, another reason is probably the significant differences of the contents of active ingredients between cortex and stele in roots of s. baicalensis. in 2-year and 15-year old s. baicalensis, the contents of baicalin, wogonoside, scutellarin, scutellarein, baicalein, and wogonin in the part of cortex were significantly higher than those of stele (p ≤ 0.01, fig. 5) . previous studies have shown that baicalein and wogonin are mainly distributed in cortex, while baicalin and wogonoside are evenly distributed in both cortex and stele (wei et al., 2015) . meanwhile, it is found that the contents of baicalin, wogonoside, baicalein, and wogonin in roots of 2-years-old s. baicalensis is higher than that of 1.5-year and 3-year-old s. baicalensis (chen and hu, 2006; li et al., 2008) . after growing for more than 3 years, the part of stele in the table 2 the contents of eight medicinal active ingredients of s. baicalensis under different treatments (mg/g). the contents of medicinal active ingredients (dry weight, mg/g) note: different letters indicate significant differences of the content of each medicinal active ingredient in the same column (p ≤ 0.05). whole root will gradually decay, and the proportion of cortex will increase year after year. therefore, the contents of five medicinal active ingredients in roots of s. baicalensis older than 4 growth years are significantly higher than those of 2 growth years. considering only land use efficiency and product yield, the contents of active ingredients, and the yield of medicinal materials in perennial s. baicalensis (more than 3 years) were both higher than those of 2 years. however, the increment of yield per hectare and per year significantly reduced in s. baicalensis growing over three years (table 1) . moreover, the increment of economic benefit per unit area and per year significantly reduced with growing years of land utilization. in addition, for s. baicalensis growing more than 3 years, the part of stele in the whole root will gradually rot and the proportion of cortex will increase. the contents of baicalin, wogonoside, scutellarin, baicalein, and wogonin in cortex were significantly higher than those in stele (p < 0.001) (fig. 5) . thus, the contents of active ingredients in roots (with decayed stele) growing more than 3 years is significantly higher than that of roots (without decayed stele) growing less than 3 years. taken together, the best harvesting year of s. baicalensis is determined as cultivated 2-3 years based on comprehensive evaluation of the content of medicinal active ingredients, the increment of annual yield, and the efficiency of land utilization. collectively, the above results not only gave interpretations for the differences of medicinal active ingredients in different growing years and different parts of roots, but also provided valuable references that old s. baicalensis (rotten or hollow stele) was best quality of chinese medicinal materials in ancient pharmacopoeia. the duration of storage time is also an important factor that effects the yield of active ingredients. in traditional processing of s. baicalensis products, the farmers usually dried the roots immediately in the sun after harvesting, and then softened the dried roots with steam and cut the soft roots into slices. finally, the dried slices were sold to pharmaceutical companies or hospitals for further processing. typically, this process will take considerable time and lead to loss of active ingredients. thus, new processing approaches are needed to solve this problem. reducing the effect of storage time is a potential way to achieve such gorals. for the industrial production of s. baicalensis, it will greatly improve efficiency and reduce cost if the fresh roots are directly used for the extraction of medicinal active ingredients. however, the medicinal active ingredients of s. baicalensis are mainly flavonoids, which are secondary metabolites synthesized by a variety of key enzymes (zhao et al., 2016b) . it is necessary to systematically reveal how the contents of active ingredients changes with the prolongation of storage time at room temperature after crushing or cutting, thereby determining whether the processing methods are effective and reliable. previous studies have demonstrated that the four main medicinal active ingredients (baicalin, wogonoside, baicalein, and wogonin) in roots of s. baicalensis are located in the downstream of flavonoid synthesis pathway (zhao et al., 2016b) . glycosides and aglycones can be mutually transformed by the enzymes of udp-glucuronate: baicalein 7-o-glucuronosyltransferase (ubgat) (nagashima et al., 2000) and glucuronidase (gus) (sakurama et al., 2013) . when the plant of s. baicalensis is affected by external stress environment, the cells will produce a large amount of h 2 o 2 (fu et al., 2018) . baicalin, a glycoside component in roots of s. baicalensis, is immediately hydrolyzed to baicalein (an aglycone component) under the action of gus (dikaya et al., 2018; matsuda et al., 2000) . in this study, we revealed the dynamic change of the effects of storage time on the contents of eight active ingredients in fresh-crushed and fresh-cut roots at room temperature. the results showed that the contents of glycosides (baicalin and wogonoside) decreased linearly with the extension of storage time after the fresh roots were crushed or cut, while those of aglycones (baicalein and scutellarin) increased linearly (p ≤ 0.01). these results indicated that the secondary metabolism in tissues of fresh roots did not stop immediately after crushing or cutting. with the extension of storage time at room temperature, the ubgat enzyme hydrolyzed the glycosides to produce glucuronic acid and aglycones in suitable conditions. based on these observations, the best processing methods for the extraction of active ingredients should be determined according to characteristics of specific products. for instance, for the extraction of chrysin, baicalein, and wogonin, the fresh slices should be stored at room temperature (22 • c) for more than 25 h after roots were fresh-crushed or fresh-cut. on the contrary, for the extraction of baicalin, wogonoside, and apigenin, the fresh slices should be extracted as soon as possible after roots were fresh-crushed or fresh-cut. compared with fresh-crushing treatment, the content of glycosides under fresh-cutting treatment in roots has a little decrease. collectively, the processing technology for fresh-crushed or fresh-cut roots of s. baicalensis should be further studied in the future. among the factors (excellent germplasm, cultivation area, water and fertilizer management, pest control, growth years, harvesting time, etc.) that affect the quality of chinese medicinal materials, the post-harvest processing has a great impact on the content of medicinal active ingredients, which would further affect the clinical efficacy and stability of tcm (wu et al., 2018a (wu et al., , 2018b xiao et al., 2016; zhao et al., 2010) . for s. baicalensis, the traditional post-harvest processing technology is to remove impurities after harvesting and to dry naturally in sun. generally, it will not directly kill the enzymes in fresh roots of s. baicalensis using steam. instead, the dried roots will be softened by steam, and then cut to slices, and finally to be dried again. previous studies have confirmed that steam treatment is better than water boiling treatment to soften the dried roots of s. baicalensis (liao, 2006) . the former has high temperature, strong penetration and good enzyme-killing effect, while the latter has the dried roots expose to water with slower softening speed so that some glycoside components will be dissolved in water (qin et al., 2017; liao et al., 2007) . therefore, the steam treatment is used to soften dried roots and to kill enzyme activity before cutting to slices, thereby preventing the content of glycosides from decreasing in traditional methods. in recent years, a series of new drugs including extracts, drop pills, formula particles and injection originated from s. baicalensis have been developed, leading to increasing demands for the raw medicinal materials of s. baicalensis. thus, it is bringing urgent needs that novel processing approaches should be proposed accordingly based on the traditional methods. to develop effective and reliable processing methods, a primary issue is that it remains unclear how the different treatments and processing technology affect the contents of medicinal active ingredients. in this study, we systematically designed six kinds of processing and technology according to several traditional treatments of post-harvest processing of s. baicalensis. the total contents of the four main medicinal active ingredients in roots of s. baicalensis using different processing treatments after harvest were shown as (from high to low): d > c-d > c-s-d > d-s-c-d > s-c-d > d-s-c (table 2) . among them, the total contents of four main active ingredients of c-d treatment declined markedly compared with those of d treatment, which may be related to the fact that baicalin and wogonoside can be transformed into baicalein and wogonin by the key enzyme ubgat during the cutting process of fresh roots of s. baicalensis (nagashima et al., 2000) . compared with other treatments of softening and slicing, the contents of active ingredients under d treatment (drying and cutting directly) have the highest levels, indicating that this treatment could effectively reduce the loss of active ingredients during the processing process. for traditional methods, it is very difficult to cut the dried roots to slices following the d treatment. meanwhile, the cutting process of dried root is easy to form debris and irregular particles, which will not pass the quality control for use in medicine. however, for pharmaceutical enterprises, it is easy to cut the dried roots directly and then extract effective active ingredients including baicalin, wogonoside, and other ingredients. as a traditional processing method, the d-s-c-d treatment typically softened the dried roots first and then cut to slices. the contents of active ingredients under such treatment is significantly higher than those of d-s-c treatment (drying-softening-cutting) (p ≤ 0.05). this result is related to the fact that moisture is often absorbed into dried roots during the process of steaming and wet roots that are not dried in time. therefore, the baicalin in roots is susceptible to be hydrolyzed into other components in moisture conditions by steaming. to prevent the reduction and conversion of glycosides, the most effective treatment should be killing the enzyme activity by steaming. in the industrial production, the steam treatment and the drying treatment with high temperature can kill the enzyme in roots of s. baicalensis to prevent the reduction or conversion of baicalin. for the efficiency of killing enzyme activity in fresh root slices of s. baicalensis, the result showed that the contents of medicinal active ingredients with drying and cutting treatment (c-d) are higher than those of c-s-d treatment (cutting-softening-drying). the most possible reason should be that the enzyme activity quickly lost under high temperature during the drying process, while the moisture could transform glycosides into aglycones in the process of steaming treatment. meanwhile, the other active components are reduced and lost with the condensation and dissolution of water vapor. the contents of active ingredients of c-s-d treatment are higher than those of s-c-d treatment. this result may be related to that the enzyme inactivation is faster and more complete in c-s-d treatment. consequently, the dried slices can retain more active ingredients in roots of s. baicalensis. in traditional processing methods, the roots of s. baicalensis need to be dried twice (one for killing enzyme activity by steam, while another for cutting to slices), which is energy-consuming and time-consuming. therefore, it is necessary to optimize the traditional processing technology of s. baicalensis to minimize energy consumption during the drying process and the softening treatment by steam. a prospective strategy is that the fresh medicinal materials being cut into slices and processed after harvest in the original cultivated areas, which will not only save time and energy during the processing process, but also maintain the quality of medicinal materials . in recent years, researchers have paid more attention to the processing technology of chinese medicinal materials using fresh slicing on the premise of ensuring the quality (tang et al., 2010) . specifically, it is clearly proposed that further studies should focus on the deep processing technology of fresh-cutting for medicinal materials in the protection and development plan of chinese medicinal materials (2015-2020). up to date, a series of studies aimed at reducing the effects of softening in dried medicinal materials and exploring the fresh-cutting methods have been reported in chinese medicinal materials including common peony (paeonia lactiflora pall.) (jin et al., 2011) , dan shen (salvia miltiorrhiza bge.) , and cassia bark tree (cinnamomum cassia presl) (luo et al., 2017) . inevitably, the traditional processing technology (d-s-c-d) for s. baicalensis have the issues of mutual conversion and hydrolysis of active ingredients. our results first demonstrated that the c-s-d treatment of s. baicalensis would be a candidate of optimal processing approaches that produce the maximum yield of active ingredients. the comparative analysis results of six processing technology in this study showed that the total contents of eight active ingredients and four main active ingredients in roots of s. baicalensis were less affected under c-s-d treatment than that of the traditional processing technology (d-s-c-d). collectively, the processing technology of fresh-cutting for s. baicalensis will become the mainstream processing technology with cost-saving, environment-friendly and energy-saving for the extraction of active ingredients in pharmaceutical enterprises in the future, which is of epochal significance for accelerating the modernization of traditional chinese medicinal materials. in this study, we first revealed the effects of growth years and postharvest processing on the contents of medicinal active ingredients of s. baicalensis. by estimating the contents of eight active ingredients (baicalin, wogonoside, baicalein, wogonin, scutellarin, scutellarein, apigenin, and chrysin) in roots of s. baicalensis of different growth years (ranging from 1 year to 15 years) using hplc, we conducted a systematic analysis to determine the optimal harvest period of this important medicinal crop. our results showed that the best harvest period for s. baicalensis should be determined as 2-3 years based on comprehensive evaluation of active ingredient content, annual yield increment, and land use efficiency. meanwhile, we compared the contents of six active ingredients in different parts (cortex and stele) of roots of s. baicalensis, and monitored the dynamic changes of the contents of active ingredients in fresh-crush and fresh-cut roots of s. baicalensis at room temperature. in addition, we observed the effects of six different post-harvest treatments on the contents of active ingredients to determine the best primary processing technology. we concluded that the contents of baicalin, wogonoside, baicalein, and wogonin in cortex were significantly higher than those in stele (p ≤ 0.05). the contents of four main active ingredients (baicalin, wogonoside, baicalein, and wogonin) under drying (d) and cutting-drying (c-d) treatments were significantly higher than those of the other four treatments (p ≤ 0.05). collectively, these results will provide valuable references for determining the optimal harvesting and processing technology that will obtain the maximum products of active ingredients for s. baicalensis. furthermore, the processing methods of softening, cutting, and drying proposed in this study 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new insights into benzylisoquinoline alkaloids metabolism scutellaria baicalensis extract and baicalein inhibit replication of sars-cov-2 and its 3c-like protease in vitro study on the feasibility of fresh cutting of cinnamomum cassia presl can chinese medicine be used for prevention of corona virus disease 2019 (covid-19)? a review of historical classics, research evidence and current prevention programs san wu huangqin decoction, a chinese herbal formula, inhibits influenza a/pr/8/34 (h1n1) virus infection in vitro and in vivo evidences for diabetes and insulin mimetic activity of medicinal plants: present status and future prospects histochemical investigation of β-glucuronidase in culture cells and regenerated plants of scutellaria baicalensis georgi artemisinin: discovery from the chinese herbal garden an efficient protocol for clonal regeneration and excised root culture with enhanced alkaloid content in thalictrum foliolosum dc. -an endemic and important medicinal plant of temperate himalayan region leaf area index, light interception, growth and steviol glycoside formation of stevia rebaudiana bertoni under field conditions in southwestern germany optimization of microwave-assisted extraction recovery of bioactive compounds from origanum glandulosum and thymus fontanesii purification and characterization of udp-glucuronate: baicalein 7-o-glucuronosyltransferase from scutellaria baicalensis georgi. cell suspension cultures pharmacopoeia of the people's republic of china. china medical science and technology press characterization of hot-air drying and infrared drying of spearmint (mentha spicata l.) leaves antioxidant and α-glucosidase inhibitory activities of different solvent extracts of skullcap (scutellaria baicalensis) effects of different softening methods on the baicalin content of baicalin decoction pieces traditional chinese medicine for covid-19 treatment scope of value addition and utilization of residual biomass from medicinal and aromatic plants β-glucuronidase from lactobacillus brevis useful for baicalin hydrolysis belongs to glycoside hydrolase family 30 genetic variation in leaf chlorophyll content of jatropha curcas l genetic characterization and phytochemical analysis of wild and cultivated populations of scutellaria baicalensis discovery of baicalin and baicalein as novel, natural product inhibitors of sars-cov-2 3cl protease in vitro study on feasibility of cutting process of fresh angelica sinensis radix plant molecular farming: much more than medicines the discovery of artemisinin (qinghaosu) and gifts from chinese medicine progress of studies on chinese herbal medicine storage method production of active compounds in medicinal plants: from plant tissue culture to biosynthesis green and efficient extraction of podophyllotoxin from sinopodophyllum hexandrum by optimized subcritical water extraction combined with macroporous resin enrichment a comprehensive review on phytochemistry, pharmacology, and flavonoid biosynthesis of scutellaria baicalensis study on the distribution and microstructure of active components in the root of scutellaria baicalensis georgi baicalein targets gtpase-mediated autophagy to eliminate liver tumor-initiating stem cell-like cells resistant to mtorc1 inhibition seeing the unseen of chinese herbal medicine processing (paozhi): advances in new perspectives plant metabolism, the diverse chemistry set of the future study on quality assessment and processing of tianma decoction pieces survey of investigations on daodi chinese medicinal materials in china since 1980s development and innovation of traditional chinese medicine processing discipline and chinese herbal pieces industry organ-specific metabolic shifts of flavonoids in scutellaria baicalensis at different growth and development stages recent advances in biosynthesis of bioactive compounds in traditional chinese medicinal plants the medicinal active ingredients and their associated key enzyme genes are differentially regulated at different growth stages in cornus officinalis and cornus controversa traditional chinese medicine in the treatment of patients infected with 2019-new coronavirus (sars-cov-2): a review and perspective impacts of recent cultivation on genetic diversity pattern of a medicinal plant, scutellaria baicalensis (lamiaceae) predicting suitable cultivation regions of medicinal plants with maxent modeling and fuzzy logics: a case study of scutellaria baicalensis in china recent applications of hydrophilic interaction liquid chromatography in pharmaceutical analysis plants for health: an ethnobotanical 25-year repeat survey of traditional medicine sold in a major marketplace in north-west yunnan study of antibacterial activity of active fraction from stems and leaves of scutellaria baicalensis georgi a unique issue in the standardization of chinese materia medica: processing the formation of daodi medicinal materials scutellaria baicalensis, the golden herb from the garden of chinese medicinal plants a specialized flavone biosynthetic pathway has evolved in the medicinal plant, scutellaria baicalensis study on feasibility of cutting fresh radix et rhizoma salviae miltiorrhizae in planting area supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.indcrop.2020.112985. key: cord-275813-iddn9onx authors: croddy, eric title: rat poison and food security in the people’s republic of china: focus on tetramethylene disulfotetramine (tetramine) date: 2003-10-09 journal: arch toxicol doi: 10.1007/s00204-003-0509-0 sha: doc_id: 275813 cord_uid: iddn9onx the last several years have seen a large number of mass poisonings in mainland china, particularly those caused by illicit rodenticides. one rat poison, tetramine (tetramethylene disulfotetramine) is responsible for a great percentage of death and injury in the people’s republic of china (prc). tetramine is an acutely toxic substance with human oral toxicity estimated as low as 0.1 mg/kg, and is widely available in open markets in mainland china—this despite being prohibited for manufacture or sale in the prc. being a gaba antagonist, and having an extremely potent effect on the brain stem, many victims can quickly fall into convulsions and die within hours following ingestion. with no known effective antidote at this time, clinical data from the prc show that acute cases of tetramine poisoning are extremely difficult to treat. the widespread use of tetramine—including its reported sale at a malaysian outdoor market in september 2002—could exacerbate its hazard to public health, particularly in those areas having large overseas chinese populations. throughout the 1990s and especially in recent years (2000) (2001) (2002) (2003) , mainland china has continued to experience a large number of accidental and deliberate poisonings due to chemical pesticides. during the last decade, public health authorities in the people's republic of china (prc) estimated that there have been 100,000 human cases of pesticide poisonings in china per year (wu and liu 2000) . this large figure is no doubt due in part simply to china's very large rural population, and because a significant percentage of its people are engaged in the agricultural sector. it is nonetheless alarming that rodenticides may alone be responsible for up to 70,000 annual poisonings in china. what is more, according to one beijing-based medical journal, a substantial portion of recent rodenticide poisonings in china have been deliberate (qiu et al. 2002) , in many cases involving the use of a relatively novel rodenticide, tetramethylene disulfotetramine, (tetramine, c 4 h 8 n 4 o 4 s 2 ; cas no. 80-12-6). the 2002 case described below is among the more recent and striking examples. in mid-september 2002, after becoming jealous of the business success enjoyed by a rival snack bar (the zhengwu pastry bar in nanjing), mr. chen zhengping (32) used rat poison to adulterate his competitor's foodstuffs. chen used an acutely toxic rodenticide consisting of the active ingredient tetramine. as a result, 42 people died and another 300 customers were poisoned after eating the tainted comestibles. on 16 september 2002, a day following the incident, chen was caught, while attempting to flee on a train, in zhengzhou (approximately 600 km northwest of nanjing). on 14 october 2002, having lost his appeal to a higher court in jiangsu province, chen zhengping was executed for murder (people's daily 2002) . tetramethylene disulfotetramine: a (not-so) novel rodenticide in 1949, chemists at bayer in germany published the synthesis of tetramine. a year later, incidentally, tetramine was found to be responsible for poisoning a large number of german furniture workers. it happened that the ''crinex'' wool used at the time had been made with a resin polymer that formed tetramine as a byproduct during processing (haskell 1956 ). further toxicological investigations discovered that tetramine was many times more toxic than strychnine, and one investigator noted in 1952 that the compound's ''high toxicity probably precludes its use as a rodenticide'' (richter 1954) (fig. 1) . still, a us patent was issued for the use of tetramine as a rat poison in 1953 (hecht et al. 1953 ). in the late 1950s, tetramine was used experimentally to discourage rodents and other scavengers from gobbling up douglas fir seeds in open fields during reforestation efforts in the united states. however, no known antidote yet exists in the event of accidental poisoning of humans or animals with tetramine. therefore, the wide application of this compound has been thought unsafe, and tetramine found very limited use in the west. tetramine falls into a category of cyclic compounds noted for their high toxicity in mammals (esser et al. 1991) . tetramine acts directly upon the brain itself, blocking the chloride channel of the inhibitory neurotransmitter receptor of c-amino butyric acid (gaba). very small amounts of tetramine, estimated as low as 0.1 mg/kg weight (oral ld 50 ) in mammals can lead to convulsions and death, with 7.0-10.0 mg/kg dosages considered lethal in humans (guan et al. 1993) ; the minimum lethal dose for humans has been estimated at about 5.0 mg/kg. the effects of tetramine can manifest themselves quickly, from about 30 minutes to a few hours following ingestion (tang et al. 2000) . symptoms of tetramine poisoning include fainting, epileptic seizures, incontinence, and foaming at the mouth. data compiled from laboratory animal studies are also instructive. one chinese medical journal described tetramine poisoning in mice the following way: ''after ingesting the bait, mice are poisoned acutely. they are excited. their tails straightened. they jump around, and occasionally screamed. it is followed by periodic or continuous spastic convulsion. their limbs become stiff. in some cases, this cycle repeats a few times. then, they die.'' (zhou et al. 1998) . clinical and anecdotal reports from the prc also noted hemoptysis among some victims of tetramine poisoning, but this symptom and its relationship to the toxicity of tetramine have not yet been satisfactorily explained. tetramine is all the more dangerous due to its high stability in water, making it a relatively persistent environmental contaminant. early investigators confirmed that tetramine remained equally toxic in water solution 6 weeks after being prepared. secondary and even tertiary poisonings with tetramine are entirely possible. roaming dogs that may eat rats poisoned with tetramine, for example, represent a potential threat to certain segments of the chinese population, as the chemical can remain at toxic levels in the tissues. in one hangzhou-based newspaper account, for example, a warning was issued concerning suspect dog meat being sold in a local market. (dushikuaibao 2001) . tragically, chinese physicians have more experience than anyone when it comes to the clinical treatment of tetramine poisoning. however, data are still incomplete as to effective treatment options. phenobarbital, when administered early, has been able to increase survivability of some victims of tetramine poisoning, while experimental use of vitamin b 6 and sodium dimercaptopropane sulfonate has shown promising results (qiu et al. 2002) . despite the large number of cases of tetramine poisoning in the prc, published clinical studies are somewhat difficult to find in the open literature. one article published in 2001, however, compiled data from 15 cases of tetramine poisoning that were treated in hunan province (xiangya hospital) over the course of a few years (1998) (1999) (2000) . in the authors' discussion of their experience in treating tetramine poisoning, the physicians noted the importance of gastric lavage for cases of acute poisoning. secondly, their empirical data suggest that plasma exchange treatment was the next best course of action. ''...[f]or 13 patients who exhibited convulsive symptoms, their condition rapidly improved following plasma exchange. although symptoms returned in some cases 12-24 hours afterwards, convulsions resolved following a second round of plasma exchange.'' finally, the authors emphasized that in acute cases of tetramine poisoning their results showed the need for aggressive therapy using anticonvulsants, therefore requiring an artificial airway: ''in securing an airway by intubation, combined with mechanical ventilation, one did not have to be reticent about administering large doses of tranquilizers for anticonvulsant therapy. furthermore, by doing so one could ascertain whether or not treatment of those critical cases will ultimately be successful.'' (li and zeng 2001) . except for tibet, open-source data from all mainland chinese provinces have recorded major poisoning epifig. 1 three different structural representations of the same compound, tetramine sodes involving prohibited rodenticides (zhou and deng 2002) . from 2000-2002, henan province alone saw 275 cases of rodenticide poisoning, 63 of these being fatal. most of these cases involved the rodenticide tetramine, variously sold as dushuqiang, sanbudao, and ''4-2-4,'' among other trade names. according to a chinese media source, at least 1,000 chinese citizens died from tetramine poisoning in various incidents during the late 1990s (xinhua news agency 2000). in a span of only 10 days during 2000, for example, henan province saw three separate dushuqiang poisoning incidents involving 340 people, most of these (305) being middle-school students. table 1 lists additional representative cases of accidental and deliberate poisonings with rodenticides in the prc. in addition to the september 2002 nanjing incident described above, here are some additional examples: -on 28 january 2002, in linxian city, hunan province, 120 middle-school students fell ill after consuming cafeteria food that had been deliberately poisoned with tetramine. it was later revealed that a fellow student-who had compiled a long record of truancy-was responsible. the student, angry that the school had informed his father of his unsavory behavior, tried to take revenge on his teacher by scattering tetramine on vegetables in the commissary during after-school hours. reportedly, the student purchased a pouch of tetramine rodenticide for the equivalent of us$ 0.16. (1 yuan). although the miscreant intended to poison only the teacher, the tainted ingredients were unwittingly used by the kitchen staff and served throughout the school population (wang 2002 one should caution, however, that statistics of poisoning incidents in the prc are incomplete due to various factors, including a tendency on the part of the chinese government to not fully divulge news on domestic affairs. whether it is the prevalence of hiv/ aids among the chinese population, foot-and-mouth disease in domestic chinese livestock (referred to officially as ''disease no. 5''), or the recent outbreak of the severe acute respiratory syndrome (sars) virus, there is a past history of reticence on the part of chinese authorities to be transparent concerning outbreaks of infectious disease and other public health problems (croddy 2002) . therefore, open-source data on rodenticide poisonings in china may be erring on the very low side. the worldwide market for rodenticides roughly breaks down into two main categories: acute rodenticides, those that kill relatively quickly, and chronic rodenticides (e.g., anticoagulant types) that may take anywhere from 1 to 10 days and multiple feedings of poisoned bait to achieve their effect. acute poisons such as hydrogen cyanide, strychnine, and zinc phosphide compounds have traditionally been used to control rodents for many years past. in recent times, however, safer compounds such as the warfarin anticoagulant agents have been adopted for control of mice and rats. the marketability of anticoagulant rodenticides-poisons that kill by causing internal bleeding in mammals-is notably enhanced by the availability of an antidote (vitamin k) in case of accidental exposure of non-target animals (e.g., people, livestock and household pets). in china, the rural customer has been particularly fond of rodenticides that act quickly, however, including the acutely toxic poisons that have been prohibited by the chinese government. (these include not only tetramine, but also silatrane, a cyclic, silicon-based compound that was investigated by south african chemical weapons specialists for use in assassinations during the 1980s). these banned rodenticides, mainly tetramine and fluoroacetate, comprise up to 80% of the illicit market for acute rodenticides in china's rural areas, and 60% overall across the country, according to a henanbased manager of a chemical firm in the prc (huashengbao 2000) . regulation of pesticides in china: more in the breach than the observance? although many pesticides have been regulated in the prc since the 1950s, illicit manufacturers in china continue to produce not only domestically banned organochlorine compounds such as ddt, but also a number of highly toxic rodenticides (zhong et al. 2003) . sales of these compounds are often conducted in large open markets with informal marketing and retail distribution networks. this fact, coupled with the very low cost of the final product (starting at us$ 0.10 per unit) makes it easy for the average chinese citizen to gain access to very toxic substances, including acutely toxic rodenticides such as fluoroacetate, fluoroacetamide, tetramine, and possibly others. chinese authorities singled out for prohibition the unregulated use of acutely toxic rat poison fluoroacetamide in 1984, and later fluoracetate as well. such laws, unfortunately, did not dissuade two individuals in gaoyao city, guangdong province, from using fluoroacetate and fluoroacetamide to perpetrate mass murder in 1995. during the spring and summer of that year, acting upon what was later described as ''superstitious influence,'' du runqiong (42) and her son tang youhua (20) , used these rodenticides to poison and kill 18 people. these individuals used both rodenticides to contaminate rice, vegetable plots, and sausages sold in the local market. their crimes also extended to their neighbors' livestock, causing the death of 243 pigs, some 3,100 chickens, and 10 oxen. during the investigation of this rather sordid affair, researchers from the china medical research institute of preventative medicine were dispatched to gaoyao city, and toxicologists from the peoples' liberation army (pla) finally identified the poisons from locally obtained samples. until du runqiong was apprehended in november 1995, many of the gaoyao city's inhabitants, fearing for their lives, panicked and fled the township. on 22 december 1995 both perpetrators were sentenced to death. among chinese analysts and those responsible for food security in the prc, there is a general consensus as to what is driving the force behind the chaotic misuse of prohibited rodenticides, particularly tetramine: -marketability. ''many customers who buy rodenticides like to see fast results; soon after laying down these highly toxic rodenticides, rats quickly die, thus satisfying this need for the consumer.'' -ease of manufacture. obtaining chemical precursors (ingredients for production) and the synthesis of these compounds are relatively easy. -high profitability. unscrupulous vendors can double their money by selling a rodenticide like tetramine, where 1 g of pure substance costs about 1 yuan to manufacture, and 1 g of rodenticide fetches about 2 yuan on the open market. -clandestine manufacture and sales. according to one chinese account, ''motivated by profits, some rodenticide producers are secretly but clearly producing these rodenticides with tacit approval of the state, some individual entities are doing so without permission. some are illicit shops, taking very toxic rodenticides and masking them as slow [anticoagulant] poisons or renaming them with monikers such as sanbudao, ''miraculous rodenticide'', and other trade names for sale on the market. -regional protectionism. corrupt local government officials allow the continued production of banned rodenticides, knowing that they can benefit from increased tax revenues as well as bribes. -weak regulatory enforcement. while the prc's ministry of health and the ministry of crop protection have investigative authority, they have no means to levy punishments on violators. conversely, ''the chinese department of market management has the authority to take punitive measures, but lacks the technical means to test for the highly toxic rodenticides.'' (fan 2002) . in (fig. 2 ). there were some markings that read ''one fell swoop'' and wendao jisi (''sniff and quickly die''). even after aggressive treatment with anticonvulsants (including lorazepam and phenobarbital) the child continued seizing and required intubation. the child survived, although a month afterward continued to suffer neurological problems (us cdc 2002) . packages of tetramine-based rodenticide were also found in an open market in penang, malaysia, in late 2002. sold under the name sanbudao (''takes three steps and keels over''), these packages of rat poison had been imported from mainland china. a chinese language article from malaysia reported how sanbudao could be purchased in three small pouches for the equivalent of 1 ringgit, or about us$ 0.25 (uer 2002) . public health authorities, particularly those serving communities with large overseas chinese populations should be on the lookout for this dangerous and unregulated rodenticide. due to the high persistence of tetramine in the environment, it is especially critical that this highly toxic and stable compound be monitored for its presence in the food chain. although aggressive surveillance is underway in the prc to find and remove tetramine rat poison from informal markets, it is unknown how effective regulatory enforcement in china has been in removing this hazard. reports from china have thus far indicated uneven progress in enforcing the prohibition of tetramine and other illicit chemical compounds for sale in open markets (beijing daily news 2002). fig. 2 package of tetramine-based rodenticide brought to new york by vacationers returning from a visit to china in 2002. after coming into contact with the powder, a 15-month-old child was permanently injured from tetramine intoxication. the name of this brand, yisaoguang (roughly translated as ''one fell swoop''), is a fairly common name for this rodenticide in the prc. it is also illegal. photo courtesy of new york city poison control center and us centers for disease control and prevention (cdc) 21 november) two dead in revenge poisoning in central china restaurant purifying the market of rodenticide china's role in the chemical and biological disarmament regimes 16 november) careful: poisoned meat finding its way to market. online version recognition of tetramethylene-disulfotetramine and related sulfamides by the brain gaba-gated chloride channel and a cyclodiene-sensitive monoclonal antibody 15 november) how to protect against further acute poisoning from rodenticides. guangming daily news website gc/ ms identification of tetramine in samples from human alimentary intoxication and evaluation of artificial carbonic kidneys for the treatment of victims the pharmacology of tetramine (tetramethylenedisulfotetramine) ôrodenticidal compositions,' farbenfabriken bayer, us patent 2 650 186 china has had over a thousand rodenticide poisonings in the first half of this year. huashengbao, via fm365 website 28 november) perpetrator in the poisoning of 72 people in wuchuan analysis of 15 clinical cases of poisoning with tetramethylenedisulfotetramine october) xi'an takes measures to cut mishap numbers. china daily (internet version) 15 october) mass food poisoning culprit executed. available online antidotal effects of vitamin b 6 and sodium dimercaptopropane sulfonate on acute poisoning with tetramethylene disulphotetramine in animals. zhonghua nei ke za zhi the convulsive action of tetramethylenedithiotetramine dushuqiang [tetramine] and treatment for poisoning sanbudao rat poison, the same used to kill a hundred people [sic] in nanjing, found for sale (and cheap) in malaysian street market. available via uer website poisoning by an illegally imported chinese rodenticide containing tetramethylenedisulfotetramine linxian city case of a 13-year-old poisoning 120 students, yunnan news online china has a ôspecial unit' against poison gas: about the anti-chemical warfare medicine special unit of the chinese academy of military medical science chinese doctor publicizes antidote of prohibited pesticide survey of organochlorine pesticides in retail milk from beijing dushuqiang [tetramine] poisonings: current state of research pathological analysis of the autopsy of five tetramine-poisoned cictims. fayixue zazhi key: cord-266211-cz7m1iqk authors: cheng, tsung o. title: the current state of cardiology in china date: 2004-03-25 journal: int j cardiol doi: 10.1016/j.ijcard.2003.10.011 sha: doc_id: 266211 cord_uid: cz7m1iqk cardiology in china has shown significant changes in the last decade or so. interventional cardiology, in particular, has shown remarkable advances, especially in the management of coronary artery disease, which, unfortunately, has shown a disconcerting increase in incidence in a country traditionally known for very low incidence of coronary artery disease. important contributing factors include increasing affluence, westernization of dietary habit and lifestyle, and rampant cigarette smoking. at present, the chinese population has an annual coronary mortality of one sixth of that reported in the west, an incidence of acute myocardial infarction of one tenth to one eighth, and a mortality of acute myocardial infarction of one eighth. the prevalence of coronary artery disease among the general chinese population (3–7%) is roughly one quarter of that among the caucasians in the west, but this will get worse for sure. china still has a lot of catching up to do to reach full modernization. there is a price that every developing country must pay for modernization. however, let the price the chinese pay not exceed the benefits derived from modernization. can we achieve a utopian stage in the 21st century in which the modern chinese retain their ancestral low rates of coronary artery disease while adapting the positive aspects of a modern western lifestyle? i used to return to china to lecture, demonstrate, and exchange scientific and medical information every 1 -2 years since 1972. i have previously reported my observations on several occasions [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] . due to increasing demand on my time by other countries around the world in the past decade, i have not been back to china as frequently in recent years. the last time i visited china before my latest visit in october 2002 was in 1996. so much changes have taken place that i felt it important to report a few of the more significant ones in modern china. incidentally, severe acute respiratory syndrome (sars), the recent epidemic that spread through populous china then spread around the world and posed as a potential threat to china's stability, is said to have originated in the southern china province of guangdong in the fall of 2002. despite the accusations that the chinese authorities have been underreporting or covering up cases of sars, i saw no evidence of such an occurrence during my visit in october 2002, which included hong kong, guangzhou, beijing, and shanghai. it only came to surface early in 2003 when, according to a good colleague of mine in guangzhou who apologized for not promptly responding to my correspondences, as he always did over the many years of our acquaintance, his hospital ''had been kept busy with quite a few cases of atypical pneumonia since the spring festival,'' another term for the chinese new year, which fell on february 1, 2003 . most cases of atypical pneumonia reported during that period were indeed cases of sars. as a matter of fact, the chinese term for sars is still atypical pneumonia . personally, i do not believe for a moment that china was underreporting or covering up cases of sars. china was simply caught offguard by the sudden appearance of this mysterious disease, which, on the surface, resembled common colds or ordinary flu. because it occurred during the usual flu season, i could empathize with china's initial ''what's the big deal?'' attitude. to me, the most important outcome of this whole incident of sars is that china's press and news media have now become completely transparent-a sign of chinese ''glasnost''. of course, sars is all history now (fig. 1 ). as i pointed out in my earlier publications [11] [12] [13] , coronary artery disease, which used to be extremely rare in old china [14] , has increased considerably in prevalence in china in the past several decades. coronary artery disease in china has climbed from the fifth most common form of heart disease in 1948-1957, to the second most common in 1958 -1968 and 1969 -1979 , and to the most common in 1980 -1989 (table 1) , where it remains until this date. this changing pattern of heart disease in china was also reflected in the changing etiologies of congestive heart failure in modern china. whereas rheumatic heart disease used to be the most common cause of congestive heart failure in the 1980s, coronary artery disease took over in the 1990s and 2000 (table 2 ). myocardial infarction, which was extremely rare in old china, has been the fifth leading cause of death in modern china [15] . i still recall that when i was a medical student, i saw only one case of acute myocardial infarction during my entire 5 years of schooling. it was such a rarity that the patient became the subject of medical grand rounds, cardiology grand rounds, ecg conference, radiology conference, physiology seminar, pharmacology round table, journal club, and research conference. i felt so sorry for that poor patient who had to be present in each of these didactic conferences. at present, the chinese population has an annual coronary mortality of one sixth of that reported in the west, an incidence of acute myocardial infarction of one tenth to one eighth, and a mortality of acute myocardial infarction of one eighth [16] . the prevalence of coronary artery disease among the general chinese population (3-7%) is roughly one quarter of that among the caucasians in the west [16] . but this will change for the worse in the years to come. part of the reason for this changing pattern is, of course, relative due to more accurate diagnosis, less people dying from malnutrition and infectious diseases, and more people living to an older age. but most of the increases are really due to the following contributing factors. modern chinese love the atherogenic fast food and devour them at an ever-faster rate. the huge success of the world's two of the best known fast-food giants, mcdonald's ( fig. 2) and kentucky fried chicken, also known as kfc (fig. 3) , is the result of a change of chinese lifestyles, which are becoming more geared to speed, convenience, and choice. although most of the chinese do not like the taste of either hamburgers (chinese prefer pork to beef) or cheeseburgers (chinese compare cheese to vomitus), they possess enough curiosity to try them. furthermore, consumers in china are buying at mcdonald's and kfc because they are fashionable in the west, not because they represent [19] . more than one third of adults in china and over half of adults in china's urban areas consume over 30% of their energy from fat [20] . as a consequence of the recent change in the dietary habits in china, the normal plasma cholesterol values in modern china have shown a steady increase. in 2003, the upper limit of normal was 6.0 mmol/l or 232 mg/dl, and the mean value was 5.06 mmol/l or 196 mg/dl [21] . these ''normal'' values, which were very similar to those reported recently from another study of 1211 retirees in beijing [22] and the chinese monica project involving 5 million chinese from 16 provinces [23] , were considerably higher than the normal values in china published in 1958 (155 mg/ dl) [24] , 1981 (191 mg/dl) [24] , and 1997 (200 mg/dl) [25] . in a country known traditionally for its low plasma cholesterol values, low incidence of coronary artery disease, and lean body build, this upward adjustment of the so-called ''normal'' values in modern china represents an alarming trend that deserves special attention. this assumes an even greater significance in view of the recent report that blood cholesterol concentration is directly related to mortality from coronary artery disease even in those with-what was, by western standards-a ''low'' cholesterol concentration [26] . in addition to the recent fast-food onslaught, there is also a new craze in china for milk. china is starting to consume more milk, a basic change in the national diet that reflects an upward shift in the expanding chinese middle class. in old china, milk was considered a luxury, costing more than water or tea. with the improvement of living standards, near doubling of milk production during the last 5 years [27] , and the fitness craze sweeping across the country, chinese are drinking more milk in record numbers-25% increase from 2001 to 2002 (q.y. ge, personal communication, april 2, 2003) . china's annual milk production has finally caught up with that of its grain alcohol [27] . so, instead of ''gan bei'' (''bottoms up'') with the traditional mao-tai at most of the state banquets, chinese hosts are now holding up glasses filled with milk. unfortunately, while the older generations of chinese have benefited from a diet high in vegetables and fruits and low in saturated fats, a move to too much milk undoubtedly would accelerate the development of atherosclerosis in modern china. such changes in china's dietary intake will have a great influence on the coronary artery disease burden, as was supported by the recently reported singapore experience in which the higher consumption of dietary saturated fat is associated with a higher serum cholesterol and higher coronary artery disease mortality in singaporean chinese compared with the chinese in hong kong and mainland china [28] . china used to be known for her slender people. i never saw a fat person in china until recent years (fig. 4 ). now china is fighting obesity, especially childhood obesity, which is as high as 28% [29] as the rest of the world [30] . excessive caloric intake from fast food [31] ; insufficient exercise from increasing availability of, and increased reliance on, automobiles [13] ; and the popularization of television result in weight gain. the effect of television viewing on pediatric obesity has recently been documented: each hourly increment of tv viewing is associated with a 1-2% increase in the prevalence of obesity in urban china [32] . the prevalence of obesity continues its upward trend in china as the rest of the world. by the end of 2000, the obesity rate of male students in beijing reached 15%, doubling that of 1990 and approaching that of developed countries [29] . traditionally, a fat child in china meant a healthy child, one who was likely to survive the rigors of undernourishment and infections. this misconception still prevails today in many parts of china, which, unfortunately, is a participant in an international epidemic of childhood obesity [33, 34] . fat children grow up to be fat adults. overweight in china [body mass index (bmi) z 25] has shown a progressive increase in both men and women over the past two decades (table 3 ) [35] . it is estimated that overweight is present in 50 -60% of northern chinese and 20% of the total chinese population [35] . obesity (bmi z 30) is present in 10% of the population in northern china and 5% in southern china; the total number of obese people in china is now estimated to be 30-40 million [35] . the chinese have a lower baseline bmi to begin with (baseline value = 21 [36] ; mean = 18.5-23.9 [37] ), and it takes less increment to reach an obese level, so that a bmi of 24 -27.9 is considered as overweight and z 28 as obese [37] . it takes smaller increments to increase the risk of hypertension, coronary artery disease, and type ii diabetes in the chinese population [36, 38, 39] . china is in the midst of an obesity epidemic [40] . obesity in china has reached such a serious stage that the chinese government has started a national campaign against it [41] . furthermore, the chinese medical association just convened its first national symposium on the prevention and treatment of obesity on march 15, 2003 in suzhou [42] . the recent report that obesity significantly raises cancer risk [43] will undoubtedly add impetus to china's war against obesity because of the chinese's inordinate fear of cancer. china is the greatest producer and consumer of cigarettes in the world [44] . one of every three cigarettes manufactured in the world is consumed in china (fig. 5 ). even more alarming is the prevalence of teenage smoking in china (fig. 6) ; three of every five chinese smokers begin smoking at the age of 15 -20 years [45] . although cigarette smoking is far less common among the chinese women than men [46] , women smoke almost as much as men in the autonomous region of inner mongolia. cigarette smoking becomes the only pastime for both men and women who are housebound by the inclement weather in the winter in the inner mongolia grasslands (fig. 7) . as the chinese saying goes, ''women uphold half of the sky''; therefore, women smoke as much as the men in inner mongolia [47] . countries such as china, with its 300 million smokers, are being targeted by the tobacco industry as stricter control on tobacco began to bite in the united states. the young smokers in china not only like to smoke foreign brands of cigarettes but also name brands. next to coca cola and mickey mouse, marlboro is the third most well-known american name in china. advertisements in the form of billboards are conspicuously shown in every major city in china (fig. 8) . despite health hazard warnings on the cigarette packs as required by the ministry of public health and uncontroversial evidence that cigarette smoking is a major cause of death in china [48] , a direct cause of coronary artery disease in china [49] , and an indirect cause of coronary artery disease by causing hypertension [50] and diabetes [44] , many chinese continue to smoke, including medical professions. on each china visit, i always inquired why so many chinese continue smoking despite the health hazards. they always pointed out to me that the late chairman mao zedong smoked (fig. 9 ) and the late chairman deng xiaoping also smoked (fig. 10 ). mao and deng were china's two greatest leaders in the 20th century and are still revered throughout china. so i believe that example-setting is very important. furthermore, despite the recent unanimous approval of the global antitobacco treaty by all 192 countries in the world health organization [51] , of which china is a member, china is still not enforcing the ban, claiming that ''individuals' rights should be respected.'' since the introduction of selective cine coronary arteriography into china in 1973 [6] , the field of interventional cardiology has been growing by leaps and bounds and is now an established discipline in china (table 4 ). selective coronary arteriography is now routinely performed in every major medical center throughout china with a very respectable complication rate. as was recently reported from the fu wai hospital and cardiovascular institute, chinese academy of medical sciences, beijing [52] , where i performed china's first selective cine coronary arteriogram in 1973 [6] , in an analysis of 9196 cases from october 1987 to december 2000, death, myocardial infarction, stroke, serious arrhythmias, peripheral vascular complications, and allergic reactions to the contrast media were 0.02%, 0.01%, 0.01%, 0.29%, 0.26%, and 0.04%, respectively, as compared to 0.10%, 0.06%, 0.07%, 0.47%, 0.46%, and 0.23% in an analysis of 222,553 cases between 1984 and 1987 from the registry of the society for cardiac angiography and interventions [53] . percutaneous transluminal coronary angioplasty (ptca) was first performed in xian, china, in 1984. percutaneous coronary intervention (pci) is growing rapidly in china ( fig. 11) at an annual rate of increment of around 40% [54, 55] . in 2001, 16,345 procedures were performed with a success rate of 97% [54, 55] . this, of course, is rather a small number as compared with the united states where, in 1999, 601,000 procedures were performed [56] . similar to the trend in the western world, the chinese cardiologists have also become more aggressive in the management of acute coronary syndromes. according to a recent report of a study, which is a part of the international multicenter registry, selective coronary arteriography was carried out in 35% of these patients, in half of whom (or 17%) ptca was performed; thrombolytic therapy was carried out in only 3% of the patients and coronary artery bypass grafting (cabg) in 4% [57] coronary stenting has also rapidly expanded in number; according to the third national coronary intervention registry, published at the end of 2002, over a 3-year period from 1999 to 2001, stents were implanted in 81% (43,304 of 53,695) of pcis with a success rate of 99% [55] . the number of pcis has surpassed that of percutaneous balloon mitral valvuloplasty, which used to be the most frequently performed interventional cardiologic procedure in china [58 -60] . this reversal in trend reflects the change in the etiologies of heart diseases in modern china over the past two decades, namely, an increase in coronary artery disease and a decline in rheumatic heart disease ( table 1) . chinese cardiologists learn fast. hypertrophic cardiomyopathy was an unfamiliar diagnosis in china until i introduced selective coronary arteriography in 1973 [6] ; 3 of 11 patients catheterized because of exertional chest pain were found to have normal coronary arteriograms but hypertrophic obstructive cardiomyopathy with a significant systolic gradient across the left ventricular outflow tract and a typical angiographic appearance. this disease entity is encountered more and more often now in china. as a matter of fact, the interventional cardiologists in china have also become quite aggressive in treating these patients with the percutaneous technique of transluminal septal myocardial ablation with alcohol, with one center alone having performed such a procedure in 119 patients with excellent short-and long-term results [61] . according to the chinese national registry, over 400 such procedures have been performed among 20 hospitals in china by the end of 2002. the chinese cardiologists have also been actively engaged in laboratory investigations to determine whether it is the volume of the alcohol injected, or the rate of alcohol injection into the first septal perforator of the left anterior descending coronary artery during septal ablation that is important. it was concluded that the size of the iatrogenically induced myocardial infarct in piglets is directly related to the volume of intracoronary alcohol injection, rather than the rate of alcohol injection [62] . frequent symposia on interventional cardiology are held regularly at both national and local levels to keep the cardiologists abreast of the latest developments in interventional cardiology. these meetings are usually supported by foreign pharmaceutical companies or/and device manufacturers, which also take care of the travel expenses of chinese cardiologists going overseas to attend international cardiologic meetings. unlike the united states where such practices are now forbidden, many chinese cardiologists who otherwise would not be able to afford such international trips on their meager salaries 1 are able to attend these cardiologic meetings in both europe and north america. upon returning to china from such meetings, they promptly report the highlights of such meetings in national or local medical journals in china. such practices serve to educate the rest of the cardiologists in china who otherwise would not have an opportunity to keep abreast of the recent advances in cardiology due either to lack of 1 despite frequent gifts from their grateful patients, which may range from a chicken from a farmer to a mercedes benz automobile from a wellto-do businessman. financial means to go overseas, or to unfamiliarity with the english language. china's first cabg operation was performed in october 1974 at beijing's fu wai hospital where china's first selective coronary arteriogram was performed in june 1973 [6] . it was a single-vessel saphenous vein graft to the left anterior descending coronary artery in a 40-year-old male patient who survived for 8 years (zhu xiaodong, md, fu wai hospital, personal communication, august 1, 1997 table 4) . one of the patients in harbin, china, has survived for more than 10 years now following the heart transplantation. as is the case with the rest of the world, the principal limiting factor in heart transplantation is scarcity of donors. the latter factor was further complicated in china by the traditional buddhist teaching that a dead person must be buried with all the organs intact to ensure the spirit's happiness. there exist rumors that hearts and other organs from executed prisoners in china have been harvested as donor organs without the explicit consent of their family members. but i am unable to confirm such rumors. however, such practices provide a useful donor source in taiwan where the condemned prisoners voluntarily initiated the process of organ donation [63] . pulmonary embolism used to be thought of as rare in china [4] . but this is no longer the case. in a recent analysis of 37 documents of chinese language case studies involving misdiagnoses of pulmonary embolism published from january 1980 to june 2001 and identified by searching the chinese biomedical literature database [64] , 310 patients with misdiagnosed pulmonary embolism were identified. the five commonest misdiagnoses were coronary artery disease in 20%, pneumonia in 14%, primary pulmonary hypertension in 10%, cardiomyopathy in 7%, and pleurisy in 6% [64] . china is launching a campaign to increase awareness on this disease, as evidenced by several recent publications in major medical journals in china [64 -66] . there are several explanations for underdiagnosing or misdiagnosing pulmonary embolism in china: (1) traditional teaching by such authorities as snapper (fig. 12) , who was highly regarded in old china as one of the most astute diagnosticians, was that pulmonary embolism was rare in china. he did not even mention it in his book ''chinese lessons to western medicine'' [14] . (2) even as recent as 1970s, pulmonary embolism was thought to be rare in china [4] the rarity of pulmonary embolism was even more remarkable when one considered the widespread use of birth control pills among the chinese women of child-bearing age [4] . perhaps the use of acupuncture anesthesia [2,7 -9] , which permitted early ambulation after major surgery, accounted for the low incidence of postoperative pulmonary embolism in china. because acupuncture anesthesia is seldom employed in modern china, this protective factor is no longer operative. (3) more accurate in vivo diagnosis of pulmonary embolism is now possible because of improved diagnostic techniques. the publishing industry in china has shown an extraordinary growth in recent years. in 1978, china published 14,987 books; 20 years later, the number was 130,613-a little more than twice that of the united states [67] . similarly, exponential growth took place for magazines (from 930 to 7999) and newspapers (from 186 to 1035) over the same period [67] . by comparison, the united states published 14,707 magazines in 1999 and 1489 newspapers in 1998 [67] . this publishing explosion was mirrored in medical publishing as well. not only the quantity but also the quality of medical books showed a great deal of improvement within a relatively short period of time. some textbooks in cardiology that were originally published as a single volume (fig. 13a ) had to be published in a twovolume set because of increased pages required to cover all the latest advances (fig. 13b) . other books, such as the one on congestive heart failure, which originally appeared as monographs (fig. 14a) , later were expanded to become textbooks (fig. 14b) . the chinese medical doctors are thirsty for new knowledge; because attendance at national and international medical meetings was restricted by financial constraints, they have to rely mostly on books and journals for their postgraduate medical education. china published some 700 medical journals in 1994 [68] (table 5 ) [69] . the top five journals represented nearly one third of the citations. this list is somewhat reminiscent of the omnipotent science citation index impact factors of these journals. according to the chinese scientific and technological journal citation reports 2001, which was published in 2002, impact factor and total citation frequency for the chinese journal of cardiology ranked 9th and 21st, respectively, among 2000 chinese scientific and technological journals (y.m. jiang, chinese journal of cardiology, personal communication, june 17, 2003) . a word about international access to the chinese medical literature through medline: users doing author searches may have difficulties with common chinese surnames, especially if only one given name initial is used [70] . the difficulty may be further compounded by the fact that chinese authors customarily spell their last names first and first names last [71 -76] . china, in both basic research and clinical investigation in cardiology, has made significant improvements and advances over the years in the following several broad areas. (217), and other countries. the growth in the number of participants from china reflects an increased interest in biomedical collaboration between us and chinese scientists. over a 10-year period from 1992 to 2002, the number of abstracts submitted from china increased from 34 to 85, and the number accepted for presentation showed a parallel increase from three to eight (table 6) . a similar trend was noticed for the american college of cardiology annual scientific meetings. such increases in contributions of our chinese colleagues to these national heart meetings are quite impressive. china is a huge country with its 1.3 billion population; one of every five persons on earth lives in china. china's unique environment, therefore, constitutes a tremendous opportunity for intervention trials. ethnic, demographic, and cultural diversities make it easier to conduct major epidemiologic studies in china. because the chinese population is more compliant than the western population, high participation rates are certain. because the chinese population is more stable than the western population, follow-up is easier and more complete. finally, the studies are much cheaper to carry out, ''practically nothing compared to what a similar trial will cost in the united states,'' as noted by fraumeni of nih according to mervis [77] . besides participating in many international trials, china also conducts several national trials on her own [e.g., tissue plasminogen activator/urokinase comparisons in china (tucc)] [78] . some of these trials carry rather cute acronyms [e.g., cast (chinese active stroke trial), cat (chinese angiotensin-converting enzyme inhibitor in acute myocardial infarction trial), cathay (chinese atherosclerosis study in the aged and young), and stone (shanghai trial of nifedipine in the elderly)], similar to the fascination with the creation of attractive trial acronyms by the western investigators [79 -83] . the use of statistical methods in chinese medical journals has been improving [84] . according to wang and zhang [84] , the percentages of original articles reporting clinical trials, prospective studies, or basic science research increased from 18% in 1985 to 31% in 1995 ( p < 0.001), of articles using statistical methods increased from 40% in 1985 to 60% in 1995 ( p < 0.001), and of those articles using appropriate statistical methods increased from 22% to 46% ( p < 0.001). in both 1985 and 1995, the most commonly used statistical methods in the chinese medical journals were t tests and contingency tables [84] . according to wang and zhang [84] , the most common errors the chinese authors committed were presentations of p values without specifying the test used, use of multiple t tests instead of analysis of variance, and use of unpaired t tests when paired tests were required. medical genetic research in china started in the late 1950s [85] . molecular genetic research started in china in the 1990s [85] . as the human genome project was initiated in the 1990s, china also launched a national human genome project as part of its contribution to international efforts to sequence the human genome [86] . china's contribution in the human genome project could be significant. according to one official from the national science foundation of china, ''the chinese account for over one fifth of the world's population, and the country has 56 ethnic groups. as a result, no databank of human genetic information can be said to be complete without a detailed study of the chinese human genome'' [86] . the project will have important practical implications, as the chinese, with their powerful sequencing capacity and capability in the genome project, are expected to contribute vital information that may lead to the early diagnosis and treatment of more than 5000 hereditary diseases [86] . in 1998, china's scientific leaders overcame skepticism from some members of the human genome project to become the only developing country to take a role in sequencing the human genome by contributing 1% of the published sequence-an achievement that is of huge symtable 6 american heart association scientific sessions abstracts submitted and accepted from china, 1992 china, -2002 china, 1992 china, 1993 china, 1994 china, 1995 china, 1996 china, 1997 china, 1998 china, 1999 china, 2000 china, 2001 china, 2002 submitted 34 23 14 37 10 25 14 60 56 67 bolic importance [87] . chinese researchers are now setting up programs in everything from stem cell research, through large-scale efforts to determine protein structures, to population studies to hunt for human disease genes [87] . there is even talk of trying to clone the endangered giant panda [87] . recently, china presented her new edition of a genetic map illustrating the no. 3 human chromosome, as part of the human genome project [88] . the new completed mapconsidered 99.99% accurate-would help improve medical diagnosis and also aid the discovery of new drugs and new treatments [88] . in the field of cardiology, china has made much progress in research work for gene therapy of hypertension [89] , myocardial infarction [90] , and congestive heart failure [91] . on the long list of organs that should be sequenced, the beijing genomics institute has already started investigations into proteomics and drug discovery, including a project to isolate the active compounds in the herbs used in traditional chinese medicine [92] . there are many chinese herbs that are widely used in this country, especially for treatment of coronary artery disease and congestive heart failure. unfortunately, they tend to interact unfavorably with commonly prescribed western cardiac drugs, including warfarin [93 -98] , digoxin [98 -101] , and hypoglycemic agents [102] . therefore, the isolation of the active compounds in these herbs will facilitate the understanding of the pharmacodynamics of these herbs and thus avoid their inadvertent adverse interactions with the western medications. cardiology in china has shown significant changes in the last decade or so. interventional cardiology, in particular, has shown remarkable advances, especially in managing coronary artery disease, which, unfortunately, has shown a disconcerting increase in incidence in a country traditionally known for its very low incidence of coronary artery disease. important contributing factors include increasing affluence, westernization of dietary habit and lifestyle, and rampant cigarette smoking. changes in china acupuncture anesthesia a view of modern chinese medicine. observations by a shanghai-born physician during his recent visit after 22 years of absence medicine in modern china china medicine as we saw it. bethesda: the fogarty international center white lecture-cardiology in people's republic of china acupuncture anesthesia for open heart surgery cardiology in people's republic of china in 1977 cardiology in china revisited barefoot doctors cardiovascular disease in china coronary heart disease in china price of modernization of china chinese lessons to western medicine suicide rates in china 1995 -99 principles and practice of clinical medicine in asia. treating the asian patient. philadelphia: lippincott, williams and wilkins china swallows fast food at an ever more rapid rate risk of having heart disease soars in china experts differ on healthiness of 'fast' salad a new stage of the nutrition transition in china extensive association analysis between polymorphisms of pon gene cluster with coronary heart disease in chinese han population a long-term followup study of serum lipids and coronary heart disease in the elderly epidemiologic study of blood lipids in the chinese population the international textbook of cardiology the textbook of modern cardiology serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations new craze seizes china's consumers: a glass of milk the emergence of coronary heart 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in suzhou overweight, obesity, and mortality from cancer in a prospectively studied cohort of us adults smoking and diabetes in chinese men teenage smoking in china smoking and health do photographs lie? smoking in china mortality attributable to cigarette smoking in china a review on studies of smoking and coronary heart disease in china and hong kong meta-analysis of risk factors on hypertension in china wha approves historic tobacco accord complications in selective coronary arteriography: analysis of 9196 cases coronary arteriography 1984 -1987: a report of the registry of the society for cardiac angiography and interventions: i. results and complications furthering the healthy development of percutaneous coronary interventions in china section of interventional cardiology, chinese society of cardiology, editorial office of chinese journal of cardiology: a data analysis of the third national coronary intervention registry treatment of coronary artery disease in the year 2003 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economy chinese medical journals; getting in touch. chinese editors and medical journals have much to offer a preliminary study of reference citations of foreign journals in articles published in the chinese journal of cardiology international access to the chinese medical literature through medline the chinese last name what's in a name-the chinese name? word order: oriental or occidental? chinese name use of surnames to identify individuals of chinese ancestry chinese last name comes first china's unique environment favors large intervention trials a randomized trial confirming the efficacy of reduced dose recombinant tissue plasminogen activator in a chinese myocardial infarction population and demonstrating superiority to usual dose urokinase: the tucc trial acronyms of clinical trials in cardiology-1994 acronymophilia: the exponential growth of the use of acronyms should be resisted acronymania, acronymophilia and acronymophobia acronyms of clinical trials in cardiology-1998 acronyms of cardiologic trials-2002 research design and statistical methods in chinese medical journals the achievements of medical genetic research in china during the past 50 years china launches genome project a great leap forward genetic map the textbook of modern cardiology relationship between apolipoprotein e gene polymorphism and myocardial infarction or its action on clinical courses a textbook on congestive heart failure from standing start to sequencing superpower warfarin danshen interaction warning about a medicinal herb herbal remedies interaction of herbal medicine with coumadin ginseng -warfarin interaction comment: drug -herb interaction herbal interactions with cardiac drugs john's wort interaction with digoxin interaction of herbal drugs with digoxin panax (ginseng) is not a panacea key: cord-266257-hp11at50 authors: zhang, yao; zhang, haoyu; ma, xindong; di, qian title: mental health problems during the covid-19 pandemics and the mitigation effects of exercise: a longitudinal study of college students in china date: 2020-05-25 journal: int j environ res public health doi: 10.3390/ijerph17103722 sha: doc_id: 266257 cord_uid: hp11at50 (1) background: the novel coronavirus disease 2019 (covid-19) is a global public health emergency that has caused worldwide concern. vast resources have been allocated to control the pandemic and treat patients. however, little attention has been paid to the adverse impact on mental health or effective mitigation strategies to improve mental health. (2) purpose: the aim of this study was to assess the adverse impact of the covid-19 outbreak on chinese college students’ mental health, understand the underlying mechanisms, and explore feasible mitigation strategies. (3) methods: during the peak time of the covid-19 outbreak in china, we conducted longitudinal surveys of sixty-six college students. structured questionnaires collected information on demographics, physical activity, negative emotions, sleep quality, and aggressiveness level. a mixed-effect model was used to evaluate associations between variables, and the mediating effect of sleep quality was further explored. a generalized additive model was used to determine the dose-response relationships between the covid-19 death count, physical activity, and negative emotions. (4) results: the covid-19 death count showed a direct negative impact on general sleep quality (β = 1.37, 95% confidence interval [95% ci]: 0.55, 2.19) and reduced aggressiveness (β = −6.57, 95% ci: −12.78, −0.36). in contrast, the covid-19 death count imposed not a direct but an indirect impact on general negative emotions (indirect effect (ie) = 0.81, p = 0.012), stress (ie = 0.40, p < 0.001), and anxiety (ie = 0.27, p = 0.004) with sleep quality as a mediator. moreover, physical activity directly alleviated general negative emotions (β = −0.12, 95% ci: −0.22, −0.01), and the maximal mitigation effect occurred when weekly physical activity was about 2500 mets. (5) conclusions: (a) the severity of the covid-19 outbreak has an indirect effect on negative emotions by affecting sleep quality. (b) a possible mitigation strategy for improving mental health includes taking suitable amounts of daily physical activity and sleeping well. (c) the covid-19 outbreak has reduced people’s aggressiveness, probably by making people realize the fragility and preciousness of life. the novel coronavirus disease 2019 (covid19) has swept across the world, causing a global pandemic [1] . on 30 january 2020, the world health organization (who) declared covid-19 an international public health emergency. until april 15, 2020, nearly 2 million confirmed covid-19 cases, including 123,010 deaths, have been reported worldwide. with respect to the covid-19 outbreak online surveys, we posted recruitment information for the longitudinal surveys on the internet via wechat moments and wechat pushes. since we intended to explore the mitigation effects of exercise on negative emotions, the participation selection criteria in this study were that college students, who stayed at home in a social distancing status, should be physically healthy and non-disabled. after seeing the recruitment information, sixty-six college students from several provinces participated voluntarily in the survey. all of them met the enrolled criteria, and none of them were diagnosed with covid-19 disease by the end of the online survey. as per national policy, participants stayed at home to implement physical distancing to stop disease transmission. they were instructed to complete the online questionnaires every half month, and the three examined times were 9:00 a.m.-12:00 p.m. on february 19, 2020, 9:00 a.m.-12:00 p.m. on march 5, 2020, and 9:00 a.m.-12:00 p.m. on march 20, 2020 . the language of all the online questionnaires was chinese, and all the questionnaires used in this study have been validated among chinese populations in previous studies. participants were asked to complete and submit the online questionnaires on time. ethical approval was obtained from the institutional review board of tsinghua university (id number: 20190091) . detailed information about this study was posted at the top of the questionnaires. survey participants were asked to sign a consent form before completing the structured questionnaire each time. a total of 70 yuan (equivalent to 10 dollars) was offered to each participant upon receiving all completed questionnaires. before the longitudinal surveys, a total of 66 college students were invited to this study. during the investigations, 66 participants who volunteered to participate in this study completed the online questionnaires twice, and 59 of them completed the surveys three times. in order to explore longitudinal evidence, the survey data for participants who filled online questionnaires at least twice were used to analyze. hence, the final sample size included in the study analysis was 66 participants. information on physical activity (pa) was collected via the short version of the international physical activity questionnaire (ipaq-s), which is suitable for people aged between 15 and 69 years and is primarily used for population surveillance of physical activity levels. the ipaq-s (7 items) has been validated in chinese with good reliability [20, 21] . participants were asked to classify their weekly pa during the recent half month into three categories: light, moderate, and vigorous. total minutes of vigorous physical activity in the last week were constructed based on two questions: "during the last seven days, how many days did you spend on vigorous physical activities like lifting, fast cycling, and fast swimming?" and "how much time did you usually spend each time on these vigorous physical activities?" total minutes of vigorous pa were computed by multiplying the daily average minutes of vigorous pa by the corresponding intensity days. likewise, the total minutes of moderate and light pa in the last week were calculated in the same way. according to ainsworth et al. [22] , the ratio of work metabolic rate to a standard resting metabolic rate (met) was used to estimate the weekly energy expenditure. energy expenditure in met-minutes per week (mets) can be estimated for specific activities by type and intensity [22, 23] . referring to previous studies [22, 23] , the average met coefficients of light, moderate, and vigorous pa in ipaq-s are 3.3, 4, and 8, respectively. the final light, moderate, and vigorous physical activity were computed by multiplying the corresponding met coefficient with the total minutes (e.g., moderate met minutes/week (mets) = 4.0 × moderate-intensity activity minutes × moderate days). the mets of total pa were calculated by adding vigorous pa, moderate pa, and light pa. sedentary behavior was defined as pa less than 1.5 mets [22, 23] . subjective sleep quality was measured using the widely used pittsburgh sleep quality index (psqi), which assesses the overall weekly sleep quality in the last month [24] . we used 19 self-rated items of the validated chinese version of the psqi (c-psqi) in this study [25] . the c-psqi used in this study includes seven sleep components: subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. each component was rated on a scale of 0-3. the global psqi score, ranging from 0 to 21, is the sum of all the component scores, and a higher global psqi score indicates poorer sleep quality. according to a previous study, global psqi with a score greater than 5 scores indicates some degree of poor sleep disorder [26] . negative emotions and mental health during the last week were measured using the depression anxiety stress scale, with 21 self-reported items (dass-21) [27] , which has been validated in the chinese population [28, 29] . this structured questionnaire was previously used to assess the immediate and sustained psychological distress of healthcare workers during the sars period [30] . the dass-21 consists of three components of stress, anxiety, and depression, each of which includes seven items. in terms of stress, participants were asked to answer questions like "i found myself getting quite upset by trivial things." with regard to depression and anxiety, participants were asked to answer questions such as "i felt that life was not worthwhile" and "i found myself in a situation which made me so anxious and i was most relieved when they ended." each item was rated on a scale of 0-3, corresponding to "totally disagree," "partially agree," "mostly agree," and "totally agree." the score of each component was calculated as the sum of scores for seven related items, with values ranging from 0 to 21. the global dass score is the sum of the three components and is used as a general indicator of mental distress. the score for each component ranges from 0 to 21, and the global dass score, which the sum of the three components, serves as a general indicator of mental distress. in addition, higher scores of stress, anxiety, depression, and global dass represent more serious negative emotions. scores greater than 10, 7, and 9 on stress, anxiety, and depression, respectively, may indicate significant levels of the corresponding negative emotions [31] . aggressiveness was measured using the buss-perry aggressive questionnaire (bpaq), which assesses aggressive emotions, intentions, or behaviors [32, 33] . the bpaq has been demonstrated to be a reliable measure of aggressiveness in the chinese population [34, 35] . the bpaq consists of four components: physical aggression, verbal aggression, anger, and hostility, with 5, 6, 3, and 8 items, respectively. each item was rated on a scale of 1 (totally disagree) to 5 (totally agree). the score of each component was the sum of scores for the corresponding items, and the overall aggressiveness score was the sum of the four components. a higher score indicates a higher aggressive level. the covid-19 disease data were extracted from the open-source git-hub packages "canghailan/wuhan-2019-ncov" and "guangchuangyu/ncov2019," which comprise cumulative numbers of confirmed, suspected, cured, and death cases at the provincial level from january 1, 2019, to the present day. we extracted the number of cumulative death cases one day before as the indicator of covid-19 outbreak severity for each province and then matched provincial-level covid-19 death cases to each participant based on home address. considering longitudinal measurements and inter-person variation, we employed a mixed-effect model with a random effect on individuals to examine the relationship between covid-19 death cases, sleep quality, physical activity, negative emotions, and aggressiveness. variables that did not change over time were controlled using this analytic approach. we used the mediation package of r software to explore the mediation effect of sleep quality on the association between covid-19 death count and negative emotions in order to discover the possible underlying influence mechanism. in addition, we examined the mitigating effects of pa on negative emotions and then explored the dose-response relationship between the global dass score, covid-19 death count, and physical activity by fitting a generalized additive model with splines. statistical analysis was performed using r software, version 3.6.3 (r project for statistical computing) and a two-tailed p < 0.05 was considered statistically significant. a summary of participants' demographic information and health behaviors at baseline is shown in table 1 . a majority of the sample comprised female participants (62.12%) and most participants were around 20 years old (20.70 ± 2.11), and only a few of the participants were from non-han minorities. most of the participants lived in urban areas during the covid-19 outbreak. with regard to health behaviors, participants exerted 354.55 mets (sd = 613.41) of vigorous physical activity every week on average. the amount of physical activity was significantly higher in male participants than female ones. likewise, male participants consumed more energy in light pa (p = 0.005), vigorous pa (p < 0.001), and total pa (p < 0.001) than did female participants. however, no significant differences were observed in terms of moderate pa and total minutes of weekly sedentary behavior, and no gender difference was observed in the groups with good sleep quality (psqi ≤ 5) and poor sleep quality (psqi > 5). it is worth mentioning that nearly 85% of respondents reported worries or concerns about covid-19 disease, and 28.79%, 45.45%, and 22.73% of them reported stress, anxiety, and depression emotions. in addition, the percentage of female young adults reporting abnormal levels of every negative emotion was higher than in male respondents, even though the differences were not statistically significant. moreover, all enrolled participants were non-smokers according to the demographic information. this may be because all of the participants were college students and the sample size in this study was not too big. trends of the covid-19 in china from january 23 to march 20, 2020 figure 1 shows the development trend of the covid-19 pandemic in china from january 23 to march 20, 2020 for the cumulative numbers of cases of confirmed, suspected, and cured patients and of deaths. the numbers of cumulatively confirmed cases and deaths continued to climb for two months, with a sharp increase in the number of cumulatively confirmed cases in the first month. during the period of repeated online surveys, from february 19 to march 20, 2020, the severity of covid-19 continued to increase and gradually reached its peak. figure 1 shows the development trend of the covid-19 pandemic in china from january 23 to march 20, 2020 for the cumulative numbers of cases of confirmed, suspected, and cured patients and of deaths. the numbers of cumulatively confirmed cases and deaths continued to climb for two months, with a sharp increase in the number of cumulatively confirmed cases in the first month. during the period of repeated online surveys, from february 19 to march 20, 2020, the severity of covid-19 continued to increase and gradually reached its peak. note: the subgraph of (a-d) refer to the relationship between date and cumulative confirmed, suspected, cured, and death counts, respectively. the chinese government declared a lockdown in wuhan on january 23, which then entered the level-1 emergency response. all provinces across china entered a state of blockade. thus, we regard january 23, 2020 as the starting point (date 1) of our study and a total of 58 days (from date 1 to date 58) were recorded until the last day of the online survey, march 20, 2020. the subgraph of (a-d) refer to the relationship between date and cumulative confirmed, suspected, cured, and death counts, respectively. the chinese government declared a lockdown in wuhan on january 23, which then entered the level-1 emergency response. all provinces across china entered a state of blockade. thus, we regard january 23, 2020 as the starting point (date 1) of our study and a total of 58 days (from date 1 to date 58) were recorded until the last day of the online survey, march 20, 2020. table 2 shows the relationships between covid-19 deaths and physical activity, along with sleep quality, aggressiveness, and negative emotions. local covid-19 death cases were negatively associated with participants' general sleep quality. every 1000 increase in local covid-19 deaths was associated with a rise of 1.37 (95% confidence interval [95% ci]: 0.55, 2.19) units in the global psqi score, indicating a decline in sleep quality. among the seven components of psqi, sleep efficiency was significantly associated with covid-19 death cases, with a 1000 increase in local death cases corresponding to a 0.29 (95% ci: 0.15. 0.44)-unit increase in sleep efficiency score, indicating reduced sleep efficiency. in addition to sleep efficiency, covid-19 death cases were also associated with decreased sleep quality and sleep duration and increased sleep disturbance and daytime dysfunction, although these associations were insignificant. however, negative emotions, global dass scores, stress, anxiety, and depression did not show any directly significant associations with the covid-19 death count. in contrast to negative emotions, the aggressiveness score was negatively associated with the local covid-19 death count. every 1000 increase in local covid-19 deaths was significantly associated with a change of −6.57 units (95% ci: −12.78, −0.36) in the aggressiveness score, indicating a declined aggressiveness level. furthermore, negative emotions can be significantly alleviated by physical activity. each 100-unit increase in mets of total physical activity corresponded to a change of −0.12 (95% ci: −0.22, −0.010) in the global dass score. physical activity also significantly alleviated depression (p = 0.040); however, the alleviation effects on stress were insignificant (p = 0.090, table 2 ). unlike negative emotions, physical activity, sleep quality, and aggressiveness was not significantly associated. based on the relationships between variables, we further explored the mediation effect of sleep quality on covid-19 and negative emotions (figure 2 ). the effects of the covid-19 death count on young adults' stress (indirect effect (ie) = 0.40, p < 0.001), anxiety (ie = 0.27, p = 0.004), and global dass score (ie = 0.81, p = 0.012) were significantly mediated by decreased sleep quality, and the mediation effect on depression was not significant (p = 0.180). however, while physical activity did not show an indirect influence on negative emotions, it did show a direct impact without mediating the effect of sleep quality (figure 3 ). quality on covid-19 and negative emotions (figure 2 ). the effects of the covid-19 death count on young adults' stress (indirect effect (ie) = 0.40, p < 0.001), anxiety (ie = 0.27, p = 0.004), and global dass score (ie = 0.81, p = 0.012) were significantly mediated by decreased sleep quality, and the mediation effect on depression was not significant (p = 0.180). however, while physical activity did not show an indirect influence on negative emotions, it did show a direct impact without mediating the effect of sleep quality (figure 3 ). we used a generalized additive model to examine the dose-response associations between the covid-19 death count, physical activity and aggressiveness, and negative emotions ( figure 4 ). as figure 4 shows, the relationship between the covid-19 death count and negative emotions as well as aggressiveness was linear with no sign of threshold or plateau, although the trends were different. moreover, the dose-response curve between negative emotions and physical activity exhibited a ushaped relationship, indicating that either an inadequate or excessive amount of physical activity worsened negative emotions. a suitable amount to minimize negative emotions occurred when weekly physical activity was about 2500 mets, corresponding to 108 min of light, 80 min of moderate, or 45 min of vigorous physical activity every day. we used a generalized additive model to examine the dose-response associations between the covid-19 death count, physical activity and aggressiveness, and negative emotions ( figure 4 ). as figure 4 shows, the relationship between the covid-19 death count and negative emotions as well as aggressiveness was linear with no sign of threshold or plateau, although the trends were different. moreover, the dose-response curve between negative emotions and physical activity exhibited a u-shaped relationship, indicating that either an inadequate or excessive amount of physical activity worsened negative emotions. a suitable amount to minimize negative emotions occurred when weekly physical activity was about 2500 mets, corresponding to 108 min of light, 80 min of moderate, or 45 min of vigorous physical activity every day. the focus of this longitudinal study is twofold: (1) to investigate the impact of the covid-19 severity on chinese college students' mental health and life status and explore the underlying mechanisms of this effect during the peak time of the covid-19, from february 19 to march 20, 2020; and (2) to assess the mitigation effects of exercise on negative emotions and advance a suitable physical activity level as a psychological intervention strategy to improve mental health. our findings suggest that the severity of the covid-19 outbreak could significantly increase people's negative emotions through declining sleep quality. in additional, maintaining regular exercise was helpful to alleviate negative emotions, and 2500 mets of pa every week was the optimal load. the focus of this longitudinal study is twofold: (1) to investigate the impact of the covid-19 severity on chinese college students' mental health and life status and explore the underlying mechanisms of this effect during the peak time of the covid-19, from february 19 to march 20, 2020; and (2) to assess the mitigation effects of exercise on negative emotions and advance a suitable physical activity level as a psychological intervention strategy to improve mental health. our findings suggest that the severity of the covid-19 outbreak could significantly increase people's negative emotions through declining sleep quality. in additional, maintaining regular exercise was helpful to alleviate negative emotions, and 2500 mets of pa every week was the optimal load. in this study, nearly 85% of respondents reported their worries about covid-19, and over 20% reported at least one form of mental distress in line with previous acute emergencies [7] [8] [9] . the prevalence of negative emotions, especially anxious emotions, was higher in this study than in previous studies, which were conducted mainly among chinese university students in the initial phase of covid-19 [11, 12] . the development trend of negative emotions may imply that the adverse impact of covid-19 on public mental health will continue to increase as covid-19 spreads across the world. furthermore, females suffered a greater psychological impact from the covid-19 outbreak, with higher but insignificant scores in stress, anxiety, and depression. the lack of significant results probably reflects the limited sample size. this finding is in line with previous epidemiological studies, which found that women were more vulnerable to developing depression or ptsd [36, 37] . we found that the covid-19 outbreak could significantly reduce young adults' sleep quality and thereby increase their global negative emotions, especially stress and anxiety. this finding was consistent with a previous study revealing that individuals with better sleep quality or lower frequency of early awakenings showed reduced morbidity rates of ptsd during the covid-19 outbreak [36] . thus, the covid-19 outbreak demonstrates an indirect influence on young adults' mental health, with sleep quality playing an important mediating role. considering that all colleges in china have shut down and may stay closed until september, chinese college students will stay at home and keep social distancing for a long time. under such circumstances, they might adopt irregular lifestyles with poor sleep quality, stress, and anxiety over their academics or future employment [1] , as well as loneliness due to the lack of communication [38] . however, unexpectedly, covid-19 might significantly reduce aggressiveness levels. we propose that this phenomenon probably results from people beginning to realize the fragility of life and cherishing every moment. furthermore, regular exercise is a good treatment for poor mental health and may directly reduce negative emotions within a certain range. this finding is in accordance with previous studies showing that daily physical activity was associated with a lower risk of psychiatric distress, regardless of form and intensity [39, 40] , that could improve immunity and maintain mood stability [41] . some indoor exercises have been recommended during the disease outbreak, such as high-intensity interval training (hiit), which helps facilitate metabolism, and yoga or relaxation training, which helps promote sleep quality and calm the mood [18, 19] . furthermore, it should be noted that the gym may be a high-risk infection area due to crowding [42] . thus, staying at home and maintaining ventilation are as important as regular exercise during the covid-19 period [42] . more importantly, the relationship between physical activity and mental health is nonlinear. in our study, 2500 mets of weekly physical activity appeared to minimize negative emotions during the covid-19 outbreak, which is equivalent to about 108 min of light, 80 min of moderate, or 45 min of vigorous physical activity every day. the recommended pa load during this special period is slightly higher than in previous studies, in which 60 min of moderate-to-vigorous pa every day is recommended to maintain physical and psychological heath [43] . this is probably because of the special period of the covid-19 outbreak: people need additional pa to offset the psychological burden and negative emotions caused by the disease outbreak and social distancing. this study has several limitations. first, considering the physical distancing status and difficulty of collecting longitudinal survey data, the sample size in our longitudinal study was not large enough and the study was performed on a relatively small group of exclusively chinese college students as respondents. this study population may not be representative of the overall mental distress pattern of ordinary people of different ages, education levels, and countries. however, the findings in this study might to some extent reflect the psychological problems and intervention needs of the public during the covid-19 disease period. second, the study participants were predominantly females, who might tend to exercise less and be more vulnerable to negative emotions than their male counterparts. thus, the associations between the covid-19 outbreak, physical activity, and psychological health may be different between females and males. in addition, the preferred methods of coping with negative emotions, such as stress, anxiety, and depression, are different in females and males. females may prefer to handle psychological distress based on avoidance and looking for social contacts. therefore, further studies with larger samples are needed to explore the differences in the effectiveness of different forms of physical activity (e.g., group video exercise or interesting online sports) by gender. third, we mainly focused on the impact of the local increases in covid-19 death counts on the negative emotions of college students in social isolation status, and we did not exclusively focus on the effects of lengthened social distancing time. however, it was possible that the relationship between the results of psychological tests and the number of covid-19 death counts might reflect the relationship between negative emotions and lengthened social distancing times. hence, more studies are needed in the future to analyze the main impact of social distancing and the interactive effects of social isolation and the covid-19 outbreak on public mental health. furthermore, due to the physical distancing status across the whole country, we only used the validated self-reported dass-21 questionnaire to measure the adverse impact of covid-19 severity on negative emotions without having psychological consultants assess their mental health status as a form of third-party verification. this limitation might have resulted in self-report bias, but the results are generally reliable and consistent with the previous applications of dass-21 in sars-related and mers-related studies. moreover, due to restrictions of sample size, we did not compare the differences in variables between serious covid-19 disease areas (e.g., inside hubei province) and non-serious covid-19 disease areas (e.g., outside hubei province). we hope that other researchers from different countries or different areas will collect data in the future to analyze the regional differences in the impact of the covid-19 on public mental health. this study also has several strengths. first, this study conducted longitudinal surveys to assess the adverse impact of the covid-19 outbreak on chinese college students' mental health, sleep quality, and aggressiveness during the peak epidemic time. in addition, unlike cross-sectional studies, this longitudinal study used a mixed-effect model with random effects on individuals to control for inter-person variation. to the best of our knowledge, this study is the first to investigate the underlying mechanism whereby covid-19 influences public mental health. most importantly, our study found mitigation effects of regular exercise and good sleep on the public's negative emotions without additional social medical burden. in addition, our study advances a suitable range of physical activity to maintain psychological health of 108 min of light, 80 min of moderate, or 45 min of vigorous physical activity daily, which we recommended for psychological interventions during the covid-19 period. in summary, during the peak phase of the covid-19 outbreak in china, the severity of the covid-19 outbreak has had an indirect effect on local young adults' negative emotions, with sleep quality playing a mediating role. to deal with negative emotions during the disease outbreak, increasing physical activity and developing good sleeping patterns are cost-effective and practical mitigation strategies for ordinary people who are forced to stay at home. developing a regular exercise habit with approximately 2500 mets of weekly physical activity is recommended during this special 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china hardest-hit areas: gender differences matter prevalence of depression in the community from 30 countries between 1994 and rules on isolation rooms for suspected covid-19 cases in gp surgeries to be relaxed dose-response relationship between physical activity and mental health: the scottish health survey objectively measured light and moderate-to-vigorous physical activity is associated with lower depression levels among older us adults debunking the myth of exercise-induced immune suppression: redefining the impact of exercise on immunological health across the lifespan infection risk in gyms during physical exercise american college of sports medicine american college of sports medicine position stand. appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license we would like to thank all the participants who participated in this study. the authors declare no conflict of interest. the institutional review board of tsinghua university (id number: 20190091) approved this research.participants' consent for publication: consent form was obtained from every participant in our study. detailed information about this study was posted on the top of the questionnaires. survey participants were asked to read all study information and sign a consent form online (answer yes/no and write signature) before completing the online structured questionnaire each time. key: cord-279227-l6keimm5 authors: li, yuxi; li, juan; zhong, dongling; zhang, yue; zhang, yonggang; guo, yan; clarke, mike; jin, rongjiang title: clinical practice guidelines and experts’ consensuses of traditional chinese herbal medicine for novel coronavirus (covid-19): protocol of a systematic review date: 2020-08-03 journal: syst rev doi: 10.1186/s13643-020-01432-4 sha: doc_id: 279227 cord_uid: l6keimm5 background: the world health organization declared on march 11, 2020, that the spread of the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has escalated from epidemic into pandemic. as the initial outbreak area, china has taken multiple active measures to deal with the epidemic. updated versions of diagnosis and treatment guideline for novel coronavirus (covid-19) patients have been issued, and traditional chinese herbal medicine has been recommended as a treatment. the objective of this study will be to summarize the recommendations in current clinical practice guidelines about the use of traditional chinese herbal medicine for covid-19 patients. we will also evaluate and report on the methodological and reporting quality of these guidelines. methods: in this systematic review, we will search for guidelines, expert consensuses, and policy documents published since december 2019 in electronic databases (e.g., pubmed, embase, and chinese databases) and on websites of governments or organizations (e.g., the national guideline clearinghouse [ngc], guidelines international network [gin], national institute for health and clinical excellence (nice), scottish intercollegiate guidelines network [sign], and who). eligible documents will be independently selected, and relevant data will be independently extracted by two reviewers. we will also independently evaluate the methodological quality and reporting quality of the included guidelines, using the appraisal of guidelines for research & evaluation (agree) ii tool and reporting items for practice guidelines in healthcare (right) statement, respectively. any discrepancies will be discussed and resolved through discussion among the reviewers. we will use the extracted information to summarize their recommendations for traditional chinese herbal formulae and chinese patent medicine for covid-19 patients and to summarize the strength and quality of these recommendations with reference to the results of agree ii and right tools. discussion: this review will summarize the recommendations in current clinical practice guidelines and provide insight into the implementation strategies for traditional chinese herbal medicine in covid-19 patients. systematic review registration: prospero crd42020179205 novel coronavirus (covid-19) pneumonia, caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was identified in wuhan, china, in late december 2019 [1, 2] . covid-19 patients mainly present with flulike symptoms (such as fever, cough, and dyspnea) and some other systemic symptoms (such as malaise, fatigue, and diarrhea) [3, 4] . with a range of 1 to 14 days for the estimated incubation period and various severity of clinical symptoms [5, 6] , human-to-human transmission of infectious disease has rapidly spread across the globe. the world health organization (who) declared a pandemic on march 11, 2020 [7] . with a global total now of more than 1 million cases, covid-19 patients have been diagnosed in more than 200 countries [8] . as the initial outbreak area, china has taken multiple active measures to deal with covid-19. the national health commission of china established the first version of diagnosis and treatment guideline of pneumonia caused by novel coronavirus on january 16, 2020. this contained the etiology of covid-19, clinical characteristics of patients, diagnosis, and treatments of this disease. as more information became available, updated versions of this diagnosis and treatment guideline were issued. since the third version of national covid-19 diagnosis and treatment guideline, traditional chinese herbal medicine has been recommended as a treatment for covid-19, based on different stages and syndrome differentiations of disease [9] . traditional chinese herbal medicine has played an important role in thousand-of-years' combat between chinese doctors and pandemic and endemic diseases. during the outbreak of severe acute respiratory syndrome (sars) coronavirus in the late 2002 in guangdong, china, traditional chinese herbal medicine showed beneficial effects such as relief of symptoms, decrease of mortality, and control of infection in patients with sars [10] [11] [12] [13] . with accumulated experiences of its anti-viral properties for the treatment of sars and strong encouragement from the chinese government [14, 15] , traditional chinese herbal medicine has also been applied in treating covid-19. the state council information office of china reported on march 23, 2020, that 74,187 covid-19 patients (91.5% of total confirmed covid-19 cases in china) had been treated with traditional chinese herbal medicine with promising outcomes [16] . along with the guideline issued by the national health commission of china, provinces, cities, and autonomous regions have also released clinical practice guidelines recommending traditional chinese herbal medicine. the syndrome differentiations, treating principles, and recommended formulae may differ across these guidelines because of the different characteristics of their respective regions and population. other reviews have been published which consider the treatment of covid-19 patients with traditional chinese herbal medicine and the guidelines for treating children with covid-19 with herbal medicine [17, 18] . the objective of this systematic review is to systematically summarize the recommendations in current clinical practice guidelines about the use of traditional chinese herbal medicine for covid-19 patients. we will also evaluate and report on the methodological and reporting quality of these guidelines. this systematic review is registered in the prospective register of systematic review (prospero) database (crd42020179205). this protocol is reported in accordance with the reporting guidance provided in the preferred reporting items for systematic reviews and meta-analyses protocols (prisma-p) statement [19] (see checklist in additional file 1). study design we will include clinical practice guidelines, experts' consensus statements, and guidance documents (systematically developed statements to assist practitioners and patient decisions about appropriate healthcare for specific circumstances) published by any advising body or healthcare organization since december 2019, which provide information on the use of traditional chinese herbal medicine therapy for covid-19 patients. participants recommendations for patients diagnosed with covid-19 pneumonia and the associated sars-cov-2 virus as confirmed by clinical tests (e.g., positive real-time fluorescent reverse transcription-polymerase chain reaction of respiratory or blood samples for sars-cov-2 virus nucleic acid, highly homologous of the respiratory specimen or blood specimen sequenced to sars-cov-2 virus). there will be no restrictions with respect to age, gender, or ethnicity. intervention we will include recommendations for chinese herbal medicine including chinese medicinal formulae and chinese patent medicine regardless of their forms (e.g., pill, powder, oral liquid). see additional file 2 for definitions and examples of chinese herbal medicine. we will exclude old versions of guidelines or consensus statement published by a single advising body or healthcare organization. we will search for guidelines, expert consensuses and policy documents published since december 2019 in the following electronic databases: pubmed, embase, chinese biomedical literature database (cbm), china national knowledge infrastructure (cnki), chinese science and technology periodical database (vip), and wanfang database (wanfang data). in addition, we will search other sources of guidelines including the following: the national guideline clearinghouse (ngc), guidelines international network (gin), national institute for health and clinical excellence (nice), scottish intercollegiate guidelines network (sign), and who. we will use search strategies that combine terms relating to novel coronavirus, traditional chinese medicine, and guideline. the search strategy for pubmed is described in additional file 3, and suitably modified search strategies will be applied to the other electronic databases. we will also search grey literature via websites of governments or organizations. no language restrictions will be applied. we will upload search results into the endnote x9 reference management software. duplicated references will be filtered and removed. two independent reviewers (yxl and dlz) will screen titles and abstracts to identify potentially eligible documents, which will be retrieved in full text for final review. any disagreements will be discussed and arbitrated by a third reviewer (ygz). we will design a data extraction form based on characteristics of included guidelines and consensuses. in order to achieve a consistency (at least 80%) in extracted items, we will pilot test the data extraction form with data extractors using a sample of eligible documents. results of this pilot extraction will be discussed among review authors and extractors before finalizing it. data extraction will be conducted independently by two reviewers (jl and yz) and will include the following data: (1) characteristics of guidelines: name, type, source, and date; (2) stage of disease; (3) syndrome differentiation; (4) treatment principle; (5) recommended formula; and (6) recommended chinese patent medicine etc. disagreements will be resolved by discussion among the review team. we will evaluate the methodological quality and reporting quality of the included guidelines using the appraisal of guidelines for research & evaluation (agree) ii tool [20] [21] [22] and reporting items for practice guidelines in healthcare (right) statement, respectively. in order to achieve consistency of at least 80% in the quality assessments, the assessors will pre-assess a sample of eligible documents and discuss their assessment among review authors and assessors. after that, two independent reviewers (yxl and jl) will appraise the quality of included guidelines. discrepancies will be discussed and resolved among the reviewers. with the information extracted from the included guidelines, we will summarize the recommendations made for traditional chinese herbal formulae and chinese patent medicine for covid-19 patients. the recommendations of prescriptions for different stages and syndrome differentiations of covid-19 will also be summarized. we will present the evidence in narrative format and tables with descriptive statistics (e.g., frequencies). the assessments from the use of the agree ii and right tools will be presented in tables with reporting rate of each item and the overall reporting rate. these findings will be discussed in light of the strength and quality of these recommendations with reference to the results of agree ii and right tools. this systematic review will comprehensively congregate information from and appraise the quality of guideline recommendations for traditional chinese herbal medicine for covid-19 patients. other reviews have either examined the application of traditional chinese herbal medicine for covid-19 patients or investigated current management for covid-19 patients. examples of other studies include ho and colleagues' work on the case definition, clinical classifications, and relevant treatments of covid-19 patients, in accordance to recommendations of the 7th edition of the national covid-19 diagnostic and treatment guideline of china [23] . in addition, du and luo have summarized the theoretical foundation and potential effect of chinese herbs on covid-19 patients [24, 25] and yang and colleagues outlined clinical data for sars-cov and compared the evidence of current applications of traditional chinese herbs in the treatment of covid-19 patients [26] . given the many guidelines and consensuses that are now being regularly updated to advise clinical practices on the use of traditional chinese herbal medicine for covid-19 patients, this review will provide an important overall summary of their recommendations and provide insight into relevant implementation strategies. there may be some limitations in our retrieving and reviewing of the evidence: (1) we will only search chinese and english databases, so we may miss guidelines published in other languages; (2) covid-19 is a very urgent public health issue requiring rapid responses, which means that the production of associated guidelines might not follow the standards for the development of guidelines in more usual times. some other considerations are that according to traditional chinese medicine, chinese herbs should be prescribed based on different constitutions of the population and the environment, and we will classify the data and discuss the results based on the theory. if changes are needed for this protocol, we will update our prospero entry as necessary. we intend to publish this review in a peer-reviewed journal. supplementary information accompanies this paper at https://doi.org/10. 1186/s13643-020-01432-4. a novel coronavirus emerging in china -key questions for impact assessment preliminary prediction of the basic reproduction number of the wuhan novel coronavirus 2019-ncov clinical features of patients infected with 2019 novel coronavirus in wuhan characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china analysis of clinical characteristics and outcomes in patients with covid-19 based on a series of 1000 patients treated in spanish emergency departments. evaluación de las características clínicas y evolución de pacientes con covid-19 a partir de una serie de 1000 pacientes atendidos en servicios de urgencias españoles who strategic and technical advisory group for infectious hazards. covid-19: towards controlling of a pandemic the covid-19 pandemic in the us: a clinical update treatment efficacy analysis of traditional chinese medicine for novel coronavirus pneumonia (covid-19): an empirical study from wuhan clinical observation on the preventive effect of kangdu bufei decoction on acute severe respiratory syndrome tcm treatment of infectious atypical pneumonia--a report of 16 cases effect of chinese herbal medicine on adrenal glucocorticoids in sars qingkailing injection () for treatment of children pneumonia induced by respiratory syncytial virus: a meta-analysis of randomized controlled trials the party group of the national administration of traditional chinese medicine conveyed the spirit of the key instructions of general secretary xi jinping and the request of premier li keqiang to study the prevention and control of novel coronavirus pneumonia (chinese) impact of herbal preparations on outcomes of highly active antiretroviral therapy: a one-year prospective cohort study the state council office held a conference on the important role of chinese medicine in the prevention and treatment of novel coronavirus pneumonia and effective drugs 2020 current state of research about chinese herbal medicines (chm) for the treatment of coronavirus disease 2019 (covid-19): a scoping review herbal medicine for treatment of children diagnosed with covid-19: a review of guidelines preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: elaboration and explanation quality assessment of clinical practice guidelines for infectious diseases in china clinical practice guidelines in india: quality appraisal and the use of evidence in their development quality of clinical practice guidelines about red blood cell transfusion highlights of traditional chinese medicine frontline expert advice in the china national guideline for covid-19 traditional chinese medicine: an effective treatment for 2019 novel coronavirus pneumonia (ncp) can chinese medicine be used for prevention of corona virus disease 2019 (covid-19)? a review of historical classics, research evidence and current prevention programs traditional chinese medicine in the treatment of patients infected with 2019-new coronavirus (sars-cov-2): a review and perspective publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations mike clarke, rongjiang jin, and yan guo designed the study. yuxi li, juan li, yonggang zhang, dongling zhong, and yue zhang drafted the manuscript. all authors approved the manuscript. this work was supported by the education fund of chengdu university of traditional chinese medicine. the funder has no role in developing this protocol.availability of data and materials not applicable. no ethics approval is required for this systematic review because we will be using information from published documents. our findings will be published in a peer-reviewed journal according to the prisma guidelines. not applicable. the authors declare that they have no competing interests.author details 1 school of acupuncture-moxibustion and tuina, chengdu university of key: cord-282871-y2i5pdmb authors: wiwanitkit, viroj title: chinese medicine in the management of new and emerging infectious diseases date: 2018-03-31 journal: digital chinese medicine doi: 10.1016/s2589-3777(19)30004-7 sha: doc_id: 282871 cord_uid: y2i5pdmb abstract emerging infectious diseases are an important problem in medicine, and many continue to pose a global threat. however, the management of new and emerging infections is usually difficult due to a lack of knowledge and tools to address the problem. the use of chinese medicine to manage new and emerging infectious diseases, however, has attracted significant attention. this brief article summarizes and discusses the use of chinese medicine in the management of new and emerging infectious diseases. infection is an important problem in contemporary medicine. there are many pathogens, including parasites, bacteria, viruses and fungi, which can cause disease in humans. sometimes, new infections caused by previously non-pathogenic organisms occur and become new problems in medicine. a single case report can signal the outbreak of a new and emerging infection, and often serves as a warning to anticipate future outbreaks [1] , which is an important problem in [2] ; even more time is usually required for the development of diagnostic and therapeutic tools [2] . searching for new therapies against new emerging infections is a critical step in management strategies. the use of chinese medicine in this regard has become an interesting avenue of investigation. in this brief article, the use of chinese medicine in the management of new emerging infectious diseases is summarized and discussed. chinese medicine is actually a valuable derivative of asian wisdom. given its long history, chinese medicine has been successfully used in the management of several diseases, including infections, for many thousands of years. there is little doubt that chinese medicine is a source of "hidden gems" for the management of several diseases. in modern medicine, a representative example of applied chinese medicine in the management of emerging infection is the case of classical drug-resistant malaria. malaria is a prevalent tropical mosquito-borne infection that is common in several tropical countries around the world. the use of classical quinine antimalarial drug has been recommended for decades. nevertheless, due to poorly controlled drug use in many developing tropical countries, the emergence of drug-resistant malaria has occurred [3] . the problem was initially encountered in southeast asia [3] , and the search for a new drug became an important issue. finally, the success in finding a new drug against classical antimalarial drug-resistant malaria was based on the reappraisal of a chinese medicine regimen. "artemisinin (qing hao su, 青蒿素)" is a traditional chinese herb with proven antimalarial activity [4] , and is effective against classical antimalarial drug-resistant malaria. in fact, the new antimalarial drug, artemisinin, was successfully developed from artemisinin (qing hao su, 青蒿素) [5] . presently, artemisinin is the drug of choice for management of classical drug-resistant malaria in tropical medicine [6] . the as mentioned, an increased role for chinese medicine in the management of new and emerging infectious diseases can be anticipated, and some reports describing its use have already been published. there are many new emerging cross-species influenza infections. in the past few years, the typical emerging influenzas are usually a serious zoonotic influenza that repeatedly occurs, with bird flu being a well-known example. as an avian-related disease, control of poultry farming is the current standard of practice against bird flu due to the lack of effective antiviral therapy, which makes the management of emerging bird flu problematic. applications for chinese medicine have, however, been found in this context. chang et al. [7] noted that "traditional chinese medicine de novo derivatives may be suitable candidates of dual-targeting drugs for influenza". the authors also noted the use of standard modern chinese medicine databases as a basic tool for new chinese medicine-based drug discovery against new and emerging influenzas [8] . of several chinese medicine regimens, the use of the edible bird's nest (ebn) has been widely proposed for its possible effectiveness against new and emerging influenzas, and its utility has been extensively studied. haghani et al. studied the "in vitro and in vivo mechanism of immunomodulatory and antiviral activity of ebn against influenza a virus infection [9] . immunomodulation via cytokine induction due to ebn has been reported [10] . haghani et al. [11] commented on "the potential of ebns as supplementary medication or alternative to antiviral agents to inhibit influenza infections". in addition to ebn, the efficacy of ginseng against emerging influenza has also been intensively studied. in an experimental animal study, dong et al. [12] found that "treatment of mice with ginsenosides (ren shen zao dai, 人参皂甙) protected the animals from lethal 2009 pandemic h 1 n 1 infection and lowered viral titers in animal lungs", and concluded that "the interference in the viral attachment process subsequently minimizes viral entry into the cells and decreases the severity of the viral infection" [12] . interestingly, the use of chinese medicine for the management of influenza is currently a common practice. at present, lian hua qing wen capsule (lqc) is a common chinese medical preparation containing flavonoids, phenylpropanoids, anthraquinones, triterpenoids and iridoids, and is widely used to treat viral influenza [13, 14] . lqc has also been used to treat and manage an outbreak of sars [13] . according to the sars crisis, leung analyzed the role of chinese medicine and reported that "the results revealed positive but inconclusive indications about the efficacy of the combined treatments using chinese medicine as an adjuvant" [16] . the author also reported that "positive effects using adjuvant herbal therapy included better control of fever, quicker clearance of chest infection, lesser consumption of steroids and other symptoms relief" [16] . [17] . the emerging infections [18] . the usefulness of case reports in managing emerging infectious disease reporting on emerging infectious diseases epidemiology of drug-resistant malaria qinghaosu and its derivatives malaria: an update poultry workers, avian flu and prevention two birds with one stone? possible dual-targeting h1n1 inhibitors from traditional chinese medicine in vitro and in vivo mechanism of immunomodulatory and antiviral activity of edible bird's nest (ebn) against influenza a virus (iav) infection edible bird's nest modulate intracellular molecular pathways of influenza a virus infected cells protective effect of korean red ginseng extract on the infections by h1n1 and h3n2 influenza viruses in mice inhibition of influenza a virus infection by ginsenosides qualitative and quantitative analysis of the major constituents in chinese medical preparation lianhua-qingwen capsule by uplc-dad-qtof-ms complementary and alternative medicine is expected to make greater contribution in controlling the prevalence of influenza traditional chinese medicine herbal extracts of cibotium barometz, gentiana scabra, dioscorea batatas, cassia tora, and taxillus chinensis inhibit sars-cov replication the efficacy of chinese medicine for sars: a review of chinese publications after the crisis experience of integrated traditional chinese and western medicine in first case of imported zika virus disease in china the need of asian pharmaceutical researchers' cooperation the author declares no conflict of interest. key: cord-296816-mzd1499c authors: huang, yanzhong title: china's response to the 2014 ebola outbreak in west africa date: 2017-01-30 journal: glob chall doi: 10.1002/gch2.201600001 sha: doc_id: 296816 cord_uid: mzd1499c beginning in march 2014, west africa has endured the largest outbreak of ebola viral disease (evd) in history. the crisis highlighted the role of china in addressing public health emergencies of international concern (pheic). through bilateral and multilateral channels, china kicked off its largest ever humanitarian mission in addressing a pheic. the unprecedented generosity served the domestic needs to prevent evd from spreading into china, but it was also consistent with china's foreign policy objective to pursue soft power in africa. while its total funding to evd control in west africa was no match of top donors like the united states, it becomes much more impressive when adjusted for gross domestic product (gdp) per capita. as beijing becomes more sensitive to disease outbreaks overseas and as the scope of its humanitarian engagement grows and diversifies, the space for china's cooperation with international actors over global health governance is expected to further expand. china been in addressing the outbreak? what factors have incentivized china to respond in the way that it did? did china contribute its fair share? and to what extent does this tell us about china's engagement in future global governance for public health emergencies? using both quantitative and qualitative data, this paper examines the patterns and performance of china's response to the 2014 ebola outbreak. the study finds that beijing has become increasingly sensitive to disease outbreaks that originate from abroad, and the expanding humanitarian engagement opens the space of international cooperation over the global governance for pheic. unlike its initial mishandling of the 2002-2003 severe acute respiratory syndrome (sars) outbreak, the chinese government's response to the ebola outbreak was swift and proactive. on march 24, 2014, right after guinea health authorities confirmed the presence of an evd outbreak, the chinese embassy sent warnings to chinese nationals there. in early april, the chinese government provided guinea with $50 000 in cash as emergency humanitarian aid. [6] this was followed by emergency assistance to the two other western african countries most severely impacted by the outbreak, liberia and sierra leone. at that time, china claimed that it was the first country to provide sierra leone medical aid to fight ebola. [7] almost at the same time, china began to undertake ebola prevention and control measures back home. emphasis was placed on monitoring passengers arriving from ebola-affected countries for fevers. in guangzhou, which has up to 200 000 african residents, [8] the local government authorities implemented de facto quarantine measures against passengers from west africa, who were asked to stay at designated hotels and report their body temperature at required intervals using global positioning system (gps)-enabled mobile phones. [9] on august 12, 4 d after the world health organization (who) declared the evd outbreak to be a pheic, china set up a joint prevention and control mechanism consisting of 22 central ministries to address ebola prevention and control and to develop a contingency plan for the outbreak. [10] by november, the mechanism had enabled the health and inspection departments to screen more than 26 000 arrivals, identifying 88 people with fevers, though no confirmed cases of ebola were found. [11] the outbreak also prompted china to accelerate the development of ebola diagnostic kits and medical countermeasures. in beginning in march 2014, west africa has endured the largest outbreak of ebola viral disease (evd) in history. as of june 2016, the virus has infected over 28 600 people and caused more than 11 300 deaths. [1] the catastrophe brought to light "massive failure of global health governance." [2, 3] but the same crisis also seemed to highlight the role of china in addressing public health emergencies of international concern (pheic). [4] while visiting west africa in august 2015, chinese foreign minister wang yi noted that china in carrying out its largest ever health aid program in history created multiple "firsts": the chinese president was the first head of state to commit explicitly to answering the call for help by three western african countries; china used large chartered airplanes to ship the first batch of badly needed anti-epidemic supplies; china for the first time deployed a whole unit of epidemic prevention forces and military medical staff abroad; china built a biosafety level 3 (bsl-3) lab overseas, and set up an infectious disease medical center in another country for the first time. [5] while the accuracy of wang's remarks is debatable, they raise interesting questions regarding china's involvement in the global response to the evd outbreak. how responsive has august, the people's liberation army (pla) academy of military medical science announced that it had developed china's first drug (jk-05) for treating ebola. in november, the chinese food and drug administration approved the test reagent developed by three chinese firms, making china one of the few countries that could produce diagnostic kits. the same month, the national health and family planning commission (nhfpc) distributed clinical guidelines on ebola response to all local health administrations and hospitals in china. [12] yet compared to its high-profile responses to the 2009 h1n1 pandemic and the 2013 h7n9 outbreak, china seemed to adopt a less aggressive domestic approach toward the 2014 evd outbreak. in sharp contrast to the zealous coverage of the previous two flu outbreaks, chinese media and society appeared nonchalant toward the possible spread of ebola in china. [13] between august and december of 2014, the author had three times visited china, but did not notice any apparent panic or fear among ordinary chinese over the potential spread of ebola in china. the relatively low-profile domestic response was not so much the result of growing confidence in the government response capacity as it was the result of a more realistic assessment of the risk that evd posed to china. a cross-sectional survey carried out in guangzhou in november 2014 found that more than half of the respondents lacked confidence in the government ability to control an evd outbreak. [14] earlier, a study conducted by chinese scientists predicted a total of 6 to 194 imported cases in china. [15] in view of the growing trade and travel links, some leading international public health experts were concerned that china was at serious risk of ebola. [16] senior chinese health officials agreed that there was risk of the virus spreading into china or chinese citizens contracting the virus overseas, but they apparently had no intention to overestimate the risk and incite major worries at home. [4, 17] after all, china did not have any direct flights to the three western african countries. according to a study published in the lancet, the top six destination countries of flights departing from west africa were all in other parts of africa followed by three european countries. china was ranked number ten in terms of passenger destinations, but the total passenger flow only accounts of 18% of that of uk and france combined. [18, 19] that being said, and the perceived low risk of ebola spread did not lead china to write off the threat of the virus completely. the evd outbreak unfolded at a time when the youth olympic games was about to be held in nanjing and a large number of africans were anticipated to visit china in late august. [20] noting, "a single ebola case during the games would become headlines overshadowing news on the games," an editorial of the official global times on august 4 called for "doing a seamless job in preventing the virus from infiltrating china." [20] there were also concerns that the ebola virus might ruin the annual world economic forum meeting in the city of tianjin, where hundreds of business and research leaders were to gather in september, and the 2014 asia-pacific economic cooperation economic leaders' meeting, which was to be held in beijing in november. the chinese center for disease control and prevention (china cdc) vowed to implement "olympiclevel preventative measures" to contain the virus. [21] in mid-august, when the youth olympics began, the government kicked off new preventive measures, including banning athletes from affected countries from competing in certain events. [22] the evd outbreak in west africa also threatened beijing's economic interests in the region. china is africa's largest trade partner and chinese firms currently engage in $15 billion worth of work in west africa. it is a key trading partner for the three most affected countries, accounting for 47% of sierra leone's total trade volume, 18% of liberia's, and 12.4% of guinea's. [23] prior to the outbreak, china's growing economic activities with africa had raised the question of whether beijing was only interested in accessing the market in order to secure the supply of natural resources in africa and not in promoting inclusive economic development in the subcontinent. during the evd outbreak, there were reports suggesting that china's efforts to develop mineral deposits and build roads in western africa might have brought infected animals into closer contact with humans, thereby facilitating the rapid spread of ebola. [24] for economic and reputational reasons, it was in beijing's interest to improve its image in the region. besides participating actively in peace building efforts, health aid had increasingly become an important foreign policy instrument for china to project in africa its soft power, defined by joseph nye as the ability to shape the preferences of others through appeal and attraction. [25] [26] [27] as the second white paper on foreign aid indicated, china emphasized the delivery of emergency humanitarian aid as a major form of china's foreign aid. [28] the ebola outbreak thus opened a window of opportunity for china to showcase its soft power in africa while foiling criticism about beijing's mercantilist behavior in the region. [29] china made no secret its intention to use the humanitarian aid as a tool to compete with other countries for soft power in africa. according to a scholar at the government think tank: as a matter of fact, china's soft power building in africa is still at its preliminary stage. in particular, china suffers from the deficit of cultural soft power in africa. china's advantages in soft power building in africa lies more in the attractiveness of its african policy, that is, foreign policy, in which health diplomacy to africa as an important component of public diplomacy is the most effective and most influential. [30] against this background, it came as no surprise that the front line of china's battle against ebola was moved beyond its borders. according to senior chinese health officials, providing aid to west africa was crucial in china's efforts to construct a "barrier" against the spread of the virus. [31] minister li bin of nhfpc was candid when she explained why china supported western africa's fight against ebola: "infectious diseases know no boundaries … china by helping west african nations is also helping itself." [32] overall, china responded to the ebola epidemic in west africa with unprecedented generosity. while it was not unusual for china to offer humanitarian aid to countries affected by natural disasters, this was the first time china extended massive humanitarian aid to countries fighting a public health emergency. by late november of 2014, china had-throughout four consecutive phases in april, august, september, and october-offered $123 million (750 million yuan) worth of humanitarian aid to the global ebola control efforts, china's largest ever response to an international humanitarian crisis. the package included the provision of in-kind contributions comprising of ambulances, motorcycles, medical equipment as well as prevention care supplies. it also included food aid, deployment of medical teams, and public health experts, as well as labs and treatment centers. unlike other donors, china also provided aid to countries surrounding the three western african countries: it provided 1800 tons of equipment and supplies to 13 countries in the region. [33] in guinea, two-thirds of the anti-ebola supplies were reportedly from china. there were also reports that by mid-october china had sent enough of the experimental anti-ebola drug (jk-05) to west africa to treat 10 000 people. [34] while the effectiveness of the drug remains unknown, another chinese-developed experimental drug (mil77) successfully treated a british military nurse who contracted ebola while serving in sierra leone. [35] chinese scientists also developed their own ebola vaccine that was found to be effective based on results of the first phase-one clinical trial. [36] unlike the other two experimental vaccines in human trials developed by the u.s. and canadian scientists, the chinese vaccine is the only one that has used genetic material from the current outbreak strain. [37] in may 2015, the who also approved an ebola test reagent developed by a chinese firm, which was ten times more sensitive than the benchmark for existing ebola diagnostic. [38] china dispatched a large number of health personnel to west africa. in august 2014, it sent three teams of infectious disease experts (totaling 115 people) to assist local medical professionals in the ebola-stricken countries. this occurred at a time when aid groups from the united states, europe, and japan were evacuating their own in droves. [29] in mid-september, a 59 member chinese laboratory team departed for sierra leone to help the country build its lab testing capacity, joining the chinese medical staff that had been on the ground virtually since the beginning. the who director-general margaret chan called china's commitment "a huge boost, morally and operationally." [39] in november, china launched a treatment center in liberia. according to the chinese ambassador to liberia, china was the only country to provide the construction of an ebola treatment unit (etu) as well as the operation and staffing of the unit. [40] this was followed by the announcement that china would send an additional 1000 personnel to help fight the outbreak, making china the largest contributor of medical staff to the crisis. [41] in sierra leone, the mobile lab that china helped construct reportedly tested 20% of the samples in the country, with 100% accuracy. in the meantime, china started to build a permanent biosafety lab in sierra leone. launched in march 2015, the lab was the first permanent bsl-3 lab in africa. by the end of the month, chinese health personnel had tested 5000 samples and treated 900 patients in west africa. [42] the number of chinese professionals would eventually reach 1200. [5] in addition, chinese health workers trained 12 000 local medical and public health personnel. [43] despite its preference for bilateral aid, some of china's aid to western africa was routed through international and regional organizations. in october 2014, china pledged to provide $6 million to the world food programme (wfp) for vital food supplies, as well as $2 million funding for who and the african union respectively. through wfp, china provided 5500 tons of food aid to the three most affected western african countries. [33] on december 2, china contributed an additional $6 million to complement un emergency efforts through the un ebola response multi-partner trust fund. [44] besides tangible assistance, chinese domestic experience in fighting major disease outbreaks offered a reference point for the three countries most affected by the ebola virus. since the virus is transmitted through contact with bodily fluids, quarantine measures-widely used in china's fight against avian flu-could help break the chain of infection. given that early symptoms of ebola infection are similar to those of h7n9, china's experience in handling the flu cases could also be useful to ebola treatment. in august 2014, the official xinhua news agency quoted who officials saying that african countries could learn from china's experience in addressing the 2013 h7n9 outbreak as well as from its successful investment in public health. [65] a chinese scholar went as far as to claim that, "china's experience [in disease prevention and control] applies to the whole world." [45] there were reports suggesting that liberia did learn from china in applying some of the public health measures such as quarantine to ebola control. [46] the role of major non-state actors such as médecins sans frontières (msf) notwithstanding, china appeared to be more responsive to the evd outbreak in west africa than many the organization for economic cooperation and development (oecd) countries in the initial stage of the crisis. in april and august 2014, it twice provided aid packages worth more than $5.5 million to the three ebola-hit countries and guinea-bissau. in comparison, large amounts of personnel and funding support from other countries did not arrive until after august and september, when evd cases mushroomed and the potential global impact became clearer. still, international pressures built with calls for china to play a more aggressive role in the global fight against ebola. president barack obama voiced his frustration that china lagged behind the united states in funding the anti-ebola effort, while a un agency criticized chinese billionaires for not contributing enough to fight the virus. [47] did china contribute its fair share to the global fight against ebola? it is hard to dispute that china trailed major oecd countries in certain aspects of health aid to western africa, such as building labs and etus. china constructed a total of 2 bsl labs, compared with 12 by the united states, 16 by canada, and 3 by united kingdom. it had only organized 1 etu with 100 treatment beds, compared with 15 by the united states with 1700 treatment beds. [48] its share in global humanitarian funding against evd outbreak was not significant, either. according to the data compiled by office for the coordination of humanitarian affairs (ocha), in 2014 china contributed a total of $47 million (1.3% of the grand total), which was dwarfed by the $1.8 billion u.s. contribution (49% of grand total). to be sure, funding from china was higher than traditional donors such as norway and switzerland, as well as countries such as india and russia. but china also lagged behind united kingdom, germany, the world bank, the european commission, france, sweden, japan, canada, and the netherlands in terms of total funding ( table 1) . total humanitarian funding as compiled by ocha nevertheless may not be an accurate indicator of china's actual contribution to the global campaign against the evd outbreak. china's contribution becomes much more impressive if adjusted according to gross domestic product (gdp) per capita. adjusting for gdp per capita takes into account the country's still daunting domestic development challenges and its large population as compared to other oecd countries. when adjusted by gdp per capita, china's contribution is still no match of that of united states, but is close to that of united kingdom, and higher than the contribution of other oecd countries. interestingly, china and india had similar aid amount/gdp per capita ratio, suggesting a similarity in the dilemma that the two countries face in balancing their domestic development needs and the growing demands for them to assume more international responsibilities (figure 1) . furthermore, the ocha data does not include all in-kind support such as ambulances, pickup trucks, motorcycles, incinerators, and personal protective equipment. it also does not include the contribution of medical staff and public health experts for ebola containment efforts, which accounts for a significant share in china's humanitarian assistance. equally important, it does not do justice to the shifting modalities of china's health aid to africa. for a long time, the chinese medical teams (cmts) posted in africa on a rotation basis have been the main instruments of china's health-related development assistance in the region. while the cmts play an instrumental role in providing routine medical services to local residents-indeed, a cmt treated the first case of ebola in conakry (guinea's capital)-they are not adaptable and flexible enough to respond to large-scale disease outbreaks. this may explain why in addition to mobilizing cmts already on the ground, china also dispatched emergency medical teams whose members were recruited directly from domestic health institutions. in addition, while beijing continued to rely on more traditional humanitarian assistance instruments such as in-kind contributions and food aid, it also diversified the modalities global challenges 2017, 1, 1600001 www.global-challenges.com www.advancedsciencenews.com of aid to building labs and treatment centers and health personnel training. this points to "a much more comprehensive, demand-driven response" to affected countries' needs. [44] in doing so beijing might still prefer bilateral aid, but a significant volume of its humanitarian aid has been channeled through multilateral international institutions, suggesting that beijing is becoming more flexible in backing coordinated international response mechanisms. [44] a lot of ink has been spilled on the implications of the 2014 evd outbreak for international relations and global governance. [49, 50] interestingly, very little has addressed china's role in the global fight against ebola. this paper argues that china's participation sheds lights on its future engagement in global governance for public health emergencies. first, china's rise in a globalized context has made it increasingly sensitive to exogenous shocks such as pheic. while china's growing interaction with the outside world makes it more susceptible to global health hazards, its reemergence as a global power with ever greater interests also means that it cannot fulfill its domestic needs without a more proactive global strategy. in the case of ebola outbreak, the risk of the virus infiltrating china, and evolving into a major outbreak was comparatively low. however, the sheer prospect of having imported cases wreak havoc on major international events china was to host, coupled with china's significant economic and political ties to africa, prompted beijing to support a swifter and more decisive approach to the evd outbreak. it also explains why china quickly scaled up its efforts after it came under fire for the level of its response to the ebola crisis. in responding to the criticism, china made it clear that its aid to western africa would not stop as long as the epidemic raged. [51] second, beijing's prompt response to the ebola crisis opens space for further international cooperation over global health security. over the past two decades, the interconnection between global health and security has attracted attention from both policy makers and scholars alike. [52] [53] [54] [55] unlike the united states and other countries, beijing has not explicitly framed the ebola outbreak as an international security threat or deployed a large number of military personnel to the affected countries (as the u.s. did). its dispatch of elite pla units to the affected countries nevertheless suggests that it did view the outbreak as an existential security threat that required a response out of the normal political boundaries. indeed, beginning in 2004 the pla has been entrusted with "new historic missions" requiring it to increase its involvement in more straightforward humanitarian and relief operations. [56] in a move that demonstrated its new power projection capabilities, it took the pla no. 302 hospital just 3 days to assemble a team of 31 medical personnel and mobilize 150 tons of material supplies for the mission to west africa in september 2014. it took the pla medical support forces in sierra leone just one week to convert a small general hospital into one specializing in treating infectious diseases, and just one month to construct a state-of-the-art ebola treatment centers (etc) with 100 treatment beds. while there is no indication that pla medical corps worked closely with their u.s. and u.k. counterparts in evd diagnosis, treatment and containment, in light of the combined international efforts in this regard chinese actions should be viewed as part of a larger effort by the richer countries to provide direct aid through personnel and materials. [57] furthermore, beijing's willingness to implicitly securitize trans-border disease outbreaks has opened a new area for future collaboration between china and other countries (e.g., the u.s.) under the global health security agenda, a global partnership that seeks to elevate global health security as a national and global priority. indeed, during the crisis chinese military personnel trained a liberian engineering company so that the latter could play an instrumental role in helping the u. s. army to construct its treatment center in the country. similarly, the u.s. air force provided large forklifts to help unload the supplies that china brought to liberia. [66] when a limited supply of zmapp (an experimental drug being tested against ebola) was quickly exhausted, a small private chinese company raced ahead in the fall of 2014 and within three months made more potentially lifesaving treatments available by producing about 100 doses of mil77 based on information in zmapp's patent. [58] meanwhile, the application of a security approach to the ebola outbreak also underscored the need to reexamine the appropriateness of quarantine measures in handling acute disease outbreaks in the future. like china, the liberian government sought to enforce strict quarantine measures and restrict the movement of people during the crisis. while it is still unknown whether this actually resulted in reduced ebola infections throughout the country, evidence did support the exacerbated conditions in the sealed districts. [59] in that sense, beijing's contribution to the fight against evd in west africa fits with hedley bull's model of a 'society of states' coming together to deal with a global public bad. [60] third, china's differentiated response toward the outbreak highlighted the challenges of reconciling the gap between domestic and foreign policy objectives. in view of the devastating power of the virus as well as the absence of core surveillance and response capacities in the three affected countries, the seemingly self-serving containment strategy contributed positively to the global efforts to stem the spread of the virus and mitigate its devastating impact in west africa. its unprecedented generosity and its decision not to evacuate its citizens from affected countries may also help china win hearts and minds in the region. but the emphasis on preventing the virus from entering china also led china to discriminate against travelers from affected countries, such as imposing restrictions from athletes who were about to compete in the youth olympics. unhappy about being stigmatized over fears of ebola in china, sierra leone and liberia decided against sending delegations to nanjing. nigeria did send its team, but it pulled out of the competition after its athletes were isolated and barred from training due to concerns over ebola. [61] while china might consider its discriminatory move necessary to protect its own people and ensure success of the games, it also tarnished its reputation and undermined its foreign policy objective of projecting soft power in the region. [62] china faced a similar dilemma when dealing with the 2009 h1n1 pandemic, where government quarantine measures targeting mexican citizens caused a diplomatic row between the two countries. [25] this gap between domestic politics and foreign policy objectives is also attested to by the general absence of chinese civil society organizations in international humanitarian efforts, even though a small number of chinese professional volunteers reportedly participated in the front-line fight against ebola by joining msf and other non-governmental organizations (ngos). [13] finally, while the crisis called for a coherent and coordinated approach to an overseas disease outbreak, the bifurcation of foreign policy and business interests in a new, globalized context makes such coordination increasingly difficult. in order to maintain laboriously built goodwill and future business opportunities in the region, it was in beijing's foreign policy interest to distinguish itself from western countries (whose workers fled west africa when ebola struck) by not evacuating the thousands of imported chinese workers at sites. [63] however, ebola's devastating impact simultaneously triggered panic among chinese nationals in the region. not surprisingly, even though beijing did not broadcast any evacuations, the number of chinese living in affected countries-which included both workers affiliated with state owned enterprises and those who came there entirely of their own initiative-dropped by nearly half in the region from a high of 20 000 chinese nationals in the summer of 2014. [64] this forced the chinese ambassador to liberia to intervene and requested local chinese companies not to allow their workers to leave the work sites. [23] moreover, as the state expanded its engagement in global anti-ebola efforts, china's private sector contribution remained negligible, especially in light of the fact that the number of billionaires in the country is second only to the united states. a un agency reportedly lashed at out china's billionaires for not contributing enough to fight ebola. in liberia, locals were disappointed with the lack of significant contributions made by a chinese mining company. [64] during 2014-2015, china demonstrated a strong commitment to evd prevention and control in west africa. through bilateral and multilateral channels, china kicked off its largest ever humanitarian mission in addressing a pheic. its health aid package included cash and in-kind contributions, the dispatch of a large number of health personnel, the construction of bsl labs and treatment centers, and the development and implementation of medical countermeasures. the unprecedented generosity served the domestic needs to prevent evd from spreading into china, but it was also consistent with china's foreign policy objective to pursue soft power in africa. while its total funding to evd control in west africa was no match of top donors like the united states, it becomes much more impressive when adjusted for gdp per capita. as beijing becomes more sensitive to disease outbreaks overseas and as the scope of its humanitarian engagement grows and diversifies, the space for china's cooperation with international actors over global health security issues will only expand. the depth and breadth of that cooperation though will continue to be constrained by the gap between its domestic and foreign policy objectives, and the bifurcation of foreign policy and business interests overseas. in short, china's response to the evd crisis in west africa has revealed both opportunities and limits for its participation in future global governance for pheic. ebola virus disease time for the reckoning the national interest embassy of the people's republic of china in the federal republic of nigeria embassy of the people's republic of china in the republic of guinea science insider [www document east china likely to handle ebola transfer cases, china daily (beijing) (accessed renmin zhengxie bao (cppcc news) the new york times xinjing bound to lead: the changing nature of american power soft power: the means to success in world politics information office of the state council, white paper on china's foreign aid china builds its soft power in africa during the ebola crisis ebola technical lunch meeting china sends thousands of doses of anti-ebola drug to africa the guardian reuters issue brief: china's role in the ebola crisis introduction at "the health sector meets the security sector" event, graduate institute the telegraph [www document the civilmilitary response to the 2014 ebola outbreak in west africa, the university of sydney disease and security: natural plagues and biological weapons in east asia living weapons: biological warfare and international security contagion and chaos: disease, ecology, and national security in the era of globalization routledge handbook of global health security the china challenge: shaping the choices of a rising power the new york times the anarchical society: a study of order in world politics the world post the people's network media interview with ministry of commerce spokesman the author would like to thank suerie moon and the harvard global health institute for their support in initiating this study. the author would also like to thank the council on foreign relations, where he is a senior fellow for global health, and ariella rotenberg, lauren greenwood, and gabriella meltzer for their research support. the author declares no conflict of interest. key: cord-258991-mrs5j2ep authors: huang, yeen; zhao, ning title: generalized anxiety disorder, depressive symptoms and sleep quality during covid-19 outbreak in china: a web-based cross-sectional survey date: 2020-04-12 journal: psychiatry res doi: 10.1016/j.psychres.2020.112954 sha: doc_id: 258991 cord_uid: mrs5j2ep china has been severely affected by coronavirus disease 2019(covid-19) since december, 2019. we aimed to assess the mental health burden of chinese public during the outbreak, and to explore the potential influence factors. using a web-based cross-sectional survey, we collected data from 7,236 self-selected volunteers assessed with demographic information, covid-19 related knowledge, generalized anxiety disorder (gad), depressive symptoms, and sleep quality. the overall prevalence of gad, depressive symptoms, and sleep quality of the public were 35.1%, 20.1%, and 18.2%, respectively. young people reported a significantly higher prevalence of gad and depressive symptoms than older people. compared with other occupational group, healthcare workers were more likely to have poor sleep quality. multivariate logistic regression showed that age (< 35 years) and time spent focusing on the covid-19 (≥ 3 hours per day) were associated with gad, and healthcare workers were at high risk for poor sleep quality. our study identified a major mental health burden of the public during the covid-19 outbreak. young people, people spending too much time thinking about the outbreak, and healthcare workers were at high risk of mental illness. continuous surveillance of the psychological consequences for outbreaks should become routine as part of preparedness efforts worldwide. coronavirus disease 2019 (covid-19, also known as 2019-ncov), a cluster of acute respiratory illness with unknown causes, has occurred in wuhan, hubei province, china since december 2019 (wuhan municipal health commission, 2020; paules et al., 2020; wang et al., 2020) . as of march 25, 2020, a total of 81,846 covid-19 cases in china have been confirmed and 3,287 chinese died from the disease. internationally, sporadic cases exported from wuhan were reported in 193 countries (such as 69,176 cases in italy, 42,058 cases in spain, and 53,588 cases in united states), 5 continents, and 1 international conveyance (712 cases in "diamond princess") (world health organization, 2020a). on january 23, wuhan city closed all access routes to stop the spread of disease. seven days later, the world health organization (who) declared the covid-19 as a public health emergency of international concern (pheic) (world health organization, 2020b). on march 11, the who declared the covid-19 outbreak could be characterized as a "pandemic" as the virus spreads increasingly worldwide. in addition to physical damage, covid-19 also has a serious impact on the mental health of the public. in january 20, china confirmed human-to-human transmission of covid-19 and some medical staff in wuhan had been infected (xinhuanet, 2020) . since then, the public has shown anxiety-related behaviors, causing a significant shortage of medical masks and alcohol across the country. on the night of january 31, due to a news that "shuanghuanglian oral liquid" could suppress covid-19 (people's daily of china, 2020), the public rushed to pharmacies overnight to buy this drug. in addition, many front-line medical staff work more than 16 hours a day on average, causing them to not getting enough sleep. unfortunately, a 37-year-old japanese government worker who was in charge of isolated returnees from wuhan was found to have died from apparent suicide (the japan times, 2020). evidence indicated that covid-19 is a distinct clade from the betacoronaviruses related to human severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) . several studies showed that mental health problems could occur in both healthcare workers and sars survivors during the sars epidemic (lee et al., 2007; lu et al., 2006; mcalonan et al., 2007) . post-traumatic stress disorder (ptsd) and depressive disorders were the most prevalent long-term psychological condition (mak et al., 2009) . similar results have been reported in the previous study of mers (lee et al., 2018) . based on the above research evidence, we have reason to speculate that the psychological condition of the public may also be affected during covid-19 outbreak. therefore, using a web-based cross-sectional study, we aimed to assess the mental health burden of chinese public during covid-19 outbreak, and to explore the potential influence factors. we hope that our study findings will provide data support for the targeted interventions on psychological health in chinese public during the outbreak. to prevent the spread of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) through droplets or contact, we used a web-based cross-sectional survey based on the national internet survey on emotional and mental health (nisemh), an ongoing, online health-related behavior survey of chinese population, to collected data. this web-based survey of the covid-19 was sent on the internet through the wechat public platform and the mainstream media. all chinese people using wechat or other social tools may see this survey, and answered the questionnaire by scanning the quick response code (qr code) of the questionnaire address or clicking the relevant link. to encourage the recruitment of potential participants, all participants in the survey can receive a report on their mental health after completing the evaluation. this web-based questionnaire was completely voluntary and non-commercial. participants answered the questionnaires anonymously on the internet from february 3 to, 2020 to february 17, 2020. all subjects reported their demographic data, covid-19 related information, and completed three standardized questionnaires which assessed their generalized anxiety disorder (gad), depressive symptoms, and sleep quality. in order to ensure the quality of survey, we set the response range of some items (e.g., the age range was limited to 6-80 years old, some items needed to be answered in reverse) and encouraged participants to answer carefully through questionnaire explanations. in addition, questionnaires that were completed <1 minute or >60 minutes would be excluded from analysis. finally, a total of 7,236 participants who completed the questionnaires (response rate of 85.3%) were included in the analysis. this study was conducted in accordance with the declaration of helsinki, and was approved by the ethics committee of huazhong university of science and technology union shenzhen hospital. electronic informed consent was obtained from each participant prior to starting the investigation. participant could withdraw from the survey at any moment without providing any justification. demographic variables included gender (male or female), age, and occupation. occupation included the following four types: (1) healthcare workers, which included doctors, nurses, and health-related administrators; (2) enterprise or institution workers, which consisted of enterprise employees, national/provincial/municipal institution workers, and other relevant staff; (3) teachers or students, which included teachers or students from universities, middle schools, or elementary schools; and (4) others, which consisted of freelancers, retirees, social workers, and other relevant staff. e. there are already targeted drugs that could cure the disease; f. taking "shuanghuanglian oral liquid" could prevent infection of this disease. of the above six questions, one point was given for each correct answer, and no points were given for each incorrect or uncertain answer. participants with scores ≥5 points, equal to 4 points, and ≤3 points were considered to quite understand, generally understand, and do not understand. we used chinese version of gad-7 (generalized anxiety disorder-7) scale to assess subject's anxiety symptoms. the gad-7 has been previously used in chinese populations, and found to have good reliability (cronbach's alpha=0.90) (tong et al., 2016; wang et al., 2018) . seven items assessed the frequency of anxiety symptoms over the past two weeks on a 4-point liker-scale ranging from 0 (never) to 3 (nearly every day). the total score of gad-7 ranged from 0 to 21, with increasing scores indicating more severe functional impairments as a result of anxiety (spitzer et al., 2006) . for the purpose of this study, we defined a gad-total score of 9 points or greater as the presence of anxiety symptoms (wang et al., 2018) . the center for epidemiology scale for depression (ces-d) in chinese version was used to identify whether participants had depressive symptoms (zhang et al., 2010) , and the chinese version of this scale has been validated and extensively utilized in chinese population (zhang et al., 2010; zhang and li, 2011) . twenty items assessed the frequency of depressive symptoms over the past two weeks on a 4-point liker-scale ranging from 0 (rarely or none of the time) to 3 (most or all of the time). the score range of the ces-d was 0-60 points, and higher scores indicated more severe depressive symptomatology (radloff, 1977) . in our study, ces-d scores greater than 28 points indicated depressive symptoms. the chinese version of the psqi (pittsburgh sleep quality index) scale was used to assess the subject's sleep quality over the past two week (liu et al., 1996) . the psqi scale contains seven components (subjective sleep quality, sleep duration, sleep latency, habitual sleep efficiency, use of sleep medications, sleep disturbance, and daytime dysfunction), and the score for each component rangs from 0 to 3 points. the global psqi score ranges from 0 to 21, with higher scores indicating more severe sleep disorder (buysse et al., 1989) . the chinese version of psqi has been demonstrated to be reliable and valid in chinese population (liu et al., 1996) , and a global psqi score greater than 7 points indicates poor sleep quality. first, descriptive analyses were conducted to describe the demographic characteristics and covid-19 related knowledge in chinese population. second, the prevalence of gad, depressive symptoms, and sleep quality stratified by gender, age, and occupation were reported, and chi-square test (χ 2 ) was used to compare the differences between groups. third, univariate and multivariate logistic regression models were performed to explore potential influence factors for gad, depressive symptoms, and sleep quality during covid-19 outbreak. odds ratio (or), adjusted odds ratio (aor), and 95% confidence interval (95% ci) were obtained from logistic regression models. all data were analyzed using statistical package for social sciences (spss) version 24.0. p-values of less than 0.05 were considered statistically significant (2-sided tests). the characteristics of participants were shown in table 1 . of the 7,236 sample analyzed, 3,284 (45.4%) were males and 3,952 (54.6%) were females, and the mean (standard deviation) age of the participants was 35.3±5.6 years. among these samples, 2,250 (31.1%) of participants were healthcare workers, 3,155 (43.6%) of participants spent 3 hours or more a day focusing on the covid-19 outbreak, and 5,702 (78.8%) of participants quite understand knowledge of the covid-19. the prevalence of gad, depressive symptoms, and sleep quality stratified by gender, age, and occupation were shown in table 2, table 3, and table 4 , respectively. the overall prevalence of gad, depressive symptoms, and sleep quality were 35.1%, 20.1%, and 18.2%, respectively. there was no statistically significant difference in the prevalence of gad, depressive symptoms, and sleep quality by gender (p>0.05, as shown in table 2 ). the prevalence of gad and depressive symptoms was significantly higher in participants younger than 35 years than in participants aged 35 years or older (p<0.001, as shown in table 3 ). compared with other occupational groups, healthcare workers (23.6%) reported the highest rate of poor sleep quality (p<0.001, as shown in table 4 ). the associations of potential influence factors with gad, depressive symptoms, and sleep quality during covid-19 outbreak were presented in in the multivariate logistic regression models, the above associations weakened but there were still statistical difference. participants under 35 years were more likely to have gad than those 35 years and older (aor=1.65, 95% ci: 1.49-2.02). besides, participants who were concerned about the covid-19 outbreak for 3 hours or more were more likely to develop gad than those less than 1 or 2 hours (aor=1.83, 95% ci: 1.53-2.19). similarly, participants under 35 were associated with higher risk for depressive symptoms than those 35 years and older (aor=1.77, 95% ci: 1.58-2.07). compared with other occupation participants, healthcare workers were more likely to report poor sleep quality (aor=1.32, 95% ci: 1.18-1.88). our web-based study shows a high prevalence of gad and poor sleep quality in the chinese public during covid-19 outbreak. anxiety symptoms were more likely to occur in people younger than 35 years and those who spent too much time focusing on the outbreak. compared with other professions, healthcare workers were associated with higher risk for poor sleep quality. our findings provided data support for accurately understanding the source of public's panic during covid-19 outbreak. the data in this study suggested that public's levels of anxiety-related symptoms increased when a major infectious disease occurred. similar to the psychological burden caused by sars (su et al., 2007) , we found that one in three participants showed anxiety disorders, and this mood was not different between male and female during covid-19 outbreak, which was different from previous research that women were more likely to have anxiety than men (guo et al., 2016; gao et al., 2020) . in addition, nearly one in five participants had depressive symptoms and sleep problems, indicating that the uncertainty of the epidemic progression would cause greater psychological pressure on the public. the possible reason for these mental problems may be related to the "hypochondriac concerns" (worry about being infected) (furer et al., 1997) and feared that the epidemic was hard to control. after multivariate logistic regression analyses, we found that age and time spent focusing on covid-19 may be potential risk factors for the psychological problems of the public. younger participants (< 35 years) were more likely to develop anxiety and depressive symptoms during covid-19 outbreak than older participants (≥ 35 years). our results were similar to those of a previous study in taiwan during sars outbreak (su et al., 2007) . in addition, we assessed the average time participants spent focusing on the covid-19 outbreak each day, and found that people who spent too much time thinking about the outbreak (≥ 3 hours) were more likely to develop anxiety symptoms. the manifestation of this panic mood may be related to the body's normal protective response to the stress caused by the epidemic (maunder et al., since january 20, 2020, zhong nanshan (the renowned chinese respiratory expert who discovered the sars virus) confirmed that there must be human-to-human transmission of covid-19 (xinhuanet, 2020), more than 40,000 medical staff have given up the spring festival holiday and voluntarily applied to fight against the outbreak in hubei province (national health commission of the people's republic of china, 2020). meanwhile, most healthcare workers in china have returned to work to cope with the further development of the disease. our findings showed that nearly one in four healthcare workers had sleep problems, which was significantly higher than other occupational groups. one possible reason is that the working time and labour intensity of healthcare workers will increase in the face of severe epidemic (such as sars and mers), causing them not to have enough time to rest, and to be prone to chronic stress and psychological distress (lu et al., 2006; lee et al., 2018; mcalonan et al., 2007) . in severe cases, a post-traumatic stress disorder (ptsd) symptoms may even occur, which is highly correlated with poor sleep (kobayashi et al., 2007) . fortunately, the chinese government has taken many strong national measures in time to avoid further spread of the covid-19 outbreak, including requiring uninfected people to isolate themselves at home, prohibiting all gathering activities, and forcing everyone to wear medical masks to enter public places. however, there is still lack of relevant research on the targeted intervention of the public's psychological problems during the covid-19 outbreak. we filled this research gap by analyzing the prevalence of mental health burden in chinese public stratified by demographic characteristics and exploring related influential factors. several appropriate interventions are recommended as follows: first, psychological interventions should be directed to vulnerable populations which include the suspected and diagnosed patients, young people, and healthcare workers, especially physicians and nurses working directly with patients or quarantined people. second, try to control and limited the time of receiving covid-19 related information within two hours a day, focus only on the necessary information (such as facts and data) and avoid receiving too many harmful rumors (grein et al., 2000) . third, maintain a normal rhythm of work and rest as much as possible, exercise regularly to promote sleep quality, and do not pay too much attention to outbreak information before going to sleep. this study has several limitations. first, since the data and relevant analyses presented here were derived from a cross-sectional design, it is difficult to make causal inferences. second, the study was limited to covid-19 outbreak, and we used a web-based survey method to avoid possible infections, causing the sampling of our study was voluntary and conducted by online system. therefore, the possibility of selection bias should be considered. third, due to the sudden occurrence of the disaster, we were unable to assess an individual's psychological conditions before the outbreak. in conclusion, we identified a major mental health burden of the chinese public during covid-19 outbreak, and young people, people spending too much time thinking about the outbreak, and healthcare workers were at a high risk of displaying psychological issues. previously, when sars occurred in china, the awareness regarding public's mental health related to the epidemic was low, and no targeted psychological guidelines was available to the public, which was in need during the pandemic period. therefore, ongoing surveillance and monitoring of the poor sleep quality was defined as individuals who scored > 7 points. validation of the generalized anxiety disorder-7 (gad-7) among chinese people with epilepsy clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china world health organization, 2020b. current novel coronavirus (2019-ncov) outbreak. accessed reliability and validity of generalized anxiety scale-7 in inpatients in chinese general hospital report of novel coronavirus-infected pneumonia in china the latest: china confirms human-to-human transmission of 2019-ncov, infections among medical staff reliability and validity of the simplified version of the center for epidemiology scale for depression in the national adult population establishing a national urban norm for the center for epidemiology scale for depression a novel coronavirus from patients with pneumonia in china the authors would like to thank all the participants in our study. in addition, we express our heartfelt respect to all healthcare workers who are fighting the epidemic on the front line. finally, we thank ms. qiaohong chen for providing professional language help. key: cord-289238-f3lv7o4d authors: wu, taixiang; yang, xunzhe; zeng, xiaoxi; poole, phillippa title: traditional chinese medicine in the treatment of acute respiratory tract infections date: 2008-08-31 journal: respiratory medicine doi: 10.1016/j.rmed.2008.03.015 sha: doc_id: 289238 cord_uid: f3lv7o4d summary aims to review the evidence from cochrane systematic reviews for the effectiveness of traditional chinese medicinal (tcm) herbs for treating acute respiratory tract infections (artis) and to discuss the limitations of current clinical trials of tcm. findings evidence from six cochrane systematic reviews was weak owing to the lack of high-quality tcm trials. limitations were usually due to biases that influenced the validity of results. conclusions tcm is widely used for treating artis. however, none of the identified studies has been well designed or conducted. in this overview, we suggest that clinical trials of tcm for artis need to be re-run in accordance with internationally recognized standards. acute respiratory tract infections (artis) range from minor (e.g. common cold) through to very serious conditions (e.g. severe acute respiratory syndrome). artis are caused by over 200 viruses or bacteria. they are transmitted directly through person-to-person contact, either by airborne droplets from a sneeze or cough, or by direct contact with nasal or throat secretions, articles freshly soiled with secretions of the nose and throat, or by transmission via an object indirectly. for example, sore throat can either be a disease in itself, or can result from other diseases, such as influenza and glandular fever. 1e4 uncomplicated artis, such as the common cold and sore throat, recover spontaneously as a result of antibodies produced by the patient's own immune system targeting the virus. in general, no specific antiviral treatment is used. treatment aims to alleviate symptoms and prevent complications. antibiotics are used for bacterial infections. however, antibiotics only have a modest effect over placebo for acute bronchitis 5 and sore throat. 6, 7 for the common cold and influenza, over-the-counter decongestants, antihistamines, cough suppressants, and expectorants may be used for symptomatic relief. traditional chinese medicine (tcm) is a unique system with special aetiology and theories for treatment. tcm drug treatment typically consists of a complex prescription of a combination of components according to tcm signs. these include whether the patients themselves feel cold and chilly; experience nasal obstruction; do not sweat; generally have a high temperature with a thin, white coating on the tongue; have a productive cough; do not feel chilly; have an elevated temperature, with a thin and slightly yellow coating on the tongue; or have a productive cough. colds are categorized as 'chills cold' or 'fever cold'. shigao (gypsum fibrosum) is used to abate fever; caihu (bupleurum chinesenes dc) and jinjie (herba schizonepetae) are used as analgesics; banxia (rhizoma pinelliae) is dispensed to loosen sputum and suppress cough; fangfeng (radix saposhnikiviae) and zhishuye (folium perillae) are used for 'chill cough'; jinyinghua (flos lonicerae) and bohe (herba menthae) for 'fever cough', and so on. elements of a tcm formulation are meant to interact and co-ordinate with each other. these may be combined in a soap-like solution, or 'decoction' of tcm. in this evidence-based review, we aim to summarize the evidence from cochrane systematic reviews for the effectiveness of tcm herbs in treating artis, and to discuss the limitations of tcm clinical trials in the field. we conducted a comprehensive search for cochrane reviews of tcm for artis. we screened the cochrane database of systematic reviews in the cochrane library, issue 3, 2007. the search string contained (traditional and chinese and medicine) or herb*. we found 70 cochrane reviews and protocols. after scrutiny, six reviews were identified that fulfilled the inclusion criteria. the six reviews related to the use of tcm in the treatment of acute bronchitis, influenza, measles, sore throat, common cold and severe acute respiratory syndrome (sars), respectively. the initial version of this review was published in the cochrane database of systematic reviews, issue 3, 2005. 8 fourteen studies were included in the review, involving a total of 2771 participants with acute bronchitis. however, study quality (randomization, blinding and allocation concealment) was poor. because the formulations used were heterogeneous, the outcomes were analyzed separately, and not combined. all the 14 formulations in the studies seemed to show significant benefits compared with conventional medicine. for example, tcm formulation 'xiao'er xiaoji zhike koufuye' oral decoction was more effective than cefotaxime plus fluimucil (n-acetylcysteine) for resolution of cough (wmd à0.62 days, 95% ci à1.12 to à0.12), for clearance of fever (wmd à1.22 days, 95% ci à1.67 to à0.77), for reducing the duration of wheezing (wmd à0.44 days, 95% ci à0.74 to à0.14), and for resolution of rales (wmd à1.00 days, 95% ci à1.47 to à0.53). 'yuxingcao' atomisation aerosol was more effective than gentamicin atomisation aerosol for resolution of cough (wmd à1.37 days, 95% ci à1.67 to à1.07), for clearance of fever (wmd à0.92 days, 95% ci à1.03 to à0.81), and for relief of rales (wmd 0.60 days, 95% ci 0.19e1.01). the tcm patent medicine 'shiwei longdanhua keli' oral decoction plus antibiotics was more effective than antibiotics alone for resolution of cough (wmd à2.40 days, 95% ci à2.84 to à1.96), for clearance of fever (wmd à0.99 days, 95% ci à1.44 to à0.54), and for resolution of rales (wmd à2.76 days, 95% ci à3.26 to à2.26). the tcm formulation 'tanreqing' injection was more effective than levofloxacin for resolution of cough (wmd à3.17 h, 95% ci à5.95 to à0.39), for clearance of fever (wmd à32.13 h, 95% ci à34.81 to à29.45), and for normalization of chest x-ray (rr 1.28, 95% ci 1.01e1.61). the major limitation of this cochrane review was that inclusion of the studies was dependent upon the term 'random' appearing in the text. the original trial authors have now been interviewed by telephone and no trial has been identified as a true randomizedecontrolled trial (rct). this particular cochrane review is in the process of being updated. according to knowledge gained during the summer of 2005, it is estimated that only a small number of claimed rcts published in china are authentic rcts. 9 the initial version of the review on chinese medicinal herbs for influenza was published in the cochrane database of systematic reviews, issue 1, 2005 . 10 eleven studies with the number of participants ranging from 52 to 479, for a total of 2088, were included. one study used a chinese patent medicine, and the other 10 studies used tcm formulations in decoctions prepared in the respective hospitals. two years after publication of the review, the review authors telephoned the 11 trial authors and found that only two studies were authentic rcts. this review is in the process of being updated and will include these new findings. of the two authentic rcts, 61 were children with influenza b infection and 951 were participants with influenza a3/h3n2. for children with influenza b, tcm eshuyou oral decoction (volatile oil extracted from zedoary) had better effects but was not significantly different to ribavirin for recovery within 3 days of treatment (12/32 vs 5/29, rr 2.18, 95% ci 0.87e5.43). for participants with influenza a3/h3n2, ganmao capsule had significantly better effects than amantadine for recovery within 2 days of treatment (168/202 vs 37/230, rr 5.17, 95% ci 3.82e6.99). the review on chinese medicinal herbs for measles was published in the cochrane database of systematic reviews, issue 2, 2006. 11 strict methods for identifying study design were used in this review. twenty-eight studies were retrieved, which claimed to randomly allocate the participants. the authors of the 19 rcts were interviewed by telephone. it was revealed that the allocation methods they had used were not true randomization. three studies were excluded owing to participant complications. the remaining six study authors were unable to be contacted and will be assessed only if they demonstrate random allocation of the participants. thus, there is currently no rct evidence for use of tcm in measles. the review on chinese medicinal herbs for sore throat was published in the cochrane database of systematic reviews, issue 3, 2007. 12 strict methods for identifying rcts were used in this review. the authors of the 54 rcts were interviewed; only seven trials involving 1253 participants were identified as using authentic randomization techniques, but otherwise had poor methodological quality raising the possibility of selection bias or detection bias, or both. conflict of interest may have been another factor in producing a positive result in three studies as the prepared drugs were made in the respective hospitals. three tcm formulations were shown to be superior to the control drug in improving recovery: ertong qingyan jiere koufuye oral decoction was more effective than fufang shuanghua koufuye decoction for acute pharyngitis (or 1.54, 95% ci 1.11e5.74). yanhouling decoction was more effective than the gentamicin atomised inhalation aerosol, a non-standard treatment, for acute pharyngitis (or 5.39, 95% ci 2.69e10.81). qinganlan liyan hanpian tablet was more effective than the fufang caoshanhu hanpian tablet for chronic pharyngitis (or 2.25, 95% ci 1.08e4.67), and four formulations were shown to be equal in efficacy to the control. the review of chinese medicinal herbs for the common cold was published in the cochrane database of systematic reviews, issue 1, 2007. 13 the strict procedure of interviewing the original trial authors of claimed 'rcts', to guarantee the validity of the allocation method used for included studies was also conducted in this review. a total of 348 trials claiming to be randomized were retrieved. the authors of 295 trials were contacted by telephone. of these studies, 234 were excluded either because the trial authors misunderstood the concept of randomization or the trials were multiple printings of same study. one hundred studies were relegated to the 'awaiting assessment' section because the trial authors could not be contacted, or refused to be interviewed. fourteen studies were identified as true rcts and were included for assessment. of the 14 studies, two tested the same preparation against the same tcm formulation control. the other 12 studies tested different preparations for patients with different types of tcm signs (zheng xing). therefore, the data were assessed separately. five studies of herbal preparations reported a statistically significantly shorter duration of symptoms after treatment with the intervention compared with the control. of the five studies, three were for children with 'fever cold' (fengre zheng). qinwen keli oral decoction was more effective than kangbingdu koufuye oral decoction (rr 2.19, 95% ci 1.61e2.96); shuanghua penwuji aerosol was more effective than shuanghuanglian qiwuji aerosol (rr 1.48, 95% ci 1.11e1.79); and tcm cream was more effective than penicillin (rr 2.10, 95% ci 1.20e 3.67). in one trial conducted for adults with 'chills cold' (fenghan zheng), sufeng ganmao koufuye oral decoction was more effective than ganmao qinre koufuye oral decoction (rr 1.43, 95% ci 1.02e1.99); in one trial in 'fever cold' (fengre zheng), qinkailing injection was more effective than lincomycine given in three doses, in the treatment of adults with the common cold (120 ml/day rr 14 an important question arose from the sars outbreak in 2003: ''why was the case-fatality rate lower in mainland china (7%, 349/5327) than in both hong kong (17%, 299/1755) and taiwan (11%, 37/346)?'' the mortality level in mainland china was also lower than that in the rest of the world (9.6%, 774/8096). 15, 16 during the early stage of the sars outbreak, western medicine, specifically corticosteroids, was combined with chinese herbal medicines in an effort to promote non-specific immunity to combat inflammation. the state administration of traditional chinese medicine, the chinese ministry of health general office, issued a rule of combining western and chinese herbal medicine (icwm) for this rapidly spreading disease. sars was classified as a plague that needed to be treated in accordance with the 'wei, qi, ying, xue and sanjiao bianzheng lunzhi' theory. in keeping with this theory, some herbal medicinal extract injections to clear fever (qin re), remove dampness (qu shi), relieve asthma (zhi chuan), promote and regulate immunologic function (fu zheng), resist viruses and remove toxins (jie du), were recommended for clinical use. 17 the cochrane systematic review, conducted by liu et al. 14 included 12 rcts, and one quasi-rct had a total of 654 participants using 12 different tcm formulations. they carried out a combined analysis of two trials using the same tcm formulation plus western medicine, and separately analyzed four studies using different formulations plus western medicine vs western medicine alone to compare mortality between the two therapies. tcm did not show any benefit in reducing mortality compared with western medicine alone (rr 0.31, 95% ci 0.07e1.38, rr 0.27, 95% ci 0.01e6.11; rr 0.41, 95% ci 0.04e4.78; rr 0.30, 95% ci 0.01e7.70; and rr 0.19, 95% ci 0.01e4.06, respectively). whether or not tcms can decrease mortality from sars remains an unanswered question (table 1 ). it is encouraging that clinical trials of tcm in artis have been conducted; however, to date these have in common a weak study design, leading to potential biases in evaluating the effectiveness of the intervention. approaches for minimizing bias such as the use of strict protocols, randomization, concealment of allocation, and double-blinding were underused in these trials. the reporting of tcm trials is usually cursory, with a lack of description surrounding important detailed information, such as how the allocation sequence was generated; recruitment and enrolment of the participants; blinding for assessors and analyzers, statistical methods and number of drop-outs. a large number of the trials claimed to be rcts; however, most of the trial authors misunderstood the concept of randomization allocation. in the reviews in which the reviewers subsequently contacted the authors, the percentage of authentic rcts was 6.7% (23/342). this highlights the need for reviewers, including those doing cochrane reviews, to use a strict method to identify whether the trial authors used the correct method to allocate participants when conducting a systematic review, and not just relying on published reports. it also emphasizes the importance of using a quality scoring system, and planning, a priori, subgroup analysis of trials based on study quality. results from larger, better-quality trials are less likely to be affected by bias and thus more likely to be valid. many trials tested self-prepared formulations of the trial authors or their colleagues, or the decoctions were manufactured by their hospitals or patients themselves. as the trialists were involved in the design of the formulations and conducted the trials, this may have biased investigators in favour of the intervention. few studies used a placebo as a control. instead 'positive effect drugs' were used. most chinese trialists select the control drugs by a rule of 'the effect was commonly acknowledged'. this rule may lead to conflict of interest bias, and subjective over-or under-estimate of the effect of the trial preparation depending on the aim of the study. if a preparation was tested as the intervention, it had a high rate of effectiveness; if used as a control drug by another author, it may have had a much lower rate of one poor-quality trial showed that tcm may decrease influenza symptoms and speed up recovery. overall methodological quality poor. no authentic trial was identified for inclusion. no evidence from rcts yet sore throat seven trials identified and included three formulations were shown to be superior to the control formulation in improving recovery. all trials were of methodologically poor quality. common cold 14 trials identified and included in five studies, treatment with herbal preparations resulted in a statistically significantly shorter duration of symptoms compared with control. sars 13 studies included tcm did not show any benefit in reducing mortality compared with western medicine alone. effectiveness. therefore, it is difficult to determine the efficacy of the intervention drug. where the intervention drug was equal in efficacy to the control drug, no conclusion could be made. sample sizes were not reported in most of the tcm studies, which makes it difficult to assess if observed differences between the two groups were statistically or clinically important, or if trials were underpowered. some studies used unequal arms in their design, with some having a small number of participants in their control group. this would contribute to selection bias. the traditional use of tcm is in contrast to the pharmacological agents used in western medicines, for which the chemical constituents, their quantities, and the percentage of any impurities of contaminants are known precisely. in addition, the variation between different production batches of western medicinal drugs is kept within specified limits. in contrast, variation between formulations and batches of pharmacological agents is inevitable in tcm, although the chinese government specifies the acceptable limits of variation. this variation is a factor that may contribute to any heterogeneity between different study results. the tcm components used in the trials were not adequately described. the variability in individual components of herbal preparations and the variability between different preparations of combination products meant that any meaningful scientific evaluation is difficult to make without precise descriptions of the components of tcm formulations for the decision makers' consideration. because of the variability, use of chinese names alone for herbal preparations is not sufficient. in addition to folk or specific tcm names, each preparation should be described, giving the internationally recognized taxonomic names (genus species) of all plants included, the plant organ, along with proportions. tcm has an overall treatment concept that differs from western medicine. when using a tcm preparation for treating a disease, the type of 'zheng', the tcm signs, of a disease has to be matched. but some studies did not state whether the tcm control drug matched the type of 'zheng' or not. if the control drug does not match the 'zheng', the interpretation of results should refer to a placebo. unmatched formulations may be detrimental to the patient. it was often necessary to include tcm signs as a secondary or an additional outcome in the trials. however, it is difficult to compare or quantify tcm signs as most of them are subjective or non-specific outcomes. for example, 'mai xiang' means pulse presentations. diagnosing 'mai xiang' in tcm is a complex technique, dependent upon the tcm physician's feelings and experience. the descriptors 'marked improvement' and 'improvement' are commonly used to assess the change in tcm signs. these are based on the participants' feelings and assessor's subjective judgment. there seems a need for tcm researchers and physicians to develop an accurate, repeatable, and simple set of tcm measures to use as outcomes in clinical trials. along with the cochrane review on chinese herbs combined with western medicine for sars, 17 there have been two other reviews published addressing the question as to whether tcm lowers case-fatality rates in sars or not. the first of these pooled results for five different tcm formulations in five studies, finding a statistically significant, lower mortality in tcm plus conventional medicine groups than in conventional medicine groups alone (rr 0.32, 95% ci 0.12e0.91). 18 in the other review 19 pooled data from four studies showed a statistically significant lower mortality in tcm plus conventional medicine than in conventional medicine alone (or 0.32, 95% ci 0.14e0.71), but a sensitivity analysis that excluded an unbalanced two-arm study in which the number of severely ill patients was higher in the conventional medicine group than the tcm group (19 vs 13) found that there was no statistical difference between the two groups (or 0.53, 95% ci 0.20e1.41). the difference in mortality between the two therapies may, therefore, have been due to selection bias. the interpretations in these two reviews by liu et al. 18 and wu et al. 19 were similar to that of the cochrane review in that tcm therapy may contribute to a decrease in mortality from sars. however, because of poor methodological quality of the included studies, the evidence was weak an affirmative conclusion cannot be drawn. the tcm effects on secondary outcomes such as symptoms, lung infiltrate absorption, dosage of corticosteroids, quality of life of sars patients, and shortening the length of stay in hospital were similar in the three reviews. 14, 18, 19 this is likely because the data for calculating the results in the three reviews were extracted from different versions of the same studies. however, the number of studies included in the three reviews and the number of participants were different. because of the issues with study quality, and the fact that these are secondary outcomes, it is difficult to draw any conclusions from the results. the limitations of the included studies in the sars reviews were similar to other studies. these included a lack of randomization description; unconcealed allocation sequence, and non-blinding. the shortcomings were obvious in most of the studies, with unbalanced arms suggested by different numbers of male and female participants. it is also reasonable to construe that it was difficult for physicians to mount and conduct rigorous rcts during an outbreak of sars. thus, the methodological issues in these trials may be a more extreme representation of the problems seen in the conduct of tcm trials generally. the sars outbreak was a rare opportunity to demonstrate the value of tcm. unfortunately, as the evidence was derived from poorly designed studies, it remains unanswered whether the use of tcm saved sars patients or not. such studies pose other considerations. as there is such a wide belief in the effectiveness of tcm in the treatment of diseases, particularly those that are not effectively treated by conventional medicine, the possibility of randomization to inactive placebo may not be acceptable to participants. another challenge will be to find acceptable 'gold standard' treatments to compare with tcm formulations. at this stage, as evidence for tcm comes from poorly designed studies, no conclusions can be drawn about the effectiveness of tcm in a range of artis. we would appeal, therefore, for future clinical trials of the effects of tcms to be conducted according to internationally acceptable standards. the consolidated standards for reporting trials of traditional chinese medicine, (consort for tcm) published in 2007, 20 should assist in the design of better-quality trials. cdc. influenza: the disease randomized placebo-controlled trials of antibiotics for acute bronchitis: a critical review of the literature antibiotics for sore throat penicillin b for acute throat infections in adults: rapid resolution of symptoms after a 7-day treatment as compared to a 3-day treatment or a placebo; a randomized double-blind study chinese medicinal herbs for acute bronchitis investigation for the quality of claimed chinese medicinal herbs for influenza chinese medicinal herbs for measles chinese medicinal herbs for sore throat chinese medicinal herbs for the common cold chinese herbs combined with western medicine for severe acute respiratory syndrome (sars) world health organization. summary table of sars cases by county world health organization. consensus document on the epidemiology of severe acute respiratory syndrome (sars chinese ministry of health general office. announcement of issue revised diagnostic criteria of infectious atypical pneumonia (draft) and recommend treatment regime and discharge reference criteria systematic review and meta-analysis on the integrative traditional chinese and western medicine in treating sars a systematic review of assessing the effect of integrated traditional chinese medicine with western medicine for severe acute respiratory syndrome consolidated standards for reporting trials of traditional chinese medicine (consort for tcm) (for solicitation of comments) we would like to thank ms liz dooley, co-ordinator of the cochrane acute respiratory infections (ari) group, and the editorial board of the ari group, for their help in writing this article and the reviews included in this article. key: cord-026721-hrxf3rr7 authors: lukin, artyom title: the russia–china entente and its future date: 2020-06-13 journal: int polit doi: 10.1057/s41311-020-00251-7 sha: doc_id: 26721 cord_uid: hrxf3rr7 the ‘strategic partnership’ between moscow and beijing is already more than two decades old and continues to evolve toward more consolidation, a trend which the coronavirus pandemic will only serve to accelerate. its current state can be characterized as a quasi-alliance, or entente. the article first examines the russia–china cooperation in the two most crucial areas—geo-economic and military. then, it asks the question whether moscow and beijing could be on the verge of forming an alliance. the article proceeds to analyze the russian–chinese interaction in the areas of eurasia where both of them have significant stakes and intersecting interests: east asia, the post-soviet space (with the focus on central asia), and the arctic. finally, the author draws up several scenarios envisioning the future of the sino-russian relationship. the contemporary quasi-alliance between moscow and beijing is already more than two decades old. the sino-russian 'strategic partnership' was proclaimed in april 1996 as the mid-1990s marked a watershed both in russia and china's foreign policies. moscow felt bitter disappointment and even anger with the west and perceived itself being treated as a defeated adversary that could at best be a junior partner in the us-dominated order. at the same time, beijing was subjected to the humiliation of the 1995-96 taiwan strait crisis, which demonstrated china's impotence vis-àvis the american superpower. after vladimir putin succeeded yeltsin in 2000, there was a brief interlude when russia attempted to strengthen relations with the west and, for a while, partnership with china lowered in importance for the kremlin. yet from the mid-2000s russia's since 2009, china has ranked as russia's top trading partner as an individual country. in 2018, for the first time, russia-china trade exceeded $100 billion, reaching $107 billion, accounting for 15 percent of russian exports and imports (rt 2019) . since the ukraine crisis in 2014, russia saw the exports and imports with all of its top ten trade partners decrease-except china. from 2014 to 2019, russia-china trade volume rose by 17% (visloguguzov 2019) . on the one hand, russia's pull into china's geo-economic orbit is inevitable, driven by the logic of the international marketplace. china needs huge volumes of natural resources and russia is a major supplier of these. on the other hand, russia's embrace of china as the main economic partner was a political decision born of the ukraine crisis and the ensuing confrontation with the west. in order to withstand western pressure russia needed a strong external partner. as alexander gabuev (2016: 3) puts it, [i]t was hoped that china would become a major buyer of siberian hydrocarbons, shanghai and hong kong would become the new london and new york for russian companies seeking capital, and chinese investors would flock to buy russian assets, providing badly needed cash, upgrading the country's aging infrastructure, and sharing technology. not surprisingly, it was in the area of hydrocarbons that russia's economic pivot to china has been the most impressive. since 2015, russia has increased the oil exports to china by 60% (kiselyov 2019) , displacing saudi arabia as china's top supplier of crude oil. in december 2019, the power of siberia pipeline started delivering natural gas to china. chinese state-owned companies are stakeholders and major buyers of liquefied natural gas from russia's projects in the arctic. russia has also been increasing food supplies to china (grove and kurmanaev 2019) . two recently completed bridges across the amur river-one for rail traffic and the other for vehicles-symbolize russia's growing closeness to china. it is remarkable that for centuries the amur has been the main boundary between russia and china, but there was not a single permanent bridge across the border river. china's economic decoupling from the usa (wang 2019 ) is likely to increase beijing's long-term interest in russian commodities. russian supplies, most of which come overland, are also more secure in the light of a possible trade embargo and naval blockade-options the usa and its allies may take in a military conflict with china. russia's turn to china-and away from the usa-is happening in the financial domain too. in 2018 russia's central bank drastically reduced the share of its assets held in the usa from 29.9 to 9.7%. at the same time, the central bank increased its chinese holdings from 2.6 to 14.1%. the share of the russian central bank's dollar-denominated reserves also decreased from 45.8 to 22.7%, while its yuan holdings jumped from 2.8 to 14.2% (bank of russia 2019). in june 2019, moscow and beijing inked an agreement to switch to national currencies in bilateral trade as they ramp up efforts to move away from the us dollar (ministry of economic development of the russian federation 2019). however, the reality of closer economic relations with china turned out to be more complicated than initially expected. the most disappointing for moscow is the failure to attract chinese fdi. as kremlin officials admit, 'it cannot be said that china invests a lot in the russian economy' (tass 2019a). so far chinese investors largely demonstrate a wait-and-see approach to russia. similar to other foreign companies, they tend to see the risks of entering russia as high, whereas the profit margins are not substantial enough to offset the risks. to chinese business, russia is of interest mainly as a supplier of natural resources such as minerals, hydrocarbons or timber. however, most of these resources are not unique and can be imported from elsewhere, as long as maritime routes remain open. marine freight is inexpensive, canceling out russia's seeming advantage of proximity to the chinese market. at the same time, the freezing winter temperatures, difficult terrain and lack of transport and energy infrastructure across much of russia often result in higher costs to extract and deliver its natural riches, compared to competitors in africa, south america or southeast asia. somewhat ironically, even though, post-2014, russia turned to china to avoid western sanctions, some chinese banks, including state-owned ones, have restricted transactions with russian clients for fear of us penalties. this reflects the reality of us financial sway over china that is unlikely to disappear in the near future (intellinews 2018). as moscow moves into beijing's economic orbit, it is still determined to avoid the level of dependency that could pose risks to russia's political independence and sovereignty. the kremlin keeps limits in place that should prevent russia from being too closely integrated with the chinese economy and save russia a significant degree of economic autonomy. in addition to refusing to sell china strategic assets, such as ports, such limits are manifested in russia's reluctance to accept chinese loans. as one observer points out, 'the russian government is careful not to incur sizeable debt to china' (kashin 2019a) , which is due not only to the kremlin's general aversion to accumulating foreign debt, but is also guided by the resolution to deny china financial leverage over russia. furthermore, moscow is in no hurry to work toward a free trade agreement with china, limiting itself to a non-tariff trade facilitation agreement that became effective in october 2019. russian officials have repeatedly stated that russia and its fellow eurasian economic union members are not yet ready to open their markets to china (evraziya.expert 2019) . technology is currently the weakest link in the sino-russian economic cooperation. technological nationalism on both sides is a major obstacle. russia and china have yet to show they can effectively collaborate on major hi-tech projects and achieve the levels of technological integration and division of labor found in the west. previously agreed projects, such as the joint development of a wide-body passenger jet able to compete with boeing and airbus, have not made much progress. this, however, can change as russia and china are losing access to western technology. as bendett (2019) pointed out. [o]ver the past couple of years, us policy has sought to limit chinese and russian engagements with the global technological ecosystem, including through sanctions and export controls. under these geopolitical circumstances, the determination of chinese and russian leaders to develop indigenous replace-ments for foreign, particularly american technologies, from chips to operating systems, has provided further motivation for cooperation. digital will be one key sector indicating the progress of russian-chinese hightech cooperation. moscow has signaled that russia will be happy to use chinese 5g and iot technology, provided the manufacture of hardware is localized in russia. huawei is expanding its presence in russia, planning, among other things, a fourfold increase of its russian-based r&d staff (makarova 2019) . that said, it remains to be seen if chinese hi-tech companies will agree to share with russia the core parts of their r&d and production processes. russian weapons sales contributed a lot to china's military modernization in the 1990s and 2000s. however, for a long time, it was india, rather than china, that was the privileged buyer of russian arms: moscow was willing to supply new delhi with some of russia's top-notch weapons and related technologies, while generally selling less advanced systems to china. this pattern changed in the mid-2010s, when moscow agreed to sell china two of its best conventional weapons, s-400 surface-to-air missile systems and su-35 fighter jets, making beijing their first foreign buyer (putz 2015; novichkov and hardy 2014) . russia's assistance to china is no longer limited to conventional weapons. in october 2019, putin made a sensational revelation that russia is helping china build a 'missile attack early warning system' (ews) that allows to detect incoming icbms (stefanovich 2019a) . only the usa and russia currently possess such systems that are crucial components of their strategic deterrence capability. this signifies a qualitative raise of the russia-china military-political and technological cooperation. russian experts expect more joint efforts by russia and china in areas such as strategic missile defense, hypersonics and nuclear-powered submarines. they note that russia's current military collaboration with china is mostly in areas which should not jeopardize russia's national security but will significantly complicate the us's military planning vis-à-vis china (kashin 2019b) . moreover, russia-china cooperation in military technology is no longer a one-way street. even though china still relies heavily on russia in areas such as high-performance aircraft engines, beijing has outpaced moscow in ai, shipbuilding and drones. as one russian military expert notes: 'in the not so distant future, china could be the one selling arms to russia, such as drones or ships…china has a potent shipbuilding industry. they make their frigates and destroyers like hot buns on a stove. it is totally possible to order hulls for our prospective ships from china' (simes 2019 first, if china were not taking part, any exercise on this scale would inherently rouse suspicion from chinese officials that the war games are aimed at them… the goal is to appear friendly, making sure that the capabilities exercised are not perceived as a threat. indeed, starting in 2014, moscow has been careful to make the exercise scenario for vostok based more on aerospace and naval attack-i.e., aimed at us expeditionary forces and their pacific allies, as opposed to a land-based contingency that implies fighting chinese forces. official chinese involvement is yet another indicator that russia and china are more inclined to balance the usa rather than each other. in august 2019, russia again invited china to take part in its main strategic maneuvers of the year, dubbed tsentr-2019. although the exercise's official focus was on 'counterterrorist' operations, the drill included repelling enemy air strikes and counterattacks against a conventionally armed state. in other words, russia and china were practicing to jointly deal with a nation-state enemy, if only at a minuscule scale (gady 2019) . in may 2015, in a move fraught with symbolism, russia and china conducted their first naval exercise in the mediterranean, nato's maritime backyard, while in 2016 and 2017 naval maneuvers were also held in sensitive geopolitical areas-in the south china sea and the baltic sea. in july 2019, russia and china conducted the first joint air force operation beyond their national borders. russian and chinese long-range nuclear-capable bombers accompanied by fighter jets and surveillance aircraft carried out a patrol over the east china sea and the sea of japan. the patrol's route ran over a sensitive area in the vicinity of the dokdo (takeshima) islands, disputed between south korea and japan. seoul claimed that a russian military plane from the joint patrol group twice violated dokdo's airspace, prompting south korean interceptor jets to fire hundreds of warning shots (lendon 2019) . china and russia apparently sought a maximum demonstration effect. russian defense minister sergey shoigu left little doubt that the joint air patrol was a signal to washington and its asian allies: 'as two neighbors seeking strategic partnership, russia and china are thus messaging to everyone that they want to ensure their security' (loktionova 2019). china's top military officials have also occasionally made statements indicating that military cooperation with russia has america as the main addressee. while in moscow for '2 + 2' talks with russian defense and foreign ministers, china's minister of defense wei fenghe said his visit was a signal to 'let the americans know about the close ties between the armed forces of china and russia' (lo 2018 continues to develop at a high level, enriching the china-russia comprehensive strategic partnership of coordination for a new era and playing a significant role in maintaining global strategic stability.' as kashin (2018) notes of russia and china, 'the scale and nature of their joint activities in the military, security, and defense technology fields are consistent with preparation for possible joint military action against a major hostile country.' the sino-russian axis is already beginning to seriously complicate the american military posture. as some american commanders acknowledge, the usa does not have the capacity to deal simultaneously with a resurgent russia in europe and the chinese challenge in the pacific (associated press 2018). a scenario in which china and russia take coordinated military actions in the pacific and european theatersfor example, china invades taiwan while russia launches a large-scale military operation in europe (newsham 2019)-no longer looks purely imaginary. northeast asia is currently the most suitable theater to operationalize an emerging military alliance of moscow and beijing. russia and china have a direct presence in the region, where they maintain substantial military potentials that-if combined-can complement each other. and importantly, it is in the north pacific where they both directly intersect with the usa. some russian analysts believe one of the next steps in the military collaboration could be forming a shared pool of support assets, such as awacs aircraft and tanker aircraft, to assist russian and chinese forces operating in the pacific (stefanovich 2019b ). if the china-russia military partnership continues its upward trend, it will inevitably affect the security order in the western pacific. joint actions by russia and china can challenge the system of us-centered alliances in east asia and alter the strategic balance there. in future, china-russia patrols and other combined military missions contesting the us military preponderance are also possible beyond east asia, for example, in the atlantic, middle east, or even the caribbean, especially as china grows its power projection capabilities and builds a network of overseas military bases, such as in djibouti and pakistan's gwadar. the rising levels of diplomatic, geo-economic and military collaboration between russia and china inevitably lead to the question whether they could be on the verge of forming an alliance. officially, both beijing and moscow have repeatedly denied any intentions to create a political-military alliance. for example, in october 2019 russian minister of foreign affairs sergey lavrov emphasized that russian-chinese relations 'have never been at such a high and trusting level in all spheres,' but asserted at the same time that 'neither russia nor china are planning to set up a [military] alliance' (tass 2019b). that said, lavrov immediately added some ambiguity to his statement, remarking that the two powers are 'allies' when it comes to 'defending international law' and opposing 'intervention in domestic affairs' (tass 2019b). in the same month, none other than putin himself called russia-china ties 'an allied relationship in the full sense of a multifaceted strategic partnership' (putin 2019a) . this is not the first time putin has characterized russia and china as 'allies'. in october 2014, meeting with premier li keqiang, the russian leader referred to the two countries as 'natural partners and allies' (ng 2014) . russian top officials' occasional use of the 'a-word' with respect to china is hardly a slip of tongue or a mere figure of speech. the ambiguity in describing the relationship with china is likely deliberate and strategic, designed to signal to the west that moscow is just one step away from forming a full alliance with beijing. xi jinping and other chinese officials have never publicly called relations with russia as 'allied'. this is not surprising as doing so would directly contradict china's non-bloc and non-alignment pledges which are still part of beijing's official doctrine. beijing might also be careful not to excessively provoke the usa with pronouncements of an alliance between america's chief great-power competitors. moreover, some prominent chinese experts publicly question the wisdom of a sino-russian alliance, citing previous precedents. former vice foreign minister fu ying reminds that there had been three alliances between beijing and moscow (concluded in 1896 , 1945 and 1950 and all three failed (ying 2016) . that said, official beijing has never refuted moscow's periodic invocation of the alliance language with respect to the russia-china ties, which can be interpreted as the desire to maintain some ambiguity [1] . the 2001 china-russia treaty of good-neighborliness and friendly cooperation may already provide some legal grounds for a military alliance. its article 9 states: 'when a situation arises in which one of the contracting parties deems that peace is being threatened and undermined or its security interests are involved or when it is confronted with the threat of aggression, the contracting parties shall immediately hold contacts and consultations in order to eliminate such threats' (ministry of foreign affairs of the people's republic of china 2001). this implicitly suggests the possibility of joint planning and joint military actions to confront common threats and adversaries. such wording is not much different to the rather vague language found in the western alliance treaties, such as nato's article 5 or article 5 of the 1960 us-japan security treaty (kashin 2019c) . all those treaties leave it up to the parties to decide whether to commit military forces to assist treaty partners in case of an emergency-and in what manner. what matters even more than the legal language is the concrete degree and scope of joint military planning, interoperability and military-technological partnership (kashin 2019c) . ultimately, there needs to be the political will to execute formal alliance commitments when push comes to shove. as evidenced by statements from some key nato leaders, such as us president donald trump and french president emmanuel macron, there is less than full confidence in the willingness of the north atlantic alliance to defend its members (economist 2019). in this sense, the russia-china strategic partnership, albeit not a formal alliance, may already be no less effective than some of the us-led treaty alliances. russia and china may or may not adopt legally binding mutual defense obligations à la nato's article 5. in the near future this seems rather unlikely, albeit not inconceivable in the longer term. what is almost certain, though, is that beijing and moscow will continue to expand and deepen their strategic collaboration in various areas tantamount to building a de facto alliance. one frequently-heard objection to the possibility of a sino-russian alliance is that russia would be a dependent and hence resentful partner. there is no denying the growing disparity in economic might between russia and china. however, economic asymmetry is not equal to political subordination. north korea, for example, depends on china for 90 percent of its trade but still retains full political autonomy. as long as russia keeps a great-power mindset and wields nuclear weapons, it will not be junior to china politically. after all, russia has been europe's resource periphery for centuries while acting politically as a great power. why not repeat the same pattern with china? furthermore, while highlighting russia's growing economic dependence on china, there is probably some underestimation of the degree to which china itself depends on russia. as long as there is the real-and rising-risk of china clashing with the us (over the south china sea, taiwan or other issues), the strong bond with russia-the only major power that can provide beijing with diplomatic support, military technology, and secure access to vital commodities-will be crucial for the prc. with moscow as a close partner, beijing can be confident about the security of its northern borders, turning them into 'a stable strategic rear area' (friedberg 2012) . for a long time, perhaps since 1945, international politics has not seen alliances made up of equal great powers. we have gotten used to the notion of an alliance that consists of the dominant power and its dependent junior partners. this is another reason why it is difficult for many experts and policymakers to imagine a sino-russian alliance. however, the return of great-power politics, which many admit is now happening, may revive the 'old-fashioned' great-power alliances between equals, with russia and china leading the way. an elegant way to make sense of the russia-china current strategic relationship is to view it as a great-power entente, falling short of a formal alliance but having grown much closer than the 'strategic partnership' the two countries established in the 1990s. an entente, as dmitry trenin (2015) reminds, is a harmonious association of two major powers based on the commonality of some key interests; the perception of common threats; a measure of foreign and security policy coordination; and a degree of empathy between their leaders. similarly, franz-stefan gady (2019) likens the contemporary moscow-beijing axis that opposes the usa to entente cordiale, the 1904 anglo-french agreement that paved the way for france and great britain to become allies against germany and the central powers during the first world war. the sino-russian entente is helped by the fact that both russia and china, in their actual foreign policies, adhere to the classic great-power logic of spheres of influence, notwithstanding their rhetoric about the primacy of the norm of sovereignty and the need to democratize international relations. there appears to be an understanding between them that moscow defers to beijing on east asian issues while, in return, the chinese recognize russia's leading political role in much of the post-soviet space and the middle east (kortunov 2017 ). china and russia are the two largest-and neighboring-powers of continental eurasia. can two tigers share the same mountain, especially when one great power is rapidly gaining strength and the other is in relative decline? and there seems to be a pattern in the history of international relations that two ambitious major powers that share a land border are less likely to make an alliance, while they are more likely to engage in territorial disputes with one another as well as rivalry over primacy in their common neighborhood. there are at least three major parts of eurasia-east asia, the post-soviet space (mainly central asia), and the arctic-where china's and russia's geopolitical interests intersect, creating potential for competition and conflict. but, on the other hand, if managed wisely, overlapping interests and stakes can also generate opportunities for collaboration. the following sections examine how russia and china are managing to keep their differences in key eurasian zones under control while displaying a significant degree of mutual cooperation. east asia this is china's 'home region', but also one where russia, by virtue of possessing the far eastern territories, is a resident power. moscow, which has traditionally been concerned with keeping sovereignty over its vulnerable far east, does not at present see china as a major security risk on russia's eastern borders. all border delimitation issues between moscow and beijing were resolved in the 1990s and 2000s, while the 2001 sino-russian treaty explicitly states that the two countries have no territorial claims to each other. furthermore, moscow is well aware that chinese military preparations are directed primarily toward taiwan, the western pacific and the south china sea, not against the russian far east. there is the cliché, persistent among the western media and commentariat, of a chinese demographic invasion of the russian far east. for example, a wall street journal article claimed recently that 'about 300,000 chinese, some unregistered, could now be settled in russia's far east' (simmons 2019) . in reality, the actual number of the chinese who live more or less permanently in the russian far east is far lower, and there are very few cases of illegal chinese migration. there is no imminent risk of the russian far east falling under chinese control demographically or otherwise. not sensing any major chinese menace to the russian far east, russia has refused to engage in rivalry with china in east asia. on the most important issues of contemporary east asian geopolitics moscow has tended to support beijing or displayed friendly neutrality. on the korean peninsula, moscow has largely played second fiddle to beijing. on the south china sea disputes, although russia's official stance is strict neutrality, some russian moves may be seen as favoring beijing. for example, following the july 2016 hague tribunal ruling that rejected china's claims to sovereignty over the south china sea, putin expressed solidarity with china, calling the international court's decision 'counterproductive' (reuters 2016) . russia shares with china the objective of reducing american influence in east asia and undermining the us-centric alliances in the region. russian weapon sales are helping china alter the military balance in the western pacific to the detriment of the usa and its allies. russia's decision to assist china with getting its own missile attack early warning system may have also been partly motivated by the desire to strengthen china vis-à-vis the usa in their rivalry for primacy in east asia. the russian ambassador to the us anatoly antonov hinted as much by saying that this strategic system will 'cardinally increase stability and security in east asia' (tass 2019c) . russian deference to china on east asian issues, albeit somewhat hurting moscow's great-power pride, makes geopolitical sense. the kremlin treats pacific affairs as an area of lower concern than europe, the middle east, or central asia. mongolia, which constitutes siberia's underbelly, is the only east asian nation that can count on russian security protection in case it finds itself in danger of external aggression, at any rate a purely theoretical possibility so far. it would be incorrect to say that russia has completely withdrawn from east asian geopolitics. in some cases, russia does act against chinese wishes in the asia-pacific. one recent example is russia's quiet determination to keep drilling in the areas of the south china sea on the vietnamese continental shelf over which china lays sovereignty claims. the russian state-owned energy company rosneft operates on vietnam's shelf, despite beijing's displeasure and periodic harassment by chinese ships (zhou 2019) . apart from the desire to make profits from the south china sea's hydrocarbons, russia may be seeking to support its old-time friend vietnam-to whom it also sells weapons-as well as demonstrate that it is still an independent actor in east asia. through such behavior on china's southeast asian periphery, the kremlin could also be sending the signal to beijing that, if china gets too closely involved in russia's backyard, such as central asia or the caucasus, russia can do similar things in china's. albeit a friction point between beijing and moscow, the activities by russian energy firms in the south china sea are unlikely to destabilize the sino-russian entente, since moscow and beijing need each other on much bigger issues. the post-soviet space russia has vital stakes in the geopolitical space formerly occupied by the soviet union and is willing to go to great lengths to defend those interests. it was, after all, a perceived brazen attempt by brussels and washington to draw ukraine into the eu's and nato's orbit that induced moscow to take drastic action in crimea and eastern ukraine, causing a rupture with the west. when it comes to moscow-beijing politics over the post-soviet space, the most problematic question is certainly about central asia, a region composed of five former soviet republics which shares borders with both russia and china. since the nineteenth century, russia has traditionally considered central asia as its sphere of influence. however, in the 2000s china began its economic expansion in the region. it is now by far the biggest trade partner for central asian states (bhutia 2019) as well as its largest source of investments. china also set up a small military presence inside tajikistan, apparently to secure a sensitive area which borders china's xinjiang region and afghanistan (lo 2019) . despite initial misgivings in moscow, china's economic penetration of central asia has not, so far, done any substantial harm to russian interests. just like russia itself, central asian 'stans' are moving extremely cautiously with respect to beijing's calls for a free trade area, fearing their economies will be devoured by china. moreover, populations in central asia, particularly in kazakhstan and kyrgyzstan, exhibit high levels of sinophobia. russia is rather confident the central asians are not going to abandon it in favor of china. on the contrary, they may need moscow even more to hedge against beijing's rising geo-economic influence. multiple predictions by western analysts that moscow and beijing would inevitably clash over central asia have thus far been proven wrong. in a stark contrast to the russian-western antagonism over ukraine, russia and china were able to establish an understanding-and strike a rather stable balance-in central asia, whereby beijing has emerged as the main economic force while moscow retains the status as central asia's chief political-military ally and partner. there will be some irritants, but a clash of chinese and russian interests in central asia is unlikely in the foreseeable future (zogg 2019) . central asia is the most important but not the only area in the post-soviet space where chinese rising involvement could potentially come at the expense of russia. in recent years, china has shown an increasing interest in the south caucasus, a strategic region comprised of the three former soviet republics of georgia, armenia and azerbaijan. the south caucasus' geographic location makes it an important part of china's belt and road initiative. as an observer notes, '[f]or all three countries, china plays the role of an alternative to russia and the west. tbilisi, yerevan, and baku are all tired of moscow, washington, and brussels eternally squabbling on their own territory. in this respect, beijing is seen as a possible counterbalance' (markedonov 2019) . there is also an issue of beijing's flirtation with belarus, russia's wayward ally. in the fall of 2019, belarus reportedly expected a 3.5-billionyuan loan from china as an alternative to funding from russia (eurasia daily 2019). moscow had earlier withheld financial assistance to force minsk to agree to closer integration with russia. if china actually helps the belarusian autocratic leader alexander lukashenko get off russia's financial hook, it will not be to the kremlin's liking. it is unlikely beijing would push the envelope in russia's 'near abroad'. china's stakes there are, in most cases, not high enough to be worth testing the strategic partnership with russia. and where china does have important interests in the post-soviet space, such as in central asia, the record so far shows that beijing is able to find mutual accommodation with moscow. the arctic apart from east asia and central asia, the arctic is another area where russia and china's interests may, theoretically, come into conflict. russia lays claims to a significant part of the arctic ocean and views it as a sanctuary vital for the country's security and economic interests, as well as for the national identity. china, on the other hand, has been displaying arctic ambitions, calling itself a 'near-arctic state' and seeking to gain access to the arctic's resources, including through the vision for the polar silk road that would see chinese ships traversing arctic routes (xinhua 2018) . until recently, russia was wary of letting china into the arctic. but this seems to be changing. the strengthened russia-china strategic partnership necessitates a more accommodating attitude by moscow toward beijing's arctic aspirations. furthermore, with a severely reduced access to western capital and technology, collaboration with china looks like the only realistic option for carrying out major projects in the russian arctic that russia cannot afford to implement on its own due to their huge costs and technological complexity. in recent years, russian officials have repeatedly stated that russia is ready for more collaboration with china in the arctic, with the two countries signing a number of agreements on arctic projects. so far the most important case of the russia-china arctic collaboration has been chinese participation as the biggest foreign stakeholder in the liquefied natural gas (lng) projects on russia's arctic shore (humpert 2019) . russia also hopes to attract chinese investment into the northern sea route, the arctic's main shipping artery and a potential maritime corridor between asia and europe (tass 2019d). the kremlin is apparently betting it will be able to manage china's rising presence in the extreme north without risking russian dominance of the arctic. russia's embrace of china in the arctic contrasts sharply with the american stance, with us officials warning that china's intentions cannot be trusted, since its 'pattern of aggressive behavior elsewhere will inform how it treats the arctic' (digges 2019). sino-russian relations are now at their highest point since the mid-1950s, when moscow and beijing were communist allies. the russia-china entente is likely to get even stronger in the wake of the coronavirus pandemic. facing an intensifying hostility from washington, beijing will need russia-its only major-power friendeven more. meanwhile, moscow looks to china, and its continued demand for russian energy and commodities, as russia's best chance to recover economically after the pandemic (gabuev 2020) . russia and china are being drawn to each other by the most elementary law of international politics: that of the balance of power. from the balance-of-power perspective, it is only natural that two lesser poles should join forces against the preponderant player in the international system-the us vladimir putin has repeatedly stated that the russian-chinese cooperation is crucial to the creation of 'a multipolar world' as opposed to 'a unipolar structure, with a single centre that governs the entire international community' (putin 2019b) . in addition to seeing washington as the main problem in terms of the structural balance of power, both moscow and beijing view the us-led west as the primary threat to their political regimes. indeed, the similarity of russia and china's contemporary political systems, both being state-centric autocracies, is another crucial pillar of their strategic entente. as a chinese researcher emphasizes, russia and china have grown 'increasingly close in their concepts of political governance' and the two countries 'have a greater stake in mutual support to counter political pressure from the west' (feng 2014). there is cross-pollination taking place between moscow and beijing on domestic political issues. for example, the ccp seems to have taken a page from putin's playbook by introducing regulations, similar to russia's legislation crippling non-government organization with foreign sponsors or partners, while moscow borrows from beijing's experience in controlling the internet. russia and china presented a united front against 'us meddling' when mass political protests were taking place in moscow and hong kong (korostikov 2019) . the personalities of the russian and chinese supreme leaders, vladimir putin and xi jinping, are another major factor in the contemporary russian-chinese alignment. putin and xi, who are almost of the same age, are getting along very well, and there seems to be a personal affinity between the two. in terms of their political philosophies, xi and putin are on the same wavelength sharing the flair for realpolitik in international affairs, coupled with a conservative and nationalistic authoritarianism in domestic politics. both leaders attach high priority to military force and the security apparatus as tools for defending national interests abroad and maintaining what they see as legitimate order at home. putin and xi may stay in power for a long time. putin's current presidential mandate expires in 2024, but the latest amendments to the russian constitution allow him to stay on until 2036. similarly, xi could remain at the helm even after his current term ends in 2022. as long as the above factors-the shared perception of the usa as the main external threat, the solidarity of autocratic illiberal regimes, and the leaders' personal affinity-continue to operate between russia and china, we may expect that the moscow-beijing axis will continue to exist, and possibly grow even stronger. it can be assumed, with some degree of confidence, that these conditions will continue in the foreseeable future, at least for the next few years. but, over the longer term, what happens to the russia-china relationship should the forces currently binding them together weaken or disappear altogether? several ideal-type scenarios can be drawn up to try to imagine the future of the russia-china strategic relations over the horizon of seven to 10 years. scenario 1. the continuation of the sino-russian entente it is quite likely that, even seven or 10 years into the future, the forces that currently sustain the moscow-beijing axis will remain in place or could even intensify. russia and china's rivalry with the usa could grow more acute, while their illiberal autocracies would become even more entrenched. this will result in the continuation of the sino-russian entente, with ever tighter political, ideological, military and economic ties between moscow and beijing, and could even see the elevation of their 'strategic partnership' to the level of a full alliance based on a formal treaty. scenario 2. russia-us rapprochement even though russian-american relations are presently at a very low point and unlikely to substantially recover any time soon, in the long term their normalization is not impossible. in fact, the usa will be under increasing structural pressure to make peace with russia as china looms as by far the biggest threat to america's positions in the international system. at some point, washington might be forced to seek moscow's collaboration in managing the massive challenge from beijing. although russia is unlikely to participate in any overt containment of china, it might, at least, agree to become a neutral player. however, washington will have to make some significant concessions to moscow, such as recognizing russia's special interests in eastern europe and lifting sanctions. the hypothetical normalization of us-russia relations would likely have a dual effect on russia's policy toward china. first, russia would relax its systemic balancing of the usa and thus have much less incentive to strategically collaborate with china, especially in the political-military domain. second, if russia feels secure on its western borders, it will have more freedom to play its own game in east asia, rather than siding with beijing, which would, to a degree, help balance china's ambitions. scenario 3. russia and china's political regimes part ways it cannot be ruled out that post-putin, russia will transition from illiberal autocracy to a more liberal and democratic regime, more compatible with western values. if it ever happens, it would weaken russia's political bonds with the ccp-dominated china, even though the extent of a negative impact is impossible to predict. some historical analogy could be gleaned from the collapse of the soviet union in the early 1990s when the post-communist and newly democratic russia under boris yeltsin, which then sought to be part of the west, had to decide about how to proceed with the post-tiananmen communist china. moscow decided in favor of good-neighborly relations with beijing, albeit at that time it was not a strategic partnership or entente. it is likely that, all other things being equal, russia and china would be able to keep generally friendly relations even if they have political regimes as different as a liberal democracy in moscow and a party-state autocracy in beijing. however, it is an open question whether they would be able to maintain their entente under such circumstances, especially if russia's political liberalization results in a substantial improvement of its relations with the west. there is the theoretical possibility of a reverse scenario, whereby russia stays authoritarian while china undergoes democratization and political liberalization. however, such a scenario is less likely as the prc's party-state appears more viable than russia's current political regime. scenario 4. china's hubris the viability of the russia-china entente is, to a significant degree, based on mutual recognition of each other as equals. moscow and beijing treat each other as co-equal great powers. but the trends that determine the balance of material power between china and russia could make the maintenance of the political equality a problematic proposition. what happens if china continues to widen the economic gap with russia-china's economy is already eight times that of russia'sand increase its lead in many crucial technological areas? the economic and technological asymmetry will also have implications for the military balance between the two: today russia is still generally considered a more formidable military power than china, but this could change in a decade or so. the situation can be exacerbated by the inevitable change in the top leadership. vladimir putin and xi jinping seem to have mutual respect for each other, but this might not be the case with their successors. think of the negative role that the toxic personal relationship between nikita khrushchev and mao zedong played in triggering the sino-soviet split in the late 1950s and 1960s. the post-xi generation of the chinese elite could well develop a superiority complex toward russia and refuse to treat it as an equal partner. russia might accept the new role of a lesser ally or it might not. if moscow, out of its great-power pride, insists on full political equality with china, that could rupture the russia-china axis. among the four presented scenarios, this one is probably the most dangerous because it involves the matters of status, rank and honor, always the core identity issues for russia and hence highly emotional (tsygankov 2012) . the sino-russian entente may or may not survive long into the future. what can be predicted with more certainty, however, is that russia and china will be highly reluctant to be drawn into a hostile relationship. moscow and beijing understand that the price of confrontation can be extremely high for both of them. history matters-and the past experience of mutual confrontation is still well remembered in both capitals. as the prc's consul general, speaking at far eastern federal university in november 2019, put it: 'the lessons from history tell us that the countries must keep friendly relations, taking into account that russia and china are each other's largest neighbors and considering that the power of each country can do fatal harm to both sides'. it is likely that the russia-china relationship will continue to be guided by rationalism and pragmatism, but, of course, there is no guarantee it will stay that way forever. 1. lower-level chinese officials can be even more ambiguous in public about the possibility of an alliance with russia. for instance, when, in november 2019, the prc's consul general in vladivostok gave a lecture on sino-russian relations at the far eastern federal university, he was asked whether russia and china would make a military alliance. the diplomat replied that there are no plans for an alliance, but added that 'one can't foresee the future'. retired us general says war with china likely in 15 years a new sino-russian high-tech partnership the eu's new central asia strategy: what does it mean for trade? eurasianet russian-chinese relations are warming the arctic. bellona, 24 may economist. 2019. emmanuel macron warns europe: nato is becoming brain-dead. 7 november belorussiya voz'met kredit u kitaya vmesto rossii. 25 october biznes stran eaes ne gotov k sozdaniyu zony svobodnoi torgovli s kitayemministr eek a contest for supremacy: china, america, and the struggle for mastery in asia razdumya ob ukreplenii kitaysko-rossiyskih otnosheniy vsestoronnego strategicheskogo vzaimodeiystviya i partnerstva na fone bolshoi turbulentnosti v mezhdunarodnyh otnosheniyah sino-russian relations: an alliance or partnership? friends with benefits? russian-chinese relations after the ukraine crisis. carnegie moscow center the pandemic could tighten china's grip on eurasia china-russia: the entente cordiale of the 21st century? 7 october, eastwest institute a surprise winner from the us-china trade spat: russian soybean farmers china acquires 20 percent stake in novatek's latest arctic lng project chinese banks comply with us sanctions against russia zapad i rossiysko-kitayskiye otnosheniya: stadii otritsaniya. valdai club tacit alliance: russia and china take military partnership to new level neobyavlenny soyuz: kak rossiya i kitay vyhodyat na novy uroven' voennogo partnerstva the current state of russian-chinese defense cooperation. cna energeticheskiye mosty evrazii vostok-2018: russia and china signal growing military cooperation. russia matters protesty vklyucheny v povestku sverhderzhav. kommersant pyongyang starts and wins. what can the losers do? russian international affairs council why russia and china are wading into a centuries' old dispute over a tiny island cluster. cnn china increases its presence in russia's former central asian backyard. south china morning post us take note: chinese, russian militaries are closer than you think, china's defence minister says. south china morning post ne sobiralis' zadirat' ssha russia and the united states in the asia pacific: a perspective of the english school huawei stalo tesno v krylatskom. kommersant russia & china agree to significantly boost trade in ruble and yuan at the expense of the us dollar treaty of good-neighborliness and friendly cooperation between the people's republic of china and the russian federation war in the taiwan strait is not unthinkable: some will lose more than others china and russia pledge to boost ties and cooperation russia ready to supply 'standard' su-35 s to china, says official. his jane's 360 excerpts from the transcript of the valdai international discussion club session vladimir putin's annual news conference. president of russia sold: russian s-400 missile defense systems to china. the diplomat putin: outside interference in south china sea dispute will do only harm russia's trade with china surges to more than $107 billion is russia worried about china's military rise? the national interest on russia's vast frontier, lots of free land and few takers russia to help china develop an early warning system rossiysko-kitayskiy patrul'. yandex.zen rossiya rasschityvayet na uvelicheniye ob'yoma kitayskih investitsiy. 3 june china not seeking military alliance-lavrov posol rf: sistema kitaya o preduprezhdenii o raketnom napadenii povysit bezopasnost' regiona. 20 october posol rossii v knr: rf i kitay imeyut real'nye perspektivy sotrudnichestva v arktike the state council information office of the people's republic of china from greater europe to greater asia? the sino-russian entente russia and the west from alexander to putin: honor in international relations chinese economists warn beijing to prepare for decoupling from us. south china morning post china's arctic policy as coastguard boats circle, vietnam prepares for bigger challenge in south china sea cooperation, co-existence or clash? china and russia's ambitions in central asia. the diplomat conflict of interest the authors declare that they have no conflict of interest. key: cord-017149-cegevjw8 authors: gassmann, oliver; schuhmacher, alexander; von zedtwitz, max; reepmeyer, gerrit title: the internationalization challenge: where to access innovation date: 2018-05-11 journal: leading pharmaceutical innovation doi: 10.1007/978-3-319-66833-8_7 sha: doc_id: 17149 cord_uid: cegevjw8 pharma innovation is becoming increasingly global, partly due to the lure of serving new markets, partly because of the need to access early new technology and talent wherever it emerges. apart from the established centers of innovation in the united states, europe and japan, india, china and singapore are rising attractors for global life science r&d. china as a pharma market and host of pharma r&d is highlighted as a case study, both from the angle of foreign r&d investors and from the perspective of indigenous chinese players. given the significant cost pressures in mature markets, reverse innovation in healthcare has drawn considerable attention by local governments. in the u.s., takeda in japan, and bayer in germany had large home markets and a substantial domestic r&d base, and hence had less pressure to internationalize their r&d activities. only in recent years, starting in the mid-1990s, increased competition from within and outside their industries forced companies from large countries to source technological knowledge on a global scale. global mergers ensued, expanding the research of r&d organizations quickly into new territories. the rise of china as an emerging market for health care and pharmaceuticals has attracted much pharma r&d investment in the mid-2000s. as a result, the top pharmaceutical companies today have r&d locations in all major markets, not just for the coordination of local clinical development projects but also for discovery research. the management of cross-border r&d is characterized by a significantly higher degree of complexity than local, single-site r&d management. the extra costs of international coordination must be balanced by synergy effects such as decreased time-to-market, improved effectiveness, and enhanced learning capabilities. top corporate managers are confronted with the task of finding the optimal r&d organization based on the type of r&d activities, the present geographic dispersion of subsequent value-adding activities such as production and marketing, and the coordination between a multitude of contributors to the r&d process. the case for r&d internationalization is not unchallenged. besides the ubiquitous cost argument, foreign r&d units are more difficult to manage, and control, and may be less efficient due to missed scale effects. table 7 .1 summarizes some of the most cited arguments against international r&d. what drives r&d internationalization? most factors are due to either science & technology-related issues or sales & output efficiency (table 7 .2). science and technology-related factors are concerned with r&d personnel qualification, knowhow sourcing and regional infrastructure. these factors are largely outside the direct influence of r&d but necessary for its fundamental operations, such as the proximity to universities or the r&d environment. proximity to markets and customers, improvements of image and collaborations are notable sales & output efficiencyrelated factors. efficiency-related criteria focus on the costs of running and the critical mass of r&d units, as well as efficient hand-over processes between r&d and other corporate functions. direct cost advantages (such as the often-publicized labor costs) rarely influence the internationalization of r&d in the long run, but other efficiency-oriented factors such as costs of coordination and transfer, and critical laboratory size do have an even bigger impact on international r&d organization. direct costs may become more important in the coming years as the other factors improve in low labor cost countries. political and socio-cultural factors such as local content rules, technology acceptance and public approval times, all play an important role in locating r&d abroad. protectionist, legal and cultural constraints imposed by national governments, however, often require a company to establish local r&d units. r&d-external forces such as a business unit's striving for autonomy and the build-up of local competence alters the original mission of a local r&d unit. this evolution may take place without hq's knowledge, particularly in strongly decentralized companies. in the pharmaceutical industry, mergers and acquisitions have significantly contributed to the internationalization of r&d, particularly with recent cross-border mergers. even though small size is a driver for internationalization, the global marketing reach of large firms facilitates the leverage of global r&d and innovation. for instance, when pfizer acquired wyeth and merck acquired schering-plough in 2009, on paper the two merged firms would have accounted for 51% of the total u.s. pharmaceutical r&d spending and 39% of total world-wide spending (comanor and scherer 2013). subsequent cost reduction programs eliminated r&d units in the combined companies, but since both domestic and foreign units were closed down, this had little effect on their new extent of r&d internationalization. rather, we (2002) 7.1 trends in r&d internationalization observed a centralization of r&d in certain internationally leading regions of innovation (centers of excellence). however, mergers are rarely driven by scientific or technological reasons. access to new markets and economies-of-scale effects are primary drivers for mergers. nevertheless, the resulting r&d conglomerate must somehow come to terms with a new and more international organization. the development of local products requires the early involvement of market and customer application know-how, which is more likely to be found in regional business units. companies with local r&d exhibit an inclination towards overemphasizing different local market specification in order to support local autonomy and independence from the parent company. host country restrictions, such as local content requirements, tolls, import quota, and fulfillment of standards, can attract r&d into key market countries (pull regulations): both the u.s. and china have plenty of such regulations attracting inbound r&d investments from overseas. on the other hand, home country restrictions may induce companies to move r&d abroad (push regulations): european regulations caused biotechnology r&d to be transferred to the u.s., and lack of homegrown talent forced swiss pharma companies to set up r&d centers abroad. a study of 9452 r&d sites across various industries (including automotive, engineering, electrical, it, software, food, chemical and pharmaceutical companies) produced the following overall results concerning international r&d locations (see also von zedtwitz and gassmann 2016): • r&d is concentrated in the triad regions of europe, the united states, japan, as well as major regional centers in south korea, singapore and other emerging economies in asia-pacific, such as india and china. china has seen a particularly strong increase of inbound r&d investments in recent years, but domestic companies are also conducting more and more r&d. compared to china and india, the other frequently mentioned bric countries-brazil, russia, and sometimes also south africa-are far behind. they lack economic and institutional attractiveness, and their domestic high-tech ecosystem is still underdeveloped, comparatively speaking. • over 70% of all research sites are in the five regions of the northeastern usa (new jersey, new york, massachusetts), california, the united kingdom, western continental europe (in particular germany), and the far east (japan, south korea). china (especially shanghai and beijing) and india (especially mumbai and bangalore) are catching up as locations for research, too. the trend of research concentration is even more apparent when only foreign research locations are considered: almost 90% are in the triad regions of the u.s., europe, and japan. • although the main regional centers for development largely coincide with the regional centers for research, development is more evenly distributed among european countries and the northeastern united states, and extends into southeast asia, australia, africa, and south america. only slightly more than half of all development sites are located in the eight most development-intensive countries. moreover, research and development sites of the same company are not necessarily co-located. this is especially true in the pharmaceutical industry, where development mandates differ so much from research. since the late 1990s many large companies have made multiple efforts to consolidate their activities in order to realize synergy and coordination potential in international r&d. transnational r&d projects are managed more easily if the r&d network consists of competence centers (pharmaceutical firms tend to be ahead in reorganizing themselves around competence centers), given that complementary competencies are provided locally. with increasing complementarities of resources, competencies, and knowledge bases, as well as the division of labor and specialization of work, synergy potentials in r&d projects can be exploited. figure 7 .1 shows a subset of 821 pharmaceutical r&d centers of the 9452 r&d locations. it presents the r&d locations of 45 pharmaceutical companies, including abbott, astrazeneca, boehringer ingelheim, j&j, eli lilly, eisai, gsk, pfizer, merck, novartis, novo nordisk, pfizer, roche, sanofi, sinopharm, takeda, or teva. the distribution of these r&d sites shows a similar pattern to global r&d dispersion across all industries but differs in the following observations: • there are very few r&d centers outside the globally most attractive countries (the triad countries, as well as china). • in the us, r&d is focused more on the north-east, in particular the tristate area, north carolina, massachusetts, and a few centers in the mid-west. relatively speaking, there is less r&d in california, but the bay area, san diego and los angeles are catching up also as hosts for pharma and biotech r&d. • in europe, r&d is concentrated in the u.k., france, germany and switzerland, mirroring the relative strength of these countries as homes of big pharma (novartis and roche are from switzerland, sanofi and servier are french, astrazeneca and gsk are from the u.k., and bayer and merck kg are german). • despite what some call japan's lost two decades, there is a strong representation of r&d in japan, led by the many japanese pharmaceutical firms, although most of them are smaller compared to their western competitors (e.g., takeda or eisai). • emerging new centers of pharma r&d are shanghai, beijing and singapore, but also india (mumbai and bangalore), and israel. given this data, the pharmaceutical industry is one of the most internationalized in terms of r&d locations. pharmaceutical companies also seem to internationalize research as fast as development (albeit for different reasons). most other industries tend to keep research at home and localize development. although not obvious from location data alone, pharmaceutical companies also tend to organize r&d as competence-based networks, as opposed to r&d hubs (e.g., automotive and chemicals), polycentric networks (e.g., local market-dependent companies such as royal dutch/shell) or centralized r&d (e.g., dominant design industries). in competence-based r&d networks, each r&d node has a clearly defined competence-and responsibility!-which it brings into the network of other r&d centers. the coordination and management of such r&d networks is more demanding and costly than rather centralized and directive r&d hubs, or the laissez-faire style of polycentric r&d networks. as a consequence, pharmaceutical companies (and many electrical and it companies, who also favor this type of r&d organization) try to coordinate r&d activities across multiple levels, including the deployment of transnational project teams, platform management, informal as well as formal network techniques. the history of novartis has been documented in detail by zeller (2001). we will focus here only on some of the more recent developments as they are representative of big pharma. in 2002, about 3000 scientists worked in 10 research centers worldwide in several therapeutic areas. only 1400 of them were employed in research centers in switzerland, along with a comparable number in pre-clinical and clinical development: more than half of the r&d workforce was located outside switzerland. novartis had 67 drug candidates in clinical development at that time. in may 2002, novartis announced it would move its global research headquarters to cambridge, massachusetts. over the following 15 years, the cambridge-based center has grown by 2000 people in r&d alone and now occupies multiple sites. in 2003, it opened a research center focused on dengue and other tropical diseases (the nitd institute for tropical diseases) in singapore. it closed its palo alto-based systemix r&d and moved it to east hanover, new jersey. in 2006, novartis opened a r&d center in shanghai, being one of the first of the big pharma to do so. over the next few years, novartis would continue to consolidate r&d in its preferred research hubs. in 2013, novartis closed its horsham, u.k., respiratory research center, its center for topical dermatology treatments in vienna, and a biotherapeutics development unit in la jolla. it also relocated oncology r&d from emeryville in california to its cambridge r&d center. in 2016, novartis closed its schlieren, switzerland-based esbatech r&d center, and moved its institute for tropical diseases from singapore to emeryville, although singapore remained a major r&d hub for novartis in asia-pacific. it also shut down its biologics group in shanghai. however, it opened a brand-new us$1 billion research center in shanghai, to become its third largest research center behind cambridge and basel. as of 2016, novartis employed 6000 scientists in its global r&d organization, almost half of them in cambridge alone. novartis's headquarters remained in basel, switzerland. chugai is one of japan's pharmaceutical pioneers. it was acquired by roche in 2002 but continues to operate independently. founded in 1925 in tokyo, it had established r&d centers in ukima, kanagawa, and shizuoka. with new ambitious research targets in the early 1980s, it started to establish overseas offices in the mid-1980s, and to invest or acquire u.s.-based biotech firms. in 1992 it set up its first international research center in korea, and expanded its london office into a fully-ledged pharma center in 1995. in the same year, it founded a research center in ibaraki, and 6 years later one in tsukuba and in singapore. with the alliance with roche in 2002, global r&d was reorganized as well. the tsukuba and the takada centers were both closed, but the forerunner pharma research company formed, as was a new clinical research center organization, which eventually also opened a base in singapore in 2011. an interesting case of internationalization is ferring pharmaceuticals. these examples are typical for the changes in global r&d in the pharmaceutical industry (see fig. 7 .2 for takeda). we see three major trends: 1. consolidation in hubs with abundance of talent and technology. 2. acquisitions of smaller competitors and biotech firms expand the geographic dispersion of r&d. 3. increased presence in asia-pacific, especially china. the last trend is also observed for global r&d in other industries, which nevertheless requires an explanation, as china is not known to be a place in which r&d is conducted easily, nor is it a country in which intellectual property-the main result of r&d work-is well protected. the healthcare context in china china is no longer a mystique country closed off to foreigners, but it is still very much misunderstood. under almost constant reform mode, the china's economy was opened up in the 1980s, picked up speed in the 1990s when it became a major destination for manufacturing investments, excelled at growth rates beyond 13% and 14% in the 2000s, when it also became attractive for r&d, but in the wake of the economic crisis of 2008 it slowed down to what is now called a "new normal" economic growth of 6-7%. it passed japan as the second largest economy in the world in 2010, and in 2015 its gdp was us$11 trillion, behind the u.s. at about us$18 trillion. despite a growing middle class (whose definition is ambiguous in china), most of china is still a developing country, which translates into great tensions about healthcare services needed and wanted, and what role the pharmaceutical industry can play in this context. improved living conditions further mean that china's population is aging fast, with the share of the population aged 65 or older to double to about 13% by 2025. china's one-child policy, although relaxed to a two-child policy in 2015, led to wealth being distributed among fewer children and family members, which means that more earnings are disposable for life-style and healthrelated products. furthermore, as china westernizes, its disease profile will become more and more comparable with the western world, including afflictions such as hypertension, cancer, diabetes, etc., for which multinational companies already have developed drugs and therapies. with a population of more than 1.3 billion, china presents a huge market opportunity as it is. a rapidly aging population (in 2015, an estimated 131 million people are aged 65 or over), coupled with new afflictions resulting from air and water pollution, pushes the emerging healthcare system to the brink, and the solutions required will need to concerted effort of government, pharmaceutical industry, and healthcare institutions. administrative hurdles, low healthcare spending, the lack of intellectual property protection and the poor distribution network infrastructure remain the biggest challenges. major pharmaceutical companies pursue aggressive growth strategies and try to benefit from the chinese market in the longer term. they invest in the sourcing of active ingredients, research and development, and the production and selling of generic and proprietary drugs. in 2002, china was still a low-tiered market of about us$6 billion in total. pharmaceutical sales grew at a cagr of 26% between 2007 and 2010, exceeding overall growth in gdp and overall healthcare expenditure (deloitte 2011). it passed us$100 billion in 2015 and is estimated to grow to us$200 billion in 2020. china has the world's fastest-growing over-the-counter (otc) drug market and is already the second largest pharmaceutical market worldwide. pharmaceutical sales amounted to 17% of total health expenditures in 2015, or us$78 per person. generics accounted for 64% of total sales, patented drugs only 22% (ita 2016). the generics market is dominated by low cost domestic producers. webber (2005) put their number at approximately 6800 chinese pharmaceutical companies, of which 5000 produced medicines (small-molecule generics and biotech products, i.e. not including herbal medicines or traditional chinese medicines) and the remainder were involved in pharmaceutical-related activities such as packaging and equipment supply. a large share of them are merely producers of raw materials (wang and von zedtwitz 2005). by 2015, this market was still highly fragmented, with 5000 domestic companies in operation, of which the top 100 accounting for only one third of the total market (ita 2016). government and chinese fda (cfda) policies have been expected to weed out those not in compliance with gmp (good manufacturing process) practices, but have made only limited progress. the 2010 strategic emerging industries initiative plans to create national champions, and policies are being put in place that seem to favor domestic over foreign companies (prud'homme 2016; ita 2016) . chinese manufacturers are very strong in their ability to copy foreign drugs, sometimes selling them under foreign labels. the vast majority of the 3000-4000 pharmaceutical products manufactured in china are copies of foreign products, either legal generics or illegal counterfeits. they serve a worldwide counterfeit market estimated to exceed us$24 billion in 2014 alone (philipp 2014), with 79% of counterfeit pharmaceuticals seized by u.s. authorities in 2008 coming from china. the situation is complex to control: in addition to the almost 5000 chinese companies involved in medicine manufacturing, there are 400,000 retail pharmacy shops, and 29,000 firms involved in shipping medical products (philipp 2014). china lacks effective regulatory control over the manufacture and distribution of active pharmaceutical ingredients (apis). chemical manufacturers only need to register with the cfda if their product is intended for medical use. the cfda has no authority to regulate them if they declare otherwise, and the cfda does not monitor or inspect apis intended for export (ita 2016) . for many chinese companies, the term 'r&d' refers mainly to the production of additional generic products particularly for china-in terms of strengths, dosage forms and even specific compounds (webber 2005). as of 2016, what constitutes a "new drug" was still of unclear definition and subject to policy debates (ita 2016). in 2015, tu youyou won the first nobel prize awarded to a chinese in physiology or medicine for her discovery of a novel malaria therapy, artemisinin. while traditional chinese medicine (tcm) has been a staple in china for a long time, it put the spotlight on the uneasy relationship between western and chinese approaches to medicine (many chinese doctors prescribe tcm side-by-side with western ethical drugs). more than 8000 (including different dosage forms) traditional chinese medicines (tcm) are manufactured and sold. with few market entry barriers, there were over 2500 tcm companies in china. tcm accounts for more than 20% of sales and is particularly strong in rural areas. tcm drugs make up 39% of the essential drug list (edl) and 46% of the national drug reimbursement list (ndrl) (export 2016). in the chinese view, tcm has already proved itself to be effective in curing many kinds of diseases, having "gone through thousands of years of clinical trials" (guo 2016, quoting wang guangji, a deputy to the national people's congress (npc) and former vice president of china pharmaceutical university who specialized in western medicine): "but important terms like yin (substance) and yang (energy), whose balance are essential for harmonious operation of the body, according to traditional chinese medicine, would hardly be accepted by foreigners." western pharmaceutical firms shy away from tcm r&d, as it is difficult to isolate single, scientifically testable compounds (waldmeir 2015). according to ye yang, deputy director of shanghai institute of materia medica, "to get a single compound out of a single plant, like in the case of artemisinin, took so many years. in traditional herbal medicine [you might have] 500-600 compounds working together. we don't have the technology to follow all of them to see how they are working individually and together." the chinese government promotes tcm, and several government departments are guiding the tcm industry's attempts to modernize. according to webber (2005) , the chinese authorities have identified two tracks for developing tcm r&d. the first is through purification and standardization to meet global standards and remove impurities such as pesticides and heavy metals. the second track is to utilize tcm as a starting point for producing novel medicines. this may be through the identification and purification of the active element(s) (often complex molecules) or the discovery and development of small molecules which mimic the activity of the original tcm. liu and xiao (2002) found that about 140 new drugs have originated directly or indirectly from chinese medicinal plants by means of modern scientific methods. the chinese government has also set clear focus on certain areas of biotech research, especially genomics research. in 1998, the ministry of science and technology established the chinese national human genome centre based in beijing and shanghai, and the beijing institute of genomics, as centers of excellence for genome sequencing and analysis, thus enabling china to join the international human genome sequencing consortium in 1999, in which china played a significant part. china now is on par with major international research leaders in areas such as gene mapping, transgenic technology for animals and plants, gene therapy technology, stem cell research, gene chips and gene research of some major diseases (webber 2005) . the country has several world-class scientific biomedical institutions-the north and south genome centers, the institute of materia medica, tsinghua and beijing universities, for example. china also has some 200 research institutes for biotechnology and more than 30 of the 150 key state laboratories in biopharmaceutical-related areas. in china, the domestic pharmaceutical research and development environment is still dominated by universities and scientific institutes rather than pharmaceutical enterprises. the industrialization of pharmaceutical research and biotechnology still lags the western world, but is catching up quickly as well (shi et al. 2014) . foreign pharmaceutical companies have conducted r&d in chins since the late 1990s, although in the earlier years the type of research done was very low key and part of larger studies that were rooted elsewhere. for instance, roche had an r&d office in shanghai long before it opened a dedicated r&d center in 2004. it was not until the mid-2000s that global pharma companies discovered chinas as a harbor for strategic r&d operations, perhaps a decade after global electronics, it and automotive firms started to invest in r&d in china. there are several reasons for this relative late arrival in china: • uncertain ip protection: china had reintroduced patent law only as recently as 1985, and neither the general public nor the scientific ecosystem was used to developing, protecting, and honoring intellectual property. the courts, the legal system, and the police had little-if any-experience in dealing with ip cases. chinese employees had little sensitivity for personal safety or safety as a public good. tacit knowledge and knowledge that was pre-patent was not easy to secure and appropriate. of course, these conditions affected also other industries, but in pharma-with its extremely long lead times-such unwanted exposure of technical knowledge is very harmful. • fragmented nature and complexity of china's market: 3700 domestic companies accounted for 75% of annual sales, of which 95% operated in the low value generics market (dierks et al. 2013) . most needs are met by local generics, with only between 6% and 7% being patent-protected innovative drugs. • price pressure: 40% of china's healthcare budget was being spent on medicine compared with 10-12% in western countries, leading to considerable political pressure to reduce prices (knowledgewharton 2013). on the other hand, there were also several strong china-specific reasons to consider r&d in china: • quick development of a middle-income market demanding medicines for their evolving needs. these needs stem from rising life expectancy, pollution, and enhanced abilities to detect and diagnose diseases. • understanding the uniqueness of the genomics and metabolomics of the chinese population gives competitive leverage to domestic r&d entrants. • access to natural products in china as sources for new chemical entities (nces). newman et al. (2003) calculated that about 60% of nearly 900 nces could be traced back to natural products. one famous example is lipitor, a statin first discovered in natural sources with sales exceeding us$10 billion annually. • access and research on tcm: china-based innovations include artemisinin, invented in china using sweet wormwood and hailed as a miracle malaria drug, sobuzoxan, an anti-tumor drug, and huperzine a (hupa), a novel alkaloid isolated from a chinese medicinal herb, which improves memory deficiencies in alzheimer patients. testing the waters for captive local r&d operations often begins with r&d collaborations. glaxosmithkline (gsk), for instance, invested over us$10 million in cooperative r&d with chinese research institutions since the mid-1990s. novartis started a collaboration with the shanghai institute of materia medica (simm), with the objective of isolating compounds from chinese medicinal plants for novartis to further screen and identify lead compounds. after an initial phase and us$2 million in funding, training and equipment, by 2004 simm had isolated more than 1800 compounds from natural herbs covering immunology, oncology, diabetes and the central nervous system. other braved the uncertain conditions and started dedicated r&d centers early. in 1997, novozymes opened an r&d center in the zhongguancun science park in beijing. costing 10 million €, the facility focused on the customized development of enzymes and processes for the chinese market. roche opened a new r&d center for 40 chemists in zhangjiang high-tech park and established r&d alliances with the state-owned genomics centers in shanghai and beijing, to conduct research in the genetic predisposition to diseases such as diabetes and alzheimer's. local r&d enabled these foreign pharma companies to enter more credibly into a dialogue with authorities and opinion leaders in the country, which ultimately is good for business in china. by the mid-2000s, the ip situation in china was better understood, other foreign multinationals had been successful with captive r&d in china, and some of pharma's r&d pioneers seemed to succeed with r&d in china as well. as a result, pharma companies started to invest more strategically in r&d in china, in the expectation to access the natural resource base in china, and to tap into an increasingly large body of medical researchers and pharmaceutical scientists. also, china is also an attractive base for clinical research, given that there were more than 300,000 hospitals and healthcare facilities. table 7 .3 presents an overview of this early stage of r&d setup in china. in july 2004, glaxosmithkline china set up an otc (over-the-counter) medicines r&d center at tianjin smith kline & french laboratories, a joint venture funded by glaxosmithkline. its aim: to excel in creating innovative science-based products to meet consumer needs and support the joint venture's vision of becoming the premier otc company in china. pfizer set up an r&d center in shanghai focusing on developing trial protocol design and assessment of trial results, and novartis built a us$100 million drug discovery research center in shanghai in 2006. the research facility, which expanded to 400 scientists by 2008, focused initially on discovering medicines to treat cancers caused by infections, which make up a considerable proportion of the cancer cases diagnosed in china. some smaller biotech firms also started local r&d in china, for instance bicoll in shanghai. while pharma r&d focused initially on shanghai and beijing, other industries explored locations in second-tier cities and interior china, a trend that pharma r&d is following only slowly. even globally, pharma r&d tends to be more concentrated in few hubs, and there is no reason to assume this should be different in china (fig. 7.3) . in the years after the global financial crisis china benefited from its domestic stimulus program, but as of 2013, china's gdp growth has marked slowed down. this is especially true for the already well developed provinces along the pacific shoreline, while many of the central provinces continue to enjoy high growth rates, albeit from a lower base level (according to the national bureau of statistics in china). cities in those provinces-e.g., chengdu, chongqing, and wuhan-are expected to become more attractive as hosts for pharma r&d. at the same time, foreign pharma companies continued to consolidate and expand r&d in their original r&d locations. roche, which has occupied the same location in shanghai since 1997, poured in rmb 1.8 billion (about us$300 million) to expand to 19 buildings covering 70,000 square meters and employing 1800 professionals. shanghai became its third most important strategic r&d site worldwide, with major projects being run from china globally. construction is under way for the roche innovation campus shanghai, as is a diagnostic manufacturing facility in suzhou; these projects cost another us$450 million. novartis, which started with a 5000-square meter facility in 2006, invested us$100 million to build a dedicated r&d facility for 400 scientists in 2007. in 2016, it opened a us$1 billion r&d center in shanghai, banking on the expectation that the chinese government's own increased spending on biomedical research and training will deliver talented and highly educated researchers. a drug for liver fibrosis was fully discovered in china and brought into the late clinical stages, with hopes running high that it will be a high-performance global drug soon. astrazeneca doubled down on its 2003 start in clinical research in china and in 2007 added a us$100 million investment in its new astrazeneca innovation center in shanghai. the center's initial research mandate was "in china, for china," but it has assumed a broader mission as a full-fledged discovery center focusing on diseases more prevalent in asia. in 2015 it made available us$150 as an initial investment in a widened collaboration with wuxi apptec (so renamed after the merger of wuxi pharmatech with apptec laboratory services) to produce innovative biological medicines in china, with several hundred million us$ earmarked for further r&d investments in china across the board. it is important to note that pharma r&d in china is still very much in its early stages, and it is far from certain that the upfront multibillion-dollar investment will indeed deliver the expected payoffs. research by grimes and miozzo (2015) showed that only 1.78% of the 9543 patents granted by the uspto between 2004 and 2014 by the top big pharma companies had chinese citations and only 1.44% had chinese inventors. of the latter, roche accounted for 65% and novartis for 18%. china's share of biotechnology patents was also at around 1%, which is the same level as its overall uspto share. while china is often credited with speed and rapid development, many of the problems that kept pharma investment away in the 1990s are perhaps still present, or at least inadequately addressed (see table 7 .4). astrazeneca's the question is whether economic growth coupled with the shaping of a positive environment will encourage increasing investment into innovative pharmaceutical r&d in china. the global pharma companies are well advised to explore the china option carefully and systematically, given the dangers involved, but certainly they are advised to take this opportunity seriously. reverse innovation in healthcare to the 2015 nobel prize for medicine to be awarded to a chinese researcher, tu youyou. innovations from emerging markets carry the stigma of being 'low cost' or 'geared towards the needs of under-developed civilzations' (for a summary of roadblocks against reverse innovation, see hadengue et al. 2017 ) and often face steep adoption and acceptance difficulties (depasse and lee 2013). western policymakers and governmental institutions have therefore launched several initiatives at making the reverse transfer of emerging market solutions (from so-called lic low-income countries) more predictable and more systematic: • prize competitions: snowdon et al. (2015) reported the results of an open competition for healthcare solutions from developing or emerging countries, with the winner to be awarded us$50,000 for further financing their project. a committee evaluated all 12 submitted projects on the basis of seven weighted criteria. apart from the winning innovation being supported through the prize money, the competing entries also benefited from project-specific feedback, and through media exposure the public was made aware of the potential of reverse innovation in health care. • crossover identifications: depasse and lee (2013) described a four-step model to transfer reverse innovations that includes a common problem identification in a lic, a dissemination analysis in that country, a crossover proposal, and subsequent dissemination in a high-income country (hic). the trick is not only to execute that crossover effectively, but also to identify suitable reverse innovation candidates and to support disseminiation in the home country. • scoring assessments: battacharaya et al. (2017) developed a two-step scoring system with eight assessment criteria, mostly for use by policymakers, public institutions or funding agencies. the purpose of this assessment is to identify potential reverse innovations and qualify them for their suitability to be transferred and applicability to an unmet need in the home country. in conclusion, the potential of reverse innovation in pharmaceuticals is still difficult to estimate, but the healthcare sector has taken a strong interest in considering any emerging solution from emerging market countries due to the mounting cost pressures in industrialized nations. pharmaceutical multinational firms that already have r&d centers in those emerging markets are well positioned to leverage their reach into different population groups not only as patient pools but also as sources of innovation, and ultimately may play an important role in acting as conduits of reverse innovation in their home countries. r&d in multinational companies has developed from centralized and geographically confined towards distributed and open structures. the pharmaceutical industry is one of the most advanced in terms of r&d internationalization, and one of the most it captures not only innovations first introduced in such markets but also those developed there (von zedtwitz et al. 2015), and it also includes truly indigenous sources of innovation rather than primarily foreign-invested subsidiaries of technology-intensive multinations in those regions the list of examples illustrating the potential that reverse innovation can have on healthcare in general and the pharmaceutical industry in particular is growing. among the first instances of reverse innovation mentioned ever are medical devices: ge's mac400 electrocardiogram from india, or ge's portable ultrasound devices developed in china. but medicines are also increasingly coming from emerging market countries: vicks honey cough drops were developed by p&g in their caracas r&d center, initially for their latin american market, only to see it do well with large populations in the u.s. and europe as well reverse innovation in healthcare specific when it comes to regulation and significance of science and technology. still, maintaining a well-balanced locally responsive and globally efficient r&d network is one of the great challenges of multinational organizations. rapidly evolving biotech firms and new pharma entrants (whether from emerging economies or in the • introduction of local culture of innovation and know-how • challenging projects coupled with bottom-up creativity • personal interactions more important in decentralized r&d • synchronization of international drug development by means of transnational project management in order to shorten r&d cycles • worldwide integrated r&d data management • acquisition of external ideas and projects as important as internal r&d • international teams require new organizations • manage platforms, not individual r&d projects • better inclusion and leverage of local university and national research programs • effective management of local open innovation partners • foster networking and collaboration in conclusion, transnational r&d management is a key ingredient to success, and the high stakes of the drug approval and medical safety have made the pharmaceutical innovation pipeline one of the best understood r&d engines (gassmann and von zedtwitz 2003b). however, there is still untapped potential to improve this engine with new technologies, new managerial approaches, and new scientific talent drawn from countries around the world. key: cord-235946-6vu34vce authors: beskow, david m.; carley, kathleen m. title: social cybersecurity chapter 13: casestudy with covid-19 pandemic date: 2020-08-23 journal: nan doi: nan sha: doc_id: 235946 cord_uid: 6vu34vce the purpose of this case study is to leverage the concepts and tools presented in the preceding chapters and apply them in a real world social cybersecurity context. with the covid-19 pandemic emerging as a defining event of the 21st century and a magnet for disinformation maneuver, we have selected the pandemic and its related social media conversation to focus our efforts on. this chapter therefore applies the tools of information operation maneuver, bot detection and characterization, meme detection and characterization, and information mapping to the covid-19 related conversation on twitter. this chapter uses these tools to analyze a stream containing 206 million tweets from 27 million unique users from 15 march 2020 to 30 april 2020. our results shed light on elaborate information operations that leverage the full breadth of the bend maneuvers and use bots for important shaping operations. the covid-19 pandemic is a defining event of the modern era, and there are few events more appropriate to apply social cybersecurity tools and concepts. at the time of this writing, the pandemic has reached almost every society in the world, with massive impact not only on the lives of those who contract it but on the social, economic, and institutional fabric of these societies. the pandemic and differing opinions on how to react to it have created a virtual battle of ideas across social media. actors ranging from soccer moms to well-resourced nation states have entered the virtual marketplace of beliefs and ideas trying to sway the beliefs, actions, and decisions of both leaders and followers. with the pandemic as the backdrop of life as we write this book, it seemed appropriate to use the social cybersecurity tools that we discussed in the previous chapters to identify and understand information operations related to there are still many questions as well as competing narratives about the origins and nature of the covid-19 coronavirus disease. the disease is caused by the severe acute respiratory syndrome coronavirus (sars-cov-2), and was the virus and resulting pandemic have radically altered the world landscape and daily life for many people. with a large portion of the world's consumers sheltering in or near their home, the world's markets have slowed, inducing the greatest global recession since the great depression [10] . it has led to the cancellation or deferment of most travel activities, sporting and entertainment events, religious and political gatherings. as of 14 april 2020, schools and universities had closed or otherwise been disrupted in 191 countries affecting 1.57 billion students (pre-primary, primary, lower-secondary, and upper secondary levels of education), or 90.1% of the total enrolled students for these categories [1] . the covid-19 pandemic has induced information warfare at multiple levels, both within and between nations. at the individual level, much of the information is in regards to safety and health during the pandemic. social media often doesn't have structural filters for good ideas, and at times poor ideas regarding health and safety have been promoted by segments of the crowd. within countries, the pandemic has created two warring factions: 1) those who think policy should prioritize the health and safety of citizens and 2) those who think policy should prioritize the national economy and maintaining the jobs and livelihoods of citizens. these factions often seem to fall along existing political party lines, with conservatives emphasizing the economy and liberals emphasizing health and safety. this policy oriented friction has contributed a large portion of the information conflict within nations. finally, the origin and nature of the covid-19 coronavirus has aggravated existing geopolitical fault lines between nations, particularly between the united states and china, with the european union, russia, brazil, and other nations participating in the conflict of narratives. as we look at information warfare and social cybersecurity in the covid-19 pandemic conversation, we attempt to illuminate information conflict across this spectrum. each country's response has varied based on its society, forms of government, and health care system. the covid-19 pandemic has served as a worldwide test of the resiliency of these systems. nations are therefore turning to information warfare to strengthen their test results while attacking the response and results of other nations, particularly those whose form of government differs from theirs. this is particularly true in the information conflict between china and united states. this chapter will showcase the use of social cybersecurity tools and theory to identify and characterize information operations in the covid-19 related twitter stream. to do this, we will start by discussing data collection and initial exploratory data analysis. then we will conduct bot detection and characterization, merging bot classification with other quantitative methods. we will then look at meme classification and analysis, highlighting the use of multi-modal data for information warfare. finally, we will briefly illustrate the use of sketch-io. throughout this chapter will highlight the importance of bend as a foundational construct for understanding modern information warfare. like most event oriented social cybersecurity data collection on twitter, our team started by establishing a twitter stream with select covid-19 related terms, periodically expanding the terms as appropriate. this gives us the main foundation of data for assessment. once we began analysis of the stream, we turned to the twitter rest api to collect other data as necessary. this additional data is often account oriented and includes timelines, friends, followers, and at times account id "re-hydration". we will discuss each of these below. for covid-19, our team began collecting data on 27 january 2020 with a limited list of keywords and expanded this list on 13 march 2020. for the data that we will focus on in this chapter, the list of keywords are: "coronaravirus", "coronavirus", "wuhan virus", "wuhanvirus", "2019ncov", "ncov", "ncov2019", "covid-19", "covid19", "covid 19". the resulting stream provided the primary data that we will focus our study on. in this chapter, we will focus on the data from 15 march 2020 to 30 april 2020. the summary statistics of this data is provided in table 1 . this is not the entire covid-19 conversation. many tweets may not contain these key words, or may be in other languages. additionally, our stream is limited to 50 tweets per second, or approximately 4.3 million tweets per day. the temporal analysis below will highlight the 4.3 million daily limit on our stream. as we go through our analysis, we will return at times to the twitter rest api to collect additional data that is not found in the stream. for example, the stream only contains an account's covid-19 content, but not all other content and topics. to get access to all content shared by an account, we will at times collect their account timeline (aka account history). there are also times we need to identify an account's friends and followers, which will also require us to call the twitter rest api. finally, at the end of our exploratory data analysis, we will try to find out if any accounts have been suspended by twitter since contributing content to our stream. we will do this by "re-hydrating" account ids in order to see if the account still exists. if the account doesn't exist, we will then test to see if the account was suspended or deleted by the user. all data analysis begins with a thorough exploration of the data. the analyst should explore all of the distributions and possible relationships in the data. in our case, this means exploring the temporal, categorical, geospatial, and quantitative distributions of various fields in the twitter data. we collected and parsed the data using the twitter col 2 python package that we created to assist with collecting and manipulating twitter data. the primary statistics for the data are provided in table 1 . we have 206 million tweets produced by 27 million users. we see that the majority of the tweets are actually retweets. in fact, only 23 million tweets (11% of the stream) is original content produced by the respective account. it is also interesting that quotes significantly outnumber replies. a quote is produced when a user references another tweet and comments on it, starting a new thread. replies, by contrast, are addressed to the original author and don't start a new thread. we see a modest number of state sponsored tweets, with substantially more amplification of state sponsored accounts. finally, for reference, this primary stream is 177 gigabytes in compressed gzip format or 1.54 terabytes in uncompressed format. next we analyze the temporal distribution of our stream. this is primarily done to study the peaks and valleys to understand when the conversation surges and ebbs. this analysis will also ensure that our tweets fall within the scope of our study (from 15 march 2020 to 30 april 2020). the temporal distribution of our stream is provided in figure 1 . this is not what we expect to see, and is definitely not what you would observe in smaller streams. given the size of our stream, we are artificially limited by twitter rate limiting. twitter limits basic streaming api's to no more than 50 tweets per second, or 4.3 million tweets per day. it is unknown what portion of the total conversation we are getting, but given that several days fall below the 4.3 million, we believe we are collecting the majority. twitter did open up a unlimited covid-19 stream in mid-may [15] , but to our knowledge this was not available during the time frame we were interested in. in order to measure the geospatial density of the data, we used a country level geo-inference algorithm created by huang and carley [11] . this model infers the country level location of tweets with 92.1% accuracy. we ran this on data from 13 april and plotted it on a chloropleth map in figure 2 with a logarithmic scale. this shows that the vast majority of the data is from the united states, with notable contributions from canada, south america, western europe, nigeria, south and southeast asia. this geospatial inference and visualization provides yet another facet of our exploratory data analysis. given both the keyords that we used and twitter users by country, this spatial distribution is essentially what one would expect. its important to explore categorical data distributions in twitter data. in addition to the retweet/reply/quote/original content distribution that we explored in table 1 , we also want to look at top languages, hashtags, mentions, and url domains. the importance of hashtags ebbs and flows with time and events. we've developed the visualization found in figure 3 to understand this changing dynamic for the top 12 hashtags found in the stream. we observe decreasing use of "corona" and increasing use of "covid19" as a hashtag to identify pandemic related content and conversation. this reflects both the naming of the virus and the increasing knowledge in the world about the virus. the full counts for languages and domains is provided in table 2 . we see that the majority of the content is in english, followed by many of the prominent world languages. the only major world language that is underrepresented is chinese, and that's because twitter is blocked by the "great firewall of china." we note that much of the data from china in this data set is actually from state sponsored chinese media. the domains include several link shorteners, multimedia companies, as well as a spattering of news media companies, including both traditional and alternative news, independent and state owned media, and both conservative and liberal leaning news sites. by its very nature social media creates links between people, and these links combine to create various types of networks. most social media have a friend or follow functionality, which creates the most obvious social network on these platforms. additionally, the online conversation itself will create links between accounts. whenever an account retweets, mentions, replies, or quotes another with twitter data, collecting friend/follower links is limited by strict ratelimiting on the part of twitter. most developer accounts are only allowed to scrape 5,000 friends/followers for one account every minute. the twitter rest api will only return 5,000 friends/followers per request. for example, at the time of this writing the primary twitter account for the united states center for disease control (@cdcgov), has 2.7 million followers. to get all of the followers for @cdcgov would take approximately 2,700,000 5,000 = 540 minutes. in other words, it would take 9 hours to scrape the followers for this single account. scraping links for all of the accounts in the covid-19 conversation (and most conversations) is therefore not realistic. for this reason we often visualize parts of the conversation network, for which we already have the data and is more useful in understanding the conversation. in our visualization of the network, we visualized the mention network, though at other times the retweet or reply network may be appropriate. the twitter json structure has all of the information we need to create mention, retweet, or reply networks. as discussed at other times in this book, we created the public facing twitter col 3 python package to collect and manipulate twitter data. the twitter col package has several functions that make it easy to parse networks from raw twitter json data. the ora software [6, 7] , both ora-pro 4 and ora-lite software 5 has functions for parsing twitter data into networks. these functions were used on the covid-19 stream. visualizing large networks can be difficult. the covid-19 mention network contains 25,673,160 nodes and 152,481,141 edges (density = 0.000000231). very few software packages can visualize a network of this size, and none of the software solutions that our team commonly uses can visualize this network. for this reason, we chose to visualize just the core of the network. to do this, we found the k-core of the network. the k-core of graph g is the maximal connected subgraph of g where all the nodes (vertices) have a degree of at least k. while experimenting with k with our mention network, we found the k = 100 was adequate. this means we will visualize the core of the mention network in which all nodes will have a degree of at least 100. this core network is dense (density = 0.000947), which means there are more edges than we are able to visualize. to sparsify the graph, we sampled one million edges to visualize. this final core network contains 159,533 nodes and 1,000,000 edges with density = 0.0000393. in figure 4 we visualize the core of the mention network colored by language using the graphistry 6 software. we could also visualize larger networks with ora-pro or the sigmanet 7 package in r. in figure 4 we see the inter-connection between the english, french, spanish, and portuguese conversations. we also can see the community groups that are clearly evident in the larger conversations, particularly the english and spanish conversation. given that we now have networks parsed from our covid-19 stream, there are a number of network science techniques that we can use to help understand this network. for now we will focus on the measuring which accounts (or nodes in the network) are the most influential (or central) to the network. measuring centrality is an important step in network science, and there are many different methods that have been published on how to do this, with each technique measuring a slightly different definition of influence and importance. for example, degree centrality measures influence by number of connections whereas betweenness centrality measures influence by those accounts that bridge communities. for our analysis, we chose to measure centrality and influence by eigenvector centrality [12] . eigenvector centrality measures influence by finding accounts that have the most connections to influential accounts. in other words, not all links are created equal, and an account is more influential if it is connected to many nodes who themselves have high scores. we believe that this mirrors the way that many people view influence in the physical world, and therefore use eigenvector centrality for our analysis. we also find that eigenvector centrality, unlike measures like betweenness, is computationally practical on large networks. the top influencers as measured by eigenvector centrality for both the mention and the retweet networks are shown below in table 3 . as we will discuss later, the central accounts in the mention network are politicians and celebrities that we expect. the central accounts in the retweet network, however, includes many bots, which we will elaborate on later. it is often important to evaluate the quantity and nature of suspended accounts in any event oriented stream. twitter and most social media companies suspend accounts that frequently violate their terms of service. these violations could include frequently posting violent, racist, or other unauthorized content. it also could be that the accounts display unauthorized automated activity (i.e. they are a bot). by identifying and evaluating suspended accounts, we get a sense of how the social media company has been "cleaning" this particular stream. to identify suspended accounts, we "re-hydrate" account ids in order to see if the account still exists. if the account doesn't exist, we will then test to see if the account was suspended by twitter or deleted by the user. the workflow begins by identifying all unique account id's in the stream. we then "rehydrate" them in batch mode using the twitter rest api. using batch mode is a fast method to "re-hydrate", but does not provide any feedback for missing accounts. having rehydrated account ids, we then identify those that are missing with m issing = t otal â�� rehydrated. there are several reasons why an account could be missing. the two most common are that the account was deleted by the user or was suspended by twitter. to determine which of these is the case, we individually attempt to rehydrate the missing ids (not in batch mode). this provides a detailed response that indicates whether the account was deleted or suspended. given the size of the covid-19 stream, we randomly sampled 1 million users from the available 27 million unique users in the stream. after "re-hydrating" in batch mode, we determined that 70,842 were missing. using this number, we estimate that 7.0842 â± 0.05% of the accounts in the stream have been deleted or suspended (estimated using 95% confidence interval). next we want to estimate the number that have been suspended. to do this we now individually attempt to "rehydrate" the missing ids. when we do this, we find that 9,639 accounts had been suspended by twitter. using this number, we estimate that twitter has suspended 0.9639 â± 0.019% (estimated using 95% confidence interval). using these ids, we made another pass through our stream, and determined that these 9,639 accounts produced 93,841 tweets that contain the terms we were filtering for the stream. running bot-hunter tier 1 algorithm on this data we find that 73.4% of the suspended users have strong bot-like characteristics. it is often helpful to sample several of the suspended accounts and view their tweets to determine if they were participating in information operations, and if so what was the message and who was the target audience. for example, the tweets of suspended account @scopatumanigga are provided in table 4 . our first observation is that nearly all statuses are retweets, which is highly indicative of bot behavior. given the account screen name and content, it appears that this likely bot account is attempting to infiltrate and influence african american virtual communities on twitter. the likely intent is to amplify racial divides in order to create instability in the united states. table 4 : tweets from suspended account @scopatumanigga rt @tonyhawk: ive been sick lately (not sick af just sick) with symptoms other than covid-19. but i know two friends in the u.s. with co rt @mvrlyns: so after the coronavirus blows over, will yall continue to practice good hygiene and sanitation? ... or will yall go back to rt @kenichial: joe biden: the tests for the coronavirus should be free bernie sanders: the vaccines and treatment for the coronavirus shou rt @workerism: haven't been able to stop thinking about this. a us pharma company with a potential covid-19 vaccine is in court trying to p rt @crypticnoone: 123movies would never do this rt @carnage45 : black athletes give back during every crisis. i'm not saying it doesn't happen but i don't be seeing tom brady, mike trout rt @shanalala : the elite getting tested without any symptoms and commoners with all the symptoms are denied tests. rt @elliecampbbell: i know its necessary to stop the spread of covid-19, but self isolation, no school etc and everything being shut/cance rt @erichaywood: there are 16 people in this photograph rt @eugenegu: @realdonaldtrump there it is. ive been deathly afraid of this exact moment where trump turns to racism and xenophobia and ca rt @baeonda: im 22 years old and i tested positive for covid-19. ive been debating on posting, but i want to share my experience especi rt @socialistwitch: coronavirus is not mother nature's 'cure' for 'evil humans'. the earth doesn't suffer from humanity. it suffers from rt @raeoflite: hi. yes, it originated in china, but the technical term is covid-19 your mom originated from the back of a buick skylark @swevenpjm @ashleytwo @lydiakahill how's this covid19 treating you bernie sanders on his way to the hospital after he sees this tweet url rt @chapatipapa: so they cashed out. hoarded supplies. moved money to companies they believe could make the vaccine, and testing kits all t rt @claireific: hey remember that time i said that tell me about tuskegee should be a required interview question for medical applicants rt @nigensei: empty hotels all over the city of las vegas and theyre putting the homeless in a fucking parking lot. rt @decaturdane: second wave??? url rt @hoodcuiture: i swear christians and colonizers never stop!! how an isolated group get infected rt @breenewsome: whyyyyyyyyyyy do we accept such a lower quality of life in this country in exchange for nothing but slogans &amp; confetti rt @ iamtiredlord: this baby was shot 20 times in the head by a grown ass man because he wanted her girlfriend who rejected him. they are 1 rt @thespinsterymc: the family members of the johnsons have made it clear that medical neglect killed them. stop romanticizing this antibla rt @lackingsaint: got to be honest, it's starting to feel like we're just doing things we feel like doing and saying it's in support of hea bot detection is a critical step for social cybersecurity workflows. as discussed in chapter 7, bot detection often helps to delineate an information warfare campaign, as well as illuminate lines of effort (topics) and target audiences. it also sheds light on the scale, level of sophistication, and at times attribution for the operation. in this section we will discuss how to appropriately deploy bot detection algorithms for social cybersecurity. we will start by estimating the accuracy of our algorithms on the given data stream as well as selecting an appropriate threshold for the data at hand (in our case the covid-19 stream). we will discuss where each of the bot-hunter tiers should be used in the workflow. having run bot-hunter on all 27 million accounts, we will use it to find influential bots, lines of effort, target audiences, and foreign influence. before using any bot detection tool on a given event or topic oriented data stream, the analysts should verify it's accuracy on the stream as well as determine an appropriate threshold. as we discussed in chapter 7, training data matters for bot detection. we need to verify that the model that we are trying to use, and its respective training data, are appropriate and predictive for our event stream. in our case that means verifying that the bot detection model works on our covid-19 stream. to make this evaluation, we need a small labeled dataset from our event stream. for the covid-19 data, we created a list of all unique user id's that were found in the data, and then randomly sampled 200 accounts from this list. we then manually labeled the accounts using a custom workflow that we've developed. after manually labeling the 200 accounts, we evaluated the proposed bot-detection algorithms on the data. with labels and bot-detection scores in hand, we can measure performance with various metrics (accuracy, precision, recall, f1 score, roc-auc, etc). these scores will tell us how well our models are generalizing to covid-19 data. the scores are shown in table 5 for default settings of threshold = 0.5 for all models. from table 5 we first and foremost determine that bot-hunter tier 1 should be our primary bot detection model, with a higher f1 score and good balance of precision and recall. from table 5 we can also determine that the botometer model as well as the bot-hunter tier 2 model don't seem to generalize as well to the covid-19 twitter stream. the bot-hunter tier 0 model, which appearing to perform well, will only be used on specific tasks because it is only able to predict english speaking accounts and because it tends to have a higher false positive rate (in this test the false-positive rate is three times larger than the bot-hunter tier 1). these scores, however, are sensitive to the threshold that we choose. in order to choose an appropriate threshold, we use our labels and bot detection scores and plot precision-recall curves as shown in figure 5 . remember that precision and recall often have an inverse relationship. as precision increases, recall decreases, and vice versa. recall monotonically decreases, whereas precision does not monotonically increase. the exact choice of the threshold will depend on the context and any related policy decisions. if the policy decision requires a low false-positive rate, then choose a threshold with high precision. if the policy decision or analytical goal requires a low false-negative rate, then choose a threshold with higher recall. for most tasks it is best to have a balance of precision and recall, which is why we often use f1 score to measure the performance of bot detection algorithms. in choosing a bot detection threshold, our goal for the covid-19 stream is to characterize the entire conversation. we want to have robust characterization of the entire forest, not necessarily precise analysis of individual trees. this goal requires a good balance between precision and recall. as indicated above, our bot-hunter tier 0 text model tends to produce a high false positive rate. for this reason, we will use a threshold of 0.7 for this model in our covid-19 stream, which cuts false positive rate by a third. for bot-hunter tier 1 we will retain the 0.5 default threshold, since it provides a good balance with precision and recall. for botometer and bot-hunter tier 2, we will use a threshold of 0.3 in order to increase recall. the adjusted performance is provided in table since the bot-hunter tier 1 algorithm is our primary algorithm, we've visualized the probability distribution for all covid-19 accounts in figure 6a with threshold = 0.5 and threshold = 0.65. here we see a large number of human accounts, as well as a large number of accounts that are in the middle, with decreasing numbers of high probability bots. the threshold = 0.5 is our default model, while we can at times use threshold = 0.65 for increased precision. note that for each actor they will have a botscore for each bot detection tool. these algorithm identified bots can be more accurately described as actors with bot-like characteristics. depending on which tool is used and which threshold is used the number of "bots" that are identified will vary. for example, on any given day depending on what is used, the number of "bots" may vary from approximately 25% to 48%. now that we have bot prediction thresholds, we can begin to use the models to understand the covid-19 stream and the conversation and actors involved in it. in figure 7 we visualize the sparsified core of the mention network (k core = 100), colored by bot prediction with bot-hunter tier 1 and threshold = 0.5. we see that bot-like accounts are highly embedded in the core of the conversation, and connect to and mention influential accounts in an effort to manipulate these personalities and their followers. in this visualization, we have also zoomed in to get a better feeling of the structure of the network and so that we can highlight the location of prominent english speaking accounts. the most surprising bot detection analysis that we found was in regards to account creation date. anytime we analyze a list of accounts, it is often enlightening to visualize a histogram of their account creation date. the twitter json contains a field in the user object that records the date, hour, minute, and second that the account was originally created. this date will be some date between march 21, 2006 (the day twitter started) and the current date. we've found it best to bin this by day. each bar in the resulting histogram will contain all accounts that were created on that day. any large spike of accounts created around the same time should cause us to dig deeper to check for the presence of a bot "army". in figure 8 we visualize the account density plot for covid-19 colored by bot percentage. the coloring indicates what portion of accounts in that bar have a bot-hunter tier 1 score greater than 0.5. green indicates bars that have few bots, while red indicates bars that have higher proportion of bots. from figure 8 we see that a large number of bot-like accounts have been created since the pandemic began and then immediately deployed into the conversation. in fact, of the 27 million accounts participating in the conversation, 1.5 million have been created since 1 february and have a bot-hunter tier 1 score greater than 0.5. undoubtedly part of this surge in accounts is created by individuals who are stuck at home and decided to create a twitter account. a significant portion, however, appears to be bot armies. these bot armies are produced by a number of actors with a variety of agendas, but likely all involve manipulation of the marketplace of beliefs, ideas, and collective action. next we want to intersect our measure of influence (eigenvector centrality) with a bot prediction score in order to identify influential bots. in table 3 we list the top 50 most influential accounts in the mention network and retweet network as measured by eigenvector centrality. table 3 also provides the bot-hunter tier 1 bot score, with red text indicating accounts that have a score greater than 0.5. looking at the macro-level comparison, we see more bots are involved with the retweet network than the mention network. this makes sense given that bots are often used to scale amplification, and the easiest way to amplify is with retweets. we also see many more verified politician, news, and government accounts in the mention network. many news accounts have "bot-like" behavior, with @foxnews, @msnbc, and @cbsnews accounts surpassing the 0.5 threshold. it has been documented that many news and celebrities can have bot-like behavior [9] , which is supported in our analysis. we also see in the retweet network that several accounts that are not classified as bots nonetheless have bot . we also note that it is possible for users to employ software or a bot on occasion from the same account. this hybrid form that is human and bot we refer to as a cyborg. cyborgs will also tend to exhibit bot like characteristics; however, they are likely to be lower in their values than a totally automated account. next we want to try to separate the stream into topic groups. we will do this with latent dirichlet allocation (lda) model [4] . to do this, we concatenated all english hashtags by account and then performed lda with k = 5. we chose to concatenate hashtags rather than use raw text for computational tractability and because hashtags provide tokens that capture the essence of topic and meaning. word clouds of the resulting five topic groups are shown in figure 9 . we see that topic groups are differentiated in some ways by geography and in other ways by politics. this topic groups allow us to segment the conversation and focus on a topic of interest, for example a certain geography (the nigerian conversation) or a specific political affiliation (the conservative political conversation). the choice of k is just as much an art as a science. if you want to get a view of the macro topics, use a smaller k, like we did here with k = 5. if you want to extract a very specific conversation (i.e. the liberal conversation in canada), you will have to increase k in order to sufficiently isolate the topic of interest. similar to topic analysis, we also want to look at community groups. while topic analysis looked at semantic topics that seem to cluster together, community groups look at accounts that tend to cluster together regardless of topic. we ran louvaine community detection [5] on both the retweet and mention network, and then looked at influential accounts and top hashtags for each of the top 10 communities. a summarization of the community groups in the retweet network are summarized in table 7 . here we see once again that some community groups are geographically and/or linguistically oriented, while others are politically affiliated. now that we've explored bots in the data, we will begin to look at other ways to characterize accounts. these include analysis of biased or questionable sources, abusive languages, and use of national flags. next we will look at the political bias found in the urls. to do this, we will use the dictionary approach presented in chapter 11. using this approach, 18.2% of the total url domains were found in the dictionary lookup that we built in chapter 11. having estimated the bias and factual content in the urls, we visualize this distribution in figure 10 where the bar plots are colored by the proportion of bot involvement. from this we first see that the highest number of urls are coming from the center and center left political bias, and generally have high factual content. we do see the presence of fake, satire, and conspiracy theory sources in this stream, which are often correlated with the low factual content seen in figure 10b . we also see that bots have a higher degree of correlation with urls from the far-right and fake-news biases, and to a lesser extent from the far-left. we also see high bot correlation with urls containing low factual content. these discoveries largely confirm our assumptions going into the analysis. we used the multi-lingual dictionary based algorithm presented in chapter 1111 to identify tweets that contain abusive language. the daily volume of abusive is presented in figure 11 . we did not normalize this visualization since our total daily count of tweets was held constant at 4.3 million tweets. if this was not true, it would be appropriate to normalize this (plot proportion instead of raw count). this allows us to identify events that seem to aggravate the population of active twitter users. the two prominent spikes are tied to political events and voices in the united states, with the first spike tied to actions by us congress and the second spike tied to comments by the us executive branch. we found that 57.7% of the accounts that share abusive content had bot like characteristics. this is significantly higher than the 41.8% of non-abusive accounts that have bot-like characteristics. this means that within the covid-19 stream bot-like accounts are used to produce or promote abusive content. as discussed in chapter 11, at times flags in the user description can indicate suspicious accounts. this is especially true with multiple flags. to explore this in the covid-19 stream, we extracted all flags in the account descriptions for all 27 million accounts. we've plotted the distribution of these in figure 12 reviewing the distributions in figure 12 , nothing in the one and two flag distribution is unexpected or necessarily cause for further exploration. once we get to the three, four, five, and six flag distributions, however, these are likely suspicious accounts. in particular many of these accounts have multiple western nations (us, canada, and european nations), and may be used to manipulate multiple western nations while appearing to be an expatriate. 6 image/meme analysis as discussed in chapter 10, memes are a powerful way to connect a message to a target audience. memes evolve as they propagate through a society. given the size of the covid-19 stream, we sampled 1 million images (approximately 10% of the total) and conducted meme classification on these. the meme-hunter model classified 37,473 images as memes. a collage of these memes is found in figure 13 . given the massive impact of covid-19 on society and daily life, many memes were innocent humor designed to help folks get through some very tough circumstances. we did find a number of political memes, however, some targeting domestic pandemic policy discussions and others targeting geo-political competition. the domestic policy memes were trying to use image and text to argue for one of the competing priorities: namely the safety of society or the economic foundation of that society. the geo-political memes were likely created by nationstates or nation-state proxies, with many memes created by russia, china, and iran, which will be discussed in more detail below. as discussed in chapter 10, the meme-hunter suite of tools includes a special meme optical character recognition (ocr) pipeline for meme images. this was also presented in detail in [3] . we ran meme ocr on the extracted memes from 1 million images, and conducted wordcloud visual analysis of the results. these results are found in figure 14 . from these results we see that a number of general coronavirus memes. we also see that a number of memes are targeting government leaders, ministers, and agencies. next we used open source facial recognition software 8 to identify prominent politicians and world leaders in the memes. facial recognition software simply identifies personalities, but does not indicate whether the meme is supporting or attacking the specific personality found. a distribution of memes about prominent us politicians and other world leaders is given in figure 15 . here we see that prominent world leaders are the target of most of the memes in our sample, with xi jinping and donald trump in the first and second place positions, respectively. this also highlights that much of the covid-19 discussion and information conflict is between the us, china, and europe. we next calculated the evolution of the 37,000 memes that meme-hunter classified in our sample. the network was created by using a vgg deep learning model [14] and extracting the last layer before softmax. using this 25,088 dimension vector to represent the image, we then conducted radius nearest neighbor graph learning with distance = 1200. in figure 16 we see that many of the darker image memes are clustered together in the center, with other prominent memes evolving in clusters that are separate components. we've highlighted the evolution and links between two of the memes. we were able to use the covid-19 data to test the sketch-io prototype application for sketching and analyzing information operation campaigns. given that our prototype application was not able to ingest the entire stream due to its size, we instead ingested all data produced by or propagating state sponsored media. the sketch-io application proved effective and responsive at quickly performing a number of battle drills to analyze this data. example usage and screenshots are provided in figure 17 . in this section we will identify overt and seemingly overt propaganda operations by nation state actors. covert and black propaganda is much harder to detect and attribute to a nation state actor (black propaganda is designed to make the victim appear to be the perpetrator). we will use the bot labeler function for finding state sponsored media and state sponsored media amplification as a proxy for finding propaganda. in figure 18 we show the number of retweets of state sponsored media accounts as measured by bot labler. this image is colored by percentage of bots that are retweeting these accounts. as indicated in chapter 11, these state sponsored media vary drastically in purpose and independence (the purpose of russian rt is different than the us voice of america). that being said, we clearly see that russia and china are investing heavily in producing and promoting state sponsored media and messages. these messages are amplified by both bots and legitimate accounts. to some extent, the covid19 pandemic seems to be a turning point for the chinese in regards to information operations. traditionally, chinese information operations focused on positive narrative largely pushed by the "50 cent army", a low-paid or otherwise coopted group of online netizens. traditionally, they did not conduct "higher risk higher reward" operations that relied on negative, antagonizing and controversial statements. this slowly started to change with the hong kong protests in 2019, and fully changed with covid-19 pandemic, with china seeming to adopt more aggressive io practices and operations. in february 2020, lijian zhao was promoted to the deputy director general, information department, foreign ministry. foreign minister zhao has a history of aggressive information operations, and seems to be implementing this in the chinese information operations as well as personally on social media. on march 12, zhao posted a tweet that suspected the us army of bringing the coronavirus to wuhan province in china (see figure 19 ). zhao seems to be a key personality leading and directing china's more aggressive approach to information operations. fig. 19 : foreign minister lijian zhao's rise to director of chinese information operations seems to correlate with a more aggressive approach than historical chinese information operations (tweet id: 1238111898828066823). chinese propaganda is amplified by chinese government representatives. chinese government officials around the world are able to amplify state sponsored media without questioning it, knowing that only approved messages are published. in the covid-19 stream, the chinese ambassador to venezuela has the 2nd highest number of state sponsored mentions/retweets. he retweeted or mentioned chinese state sponsored spanish and english covid-19 content 769 times. the increasing penetration of chinese state sponsored media around the world is pushed by these legitimate accounts. it also appears that china often uses trolls instead of bots. with easy access to human capital, the chinese seem to prefer the control and nuance that trolls allow compared to a bot army. many of the suspicious chinese accounts contain enough nuance and temporal patterns to consider them a troll rather than a bot. we see increased use of meme warfare by china in the covid-19 stream. historically, china has seemed hesitant to use memes, potentially because memes propagate through evolution, and this evolution is outside of the control of the state [2] . china has especially been concerned with the evolution of memes within their own population, and has banned some memes [3] . in covid-19, however, we see them developing and deploying memes in a way that is more akin to russian information operations. an example of a chinese meme is provided in figure 20a . here we see a message tied to an image that has clear cultural relevance and traction within the target audience. additional examples of chinese memes that were found using the bot-match methodology are provided in figure 26 below. we also found evidence that china is starting to interlace adult oriented and humorous content with their information in order to increase traffic, particularly from certain demographics. examples of this are found in figure 21 ). this has historically been a key part of russian io, and it seems that china is increasingly adopting similar practices. explicit adult content is often designed to attract and manipulate the minds of young impressionable men. in the chinese propaganda, we see some propaganda uses chinese language while others uses english language content. the english text is often accompanied by memes that connect the message with american audiences. the english language propaganda is arguably targeting american audience, attacking leaders and institutions in america. it is also designed to strengthen american's view of china, chinese leadership and the chinese communist party (ccp). the propaganda that uses chinese language text is arguably targeting chinese audiences within china's borders as well as in other asian countries. this propaganda is designed to increase nationalistic fervor within china's borders. within the chinese propaganda that we viewed, the vast majority was singularly focused on the united states. this differs from russian information operations, which focuses more broadly on the west, adding european actors to their list of targets. within the covid-19 stream, russia appears to be staying with their historical information playbook. with extensive experience in manipulating world opinion with their "active measures" throughout the cold war, russia has long had one of the most aggressive and well-resourced information operations capabilities among nation states. russia's information operations are tightly coupled with their other cyber operations. russian information operations rely on increasing penetration of their state sponsored media around the world. rt, sputnik, and other state sponsored media outlets offer news in many languages around the world. these media outlets offer news stories that support russian information narratives, as seen in figure 22 . in this figure that russia provided more help to the italian population than did the european union. as seen in figure 22b , russian operations still use large and sophisticated bot "armies" to push their content. this observation is supported by the quantitative analysis seen in figure 18 , which shows the amplification of russian state sponsored messages is 78% bots. as indicated above, russian operations target the west in general, with european targets receiving almost as much emphasis as the united states. this differs from chinese operations, which seem to primarily target the united states, with smaller efforts directed at europe. in figure 23 we see examples of russian state media trolling the west. while russian state sponsored media advertise themselves as news organizations, this content is arguably well beyond reporting unbiased news. on 6 april 2020, iran initiated a concerted attack on the united states trying to encourage california to exit the union. most of this effort was tagged with #calexit. by the time the dust settled approximately 30k tweets had been launched by a several thousand strong bot/troll army. this is not the first time that #calexit (or other similar messages like #texit), have become trending hashtags on twitter largely due to foreign information operations. the 6 april surge appears to be largely iranian influence operation that was triggered by domestic political tension in the united states. in the days and weeks preceding 6 april, tensions between us national leadership and california leadership intensified, and the governor of california referred to california as a "nation-state" [13] . the iranian government and/or proxies appeared to be monitoring these political tensions in the united states, and timed their #calexit campaign to capitalize on them. this 24 hour information operation had some creative content with many human/troll accounts and limited automation. the creative content can be seen in the meme collage in figure 24 . as discussed in chapter 9, bot-match can be a very powerful tool for finding similar accounts given a seed account. bot-match allows you to find similar accounts where similarity can be defined by network proximity, semantic proximity, or a combination of both. the size of our network and tweet corpus limit the number of models available for measuring similarity. we first concatenate all user text, thereby aggregating content to the account level. because of the size of our corpus, we then used cosine similarity on a document-term matrix (also known as a bag-of-words) with 4000 top words. this was created for english tweets. we used this to identify accounts that were propagating chinese propaganda in english. we used @safisina1 as our seed account (this account was discovered above in figure 20b ). we illustrate in figure 25 how we recursively build out the chinese propaganda network with bot-match. notice that we did not have to conduct any elaborate labeling or training process, we just needed to start with our seed node and the document-term matrix. all accounts seen in figure 25 are amplifying chinese state sponsored media, and are each embedded in slightly different networks. using the bot-match methods illustrated in figure 25 , we were able to identify approximately 20 additional accounts that appeared to be propagating chinese propaganda targeting america. we then used the twitter rest api to scrape the timeline history of these accounts, extract image links, and run meme-hunter on the images shared by these accounts. we found that indeed all of these accounts were conducting very targeted information operations against the united states around the covid-19 pandemic as well as the american protest that followed the death of george floyd at the hands of minneapolis police officer. a collage of a sample of these targeted memes is provided in figure 26 . throughout our analysis of foreign influence, we observed their use of the bend forms of maneuver. we continue to observe that russia closely intertwines narrative and network maneuvers. they conduct long and protracted efforts to infiltrate target audiences before interjecting narrative. china, while working hard to control and manipulate the narrative, does not appear to infiltrate targeted subcultures. they do appear to tie their narrative to the target audience culture as seen above with memes based on the friends sitcom as well as memes that use the george floyd protests to support pro-ccp policies. with the limited network maneuver, it remains to be seen whether their information operations gain traction or simply become a "shot in the dark." iran also appeared to launch large attributed information campaigns focused on a specific narrative such as #calexit, without first preparing target networks. once again, these operations may become information warfare "chaff" with limited effects. the primary goal of this case study was to illustrate social cybersecurity workflows in a relevant event. using the apt covid-19 twitter stream from 15 march to 30 april 2020, we demonstrated how to collect the data, conduct initial exploratory data analysis, conduct and use bot and meme classification and exploration, conduct account characterization, and demonstrate the role of sketch-io and the bend framework. this chapter therefore serves as an example for social cybersecurity researchers on how to leverage these tools to identify and characterize offensive information operations targeting their society, institutions and culture. in regards to the covid-19 pandemic, we found large information operations trying to manipulate domestic and international perceptions, beliefs, and actions. at the domestic level the information conflict was largely over pandemic policy, particularly whether public safety or the economy were more important. at the international level we identified attempts to manipulate international perception of the origins of the disease as well as perceptions of each countries handling of the disease. we also see nation-state efforts to amplify tensions and drive wedges in existing fissures in rival nations. throughout the data we see bots and trolls used to scale and spread narrative, therefore acting like a "forcemultiplier" in information operations. we see russia continue to use memes, and china massively increase their use of memes in information warfare. both nations study their target audience and choose relevant cultural artifacts to connect their memes and messages to the target audience. even as the covid-19 coronavirus moved much of business and society to use virtual platforms for social interaction as well as business and collaboration, it also allowed many nation-states to increasingly use virtual platforms for competition in the information space with ramifications for geo-politics. while the effects of these campaigns are hard to measure, their scale and persistence require social cybersecurity policy and process. characterization and comparison of russian and chinese disinformation campaigns the evolution of political memes: detecting and characterizing internet memes with multi-modal deep learning latent dirichlet allocation fast unfolding of communities in large networks ora: a toolkit for dynamic network analysis and visualization ora user's guide 2020 the rise of social bots classification of twitter accounts into automated agents and human users ieee/acm international conference on advances in social networks analysis and mining the great lockdown: worst economic downturn since the great depression imf blog on predicting geolocation of tweets using convolutional neural networks a new status index derived from sociometric analysis coronavirus in california: gavin newsom's response -the atlantic very deep convolutional networks for large-scale image recognition overview twitter developers this work was supported in part by the office of naval research (onr) multidisciplinary university research initiative award n000140811186, award n000141812108, onr award n00014182106 and the center for computational analysis of social and organization systems (casos). the views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the onr or the u.s. government. key: cord-014897-rnrlslfh authors: rong-bing, wang; jun-min, liu; yu-yong, jiang; yun-zhong, wu; xiao-jing, wang; pin-pin, chi; feng-xia, sun; lian-yin, gao title: therapeutic effects of integrated traditional chinese medicine and western medicine in treating severe acute respiratory syndrome date: 2003 journal: chin j integr med doi: 10.1007/bf02838610 sha: doc_id: 14897 cord_uid: rnrlslfh objective: to improve the effects of treatment of severe acute respiratory syndrome (sars) and to explore the clinical significance of integrated traditional chinese medicine and western medicine (icwm) in the treatment of sars and its influence on the chief indexes in the process of the disease.methods: the clinical study involving observation of 135 patients of sars was conducted in the randomized, synchronously controlled and open way. the patients were divided into two groups, 68 in the icwm group and 67 in the control group, all of whom were treated with the same basic treatment of western medicine, but to the icwm group, chinese drugs for clearing heat, detoxifying and removing dampness were given additionally. the comprehensive effect on relieving fever, cell-mediated immunity, pulmonary inflammation and secondary infection was compared between the two groups.results: the therapeutic effect in the icwm group was better than that in the control group in such aspects as steadily lowering body temperature, alleviating general symptoms, accelerating the absorption of pulmonary infiltration and easing cellular immunity suppression.conclusion: the therapeutic effect of icwm is better in treating sars than that of western medicine alone. severe acute respiratory syndiome (sars) is an acute infectious disease caused by a new kind of coronavirus, and as it is strongly infective, highly mortal and liable to affect human beings, it severely threatens human health, influences their daily life and productive activity. now, the microbiological characteristics of sars related virus and its infection mechanism are being deeply studied but there has been no specific treatment for sars found so far. in order to elevate the therapeutic effects, lighten patients" symptoms, improve the pulmonary inflammation and cellular immune inhibition that occurred in the course of the illness, a clinical study of the treatment of 68 sars patients with integrated traditional chinese and western medicine (icwm), which was controlled with 67 patients treated with western medicine alone, was carried out. the results are reported as follows. the standard for diagnosis, typing and discharging of sars patients promulgated in may 3rd 2003 by the ministry of health was adopted. patients younger than 18 years or older than 65 years and complicated with severe systemic diseases or women in pregnant or lactation stage were all excluded from this study. the 135 patients enrolled were inpatients of the authors" hospital, hospitalized between april 10th and may 26th, 2003, with their diagnosis confirmed. the patients were divided according to the sequence of enrolling into two groups. the 68 patients in the treated group were 27 males and 41 females; aged from 18 to 56 years, 35.5 ! 10.8 years on average; their course of disease 6.41 + 4.14 days; 36 of them were of the general type and 32 of the severe type. the 67 patients in the control group were 23 males and 44 females; aged from 20 to 65 years, 38.7• years on average; their course of disease 7. 54 • 4. 69 days; 39 of them were of the general type and 28 of the severe type. the two groups were not different in sex, age, course of disease, clinical typing as well as their lymphocyte count and x-ray chest manifestation, and thus they are comparable. the basic treatment recommended by the group of sars specialists from the command cen-beijing ditan hospital, beijing (100011) correspondence to : dr. wang rong-bing tel/fax: 010-64211031-2328 e-mail: jyy70@126, corn ter of the ministry of health was applied to both groups, which includes intravenous injection of methylprednisolone 80--160 mg and ribavirin 0. 75--1.5 g per day for 2 weeks; azithromycin 0.5 g per day for 5 days; levofloxacin 0.4 g per day for 7 days; thymus peptide 100--200 mg per day with the course of treatment and the general supportive therapy unlimited. all the patients received oxygen inhalation by nasal tube, and mechanical ventilation was used when necessary. based on the above-mentioned basic treatment, chinese drug therapy was given additionally to the treated group following the therapeutic program recommended by the specialists group of state tcm administration. for patients in the developing stage, guoyao no. 2 ( [ ]~j 2 ~) , consisting mainly of gypsum, bitter apricot seed, scutellaria root, atractylodes rhizome, ternate pinellia rhizome, purple gromwell, etc. was given; for patients in the critical stage, guoyao no. 3 ([] ~ 3 ~=~), consisting mainly of buffalo horn, raw rehmannia root, figwort root, honeysuckle flower, etc. was given; and for those in the recovery stage or with the course of disease over 3 weeks, guoyao no. 4 ( [ ] ~ 4 ~-) , consisting of glehnia root, dwarf lilyturf root, red sage root, red peony root, american ginseng, etc. was given. all the recipes were given one dose a day, made into decoction of 200 ml, and taken 100ml in the morning and evening respectively. the course of tcm treatment to all the patients was over 2 weeks. 1. changes of symptoms and signs of all patients in the therapeutic course were recorded. 2. physical and chemical examinations were carried out before and after treatment to observe the changes of body temperature, blood routine, sero-zymogram, t-lymphocyte and its subsets, and x-ray chest figure. 3. in part of the patients, pharyngeal gargle and urine were taken to detect the sars-associated coronavirus (sars-cov) rna by pcr and their blood level of anti-sars-cov igg was detected by elisa. these tests were performed by the national center for diseases control (cdc) or the beijing cdc. 4. occurrence of complications, especially secondary infection, were observed in patients whose course of illness was over 4 weeks. t-test, 2( 2 test and rank-sum test were adopted with spss 10.0 software. according to literature (1~ , a patient who had his/her body temperature lowered to normal range for over 7 days, symptoms of respiratory tract obviously improved and the lung lesion in x-ray chest film significantly absorbed was regard as the standard for discharged from hospital, otherwise, he or she was considered as un-cured. shown in table 1 . results showed that the positive rate of sars-cov rna in pharyngeal gargle tested during hospitalization (t1), and that in urine tested 20 days after hospitalization (t2), as well as the blood anti-sars-cov-igg (t3) detection were similar in the two groups, showing insignificant difference between them ( all p > 0 . 0 5 ) . as shown in figure 1 , the body temperature of patients in the two groups before treatment was not different significantly . two and three days after admission, the body temperature of patients in the control group was significantly higher than that in the treated group ( p % 0 . 0 1 ) , and it was only in the time of the 4th day to the 14th day after admission that the body temperature in the two fig. 1 body temperature of the patients in the two groups groups came to be equal finally, suggesting that the defervescent effect of icwm treatment was on an even keel. as shown in table 2 , the lymphocyte count and lymphocyte subsets cd3 and cd4 in most patients of both groups before treatment were low, especially in the treated group, but the inter-group comparison showed no significant difference (the non-normally distributed material was analyzed with rank-sum test, p%0.05). the condition of the asrs patients with continuous low lymphocytes count was always severe. the three parameters all raised in the recovery stage, and the increment of cd3, cd4 and cd8 was all higher in the treated group than that in the control group respectively, showing significant statistical difference (p<0.05 or p<0.01), suggesting that the icwm treatment has rather better effects in protecting cellular immune and promoting recovery of immunity. as shown in table 3 , before treatment, inflammation of various degrees appeared in all the patients" lung. after being treated for 3 weeks, by xray examination, it was found that the inflammation was improved to some extent or basically absorbed, and the number of patients with their lesion completely absorbed in the treated group was higher than that in the control group (p~0.05), but the absorption time between the two group was not different significantly. as shown in table 4 , the total dosage, time and the daily average dose in individual patients of methylprednisolone used in the treated group were lower than those in the control group, but showed no statistical inter-group significant difference (by rank-sum analysis, p~0.05). the number of patients suffering from secondary bacterial or fungal infections, or complicated with digestive tract bleeding in the treated group were 5 (7.4 %), 2 (2.9 ~) and zero respectively, which were less than those in the control group: 9 (13.4~ 5 (7.5%) and 4 (6.0%) respectively, but the difference between the two groups showed no statistical significance (all p~0.05). since decreasing and controlling secondary infection was of vital importance to lowering of mortality, it may be something that explains the better therapeutic effect obtained by icwm. among the 68 patients in the treated group, 66 (97.1%) were discharged and 2 (2.9%) uncured, while in the 67 patients in the control group, 58 (86.6%) cured and 9 (13.4~) uncured, comparison between the two groups showed significant difference (p~0.05). the icwm therapeutic mode is something special in chinese clinical medicine, and icwm treatment has won certain effect in treating sars. at the present there is no specific treatment directly against sars virus, and the mechanism of sars is still unclear. western medicine is used as symptomatic and supporting therapy, taking inhibition of the super-strong immune reaction and controlling the complication as its aim of treatment, while chinese medicine is used, starting from syndrome differentiation, combining the old and new experience in treating febrile diseases, to form various therapeutic principles suitable to different phases, with clearing heat, removing dampness and benefiting fei (j]i~i) as the mainstay of treatment throughout the whole course. icwm treatment could, getting tcm and wm complementing each other, reduce the adverse effect of drugs and enhance the integral therapeutic effect. fever is a common symptom revealed in sars patients. though a self-protection mechanism of the body, it could induce serious accompanying pathological affection. in this study, it was shown that fever was relieved rapidly in all the patients in both groups due to the rapid defervescent effect of cortical steroid, which covered the fever abating effect of chinese drugs. however, the mitigatively deprived curve of body temperature in the treated group showed that medication of chinese drugs could abate the body temperature and improve systemic symptoms on an even keel through some mechanisms in inhibiting virus induced immune injury to relieve the inflammatory reaction. clinical observation also indicated that chinese drug predominated therapy is safe and effective for treatment of patients with no serious toxic symptoms or unsuitable to be treated by cortical steroid. obvious deprivation of lymphocytes, which indicates the damage of immune mechanism of the organism, has not only significance in diagnosis, but also in prognosis of the disease. this study shows that icwm can reduce the extent of lymphopenia effectively and improve the restoring of lymphocytes in the recovery stage, indicating that chinese drugs can protect cellular immunity or antagonize the inhibition of cortical steroid on cellular immunity. although the clear mechanism is still awaiting for further study, the results of this study has already illustrated the effect of chinese medical concept of regulating body immunity through adjusting yin-yang, maintaining stability of inner environment in human body, supporting the healthy energy and dispelling evil-pathogens and improving stress response. the pathogenesis of sars is still under research. it has been confirmed that one of the causes of sars is the immuno-pathological damage, and with the lung as the target organ, its pathological basis is the endothelial injury of pulmonary capillaries, which further induced the inflammatory change of alveoli, hyaline membrane formation, interstitial inflammation and consolidation of the lung. therefore to hold back the developing of pulmonary lesions and promote the absorption of inflammation are important therapeutic ways against sars. the better therapeutic effects in repairing pulmonary injury and inflammation absorption shown in the treated group in this study may be related with the effects of chinese drugs in lightening immuno-pathological damage, disintegrating toxic metabolites, and antagonizing the adverse effect of large amount steroid, which could inhibit the pulmonary fibrosis so as to affect the repairing of tissues. there are many lethal factors that could cause death to sars patients, among which secondary infection caused by serious destruction of immune function and utilization of steroid is an important one. in patients in the late stage, such infectionrelated syndromes as fungal infection, septicemia and disseminated intravascular coagulation could be seen. this study showed that there was a lowering trend of secondary infection of sars in the treated group as compared with the control group, suggesting that chinese drugs have certain effects in protecting cellular immunity and enhancing the resistance of the organism against infection. traditional chinese medicine possesses lots of clinical experience and rational recognition on treatment of viral infected diseases, puts much thought on the principle of prevention first, and asserts that treatment of sars should be done early and quick, with much stress paid to preventing its transferring. the recipes used in this study were formulated by several chinese medical specialists who combined old and new experience. it could be prospected that the method and efficacy of icwm treatment in treating sars shall be further improved and bettered inevitably along with deepening research on the disease and precise screening on recipes and programs. clinical diagnostic standard of infectious atypical pneumonia key: cord-279960-1phc0wds authors: zhao, ai; li, zhongyu; ke, yalei; huo, shanshan; ma, yidi; zhang, yumei; zhang, jian; ren, zhongxia title: dietary diversity among chinese residents during the covid-19 outbreak and its associated factors date: 2020-06-06 journal: nutrients doi: 10.3390/nu12061699 sha: doc_id: 279960 cord_uid: 1phc0wds covid-19, a public health emergency of international concern, has imposed enormous challenges on the health system, economy, and food supply and has substantially modified people’s lifestyles. this study aimed to (1) explore the dietary diversity during the lockdown time in china and (2) examine factors associated with dietary diversity including socio-economic characteristics, sources for food and food purchases, and specific dietary behaviors responding to covid-19 and isolation. a cross-sectional questionnaire-based survey was conducted online in march 2020. multi-stage sampling was used to recruit participants living in hubei province and other parts of china. dietary diversity was assessed using the household dietary diversity score (hdds) and clustering analysis was used to categorize people with different propensities of methods for purchasing or obtaining foods. logistic regression was used to model the associations among hdds, participants’ characteristics, approaches to purchase or obtain food, and behaviors adopted to cope with covid-19. results: a total of 1938 participants were included in the analysis. the overall mean hdds was 9.7 ± 2.1, and the median (25th, 75th) was 10 (8, 12). there were relatively low consumptions of fish, legumes, and miscellaneous foods (e.g., processed food like snacks and beverages). after adjusting for age, family income, and geographic regions, people living in places where laboratory confirmed covid-19 cases were above 500 (or(adjusted) = 0.79, 95%ci 0.65, 0.96), or living in hubei province (or(adjusted) = 0.60, 95%ci 0.39, 0.93) had a lower hdds. during isolation time, the most common sources for food and food purchases were in-house storage and in person grocery shopping. more than half of the participants (55.9%) purchased food at least once via online ordering and delivery services. there was no significant difference in hdds among people with distinct dependences on different ways to obtain or purchase food (i.e., dependence on in-person grocery shopping, dependence on both in-house storage and in-person grocery shopping, or dependence on online food purchasing). we also identified a total of 37.7% participants who consumed certain foods or nutritional supplements to cope with covid-19, which included vitamin c, probiotics, other dietary supplements, alcohol, and vinegar. people who reported these specific dietary behaviors had a significantly higher hdds (or(adjusted) = 1.23, 95%ci 1.02, 1.45) than those who did not do so. this study revealed an overall good dietary diversity among the studied chinese residents during the covid-19 pandemic. however, we observed a lower dietary diversity among people living in areas with a high number of confirmed covid-19 cases. online ordering and delivery services were popular and could serve as a feasible method to obtain and purchase food, contributing to ensure diversified diets during the time of lockdown. certain dietary behaviors associated with covid-19 were also identified and had significant impacts on hdds. the coronavirus disease 2019 ("covid-19") has emerged rapidly as a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), responsible for an outbreak that took place in december 2019 in wuhan, china [1] . due to the highly contagious nature of this novel coronavirus, hubei and other provinces in china have adopted several unprecedented measures to control the transmission of covid-19 including the suspension of public transportation, restricted access to communities, closure of public spaces, and management such as hospitalization and isolation of confirmed and suspected cases [2] . chinese residents living both in and outside hubei had been required to stay at home to self-isolate since 27 january 2020. by 15 april 2020, this virus had reached a total of 213 countries, resulting in more than 1.9 million laboratory-confirmed infections and 120,000 deaths [3] . consequently, more than 40 countries and areas including italy and regions in the united states have started implementing similar lockdown and "shelter in place" measures as those in china since 1 april. even though most supermarkets and grocery stores remain open during the isolation period, food supply as well as safe and adequate access to foods have become major concerns regarding the essential needs among the general populations due to the restrictions of transportation, self-reduction of outside activities, and lack of enough labor force, especially in areas severely affected by covid-19. on 31 march, the united nations stated that covid-19 has threatened the food supply chain globally, and it is estimated that this situation may worsen in april and may [4] . foods contain essential nutrients and important phytochemicals that not only support basic biological functions in living organisms, but also exert protective and complementary effects on preventing and treating diseases including infections [5] [6] [7] . although no nutrients have been scientifically proven to specifically benefit the prevention or treatment for covid-19, a balanced and diversified diet is, undoubtedly, crucial in maintaining a properly functional immune system and providing sufficient nutrients for recovery [8, 9] . however, as above-mentioned, restriction in social activities and mobility impose potential barriers in people's access to food. on the other hand, when a stressful situation of this magnitude arises, people often experience substantial changes in their emotions, which may subsequently lead to modifications or development of some dietary behaviors such as seeking relief or cure from certain foods [10] . those alterations in activities and behaviors during a pandemic period collectively influence and potentially impair food diversity. currently, little is known about the dietary diversity during covid-19 pandemic. china has been experiencing a rapid growth of online food ordering and delivery services in recent years. according to "chinese restaurant super digital time insight 2020", in 2019, the total value of food delivery service reached 727.4 billion chinese yuan [11] . especially, in the recent self-isolation and "stay at home" time, online food shopping has gained in popularity because of its apparent role in reducing unnecessary person to person contact. in china, delivery services including food delivery have resumed since 28 january, and by early february, most delivery services have gone back to normal and cover most parts of china [12] . people are able to purchase not only processed foods like fast foods and restaurant takeout, but also fresh produce (i.e., fruits and vegetables), fresh meat, and grains via online food ordering and delivery services, thereby possibly increasing food accessibility. for this reason, proper measurements and evaluations are needed to investigate the potential benefits of this relatively novel and modern approach for food purchasing in maintaining dietary diversity during isolation time. to the best of our knowledge, no study has reported on dietary diversity during isolation time in china and other areas. this study was conducted via a quick online survey to assess dietary diversity among chinese residents during the time of isolation and "staying at home" due to covid-19 and to explore its associated factors. this cross-sectional study was composed of a questionnaire-based survey conducted in march via chinese e-questionnaires using wenjuan xing (wenjuan xing tech co. ltd., changsha, china), a widely used online platform in china and distributed via the most common social media used in china "wechat" (tencent inc. shenzhen, china). a multistage sampling method was used. we purposefully selected and included people living in hubei province, the hard-hit area by covid-19 outbreak in early 2020, china and people living in north, south, and central china. then, the "snowball sampling" method was used to recruit more participants. to identify the respondents' attitude in completing the questionnaire, one question "did you seriously look through the questions and answer the questions according to your actual situation" appeared in the middle part of the questionnaire. a total of 2021 chinese residents participated in this survey. the inclusion criteria were (1) living in mainland china, and (2) aged from 18-80 years old. the exclusive criteria were (1) people infected with covid-19, (2) who have disease which impacts of normal eating, and (3) who did not seriously respond to the questions in this survey. after all the data had been collected, the final analysis included 1938 participants (people who did not seriously respond to the questions (n = 10), who were living outside mainland china (n = 12), who were aged <18 y or >80 y (n = 55), who were infected with covid-19 (n = 2), or who had missing data on key questions (n = 3) were excluded. one participant self-reported no food intake in the past several days was also excluded). the geographical distribution of participants is displayed in figure 1 . this cross-sectional study was composed of a questionnaire-based survey conducted in march via chinese e-questionnaires using wenjuan xing (wenjuan xing tech co. ltd, changsha, china), a widely used online platform in china and distributed via the most common social media used in china "wechat" (tencent inc. shenzhen, china). a multistage sampling method was used. we purposefully selected and included people living in hubei province, the hard-hit area by covid-19 outbreak in early 2020, china and people living in north, south, and central china. then, the "snowball sampling" method was used to recruit more participants. to identify the respondents' attitude in completing the questionnaire, one question "did you seriously look through the questions and answer the questions according to your actual situation" appeared in the middle part of the questionnaire. a total of 2021 chinese residents participated in this survey. the inclusion criteria were (1) living in mainland china, and (2) aged from 18-80 years old. the exclusive criteria were (1) people infected with covid-19, (2) who have disease which impacts of normal eating, and (3) who did not seriously respond to the questions in this survey. after all the data had been collected, the final analysis included 1938 participants (people who did not seriously respond to the questions (n = 10), who were living outside mainland china (n = 12), who were aged <18 y or >80 y (n = 55), who were infected with covid-19 (n = 2), or who had missing data on key questions (n = 3) were excluded. one participant self-reported no food intake in the past several days was also excluded). the geographical distribution of participants is displayed in figure 1 . [13] . bubble size in the bubble plot represents the sample size of every investigation point. the questionnaire contained four parts: socio-demographic characteristics, household food diversity, sources of the food (methods for purchasing or obtaining food), and specific dietary behaviors to cope with covid-19. the number of confirmed cases by 31 march in each province in china was obtained from the distribution of covid-19 report that is accessible on the chinese center for disease control and prevention website (imported cases not included) [13] . the isolation status (still working outside [13] . bubble size in the bubble plot represents the sample size of every investigation point. the questionnaire contained four parts: socio-demographic characteristics, household food diversity, sources of the food (methods for purchasing or obtaining food), and specific dietary behaviors to cope with covid-19. the number of confirmed cases by 31 march in each province in china was obtained from the distribution of covid-19 report that is accessible on the chinese center for disease control and prevention website (imported cases not included) [13] . the isolation status (still working outside home, self-isolation at home, close contact isolation, and infected with covid-19) and frequencies of outside activities were also recorded. we evaluated dietary diversity using household dietary diversity score (hdds), a measure that reflects household food accessibility [8] . in total, the intakes of 12 food groups over the last 24 h (food eaten outside and at home) were investigated including (1) cereals; (2) roots and tubers; (3) vegetables; (4) fruits; (5) meat, poultry, and offal; (6) eggs; (7) fish and seafood; (8) pulses, legumes, and nuts; (9) dairy products; (10) oils and fats; (11) sugar and honey; and (12) miscellaneous such as condiments, snacks, and beverages. values for each food group were assigned as "0" or "1", "0" for not-consumed and "1" for consumed in the last 24 h. proportions of participants who consumed each food group were calculated. also, the total scores of 12 groups were calculated for estimating the dietary diversity, which could range from 0 to 12. a higher score indicates a higher dietary diversity. to investigate food sources during isolation time, we asked participants to select from four of the most common approaches to obtain or purchase different kinds of foods (12 food items in the hdds) based on the ones that they had used. the four approaches were (1) using food stored in house before self-isolation; (2) purchasing food from traditional markets and grocery stores in person; (3) using online food ordering and delivery services (including purchasing both raw ingredients and prepared meals from restaurants); and (4) dependent on government-or community-based food distribution. we also explored certain dietary strategies that participants adopted to cope with covid-19 by using several "yes" or "no" questions such as "whether participants increased consumption of vitamin c, probiotics, any other kinds of dietary supplements, chinese herbs, vinegar, and alcoholic beverages or not". in addition, one open question was used to identify any other previously unspecified foods consumed to cope with covid-19. participants answered the questionnaire anonymously. informed consent was obtained from participants who confirmed their willingness to participate voluntarily prior to the survey. data were analyzed using the software sas version 9.4 (sas institute, cary, nc). hdds were presented as means ± standard deviation (sd) and median (25th, 75th percentiles) and were tested using the independent t-test and variance analysis. the proportions of participants who consumed each food group in the last 24 h were presented as numbers (percentage). to explore the participants' behaviors in acquiring foods, we first calculated the propensity of choosing different approaches for obtaining or purchasing foods among our participants. for each food group, there were four pre-defined approaches (in-house storage, in-person grocery shopping, online shopping, or government and community-based food distribution programs) to obtain the food. we gave one point when participants purchased or obtained food from each food group with one of the four approaches. the total propensity score of utilizing each approach to obtain or purchase 12 groups of food for individual participants could range from 0 to 12. based on the total propensity scores of each approach, major patterns of purchasing and obtaining foods were identified with the hierarchical cluster and k-means clustering method. we first randomly selected 30% of participants that were then used in the hierarchical cluster analysis to determine the proper number of clusters. three clusters were identified by k-means cluster analysis. people in cluster 1 showed dependence on in-person grocery; people in cluster 2 depended on both in-person grocery and in-house storage; and people in cluster 3 showed more dependence on online food ordering and delivery services. hdds was divided into two groups based on its median (high (>=median) and low (<median) hdds). logistic regression was used to model the associations among hdds, participants' characteristics, approaches for food purchasing/sourcing, and certain dietary strategies to cope with covid-19. we adjusted for potential socio-demographic confounders (age, household average annual income, and geographic region) in the fully adjusted models. a p-value < 0.05 was considered statistically significant in all analyses. the heat map of the geographical distribution of covid-19 cases in mainland china and the bubble plot of study sample sizes were created using r version 3.6.3 with the packages "ggplot2", "maptools", "rgdal", and "sp" [14] . the base map was obtained as a shape file from the national fundamental geographic information system, china. cumulative numbers of confirmed cases of the covid-19 were calculated at the province (autonomous regions or municipalities directly under the central government included) level and coded with color. the lighter the color, the fewer the cases. bubble sizes in the bubble plot proportionally represent the numbers of participants at each sampling point. a total of 1938 participants were included in the analysis. the overall average hdds was 9.7 ± 2.1, median (25th to 75th) is 10 (8 to 12). proportions of participants who consumed each food group in the last 24 h are shown in table 1 . the cereals group had the highest consumption, whereas the fish, legumes, and miscellaneous had relative low consumptions. compared to people aged above 45, those aged from 18-45 years have a diet with a lower diversity score. living in urban areas was associated with a significantly higher hdds than those living in rural areas. meanwhile, the hdds increased with family income ( table 2 ). during the isolation time, the most common food sources were in-house storage and in-person grocery shopping. the participants' choices of approaches to obtain or purchase foods during isolation are shown in figure 2 . the most frequently purchased foods for in-person grocery shopping were fruits (80.1%), vegetables (77.2%), and eggs (71.8%). a total of 55.9% people used online ordering and delivery services at least once. miscellaneous food (such as condiments, fast food, and snacks) (26.2%), fruits (26.2%), and dairy products (22.8%) were the most commonly purchased foods via online food ordering and delivery services, whereas oil and fats and sugar and honey were the least purchased. during the isolation time, the most common food sources were in-house storage and in-person grocery shopping. the participants' choices of approaches to obtain or purchase foods during isolation are shown in figure 2 . the most frequently purchased foods for in-person grocery shopping were fruits (80.1%), vegetables (77.2%), and eggs (71.8%). a total of 55.9% people used online ordering and delivery services at least once. miscellaneous food (such as condiments, fast food, and snacks) (26.2%), fruits (26.2%), and dairy products (22.8%) were the most commonly purchased foods via online food ordering and delivery services, whereas oil and fats and sugar and honey were the least purchased. there were 722 (37.7%) participants intentionally consumed dietary supplements, chinese herbs, or specific foods because of covid-19. a total of 31.2% of participants consumed various dietary supplements or chinese herbs (18.2% for vitamin c, 11.7% for probiotics, 8.0% for other dietary supplements, and 9.6% for chinese herbs) to cope with covid-19. meanwhile, there were 10.6% and 16.0% of participants who once purposely consumed alcohol and vinegar to cope with covid-19. hdds was further divided into two groups based on its median value (hdds = 10) and used as a binary outcome (<10 = 0 = low hdds; >=10 = 1 = high hdds). logistic regression was used to explore the associations among hdds and the factors listed in table 3 . we found that people who lived in the places where laboratory confirmed covid-19 cases were above 500 or in the hubei province had significant lower odds of high hdds. isolation status, frequencies of outdoor activities, and frequencies of going out to purchase food were not associated with hdds. based on k-means clustering analysis, participants were clustered into three groups. people in cluster 1 showed dependence on in-person grocery shopping for food; people in cluster 2 depended on both in-person grocery and in-house storage; and people in cluster 3 depended mostly on online food shopping. hdds was not associated with dependences on different approaches to purchase food. interestingly, people who reported adoptions of certain dietary behaviors to cope with covid-19 had higher odds of being in the high hdds group than people who did not report doing so. as a declared public health emergency of international concern, covid-19 has rapidly spread from wuhan, hubei to other parts of china and countries worldwide. this pandemic imposes enormous challenges on the health system, economy, and food supply globally and locally [4, 15] . meanwhile, covid-19 and subsequent measures to prevent its spread have substantially changed people's lifestyle. there have been several studies reporting on people's behaviors during pandemic such as consciously avoiding crowded places and wearing masks [16] . on the other hand, psychologically, people may feel anxious during outbreaks of infectious diseases, which impacts their sleep quality and other health related quality of life [17] . nonetheless, there are not many, if any, studies that have examined dietary diversity during an epidemic or a pandemic. we believe that the current study is the first to report dietary diversity among chinese residents during the covid-19 pandemic period. our study showed an overall good dietary diversity in the study sample, though there was a reduction in diversity in places where more covid-19 cases were confirmed. to our best knowledge, this is also the first study to explore potential factors associated with dietary diversity in a pandemic. we found dietary diversity did not vary across different approaches to obtain or purchase foods, which provides evidence supporting that online food ordering and delivery services could achieve a similar dietary diversity as in-person groceries and in-house storage do. in addition, several specific dietary behaviors were identified during the covid-19 outbreak and they contribute to higher odds of high dietary diversity. to ensure a good nutritional status during lockdown, as early as 8 february, the national health commission of china published the "dietary guidelines for the prevention and treatment of novel coronavirus", which advocates a diverse diet for the general public [18] . the world health organization (who) recommends that "if you must stay at home, maintain a healthy lifestyle-including proper diet, sleep, exercise and social contacts" [19] . however, the degree to which people have followed these recommendations is unknown. in this study, we focused on dietary diversity and found an overall relatively high diet diversity (average hdds = 9.7 ± 2.1, 25th to 75th were 8 to 12) when the "shelter in place" was in effect in china (the current study was carried out in march). this number is higher than the hdds reported pre-covid-19 in indonesia (9.1), south africa (8.0), and rural cambodia (4.7) [20] [21] [22] . the hdds is usually used to reflect food accessibility [8] . access to food is a critical component of food security and plays a vital role in health and health disparities [23] . several studies have demonstrated that the hdds is inversely associated with the risk of malnutrition. for instance, one study in south africa showed that children with high hdds (>8) had a significantly lower wasting rate [21] . in ethiopia, when the hdds drops below four, adolescents are likely to suffer from underweight [24] . it is encouraging that the hdds reported in the current study suggested an overall good food accessibility and low risk of malnutrition among the chinese residents surveyed during the covid-19 pandemic. among the 12 food groups assessed in the hdds, fish, legumes, and miscellaneous foods had relatively low consumption during the last 24 h. miscellaneous foods include most seasoning, snacks, beverage, and instant meals that can be highly processed. they tend to be deprived of essential nutrients, are energy dense, and are less healthy compared to freshly home-made meals [25] . many studies have shown that the high consumption of such foods contributes to excessive weight gain and increased risks of chronic conditions such as cardiovascular diseases and obesity [26, 27] . these pre-existing conditions have been reported to increase the severity of covid-19 infection and potentially worsen the disease outcome [28, 29] . noteworthy, in our study, the consumption of miscellaneous food was relatively low (56.9% participants), which may lower the total dietary diversity score. however, as discussed above, low consumption of processed food may also bring potential health benefits. further investigations are needed to measure the consumption of processed foods and its effects on health during disease outbreaks. insufficient intake of fish and legumes in the chinese population were also observed in a previous study conducted before the covid-19 pandemic [30, 31] . however, due to cultural preferences in the chinese population for fresh foods that are likely to be negatively affected by the lockdown policy, it is unsurprising that the intake of food like fish and seafood, whose tastes and flavor largely depend on the freshness of the raw materials, may decrease [32] . to improve the residents' access to fresh fish, wuhan city implemented a working program to promote the consumption of fresh fish in every local community on 12 march [33] . legumes including fresh beans, soybeans, and pulses provide fiber, protein, vitamins, minerals, and phytochemicals such as phytosterols that have been suggested to modulate immune system and exert protective effects against inflammation and oxidative stress [34, 35] . in addition, because legumes and fish are both excellent sources of high-quality protein and low in fats, interventions and policies are needed to encourage the inclusion of these two food groups to achieve more balanced and diversified diets rich in nutrients, in particular, during pandemics like covid-19. participants in this study were distributed across 31 provinces and cities in china. we observed a slightly lower hdds among people living in the areas where more covid-19 cases had been confirmed. similar concerns were raised in the areas hit hardest by ebola in 2014 and 2015. in guinea and liberia, where food became unavailable and food insecurity rose rapidly, people shifted toward a less nutritious diet with limited diversity [36, 37] . those findings indicate that areas with high incidence of infectious diseases like covid-19 should pay more attention to dietary diversity, especially in the areas where people are required to self-isolate at home and food supply mostly depends on government or community-based food distribution programs. meanwhile, more novel strategies should be developed to meet the needs of adequate and diverse food supply in this particular time. as reported by the study participants, in-house storage and in-person grocery shopping were still the major sources of food supply during lockdown. meanwhile, online food ordering and delivery services have gradually become an important method to purchase food in the daily lives of chinese residents [11] . in this study, 55.9% participants used online ordering and delivery services at least once. the clustering analysis grouped study participants into three clusters based on their methods for purchasing or obtaining foods. when comparing the hdds among people with different preferences for purchasing foods, we found that participants who purchased food primarily via online food shopping, or who depended on in-house storage and in-person grocery shopping, or purchased the most food in person from grocery stores had similar hdds. in addition, we observed that fruits and dairy products were the most common food purchased via online services, which are also the food groups recommended in the chinese dietary recommendation responding to covid-19 [18] . therefore, online ordering and delivery services may serve as a feasible solution to sustain stable food supply and adequate food access in the covid-19 pandemic as it can maintain dietary diversity and potentially reduce the spread of virus by limiting person to person contact. on 10 february, the chinese state administration for market regulation promulgated specific regulations corresponding to the online food ordering and delivery services, which requires checking the deliveryman's temperature daily, disinfecting the equipment, requesting staff wear gloves and masks during delivery services, etc. [38] . these requirements may be helpful in curtailing the covid-19 pandemic, but further evaluations on their effectiveness in slowing the growth of covid-19 cases are still needed. furthermore, other potential concerns on food delivery such as the risk of food contamination should also be taken into consideration. disease outbreaks often influentially impact health-related behaviors. joseph et al. reported that comparing health-seeking behaviors in the post-and pre-sars epidemic period in 2003, people were more likely to adopt a healthier diet, especially among those who were worried about contracting the virus [39] . interestingly, our study found that 31.2% of our participants intentionally consumed vitamin c, probiotics, and other dietary supplements to cope with the novel coronavirus outbreak. meanwhile there were 10.6% and 16.0% of participants once purposely drinking alcohol and vinegar, respectively. these behaviors are likely to be caused by rising concerns in this stressful time of covid-19 pandemic. intriguingly, we observed higher hdds among participants with those behaviors. we infer that it may be because the people who have these behaviors may also pay more attention to diet. however, it should be noted that none of these behaviors has been officially recommended and they are not supported by rigorously tested scientific evidences. for instance, the idea of drinking high liquor to prevent viral infection emerged soon after several chinese scientists announced that 75% medical alcohol could inactivate the virus. although the chinese government had already dismissed this rumor since 22 january [40] , there were still more than 10% of the studied population purposely drinking more alcohol. this behavior has also been reported in many other countries. according to the report from tasnim news agency on 27 march, there have been at least 2197 people poisoned and 244 deaths in iran due to the consumption of toxic alcohol (methanol based beverage) that was believed to prevent covid-19 by some people [41] . another interesting phenomenon is that 16% of the studied participants had drunk more vinegar to fight against the virus, which could also be seen in 2003 during the sars pandemic [42] . unfortunately, no scientific evidence has proven the effectiveness of drinking vinegar in lowering the risks of viral infection or mortality. based on the online survey methodology, hdds was used in this study for its convenience, and to some extent, it could reflect the food accessibility and predict the risk of malnutrition. however, it does not quantify the amount of actual food intake and, therefore, we could not estimate the level of nutrient sufficiency or deficiency. additionally, according to a validation study, the current components of indicators in hdds do not provide a reliable way to reflect the household-level access to food [43] . no previous chinese study has used this indicator, so the reliability was unknown in the chinese population. in addition, the hdds was designed with an interview methodology and there is no pre-test of its efficiency on self-completion. the e-based questionnaire may also lead to selection bias. the majority of participants in the current survey were young and highly educated. elders and people with relatively low socio-economic status could not be easily reached in this study, however, they are often the more vulnerable groups during the covid-19 pandemic. further studies should focus on these populations and provide specific strategies to ensure their nutritional status. another unfortunate limitation in current study is that we could not obtain the anthropometric data, hence the direct health outcomes could not be observed. the impacts of dietary intake during pandemic on health such as weight change and immune functions need to be evaluated. this study reported on dietary diversity in mainland china during the covid-19 pandemic and revealed a generally good dietary diversity among the chinese residents studied. however, people living in areas with a high number of confirmed covid-19 cases had a lower hdds. several dietary behaviors used to cope with covid-19 were identified including increased consumption of vitamin c, probiotics, other dietary supplements, alcohol, and vinegar. people with these behaviors had a higher hdds. during lockdown, in-house storage and in-person grocery shopping were the primary ways to obtain food. there was no difference in the hdds among people who depended more on in-person grocery shopping, in-house storage, or online ordering and delivery services to obtain or purchase foods. based on the current study, we have proposed the following recommendations. (1) evidence based dietary recommendations and health education are needed to encourage a more balanced and diversified diet and to prevent inappropriate eating behaviors, especially in areas severely impacted by covid-19 and the lockdown policy. (2) cautiously monitored and regulated online ordering and delivery services could serve as a feasible method for food purchases, which ensures dietary diversity. (3) more studies are urgently needed to identify potential nutritional concerns for different populations with various health conditions and socio-demographic characteristics during pandemics and provide corresponding strategies. author contributions: a.z. designed the research. a.z., and z.l. wrote the manuscript. a.z., j.z., and z.r. performed the statistical analyses. y.k., s.h., and y.m. collected the data; y.z. participated in the discussion and revised the manuscript. all authors have read and agreed to the published version of the manuscript. funding: this research received no external funding. the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china. chin knowledge, attitudes, and practices towards covid-19 among chinese residents during the rapid rise period of the covid-19 outbreak: a quick online cross-sectional survey coronavirus disease (covid-2019) situation reports shared responsibility, global solidarity: responding to the socio-economic impacts of covid-19 vitamin c and immune function effects of probiotics, prebiotics, and synbiotics on human health household dietary diversity score (hdds) for measurement of household food access: indicator guide version 2. academy for educational development nutrition, immune response, and outcome outbreaks can be stressful chinese restaurant super digital time insight the vast majority of express delivery companies across china resumed normal work chinese center for disease control and prevention. the distribution of covid-19 the r project for statistical computing social capital and sleep quality in individuals who self-isolated for 14 days during the coronavirus disease 2019 (covid-19) outbreak in january 2020 in china covid-19): emerging and future challenges for dental and oral medicine national health commission of china, dietary guidelines for the prevention and treatment of novel coronavirus coping with stress during the 2019-ncov outbreak household dietary diversity and child stunting in east java, indonesia. asia pac household food insecurity along an agro-ecological gradient influences children's nutritional status in south africa dietary diversity score: a measure of nutritional adequacy or an indicator of healthy diet? food insecurity and chronic disease: addressing food access as a healthcare issue consumption of animal source foods and dietary diversity reduce stunting in children in cambodia characterization of the degree of food processing in relation with its health potential and effects ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (nutrinet-santé) high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation coronavirus disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up consumption of dried legume and legume products among adults aged 18-59 years old in 15 provinces of china in 2015 consumption of marine food consumption among adults aged 18-59 years old in 15 provinces of china in 2015 food, eating behavior, and culture in chinese society wuhan: ensure household has fresh fish phytochemicals for health, the role of pulses nutritional and health benefits of pulses impact on food security and livelihoods. action against hunger uk. 2015. available online ebola to worsen food security conditions in liberia, sierra leone and guinea notice of market regulation on further strengthening food safety supervision during the prevention and control of the covid-19 impacts of sars on health-seeking behaviors in general population in hong kong alcohol drinking cannot help for preventing the corona virus iran confronts deadly alcohol crisis in midst of dealing with coronavirus help-seeking pattern of college students during the time of severe acute respiratory syndrome. chin verifying validity of the household dietary diversity score: an application of rasch modeling this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license we would like to sincerely thank our friends who helped us forward the questionnaires. the authors declare no conflicts of interest. key: cord-278817-dfxly2qg authors: xiaoyan, li; lundborg, cecilia stålsby; banghan, ding; bojun, chen; hong, zhou; jiqiang, li; aihua, ou; wenwei, ouyang; zehuai, wen; chuanjian, lu; marrone, gaetano title: clinical outcomes of influenza-like illness treated with chinese herbal medicine: an observational study date: 2018-02-28 journal: journal of traditional chinese medicine doi: 10.1016/j.jtcm.2018.02.011 sha: doc_id: 278817 cord_uid: dfxly2qg abstract objective to present and analyze treatments and clinical outcomes of chinese patients with influenza-like illness. methods we conducted a multi-site observational study from december 2009 to april 2010. patients with influenza-like illness from 45 hospitals were enrolled. patients received chinese herbal medicine (chm), conventional treatments, or chm plus conventional treatments (combination treatment) according to the guidelines for influenza a/h1n1 2009 in china. the primary outcomes were the time to alleviation of symptoms and the incidence of complications. the secondary outcomes were the time until becoming afebrile, incidence of severe illness, testing negative on an influenza a viral test, and total medical fees. results in total, 5967 patients were enrolled. the percentages of patients prescribed chm alone, conventional treatment, and combination treatment were 27.8%, 5.1%, and 67.7%, respectively. there were no significant differences in the time to alleviation of symptoms, incidence of complications, time to becoming afebrile, or rate of severe illness among the chm, conventional, and combination treatment groups. the rates of testing negative on the influenza virus a rapid test and h1n1 virus test were 90.3% and 76.3%, respectively. however, significant differences were found in the total medical fees among the three groups: chm treatments were more economical than the other two treatments. conclusion the efficacy of chm for influenza-like illness was not different from that of conventional treatments, but it was more economical. in 2009, a novel swine-origin influenza a (h1n1) virus rapidly spread from china to many countries around the world, prompting the world health organization (who) to declare a pandemic on 11 june 2009. 1, 2 the first case of h1n1 infection in china was reported on 9 may 2009. 3 since then, the number of cases has continuously increased. as of 31 march 2010, more than 127 000 laboratory-confirmed cases had been reported in 31 different provinces; this included 800 deaths. 4 symptomatic care and antiviral therapy are the main treatments for h1n1. 5 the neuraminidase inhibitors oseltamivir and zanamivir have been recommended by the who for patients who have or are at high risk of developing severe or progressive clinical illness. however, there is growing evidence that neuraminidase inhibitors are resistant to influenza viruses. 6, 7 chinese herbal medicine (chm) has a long history of use in the treatment of infectious disease. chm has its own theoretical system with many important scientific contributions, such as shang han za bing lun 8 and wenbing tiaobian. 9 chm has been widely used for colds and influenza in clinical practice in china. at the time of the severe acute respiratory syndrome outbreak in 2003, studies revealed evidence of potential positive effects of chm, 10, 11 providing valuable information regarding the treatment of influenza a. moreover, during the early stages of the h1n1 outbreak, clinical practice outcomes indicated that chm had the potential effect of alleviating symptoms and shortening the course of treatment. 12, 13 therefore, chm may be a promising alternative or complementary therapy for influenza. however, more concrete clinical evidence is needed to demonstrate its effectiveness. the present study began in december 2009 in china and was supported by the chinese government's program on "clinical research on h1n1 pandemic influenza treated with chm." 14 the aim of the study was to determine how chinese physicians treated patients with influenza-like illnesses in clinical practice and compare the effectiveness of different treatments for influenza. this multi-site observational study was conducted during the h1n1 outbreaks in china from december 2009 to april 2010. the study was conducted in 45 hospitals (including chinese medicine hospitals, general hospitals, and infectious disease hospitals) from 16 provinces in 6 different regions. the study was conducted under the supervision of the guangdong provincial hospital of chinese medicine (gphcm). all enrolled participants were observed and followed up during their disease course. all observations and follow-up ceased within 7 days of the end of treatment. the study was registered on 10 february 2010 in the chinese clinical trial registry (chictr-och-10000780) (http: //www.chictr.org.cn/). all eligible participants were outpatients diagnosed with suspected influenza a, either clinically or based on laboratory tests in accordance with the guideline released by the chinese ministry of health. 15 physicians prescribed medication according to the patients' conditions. the study did not control for the treatment prescribed. physicians selected chm or conventional treatments with reference to the guidelines released by the chinese ministry of health. the different treatments are defined as follows. (a) chm is a traditional medical practice in china with its own diagnosis system and treatment principles. it was defined as the use of decoctions or products of chinese patent medicine at least three times over the course of the disease in this study. (b) conventional treatment is a conventional medical practice based on western medicine principles. in this study, it included symptomatic treatments (routine conventional treatments for relieving symptoms such as fever, coughing, and phlegm production), antiviral treatments (routine use of antiviral drugs such as oseltamivir for at least 3 d over the course of the disease), and antibiotics (included because we found that some doctors prescribed antibiotics for patients with influenza). (c) combination treatments were defined in this study as chm plus conventional treatments. the primary outcomes included the time to alleviation of symptoms and the incidence of complications. the time until alleviation of symptoms was defined as the number of days between the date on which the patients visited the doctor (baseline date) and the date on which all main symptoms had been alleviated for > 24 h. the main symptoms included nasal congestion, sore throat, cough, myalgia, fatigue, and headache. a four-level scale was used to evaluate symptoms: none, mild, moderate, and severe. possible complications included bronchitis, pneumonia, tonsillar abscess, and several other complications described in the who h1n1 guidelines. 5 the secondary outcomes were as follows. (a) the time until becoming afebrile, defined as the number of hours between the time at which patients visited the doctor and the time at which their temperatures dropped below 37.3 ℃ for a period of > 24 h. (b) the incidence of severe illness due to influenza, characterized the following symptoms and signs: 15 (a) high fever (> 39 ℃) lasting for 3 d; (b) heavy coughing, purulent sputum, bloody sputum, or chest pain; (c) rapid breathing, difficult breathing, or cyanosis of the lips; (d) altered mental status, blunted responsiveness or sensibility, drowsiness, dysphoria, or convulsions; (e) severe vomiting or diarrhea or dehydration; (f ) signs of pneumonia on imaging examinations; (g) rapid increase in myocardial enzymes, such as creatine phosphokinase (ck) or creatine kinase isoenzyme (ck-mb); or (h) aggravation of existing physical illnesses. (c) negative result on the influenza a viral test. (d) total medical fees, including medication fees and clinic fees. the patients' demographic data, vaccination history, history of recent contact with patients with influenza, history of serious medical problems, medications, and treatment costs were all recorded, and influenza-like symptoms were assessed during the study. we also collected laboratory test results if available, such as vital signs, blood test results, urine test results, liver function test results, renal function test results, electrocardiogram findings, chest radiography findings, influenza virus a rapid test results, and influenza h1n1 virus test results. a pre-developed case report form was used to collect all data. patients were required to record their symptoms, body temperature, and medication taken in daily diaries. researchers followed up all patients via telephone calls and/or in-person interviews each day for a maximum of 7 d after treatment. the patients were withdrawn from the study if their condition became severe or they died of influenza or any other causes. all physicians from the various centers were trained before the study. an independent organization, the guangdong international clinical research center of chinese medicine, conducted data monitoring. the case report forms from all of the centers were delivered to gphcm after being reviewed. eight data entry operators were trained in double entry with epidata v3.1 software (epidata association, odense, denmark). the database was locked after all data had been cleaned. for sample size calculation, we assumed that the time to alleviation of symptoms (the main outcome) was 4.0 d for chm treatment, 4.2 d for conventional treatment, and 4.2 d for combined treatments; the standard deviation was 2.2 according to the data from the pilot study. using analysis of variance to compare the outcome between groups, a power of 0.8, and significance level of 0.05, we found that 5250 patients were needed in the study. pass 11 software (ncss, kaysville, ut, usa) was used to calculate the sample size. missing data regarding symptoms and body temperature were replaced by last observation carried forward (locf). participants, who had taken medicine and had undergone collection of outcome data at least once, were analyzed. the pasw statistics 17.0 software package (spss inc., chicago, il, usa) and stata software 13 (stata corp., college station, tx, usa) were used for the statistical analysis. either a t-test or the mann-whitney test was used to compare continuous variables in the two groups. one-way analysis of variance or the corresponding non-parametric kruskal-wallis test was used to compare continuous variables in more than two groups; the χ 2 test was used to compare categorical variables. to control for confounders in different groups, either a binary or ordinal logistic regression model was performed to compare the time to alleviation of symptoms, time until becoming afebrile (categorized as either >24 or <24 h), incidence of complications and severe illness, and probability of testing negative on the influenza a viral test between the groups. the baseline variables were selected as covariates in the multivariable regression model if the p-value was <0.20. total medical fees were compared between the groups with a generalized linear model. for all final regression models, parameter estimates were adjusted for both confounding variables and for cluster sampling at the hospital level. a p-value of <0.05 was considered statistically significant in the final models. during the influenza a/h1n1 outbreak from december 2009 to april 2010, 22 531 potentially eligible outpatients with influenza-like illness visited fever clinics or emergency rooms of 45 hospitals in 16 provinces of 6 regions of china. in total, 5967 patients were enrolled in the study after screening. of these 5967 patients, 11 discontinued treatment immediately after prescription and 62 were lost to follow-up after the first visit. therefore, 73 patients were excluded from the analysis because of a lack of data to evaluate the treatment effectiveness. the final analysis included data from 5894 patients: 1,641 (27.8% ) in the chm group, 295 (5.1% ) in the conventional treatment group, and 3958 (67.1% ) in the combination treatment group. a flow chart of the study is shown in figure 1. the number of eligible patients in each hospital ranged from 10 to 781, as shown in figure 2 . the baseline characteristics of patients in the chm group, conventional treatment group, and combination treatment group are shown in table 1 . chm, both alone and in combination, was used more frequently than conventional treatment in patients with a history of serious medical problems. the mean age of the 5894 patients was 26.1 years. the mean body temperature at baseline was 38.3 ℃. only 146 (2.5%) patients had received an influenza vaccination before the study. the influenza virus a rapid test positive rate was 11.2% among the 4972 patients who took the test. all baseline variables except sex, diastolic blood pressure, influenza vaccination, sore throat, and coughing were unbalanced between the groups (p < 0.05). one aim of the study was to collect data on how physicians treated patients with influenza a/h1n1. from table 2 , we can see that the percentage of patients prescribed chm alone was 27.8%. a total of 5.1% were prescribed conventional treatments and 67.1% were prescribed combination treatments. we examined all treatment data in this study and calculated the frequency of chm, symptomatic treatment, antiviral treatment, and their combinations ( table 2 ). the numbers of patients for whom at least one of the following medications was used were as follows: chm: 5599 (95.0%), symptomatic treatment: 3522 (59.8%), antiviral treatment: 327 (5.5% ), and antibiotic treatment: 1648 (28.0%). after evaluating the concomitant diseases of patients who had accepted antibiotic treatment, we found that only 160 patients needed antibiotics for infectious diseases. therefore, irrational use of antibiotics for influenza may have occurred in 1488 (25.2% ) patients. chm combined with symptomatic treatment was the most common treatment, and nearly one-third of the patients (27.8% ) received chm treatment alone. the rates of use of chm in chinese medicine hospitals and non-chinese medicine hospitals were 95.7% and 91.0%, respectively. the mean time until alleviation of symptoms was 4.2, 4.4, and 4.4 d, respectively, in the chm group, conventional treatment group, and combination treatment group. alleviation of symptoms primarily occurred before the fifth day, and the symptoms of only 612 patients (10.4% of 5894) did not disappear after that time. an ordinal logistic regression model was used to adjust for confounding factors and compare the effectiveness among the three treatment groups (table 3) . the dependent variable was number of days (1-7) until the alleviation of symptoms after the start of treatment. as shown in table 3 , after adjusting for cluster effects, there were no statistically significant differences between the conventional treatment group and the other two groups. additionally, the patients who had had an influenza vaccine, a history of recent contact with patients with influenza, cough, or a higher temperature needed more days to recover from all symptoms. the mean time until becoming afebrile was 40.0, 42.0, and 39.8 h in the chm group, conventional treatment group, and combination treatment group, respectively. just over half (50.9% ) of the 5894 patients became afebrile within 24 h of treatment. the results shown in table 5 indicate that no significant difference was found between chm (chm group and combination treatment group) and conventional treatment. of the 5894 patients, severe influenza occurred in 19 (0.32%): 5 cases (0.30%) in the chm group, 1 case (0.34% ) in the conventional treatment group, and 13 cases (0.44% ) in the combination treatment notes: chm: chinese herbal medicine; sbp: systolic blood pressure; dbp: diastolic blood pressure; sd: standard deviation. total symptom score: a score of 0 (none), 1 (mild), 2 (moderate), or 3 (severe) was assigned to the six main symptoms (nasal congestion, sore throat, coughing, myalgia, fatigue, and headache). the total symptom score for each participant was obtained by summing the scores of each of these six symptoms. group. binary logistic regression analysis (table 6) showed no statistical significance among the three groups. only 175 patients who tested positive on the influenza virus a rapid test at baseline tested positive again on the fifth day after treatment. a total of 158 of these patients (90.3% ) tested negative. only 38 patients with confirmed h1n1 virus at baseline were retested after treatment, and 76.3% (29/38) of these patients tested negative after treatment. the proportion of missing data was so high for this outcome that we did not perform comparisons among the groups. the mean total medical fees in the study was ¥117.7 (18.1 usd): ¥72.5 in the chm group, ¥123.0 in the conventional treatment group, and ¥135.9 in the combination treatment group. a general linear model was used to compare fees among the three groups. both un-adjusted and adjusted estimates differed significantly among the three groups. sex, a history of serious medical problems, height, weight, systolic blood pressure, pulse rate, respiration, temperature, and total symptom score at baseline were adjusted for in the model because the fees were found to be statistically significant (p < 0.05) in the bivariate analysis by single-factor analysis. table 7 shows that significant differences were found during the comparison of total medical fees among the three groups. the chm treatments were more economical than the other two treatments. in total, 46 cases of adverse events were reported among the 5,894 patients: 26 cases of diarrhea, 14 cases of vomiting, 2 cases of combined diarrhea and vomiting, 2 cases of allergic reaction, 1 case of syncope, and 1 case of tinnitus. the 46 cases included 37 mild and 9 moderate adverse events. eight cases were in the chm group and 38 were in the combination treatment group. this study was performed to analyze clinical treatments in patients with influenza-like illness in china and compare the effectiveness of different influenza a treatments, especially chm. the study showed that chm was used extensively in both hospitals that were and were not focused on chinese medicine. chm combined with symptomatic treatment was the main form of therapy for influenza-like illness in clinical practice, especially for patients with severe symptoms. chm, both alone and in combination with western medicine, was used more frequently than conventional treatment in patients with a history of serious medical problems. these findings differ from those of a study titled "treatment of influenza: chinese medicine vs. western medicine." 16 according to that study, patients with mild illness preferred chinese traditional medicine for treatment of symptoms, specifically fever. western medicine was preferred by patients with complicated illnesses because it appeared to be more comprehensive and effective than herbal medicine. 16 there was limited evidence to support this claim at that time, and the author arrived at this conclusion from clues based on the patients' choices. 16 our study provides evidence based on data from the times at which traditional chinese medicine was used and conventional treatments were resumed in clinical practice. in this study, no significant differences were found in the time to alleviation of symptoms, incidence of complications, time until becoming afebrile, or rate of severe illness among the chm, conventional treatment, and combined treatment groups. however, significant differences were found in the total medical fees among the three groups; chm treatments were more economical than the other two treatments. in recent years, several clinical studies of h1n1 have been performed to evaluate the efficacy of chm. these have included studies on lianhuaqingwen capsules 17 and maxingshigan-yinqiaosan. 18 these two forms of chm demonstrated potential positive effects against h1n1. however, a systematic review determined that confirmative conclusions on the beneficial effects of chinese herbs on h1n1 influenza could not be reached because of the lack of both a placebo-controlled trial and repeated intervention tests. 19 two other systematic reviews of chm for influenza also showed that chm has potentially positive effects in the treatment of influenza but that current evidence remains weak. 20, 21 therefore, chm has yet to show a clear advantage over conventional treatments in the treatment of influenza. one strength of this study is that a large number of patients with influenza-like illness were enrolled during the 5-month outbreak of influenza a/h1n1 in china. furthermore, the sample collected covered most regions of china. another strength is that we had 80% power for the primary outcome, meaning that the negative results (no significant differences) were unlikely due to a small sample size or chance. the main limitation of this study is that it was an observational study without a control group. it was thus difficult to isolate the efficacy of the three treatments. the samples in the three groups were not randomized and were therefore uneven. even if we had tried to adjust for possible confounders in the analysis, we might have overlooked several of them, thus biasing our results. in conclusion, although chm does not have a better effect on influenza than conventional treatments, it is more economical. these findings serve as an overview of treatments for influenza-like illness using chm in china and provide a basis for future research on this topic. future randomized controlled trials should be conducted to evaluate and confirm our findings. new influenza a (h1n1) virus: global epidemiological situation systematic review of clinical and epidemiological features of the pandemic influenza a (h1n1) clinical and epidemiologic characteristics of 3 early cases of influenza a pandemic (h1n1) 2009 virus infection, people's republic of china ministry of health of the people's republic of china. the prevention and control work about flu a h1n1 in china clinical management of human infection with pandemic (h1n1) 2009: revised guidance a review of the antiviral susceptibility of human and avian influenza viruses over the last decade rebelo-de-andrade h. influenza a (h1n1)pdm09 resistance and cross-decreased susceptibility to oseltamivir and zanamivir antiviral drugs shanghan zabing lun wen bing tiao bian the efficacy of chinese medicine for sars: a review of chinese publications after the crisis the lesson of supplementary treatment with chinese medicine on severe laboratory-confirmed sars patients a report of six confirmed flu a h1n1 cases treated by chinese and western medicine broad prospects of traditional chinese medicine for flu a h1n1 conference of the government program topic on 'prevention of infectious diseases with chm ministry of health of the people's republic of china. diagnosis and treatment for flu a h1n1 (third version treatment of influenza: chinese medicine vs. western medicine efficacy of lianhuaqingwen capsule compared with oseltamivir for influenza a virus infection: a meta-analysis of randomized, controlled trials oseltamivir compared with the chinese traditional therapy maxingshigan-yinqiaosan in the treatment of h1n1 influenza: a randomized trial chinese herbal medicines for the treatment of type a h1n1 influenza: a systematic review of randomized controlled trials traditional chinese medicine for the treatment of influenza: a systematic review and meta-analysis of randomized controlled trials chinese medicinal herbs for influenza we would like to thank the following study sites for participant enrollment and data collection: anhui pro key: cord-013405-68777jts authors: lu, wenze; ngai, cindy sing bik; yang, lu title: the importance of genuineness in public engagement—an exploratory study of pediatric communication on social media in china date: 2020-09-27 journal: int j environ res public health doi: 10.3390/ijerph17197078 sha: doc_id: 13405 cord_uid: 68777jts there is a growing need for the public to interact with pediatricians through social media in china, and genuineness is a crucial factor contributing to effective communication, but few studies have examined the relationship between genuineness and its effect on public engagement. this study developed a four-dimension framework including self-disclosure, genuine response, functional interactivity, and genuineness in chinese culture to investigate the effect of genuineness in the communication of chinese social media influencers in pediatrics on public engagement. content analysis was employed to examine these dimensions and the related public engagement in 300 social media posts on the largest microblogging site in china. the findings indicate that genuine response was positively associated with the number of comments and positive comments, while negatively related to the number of shares. functional interactivity made the site more appealing, resulting in likes and shares. genuineness in chinese culture was reflected in engagement through sharing posts by the public. this study is the first to develop an integrated framework to measure genuineness in online health communication and contributes to the understanding of the effect of genuineness on chinese public engagement in social media. child health and development has been one of the biggest issues in the world health organization. in recent years, chinese president xi jinping has put public health at the center of the country's policy-making agenda, clarifying the need to include public health in official government policy. "the healthy china 2030 planning outline", issued by the chinese state council, is the first long-term strategic plan of public health developed at the national level in china [1] . one of the aims in the plan is to enhance children's health and reduce children's mortality by the construction of pediatrics and the prevention of pediatric critical diseases [2] . as an important area of study in public health, children health advocates the prioritization of children healthcare in public health community as a basis for the improvement of national health [3] . concerning this great emphasis on children's health, sustainable investment and efforts have been put into relevant fields, especially online. chinese premier li keqiang once put forward a guideline named "internet+," aiming to integrate online resources with other domains including education, logistics, and health care. social media is of particular importance in disseminating health information and promoting health communication as china records the world's largest number of registered social media users [4] [5] [6] . of all the social media in china, sina-microblog (aka weibo) is one of the most popular platforms for health communication, with 516 million active online users at the end of 2019 [4] . in recent years, the number of doctors' the constituent parts of online messages to be employed when they attempt to engage the public in health conversations through social media. moreover, a better understanding of how people view doctors' online health communication would strengthen the value of the principles that guide good communication. among all the driving factors in health communication, genuineness has been suggested as a contributing factor in effective medical communication, especially in patient-centered psychotherapy [21] . norcross and newman [22] pointed out that health practitioners considered doctors' genuineness as "important for significant progress in psychotherapy, and, in fact, fundamental in the formation of a working alliance" (p. 104). likewise, therapists' characteristics, especially genuineness, authenticity and honesty can enhance their credibility which was essential for promoting therapeutic alliance and patients' trust [23] [24] [25] . genuineness has been widely studied in face-to-face communication between doctors and patients. little attention has been paid on the importance of genuineness on health communication in the context of social media. due to the absence of concrete operational dimensions in studying genuineness, we developed an integrated framework that included four dimensions-"self-disclosure", "genuine response", "functional interactivity" and "genuineness in chinese culture", for examining genuineness in social media communication based on previous studies in health communication, dialogic communication, and the study of chinese culture. the first three are universal dimensions that occur regardless of the cultural context while the fourth dimension is a cultural determined dimension which is essential to chinese communication. there is no universally agreed-upon definition of genuineness. however, the common features of genuineness focus on "self-dimension," referring to transparency, realness, and the authenticity of one's mind and behavior. in the medical field, landreth stated, "the most significant resource the therapist brings to therapy relationship is the dimension of self. skills and techniques are useful tools, but therapist's use of their personalities is their greatest asset" ( [26] , pp. 104-105). egan also specified that genuineness is "beyond professionalism and phoniness" ( [27] , p. 55). it refers to an attitude or behavior that can only be expressed if the doctor is self-aware [28] . similarly, studies have noted that doctors' genuineness could be conceptualized as being real, being their true authentic self, and getting rid of dishonest and false behavior [29] . nevertheless, how to concretely perceive genuineness via "self" has been understudied. previous studies once demystified the idea that "self-dimension" of doctors' genuineness could be identified by self-disclosure during the health care process [30] [31] [32] . self-disclosure is defined as being willing to consciously and intentionally reveal personal feelings, life experiences, and professional knowledge in the process of communication to establish a positive relationship [30] . self-disclosure has received extensive attention in medical research because of its benefits to patients' positive health practices and doctor-patient relationships [31] . previous research [30] [31] [32] found three main types of self-disclosure being preferred by the doctors, namely the disclosure of personal thoughts/feelings, disclosure of personal life, and disclosure of personal expertise (e.g., pediatrics, neurology and psychiatry). a study reported [31] that patients liked their doctors more when doctors disclose personal feelings and thoughts. patients viewed an act of expressing feelings and thoughts from doctors as friendly and helpful because it encouraged patients to participate in a dialogue and enhance patient's self-exploration [31] . another study suggested that when a doctor disclosed his/her own lifestyle (e.g., positive health behaviors or daily activities), patients considered the doctor to be more credible and approachable [32] . likewise, patients particularly valued when doctors disclosed the accumulated skills, experience, and specific expertise in the field [28] [29] [30] . expanded on the previous studies, our study aims at investigating these three types of self-disclosure exhibited in the smip communication, and how public responded to different types of disclosure. in addition to self-disclosure, prior studies [33] [34] [35] [36] confirmed that genuineness could be manifested when healthcare workers communicate consistently and provide expertise and emotional support to patients. in the health communication, a consistent response from doctor matters because it reflects "the degree to which one person is functionally integrated in the context of the relationship with another, such that there is an absence of conflict or inconsistency between their total experience, their awareness, and their overt communication in their congruence in the relationship" ( [34] , p. 12). a genuine response is not a response that simply expressed yes or no answer or a simple act of reaction (e.g., smile/cry). it emphasizes on the recognition of interlocutors' concerns, thereby providing professional and emotional support to address their problems [33] [34] [35] [36] . a genuine response to a patient's question or concern, is useful for building a positive therapeutic relationship [35] . yet, an absence of an analytical framework for examining genuine response was noted. as such, we have modified frameworks from previous studies [33, 36] on health communication studies and proposed three main sub-dimensions to measure genuine response: (1) consistency, (2) knowledge, skill, experience and treatment advice, and (3) facilitation of hopefulness. consistency emphasizes on whether patients' concerns are well understood, and the response is on the right track [33, 36] . van et al. [36] noted that healthcare workers often rephrase or repeat the patient's questions or concerns before providing follow-up treatment and explanation to demonstrate their understanding on patients' needs. bottorff et al. [33] pointed out that nurses who responded with expert knowledge, such as treatment and medical advice were able to reduce patients' anxiety and uncertainty. they suggested that such responses enable patients to make informed decision-making and be more actively involved in a dialogue [33] . moreover, previous research [33, 35, 36] indicated that nurses usually communicated emotional support through facilitation of hopefulness with patients during a therapeutic process. bottorff et al. [33] and van et al. [36] found that facilitation of hopefulness that nurses adopted in interactions contributed to reassuring patients and avoiding escalation of emotional instability, thereby leading to positive outcomes of treatment. in view of these, we intend to investigate and reveal genuine responses in smip messages by examining the three sub-dimensions adapted from previous studies on health communication [33, 36] . in addition to health communication studies, this study drew on insights from dialogic communication theory in public relation and communication studies where functional interactivity serves as one of the principle elements in creating a genuine and dialogic communication online [37] . functional interactivity refers to the interface's elements that allow an online user to interact with someone/an organization and build a dialogue between interlocutors [38] . such elements include hyperlinks, multimedia, live-chat rooms, and questions [39] . functional interactivity is of particular importance in social media communication where dynamic, two-way interactive communication is advanced by the proliferation of social media [40, 41] . for a genuine and dialogic communication to emerge [37, 40] , interactive functions including "generation of return visits," "conservation of visitors," and "dialogic loop" were deemed necessary. the "generation of return visits" emphasizes on the return visit of the public while the "conservation of visitors" highlights the importance of connecting the public to the smi. both "generation of return visits" and "conservation of visitors" could be achieved by providing external links and hashtags to engage the public [41, 42] . "dialogic loop" placed much attention on promoting dialogue between smi and the public where strategies including providing frequent responses, asking questions, and using multimedia are most employed [41, 42] . subsequently, this study examines the use of interactive functions for building genuine dialogue in smip communication and their association with public engagement. if the first three dimensions of genuineness are universal dimensions that occur regardless of the cultural context, the fourth dimension can be identified as a cultural determined aspect which is essential in chinese communication. in chinese culture, honesty and kindness are viewed as necessary components for developing genuine dialogue [43] [44] [45] [46] , and therefore, are of particular value to the chinese audience. honesty is the essence of confucianism and has a deep impact on the moral personality development [47] . kindness, along with compassion, care, friendliness, righteousness, and affection, is one of the confucian values about a "good person" in chinese culture [48] . a kind individual is positively related to excellent job performance [49] . zhang et al. [50] also illustrated that the kinder a nurse is, the more satisfied patients are. the genuineness in smip communication that attributes to the portrayal of a positive personality trait [46, 47] , could be measured by the use of lexical indicators for the expression of honesty and kindness [43] [44] [45] [46] . honesty in the chinese culture is denoted as the moral quality of being consistent in words and deeds; opposite to hypocrisy; loyalty and open-mindedness; no lying, no fraud, no exaggeration, no distortion of facts [51] . as such, we postulate that lexical indicators related to (1) reasoning and explanation (e.g., because, so), (2) personal sharing and views (e.g., i think, i contend, i prefer), and (3) truth/facts (e.g., in fact, the truth is, the evidence reveals) are important in expressing honesty. kindness in the chinese culture denotes personalities of being friendly, harmonious, kind-hearted and nice, and behaviors of altruistic, affectionate, righteous, and caring [52, 53] . in smip communication, we expected kindness to be expressed through the use of lexical indicators related to (1) caring (e.g., is that okay, are you satisfied, is this clear for you), (2) friendliness (e.g., hello, could you please, welcome), (3) gratitude (e.g., thanks, appreciate it), (4) blessing (e.g., wish you, no worries, everything will be fine), and (5) compliment (e.g., good question, you are right). in our study, public engagement refers to the public's responses to the content communicated via social media which reflects the public's cognition and attitude on a particular issue [54] . different level of public engagement on social media reveals their trust and relationship with involved members [20, 55] . previous research has studied public engagement in different contexts with varied definitions. in corporate-stakeholder communication, bruce and shelley defined public engagement as "the interaction between an organization and those individuals and groups that are impacted by, or influence, the organization" ( [56] , p. 30). in ceo communication, men et al. conceptualize public engagement "as a behavioral construct focusing on publics' interactions with ceos" ( [57] , p. 87). in government communication, public engagement refers to the involvement of citizens in public affairs [58] . in this aspect, public engagement aims to boost mutual understanding and build up a good relationship between the local government and the public [58] . in recent years, scholars have started to study public engagement and perception in an online context due to the arrival of global social media platforms [59, 60] , such as weibo, youtube, twitter, and facebook, which all include the common feature of real-time public interaction. social media includes a variety of functions to engage with the public (e.g., blogs, photo sharing, video sharing, live chatting, and co-generation of content), and offers the ability to express attitudes via reaction buttons, appearing at the bottom of the relevant content: like, share, and comment [60] . "like" is an indicator to express awareness and interest, which can be used to identify the popularity of messages [61, 62] . "share" provides the opportunity to connect the organizational message to one's social group, and "comment" enables direct dialogue with organizations [61] . these engagement indicators fall into different engagement levels. like is the lowest level of engagement as it requires less cognitive effort and commitment than other indicators [62] . share has a higher engagement level [63] , as it can be viewed not only as an important indicator of user recognition but as user recommendation. this indicates that sharing requires certain time to evaluate the post's value [64] . a comment is the highest level of public engagement, as it requires more effort by the public to figure out the meaning of posts and directly respond to the messages with words or descriptors [61] . the number of likes and shares may indicate an overall positive effect but analyzing constituting parts embedded in comments helps estimate outcomes more concretely and accurately [65] . for instance, fan [66] argued that how people perceive products could be revealed in the comments thread. by studying the comments, the organization will know the weaknesses and affordances of products. public perceptions towards the content can also be amplified or constricted by reviewing other users' comments [67] . therefore, comments can be quite persuasive on affecting public opinions [68] . the present research categorizes comments as the high, shares as the intermediate, and likes as the low level of public engagement indicators. beyond the three engagement indicators, we paid particular attention to the valence of positive user comments. kim and yang [63] found that positive comments towards an organization are more likely to affect how people remember the organization, and further influence the organization's reputation. in tourism, for example, positive e-comments on businesses strongly influence travelers who read e-comments when they decide to select a hotel [69] . in the health field, positive online comments were positively associated with the effectiveness of anti-smoking persuasion on the public's attitudes [70] . given the impact of smip on public views and boosting children's health, we aim to identify the effectiveness of genuineness, one of the most influential driving factors in health communication, in smip's online communication. the paper employs the coding framework of four genuineness dimensions generated from dialogic communication, health communication and chinese cultural studies to examine the association between genuineness and public engagement. further, it provides an in-depth understanding on the relationships between genuineness and public reception indicators (i.e., likes, shares, comments, and positive comments). for the first research question (rq), we aim to investigate the association between the four dimensions of genuineness and public engagement, therefore the following research question is put forward: rq1: what is the association between the four dimensions of genuineness ("self-disclosure", "genuine response", "functional interactivity" and "genuineness in chinese culture") and public engagement? to fully understand the relationship within sub-dimensions in each dimension and public engagement, our second set of research questions is formulated as follows: rq2a: what are the associations within the sub-dimensions of "self-disclosure" ("disclosure of personal life", "disclosure of personal thoughts and feelings", and "disclosure of personal expertise in pediatrics") and public engagement? rq2b: what are the associations within the sub-dimensions of "genuine response" ("consistency", "knowledge, skill, experience and treatment advice", and "facilitation of hopefulness") and public engagement? rq2c: what are the associations within the sub-dimensions of "functional interactivity" ("the generation of return visits and conservation of visitors", and "dialogic loop") and public engagement? rq2d: what are the associations within the sub-dimensions of "genuineness in chinese culture" ("honesty" and "kindness") and public engagement? first, we employed a self-developed python program programmed by our research assistant with a postgraduate degree in computational science to identify the top pediatricians based on their number of followers in weibo, one of the largest microblogging sites in china. the crawler is designed to search and identify verified pediatrician using the keywords "pediatrician" and the label "v-users". "v-users" referred to verified users where doctors need to submit their medical certificates to weibo to prove their authenticity. once approved, the letter "v" with a yellow badge will be assigned to these doctors' profile pictures. verified pediatricians are preferred in our study, as they are much more influential in the social media community than non-verified ones [71] . the identified pediatricians with the highest number of followers in march are recognized as social media influencers in pediatric (smip) in our study as they are well connected and persuasive in their field. as an exploratory study, we scrutinized the number of posts published by these top 10 smip for six months (from march 1 to august 31, 2019), to ensure that they are active communicators online. subsequently, we replaced two inactive users who published fewer than two posts/day on average with the next two smip on the list. table 1 presents the final list of top 10 smip. unlike twitter, weibo tends to change its open api at times for the purpose of data security and timely technical updates. moreover, weibo has a strict "restrictions on the api usage rate and unsolicited data requests" ( [72] , p. 597). therefore, we had to manually collect the smip posts, record the number of comments, likes and shares and analyze positive comments for our study. due to the complexity of the ten sub-dimensions embedded in the four dimensions of genuineness, we decided to code the sub-dimensions manually to ensure an accurate interpretation [54] on the use of genuineness in the smip posts. taking all these into considerations, we decided to harvest a sample size of 300 posts to represent the target population. we have employed the sample size calculator developed by the australian statistics bureau [73] to estimate a sample size of 300, giving a confidence level of 95%, a confident interval of 0.056, and standard error of 0.029. through systematic random sampling, we randomly sampled 30 posts from each smip's weibo account between march 1 and august 31 in 2019 for content analysis. content analysis was employed to examine the four dimensions of genuineness adopted in the 300 posts of the top 10 smip on weibo. content analysis is a widely employed method in the study of media communication [74] and can be applied to "virtually any form of linguistic communication to answer the classic questions of who says what to whom, why, how, and with what effect" ( [75] , p. 268). it is concerned with the context where the occurrences of words, signs, and sentences are examined to provide in-depth understanding [74, 76] . researchers could adapt and integrate framework from previous research for conducting coding in content analysis [74, 76] . in this study, we have drawn insights from health communication, dialogic communication and chinese cultural studies (see sections 1.2.1-1.2.4) to develop a four-dimension framework in genuine communication for pediatricians. a code book that includes the four dimensions of genuineness, the ten sub-dimensions, and descriptors to investigate the genuineness in smip's communication has been developed (see table 2 ). the coding procedure of each dimension is listed below: for the dimension of "self-disclosure", we coded the pediatrician's willingness to disclosure information related to his/her: (1) personal life, (2) personal feelings and thoughts, and (3) personal expertise in pediatrics [30] [31] [32] in the post on sentence basis. for the dimension of "genuine response", we coded to reveal if the pediatrician demonstrates: (1) consistency, (2) knowledge, skill, experience and treatment advice, and (3) facilitation of hopefulness in his/her response in comment thread on sentence basis [33] [34] [35] [36] . for the dimension of "functional interactivity", we coded the number of interactive elements (e.g., links, hashtag, multimedia, responses) used to facilitate: (1) "the generation of return visits and conservation of visitors," and (2) creation of "dialogic loop". refs. [37, 39, 41, 42] in the post and comment thread. for the dimension of "genuineness in chinese culture", we coded the number of lexical indicators that demonstrates pediatrician's personality: of (1) honesty, and (2) kindness [43, 45, 46] ; refs. [50] [51] [52] [53] in the post and comment thread. to ensure a high accuracy of analysis, a face-to-face meeting was held by the first author and the second author before the coding exercise. the authors identified the related descriptors, including lexical indicators and features in each dimension. relevant examples were retrieved from the database collected to guide the coders in the process of coding. the first author and a well-trained research assistant who possesses a ma in communication conducted the coding in this study. table 2 presents the four dimensions, ten sub-dimensions, and descriptors of the code book. the related examples extracted from the database could be found in appendix a. for the evaluation of public engagement, the number of shares, likes, comments, and positive comments were identified. beyond three engagement indicators, we paid particular attention to the valence of positive user comments, as positive comments can contribute to the excellent reputation of social media influencers and enhance public trust [65, 77] . online positive comments are characterized by the expression of compliment and affirmation, admiration and gratitude, usefulness and goodness [78] . in the corpus of this study, the comments, such as "thank you doctor," "beneficial advice," "great," and "feel the same way" were recorded. lexical indicators related to reasoning and explanation, e.g., because, so; lexical indicators related to personal sharing and views, e.g., i think, i contend, i prefer; lexical indicators related to truth/facts, e.g., in fact, the truth is, the evidence reveals expressions of care, e.g., is that okay, are you satisfied, is this clear for you; expressions of friendliness, e.g., hello, could you please, welcome; expressions of gratitude, e.g., thanks, appreciate it; expressions of blessing, e.g., wish you, no worries, everything will be fine; expressions of compliments, e.g., good question, you are right. the coding was conducted by the first author, the primary coder, and a well-trained research assistant who possesses a ma in communication. to ensure inter-rater reliability on the coding of "self-disclosure", "genuine response", "functional interactivity", "genuineness in chinese culture", and public engagement, the coders were highly trained on the coding scheme. any disagreement between the two coders was discussed in the coding process until the agreement was achieved. the measure of interrater reliability was based on the co-coding of 60 posts from the top two smip (20% of the total number of posts studied). for all categories, the average agreement was higher than 0.95, and the average cohen's kappa was greater than 0.9, indicating an almost perfect agreement [79] . please refer to table 3 for the interrater reliability of all categories. since the content in posts and responses in comment threads varied from two words to 140 words, all coded data have been standardized, especially the coding done on sentence basis. as such we have standardized the coding data of the sub-dimensions in "self-disclosure" and "genuine response" by dividing the number of sentences yielded in each sub-dimension in every post by the overall number of sentences in each post. as for the sub-dimensions of "functional interactivity" and "genuineness in chinese culture", we standardized the data by dividing the number of features harvested in each sub-dimension in every post by the total count of features in each post. as likes, shares, comments, and positive comments are count outcomes, poisson regression was employed for statistics analysis. however, we found overdispersion exhibited when testing for assumptions in poisson regression. then we decided to employ negative binomial regression to replace poisson regression as suggested in previous research [80, 81] . negative binomial regression (nb2) fits various types of data arising in communication research [81] , and "the negative binomial model is a more general model compared with the poisson regression model that relaxes the strong assumption that the underlying rate of the outcome is the same for each included participant" [82] (p. 3). moreover, negative binomial regression allows various information to be included [82] ; it is appropriate for the data in this study, especially in the presence of overdispersion. thus, rq1 and rq2 were examined via negative binomial regression in which likes, shares, comments, and positive comments were taken as dependent variables. for the examination of associations between the four dimensions and public engagement in rq1, standardized data in the sub-dimensions were summed up in the related dimension. for instance, the data in "disclosure of personal life", "disclosure of personal feelings and thoughts", and "disclosure of personal expertise" were combined to form the "self-disclosure". as for rq2, we used the standardized data in the sub-dimensions to examine if there was a significant association between sub-dimensions in each genuineness dimension and public engagement. in this section, we aim to reveal the association between the four dimensions of genuineness and public engagement and then identify different levels of impact of sub-dimensions in each genuineness dimension on public engagement. in response to rq1, the nb2 findings indicated the number of "genuine response" was positively associated with the number of comments and positive comments, but negatively related to number of shares. for every extra sentence on "genuine response", 1.344 times more comments were generated, a statistically significant result (p < 0.0001). similarly, there was a 16% increase in the number of positive comments for each extra sentence on "genuine response" (p = 0.0001). likewise, a positive association was found between the occurrence of "functional interactivity" and shares, whereas there was a negative correlation with comment and positive comments. a 19.8% increase in the number of shares is expected for every extra feature in "functional interactivity" found (p = 0.0001). in addition, the frequency of "genuineness in chinese culture" was positively related to the number of shares. for every extra lexical indicator in "genuineness in chinese culture", 1.122 times more shares were generated (p = 0.003). table 4 summarizes the negative binomial regression results on the four dimensions of genuineness and public engagement. the results above show that three sub-dimensions of genuineness, namely "genuine response", "functional interactivity" and "genuineness in chinese culture", have significant associations with public engagement on social media. therefore, we intend to further examine the association between the sub-dimensions in the four genuineness dimensions and public engagement. table 5 summarizes the negative binomial regression results on the sub-dimensions of "self-disclosure", "genuine response", "functional interactivity", "genuineness in chinese culture" and the number of shares, likes, comments and positive comments. in response to rq2a, we found that in the dimension of "self-discourse", "disclosure of personal life" had positive effects on the number of user shares and likes, while "disclosure of personal expertise in pediatrics" is positively associated with number of shares. for every extra sentence in "disclosure of personal life" and "disclosure of personal expertise in pediatrics", 1.23 (p = 0.003) and 1.13 (p = 0.005) times more shares were generated. for every extra sentence in "disclosure of personal life", 1.26 times (p = 0.0003) more likes were expected. however, the "disclosure of personal thoughts and feelings" was negatively associated with the number of comments. for every extra sentence in "disclosure of personal thoughts and feelings", 0.89 times (p = 0.033) fewer comments were expected (see table 5 ). regarding the sub-dimensions in "genuine response" (rq2b), our findings revealed that "consistency" had positive effect on the total number of likes, comments, and positive comments. 1.402 times more likes (p = 0.0003), 1.581 times more comments (p < 0.0001) and 1.347 times more positive comments (p = 0.001) were witnessed for every extra sentence on "consistency" provided. similarly, the sub-dimension of "knowledge, skill, experience and treatment advice" was positively associated with the number of comments and positive comments. for each extra sentence on "knowledge, skill, experience and treatment advice", 1.342 times more comments (p < 0.0001) and 1.166 times more positive comments (p = 0.013) were yielded. however, the sub-dimension of "facilitation of hopefulness" was negatively associated with the number of likes and shares. for every extra sentence on "facilitation of hopefulness", 0.55 times fewer shares (p = 0.001) and 0.742 times fewer likes (p = 0.023) were generated, as presented in table 5 . for the dimension of "functional interactivity" (rq2c), the "generation of return visits and conservation of visitors" had positive effects on the total number of shares and likes, whereas "dialogic loop" had a negative association with the number of comments and positive comments. p < 0.05 *, p < 0.01 **, p < 0.001 ***, p < 0.0001 ****. table 5 . negative binomial regression results on the sub-dimensions of "self-disclosure", "genuine response", "functional interactivity", "genuineness in chinese culture" and the number of shares, likes, comments and positive comments. p < 0.05 *, p < 0.01 **, p < 0.001 ***, p < 0.0001 ****. for every additional "conservation of visitors and the generation of return visits" included, the shares and likes increased by 43% (p = 0.001) and 22% (p = 0.018) respectively while comments and positive comments decreased by 84% (p = 0.005) and 88% (p = 0.015) for every extra feature of "dialogic loop" provided, as shown in table 5 . last but not least, "honesty" in the dimension of "genuineness in chinese culture" (rq2d) had a positive association with the number of shares, likes, and positive comments in contrast to kindness, which showed no significant association. for every extra lexical indicator on "honesty", 1.158 times more shares (p = 0.001), 1.106 times more likes (p = 0.0004), and 1.07 times more positive comments (p = 0.007) were generated, as presented in table 5 . our results revealed that a variety of genuineness dimensions was employed by the smip to communicate with the public on social media. the findings yielded insights into how the "genuine response" alongside "functional interactivity" and "genuineness in chinese culture" played an active role in engaging the public. corroborated with previous studies [33, 36, 83] , our findings revealed that responses with high level of consistency and expert knowledge were positively associated with public engagement (table 5) . a doctor responded by acknowledging the public's need helps develop a trustful relationship [84] , even in online doctor-public communication. furthermore, response with medical knowledge and treatment advice indicates the doctor's understanding of patient's concerns and his/her intention to address the issues [85] . this could be the reasons attributing to the positive association between "genuine response" and the number of likes and comments, especially the positive comments. "genuine response" that aimed to address patients' concerns created more opportunities for the public to express feelings (e.g., grateful, satisfied) in the comment threads, and allowed them to continually ask questions if their concerns were not fully addressed. the phrases "thanks, doctor," "beneficial advice," "learn a lot," "really appreciate your patient guidance" and "what i need to do in the next step" were frequently unveiled under the comment threads. in line with previous studies [37, 40, 42, 57] , our results also revealed the strong effect of "functional interactivity" on public shares (tables 4 and 5) . we found a range of interactive features, in the form of links/hashtags, such as "#simp name+topic#", "@+other online users name" and "link to other weibo pages", employed on the smip posts which foster the public's access to various and detailed information. hashtags lead users to daily hot topics where users can make synchronous conversations, discuss relevant issues with others, and share insightful ideas [57] . links enable users to return the site and increase the time of stay when reading messages [42] . owing to word limit on weibo, the smip messages may not explain the ins and outs of a health problem thoroughly. the offering of external links expands messages in greater detail and strengthens the usefulness of corresponding posts, thereby fostering information sharing. given that the act of sharing can potentially reach out to a large audience, online doctors can adopt interactive elements to express genuineness and extend their influences. noticeably, the sub-dimension "honesty" positively engendered public engagement of likes, shares and positive comments ( table 5 ). the expressions in honesty mainly involve verbs and adverbs related to explanation, personal views, and facts, such as "for instance," "include," "i think," "i suggest," "according to," and "the document shows." tuckett [86] specified that "honesty" is "perceived as truth-telling" (p. 500), and the extent to which truth-telling is preferred is highly related to culture and context. as noted in previous study [86] , "honesty" is a fundamentally ethical principle in doctor-patient relationships. the majority of patients in china demonstrate that they want truthfulness and authenticity about their illness, which could enable them to manage uncertainty and make decisions independently [50] . this might also explain the negative association between sub-dimension of "facilitation of hopefulness" in the "genuine response" and shares and likes. to some extent, expression of hopefulness is intended to comfort patients instead of telling the whole truth [33, 36] , and the truthfulness of such expressions often arises suspicion. also, the shared post represents the user [62] . a previous study [87] found that online self-presentation was a crucial part of impression management, in which the public carefully evaluated someone by how he presented himself. this suggests that sharing requires more cognitive effort [64] . given that "honesty is the traditional morality of chinese nationalities and is regarded as the basis of the making of a man" ( [88] , p. 177), it is not surprising to see the public's willingness in sharing "honest" so as to promote positive personality traits on social media. despite previous studies suggested doctor's "self-disclosure" may have a positive impact on patients' reactions and foster a stronger therapeutic relationship, our results reveal that "self-disclosure" has no significant association with any level of public engagement (table 4 ). beach et al. [89] argued that doctors' personal disclosure to patients have sometimes been regarded as a boundary transgression. doctors should be more careful about disclosing personal information [86] . "self-disclosure" has been viewed as a positive intervention in doctor-patient communication but it could also hinder effective communication and lead to negativity [90] . kelly and achter [91] found that patients concerned the helpfulness and benefits of the disclosure information from doctors for their decision on engagement. if they think the information would be useful for their situations, they are willing to further interact with doctors and listen to their suggestions [92] . however, given that "self-disclosure" messages in this study mainly involve personal life, opinions, and feelings that may not be relevant to the public's concerns and problems, a lower level of public engagement is expected. forest and wood [90] commented that it is not surprising that people may disapprove or doubt the information provided by therapists who share personal opinions and experience frequently. likewise, disclosure of personal expertise may involve the discouraging expressions [92] , which makes the public feel sad and stressful. in addition, mcdaniel et al. [93] found that the frequent statements about the doctor's personal life (e.g., family, habit) and professional information are, occasionally, of little value to impair the doctor-patient relationship because they may result in fewer opportunities for patients to express themselves. general information is prevalent in smip's posts on weibo as each post is limited to 140 words, but there are a variety of followers with different needs. in other words, the posts cannot meet everyone's demands even though smip want to provide detailed information. therefore, the public may not react to some information that is not tailored to their problems. academically, this study contributes to the research of health communication in the following aspects: (1) developed an integrated framework to conceptualize and measure genuineness in social media communication and (2) shed lights in the understanding of effect of genuineness on chinese public engagement in smip online communication. in terms of practical implications, this study provides insights to health information providers such as pediatricians in engaging public on social media communication. for instance, the use of "genuine response" could raise public awareness which in turn facilitates the fostering of a healthy lifestyle. this study also has strong social implications. in recent years, the chinese government has placed public health at the center of the country's entire policy-making agenda and initiated a national long-term strategic public health plan. one of the missions is to improve the well-being of citizens coding items examples genuine response 1. consistency rephrase public's question and concern no 1: mar.10, 06:00 user one: 你好医生, 宝宝9个月，能逗笑，会发妈妈的音，能抓玩具，能扶着腋窝 站立，不能独坐超过7.8秒，要东倒西歪的，趴几秒也要哭就把两只手放两边，请 问这种情况做康复能好吗？ literal translation: hello doctor, my baby is 9 months old. he can laugh, make the voice of "mommy", grasp toys, and stand by armpit, but can not sit alone for more than 7 or 8 seconds. he often comes to cry for a few seconds when he is prostrating. i wonder whether he would recover from this situation? pediatrician: "9个月，能逗笑，会发妈妈音，能抓玩具，能扶着腋窝站立，不能独 坐超过7.8秒，趴几秒也要哭就把两只手放两边。"据叙述，大运动发育落后。"能 扶着腋窝站立"这一定是家长扶着孩子站，不利于大运动发育，反而会有消极作 用。建议看神经康复科医生，是发育问题，还是家长养育问题。 literal translation: "nine months, can make you laugh, can make your mother's voice, can grasp toys, can stand by your armpit, cannot sit alone for more than 7 or 8 seconds, can cry even if you lie down for a few seconds." according to your illustration, it could be said that the development of large motor skills is backward. "can support the armpit to stand" indicates parents was helping the child to stand, which is not conducive to the development of large motor skills and will have a negative effect. i suggest you should consult a neurologist to see if it is a developmental or a parenting problem. provide treatment advice to address public's concern no 2: may.9, 23:11 user one: 您好 吖一岁15天 不吃奶瓶已经十天了 只吃亲喂 奶量肯定不够 什么缘 故？怎么办呢？ literal translation: hello, my son is one year and 15 days old and has not fed by bottle for 10 days. i think the amount of breast-feeding may not be enough. what is the reason and what shall i do? pediatrician: 可以杯子喂奶 同时试试奶酪和酸奶。 literal translation: you can try to feed him by a cup. at the same time, feed him with some cheeses and yogurt. literal translation: as long as the mother has no discomfort after perming and dyeing her hair, she would not affect her children through breastfeeding. just keep in mind that do not let the child lick his/her mother's hair. everyone has a desire for beauty. after giving birth to the baby, most mothers want to recover their body shape and bright skin as soon as possible. thus, hair dyeing, perm, fingernail dyeing can be carried out. mothers will take care of themselves. literal translation: my son has 2 teeth within 8 months. when he was one year and 3 months old, he only had 8 teeth; at present, he is one and a half years old but only with 4 teeth growing. we eat the food, e.g., cod liver oil filled with calcium everyday, so what is wrong? pediatrician: 只要有牙齿出就说明牙齿发育没有问题，耐心等待即可。放轻松。 literal translation: as long as you can see teeth out and growing, there is no problem with tooth development. just be patient and relax. link to the pediatrician's clinic/organization/own weibo page no.3: mar.31, 12:05 哺乳期妈妈生病就要扛吗？还可以喂奶吗？很多妈妈在哺乳期的时候，十分谨慎， 生怕自己生病后不能哺乳，从而影响宝宝生长。有的则是因为家里老人怪自己生 病，怕传染给孩子。这个问题，点击"《我的诊室》"了解更多，网页链接 literal translation: is it necessary for lactation mothers to endure illness with silence? can they still provide breastfeeding? many mothers fear that they may not be able to breastfeed when they are ill in case of affecting the growth of their babies. some concern that the child's grandparents will blame them for being sick and infecting their children. for this concern, click "my clinic" to learn more link to other social networks in which the pediatrician is present no.1: apr.21, 06:22 孩子出现喂养不适很可能与疫苗有关，但不应该是大问题。如果孩子没有新的不 适，家长耐心等待，1-2周会自然恢复。还要关注排便情况。#崔玉涛讲疫苗#。 literal translation: feeding discomfort in children is likely to be related to vaccines, but it is not a big problem. if the child has not emerged new discomfort, the parents need to wait patiently. the child will recover naturally in 1-2 weeks. also, you should pay attention to defecation. #cui yutao talks about vaccines#. healthy china 2030 (from vision to action) outline of healthy china china cdc's chief expert of maternal and child health guizhou province# <the first story of my experience with dongzhai children >, all the things we are insisting on are worthwhile healthy china 2030 (from vision to action) outline of healthy china china cdc's chief expert of maternal and child health weibo monthly active users reach 516 million and barriers to entry remain solid how the public uses social media wechat to obtain health information in china: a survey study a new dimension of health care: systematic review of the uses, benefits, and limitations of social media for health communication china health science popularization alliance officially established the impact of social media influencers on purchase intention and the mediation effect of customer attitude opinion leadership in a computer-mediated environment the network effect on information dissemination on social network sites exploring factors influencing chinese user's perceived credibility of health and safety information on weibo functional interactivity in social media: an examination of chinese health care organizations' microblog profiles social support on weibo for people living with hiv/aids in china: a quantitative content analysis. chin smoking prevention in china: a content analysis of an anti-smoking social media campaign when health information meets social media: exploring virality on sina weibo characterizing depression issues on sina weibo attention, attitude, and behavior: second-level agenda-setting effects as a mediator of media use and political participation let the talk count: attributes of stakeholder engagement, trust, perceive environmental protection and csr. sage open customer agility and responsiveness through big data analytics for public value creation: a case study of houston 311 on-demand services citizen participation, community resilience and crisis-management policy conceptual considerations regarding self-disclosure: a relational psychoanalytic perspective psychotherapy integration: setting the context the significance of therapist genuineness from the client's perspective therapist nonverbal behavior and perceptions of empathy, alliance, and treatment credibility perceived therapist genuineness predicts therapeutic alliance in cognitive behavioral therapy for psychosis therapeutic limit setting in the play therapy relationship the skilled helper: a problem-management approach interpersonal skills in nursing child-centered play therapy: a practical guide to developing therapeutic relationships with children the gift of therapy: reflections on being a therapist is psychotherapy more effective when therapists disclose information about themselves? physician disclosure of healthy personal behaviors improves credibility and ability to motivate comforting: exploring the work of cancer nurses good communication in psychiatry-a conceptual review nurses' perceptions of facilitating genuineness in a nurse patient relationship how activist organizations are using the internet to build relationships understanding interactivity of cyberspace advertising designing interactivity in media interfaces: a communications perspective social impact in social media: a new method to evaluate the social impact of research a study on dialogic communication, trust, and distrust: testing a scale for measuring organization-public dialogic communication (opdc) building dialogic relationships through the world wide web advocate traditional concept of honesty cultivate modern honesty spirit the factor structure of chinese personality terms a. i am, ergo i shop: does store image congruity explain shopping behaviour of chinese consumers? creative education: explanation of cultural philosophy-on cultural characteristics of creative education in primary school. theory pract on honesty of confucius and its modern sense measuring the personality of chinese: qzps versus neo pi-r the role of character strengths for task performance, job dedication, interpersonal facilitation, and organizational support the personality profile of excellent nurses in china: the 16pf chinese personality; structure and measurement processes and preliminary results in the construction of the chinese personality scale (qzps) grappling with the covid-19 health crisis: content analysis of communication strategies and their effects on public engagement on social media public engagement as a means of restoring public trust in science-hitting the notes, but missing the music? 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implications for meta-analyses a model of empathic communication in the medical interview development of the trust in physician scale: a measure to assess interpersonal trust in patient-physician relationships how does physician advice influence patient behavior? evidence for a priming effect truth-telling in clinical practice and the arguments for and against: a review of the literature strategic self-presentation online: a cross-cultural study historical origin of the morality of "honesty" and "honesty" education for college students what do physicians tell patients about themselves? a qualitative analysis of physician self-disclosure when social networking is not working: individuals with low self-esteem recognize but do not reap the benefits of self-disclosure on facebook self-concealment and attitudes toward counseling in university students to seek help or not to seek help: the risks of self-disclosure physician self-disclosure in primary care visits: enough about you, what about me? this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license exemplification of four genuineness dimensions and relevant expression identified in the corpus.coding items examples self-disclosure 1. disclosure of personal life no. 7: may.12, 20:36 上午带小七一起去仙林金鹰广场观看全民营养周启动仪式，仪式活动很棒，小七表 现也很棒，天很热，小七全程很认真地看完。午餐时饿了，吃哈密瓜，鸡翅，意大 利面，还吃了半块含有牛奶和鸡蛋甜点，本来知道她会过敏，不给她吃，抢着要 吃，不过吃了没有出现明显过敏症状。 literal translation: in the morning, i took xiaoqi to xianlin golden eagle square to watch the launching ceremony of national nutrition week. the ceremony was great. xiaoqi performed well. it was scorching, but xiaoqi watched the whole process carefully. i ate cantaloupe, chicken wings, spaghetti, and half of the dessert at lunch. i knew that she would be allergic, so i did not give the food to her. however, she insisted on eating them, and i had not found any obvious allergic symptoms with her after eating. literal translation: experts research shows that from the perspective of health economics, the early childhood investment is the highest ratio of human capital input to output in the whole life cycle. the early return on investment is more than 1:7, so the development of early childhood potential not only determines the development potential of individuals but also profoundly affects the competitiveness of our country's human resources. literal translation: good question! first of all, we should ensure the intake of vegetables for the kids. vegetables contain vitamin k, which is produced by healthy intestinal flora. eating green leafy vegetables has many advantages for both children and adults. there is a mixture of vitamin d3 and vitamin k2 for now. key: cord-030821-kr9i33dy authors: yan, fei title: managing ‘digital china’ during the covid-19 pandemic: nationalist stimulation and its backlash date: 2020-08-25 journal: postdigit sci educ doi: 10.1007/s42438-020-00181-w sha: doc_id: 30821 cord_uid: kr9i33dy nan understanding the management and control of digital information is imperative in modern politics, particularly in authoritarian countries like china where the state keeps a very careful eye out for any information it deems challenging to its legitimacy. as the coronavirus has spread all over the world, china has become the focus of international criticism for its lack of transparency in dealing with its emergence in early stages (patten 2020) . the chinese people have also questioned their government, yet it is less known how the government's handling of the coronavirus is viewed and evaluated domestically. chinese traditional media such as newspapers are closely controlled and monitored by the government, so the internet and social media have become the major arenas of criticism. before the pandemic, china's internet was already one of the most heavily policed in the world. in order to keep ahead of public opinion, the chinese government has closely 'monitored, guided, censored, and often directly engineered the information that circulates through china's networks' (schneider 2018: 10) . in 2011, china established the office of cyberspace administration of china dedicated to managing the country's digital space. 1 the chinese government has come to see the digital world as just another part of its sovereign 'territory,' which needs to be managed and controlled. then, how has the chinese government responded to the voice of the people and what strategies has it adopted in order to deal with the challenges it perceives arising from the digital world? this article examines some of the most hotly debated issues on the chinese internet and social media during the covid-19 pandemic. analysis shows that the chinese communist state has updated itself with a 'marriage' between digital technologies and nationalist ideologies, thus gaining the ability to reshape important narratives on the internet and social media while also having to confront the inevitable backlash from this manipulation. the coronavirus had begun to spread through china by december 2019 at the very latest. however, most chinese people were unaware of the growing threat until 20 january when the well-known doctor zhong nanshan issued a tv warning of how easily this new virus could be transmitted from person to person. (zhong had become celebrated in 2003 for his similar warning about the risk of sars.) three days after zhong's tv appearance, the government in wuhan, where the virus was first detected, announced the lockdown of the city. this decision came as a shock to many chinese, and while they started to take the issue more seriously, dissatisfaction and anger also proliferated on social media. people criticized the government for lacking transparency and for delaying an official warning. they were especially furious about the fact that the government in wuhan did not report any new cases of infection between 6 and 17 january when the city was hosting important political events (daily mail 2020). this rising anger among the chinese populace came to a head on 7 february when the 'whistleblower' dr. li wenliang, an ophthalmologist at a hospital near the wuhan seafood market, died of the virus after becoming infected at work. great numbers of chinese people paid tribute to him on social media. the famous lines of 'no man is an island' by the english metaphysical poet john donne was widely shared on the internet in reference to dr. li, who had become a national hero and a symbol of people's anger over the authorities' initial response to the emergence of the virus (donne 2019). 2 arguably this could have been a moment of hope, a catalyst for change. it was even claimed that dr. li's death posed the 'greatest threat' to the chinese ruling regime (kate and martin 2020) . chinese authorities quickly responded to the clear expression of public anger about the fate of dr. li, announcing on the very day of his death that there would be an official police investigation. subsequently, dr. li was officially declared a 'martyr.' meanwhile, information and theories perceived as critical of the government started to disappear from chinese social media. from this point, the chinese government seemed determined to control any narrative which could be perceived as threatening its authoritarian grip on the country (pendlebury and naish 2020). new governmentpromoted narratives invoked nationalist ideologies. one clear target of this propaganda was so-called overseas anti-china powers, who had allegedly used the case of dr. li to blame china for covering up the virus (global times 2020). the new government narratives resonated easily with the chinese people, who had long been subjected to political indoctrination through the state-controlled media and schooling system. scholars of chinese nationalism and political education point out that in the post-mao era, and particularly after the tiananmen square protest, patriotism had become the ideological cornerstone in chinese 'thought work,' replacing socialism (he and guo 2000; hughes 2006; vickers 2009; zhao 2004) . this involved highlighting the 'one hundred years of humiliation' that china had suffered at the hands of the western imperialist powers since the time of the opium wars (1840) and the resulting collective sense of 'victimhood' from that humiliation (mitter 2003) . when china ended up under increasing pressure from the international community because of its mishandling of the virus, the government sought to stimulate nationalist sentiment and chose to re-interpret criticisms from other countries as a new form of imperialism. as a result, any criticism by the chinese people of their own government over the handling of the pandemic is regarded as 'handing over knives' to enemies and hence becomes 'unpatriotic' (davidson 2020) . the effect of this strategy soon appeared in another major internet-fueled controversy-fang fang's wuhan diary. fang is a wuhan-based novelist who started to sympathetically document the difficulties of the city's inhabitants under the sudden lockdown. in spite of constant official censorship, millions followed her account online as she revealed her mounting frustration with the officials. fang's online diaries presented an unwelcome challenge to the state narrative, which by this time was concentrated on promoting the triumphs of the chinese government in winning the war against the virus and contrasting its success with its 'failing' western counterparts who were presented as struggling ineffectually to combat the spread of the pandemic. an internet propaganda campaign was duly mounted, with the clear aim of vilifying and demonizing fang. she was denounced by an online army of ultra-nationalists for 'betraying the motherland' (davidson 2020) , particularly when her diaries were published in english under the title wuhan diary: dispatches from a quarantined city (fang 2020) . many ordinary people were persuaded that fang was indeed a traitor. fang and her english translator were the subject of death threats (ehret 2020; feng 2020) . academics who had supported fang on social media were abused and subsequently placed under official investigation for 'making inappropriate remarks' about china (shepherd 2020) . at the time of writing, one of these academics (liang yanping) had been banned from teaching by her university (zhuang 2020) . while ideological tools such as nationalism are indeed very useful in manipulating online discourse, it appears that chinese officials have possibly underestimated its unexpected negative consequences. this state-sponsored 'reprogramming' has seemingly instilled in people an ill-thought-out ideology based on fear and ultra-patriotism which 'creates all manner of domestic and international contradictions' (schneider 2018: 229) . for instance, chinese students studying abroad were refused permission to re-enter china after their places of study had become epicenters of the virus. in the early days of the pandemic, many of these students had previously done their very best to help their native country by gathering and posting masks and other protective equipment back home. rather than expressing sympathy for these students, many people on the chinese internet blamed them for exposing china to the risk of a second wave of the virus, and some were hostile to their choice of studying abroad as they believed this demonstrated a future intent to betray china (li 2020 ). this issue caused huge public controversy and great distress to the students themselves-followed by an enormous amount of confusion for students and their families, who had believed the nationalist propaganda that 'your motherland will always be there to protect you when you are in danger overseas' (stevenson and may 2020) . 3 ironically, many chinese students studying overseas are in fact hyperpatriotic in defending their country abroad (he 2015) . yet incidents such as this, fueled by the accusatory propaganda on social media, may just be prompting them to reflect upon their previous assumptions, rethink their identity as patriotic citizens, and reexamine their relationship with the chinese state which seemed to have turned its back on them in the time of need. a further issue has been the unfortunate association of chinese nationalism with the racial aspect of chinese identity (dikötter 1992) . chinese officials often claim that racism is a western phenomenon, yet racial discrimination against other ethnic groups, and black people in particular, has been exacerbated during the covid-19 pandemic (hrw 2020). chinese people have come to fear that african immigrants could be spreading the virus, and there is evidence that black people in china have been treated in a most unpleasant and discriminatory manner. for example, social media videos showed some black people in guangzhou (which has a sizeable african population) being expelled from their residences, and others 'who appear to be of african origin' were banned from entering restaurants such as mcdonalds (deabler 2020) . damning accusatory rumors circulated on social media such as '300,000 black people in guangzhou are setting off a second epidemic' along with comments like 'the blacks are an inferior race,' 'use the opportunity of the epidemic to kick the blacks out,' and 'do not let them stain the chinese race' (deabler 2020) . consequently, tensions between native chinese and african immigrants in guangzhou have naturally became inflamed. and there are further unfortunate consequences. when the unfair treatment of african immigrants and the use of racist language were reported back to their countries of origin, there was an inevitable fierce backlash against chinese officials (burke et al. 2020 ). on the other hand, when chinese citizens saw social media videos showing chinese officials being blamed by diplomats of african countries (who are china's important strategic partners of the belt and road initiatives) (hrw 2020), some chinese citizens, infected with nationalist propaganda, blamed their government for being 'too soft on foreigners' and reducing its own people to 'second-class citizens.' in this and other ways, identity games with ill-conceived concepts of racism under the umbrella of nationalism have backfired on the chinese government. while the internet and social media have provided the chinese people with the means to express and exchange their ideas more easily, these technological opportunities have not promoted a 'habermasian public sphere' which could facilitate china's transition to a liberal, democratic system of government (schneider 2018: 11) . instead, the chinese government has taken their overarching model of media management and has creatively extended it to its digital world (schneider 2018: 24) . the chinese state has used up-to-date digital technology to control the content of its internet output by managing narratives which promote its political agenda. by being the most powerful player in china's digital world, the ruling regime has managed to simultaneously deploy 'hard' power (censorship) and 'soft' power (reshaping public opinion by promulgating ideologies such as nationalism) to manage and control 'digital china.' the chinese state is employing its digital skillset to control its citizens, rather than the other way around. china fails to stop racism against africans over covid-19. the guardian the coronavirus facts china wants the world to forget: beijing releases a covid-19 timeline -but fails to include whistle-blowers, huanan food market and 'the order to destroy all samples'. daily mail chinese writer faces online backlash over wuhan lockdown diary. guardian mcdonald's in china apologizes for notice banning black customers from entering restaurant. fox news the discourse of race in modern china devotions upon emergent occasions: together with death's dual. chalemette: parables chinese writer fang fang faces backlash and death threats for 'wuhan diary wuhan diary: dispatches from a quarantined city wuhan diary' brings account of china's coronavirus outbreak to english speakers taking li's death as a tool to stir up anti-govt sentiment on chinese social media is part of overseas separatists' customary tactics, as they used in #hk protest. such move is obnoxious and childish identifying with a "rising china"? overseas chinese student nationalism nationalism, national identity and democratization in china china: covid-19 discrimination against africans. human rights watch chinese nationalism in the global era the death of a doctor poses the greatest threat to china's xi yet. bloomberg trapped abroad, china's 'little pinks' rethink their country. the new york times old ghosts, new memories: china's changing war history in the era of post-mao politics china's nasty, lying, bullying communist regime must face the judgment of the world over the coronavirus pandemic". daily mail china's deadly legacy: the coronavirus cover-up was one of the most grotesque deceptions by a totalitarian government ever -now beijing will use the pandemic it sparked to help achieve its goal as no1 world superpower. daily mail china's digital nationalism fang fang's 'wuhan diary' sparks tussle over virus narrative. financial times, 15 may coronavirus strands china's students, in a dilemma for beijing the opportunity of china? education, patriotic values and the chinese state a nation-state by construction: dynamics of modern chinese nationalism chinese professor banned from teaching over hong kong protest comments, south china morning post key: cord-252531-i3b647wv authors: song, zaiwei; hu, yang; zheng, siqian; yang, li; zhao, rongsheng title: hospital pharmacists’ pharmaceutical care for hospitalized patients with covid-19: recommendations and guidance from clinical experience date: 2020-04-03 journal: res social adm pharm doi: 10.1016/j.sapharm.2020.03.027 sha: doc_id: 252531 cord_uid: i3b647wv abstract objective to discuss hospital pharmacists’ role in providing pharmaceutical care for hospitalized patients with covid-19 to promote patient care and management during the pandemic. method based on the method of evidence-based pharmacy, clinical evidence of therapeutical drugs for covid-19 were retrieved and summarized. based on clinical experience chinese hospital pharmacists gained from providing pharmaceutical care services during covid-19 pandemic, taking covid-19 hospitalized patients’ needs into consideration, the methods and strategies hospital pharmacists shall use to provide pharmaceutical care were analyzed and summarized. results hospital pharmacists shall support pharmaceutical care services by participating in making evidence-based decisions for medication, monitoring and evaluation of medication safety and efficacy, providing strengthened care for special population and patients with combined underlying diseases, monitoring and management of convalescent plasma therapy, providing emotional counselling and psychological support, and providing scientific information about covid-19 vaccines. conclusion the need of pharmaceutical care services in covid-19 hospitalized patients during this pandemic was quite distinguished from the past. hospital pharmacists shall join the collaborative multidisciplinary team to improve covid-19 patients’ outcome and reduce mortality, and to facilitate the pandemic control. in december 2019, the coronavirus disease 2019 (covid-19) epidemic caused by the novel coronavirus (sars-cov-2) first emerged in wuhan, followed by a worldwide outbreak in many countries and regions in succession. on march 12, 2020, the world health organization (who) declared covid-19 epidemic a "pandemic" worldwide. 1 according to the latest updates from who (march 30), 693224 cases have been confirmed with covid-19 in total worldwide, causing 33106 deaths. who has increased the risk assessment of covid-19 to very high at global level. 2 currently, the covid-19 pandemic is posing a major challenge to global public health, and seriously endangering the economy and the society. as the forefront of the outbreak, china formulated and launched a series of emergency plans and supports in response to the covid-19 pandemic in the first place. effective measures have been taken to control the pandemic in a timely manner. according to the principle of "centralizing patients, centralizing experts, centralizing resources, and centralized treatment", all confirmed cases of covid-19 have been admitted into designated hospitals for standardized inpatient treatment, 3 which has greatly improved patients' outcomes, reduced mortality, and effectively contained further spread of the pandemic. on march 19, china reported no domestic new case for the first time, and the first prevail peak period of the pandemic was over, which was highly spoken as "an amazing achievement" by who. clinical treatment and management of covid-19 hospitalized patients is constituting a prominent challenge worldwide. some patients may quickly progress to severe or critical cases, with acute respiratory distress syndrome (ards), sepsis and multiple organ dysfunction, particular in patients with complicated underlying diseases (diabetes, cardiovascular disease, malignancy, etc.). 4, 5 therefore, personalized, collaborative and multidisciplinary management is of great significance to improve patients' outcomes. with the pandemic getting increasingly serious, chinese solution of "centralizing covid-19 patients and centralized inpatient treatment" provides certain reference for other countries to control the pandemic. according to international pharmaceutical federation (fip) guidance for pharmacists, 6 as a member of the healthcare professionals, it's one of the most essential responsibilities for hospital pharmacists to join the medical collaborative team and provide pharmaceutical care services to covid-19 patients. for covid-19 patients receiving centralized hospitalized treatment, pharmaceutical care services are https://doi.org/10.1016/j.sapharm.2020.03.027 received 31 march 2020; accepted 31 march 2020 indispensable supplement for clinical treatment and management, which is of great significance for improving the level of drug therapy, improving patient's outcome and promoting the overall pandemic control. detailed and feasible suggestions on clinical diagnosis and treatment were provided in clinical management guidance from national health committee (nhc) of china, who, and centers for disease control and prevention (cdc) of the united states. [7] [8] [9] however, it's worth mentioning that, most of the available guidance did not revolve detailed suggestions on therapeutic drugs or pharmaceutical care services. currently, community pharmacists can provide strengthened pharmaceutical care and public health services following feasible instructions. 10, 11 however, for hospital pharmacists, recommendations and guidance on providing covid-19 hospitalized patients with pharmaceutical care is still lacking, and need to be established urgently. based on the chinese perspective of "centralizing covid-19 patients and centralized inpatient treatment", the purpose of the paper is to establish an integrated strategy for pharmaceutical care services, which focus on covid-19 hospitalized patients and hospital pharmacists. finally, it aims to provide guidance for hospital pharmacists to participate in the multidisciplinary team to improve covid-19 patients' outcome and reduce mortality, and to facilitate the pandemic control. after the diagnosis of covid-19 infection, patients need to be admitted to designated hospitals for centralized and standardized inpatient treatment. currently, no specific drug has been confirmed to treat covid-19, and drugs of pre-approval access are still in ongoing clinical trials. the safety and efficacy of these medications remains unclear, and some drugs (such as lopinavir-ritonavir and arbidol) may cause serious adverse reactions. therefore, hospital pharmacists should actively participate in making evidence-based decisions for medications, and assist clinicians in formulating and adjusting drug regimens of covid-19 patients. meanwhile, hospital pharmacists should provide close monitoring and evaluation of medication safety and efficacy, management of drug interactions, and monitoring and management of convalescent plasma therapy. based on the characteristics of special populations and patients with underlying diseases, pharmacists should provide strengthened pharmaceutical care services. in addition, the emotional status of covid-19 patients is also an important factor affecting the treatment and prognosis of the disease. it's necessary for hospital pharmacists to provide covid-19 patients with emotional counselling and psychological support. given the importance and urgency of covid-19 vaccine development for the control of global pandemic, hospital pharmacists should also provide vaccine-related scientific information to patients. to this end, the pharmaceutical care framework of covid-19 hospitalized patients for hospital pharmacists was researched and constructed (see fig. 1 for details) to help promote the pandemic control and patient management. currently, most of the covid-19 therapeutic drugs are in ongoing clinical trials and remain pre-approval access. combining the available evidence, clinical experience and patients' individual characteristics, providing patients with evidence-based treatment and care is of great significance. as a member of healthcare professionals, hospital pharmacists should give full play to the specialty of pharmacy, and fully combine clinical guidance and clinical research to assist clinicians in formulating and adjusting the medication regimens for hospitalized patients with covid-19. based on the method of evidence-based pharmacy, pubmed, embase, cochrane library and chinese database were retrieved systematically on march 25, and clinical guidance from chinese, american, who authorties were searched manually. advances in therapeutical drugs for covid-19 were analyzed and evaluated, and were summarized in table 1 . in addition, the american sosiety of health-system pharmacist (ashp) provided an evidence table for covid-19-related treatment to help practitioners better understand current treatment options. 12 based on these available evidence, hospital pharmacists should help to formulate medication regimens for hospitalized patients with covid-19 after fully balacing clinical benefits and the risk of medications. antiviral drugs recommended by the latest chinese guidance 7 include interferon-α, lopinavir-ritonavir, arbidol, chloroquine phosphate and ribavirin. and favipiravir is recommended to be included in chinese guidance. 13 regarding to clinical researches, currently, the results of lopinavir-ritonavir, arbidol and hydroxychloroquine sulfate on covid-19 treatment have been reported in 6 studies. [14] [15] [16] [17] [18] [19] [20] [21] for lopinavir-ritonavir: a randomized, controlled, open-label trial 14 suggested, for patients with severe covid-19, lopinavir-ritonavir treatment beyond standard care did not significantly accelerate clinical improvement or reduce mortality (p > 0.05). for patients with different clinical classifications, a retrospective study 15 found that lopinavir-ritonavir combined with other antiviral drugs can shorten the time of viral nucleic acid turning negative and improve the results of lung ct imaging (p < 0.05), but the effect on clinical improvement was not significant (p > 0.05). for arbidol: a multicenter, prospective study 16 reported, compared with dual combination of lopinavir-ritonavir and interferon-α-2b, triple combination of arbidol can shorten the time of viral nucleic acid turning negative and hospitalization time (p < 0.05). in addition, a retrospective study 17 showed no significant difference of the time of viral nucleic acid turning negative among arbidol treatment, lopinavirritonavir treatment and control group (p > 0.05). for hydroxychloroquine sulfate: an open-label, non-randomized clinical trial 18 suggested, compared with the rate of viral nucleic acid turning negative of control group (12.5%), combination of hydroxychloroquine sulfate and azithromycin (100%) and monotherapy of hydroxychloroquine sulfate (57.1%) significantly improved the rate of viral nucleic acid turning negative (p < 0.001). the effect of hydroxychloroquine sulfate is reinforced by azithromycin. and such combination may both act as an antiviral therapy against sars-cov-2 and prevent bacterial super-infections. however, a prospective study 19 showed that, for patients with moderate covid-19, the effect on the rate and the time of viral nucleic acid turning negative were not significant. in addition, remdesivir, favipiravir, ribavirin, chloroquine phosphate and other antiviral drugs are still in ongoing clinical research, and the results remain unpublished. it's worth mentioning that, although clinical evidence is lacking, fda issued an emergency use authorization (eua) for emergency use of oral formulations of chloroquine phosphate and hydroxychloroquine sulfate for the treatment of covid-19. 20 hospital pharmacists should combine the available evidence, fully evaluate patients' own conditions, and use antiviral drugs rationally. according to who guidance, 8 systemic corticosteroids are not recommended to be routinely used for treatment of viral pneumonia outside of clinical trials. cdc guidance 9 recommended that corticosteroids should be avoided unless indicated for special reasons. according to guidance from fip, 6 nhc of china 7 and chinese pharmaceutical association(cpa), 13 for patients with progressive worsening of oxygenation indicators and rapid progress in imaging, corticosteroids can be used conditionally in a short period of time. a retrospective study 21 showed that for covid-19 patients with different clinincal classification, low-to-moderate corticosteroids have no significant difference in the time of virus clearance. for moderate cases, low-tomoderate corticosteroids have no significant difference in the time of improvement of lung imaging. therefore, before taking corticosteroids into account, pharmacists should fully evaluate the patients' individual conditions, and carefully balance clinical benefits and the medicaiton risk. according to who guidance, 8 empiric antimicrobials should be used to treat all likely pathogens causing sari and sepsis as soon as possible. chinese guidance 7 recommended that blind or inappropriate use of antibiotics should be avoided, especially the broad-spectrum antibiotics. cpa guidance 13 recommended that inappropriate use of antibiotics should be avoided. etiological tests should be taken if necessary, and antibiotics should be selected carefully based on patients' individual conditions and risk. therefore, pharamcists should actively attend anti-infection consultations and formulate rational antimicrobial medication regimens for covid-19 patients, combing available evidence and patients' conditions. in addition to current antiviral drugs recommended by the latest chinese guidance, 7 tocilizumab is recommended for severe patients with extensive lung disease and elevated il-6 levels. for severe patients with rapid disease progression and excessive activation of inflammatory response, short-term corticosteroids could be considered to use at early stage. some therapeutic drugs may cause serious adverse reactions, including hemolytic anemia, cardiotoxicity, infection, femoral head necrosis, and teratogenic effects. therefore, pharmacists should cooperate with clinicians to formulate medication regimens to avoid inappropriate high-dose medications or multi-drug combinations. besides, pharmacists should closely monitor the safety of drugs, identify adverse drug events early and adjust the medication regimens timely when attending pharmaceutical ward round and consultations. no specific therapeutic drug has been proved to treat covid-19 currently. related antiviral drugs of pre-approval access are in ongoing clinical trials, including anti-influenza drugs, anti-hiv drugs and anti antiviral medications are related to many drug interactions. severe covid-19 patients tend to have underlying diseases, and the combined symptomatic drugs are more complicated. therefore, in order to avoid symptoms aggravation due to drug interactions, pharmacists should be highly vigilant for potential drug-drug or drug-food interactions, strengthen the management of patients' medication and diet. taking lopinavir-ritonavir as an example, clinicians and pharmacists should avoid combining other drugs metabolized by the cyp3a enzyme (nifedipine, atorvastatin, midazolam, etc.), and educate patients not to eat foods that affect the cyp3a enzyme (grapefruit, honey, etc.). in addition, in the current clinical practice, it has been proved that integrated traditional chinese and western medicine has a certain effect on covid-19. pharmacists should also strengthen the interaction management between traditional chinese and western medicine, and recommend patients to take medicines at intervals. in general, human at all ages can easily be infected with covid-19. pharmacists should particularly strengthen pharmaceutical care for special population, such as pregnant or lactating women, children, adolescents and elderly patients. for pregnant patients, the physiological factors of pregnancy should be taken into full consideration. it is recommended to use medications with fda pregnancy category b or c, and avoid using medications of d class. 22 regularly monitor vital signs of patients and fetuses during medication use, and adjust medication regimens if necessary. to prevent the spread of the sars-cov-2 and prevent drugs' harm to infants through breast milk, pharmacists should advise lactating patients to suspend breastfeeding. 23 as the safety and efficacy of antiviral drugs for children and adolescents remains unclear, medication regimens should be formulated carefully. for critically ill children, drugs for adults could be considered and dosage must be adjusted. 24 for elderly patients with impaired immunity or complicated chronic diseases, pharmacists should adjust the dosage according to their liver and kidney function, manage medications for secondary prevention, and pay close attention to drug interactions. covid-19 patients with combined underlying diseases (diabetes, cardiovascular disease, chronic obstructive pulmonary disease (copd), malignancy, bacterial or fungal infections and organ transplantation, etc.) are prone to disease progress. medication regimens for those patients are more complicated in general. 25 there are many interactions between antiviral drugs and other symptomatic drugs, and medication efficacy and safety may be affected. pharmacists should strengthen pharmaceutical care for those patients with combined underlying diseases. therapeutic drug monitoring (tdm) should be strengthened, such as lopinavir-ritonavir and anti-infective drugs (voriconazole). clinical indicators (inr, blood glucose and blood pressure) should be monitored closely and dosage should be adjusted if necessary, for example, ribavirin may reduce the anticoagulant effect of warfarin, lopinavir-ritonavir may worsen diabetes and enhance the anti-hypertensive effect of nifedipine. for covid-19 patients with rapid disease progression, severe or critical condition, the convalescent plasma therapy (cpt) can be applied. 26 the plasma of convalescent utilizes a certain titer of virusspecific antibodies, through which patients receive the plasma infusion to obtain passive immunity and remove pathogens in the blood circulation. cpt is an effective therapy choice, and has been successfully applied to the treatment of sars and h1n1 influenza. 27 before conducting cpt, pharmacists should assist clinicians in assessing patients' indications of cpt, combining with allergy history, contraindications of plasma transfusion, and individual clinical conditions. also, the infusion dose should be formulated based on patients' weight and clinical condition, usually ranging from 200 ml to 500 ml (4-5 ml/kg). when performing cpt, pharmacists need to closely record and monitor adverse effects of plasma transfusion before, during, and after transfusion, and cooperate with clinicians to manage adverse effects. common adverse transfusion reactions include transfusion-related circulation overload, acute lung injury, dyspnea, allergic, hypotension, non-hemolytic febrile, acute hemolytic transfusion reactions, and delayed hemolytic transfusion reaction, infectious transfusion reaction, etc. the outbreak of covid-19 and the change of daily life after hospitalization, together with the uncertainty about the disease progress may lead to anxiety, panic, concern and excessive pessimism in some patients confirmed with covid-19. pharmacists should pay full attention to the mental health and emotional management of patients during pharmaceutical care. 28 timely emotional counselling and psychological support shall be provided to help patients properly understand the covid-19 and enhance confidence. for mild or moderate patients, pharmacists may encourage them to take adequate exercise (such as dancing) to enhance the immunity and relieve negative emotions. if the patients are considered having severe psychological problem, referral to psychiatrists shall be made. for patients with mental disorders (such as depression and anxiety disorder), pharmacists should pay close attention to their psychotropic medication compliance and assist psychiatrists in providing psychological intervention. vaccination is one of the most effective methods to halt the spread of covid-19 at the global level. pharmacists should provide patients with scientific information about vaccine development. at present, recombinant adenovirus vector vaccines ad5-ncov (chinese clinical trial registry, no.chictr2000030906) and nucleic acid vaccine mrna-1273 (clinicaltrials.gov, no.nct04283461) have entered phase 1 clinical trials in china and the us respectively. meanwhile, 52 candidate vaccines are under pre-clinical research for evaluation of safety and efficacy. 29 it is expected that by april 2020, more vaccines will enter clinical researches or emergency use. 6 for subjects participating in vaccine-related clinical trials, hospital pharmacists should assist clinicians and immunologists to closely monitor their clinical manifestations and adverse reactions after vaccination. pharmacists should also collect data on vaccines effectiveness and safety during pharmaceutical care if it is under the premise of medical ethics and promote the clinical research of the covid-19 vaccines. for hospitalized patients with covid-19, pharmaceutical care services are indispensable supplements for clinical treatment and management. hospital pharmacists providing targeted pharmaceutical care is of great significance for improving the level of drug therapy. based on the chinese perspective of "centralizing covid-19 patients and centralized inpatient treatment", the paper established a pharmaceutical care framework of covid-19 hospitalized patients, including participating in making evidence-based decisions for medication, monitoring and evaluation of medication safety and efficacy, strengthened care for special population and patients with combined underlying diseases, monitoring and management of convalescent plasma therapy (cpt), providing emotional counselling and psychological support and providing scientific information about covid-19 vaccines. the paper aims to provide reference for hospital pharmacists in providing patient care services, to improve patient's outcome and reduce the overall mortality, and finally to support hospital pharmacists' in making contributions to the control of covid-19 pandemic. the study is supported by grants from national major scientific and technological special project (zx09304012-008). all authors declared that they have no conflicts of interest. rolling updates on coronavirus disease (covid-19): who characterizes covid-19 as a pandemic world health organization national health commission of the people's republic of china clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. the bmj international pharmaceutical federation. coronavirus sars-cov-2/covid-19 pandemic: information and interim guidelines for pharmacists and the pharmacy workforce national health commission of the people's republic of china. diagnosis and treatment protocol for covid-19 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efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia. chin j of infect dis hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial a pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (covid-19) letter of emergency use authorization to allow hydroxychloroquine sulfate and chloroquine phosphate to be distributed and used for certain hospitalized patients with covid-19 retrospective study of low-to-moderate dose glucocorticoids on viral clearance in patients with novel coronavirus pneumonia recommendations for management of novel coronavirus (2019-ncov) infected maternal women in henan province china chinese physician society of obstetrics and gynecology, chinese medical doctor association. proposed management of 2019-novel coronavirus infection during pregnancy and puerperium chinese pharmaceutical association. coronavirus 2019-ncov infection: expert consensus on guidance and prevention strategies for hospital pharmacists and the pharmacy workforce pharmacological care strategy for antivirals in patients with covid-19 complicated by underlying disorders national health commission of the people's republic of china. the clinical guidance of convalescent plasma therapy convalescent plasma as a potential therapy for covid-19 2019-ncov epidemic: address mental health care to empower society. 2019-ncov epidemic: address mental health care to empower society world health organization. draft landscape of covid-19 candidate vaccines-26 we thank the international pharmaceutical federation, the chinese pharmaceutical association, the peking university third hospital for their support to this article. key: cord-248932-i1v2lyd2 authors: madraki, golshan; grasso, isabella; otala, jacqueline; liu, yu; matthews, jeanna title: characterizing and comparing covid-19 misinformation across languages, countries and platforms date: 2020-10-13 journal: nan doi: nan sha: doc_id: 248932 cord_uid: i1v2lyd2 misinformation/disinformation about covid-19 has been rampant on social media around the world. in this study, we investigate covid-19 misinformation/ disinformation on social media in multiple languages farsi (persian), chinese, and english, about multiple countries iran, china, and the united states (us), and on multiple platforms such as twitter, facebook, instagram, weibo, and whatsapp. misinformation, especially about a global pandemic, is a global problem yet it is common for studies of covid-19 misinformation on social media to focus on a single language, like english, a single country, like the us, or a single platform, like twitter. we utilized opportunistic sampling to compile 200 specific items of viral and yet debunked misinformation across these languages, countries and platforms emerged between january 1 and august 31. we then categorized this collection based both on the topics of the misinformation and the underlying roots of that misinformation. our multi-cultural and multilingual team observed that the nature of covid-19 misinformation on social media varied in substantial ways across different languages/countries depending on the cultures, beliefs/religions, popularity of social media, types of platforms, freedom of speech and the power of people versus governments. we observe that politics is at the root of most of the collected misinformation across all three languages in this dataset. we further observe the different impact of government restrictions on platforms and platform restrictions on content in iran, china, and the us and their impact on a key question of our age: how do we control misinformation without silencing the voices we need to hold governments accountable? along with the covid-19 pandemic crisis, an infodemic (world health organization, 2020) crisis has affected all aspects of human lives from elections to public health response around the world. social media has played a critical role in this infodemic crisis. first, social media offers a free and easy-access platform for users to share content (both true and false) in the form of posts, videos, pictures, and memes, all with a wide range of audiences (weinberger, 2011) . second, the covid-19 outbreak has forced people around the world to be quarantined and consequently interactions have shifted away from face-toface interactions and even more towards online/social media interactions. this means that more people are exposed to unreliable content circulating on social media and many users struggle with distinguishing between facts and lies/fictions about covid-19. since the beginning of the pandemic, some official efforts have been implemented to debunk these lies and inaccurate information circulating on social media, despite substantial disagreement about which corrective measures for fact checking are practical and appropriate for massive social media platforms. still, these efforts seem not enough and there is a widespread consensus that an integrated sustainable global effort is warranted across different languages and through different platforms as are targeted in our study (dizikes, 2020; pennycook et al., 2020a) . in the literature, the problematic information has been categorized into misinformation, disinformation, and malinformation, with some debate about definitions (karduni, 2019; wardle, 2017) . in this paper, we consider the following definitions: misinformation is incorrect information created without the intention of causing harm (e.g. encouraging people to wear a face shield without realizing how ineffective it could be). disinformation is incorrect information and intentionally created to hurt an individual, a group, or a country (e.g. a drug company spreading out a false rumor that its new medicine can cure covid-19 with an intent to increase profit.) mal-information is correct information (based on reality), but used to cause harm to an individual, a group, or a country (e.g. justifying the high rate of confirmed cases by claiming that it is because of increasing the rate of testing.) (infodemic toolkit, 2020; kujawski, 2019; wardle, 2019) . distinguishing between these three categories, particularly misinformation and disinformation, can be difficult or even impossible in some cases as can require assessing the intent of the creator. thus, more broadly, here in this paper, we will use the general term 'misinformation' to refer to all three categories. according to a study from oxford university, misinformation is also often true information reconfigured or recontextualize and less commonly fabricated (brennen et al., 2020) . this reconfigured information can circulate even faster than fully fabricated stories, taking in 87% of the interactions in one study (brennen et al., 2020) . in this paper, covid-19 misinformation, broadly defined to include disinformation and mal-information as well, will be investigated within multiple languages (chinese, english, and farsi) about multiple countries (china, iran, and the usa) on different social media platforms. the covid-19 pandemic broke out first in wuhan, china in december 2019. then, iran became a hotspot in february 2020. the usa has been a clear hotspot as well with 22% of confirmed world-wide covid cases despite only 4.25% of the world population (dong et al., 2020) . we chose these three countries as a lens through which to consider major differences between covid-19 misinformation around the world. we show how examining social media misinformation from the perspective of one country, one language, or one platform, misses important and more holistic aspects of the pandemic. through this research, we build a more comprehensive picture of how misinformation has exacerbated the covid-19 crisis around the world. our research team includes native speakers of chinese, english, and farsi who were born and raised in china, iran, and the usa. to the best of our knowledge, we are the first to examine the multilingual social media landscape by using the opportunistic sampling method to collect a dataset of verified and viral covid-19 misinformation across 3 languages: chinese, english, and farsi. our multicultural and multilingual team observed that the nature of covid-19 misinformation on social media varies in substantial ways across different languages/countries depending on the cultures, beliefs, religions, popularity of social media, types of platforms, freedom of speech, the power of people versus governments, etc. based on these observations, we proposed a novel and comprehensive categorization of the covid-19 misinformation based on their topics and roots such that these categories are all relevant and extendable in all three languages. it is worth noting the difference in government policies for controlling misinformation in iran, china, and the usa. china has strict government control over which platforms can be used and enforces these controls. approved platforms aggressively remove misinformation of some kinds, but not all. iran also has laws restricting which platforms can be used, but does much less to actually enforce these laws. it makes some platforms more inconvenient to use, but does less to actually prevent it. the usa has some new laws restricting the use of social media platforms, specifically chinese social media platforms. whether these laws will stand remains to be seen. there are some attempts to control the flow of some types of misinformation on platforms like twitter and facebook based on self-regulation by the platform and not government regulation. throughout our study, we examine the impact of these different approaches on the types of misinformation spreading. misinformation is not a new phenomenon, it has been around for centuries in the forms of rumors, gossip conspiracy theories, etc. (burston et al., 2018) . however, the emergence of the publishing industry in the 15th century provided an official modern platform for misinformation. the 21st century has been characterized by the explosion of information through the internet. the technology, particularly social media, has amplified the spread of misinformation and its adverse impacts by providing a fast and free channel to share any information whether true or false (lazer et al., 2017) . since the beginning of the pandemic, catastrophic and lifethreatening impacts of tremendous amounts of misinformation circulating on social media have appeared (donovan, 2020) . for instance, due to fake news, some individuals used toxic home remedies resulting in injury and death (vigdor, 2020a ). misinformation has provoked many people to hoard some vital necessary products (e.g., n95 mask, sanitizers, toilet papers, etc.) causing a shortage of supplies for essential workers (vigdor, 2020b the closest related work to this research is the 2020 misinfodemic report developed by meedan and written by alimardini et al (alimardani & elswah, 2020) . this qualitative report considers a more global response to misinformation, showcasing seven countries compared to several united states-only studies. meedan divides their report into the crumbling of public trust, informal leaders of information, and impact of the infodemic on governance. their coverage of countries is extensive, but our research adds a balance of qualitative and quantitative analysis comparing countries, languages and platforms within our sample. purely quantitative research that involves misinformation globally has been done by pew research. they surveyed social media users within several countries about how often they encounter obviously fake content (silver, 2020) . this study tries to point researchers toward countries that seem to be encountering misinformation more frequently. this type of quantitative research does not dive as deeply into the content, topics and root of misinformation present within each country surveyed. twitter, facebook, instagram, whatsapp, weibo, wechat and tiktok are the most popular social media platforms in china, iran, and the usa. however, due to the censorship and political reasons, some strict restrictions have been imposed on these platforms in some cases (rachman, 2020) . whatsapp is a cross-platform encrypted messaging application acquired by facebook, and its monthly active users have reached 2 billion as of march 2020 (clement, 2020b) . it has 68.1 million users just in the usa as of 2020 (andjelic, 2020) . whatsapp is completely banned in china. whatsapp is legally allowed to be used in iran and has become even more popular in iran after the iranian government blocked telegram in 2018 which used to be the most popular messaging application in iran. the government claimed that telegram had endangered national security (erdbrink, 2018) . whatsapp has become a makeshift social media platform in iran as group chats have begun including thousands of members forwarding and sharing information. although the government has blocked many social media platforms officially, many iranians still use vpn and proxy anti-filter apps/tools to access blocked social media. however, this access is more limited and requires some technical tools and skills. this has helped to drive usage towards whatsapp which is a private end-to-end encrypted messaging platform without tracing capabilities. partly as a result, whatsapp has become a major source of misinformation in iran and many other countries (alimardani & elswah, 2020) . whatsapp recently limited the number of times users can forward a message to only five times, in an attempt to fight against misinformation (kastrenakes, 2019). tiktok was developed by bytedance (字节跳动), a chinese company in beijing. tiktok has a version used only in china called douyin (抖音) to separate the domestic users from international users. due to the concern of cyber security, tiktok operation in the usa will be transferred to a new company named tiktok global and will cooperate with oracle and walmart to ensure the data safety (lin, l., 2020). tiktok is allowed to be used in iran. keywords and hashtags are the major methods to search on social media and we use both to collect our data set. all platforms named in this study supports both keywords and hashtag search. hashtags on whatsapp might not be as popular as other platforms however this function makes the search process very easy even through a private message chain (patkar, 2013) . unlike hashtags on american platforms, a hashtag on weibo is owned by a host. also, each hashtag has its own unique webpage, which is called 超级话题 (i.e., topic or super topic). since january 2020, many super topics have appeared around covid-19 on weibo. figure 1 shows a sample of super topic webpage on weibo. the topic host and the largest contributor to this topic is a state media. although english hashtags are allowed on weibo, almost all hashtags are in simplified chinese. weibo needs the symbol "#" before and after a term to function as hashtags, unlike twitter which only needs "#" before. wechat channels is a popular feature of wechat and contain public feeds of content. hashtag and keywords search can be used in wechat channels. selecting an appropriate sampling methodology is a major challenge when it comes to social media studies. nonbiased sampling from social media is often difficult because the dataset is so highly dynamic, massive in size, and difficult to filter. the sheer volume of data--facebook has over 350 million users and twitter has a rate of 17,000 tweets per minute--makes the gold standard of data acquisition, true random sampling, challenging. this can be even more complicated when sampling for misinformation since our underlying population is not all posts, but those posts that contain misinformation that has been refuted or debunked by recognized fact-checking organizations. hashtag and keyword filters do not necessarily guarantee to find misinformation, and even if a suspected post is found, we are reliant on the efficiency of journalists in fact-checking posts and content which is also biased by the particular needs and intentions of journalists and respective media outlets (pingree et al., 2018) . in this study, we utilized an opportunistic sampling strategy, meaning that our sampling was determined by the population, or presence of misinformation on social media, that was available and officially debunked at the time, and our abilities to find them. we used chinese, english, and farsi hashtag and keyword filters to collect 200 specific items of debunked misinformation that spread virally between january 1 and august 31. when we encountered a particular item in one of our languages, first we used fact checking organizations to see if that claim had been debunked using fact-checking sources such as international fact checking network (ifcn), platform based factchecking tools in twitter, facebook and google, and organizations using claim review (poynter, n.d.; schema, 2014) . the item is logged only if we could find a verified debunking source; otherwise, it is discarded. we estimate that number of logs could be doubled if we did not have the debunking constraint. then we watched for posts with the same claim in our other languages and on other platforms. we also sought out independent media reports beyond our own direct experience that the referenced claim was spreading virally. thus, each of these 200 items of misinformation in our study represents thousands of posts repeating the same debunked claim, often across multiple languages and platforms. out of these 200 collected pieces of misinformation, 54 are in chinese, 156 in english, 111 in farsi. we admit that our data set may be unintentionally biased considering the biased nature of social media and the fact that all authors are currently in the usa, so we might be more exposed to english misinformation. furthermore, due to the lack of copyright laws enforcements in iran, a single piece of misinformation might have been repeatedly debunked by too many sources which prolongs and complicates the search process for new pieces. figure 3 represents a clearer breakdown of our collected data and the overlaps in misinformation across languages. strict filtering and censorship policies for chinese social media is a major factor in the notably lower totals. this can be considered as a benefit of the aggressive censoring of some types of misinformation in china. however, this could come at the expense of silencing voices that are needed to counter other kinds of misinformation. this is a key question being explored in this paper. there are 14, 64, 29 pieces of misinformation found exclusively in chinese, english, and farsi only, respectively. out of overall 200 pieces of misinformation, 53 occurred in only farsi and english (26%) which is the largest overlap among possible pairs of languages while farsi and chinese have the least overlap (less than 1%). of the 200 collected pieces of misinformation, 14% have been found in all three languages. given the complicated nature of tracking misinformation across multiple languages' social media landscapes, a comprehensive categorization over the topics of covid-19 misinformation was critical to analyze the catastrophic infodemic occurring during this global pandemic. we identified 10 top level categories for the topics of covid-19 misinformation. we found that these proposed categories were inclusive enough to cover the chinese, english, and farsi misinformation in our collection. these categories are also extendable to also cover the possible future misinformation. the description of these categories are as follows: includes rumors, actions, and false claims to manipulate the official statistics of death and confirmed cases including exaggerating or downplaying the numbers. includes conspiracy theories and rumors spread out about other countries' roles related to the new virus. 9. virus transmission: includes topics related to misleading, superstitious, or fake, methods by which the virus can transmit, asymptomatic period, basic reproduction number (r0). 10. others: includes topics such as contact tracing (pros and cons of contact tracing, and rumors about the amount of personal information needed to be collected for the contact tracing purposes); recovery (the length of recovery periods, antibody level after the recovery, immunity of recovered patients, etc.); prediction of the pandemic; compensations, and more topics; etc. the topics for each of our collected samples were inductively examined to be specific to covid-19 misinformation and accordingly classified within the proposed 10 categories. figure 4 represents the proportion of each topic within our overall collection across languages. about a quarter of the total collected misinformation in our sample fell under the topic of prevention-individual. also, the top three topics of the collected misinformation mostly concern the individual behavior. in a few cases, the same claim has been reported in more than one category, e.g., "drinking bleach" has been circulating on social media as both a cure and prevention method. in fact, this high proportion of misinformation within the context of individual behavior verifies the vulnerability of users to misinformation to cope with uncertainty and uncontrollability of pandemic circumstances. an interesting observation on the topics of misinformation in these three languages is that the percentage of categories in english and farsi are comparable. furthermore, the top two categories for both farsi and english are "prevention-individual" and "virus transmission". this suggests that the iranian laws coupled with weak enforcement still allows misinformation of a similar kind to flow in iran as in the usa with fewer laws and restrictions. the greatest difference in english and farsi belongs to the category of misinformation related to "other countries". meanwhile, chinese and farsi misinformation within this category have similar records. since most of the chinese and farsi rumors about other countries have political roots and considering the controlling governments in iran and china, such similarity is not surprising. it is interesting that despite tight control of other kinds of misinformation in china, this category is still specifically allowed to flow. the top category of the chinese sample belongs to the topic of "origin" of the virus which is actually still a question mark for the world. we also observed a larger variety of topics in english which explains the relatively higher percentage of english misinformation categorized as "others". for instance, misinformation related to contact tracing could only be found in the usa. one of the reasons could be the fact that some laws and rules vary from one state to another in the usa (e.g., misinformation about federal and state compensation and financial support from businesses and individuals) and this confusing landscape of varying laws opens up space for misinformation to flow. in this section, we delve beyond a classification of misinformation by topic to the roots of misinformation. for example, jang et al. reported that most misinformation stems from a false statement quoted by a public figure; or is deliberate misinformation used for a particular purpose (jang et al, 2018) . we found that covid-19 misinformation also followed this same pattern. we identified the following six categories for the roots of the misinformation. it should be noted that we use the term "root", but we could have instead used terms such as "reason" for or "source" of misinformation. 1. political-related roots: a false statement quoted by a political figure; or related to governments and the relationship between countries; or used for political purposes, e.g., elections. 2. medical/science-related roots: a false statement quoted by someone claiming to be a medical expert, e.g., doctors, nurses, etc.; or a false perception related to medical research outcomes. statement quoted by a celebrity, influencer, or popular/public figure in the media field; or, a misleading/false content such as a video, photo or an article gets viral through media, e.g., tv, press, etc. 4. religious-related roots: a false statement quoted by a religious figure; related to religious and/or traditional and superstitious beliefs. 5. criminal-related roots: a false statement which has been claimed by a scammer or hackers for criminal purposes such as fraud, access to personal information. 6. others: any other false statements that cannot be substantiated to be related to the mentioned categories including hoaxes, jokes and other undesignated misinformation. for each of our 200 pieces of misinformation, we attempted to track the source that led to this content going viral. the roots of misinformation collected in our sample are verified by reliable references and categorized in one of these six categories by human annotators. if a false statement has been quoted by multiple sources, then the source which made the statement goes viral will be considered as the root of the statement. as figure 5 represents, more than one third (33.5%) of the misinformation has been related to political roots which is alarming and shows the critical role of governments and political figures in the infomedic. for example, researchers analyzing 38-million english-language articles about the pandemic found that usa president trump was the largest driver of the infodemic over that sample (evanega et al., 2020) . we could not verify the roots of 24% of our sample, indicating the breadth and diversity of covid-19 misinformation; these have been categorized as "others". the three countries selected in this paper have their own unique characteristics and cultural structures and here we further discuss the roots of misinformation, particularly the religious and political roots, separately in iran, china, and the usa in the following subsections as well as a discussion of commonalities across these countries. the covid-19 misinformation circulating on chinese social media landscape reflects significant differences in political systems between china and the western world. for such reasons, misinformation from the western world is translated, filtered, and reflected in chinese social media. a primary root of misinformation circulation in china is the presence of fake science-based claims. when considering chinese social media, it is important to consider the systems of aggressive censorship in china that results in a strict politically filtered internet. global misinformation which has been translated and reflected in chinese social media environment can be considered politically biased since the vast majority of social media in china is tightly controlled by the state. an interesting trend observed in chinese social media is that some already debunked misinformation from the rest of the world, especially the usa, has been translated and widely shared in chinese platforms to criticize the western world's attempts to fight covid-19. this pattern of disclosing the debunked misinformation is a politically manipulated misinformation per se. thus, we can only call this type of message pseudo "misinformation" (e.g. reports of president trump suggested injecting bleach to treat . in this case, it appears that the reason this misinformation is allowed to flow is more of a criticism of the usa and the susceptibility of its citizens to misinformation that appears clearly ridiculous to the average chinese citizen. through translating and sharing this message, people in china have been shocked to see such clear misinformation from the usa president and will further believe in more similar information regarding the unsuccessful control of covid-19 in the usa. much of the true misinformation in china are fake-science misinformation based on some assumption without sufficient evidence and scientific work to support it. though a post may point to scientific sources to back up the claim, it is difficult for most people to verify the source due to the language barrier. specifically, most people do not have the capacity of reading research publications in english or even of translating the name of the journal. this style of post can be used to give the impression of a scientific evidence that may not exist. in our chinese samples, the largest category of roots of misinformation belongs to politics (41%) which is aligned with our analysis for english and farsi samples (figure 6-a) . due to tight controls and censoring in china, collecting samples of covid-19 misinformation in chinese has been relatively harder than english and farsi. also, identifying the roots of the collected covid-19 misinformation is complicated. the roots of 24% of the chinese misinformation remain undesignated and categorized as "others". surprisingly, a large proportion of covid-19 misinformation in chinese has been started by celebrities and/or pop culture (20%) which is larger than the english and farsi corresponding category. unlike the iran and usa, most chinese are irreligious and atheist (huff post & briggs, 2011; noack, 2015) . however traditional chinese beliefs have been identified among covid-19 misinformation in chinese (only 2%) and categorized as having religious roots. we could not identify any misinformation in chinese associated with the criminal roots (0%). this is a strong result and could be considered one benefit of tight government control over social media in china. confronted with the impact of misinformation on western democracies (e.g. advice to drink bleach), chinese citizens could be convinced that the aggressive censorship policies help keep their society safer for criminal elements and viral misinformation. misinformation in the usa is commonly in the form of counter-expertise, the rejection of mainstream academic expertise, which dates back to the 19th century (douglas, 2018) . this form of misinformation began with christian fundamentalists rejecting evolution as it contradicted the bible (douglas, 2018) . since then, counter-expertise looks to distrust mainstream scientific media by promoting alternative thoughts through alternative media. this alternative media happens to be far more susceptible to misinformation (douglas, 2018) . such alternative media has released misinformation throughout the pandemic, with fox news ("fox's dr. marc siegel", 2020) stating "the virus should be compared to the flu because at worst case scenario it could be the flu". across the usa, churches have successfully resisted complying with government-led preventive measures and health orders. a recent study shows that 71% of protestant/evangelical ministers held in-person worship as of july 15, 2020 (vondracek, 2020) . the persistence to stay open and hold in-person worship has led to churches becoming hot spots for positive cases (conger et al., 2020) . father joseph illo, leader of the star of the sea church, sent out misinformation to churchgoers stating that "the news reports about covid are largely unreal" (bisacky, 2020) . however, not all churches within the usa are rejecting mainstream media or health orders. the current politically polarized atmosphere in the usa is also a major driver of misinformation. misinformation related to politics is often fabricated to create confirmation bias among readers, subsequently leading to heightened ingroup/party identification and polarization (douglas, 2018 ) (e.g. "the political party i identify with fought for the right thing, as opposed to the other party"). covid-19 misinformation spread by political figures in the usa may be a symptom of deflection and scapegoating due to inadequate administrative response. usa government sources have suggested a conspiracy theory that covid-19 was created in a chinese laboratory (aljazeera news, 2020). deflection is apparent as the usa president donald trump suggested "quick fixes" and "cures", such as hydroxychloroquine, azithromycin, and convalescent plasma (caplan, 2020) , that have limited testing and results as potential cures or "game changers in the history of medicine". it is necessary to acknowledge the severity and seriousness of the spread of misinformation from the usa public officials. in our collection of misinformation samples from the usa about one third (31%) have political roots ( figure 6-b) . while the spread of information from public officials to win elections is not new, the role of the mass media as a corrective measure on this behavior has changed. the media is now competing with social media for advertisements, which has resulted in pressure to cater content to users, further perpetuating political polarization (scheufele & krause, 2019) . from drastically downplaying the seriousness of the virus to stating that "one day it's like a miracle, it will disappear" (the white house, 2020), the usa government has contributed heavily to covid-19 misinformation on all media platforms. the role of celebrities in driving american culture (clemmons, 2018) and the power of american public figures' words should not be underestimated. in our sample, 13% of the collected misinformation in the usa has been directly traced back to a celebrity, influencers or popular figure. for example, on july 31, 2020 instagram removed madonna's post "for making false claims about cures and prevention methods for covid-19" (solis, 2020) . false statements by self-claimed medical related crew or wrong and manipulated interpretation from medical facts are another major root of misinformation in the usa (22% of our sample represented in figure 7 -b). covid-19 misinformation has hit iran harshly. two major reasons have been identified for creating and spreading misinformation: first, discourse about covid-19 is politically manipulated by the government (alimardani & elswah, 2020); second, official religious figures have interfered with covid-19 related issues and religion has been a barrier for ordinary hardliners to be unbiased. in general, social media reflects that people do not trust the covid information released by either government or religious officials. when the official channels of communication of information fail, people start clinging to their own unofficial channels of information gathering without monitoring the validity of the information which eventually intensifies the spread of misinformation. iran has a controlling and conservative government which micro-manages all aspects of people' lives. this characteristic of the government politicizes every subject including the pandemic. thus, it is not surprising that much of the covid-19 misinformation found in farsi has political roots. an ironic piece of misinformation with political roots in iran is that the government believes the covid-19 misinformation present in iran has been started mainly by "enemies", referring to the usa government ("bbc news persian", 2020). another example of political misinformation is that the iran government promoted a fake testing technology called "coronavirus remote detectors" which can detect infected individuals from a distance of 109 yards. the unveiling ceremony on april 15th went viral all-over the iranian press and social media. religion has also played a critical role in spreading covid-19 misinformation in iran. for instance, some official religious hardliners falsely believe that sacred protection from religious shrines would prevent infection (malekian, 2020) . in iran, some shiite muslim religious figures often use people's faith to oppose "westernized" facts, sometimes including scientific facts. for example, on february 24, 2020, a religious figure, ayatollah abbas tabrizian, advised people to rub their anuses with violet oil to prevent and cure covid-19. this post on his official telegram channel (with more than 200,000 followers) has been viral on all farsi social media. users reshared this post with mixed reactions that included both adherence and ridicule (the new arab, 2020). as it was expected, in our collected farsi sample, the top category of roots of misinformation belongs to politics (27%) (figure 6 -c). the next largest proportion of the misinformation has medical/science roots including both western misinformation and local and traditional persian remedies. about 11% of our sampled misinformation has religious roots. considering the bold role of religion in iran, this rate seems relatively low. however, the virality of this misinformation has been substantial, such that some of the misinformation is still circulating on social media, even after it officially got debunked. some however have been transformed into sarcasm to be used as a form of protest against hard-core religious figures. a b c figure 6 : proportion of the chinese (n=54), english (n=156), and farsi (n=111) collected data across the proposed categories for roots of covid-19 misinformation. a recent study showed that there is an intersection between fake news and religion in societies with religious background (douglas, 2018) . our observation on this matter in iran is aligned with this study given the islamic background of iran (11%). however, our sample could not confirm the same result in the usa and china. given the impact of the christian community in the usa (bailey, 2019), 3% religious roots for the english misinformation was surprisingly lower than our initial expectation. when politics and government play a significant role in the destiny of a society (which is the case in iran, china, and the usa), a political polarization phenomenon will emerge (facing history and ourselves, 2020). political polarization has been known as an important factor to spread misinformation in a society and the meaningful relationship between misinformation and political polarization has been profoundly investigated in the literature ( the absence of misinformation with criminal roots in chinese social media is notable. this is an example of a key difference in how government strategy directly influences the types of misinformation to which the public is exposed. as a result, some societies are more vulnerable to criminal misinformation. given that politics was the largest root of misinformation across all three languages in this dataset, all societies are extremely vulnerable to government misinformation. however, some have more potential to counter government misinformation with information from private sources. in many ways, this is perhaps the key question for countries and societies around the world going forward in deciding how they want to control misinformation and infodemic. for liberal democracies, a key challenge is determining how to control misinformation without silencing the voices needed to hold government misinformation accountable. our major goal is to analyze the covid-19 misinformation on different social media platforms across different languages to gain a more holistic, global understanding of the misinformation's landscape. this effort is an initial step to diminish the current infodemic happening along with the pandemic. by increasing public knowledge of the adverse impacts of misinformation on public health during the pandemic, many lives could be saved. to achieve our goal, the opportunistic sampling approach was utilized to compile 200 pieces of verified misinformation posted virally in chinese, english, and farsi across twitter, facebook, weibo, wechat, whatsapp, instagram, and tiktok between january 1 and august 31. each of these 200 pieces represented thousands of posts across platforms and often across languages. then, a classification approach was proposed to categorize the collected misinformation based on both their topics and roots. we identified 10 high level topics being inclusive and relevant in all three languages. we also identified 6 major categories for the roots of misinformation. our study yielded the following important results: • politics was the largest root of misinformation across all three languages in this dataset. • overall, the english and farsi samples have more in common in terms of the topic of misinformation than chinese specifically regarding individual prevention methods. • the absence of misinformation with criminal roots and fewer categories of misinformation overall in chinese social media is notable and points out a critically important tradeoff in the control of misinformation. we note important differences in how government controls on social media platforms drive usage onto some platforms and away from others, with different infrastructure for tracking and controlling misinformation. understanding how different countries utilize social media and their restrictions gives better insight as to how to regulate disruptive behavior. a key challenge going forward for all societies and countries will be in determining how to control misinformation without silencing the voices needed to hold governments accountable. overall, it is clear how focusing beyond english, beyond the usa, and beyond the usa-based social media platforms are essential to providing a clear understanding of the effects of misinformation and the effectiveness of misinformation control strategies around the world. muslims 'immune to coronavirus' some imams in somalia say, putting public at risk trust, religion, and politics: coronavirus misinformation in iran whatsapp statistics: revenue, usage, and history. fortunly christianity is declining at a rapid pace, but americans still hold positive views about religion's role in society rouhani: the conspiracy of our enemies to shut down the country for fear of the corona concerns raised after san francisco church shares misinformation on covid-19 types, sources, and claims of reuters institute for the study of journalism a brief history of fake news trump opened the floodgates for convalescent plasma too soon stop the spread of rumors coping with stress coronavirus: video of an undertrial in mumbai falsely viral as nizamuddin markaz attendee spitting at cop statistics: weibo monthly active users (mau) & dau. china internet watch wechat statistical highlights 2020; miniprogram dau>300m number of monthly active facebook users worldwide as of 2 nd quarter 2020 (in millions) number of monthly active whatsapp users worldwide from the psychology of secular saints: americans worship celebrities for better or worse churches were eager to reopen. now they are confronting coronavirus cases 10 most popular social media sites in china the catch to putting warning labels on fake news social-media companies must flatten the curve of misinformation an interactive web-based dashboard to track covid-19 in real time religion and fake news: faith-based alternative information ecosystems in the the psychology of conspiracy theories coronavirus misinformation: quantifying sources and themes in the covid-19 'infodemic'. the cornell alliance for science iran, like russia before it, tries to block telegram app explainer: political polarization in the united states the coronavirus doesn't discriminate, but u.s. health care showing familiar biases iran ranked world's 7 th instagram user. financial tribune marc siegel says "worse case scenario study: rising religious tide in china overwhelms atheist doctrine an empirical investigation of network polarization a computational approach for examining the roots and spreading patterns of fake news: evolution tree analysis which countries block twitter & which no longer ban twitter? hidemyass human-misinformation interaction: understanding the interdisciplinary approach needed to computationally combat false information whatsapp limits message forwarding in fight against misinformation. the verge melanin doesn't protect against coronavirus coronavirus goes viral: quantifying the covid-19 misinformation epidemic on twitter combating fake news: an agenda for research and action mass polarization: manifestations and measurements tiktok owner puts deal with oracle 10 twitter statistics every marketer should know in 2020 could covid-19 inspire the faithful? scholars predict spirituality surge in our future iranian hardliners accused of breaking into shrines closed to prevent coronavirus spread twitter is banned in china, so how does it have 10 million users there? tech times taking stock with teens® − piper sandler completes 39 th semi-annual generation z survey of 5 map: these are the world's least religious countries the u.s. national pandemic emotional impact report 3 secret ways to use hashtags you've never tried before. make use of the implied truth effect: attaching warnings to a subset of fake news headlines increases perceived accuracy of headlines without warnings fighting misinformation on social media using crowdsourced judgments of news source quality it was already dangerous to be muslim in india. then came the coronavirus checking facts and fighting back: why journalists should defend their profession verified signatories of the ifcn code of principles. ifcn code of principles chinese censorship is spreading beyond its borders 10 american teens use tiktok. statista many black, asian americans say they have experienced discrimination amid coronavirus claimreview -schema.org type science audiences, misinformation, and fake news misinformation and fears about its impact are pervasive in 11 emerging economies these celebrities have been flagged on social media for spreading coronavirus risk for asians, africans, caucasians− revealed japanese and chinese at highest risk for coronavirus applying essential oil to anus 'cures coronavirus is the new crown virus a laboratory biochemical weapon? only infect asians? why are conspiracy theories soaring? scholar analysis: the government deliberately nurturing and condoning remarks by president trump in meeting with african american leaders. the white house man fatally poisons himself while self-medicating for coronavirus, doctor says a hoarder's huge stockpile of masks and gloves will now go to doctors and nurses 71% of churches meeting for in-person worship, study finds. washington times information disorder: toward an interdisciplinary framework for research and policy making understanding information disorder too big to know: rethinking knowledge now that the facts aren't the facts, experts are everywhere, and the smartest person in the room is the room 1st who infodemiology conference. who the authors would like to kindly acknowledge assistance from gillian kurtic and yan chen for contributions to the paper including help reviewing, organizing, and formatting. we also thank dr. ricardo baeza-yates for his detailed feedback, wise advice and thought-provoking questions. we gratefully acknowledge funding from clarkson university epidemic and virus-related research innovation fund. key: cord-030959-olcz7g19 authors: hussain, ejaz; rao, muhammad furqan title: china–pakistan economic cooperation: the case of special economic zones (sezs) date: 2020-08-28 journal: fudan j doi: 10.1007/s40647-020-00292-5 sha: doc_id: 30959 cord_uid: olcz7g19 this article attempts to underscore the extraordinary significance of special economic zones (sezs) in the industrialization and economic growth of pakistan as well as the development and consolidation of china–pakistan economic corridor (cpec)—which is a core component of the belt and road initiative (bri). though pakistan has previously experimented with sezs, its scale, outreach and impact on the country’s economy and society remained very limited. thus, the proposed sezs under the cpec offer new opportunities for mutual economic cooperation, investment, human resource development, sustained industrialization and, above all, the consolidation of cpec. nevertheless, there are several challenges ranging from structural issues to security problems that the proposed sezs, in particular, and cpec, in general, face. the article, thus, provides a comprehensive set of strategies to convert challenges into capabilities. pakistan experienced slow growth rate ranging from 0.4% in 2008-2009 to 4.24% in 2014-2015. 1 nevertheless, owing to certain strategic and economic developments that include the construction of china-pakistan economic corridor (cpec), the country's economy reflected positive trends in all major sectors of the economy during 2014-2018. therefore, the gdp growth rate stood at 5.2% (revised) in 2018. 2 though the global donors and ratings institutions are pinning hope on the country's economic potential to rise as a fast-growing and promising regional economy, pakistan, due to prevailing structural constrains, is still struggling with its stated economic goals that include around 8% annual growth rate. 3 in addition, during the first quarter of fiscal year 2018-2019, the gdp growth rate has dropped from 5.2 percent to 3.8 percent. 4 importantly, owing to covid-19, the country's gdp growth rate for 2020-2021 has been projected negatively. 5 in the wake of sustained economic growth regionally if not globally, it is pertinent for pakistan to revisit its economic policy for the country possesses certain infrastructural, demographic and human resource potential that can play a pivotal role in shaping the socioeconomic profile of the country in an unprecedented manner. for instance, during the past four decades, pakistan's manufacturing sector registered an average annual rate of around 7% despite a slowdown in recent years. this marks resilience of the pakistani industries and entrepreneurs, which is very crucial for sustained economic growth. 6 in order to achieve the stated annual growth rate, realize full potential of its natural and human resources, improve upon its agriculture and manufacturing sector and, overall, rise as a stable regional economy, pakistan has already taken certain concrete measures. in this respect, the launch in 2015, of the landmark project of coordination and cooperation between china and pakistan, namely the china-pakistan economic corridor (cpec), has emerged as an icon for fast-tracked industrial development and dissemination. thus, in the context of cpec, pakistan aims to establish financially vibrant, socially visible and potentially productive industries to initiate a new era of industrialization that includes high-end textiles, telecom, engineering, knowledge-based manufacturing, sea products and sophisticated storage facilities for fruits and vegetables, jointly or separately with chinese companies to be based in special economic zones (sezs). "while embarking on the [new] phase of industrialization, pakistan faces a number of issues that have so far restricted industries to realize their growth potential. these include, low investment, dispersal of industries across country, weak institutions, low quality human resources, shallow tooling skills owing to lack of depth in vocational expertise, lack of modern technology, high business cost, brain-drain, low quality hard and soft infrastructure, etc." argued mahmood. 7 expectedly, the sezs under cpec offer lifetime opportunity for pakistani companies to work in tandem with their chinese counterparts for the development of export-oriented manufacturing industries, while striving to overcome the abovementioned issues with the assistance of reformed public sector institutions. the sezs with new business models are likely to generate reasonable jobs, develop industrial and business infrastructures and establish domestic value chains connected regionally and extra-regionally. thus, the special economic zones are expected to provide much needed impetus to stimulate economic activities across the country. 8 moreover, given the relatively successful record of china in constructing and running several sezs, pakistan finds an opportunity to capitalize on the chinese experiences and, importantly, investment, human resources and technology in establishing china-led industrial parks. in this new phase of industrialization under the framework of china-pakistan economic corridor, pakistan is expected to have a number of opportunities to capitalize on. nevertheless, the country's leadership, both civil and the military, would also face multiple challenges at the policy and operational level. in order to turn cpec into a success story for bilateral economic confidence and, overall, for the positive projection of the belt and road initiative (bri), the construction of special economic zones, thus, assumes extraordinary significance. in view of the foregoing, this article, therefore, is an attempt to underscore the overwhelming significance of special economic zones for the expansion and consolidation of china-pakistan economic corridor-which is a core component of the belt and road initiative. in doing so, the article attempts to address the following questions: did pakistan ever venture in sezs pre-cpec? what are the nature, character, geographic scale and socioeconomic outreach of the proposed sezs under cpec? what type of challenges the proposed sezs, especially the rashakai special economic zone-which is prioritized in terms of construction by the two governments on april 29, 2019-face? are there any solutions to the identified set of challenges? this article, in the following sections, addresses these questions empirically. in this respect, qualitative method is employed, while data include both primary and secondary sources. 9 nonetheless, before so doing, it is prudent to review the major works on sezs in order to draw cross-regional insights that would be useful for the identification of challenges and the formulation and implementation of strategies. human beings, since antiquity, are instinctively inclined toward socialization which gradually generated a sense of commodity exchange. the structural transformation from the paleolithic period to the neolithic era marked the differentiated primacy of agrarian relations cross-regionally. 10 the early civilizations enriched human organization culturally, artistically and intellectually. the advent of "common era" witnessed the feudalization of, for instance, the european society where the means of production-essentially agrarian in nature and character-were controlled by the higher echelon of the empire-state. in the middle medieval to the late medieval period in world economic history, the contribution of the non-western world was remarkable in terms of proto-trade of, for example, silk, gunpowder and paper technology from china. 11 thus, the antecedents of modern "industrialization" could be observed in the sustained exchange relations among the ottoman empire, the qing dynasty and various european dynasties. while the asian empire-states could not pursue industrialization on account of strategic and political calculations, the europeans, especially the british, took lead in setting up a variety of industrial units across the country in the thirteenth century onwards. 12 such institutional changes, thus, brought forth structural transformation of the market relations from feudalism to capitalism. moreover, it also had a bearing on the nature of political relations that, on account of the european revolutions, i.e., 1688, culminated into the formation of the nation-state post-french revolution. ironically, however, the modern nation-states of europe and later north america adopted a contradictory approach by extracting raw material from the non-western world in order to sustain industrialization at home. this process of structural exploitation ultimately resulted into colonialism of the asian and african societies and markets from the nineteenth to the mid-twentieth century. 13 nonetheless, the capitalist colonial hegemony was challenged by mostly socialist forces during the first world war, i.e., the russian revolution (1917), onwards till the final phase of decolonization in the 1960s. 14 in the post-second world war period, the united states emerged as the leader of the capitalist bloc, whereas the ussr and the people's republic of china, as it emerged as a sovereign nation-state in 1949, represented the socialist model of governance and economy. it is in this context of the cold war geoeconomics that the western world, in order to expand its industrial production, invested innovatively in finding new means for enhancing its manufacturing sector and broadening the export base. the british, again, took lead, in this respect, by establishing the first modern export processing zone (epz) in ireland in 1959. 15 the following decade witnessed the establishment of epzs in barcelona (spain) and puerto rico (usa). in asia, india became the first country to conceptualize epz and, consequently, established its first epz in kandla (gujarat) in 1965. [t]he development of free trade zones got a significant boost in the 1960s and 1970s because growing international specialization, global production relocation by transnational corporations and an increasing orientation by host countries towards exports necessitated the development of special economic zones. in this respect, one of the most startling success stories of sezs comes from china. the country adopted the free zone policy later than india and it only embraced the concept of sezs in the late 1970s. the first wave of sezs was established in china in 1980. since then, sezs have become a spectacular success and have emerged as a major driver of growth and exports in china. 17 as the preceding indicate, china has, in the last forty years, emerged as the world's second largest economy. importantly, it has lifted around 800 million people from abject poverty since 1979 as a result of its "reform and opening up" policy which underscored the importance of special industrial zones, particularly in the shenzhen region, 18 to realize industrial growth. 19 besides india and china, in asia quite a number of developing countries such as bangladesh-with currently high gdp growth rate after india in south asia 20 -the asean nations and other "emerging countries" are accruing economic dividends from effective operationalization of sezs. 21 in addition, russia, in recent times, has also ventured in industrial "clusters" to diversify its industrial production and alleviate regional economic disparity in the wake of the 2008 global financial crisis. 22 last but not least, the african countries-in order to achieve economic growth through promotion of their exports-are also engaged, in certain cases with the chinese collaboration, in the construction of special economic zones. 24 the popularity of sezs has, thus, increased in last two decades. for example, there were around 176 sezs in 47 countries in 1986, whereas, as per the international labor office's estimation in 2006, the number stood at 35,00 in 130 countries in 2006. 25 in addition, based on various studies, the word bank, in 2017, put the number of sezs approximately at 43,00, globally. 26 according to a study published, in 2019, by the united nations conference on trade and development (unctad) "there are nearly 5400 sezs today, more than 1000 of which were established in the last five years. at least 500 more zones (approximately 10 per cent of the current total) have been announced and are expected to open in the coming years." 27 as far as pakistan is concerned, in the pre-cpec period (pre-2013), it had already experimented in export processing zones and, importantly, the country hosted certain number of sezs at various locations. this is further discussed in the following section. historically, almost every district of pakistan had an sez with proper infrastructure and various incentives for local and international investors (see table 1 ). for example, punjab, the population-wise largest province, hosts around twenty sezs, whereas sindh, balochistan and khyber-pakhtunkhwa (kp) carry thirty, seven and twelve sezs, respectively. out of the above-mentioned, certain such zones were successful in terms of established industry and generation of employment and capital; there are failed cases, too. the failure of such industrial parks can be ascribed to their remoteness from the major urban and industrial areas. for example, the rashakai economic zone is located some 70 km away from peshawar-which is the provincial capital of kp and major urban hub from a commercial perspective. similarly, khairpur economic zone is established some 30 km away from khairpur city. moreover, certain major cities of pakistan also host certain industrial clusters (small industrial units which are not part of an sez) because of their added strength in skilled workforce, availability of raw material, supporting institutions and strong historical linkages with the local and global supply chains. for instance, such clusters include sports and surgical clusters in sialkot, textiles cluster in faisalabad, fan cluster in gujarat and engineering cluster in gujranwala-all these cities are located at considerable distance in punjab. in addition, there are certain industrial parks (specialized industrial units which formally are not part of an sez) in pakistan which include rachna industrial park (lahore), marble city (lahore) and textile city (port qasim, karachi). the distance between lahore and karachi is around 1200 km. some of the newly established industrial estates consist of value addition city (sheikhupura-faisalabad expressway), m-3 industrial city (faisalabad) and quaid-i-azam apparel park (m-2 lahore). 28 china and pakistan signed the memorandum of understanding (mou) in 2013 that served as the cornerstone of the china-pakistan economic corridor. the 2015 visit of pakistan by the chinese president xi jinping formalized cpec in terms of allocation of 46 billion us$. 29 by the end of 2017, the sum total of loans and investment under cpec has crossed 60 billion us$. significantly, the early harvest projects under cpec have already been operationalized and scores of projects in port, energy, railways, roads, etc., are currently underway. 30 to consolidate cpec and enhance bilateral economic cooperation, the chinese and pakistani governments concluded, in the sixth joint cooperation committee (jcc) held in december 2016, to establish special economic zones. 31 the total number of such sezs varied from initially over hundred to gradually reduced to forty-six. 32 however, later, the pakistani authorities, in particular, the ministry of planning, development & reform and the board of investment (that works under the prime minister secretariat) proposed the construction of nine industrial zones in different parts of pakistan. its outline is given in table 2. as the table above rashakai economic zone (kp) and dhabeji (sindh). 33 most recently, however, pakistan's prime minister imran khan-during the course of participation in china's second belt & road forum (brf) of the bri-has signed various agreements with his chinese counterparts. importantly, one of the agreements was related to the construction of rashakai economic zone as a topmost priority. 34 importantly, as per official updates, groundbreaking of rashakai economic zone is expected in 2020. 35 the feasibility work on remaining sezs is underway in accordance with the second phase of cpec. 36 the proposed sezs offer multiple opportunities to both the chinese and pakistani government, firms and people. the following section of the article discusses it in detail. pakistan requires a developed industrial sector to lay a solid foundation for its economic recovery and revival; the special economic zones are supposed to provide a wide range of opportunities to sustain enhanced industrialization. through industrial zone production and export hubs of high-quality manufactured goods, pakistan is likely to be favorably positioned in the regional and international market. whereas cpec is expected to enhance investment and infrastructure in pakistan and the western part of china, the construction and optimization of the proposed sezs are likely to boost up industrial growth and economic activity not only within pakistan but also between china and pakistan. the following opportunities are expected to come with the establishment of the sezs. to begin with, the proposed special economic zones are expected to work as a strong economic incentive for pakistani authorities to introduce reforms in order to improve upon domestic business environment, governing behavior, productive capacity, export base and enhance commercial attractiveness for further foreign investments. furthermore, industrialization with a new face is likely to create jobs for the country's large but underemployed population. the intended industrial activity under sezs in general and cpec in particular would expectedly generate employment for the growing educated workforce. in addition, capacity-building efforts through vocational and technical training would also help local workforce to catch up in quality skills. 37 secondly, the sezs offer an opportunity to attract pakistani diaspora with their skills and knowledge along with their accumulated capital for more profitable prospects in the country. the sezs can enable firms to agglomerate and get benefits of external economies and will thus provide opportunity to put domestic industries on a higher path of the learning curve. thirdly, trade generation opportunities are likely to induce both the states improve and strengthen bilateral trade regime. moreover, within sezs, pakistani companies either competing or complementing chinese companies would learn latest business and trade techniques from their chinese counterparts. in addition, the global firms that are overwhelmingly organizing their production and trade in increasingly complex global value and supply chains-and are, thus, looking for the least costly locations-special economic zones can provide a platform to reap the benefits of such opportunities that are literally ignored by the pakistani authorities. 38 fourthly, the agreed upon sezs offer an opportunity to strengthen technology cooperation between chinese and pakistani companies. moreover, the sezs provide with opportunity to manage labor pooling, thus cutting down search cost and reducing unemployment of skilled labor. besides, while working within a sez, there could be a strong possibility of nourishing innovative ideas that can be disseminated across companies and corporations. lastly, the proposed sezs, which would be operationalized in the second phase of china-pakistan economic corridor (2020-2025), carry the potential to establish linkages with the huge chinese market; and the chinese sezs, in this respect, may create a strong and sustainable business integration through trade and investment. nonetheless, these potential set of opportunities is prone to multiple challenges which are indicated in the following section. indubitably, china-pakistan economic corridor is a well-thought-out long-term project aiming at bilateral trade and commercial cooperation. 39 though the cpec is at its initial phase, some of its early harvest projects have already been completed and the second phase kick-started in 2020. 40 however, there are voices from within, if not outside, pakistan that approached the corridor extremely critically. regardless, the pakistani government held its ground and the project is now entering into its next phase where special economic zones are supposed to act as an economic pillar of cpec. however, the construction and function of the sezs are likely to face a set of challenges, which are categorized, in the following, as structural, political and security challenges. one of the major structural challenges pertains to the location of a special economic zone. as will be discussed in the next section, politics, at all level, does influence public policy in pakistan. therefore, each of the four provincial governments, the local and provincial political parties and regional stakeholders differ over the 38 "pakistan, china jointly working for establishment of special economic zones," the nation, 7 january, 2018. https ://natio n.com.pk/07-jan-2018/pakis tan-china -joint ly-worki ng-for-estab lishm ent-of-speci al-indus trial -zones (accessed on 23 april 2019). 39 site of a sez and present(ed) a respective province and/or region such as gilgit-baltistan as a perfect natural location-which might not be the case in pure economic terms. moreover, pakistan's human resources are not attuned to the proposed sez requirements. neither they are proficient enough to operate chinese technological tools and machines. this will be a major challenge for the government to fully benefit from employment opportunity offered by the sezs. 41 access to finance could be termed as equally important impediment for the growth of industries. such a problem doubles in magnitude with reduction in size of a firm. pakistani governmental bodies generally lack experience and knowledge in sezs management, i.e., doing business with foreign investors. it may seriously hinder the implementation capacity of the government institutions. therefore, the challenge posed is to develop requisite capacity of public sector institutions. furthermore, the creation of environment for fast and effective dissemination of technology is necessary. ensuring adequate number and size of allied and supplier firms and locating them in sezs to draw benefits of external economies will be a major challenge, too. similarly, local connectivity, inter-zonal liaison and provision of utilities would be a structural impediment to be taken care of. besides, the incidence of financial corruption is a serious challenge in so far as transparency of various cpec projects is concerned. 42 by and large, structural challenges point to consistency in economic policies, avoidance of sudden policy reversal, transparency in decision-making, eradication of corruption and expansion of financial markets to provide enough finance to industries, availability of qualified manpower through vocational training and conducive business environment including effective property rights protection and fair and speedy dispute resolution mechanism. 43 one of the main political challenges relates to due share in cpec and the sezs on the behalf of provincial governments, regional and local stakeholders. in 2015, when the chinese president xi jinping formally launched cpec, the khyber-pakhtunkhwa and balochistan government and the regional political parties differed, for example, over "cpec routes." the so-called route controversy 44 was blamed on the punjab (and the federal) government which were held partisan by the opposition political parties such as pakistan tehreek-e-insaf (pti) and pakistan people's party (ppp). importantly, political parties based in non-punjab provinces, especially balochistan that hosts gwadar port, raised questions on the feasibility, outreach, functions and strategic implications of the china-pakistan economic corridor. in a similar vein, local politicians and rights activists from, for example, gilgit-baltistan highlighted the potential risk for physical environment owing to cpec traffic chains. 45 in order to address the grievances of the smaller provinces, the federal government of pakistan led by pakistan muslim league-nawaz (pml-n) held a series of meetings with key leaders of provincial governments, regional dispensation and proclimate change associations. particularly, the sharif government (2013-2017) 46 was able to organized all parties conference on cpec more than twice. consequently, the mainstream and regional political parties and groups in general and the federal and provincial governments in particular achieved consensus on the nature and character of china-pakistan economic corridor. thus, the "route controversy" was amicably resolved with due share of roads and railways provided to different provinces and regions. 47 the foregoing, however, did not result into silencing the debate over cpec. little wonder, senator mir hasil bizenjo, 48 who was federal minister for ports and shipping, argued on the floor of the country's senate that "91 per cent of the revenues to be generated from the gwadar port as part of the china-pakistan economic corridor (cpec) would go to china, while the gwadar port authority would get 9pc share in the income for the next 40 years." 49 in addition, the cpec long term plan (ltp) has invited concerns and questions from stakeholders and analysts alike. by and large, the political elite and public at large from smaller provinces demanded more transparency and fair play in terms of detailing publicly the pros and cons of different agreements reached between chinese and pakistani authorities. indeed, the current pakistan tehreek insaf (pti) government led by prime minister imran khan initially viewed certain cpec projects skeptically. 50 this means that though cpec has been successful in terms of acceptability as a mega economic project between china and pakistan, it still requires further fine-tuning at the popular level. 51 if one goes by the foregoing, it is speculated that the construction of the special economic zones would not be free of political challenges emanating 45 lan jiang, "impact of local politics on cpec: research focusing on several energy programs" (paper presented at the international academic seminar on industrial cooperation and construction of industrial zones, cpec, peking university, beijing, 2018). 46 nawaz sharif was disqualified by the county's supreme court on 28 july 2017. the term sharif government refers to the period during which he served as pakistan's prime minister (july 2013 to july 2017). 47 ahmad noorani, "cpec route controversy routed," january 16, 2016. https ://www.thene ws.com.pk/ print /90708 -cpec-route -contr overs y-route d (accessed on 2 january 2019). 48 mir hasil bizenjo was the president of national party (np) that is nationalist in nature. 49 primarily from non-punjab provinces and autonomous regions. already there has been considerable debate registered on the location, size and number of special economic zones by the kp and balochistan, if not sindh, based nationalist political parties such as pakhtunkhwa milli awami party (pkmap), awami national party (anp) and the national party (np). little wonder, in initial meetings between the federal and provincial government, the number of sezs was reduced from hundred plus to forty-six whereby each government strove to host maximum number of sezs in order to uplift a respective province from poverty, economic slowdown and unemployment. 52 however, further negotiations among the regional, provincial and federal stakeholders brought the proposed number of sezs down to nine whereby each province, islamabad capital territory (ict), and region host one each. apparently, this seems a fair start in terms of equitable distribution numerically; however, issues and concerns regarding the size (the largest size sez is proposed for punjab) and economic competitiveness, industrial base of a province/region and overall economic indicators of an area may pop up in the following years if not months. as per the political culture of pakistan, political parties and politicians, at all level, see to their petty interest and that too at the expense of national interest. thus, it is very likely that sezs are further highlighted on partisan lines where each stakeholder tends to get the lion's share. political disagreements and tussles, thus, amount to serious political challenges that demand serious and steady debate, negotiations and conflict resolution mechanism. pakistan is facing serious threats in the form of religious extremism and terrorism. modern terrorism that pakistani society and state is suffering from is essentially post-9/11. when the pakistani military regime led by general pervez musharraf (1999) (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) decided to support the usa-led war on terror against the taliban and al-qaeda, the latter, in reaction, took on pakistan by invoking (suicide) terrorism as a strategic weapon. consequently, around thirty thousand pakistanis, both civil and law enforcement, have lost their lives in multiple incidences of terrorism from 2003 till 2019. though the number of civilian and security personnel fatalities has comparatively gone down since 2014 due largely to the various military operations, the phenomenon of terrorism has yet not been wiped out completely. for example, during 2013-2019, 6528 civilians and 2312 security personal lost their lives in (suicide) terrorism. 53 in addition, by august 21, 2020, 28 civilians and 125 security personnel lost their lives in 112 incidences of terrorism in pakistan. 54 given opportunity, a terrorist organization such as tehreek taliban pakistan (ttp) and/or jamaat-ul-ahrar (jua) strikes mostly on the country's minorities, i.e., christians, in mostly far flung areas such as quetta; the latter witnessed, on april 12, 2019, another deadly terror attack on its hazara minority that lost 20 lives, whereas 48 people were injured. 55 here, it is pertinent to mention that a chinese couple was initially kidnaped and ultimately killed in quetta in 2017 by a terrorist organization. 56 moreover, the chinese consulate in karachi was attacked by terrorists belonging to balochistan liberation army (bla); the attack was foiled by pakistani security forces with the loss of two policemen. 57 anti-pakistan terrorist networks work in tandem with regional proxies and powers such as india whose intelligence operator, kulbhushan jadhav, was arrested near iran-pakistan border by pakistan's security forces. 58 it is no secret that the current indian prime minister, narendra modi, had talked publicly against china-pakistan economic corridor. 59 in the context of domestic and regional security threats to its sovereignty, in general, and cpec, in particular, the pakistan state has taken due measures that include pooling up a special armed force, 60 consisting of military and the civil law enforcement institutions, for the protection of cpec projects and personnel. thus, china-pakistan economic corridor has, so far, survived major terrorist attack on its infrastructure, equipment and workforce. however, potential security threats ought not to be ignored. this then raises security concerns for second phase of cpec whereby special economic zones are accorded top priory by the chinese and pakistani government. will the local, provincial or federal government provide security to the sezs at, for example, different stages of construction? if it is a joint venture of, for instance, provincial and federal government, which government will call the shots? who will bear the financial and logistical cost? if it is the sole responsibility of the provincial government, will a province be able to manage a sez's security on its own? overall, will the chinese companies and workforce be satisfied with the security arrangements provided by the pakistani authorities? the foregoing has, thus, highlighted major security challenges to the sezs, in particular, and, cpec, in general. the next section of the paper attempts to provide a set of strategies vis-à-vis the posed challenges whose solutions will ensure the safety of not only the special economic zones but also that of pakistan's society and economy. the following are certain strategies to tackle structural, political and security challenges. these strategies, it is posited, can deliver tangible results if implemented in letter and spirit. pakistan has to take a number of steps in close collaboration with china to transform the highlighted challenges into capabilities. as far as structural challenges are concerned, the fundamental principle that pakistani government ought to abide by is the economic competitiveness of the area where a special economic zone is proposed. it is important that during consultation on site selection, all the concerned stakeholders be on board. second, the pakistani authorities need to initiate policies in coordination with pakistani and chinese companies. the pakistani firms should learn from the chinese experiences for effective policy implementation. in this respect, it is advisable to implement the special economize zone act 2012 (revised) that was promulgated before the launch of cpec so that economic aspirations of both the chinese and pakistani investors are realized. moreover, to train the sezoriented workforce, it is pertinent to establish modern vocational and technology institutions while taking inference from the chinese vocational education and technology know-how since they are comparatively state of the art in terms of innovation and dissemination of skills. 61 in order to make sezs an effective strategy and specimen for industrial growth, its financial side cannot be ignored. in this respect, the pakistani and chinese governments ought to work in tandem to devise a policy to provide adequate funds to small-to medium-size firms that lack indigenous financially stability. nevertheless, such financials should be firm-friendly to attract further investment nationally and (extra-)regionally. here, the role of pakistani diaspora could be very handy since they deposit, on average, around 10 billion us$ in remittances per annum. 62 furthermore, it is essential for pakistani and chinese authorities to make special economic zones a part of global supply chain and global value chain by increasing the competitiveness of supplier firms with improved reliability and efficiency. this can be achieved by introducing business supporting policies, modernizing trade facilitation system and infrastructure, devising a special cadre of customs officials and staff, cutting on delays, bureaucratic hurdles and, importantly, eradication of financial corruption. in addition, there is a need to promote sezs as enclaves of good practices and self-containment, supported by sound infrastructure and service provider firms. ideally, the pakistani government should engage a private firm to develop and manage the sezs, while the government should be an active player in provision of transport, electricity, water, telecommunications, waste disposal and other infrastructures to link sezs with global and local supply chains. 63 besides, the pakistani government ought to accord complete and secured property rights protection to ensure sustainability and attract chinese firms. in this respect, market access is to be ensured through efficient transportation system. 64 such measures will help improve transportation of much needed raw materials and finished goods. last but not least, pakistan ought to negotiate with chinese government to secure duty-free status to exports originating from the sezs. to realize it, pakistani authorities should promptly conclude special trade agreement for sezs in addition to the existing bilateral free trade agreement. since china has already effectively positioned its sezs to establish linkages with allied and supplier industries, pakistan should act fast to capitalize on the chinese experiences. in this respect, it is suggestive to create complementarity between pakistani and chinese sezs for mutual advantage and connectivity. as discussed earlier in the paper, politics affects policy and in the pakistani case, it did affect (economic) policies for the country's history is replete with cases where long-term economic plans suffered from political instability. 65 therefore, to make cpec a success story, pakistani politicians and political parties have their work cut out. in this respect, it is urgently required on the part of the federal government to engage regional and nationalist political parties in debate and discussion on the pros and cons of cpec in general and sezs, in particular. perhaps there is no harm in gradually increasing the equitable number and size of industrial zones in different parts of pakistan. such a policy measure will help generate political confidence and economic collaboration among the four provinces, regions and the federal government. more sezs mean more local and regional participation in cpec and economic growth and social progress of the country. moreover, the expansion of further sezs in close partnership with local and provincial authorities is likely to assuage local and regional socioeconomic grievances by engaging local skilled manpower of, for example, gilgit-baltistan and balochistan in the sezs in particular and cpec in general. 66 to realize the foregoing, it is suggested that the federal government does not ignore local and regional political aspirations. importantly, the mainstream political parties, which are major stakeholders of cpec, ought not to sideline nationalist political parties of kp, sindh and balochistan. thus, there is need of developing an effective mechanism for inter-parties coordination and policy formulation. at the moment, the federal government conducts all parties conference (apc) to discuss serious policy issues of national magnitude. this, in my view, is a ad hoc measure. a long-term institutional solution lays in the establishment of a permanent interparties coordination body responsible for holding meetings, generating consensus on policy issues and, overall, ensuring participation and policy role of smaller political parties. as already discussed in the preceding sections, pakistan is mired in multiple problems of which bad governance and insecurity are quite alarming for without orderly rule; it is impossible to achieve economic growth and societal development. since cpec is a joint venture, it is equally essential to ensure safety of the (non-) cpec workforce and logistics along with heavily invested corridor infrastructure. to begin with, china-pakistan relations have achieved "a factor of durability". 67 what this implies in strategic and military terms is that both the countries amicably resolved potential areas of conflict, i.e., broader management, and, importantly, consolidated bilateral relations since the mid-1960s. consequently, since 2015, china-pakistan relations have taken a new turn where geoeconomics is predicated on geopolitics in terms of formalization of cpec. a considerable section of the chinese workforce is engaged in gwadar, balochistan, where more than fifty major projects in infrastructure and energy are underway. 68 the pakistani authorities, being aware of restive security situation particularly in balochistan and generally in the rest of the country, established a security regime to safeguard the chinese labor from mostly internal threats. 69 in october 2019, the special security division (ssd) has been expanded in terms of establishment of its "southern" command that would exclusively ensure safety of the chinese executives and workers in balochistan and karachi. 70 though the kidnapers in balochistan killed two chinese nationals in 2017, the overall safety of the chinese workers has been duly ensured by the government of pakistan. moreover, recently there have been reports of some chinese nationals having been involved in the so-called marriages scandal; their cases are being invested by the country's law enforcement as per the law. 71 nevertheless, the chinese citizens working in pakistan have overwhelmingly demonstrated goodwill and good conduct. at the moment, the majority of pakistanis perceive them friendly people from a friendly country. nevertheless, given the chaotic security situation in parts of pakistan, public safety remains a big challenge for pakistani law enforcement which, as mentioned above, is taking due measures to enhance security. in addition, in order to improve cpec security in general and that of sezs in particular, pakistani authorities would have to tackle terrorism on multiple levels. strategically, pakistan needs to engage with its neighbors meaningfully. here, china can play a role by encouraging regional cooperation and peace. indeed, the quadrilateral afghan peace process is a step in the right direction. moreover, china-iran-pakistan trilateral engagement carries the potential to devise a collective response to anti-peace elements in the south asian region. in this respect, the visit, on april 21, 2019, of pakistani prime minister imran khan to iran was very crucial given growing strategic uncertainty in the south asian region. 72 khan paid another visit to tehran on october 13, 2019, in order to "mediate" between iran and saudi arabia. 73 if this materializes, it will carry positive implications for cpec in particular and the belt and road initiative in general. importantly, china may also convince the usa-another major stakeholder in the region-to engage pakistan, afghanistan and india in a manner that reduces strategic uncertainty. politically, pakistani government should strive to negotiate with the locally active extremist and insurgent groups. ideologically, there is a growing need to conceive and implement a pluralist narrative to counter hate mongers in pakistani society. above all, china and pakistan would have to play a central role by reinforcing the importance of peace and stability locally, nationally and transregionally. the former must understand the precarious security situation pakistan is facing where it lost around 30,000 thousand civilians and security personnel in past nineteen years. 74 nevertheless, pakistan must revisit its policies that might have provided an enabling environment to anti-humanity forces. the latter though have been militarily neutralized by the law enforcement of pakistan, certain militant organizations such as jamat-ul-ahrar and ttp, whose captive spokesperson ehsanullah ehsan escaped from detention in pakistan in february 2020, 75 still pose security challenge. such organizations are always in search of soft targets to destabilize pakistani state, society and economy. last but not least, for effective cpec security, pakistan has to take certain extraordinary measures. on the one hand, there is need to devise a strategy to have local and provincial law enforcement apparatuses, i.e., police, frontier constabulary, on board while enhancing policy and operational capacity of civil law enforcement along with improving human intelligence of strategic locations along cpec including the special economic zones. on the other hand, the local, provincial and federal governments ought to chalk out a policy framework under which the country's armed law enforcement could work effectively. the recently established cpec authority seems a step in the right direction. 76 moreover, during the visit of pakistani civil-military leadership to china in october 2019, the two sides reiterated bilateral commitment to expand cpec and speed up work on the sezs. 77 lastly, for effective surveillance of sezs and gwadar port, the chinese government can be helpful in terms of provision of sophisticated gadgets to enhance physical and infrastructural security of the enclave. within the gwadar enclave, the chinese may, in consultation with pakistani authorities, operate on its own. nonetheless, handing over of overall security of gwadar and sezs to chinese companies, both public and private, would not be suitable idea and practice given pakistan's bad experiences with american cia and blackwater. 78 since 9/11, pakistanis are overwhelming anti-usa, whereas china's perception at the popular level is, overall, positive. 79 the chinese authorities should stay mindful of popular perception. 20 killed, 48 injured in attack targeting hazara community in quetta islamabad confirms death of chinese couple abducted from quetta terror attack on chinese consulate foiled; 3 terrorists killed who is kulbhushan jadhav? pm modi raises india's concern over cpec which runs through pok cpec: governance and security challenges-implications for the belt and road initiative a historical analysis cpec projects cpec: governance and security challenges-implications for the belt and road initiative iqrar ul hassan of sar e aam exposed pak china marriages prime minister imran khan reaches iran for 2-day official visit khan leaves for tehran to mitigate tensions between iran and saudi arabia fatalities in terrorist violence in pakistan taliban militant flees prison, claiming deal with pakistani security forces post-9/11, both the countries started exploring new angles to enhance strategic cooperative partnership. with the launch of china's belt and road initiative in 2013, the china-pakistan economic corridor-as a core component of the bri-was formalized in 2015. the corridor adds not only economic dimension to bilateral relations but also serves as a catalyst for the consolidation of mutual trust and the realization of economic development of pakistan whose economy is currently underperforming. at the core of cpec lies the concept of special economic zones whose proposed number stands at nine of which, initially, four were selected for early construction pakistan establishes cpec authority china resolve to strengthen strategic partnership as pm imran concludes visit china-pakistan economic corridor after years of tension, anti-american sentiment ebbs in pakistan the remaining sezs would be established and made operational in the ongoing second phase (2020-2025) of china-pakistan economic corridor. indubitably, special economic zones offer a set of opportunities to both china and pakistan-ranging from infrastructural development to industrial cooperation. nonetheless, the sezs are prone to multiple challenges including security problems in addition, he has contributed to peer-reviewed journals such as armed forces & society and chinese political science review. dr hussain has been a visiting fellow at fudan university. he is daad, fddi and fulbright fellow. moreover, he taught at comsats university, islamabad, fc college university, lahore, and shanghai international studies university (sisu) he received certification in new media and communication from renmin university of china in 2015 key: cord-272465-i2l4cq8h authors: law, betty yuen kwan; mok, simon wing fai; wu, an guo; lam, christopher wai kei; yu, margaret xin yi; wong, vincent kam wai title: new potential pharmacological functions of chinese herbal medicines via regulation of autophagy date: 2016-03-17 journal: molecules doi: 10.3390/molecules21030359 sha: doc_id: 272465 cord_uid: i2l4cq8h autophagy is a universal catabolic cellular process for quality control of cytoplasm and maintenance of cellular homeostasis upon nutrient deprivation and environmental stimulus. it involves the lysosomal degradation of cellular components such as misfolded proteins or damaged organelles. defects in autophagy are implicated in the pathogenesis of diseases including cancers, myopathy, neurodegenerations, infections and cardiovascular diseases. in the recent decade, traditional drugs with new clinical applications are not only commonly found in western medicines, but also highlighted in chinese herbal medicines (chm). for instance, pharmacological studies have revealed that active components or fractions from chaihu (radix bupleuri), hu zhang (rhizoma polygoni cuspidati), donglingcao (rabdosia rubesens), hou po (cortex magnoliae officinalis) and chuan xiong (rhizoma chuanxiong) modulate cancers, neurodegeneration and cardiovascular disease via autophagy. these findings shed light on the potential new applications and formulation of chm decoctions via regulation of autophagy. this article reviews the roles of autophagy in the pharmacological actions of chm and discusses their new potential clinical applications in various human diseases. autophagy is the catabolic process in which eukaryotic cells engulf and lysosomally digest intracellular contents. the process maintains metabolic balance and cellular quality by removing dysfunctional cytoplasmic constituents and recycling basic molecular building blocks. macroautophagy envelops and delivers the unfavoured intracellular contents to lytic compartment through the doubled-membraned autophagosome [1] . autophagy-related proteins (atg) are the main underpinning mechanistic component of macroautophagy. about 30 mammalian homologs of yeast atg have been discovered. these proteins are responsible for the nucleation and elongation of the isolation membrane through protein complex formation [2, 3] . basal autophagy retains proper physiological functioning of cells through the control of cellular homeostasis, metabolic balance, and protein structural integrity. additionally, macroautophagy is known as type ii programmed cell death with its molecular regulation intricately interconnecting with the apoptotic mechanism [4] [5] [6] [7] . growing evidence also suggests involvement of macroautophagy in innate and adaptive immunity [8, 9] . therefore hampered autophagy is closely associated with proteinopathies, metabolic and immunological disorders. in fact, macroautophagy failure is the molecular culprit of aberrant proteins accumulation in neurodegenerative diseases such as prion, alzheimer's and parkinson's [10] [11] [12] . in metabolic diseases, altered macroautophagy is related to the mammalian tor performs its function by complexing with other proteins, and appears in two constitutively different forms which are the target of rapamycin complex 1 and 2 (mtorc1 and 2) [53] . canonically, mtorc1 masters the repression of autophagy responding to growth factor, hormone and amino acid signaling by direct interaction with the atg machinery and interference of autophagosome formation [54, 55] . compared with mtorc2, mtorc1 is better characterized which together with the tsc1/2 (tuberous sclerosis complex 1/2) complex, an mtorc1 activities suppressor, underpinning the central molecular governance of mtor cascade. this pathway contributes mainly to the integration of growth factor and insulin signaling. the tsc1/2 complexes collect the signals from cellular sensor such as insulin receptor at the plasma membrane. class i ptdlns3k is then activated and phosphorylates phosphatidylinositol (4,5)-bisphosphate (pip 2 ) to phosphatidylinositol (3, 4, 5) -bisphosphate (pip 3 ). while class iii ptdins3k product pi3p is critical for autophagy, pip 3 generated by class i ptdlns3k are inhibitory. pip 3 subsequently recruits and activates pkb [56] . during cellular energy stress, the amp: atp ratio is increased because of intracellular atp depletion [57, 58] triggering the upstream activator of ampk, liver kinase b1 (lkb1 kinase) [59] . the activated ampk can interact directly with the regulatory-associated protein of mtor (raptor) subunit of mtorc1 inactivating the protein complex thereby upregulating autophagy [60] . cytosolic calcium ion (ca 2+ ) concentration is another positive stimulation of ampk-induced autophagy which is initiated by ca 2+ /calmodulin-dependent kinase kinase β (camkkβ) and endoplasmic reticulum-localized bcl-2 [61] . accumulation of misfolded proteins is the common feature of the different neurodegenerative diseases [62] . the self-eating property of autophagy is cytoprotective which assists the clearance of the defective β-sheets enriched protein structure [63] [64] [65] [66] [67] . clinically, the beclin 1 level of ad's brain are found to be significantly depressed [68] . transgenic mouse overexpressing beclin 1 could improve parkinson's disease (pd) progression by reducing α-synuclein aggregation through the enhancement of autophagy [69] . mutant huntingtin (htt) forms, the main source of neurotoxic activities of huntington disease (hd), are sensitive to beclin 1 level as demonstrated by the increased accumulation of htt upon beclin 1 deficiency [70] . a mouse model of ad and in vitro studies showed that rapamycin effectively induced amyloid-β (aβ) clearance, and soothed the cognitive deficit [71] . lithium inhibits inositol monophosphatase (impase) which reduces free inositol and ip 3 levels promotes the removal of htt of hd and α-synuclein via autophagy [72, 73] . repressing ip 3 synthesis with the sodium salts of carbamazepine and valproate could induce similar therapeutic effects in the experimental models of hd [73] [74] [75] . another mtor-independent autophagy inducer, trehalose, is also relevant to htt, α-synuclein and tau aggregations [76, 77] . most tumor suppressors and oncogenes are actually cellular metabolism regulators responsible for metabolic pathways including aerobic glycolysis, glutaminolysis and one-carbon metabolism [78] . the major cellular energy monitor ampk, and hence the downstream autophagy up-regulated by the kinase, are closely related to cancer progression in response to metabolic stresses. ampk activators such as 5-aminoimidazole-4-carboxamide riboside (aicar) are strongly cytotoxic to the in vitro models of hepatic, gastric and prostate cancers [79] [80] [81] . many other molecular messengers along the autophagy pathways are cancer-related. for example, the induction of the oncogenic mtorc1 attenuates autophagy and support cancer development [81] [82] [83] [84] . clinical trials with cytotoxic drugs rapamycin, temsirolimus and everolimus targeting mtorc1 to induce autophagy have been reported [85] . therefore, cancer intervention with the use of autophagy inducers can trigger both autophagic cell death and physiological changes, such as cell cycle arrest, on cancer cells. this is of particular interest for most cancers and malignancies in regard to apoptotic resistance towards chemotherapies [86] . the systemic balance of glucose and fatty acid is frequently lost in patients enduring metabolic syndromes such as obesity and glucose intolerance. it is evident that the corresponding complex regulatory networks are linked up by autophagy [87] . chronic consumption of diets with high nutrient abnormally activates mtorc1 [88] . the de novo hepatic lipogenesis can then be stimulated by mtorc1 and its substrate sterol regulatory element-binding protein 1c (srebp-1c) during the obese state [89, 90] , which further dampens the expressions of the atgs lc3, beclin1, atg5 and atg7 and thus the autophagic process [91] . while activating autophagy with pharmacological inducers seems to be an ideal method for improving metabolic disorders, caloric restriction appears to be the best strategy for controlling these disorders [92] . autophagy functions as an immune effector and directly delivers the intracellular microorganism or their components [9] into the lysosome through a specific form of selective autophagy called xenophagy [93, 94] . several medically important bacterial pathogens, such as mycobacterium tuberculosis (mtb), group a streptococcus, salmonella, shigella and listeria can be degraded by xenophagy. the sindbis virus, herpes simplex virus and the parasite toxoplasma gondii can also be eliminated by xenophagy [93, 95, 96] . beyond the invading microbes, autophagy also targets the innate and adaptive immunity for preventing infections. autophagy negatively regulates il-1β and il-18 expression through maintaining the quality of the intracellular milieu [97] . the overexpression of il-1β and il-18 of lipopolysaccharides (lps)-stimulated macrophages with the loss of atg16l1 further clarified the role of autophagy in inflammatory immune responses [98] . in vitro studies have verified the potential of some autophagic inducers in infection therapy. the hormonally active form of vitamin d1, 25d3, enhanced macrophage autophagy and prevented human immunodeficiency virus (hiv) replication [99] . similarly, the small molecule pdk1 inhibitor ar12 cleared francisella tularensis [100] and salmonella enterica serovar typhimurium [100] . the therapeutic effects of the antibiotics cocktails containing isoniazid and pyrazinamide towards mtb-infected host cells also corresponded to their autophagy-inducing properties [101] . autoimmunity is the aberrant activation of immune systems towards self-antigens due to central intolerance [102] . autophagy is essential for loading the mhc ii compartment with intracellular antigens, a process involving the atg-lysosome interaction [103] , implicating the importance of autophagy in the determination of cd4 + t lymphocytes receptor repertoire. also, the autoreactive thymocytes that have been programed in thymus can be eliminated by autophagy [104] . besides, the autophagic activity is positively correlated with macrophagic expression of the proinflammatory cytokines tnf-α and il-6 which may also contribute to sle pathogenesis [105] . glucocorticoids since autophagy dysregulation underlies a broad range of pathological conditions, the successful therapeutic outcomes of using autophagy modulators, along with the expanding discoveries regarding the molecular basis of autophagy, suggest the need of intensively investigating the pharmaceutical potential of compounds with autophagy-adjusting ability (table 1) . while a number of synthetic autophagy regulators, such as tamoxifen, sorafenib and the water-soluble synthetic rapamycin temsirolimus, have been reported [112] [113] [114] , natural autophagic compounds from chms are of interested because of their potential new therapeutic applications ( figure 1 ). since autophagy dysregulation underlies a broad range of pathological conditions, the successful therapeutic outcomes of using autophagy modulators, along with the expanding discoveries regarding the molecular basis of autophagy, suggest the need of intensively investigating the pharmaceutical potential of compounds with autophagy-adjusting ability (table 1) . while a number of synthetic autophagy regulators, such as tamoxifen, sorafenib and the water-soluble synthetic rapamycin temsirolimus, have been reported [112] [113] [114] , natural autophagic compounds from chms are of interested because of their potential new therapeutic applications ( figure 1 ). induction of autophagic cells death in glioblastoma, gastric adenocarcinoma [158] ; inhibition of iav-induced autophagic cell death [159] fructus piperis longi (bi bo) warms cold, expels cold, relieves pain piperlongumine promotion autophagic cell death of breast, kidney, prostate and lung cancer cells [160, 161] blood regulating drugs rhizoma curcumae longae (jiang huang) regulates blood, moves blood, moves and regulates qi, descends the qi curcumin hinders α-synuclein accumulation in neural cells and suppression of the proliferation of glioma cells through induction of autophagy [162, 163] radix salviae miltiorrhizae (dan shen) moves blood, breaks up blood stasis, cools heat, cools blood tanshinone iia induction of autophagic cell death of leukemia via activation of ampk/mtor, erk/mtor and p70 s6k signaling [164] ligusticum wallichii (chuan xiong) moves blood, moves and regulates qi, dispels wind ligustrazine induction of cytotoxic effects in hepatocellular carcinoma and protection of the kidney from neurotoxicity through autophagy [37, 165] external using drugs venenum bufonis (chan su) opens the orifices, detoxifies, relieves pain bufalin induction of cell death in hepatoma cells and suppression of colon cancer cells proliferation through autophagy [166, 167] gamboge (teng huang) detoxifies, disperses swelling, antiparasitic, alleviates itching gambogic acid amelioration of bladder cancer and induction of cytotoxic in leukemia cell through autophagy [168, 169] spirit calming drugs radix polygalae (yuan zhi) anchors the yang, dislodges phlegm, opens the orifices onjisaponin b acceleration of the degradation of mutant α-synuclein and huntingtin in pc-12 cells through autophagy [170] ganoderma lucidum (ling zhi) tonifies the heart and qi, calms and anchors the spirit ganoderic acid c2 reduction of accumulation of mutant huntingtins in pc-12 cells, induction of autophagic cell death in melanoma cells [171] caulis polygoni multiflori (shou wu teng) calms and anchors the spirit, anchors the yang anthraquinones induction of autophagic cell death in c6 and u251 [172] fructus schisandrae (wu wei zi) harmonizes and tonifies the yin and qi, secures the essence schisandra total lignin inhibition of d-galactose-induced brain tissue aging through autophagy [173] semen ziziphi spinosae (suan zao ren) tonifies yin and blood, astringes and collects, anchors the yang jujuboside a, jujuboside b jujuboside b induces autophagic cell death in ags and hct 116 human cancer cells and suppresses tumor growth [173] succinum (ambrum) calms and anchors the spirit, sedates and cools the heart vitamin e succinate (ves) ves-induced autophagy participates in sgc-7901 cell protection by inhibiting mtor axis phosphorylation [174] 3. heat-clearing drugs are used to clear damp-heat, fire or heat in the blood and body fluids to maintain regular body temperature and normal hemostatis of body [115, 175] . radix scutellariae (huang qin) has been shown to modulate inflammatory diseases like gastroenteritis and hepatitis, and is also effective in controlling tumorigeneses [176] . the two main active components, baicalin and wogonin inhibit the release of proinflammatory mediators from different immunocellular components [177, 178] . baicalin and wogonin might be effective for inducing cytotoxicity or inhibiting proliferation in various human hepatoma [116] . the anti-cancer effects of radix scutellariae such as induction of cell death and cell cycle arrest could be mediated through autophagy [179] . although the involvement of autophagy in the radix scutellariae-triggered anti-inflammatory property is still elusive, the progression of gastroenteritis and hepatitis are highly autophagic-related [180] , suggesting the potential autophagic role of radix scutellariae in such diseases. all these observations suggest that a main part of the clinical functions of radix scutellariae as documented in chinese traditional medical references are manifested via autophagy. cortex phellodendri (huang bo) with berberine as its active ingredient after bark extraction has been traditionally prescribed for the treatment of pneumonia, tuberculosis, meningitis and liver cirrhosis [181, 182] . cortex phellodendri is anti-inflammatory in nature, which helps to eliminate invading pathogens, ameliorates acetaldehyde-induced hepatic nf-κb activation during cirrhosis [183, 184] , and inhibits glial proinflammatory inos (nitric oxide synthase) and tnf (tumor necrosis factor)-α activity [185] . berberine modulates autophagic processes through the ampk/mtor signaling pathway [117, 186] , therefore, the observed anti-inflammatory capability of cortex phellodendri was likely related to berberine-induced autophagy [118, 187] . recently, the dietary supplement nexrutine ® which contains berberine, has been found to have therapeutic potential towards melanoma, multiple myeloma, prostate, pancreatic, breast and non-melanoma skin cancer [188] [189] [190] [191] [192] . since berberine could induce both apoptosis and autophagy during tumorigenesis [193] , autophagy may be responsible for the newly discovered anti-cancer properties of cortex phellodendri. rhizoma coptidis (huang lian), containing the active component berberine, has been traditionally used in alleviating inflammatory disorders, including type ii diabetes. pharmacological studies have reported the anti-inflammatory effects of rhizoma coptidis. for example, berberine was effective in repressing the adverse responses caused by atherosclerosis (as) [194] . rhizoma coptidis was beneficial to the treatment of intestinal infections [195, 196] , and gut-associated abnormalities such as irritable bowel syndrome [197] . furthermore, berberine induced autophagy [117, 186] and suppressed the pro-inflammatory phenotype of macrophages [118] . in response to the anti-diabetic effect of rhizoma coptidis, autophagy was important for regulating the synthesis and secretion of insulin by pancreatic β-cells [17] . recent studies have also reported the potential of rhizoma coptidis in neurodegeneration therapy [198, 199] . with the protective role of autophagy in neurodegenative and inflammatory diseases, it is notable that the protective effect of rhizoma coptidis may be regulated through autophagy. radix sophorae flavescentis (ku shen) was used to alleviate toxicity, killed parasites and induced diuresis according to chinese medicinal theory [200] . many traditional formulas contain radix sophorae flavescentis, for example, "xiaofeng san" was prescribed for treating cutaneous disorders [201] , and "sanwu huangqin tang" has long been used for post-partum fevers arising from reproductive organ infections during childbirth [202] . these therapeutic effects suggest the immunomodulatory and anti-inflammatory function of radix sophorae flavescentis may be attributed to the maintenance of systemic homeostasis by clearing off metabolic wastes through autophagy. the active component of radix sophorae flavescentis is matrine, which is pharmacologically related to the suppression of inflammation by inhibiting neutrophil infiltration and oxidative stress, as well as reducing the production of inflammatory mediators [203] . also, matrine has been reported as t cell anergy inducer through regulating the expression of anergy-associated genes such as jumonji and cd98 [204] . the autophagic effects of matrine have suggested radix sophorae flavescentis as a promising anti-cancer herb. for example, matrine was able to induce autophagic cell death against certain cancers [119, 205, 206] , a pharmacological action which has not been reported in chinese medicinal documents. although no direct linkage between radix sophorae flavescentis-induced autophagy and its traditional immunity regulatory effects has been reported, owing to the significant role of autophagy in immunomodulation, the involvement of such a process cannot be neglected. herba rabdosiae (dong ling cao) has been extensively used in cancer therapy [207] . this herbal drug was also effective in encountering inflammation, oxidative stress and pathogen invasion [207] . oridonin, an active component of herba rabdosiae, attenuated neuroinflammation and associated oxidative stress by repressing the microglial production of nitric oxide and pro-inflammatory cytokines like il-1b and il-6 [208] . oridonin inhibited cancer growth by repressing the expression of proinflammatory mediators like il-33 and bone morphogenetic protein-2 (bmp-2) [209] . therefore, the traditional anti-cancer property of herba rabdosiae is highly correlated to autophagy. radix isatidis (ban lan gen) is a popular herbal medicine, especially after the severe acute respiratory syndrome (sars) epidemic, for its clinical applications in upper respiratory tract infections, including the nose, throat, and sinuses [210] . it is also prescribed for other viral infections like measles and hepatitis [211, 212] , etc. the active components of radix isatidis are bis-benzylisoquinoline alkaloids-fangchinoline and tetrandrine. these active ingredients interact with invading pathogens and modulate the host responses. for example, fangchinoline could stop the replication of human immunodeficiency virus (hiv) type 1 by disturbing the proteolytic process of viral gp160 [213] ; tetrandrine suppressed hepatitis through the repression of nf-κb activation [214] . in addition, fangchinoline activated autophagic cell death through the p53/sestrin2/amp pathway in hepatocellular carcinoma [127], whereas tetrandrine inhibited leukemia cell proliferation and induced autophagy in vivo. to our knowledge, the use of radix isatidis in anti-cancer therapy has not been reported, therefore, these findings shed light to the development of the new usage of radix isatidis in oncology through induction of autophagy. however, the role of autophagy in mediating the traditional anti-inflammatory function of radic isatidis remains to be investigated. stephania japonica (qian jin teng) has been traditionally used for relieving fever, diarrhea, dyspepsia and urinary disease [215] . cepharanthine and dauricine are the active components of the herb that have been commonly used for inflammatory and immunological disorders in chinese medicine [216, 217] . animal and in vitro studies illustrated that cepharanthine suppressed cytokine synthesis, platelet aggregation, plasma membrane lipid peroxidation, and nuclear factor-κb (nf-κb) stimulation [217] . the herb also facilitated the removal of free radicals and alleviated oxidative stress [218, 219] . dauricine exhibited similar anti-inflammatory effects through repressing the expression of inflammatory indicators such as myeloperoxidase, il-1bβ and tnf-α [220] . recently, these two compounds have been postulated as novel anti-cancer drugs. for example, cepharanthine abolished the drug resistance property of cancer cells by modulating the activities of multidrug resistance factor abcc10 (mrp7) and atpase [221] . dauricine had been reported to suppress cancer proliferation and invasion, and promote apoptosis through the nf-κb signaling pathway [216] . although documentation associating autophagy with the immunomodulatory effects of cepharanthine, dauricine or stephania japonica is scarce, our laboratory discovered that both bioactive components induced autophagic cell death in apoptosis-resistant cancer cells [26] . these findings suggest cepharanthine and dauricine repress cancer growth through autophagy induction, and stephania japonica may be a potential pharmaceutical agent for cancer. rhizoma polygoni cuspidati (hu zhang) has been used to relieve inflammation, coughing, fever, and provide diuretic, emmenagogue, emollient and stomachic actions [222, 223] and against tumor activity [223] . resveratrol, the active compound of rhizoma polygoni cuspidati, is a natural antibiotic [224] which inhibits the growth of bacteria and fungi [225, 226] . resveratrol exhibited its anti-inflammatory effect through inhibiting pro-inflammatory mediator synthesis [227] . resveratrol also repressed tumorgenesis [228] [229] [230] . increasing evidence has shown the autophagic role of resveratrol. for example, resveratrol attenuated the inflammatory phenotype of vascular endothelium through up-regulation of autophagy [128] , and induced autophagic cell death in glioma and adenocarcinoma [129, 130] . recently, resveratrol-induced cardioprotection was found to associate with mtorc2-mediated autophagy and the up-regulation of antioxidant proteins [231, 232] . therefore, autophagy could be the underlying molecular mechanism responsible for the protective effects of rhizoma polygoni cuspidati. herba scutellariae barbatae (ban zhi lian) has long been used for cancer therapy [233] . it is also effective in treating inflammatory-related symptoms, for example, furunculosis, pyogenic infections, traumatic injury, edema, venomous snake bite, and jaundice [234] . the active ingredient of the herb, pheophorbide, inhibited cytokines expression and monocyte activities, down-regulated macrophage expression of inos, and scavenged reactive oxygen species (ros) [235] . in addition, pheophorbide was cytotoxic to hepatocellular carcinoma [236] and breast adenocarcinoma [131] . thus far, literatures correlating pheophorbide and autophagy were mostly about the photodynamic therapy of tumorigenesis involving the induction of autophagy and cancer cell death. in breast adenocarcinoma, pheophorbide induced autophagy through the erk signaling pathway [131] . it also induced both apoptosis and autophagy via erk1/2 and p38 in skin cancer [237] . such autophagy-related therapeutic effect of pheophorbide has also been described in oral squamous carcinoma cells and hormone insensitive prostate cancer [132, 133] . accordingly, the anti-cancer effect of herba scutellariae barbatae could be partly mediated by autophagy. nelumbo nucifera (lian hua) has been used for maintaining homeostasis, reducing anxiety, acting against bleeding, and repressing inflammation [238] . neferine is one of the active components responsible for maintaining glucose and lipid balance during starvation [239] . anti-inflammatory and anti-oxidative effects of neferine in neurodegenerative disease by suppressing nf-κb activation and lipid peroxidation have also been reported [240] . protective effects of neferine towards inflammation and oxidative stress were observed in pulmonary fibrosis [241] . emerging findings suggest that autophagy is one of the pharmaceutical targets of nelumbo nucifera. for example, neferine attenuated mutant huntingtin toxicity by inducing the ampk-mtor-dependent autophagic pathway [134] . such findings correlated the psychopathological regulatory effects of neferine to autophagy. neferine induced autophagy via the ros mediated pathway in lung cancer [135] , and was found effective in suppressing hepatocellular carcinoma [242] . these findings confirmed the role of the compound in controlling inflammatory progression and its novel usage in tumorigenesis. therefore, triggering autophagy by nelumbo nucifera could be a new pharmaceutical strategy for encountering inflammatory, neurodegenerative and cancerous diseases. syzygium samarangense (lian wu) possessing the anti-free radical ability is indigenously used to manage inflammation-related conditions and removal of oxidative stress [243, 244] . dimethyl cardamonin (dmc) is the active compound isolated from the leaves of syzygium samarangense contributing mainly to the anti-inflammatory and anti-oxidative properties. dmc protected the cells from ros damage by modulating the glutathione s-transferase and superoxide dismutase (sod) activities [245, 246] . the compound also attenuated nf-κb activation and relieved cellular inflammatory phenotype with decreased serum level of proinflammatory cytokines [247, 248] . recent studies have suggested autophagy induction by dmc was associated with proliferative arrest in colorectal carcinoma by stimulating the p53/jnk-dependent signaling [249, 250] . the therapeutic effects of dmc-induced autophagy have also been reported in cancers of the pancreas and prostate, myeloid leukemia and multiple myeloma [136] . although the autophagic role of syzygium samarangense in anti-inflammation remains to be elucidated, the induction of autophagy is highly correlated to the syzygium samarangense-induced anti-cancer effects. trichosanthes kirilowii (cucumber) has been used as folk medicine for the treatment of inflammation and cancer [251] . pharmacological research further proposed trichosanthes kirilowii as a potential remedy for suppressing hiv replication [252] . cucurbitacin d, a major component of the herb, is an anti-inflammatory compound which inhibited pro-inflammatory mediator production via inos and nf-κb signaling [253, 254] and cyclooxygenase-2 (cox-2) [255] . cucurbitacin d was effective in the protection against hepatic and cardiovascular damages, the alleviation of diabetic condition, and the removal of invading microbes [256, 257] . cucurbitacin d could be used for repressing tumorigenesis of colorectal carcinoma [258] , breast adenocarcinoma [259] , and leukemia [260] . recent findings have demonstrated that structural analogues of cucurbitacin d, for example, cucurbitacins b, e and i, induced autophagy and are potentially beneficial to cancer intervention. cucurbitacin b triggered autophagy in breast cancer cells by manipulating the ros activities [137] , and in melanoma cells via c-jun n-terminal kinase (jnk) activation [138] . cucurbitacin e induced autophagy in cervical and breast cancer cells via activation of ampk signaling [261] . similar therapeutic effects have also been reported in cucurbitacin i treatment of glioblastoma [262] . all these observations point towards the likelihood of involvement of cucurbitacin d in autophagy-induced anti-tumor effects. mallotus philippensis (cu kang chai) has been used for alleviating inflammatory symptoms caused by bronchitis, rheumatism and infection. the herb is useful in eliminating parasite invasions such as tapeworm [263] . rottlerin, one of the major active components of the herb, also manifested potent anti-inflammatory properties. rottlerin regulated inflammatory mediators including cox, protein kinase c δ, lipoxygenase, heme oxygenase and nf-κb [139] . besides, it also suppressed the progression of malignant cancers by increasing the susceptibility of cancer cells towards apoptosis [264] [265] [266] . in addition, the anti-tumor effects of rottlerin were associated with its autophagy activation property in certain cell types [140, 267, 268] . rottlerin induced apoptosis and autophagic cell death in prostate [141] and pancreatic cancers via the inhibition of pi3k/akt/mtor signaling [142] . rottlerin also triggered apoptosis and autophagic cell death in fibrosarcoma cells through a pi3k/akt/mtor-independent pathway [140]. these findings, together with the protective role of rottlerin in preventing the spreading of misfolded proteins including prion protein, amyloid aβ, and α-synuclein [139], suggest that mallotus philippensis could be used as a novel therapeutic intervention for cancer-related and neurodegenerative disorders based on its autophagy-inducing ability. whether autophagy is involved in the traditional anti-inflammatory effects of rottlerin or mallotus philippensis is yet to be determined. rhizoma anemarrhenae (zhi mu) has been used for minor symptoms like cough, fever and constipation [269, 270] . the herb was also effective in treating diabetes [271] . one of the active components extracted from rhizoma anemarrhenae, timosaponin aiii, relieved inflammation and oxidative damages by regulating the cytosolic ca 2+ concentration of endothelial cells [272] , and neutrophilic superoxide generation stimulated by arachidonic acid [273] . recent pharmacological studies demonstrated that the anti-tumor effect of timosaponin aiii was associated with autophagy. timosaponin aiii elicited autophagy and cytotoxicity in cervical cancer which was independent of apoptosis [274] . it also repressed mtor activity, triggered er stress and autophagic cell death in breast cancer [275] . as demonstrated in an insulin resistance rodent model, timosaponin aiii-induced autophagy may be responsible for its diabetes-ameliorating effect through activation of ampk [271] . in neurodegeneration model, timosaponin aiii activated autophagy and facilitated the downstream sequestration of aggregation-prone ubiquitinated proteins [143] . these findings implied the pharmaceutical potential of applying rhizoma anemarrhenae for the treatment of cancers and neurodegenerative diseases. these herbs are used when the zheng qi (normal body condition or upright qi) is weakened, for example, during recovery from illness, during childhood or in old age. the herbs have the ability to tonify (bu), nourish, supplement and strengthen human body [115, 276] . radix glycyrrhizae (liquorice, gan cao) is traditionally used as adjuvant to modify the efficacy of other herbs in a single prescription of around 80% of chinese herbal formulas [277] , which acted against inflammatory symptoms such as relieving cough, sore throat and phlegm production. it is important for maintaining a proper stomach function and is used for stomach ulcers. licochalcone a (la) and isoliquiritigenin (isl) are compounds extracted from radix glycyrrhizae. la exhibited anti-inflammatory effects which suppressed pro-inflammatory mediator expression [278, 279] , and cleared cellular oxidative stress [280] . isl demonstrated anti-oxidative [281] and immunomodulatory effects [282] . of note, emerging data suggest that the anti-cancer properties in both compounds are associated with autophagy. la induced autophagy via pi3k/akt/mtor signaling which repressed cervical cancer growth [283] . androgen-sensitive prostate adenocarcinoma and adenoid cystic carcinoma were sensitive to la-and isl-induced autophagic cell death mediated by mtor inhibition [146, 284] . isl also suppressed breast cancer progression through autophagy induction [285] . therefore, radix glycyrrhizae has the chemotherapeutic potential to function as an effective cancer therapeutic. further investigation is needed for clarifying the mediating role of autophagy in the traditional anti-inflammatory effects of the herb. radix dipsaci (xu duan) has been used for intervention in osteoporosis, strengthening of tendons and ligaments, and alleviating joint stiffness symptoms by promoting blood circulation in close proximity to the affected areas. the herb exhibits anti-inflammatory properties as reflected by its application in reducing abscesses, swellings, and sores [286] . in addition, radix dipsaci helped to prevent abortion, which implies a regulatory role in the immune system [287] . akebia saponin pa (as) is one of the bioactive components found in radix dipsaci, as induced autophagic and apoptotic cell death of gastric cancer cells through both the ampk/mtor and pi3k/akt/mtor signaling and the downstream activation of p38/jnk molecular pathway, which facilitated capase-3-dependent apoptosis [147] . this finding pointed towards the potential therapeutic role of radix dipsaci in cancers. also, the possibility that autophagy may participate in the immunomodulatory and anti-inflammatory functions of radix dipsaci should not be ignored. radix ginseng (ren shen) has been prescribed for maintaining bioenergetics balance as suggested by chinese herbalists for breathlessness, anorexia, hypodynamia, and diabetes [288] . since, one of the main functions of autophagy is to retain energy homeostasis, it may be related to the traditional use of ginseng as mentioned. pharmacological studies revealed that the bioactive ginsenosides including rb1, rg1, rg3, rh1, re, and rd [289] ameliorated inflammation, removed oxidative stress, stimulated immune system and regulated apoptosis. therefore, radix ginseng may cure more diseases than traditionally known. radix ginseng illustrated beneficial effects in neurodegenerations in part due to its anti-oxidative [290] and anti-apoptotic properties [291] . similar therapeutic uses of radix ginseng have also been reported in cardiovascular disease [292] , and cancers [293] . recent researches have focused on studying the autophagic mechanisms of radix ginseng. rb1 suppressed neurotoxicity through inhibiting autophagy by beclin-1 downregulation [148] . the compound could also enhance cardiac muscle cell survival through autophagy [149] . the minor rb1-derived ginsenoside f2 [294] and rg3 could regulate autophagy leading to the suppression of breast cancer stem cells [295] and hepatocellular carcinoma [296] , respectively, suggesting the role of autophagy in the potential new therapeutic action of ginseng. peschiera fuchsiaefolia (dao zhong sha ma cha) showed in vitro antimalarial activity against plasmodium falciparum [297] . voacamine (voa), a bioactive alkaloid extracted from the herb [298, 299] , has been reported to induce autophagic cell death of multidrug-resistant osteosarcoma, and inhibit the action of transporter p-glycoprotein (p-gp) [150] . voa is the ligand of p-gp which expresses in kidney, gastrointestinal tract, brain, etc. [300] . in fact, diabetes mellitus is associated with p-gp dysregulation [301] . also, the blood brain barrier (bbb) p-gp was associated with abnormal protein aggregation in alzheimer's and parkinson's diseases, suggesting the potential use of the herb in neurodegenerative disorders [302] . therefore, the well-known autophagic involvement in diabetes mellitus and neurodegenerations strongly advocated that peschiera fuchsiaefolia may act therapeutically as novel autophagy regulators under such pathological conditions. radix ophiopogonis (mai dong) has been used for treating inflammatory symptoms such as cough and phlegm production, and cardiovascular diseases [303] . ophiopogonin (op)-b is one of the bioactive components, and was found to be an inducer of autophagy. in non-small cell lung cancer, op-b up-regulated autophagy of tumor cells through pi3k/akt pathways, and induced apoptosis-independent cell death and silences [144] . another active constituent, op-d exhibited anti-inflammatory effects through direct inhibition of mitochondrial ros synthesis [145] . however, such an anti-inflammatory effect was not related to op-d-induced upregulation of autophagy, as the compound could in fact suppress autophagy per se [145] . therefore, owing to the close relationship between inflammation progression and autophagy, together with the autophagy modulating role of op-b and op-d, it is predicted that the compounds may contribute to the anti-inflammatory activity of the herb by regulating autophagy. also, the findings of op-b in inducing autophagic cancer cell death suggest the alternative use of radix ophiopogonis in cancer therapy. these drugs help our body defenses against external stimulus, including invading pathogens, cold, heat, damp-wind or summer heat that may have a noxious effects on the human body, by maintaining a normal and healthy status of organ such as the stomach (wei qi) [115, 276] . radix bupleuri (chai hu) has been used for counteracting different inflammatory conditions including pancreatitis, liver cirrhosis and fever, infections like malaria and common cold, modulating abnormal lipid metabolism and relieving depression [304] . the bioactivities of the main components, the saikosaponins, are responsible for the mentioned clinical indications. for instance, saikosaponins modulated host immunity by manipulating pro-inflammatory mediator release and lymphocyte responses [305] . saikosaponins also repressed viral replication [306] and fever [307] , reduced hepatotoxicity [308] and acted as tranquilizers [306] . direct evidence for the participation of autophagy in regulating such activities is however lacking. however, contemporary studies verified the anti-tumor effect of saikosaponins, in particular ssd (saikosaponin-d), through autophagy regulation. ssd was cytotoxic to different cancers, such as breast and cervical cancers by increasing autophagy-induced er stress via the camkkβ-ampk-mtor signaling [25, 31] . in fact, formulated decoctions containing radix bupleuri have been prescribed for cancer therapy [309] , which supports the idea that radix bupleuri is a novel autophagy enhancer exhibiting therapeutic effects towards cancers. rhizoma zingiberis recens (sheng jiang) has been used for centuries for the treatment of colds, arthritis, migraines, nausea and hypertension [310, 311] . 6-gingerolis is the most abundant bioactive ingredient found in rhizoma zingiberis recens. it suppressed oxidative stress by inhibiting inos activity of activated macrophage [312] . 6-gingerol affected the anti-inflammatory properties by regulating ca 2+ , which may be related to the regulation of autophagy [313] . the anti-mentic qualities of rhizoma zingiberis recens are also related to 6-gingerol through inhibition of the function of serotonin 3 receptor [314] . in addition, rhizoma zingiberis recens-mediated new anti-tumor functions via autophagy induction were further clarified. for instance, 6-gingerol induced cervical cancer cell death by upregulating caspase 3-mediated apoptosis, and autophagy partly via the repression of akt signaling [315] . in pancreatic cancer, 6-gingerol induced cytotoxicity exclusively through autophagy by activating ampk-mtor signaling, which is a process independent of necroptosis and apoptosis [151] . these herbs are responsible for treating painful obstruction (bi) syndromes due to wind (wind-bi syndrome), cold (cold-bi syndrome), dampness (dampness-bi syndrome) or heat (heat-bi syndrome), which are caused by poor qi or blood circulation [115, 276] . radix tripterygii wilfordii (lei gong teng) has been used for the treatment of inflammation and overactive immune system, including rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis [316] . celastrol is the bioactive component responsible for exhibiting the anti-inflammatory and anti-oxidative effects for alleviating autoimmune disorders such as chronic inflammation, neurodegenerative disease, and asthma [317] . recent findings suggested the use of celastrol in cancer therapy as demonstrated by its inhibitory effects in different tumors [318] . emerging data revealed that autophagy was one of the molecular machineries mediating these celastrol-induced therapeutic functions. by regulating the ros/jnk signaling pathway, celastrol triggered autophagy and apoptosis which further repressed the proliferation of osteosarcoma cells in both animal and cellular models [152] . beside, autophagy induction by celastrol through the inhibition of pi3k/akt/mtor signaling, have demonstrated therapeutic potential in inflammatory disorders such as crohn's disease, which implies that the traditional functions of radix tripterygii wilfordii are mediated through the regulation of autophagy [319] . the compound also prevented neurodegeneration by inducing autophagy in affected neuronal cell death via the targeting jnk and pten-akt/mtor network [153] . radix stephaniae tetrandrae (fang ji) is used for the treatment of edema, anti-hypertension and analgesic, and was usually used as decoction such as "fang ji huang qi tang" [320] . the main bioactive constituents of the herb are fangchinoline and tetrandrine. both compounds are able to modulate cytokine expression and exhibit anti-inflammatory effects [321] . fangchinoline reduced blood glucose levels, scavenged free radicals and reduced oxidative stress [322] . tetrandrine exhibited anti-hypertensive action by disrupting ca 2+ movement and no synthase activity [323] . although the role of autophagy modulation in such alteration of glucose and ca 2+ level remains elusive, both fangchinoline and tetrandrine have been reported to contribute their anti-tumor effect through autophagy. the proliferation and invasion of gastric cancer cells could be suppressed by fangchinoline mediated inhibition of pi3k/akt signaling [324] . the compound also triggered autophagic cell death by targeting the p53/sestrin2/ampk signaling in hepatocellular carcinoma [127] . in leukemia cells, autophagy was induced by tetrandrine through the upregulation of notch1 and ros signaling [154] . these autophagy-related anti-tumor activity stimulated by fangchinoline and tetrandrine encourage the further development of radix stephaniae tetrandrae as an effective drug for cancer therapy. radix plumbaginis zeylanicae (bai hua dan) has effects in relieving pain, activating blood circulation, and is used for menstrual disorders, detoxification, and elimination of intestinal worms. plumbagin, the bioactive component of the herb, is well known for its therapeutic safety and effectiveness [325] . pharmacological studies demonstrated that plumbagin modulates the immune system and resolves inflammation [326, 327] . the compound facilitates microbe clearance [328] and modulates lipid metabolism [329] . however, the role of autophagy in mediating these traditional functions of the herb remains to be elucidated. recently, the anti-tumor activities of plumbagin have been increasingly reported [155, 330] . the anti-tumor properties of plumbagin were attributed to the autophagy induction ability of the compound. for instance, plumbagin induced autophagic cell death in breast cancer via the akt/mtor signaling pathway [155] . the compound also triggered apoptosis and autophagic cell death in lung cancer and tongue squamous carcinoma cells through the mtor signaling pathway [331] . these herbs are prescribed when there is an accumulation of dampness. this kind of disturbance in body fluid (water) metabolism is related to a dysfunction of the lung, spleen, kidney or bladder [115, 276] . rhizoma alismatis (ze xie) is derived from the stem tuber of alisma orientale [332] . the herb reduces the circulatory levels of cholesterol and blood sugar, and promotes urine production and perspiration, which helps to resolve symptoms like chronic nephritis and edema [333] . alisol b is the active component of rhizoma alismatis which improved lipid metabolism by inhibiting the absorption and synthesis of cholesterol [332] . alisol b23-acetate, another important constituent of rhizoma alismatis, participates in inhibiting antibody-mediated allergic reactions, and lipopolysaccharide (lps)-induced inos and no production [334] . up to now, it is still questionable if autophagy mediates the traditional functions of rhizoma alismatis or its bioactive constituents as mentioned. however, alisol b has been reported as a new autophagy inducer functioning through activation of camkk/ampk/mtor signaling, induction of apoptosis and triggering of cell death in breast cancer cells [156] . the anti-tumor effects of alisol b23-acetate have also been reported in hepatocellular carcinoma [156] . therefore, rhizoma alismatis has high potential to be developed as an anti-cancer drug through regulation of autophagy. cortex magnoliae officinalis (hou po) helps remove chest stuffiness due to phlegm accumulation, and relieves distension, which suggest its regulatory role in the immune system [335] . in consistence with the clinical indications of cortex magnoliae officinalis, the bioactive component, magnolol, alleviated acute pain and endothelial damage stimulated by inflammation [336] . other pharmacological effects of the compound included the reduction of anxiety and irritability via the regulation of γ-aminobutyric acid (gaba) receptor expression [337] . magnolol also possessed anti-fungal properties [338] , and was applied for bone repair by regulating the activities of osteoclasts and osteoblasts [157] . magnolol also interplayed with the autophagic process which was beneficial to cancer therapy, but seemed not to be related to the traditional immunomodulatory effects of the herb. it induced autophagic cell death of lung cancer by blocking the pi3k/pten/akt pathway [339] . ery5, a compound derived from magnolol, activated autophagy and suppressed angiogenesis, causing apoptosis-independent cytotoxicity in prostate cancer cells [336] . based on these observations, the effects of cortex magnoliae officinalis on autophagy appear to be a valuable research niche in the search of new cancer treatment modalities. these herbs are used to warm the interior organs, expel cold, tonify yang and rescue harmed yang qi and relieve pain. interior cold of the human body can be caused by exogenous cold, or kidney yang deficiency which finally results in spleen and heart yang deficiency [115, 276] . fructus evodiae (wu zhu yu) was effective for the treatment of gastrointestinal and menstrual disorders, postpartum hemorrhage and headaches [340, 341] . pharmacological studies of the bioactive component, evodiamine, showed that the compound is anti-inflammatory in nature by inhibiting cox-2 expression [342] , and inducing blockage of preadipocytes differentiation [343] . evodiamine also induced apoptosis and suppressed proliferation of cancer cells [158] . in addition, evodiamine could induce autophagic cell death in glioblastoma by quenching calcium/jnk signaling and apoptosis [158] . through the modulation of beclin-1 and bcl-2 expression, evodiamine induced autophagic cell death and apoptosis of gastric adenocarcinoma cells, respectively [344] . in a drug screening test, evodiamine was found to inhibit autophagic cell death of infected cells upon viral inoculation of influenza a through ampk/tsc2/mtor signaling [159] . therefore, evodiamine regulated autophagy through a complex molecular network, further verification of such a circuit would help to discover and standardize the novel usage of evodiamine and fructus evodiae. further investigations correlating autophagy induced by evodiamine or fructus evodiae to their traditional use should also be undertaken. fructus piperis longi (bi bo) represses cough and fever, relieves allergic symptoms like asthma, helps cease pathogen invasions, reduces blood glucose level, induces coronary vasodilation and treats jaundice [345] . the active components, piperlongumine and its derivatives, inhibit pro-inflammatory mediator synthesis [346] . these compounds remove oxidative stress and prevent cardiac damage caused by ros [347] . they also inhibit platelet aggregation and are used as crude drugs for promoting peripheral blood circulation [348] . amongst the diverse pharmacological activities, the potential piperlongumine-induced cytotoxic effects towards the different cancer cells have aroused the most attention [349, 350] . for example, autophagy induced by piperlongumine mediates the anti-tumor effects of the compound. piperlongumine attenuates akt/mtor signaling and promotes autophagic cell death of cancer cells originated from breast, kidney, prostate and lung [160, 161] . piperlongumine induces autophagy by targeting the p38 signaling in osteosarcoma [351] . apart from regulating tumorigenesis, the traditionally reported anti-inflammatory effect of the compound partly results from autophagy enhancement [352] . these herbs are used to treat malfunctions in maintaining normal blood hemostasis, such as: (1) mild forms of blood stagnation caused by slow blood flow which may lead to blood stasis; (2) severe forms of stagnation due to congealment of phlegm, heat or cold, which lead to formation of solid masses and blood circulation stasis [115, 276] . rhizoma curcumae longae (jiang huang) is a safe chm for alleviating intermittent fever and inflammation of the bronchi, kidney and gall bladder, counteracting infections such as leprosy and cold, and treating of edema, diarrhea and cancer [353, 354] . curcumin, the main bioactive component of rhizoma curcumae longae, possesses a unique structure amongst other active constituents extracted from the herb. such characteristics conferred curcumin with pharmacological properties per se correlating with the clinical efficacy of rhizoma curcumae longae. the compound has been associated with the capability of preventing inflammation [355] , tumor progression [356] , and oxidative stress accumulation [357] . of note, curcumin was pharmacologically beneficial to neurodegenerative disorders [358, 359] . the compound was particularly suitable for neurodegeneration intervention since the compound could cross the bbb after oral administration, acting as an anti-inflammatory and antioxidant drug, and amyloid aggregation inhibitor [360, 361] . in a parkinson's disease model, curcumin triggered autophagy in neural cells by suppressing the mtor/p70s6k signaling which hindered the downstream α-synuclein accumulation [162] . in addition, curcumin-induced autophagy was correlated to its anti-cancer properties. by the up-regulation of erk1/2 and akt/mtor/p70s6k signaling, curcumin induced autophagy and suppressed the proliferation of glioma cells [163] , suggesting the possible autophagic role of curcumin in various disease models. radix salviae miltiorrhizae (dan shen) has been shown to prevent platelet aggregation and facilitate fibrinolysis [362] . it is a traditional remedy for managing coronary heart disease [363] . the herb was also used as ingredient in formulations for diabetes such as "tangzhiqing" [364] , and was prescribed for hepatic and renal disorders [365] . tanshinone iia is the main bioactive component abundantly found in radix salviae miltiorrhizae. it modulates inflammation and host immunity by acting on multiple targets depending on the cell types [366] . for instance, tanshinone iia inhibited macrophagic nf-κb activation via the erk1/2, p38 and jnk pathways [367] . in line with the clinical indications of radix salviae miltiorrhizae, tanshinone iia was cardioprotective through its action upon calcineurin/nfatc3 pathway [368] . intriguingly, calcineurin regulated ampk-dependent autophagy of cardiomyocytes upon oxidative stress [369] implying that the process may underlie the cardioprotective function of radix salviae miltiorrhizae. in terms of autophagy regulation, tanshinone iia has been reported to induce autophagic cell death of leukemia via activation of ampk/mtor and erk/mtor, as well as p70 s6k signaling [164] . such observations suggested new potential uses of radix salviae miltiorrhizae in the treatment of cancer via autophagy. rhizoma chuanxiong (chuan xiong) is well known for its efficacy in improving blood fluidity, coronary and systemic circulation [370] . contemporary studies have demonstrated that the herb modulates the proliferation of vascular smooth muscle cells [371] and prevents endothelial cell damage [372] . ligustrazine (tetramethylpyrazine) is the active constituent which increases myocardial contractility and coronary circulation [373] . in addition, this single molecule acts as an anti-oxidant to remove superoxide anion, hydroxyl and lipid peroxyl radical which induce oxidative damages in tissues [374] . however, it is not known if autophagy is modulating the cardioprotective functions of the herb. ligustrazine exhibits neuroprotective and anti-inflammatory effects on brain disorders such as cerebral ischemia, through elevating nuclear factor e2-related factor 2 (nrf2)/heme oxygenase-1 (ho-1) expression [375] . recently, ligustrazine has been reported to induce autophagy which was associated with cytotoxic effects toward hepatocellular carcinoma [37] . the ligustrazine-induced autophagic effect has also been demonstrated in protecting the kidney from neurotoxicity [165] . therefore, the mechanisms underlying the rhizoma chuanxiong or ligustrazine-induced autophagic process are intricate. further investigations are needed to support the usage of the herb in pathological condition such as cancer and inflammation conditions. these kinds of compounds are applied to eliminate toxins, kill parasites, diminish swelling, relieve pain, expel pus and abscesses, improve wound healing, stop itching or bleeding [115, 276] . venenum bufonis (chan su) is famous for its clinical application in resolving cardiovascular and inflammatory symptoms, including sore throat and tonsillitis, promoting urine production, and acting as an analgesic agent [376] [377] [378] . in modern chinese medicine, venenum bufonis was used in liver cancer therapy [378] . bufalin is one of the constituents of venenum bufonis exhibiting bioactivities related to the clinical indications described [379] . recently, bufalin was found to regulate autophagy via cell type-dependent mechanisms to suppress tumorigenesis. in liver cancer, bufalin interacted with the atg8, jnk, becn-1 and tnf signaling, and stimulated autophagic cell death of hepatoma cells like huh7, hep3b and ha22t [380] . on the other hand, bufalin stopped the proliferation of hepatocellular carcinoma by activating autophagy through the akt/mtor and ampk/mtor pathways respectively [166] . the bufalin-induced autophagic cell death also effectively suppressed colon cancer cell proliferation via jnk activation [167] , and the pten/akt pathways [381] . through targeting ampk and the downstream p70s6k, bufalin modulated the apoptotic and autophagic activities of glioma cells [382] . collectively, these findings support the traditional use of venenum bufonis in the treatment of cancerous diseases via autophagy regulation. garcinia hanburyi (teng huang) was used traditionally for treating inflammatory conditions and immunity dysregulation such as ulcerative gingivitis, skin infection, scald and burn, and chronic eczema [383] . the herb was also applied to cease traumatic bleeding, attacking toxin and parasites [383] . gambogic acid is the major active ingredient of garcinia hanburyi biologically alleviating pain, inflammation, and fever [384] . recent investigations strongly suggest that gambogic acid is anti-tumor in nature by suppressing the proliferation of cancers of lung [385] , liver [385] , blood [386] and stomach [387] . further studies revealed that gambogic acid triggered autophagy and ameliorated bladder cancer by modulating the beclin-1, p62 and nf-κb activities [168] . by up-regulating the beclin-1 expression, gambogic acid induced cytotoxic in leukemia cells through the induction of autophagy and apoptosis [169] . apparently, garcinia hanburyi and gambogic acid have the potential to be further developed as novel and effective anti-cancer therapeutic strategy. it is also important to verify if autophagy is mechanistically meditating the garcinia hanburyi-induced inflammatory and immunological regulations. these herbs can be used to treat mental syndromes related to heart (blood and yin) deficiency such as over-activity of the heart, nervousness, fright, restlessness, irritability, insomnia, palpitations or anxiety; or treat syndromes related to liver (yin and yang) deficiency such as dizziness and headaches. this group of drugs is also prescribed to pacify internal wind which can contribute to tremor, spasms, paraesthesias of the limbs, dizziness or difficulties in walking [115, 276] . radix polygalae (rp) (yuan zhi) is commonly prescribed in many classical decoctions such as "kai xin san" [388] , and "ding zhi wan" [389] for the treatment of forgetfulness [390] , anxiety [391] , insomnia or depression [392] . recent pharmacological studies have also reported the sedative-hypnotic [391] , memory improving [390] , cognitive recognition enhancing [393] , antidepressant [392] and neuroprotective effects [170] of rp. rp was reported to inhibit the phosphatidylinositol 3-kinase (pi3k)/akt or activate the n-methyl-d-aspartate (nmda) signaling pathways [394, 395] . the active ingredients of rp such as onjisaponin b and other identified saponins, were proved to accelerate the clearance of neurodegenerative disease proteins such as huntingtin and α-synuclein, reduce aggregation and toxicity of mutant proteins through the induction of autophagy [170, 396] . therefore, rp may play its traditional sedative effect through degradation of unwanted proteins or organelles by autophagy. ganoderma lucidum (ling zhi) is having efficacy in replenishing qi, stabilizing the nervous system and relieving cough and asthma, is commonly prescribed to treat insomnia, palpitation, cough and phlegm. it exerts tranquilizing effects through tonifying the heart, qi and blood. triterpenes are the major components of ganoderma lucidum. pharmacological studies have demonstrated that both ganoderma lucidum extract and ganoderic acid c2 could reduce accumulation of mutant huntingtins in pc-12 cells, alleviate neurotoxicity and behavioral deficits induced by 3-nitropropionic acid, and prevent or reverse memory loss resulting from sleep deprivation [171] . additionally, it was also reported that ganoderma lucidum triterpene extract (glt) suppressed the proliferation of human colon cancer cells and inhibited tumor growth in a xenograft model, which were associated with the induction of autophagic cell death [397] . furthermore, ganoderic acid activated autophagy, which facilitates immune recognition of cd4 + t cells; induced autophagic cell death and apoptosis of melanoma [398] ganoderma lucidum triterpene extract induced autophagy which inhibited the development of colon cancer via p38 mapk signaling [397] ; and suppressed gastric cancer cells through the repression of p62 [399] . all these findings suggest that the traditional therapeutic role of ganoderma lucidum is in part related to autophagy regulation, which may also be responsible for the novel use of the herb in cancer treatment. caulis polygoni multiflori (shou wu teng) has been prescribed for nourishing blood, tranquilizing the mind and dispersing wind to treat insomnia, numbness of the skin and rheumatism in traditional chinese medicine. it was often combined with semen ziziphi spinosae (suan zao ren) and cortex albiziae (he huan pi) to treat insomnia, distraughtness and dizziness. modern pharmacological study has suggested an effect of caulis polygoni multiflori extract in protecting rats against ccl 4 -induced hepatotoxicity through its antioxidant activities [400] . the major active ingredients of shou wu teng, anthraquinones, possessed similar chemical structures but different bioactivities. for example, emodin, the most abundant anthraquinone in rhubarb, inhibits cellular proliferation and prevents metastasis of cancers through apoptosis. another major anthraquinone in rhubarb, rhein, inhibits the uptake of glucose and leads to cancer cell death caused by changes in membrane-associated functions [401] . ananthraquinone-containing extract of shou wu teng possesses myocardial protective effects by maintaining antioxidant status under oxidative stress conditions [402] . abnormal aggregation of tau protein is highly correlated with the pathogenesis of alzheimer's disease (ad), therefore, with the ability in mitigating aggregation and cytotoxicity of tau [403] anthraquinones possesses high potential in modulating ad. together with the fact that ananthraquinones were able to induce autophagic cell death in cancer cells [172] , shou wu teng may exert its traditional sedative function through the induction of autophagy, which was highly related to the modulation of neurodegenerative disease proteins, as well as cancers [172] . fructus schisandrae (wu wei zi) has been prescribed to replenish qi, nourish the kidneys and tranquilize the mind to produce a sedative nephroprotective effect. besides, sc extract was co-administered with other medicine for reducing immunosuppressive drug (cyclosporine a)-induced side effects [404] . schisandra total lignin (stl), the major active ingredient of fructus schisandrae, delayed mouse brain aging by attenuating apoptosis [405] . in vivo experiments further demonstrated stl inhibited the d-galactose-induced brain tissue aging through regulating autophagy and inhibiting apoptosis in the mice. it has been reported that longevity-promoting regimens such as caloric restriction or inhibition of tor is associated with induction of autophagy [173] . therefore, autophagy may be the mechanism responsible for the sedative and anti-ageing effect of fructus schisandrae. semen ziziphi spinosae (suan zao ren) is commonly prescribed as "suan zao ren tang" for sedation, nourishing the nerves, insomnia, palpitations, anxiety, dizziness, dry mouth and throat, red tongue, and clinical treatment of neurasthenia, heart neurosis and menopausal syndrome due to deficiencies of the heart and liver [406, 407] . the active component of semen ziziphi spinosae, jujuboside b, was reported to inhibit platelet aggregation and target cardiovascular diseases associated with platelet hyperaggregation [408] . furthermore, the anti-tumor activity of jujuboside b was reported to be associated with the induction of apoptosis and autophagy [409] . another active neuroprotective component from semen ziziphi spinosae, jujuboside a, could mitigate learning and memory impairment in mice, by reducing the level of aβ , and inhibiting the activities of acetylcholinesterase (ache) and no in the hippocampus and cerebral cortex of mice [410] . with its traditional effects in tranquilizing the mind and nourishing heart, blood and qi, current pharmacological studies have confirmed the neuroprotective and autophagic role of semen ziziphi spinosae. as autophagy was highly correlated to the maintenance of cellular homeostasis, which was important for normal function of brain, autophagy may be responsible for the pharmacological action and sedative effects of semen ziziphi spinosae. succinum (ambrum) has been prescribed for relieving convulsion, tranquilizing the mind, activating blood and removing stasis, inducing diuresis, treating irritability, epilepsy, algomenorrhea and amenorrhea in tcm [411] . it was commonly prescribed with rhizoma acori graminei (shi chang pu) and radix polygalae (yuen zhi) in "hu po ding zhi wan" for treating palpitations, insomnia and forgetfulness [412] . vitamin e succinate (ves), one of the active components of ambrum, was proved to induce autophagy via the inhibition of mtor [174] . besides, ves worked as an anti-neoplastic agent through regulating apoptosis in cancer cells [413] . as autophagy is also highly correlated with modulation of cancers, with the recently identified anti-cancer effect of jujuboside b and ves through induction of autophagy, both semen ziziphi spinosae and ambrum may possess new applications in anti-cancer therapy via its traditional tranquilizing effect, which was highly associated with the beneficial effect of autophagy. in addition, the chinese medicinal herbs including nelumbo nucifera, rhizoma acori graminei, radix salviae miltiorrhizae and radix ginseng also participate in tranquilization of the mind [414] . nelumbo nucifera treats palpitations, insomnia and dreamful sleep [415] in tcm. it is commonly prescribed as a formulation with radix polygalae, semen ziziphi spinosae and radix salviae miltiorrhizae. the active component of nelumbo nucifera, neferine, was identified as a novel autophagic enhancer which facilitates the degradation of mutant neurodegenerative disease proteins in vitro [134] . with the beneficial effect of autophagy in maintaining normal homeostasis in cells, sedative tcms may play protective role in neurodegenerative diseases, through the removal of disease proteins by autophagy. preclinical or clinical models showed that pharmacological inhibition of autophagy can enhance the sensitivity of tumor cells towards multiple anti-cancer drugs. for example, inhibition of autophagy enhanced apoptosis induced by cetuximab [416] or vorinostat [417] . while cq enhanced the therapeutic efficacy of saracatinib [418] in prostate cancer xenograft model, inhibition by 3-ma increased fluorouracil (5-fu) [419] induced apoptosis with tumor regression in colon cancer xenografts. among these autophagy inhibitors, only cq or hcq were studied in humans as they cross the blood-brain barrier with hcq much preferred to human due to the less severe side effects [420] . based on these preclinical data, phase i or ii trials were performed to evaluate the combinational use of autophagy inhibitors (hcq or cq) with various anti-cancer cytotoxic agents. however, there are limitations for their use in clinical practice due to the long half-life and high effective concentration of hcq. a phase i trial was performed to evaluate the combined use of hcq with temozolamide [421] and radiation in glioblastoma patients. phase i or ii clinical trials evaluating the combination use of bortezomib and cq [422] are ongoing in patients with recurrent carcinoma. a phase i trial of 2-deoxyglucose [423] , an agent that blocks glucose metabolism, showed a reduction in autophagy, suggesting the role of autophagy in cancer therapy. similarly, the clinically used mood stabilizers lithium (valproate and carbamazepine) [73] , induce mtor-independent autophagy and enhance the cellular degradation of aggregate-prone mutant huntingtin and α-synuclein. the hypertensive agent rilmenidine [424] , a us food and drug administration-approved compound, showed protective effect in huntington's disease models and is now under further clinical trials. protein phosphatase 2a (pp2a) agonists [425] which favor induction of autophagy are currently under clinical trials for alzheimer's disease. the clinically used approved antidiabetic drug, metformin [426] , attenuates disease development in some neurodegenerative diseases via ampk activation. 2-hydroxypropyl-β-cyclodextrin [427] , effective in enhancing the clearance of lipids or autophagic substrate burden, can mitigate neurological deficits in an npc mouse model and is currently under early clinical trials for treating npc. another lipofuscinolytic agent, centrophenoxine [428] , is an anti-aging antioxidant which possesses potential protective effect for late-stage dementia in small early clinical trials. however, factors such as blood-brain barrier penetration power of the compounds and cellular heterogeneity of brain tissue can also affect the clinical neuroprotective efficacy of autophagy drugs. for example, the different responses of neurons and glia to autophagy or drug must be considered in clinical trial evaluations [429] . although the molecular mechanisms and functions of many autophagy modulators isolated from chm were intensively studied, we are still far away from translating these traditional herbs or compounds into clinical applications. knowledge concerning autophagy research is mainly related to non-selective autophagy describing the molecular responses upon starvation. however, increasing studies are evidencing the significance of selective autophagy which involves specific molecular mediators targeting particular kinds of unwanted intracellular materials [430, 431] . therefore, it is important to clarify the potential discrepancies between selective and non-selective autophagy in terms of their response towards different therapeutic agents. on the other hand, the time of starting the autophagy modulatory treatment should also be considered. for example, early cancer development is likely to be prevented by autophagy induction, as cancer cells exploit nutrients generated by autophagy to survive under the stressful cellular environment at the later stages [432, 433] . it is also important to take into account the cells type-specific property of autophagy which may otherwise minimize the efficacy of the applied herbs, and result in unfavourable side effects. the heterogeneous cell types as presented by hepatic lobules can well explain such a scenario. the liver consists mainly of parenchymal cells (hepatocytes) and around 40% of non-parenchymal cells such as hepatic stellate cells (hscs) [434] . the functional consequences of autophagy induction on these cells vary under different diseased conditions. autophagy of hsc activated during the end stage of chronic liver disease and hepatic fibrosis could be alleviated by autophagy repression in vitro [435] [436] [437] . in contrast, autophagy stimulation is beneficial upon most of the parenchymal cells-related hepatic malignancies. therefore special caution would need to be taken when applying the autophagic modulators in cancer therapy. an increasing number of chinese herbal medicines (chms) have been discovered as autophagy modulators. such autophagic-regulatory effects are therapeutically beneficial to a broad range of disorders which are consistent with their traditional usage. interestingly, many chm-induced autophagy findings described in this review also demonstrate novel applications in various pathological conditions. these potential therapeutic functions can be summarized into: (1) anti-cancer; (2) neuroprotective; (3) cardiovascular-protective; and (4) antiviral applications. for example, through the activation of autophagic cell death, tumorigeneses can be repressed by cortex phellodendri, radix sophorae lavescentis, radix isatidis, and stephania japonica which are not associated with cancer therapy according to chinese herbology. in fact, a plethora of chms having similar potential in preventing cancer progression have not been studied before. these herbs include nelumbo nucifera, syzygium samarangense, mallotus philippensis, rhizoma anemarrhenae, radix glehniae, radix ophiopogonis, radix glycyrrhizae, radix dipsaci, radix ginseng, radix codonopsis, rhizoma atractylodis macrocephalae, ganoderma lucidum, radix bupleuri, rhizoma zingiberis recens, radix tripterygii wilfordii, radix stephaniae tetrandrae, rhizoma alismatis, cortex magnoliae officinalis, fructus piperis longi, radix salviae miltiorrhizae, rhizoma chuanxiong, garcinia hanburyi, radix plumbaginis zeylanicae, and fructus evodiae. in contrast, fructus evodiae can inhibit autophagic cell death of influenza-infected cells which provides insight to the search of chms sharing such anti-viral properties. in the case of neurodegenerative disorders, nelumbo nucifera, mallotus philippensis, rhizoma anemarrhenae, radix ginseng, radix tripterygii wilfordii, and rhizoma curcumae longae can trigger previously unidentified autophagy-mediated neuronal survival. these groups of novel neuroprotective herbs may help remove misfolded protein aggregates via autophagy activation. also, rhizoma polygoni cuspidate can upregulate the cardiac myocytic autophagy to eliminate damaged proteins uncovering the innovative use of the herb in cardiovascular disorders. it should also be noted that a single chm usually contain more than one bioactive component. therefore, the downstream molecular networks modulated by these chms are complicated. precise investigations concerning how chms may influence the intricate autophagy machinery is needed, and will be a major challenge for further developing chm as practical autophagy regulators. when compared with western medicines, most of the reviewed autophagy modulators here are bioactive components constituting the chms, which have long been prescribed as decoctions or formulations in the chinese community with well-known pharmacological action, toxicity or side effects. therefore, clinical trials using these natural herbs may be more safe and reliable. also, the philosophy of chm emphasizes the comprehensive and persistent body balance, which tailors them to deal with the autophagy-related diseases, which are pathologically associated with the loss of overall cellular and physiological balance. in addition, 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tzq-f, a new kind of traditional chinese medicine the general situation and progress of the modern research of red sage root (radix salviae miltiorrhizae) anti-inflammatory and immunomodulatory mechanism of tanshinone iia for atherosclerosis tanshinone iia inhibits lps-induced nf-κb activation in raw 264.7 cells: possible involvement of the nik-ikk, erk1/2, p38 and jnk pathways tanshinone iia protects against cardiac hypertrophy via inhibiting calcineurin/nfatc3 pathway calcineurin suppresses ampk-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress advances of ligusticum chuanxiong inhibition of rat vascular smooth muscle cell proliferation by extract of ligusticum chuanxiong and angelica sinensis protective effect of ligusticum chuanxiong and angelica sinensis on endothelial cell damage induced by hydrogen peroxide ocular and cardiovascular pharmacology of tetramethylpyrazine isolated from ligusticum wallichii franch scavenging effects of tetramethylpyrazine on active oxygen free radicals tetramethylpyrazine reduces cellular inflammatory response following permanent focal cerebral ischemia in rats studies on cardiotonic steroids from the skin of japanese toad pharmacology and toxicology of toad venom bufotalin from venenum bufonis inhibits growth of multidrug resistant hepg2 cells through g2/m cell cycle arrest and apoptosis cardiac glycosides are potent inhibitors of interferon-β gene expression bufalin induces g2/m phase arrest and triggers autophagy via the tnf, jnk, becn-1 and atg8 pathway in human hepatoma cells bufalin inhibits hct116 colon cancer cells and its orthotopic xenograft tumor in mice model through genes related to apoptotic and pten/akt pathways bufalin induces the interplay between apoptosis and autophagy in glioma cells through endoplasmic reticulum stress anti-inflammatory, analgesic and antipyretic activities of the extract of gamboge from garcinia hanburyi hook f general gambogic acids inhibited growth of human hepatoma smmc-7721 cells in vitro and in nude mice gambogic acid, a novel ligand for transferrin receptor, potentiates tnf-induced apoptosis through modulation of the nuclear factor-κb signaling pathway gambogic acid-induced g2/m phase cell-cycle arrest via disturbing cdk7-mediated phosphorylation of cdc2/p34 in human gastric carcinoma bgc-823 cells characterization of multiple constituents in kai-xin-san prescription and rat plasma after oral administration by liquid chromatography with quadrupole time-of-flight tandem mass spectrometry a representative prescription for emotional disease, ding-zhi-xiao-wan restores 5-ht system deficit through interfering the synthesis and transshipment in chronic mild stress-induced depressive rats effects of tenuifolin extracted from radix polygalae on learning and memory: a behavioral and biochemical study on aged and amnesic mice anxiolytic and sedative-hypnotic activities of polygalasaponins from polygala tenuifolia in mice preclinical evidence of rapid-onset antidepressant-like effect in radix polygalae extract polygalasaponin xxxii from polygala tenuifolia root improves hippocampal-dependent learning and memory polygalasaponin f induces long-term potentiation in adult rat hippocampus via nmda receptor activation clionosterol and ethyl cholestan-22-enol isolated from the rhizome of polygala tenuifolia inhibit phosphatidylinositol 3-kinase/akt pathway identification of novel autophagic radix polygalae fraction by cell membrane chromatography and uhplc-(q)tof-ms for degradation of neurodegenerative disease proteins triterpenes from ganoderma lucidum induce autophagy in colon cancer through the inhibition of p38 mitogen-activated kinase (p38 mapk) a possible cross-talk between autophagy and apoptosis in generating an immune response in melanoma methanolic extract of ganoderma lucidum induces autophagy of ags human gastric tumor cells antioxidant activities of polygonum multiflorum thunb., in vivo and in vitro anti-cancer properties of anthraquinones from rhubarb myocardial protective effect of an anthraquinone-containing extract of polygonum multiflorum ex vivo anthraquinones inhibit tau aggregation and dissolve alzheimer's paired helical filaments in vitro and in cells pharmacokinetic and nephroprotective benefits of using schisandra chinensis extracts in a cyclosporine a-based immune-suppressive regime schisandra total lignin attenuates apoptosis of endoplasmic reticulum pathway to delay mouse brain aging clinical efficacy of traditional chinese medicine, suan zao ren tang, for sleep disturbance during methadone maintenance: a randomized, double-blind, placebo-controlled trial suan zao ren tang as an original treatment for sleep difficulty in climacteric women: a prospective clinical observation zizyphus jujuba and its active component jujuboside b inhibit platelet aggregation antitumor activity of jujuboside b and the underlying mechanism via induction of apoptosis and autophagy jujuboside a, a neuroprotective agent from semen ziziphi spinosae ameliorates behavioral disorders of the dementia mouse model induced by aβ 1-42 identification and clinical application of amber analysis on characteristic of kaixin powder and its similar prescriptions vitamin e succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (apo2 ligand) in vivo analysis of rule and clinicance of mind-calming medicine purgative genome of the long-living sacred lotus the epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating hif-1 α and bcl-2 and activating the beclin 1/hvps34 complex autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation autophagy blockade sensitizes prostate cancer cells towards src family kinase inhibitors inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model the role of autophagy in cancer: therapeutic implications pharmacokinetic analysis and pharmacodynamic evidence of autophagy inhibition in patients with newly diagnosed glioblastoma treated on a phase i trial of hydroxychloroquine in combination with adjuvant temozolomide and radination (abtc 0603) the antidepressants maprotiline and fluoxetine induce type ii autophagic cell death in drug-resistant burkitt's lymphoma targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies autophagy modulation as a potential therapeutic target for diverse diseases pp2a blockade inhibits autophagy and causes intraneuronal accumulation of ubiquitinated proteins amp-activated protein kinase: a potential player in alzheimer's disease chronic cyclodextrin treatment of murine niemann-pick c disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression gerontopsychological studies using nai ("nürnberger alters-inventar") on patients with organic psychosyndrome (dsm iii, category 1) treated with centrophenoxine in a double blind, comparative, randomized clinical trial the role of autophagy in neurodegenerative disease selective autophagy mediated by autophagic adapter proteins atg8-family interacting motif crucial for selective autophagy deconvoluting the context-dependent role for autophagy in cancer autophagy as a target for anticancer therapy cooperation of liver cells in health and disease liver fibrosis a role for autophagy during hepatic stellate cell activation effects of fufang biejia ruangan pills on hepatic fibrosis in vivo and in vitro effect of bupleuri radix extracts on the toxicity of 5-fluorouracil in hepg2 hepatoma cells and normal human lymphocytes key: cord-023837-kenstpja authors: nan title: china date: 2019 journal: the statesman&#x02019;s yearbook 2019 doi: 10.1007/978-1-349-95321-9_204 sha: doc_id: 23837 cord_uid: kenstpja nan yuan dynasty in 1271, swept into southern china. the mongol yuan dynasty adopted chinese ways but was overthrown by a nationalist uprising in 1368, led by hongwu (1328-98), a former beggar who established the ming dynasty. the ming empire collapsed in a peasants' revolt in 1644. the capital, beijing (peking), was only 64 km from the great wall and vulnerable to attack from the north. within months the peasants' leader was swept aside by the manchus, whose qing dynasty ruled china until 1911. preoccupied with threats from the north, china neglected its southern coastal frontier. the portuguese, who landed on the chinese coast in 1516, were followed by the dutch in 1622 and the english in 1637. the qing empire expanded into mongolia, tibet, vietnam and kazakhstan. but by the 19th century, under pressure from rural revolts ignited by crippling taxation and poverty, the qing dynasty was crumbling. two opium wars (1838-42; 1856-58) forced china to allow the import of opium from india into china, while britain, france, germany and other european states gained concessions in 'treaty ports' that virtually came under foreign rule. the taiping rebellion (1851-64) set up a revolutionary egalitarian state in southern china. the european powers intervened to crush the rebellion and in 1860 british and french forces invaded beijing and burnt the imperial palace. further trading concessions were demanded. a weakened china was defeated by japan in 1895 and lost both taiwan and korea. the xenophobic boxer rebellion, led by a secret society called the fists of righteous harmony, broke out in 1900. the guangxu emperor attempted modernization in the hundred days reform, but was taken captive by the conservative dowager empress cixi who harnessed the boxer rebellion to her own ends. the rebellion was put down by european troops in 1901. china was then divided into zones of influence between the major european states and japan. with imperial authority weakened, much of the country was ripe for rebellion. in 1911 the kuomintang (guomintang or nationalist movement) of sun yet-sen (sun zhong shan; 1866 -1925 ) overthrew the imperial system. the authoritarian yuan shih-kai ruled as president from 1913 to 1916. following the overthrow of yuan, china disintegrated into warlord anarchy. in 1916 sun founded a republic in southern china but the north remained beyond his control. reorganizing the nationalist party on soviet lines, sun co-operated with the communists to re-establish national unity. but rivalry between the two parties increased, particularly after the death of sun in 1925. after sun's death the nationalist movement was taken over by his ally chiang kai-shek (jiang jie shi; 1887 -1976 . as commander in chief of the nationalist army from 1925, chiang's power grew. in april 1927 his campaign to suppress the chinese communist party saw thousands of communists slaughtered. the survivors fled to the far western province of jiangxi. in 1928 chiang's army entered beijing. with the greater part of the country under chiang's rule, he made nanjing the capital. in 1934 the communists were forced to retreat from jiangxi province. led by mao zedong (mao tse-tung; 1893 -1976 they trekked for more than a year on the 5,600-mile long march, eventually taking refuge in shaanxi province. in 1931 the japanese invaded manchuria. by 1937 they had seized beijing and most of coastal china. the nationalists and communists finally co-operated against the invader but struggled against the superior japanese forces. during the second world war , a nationalist government ruled unoccupied china ineffectually from a temporary capital in chongqing. at the end of the war, nationalist-communist co-operation was short-lived. the soviet union sponsored the communist party, which marched into manchuria in 1946, beginning a civil war that lasted until 1949. although the nationalist forces of chiang kai-shek received support from some western countries, particularly the united states, the communists were victorious. on 1 oct. 1949 mao declared the people's republic of china in beijing. chiang fled with the remains of his nationalist forces to taiwan, where he established a government that claimed to be a continuation of the republic of china. at first recognized as the government of china by most western countries, taiwan kept china's security council seat at the united nations until 1971. chiang's authoritarian regime was periodically challenged by red china, which bombed taiwan's small offshore islands near the mainland. in the 1960s and 1970s, taiwan gradually lost recognition as the legitimate government and in 1978 the usa recognized the people's republic of china. in 1950 china invaded tibet, independent since 1916. chinese rule quickly alienated the tibetans who rebelled in 1959. the tibetan religious leader, the dalai lama, was forced to flee to india. since then, the settlement of large numbers of ethnic chinese in the main cities of tibet has threatened to swamp tibetan culture. during the 1950s and 1960s china was involved in a number of border disputes and wars in neighbouring states. the communists posted 'volunteers' to fight alongside communist north korea during the korean war . there were clashes on the soviet border in the 1950s and the indian border in the 1960s, when china occupied some indian territory. from the establishment of the people's republic of china, communist china and the soviet union were allies. communist china initially depended upon soviet assistance for economic development. a soviet-style five-year plan was put into action in 1953, but the relationship with moscow was already showing signs of strain. by the end of the 1950s the soviet union and china were rivals, spurring the chinese arms race. chinese research into atomic weapons culminated in the testing of the first chinese atomic bomb in 1964. mao introduced rapid collectivization of farms in 1955. the plan was not met with universal approval in the communist party but its implementation demonstrated mao's authority over the fortunes of the nation. in 1956 he launched the doctrine of letting a 'hundred flowers bloom', encouraging intellectual debate. however, the new freedoms took a turn mao did not expect and led to the questioning of the role of the party. strict controls were reimposed and free-thinkers were sent to work in the countryside to be 're-educated'. in may 1958 mao launched another ill-fated policy, the great leap forward. to promote rapid industrialization and socialism, the collectives were reorganized into larger units. neither the resources nor trained personnel were available for this huge task. backyard blast furnaces were set up to increase production of iron and steel. the great leap forward was a disaster. it is believed that 30m. died from famine. soviet advice against the project was ignored and a breakdown in relations with moscow came in 1963, when soviet assistance was withdrawn. a rapprochement with the united states was achieved in the early 1970s. having published his 'thoughts' in the 'little red book' in 1964, mao set the cultural revolution in motion. militant students were organized into groups of red guards to attack the party hierarchy. anyone perceived to lack enthusiasm for mao zedong thought was denounced. thousands died as the students lost control and the army was eventually called in to restore order. after mao's death in 1976 the gang of four, led by mao's widow jiang qing, attempted to seize power. these hard-liners were denounced and arrested. china effectively came under the control of deng xiaoping. deng pursued economic reform. the country was opened to western investment. special economic zones and 'open cities' were designated and private enterprise gradually returned. improved standards of living and a thriving economy increased expectations for civil liberties. the demand for political change climaxed in demonstrations by workers and students in april 1989, following the funeral of communist party leader hu yaobang. in beijing where demonstrators peacefully occupied tiananmen square, they were evicted by the military who opened fire, killing more than 1,500. hard-liners took control of the government, and martial law was imposed from may 1989 to jan. 1990 . since 1989 the leadership has concentrated on economic development. hong kong was returned to china from british rule in 1997 (for the background, see page 337) and macao from portuguese rule in 1999. the late 1990s saw a cautious extension of civil liberties but chinese citizens are still denied most basic political rights. beijing was chosen for the 2008 olympic games. china's treatment of tibet came under the international spotlight in the build-up to the games, following violent protests in tibet's capital city, lhasa. the arrest by japan of a chinese trawler in disputed waters in 2010 marked the beginning of heightened tensions between the two nations in the east and south china seas. in 2011 china became the world's second largest national economy. in nov. 2012 the communist party congress selected xi jinping to succeed hu jintao as president from march 2013. in sept. that year, former leadership hopeful bo xilai received a life sentence for corruption in one of china's highest-profile trials in decades. in oct. 2015 the government announced the end of the country's one-child policy. a month later, the presidents of china and taiwan met for talks-the first time that leaders from the respective territories had met since 1949. on the economic front, gdp growth in 2015 was at its lowest level for a quarter of a century. china is bounded in the north by russia and mongolia; east by north korea, the yellow sea and the east china sea, with hong kong and macao as enclaves on the southeast coast; south by vietnam, laos, myanmar, india, bhutan and nepal; west by india, pakistan, afghanistan, tajikistan, kyrgyzstan and kazakhstan. the total area (including taiwan, hong kong and macao) is estimated at 9,572,900 sq. km (3,696,100 sq. miles). a law of feb. 1992 claimed the spratly, paracel and diaoyutasi islands. an agreement of 7 sept. 1993 at prime ministerial level settled sino-indian border disputes which had first emerged in the war of 1962. china's sixth national census was held on 1 nov. 2010. the total population of the 31 provinces, autonomous regions and municipalities and of servicemen on the mainland was 1, 339,724,852 (652,872,280 females, representing 48·73%); density, 140 per sq. km. china's population in 2010 represented 19% of the world's total population. the population rose by 73,899,804 (or 5·84%) since the census in 2000. there were 665,575,306 urban residents, accounting for 49·68% of the population; compared to the 2000 census, the proportion of urban residents rose by 13·46% (reflecting the increasing migration from the countryside to towns and cities since the economy was opened up in the late 1970s). population estimate, dec. 2016: 1,382,710,000. china has a fast-growing ageing population. whereas in 1980 only 5·2% of the population was aged 65 or over and by 2010 this had increased to 8·2%, by 2030 it is expected to rise to 17·2%. long-term projections suggest that in 2050 as much as 27·6% of the population will be 65 or older. the population is expected to peak at 1·42m. around 2028 and then begin to decline to such an extent that by around 2050 it will be back to the 2011 level. china is set to lose its status as the world's most populous country to india in about 2022. the un gives a projected population for 2020 of 1,424·55m. 1979 regulations restricting married couples to a single child, a policy enforced by compulsory abortions and economic sanctions, were widely ignored, and it was admitted in 1988 that the population target of 1,200m. by 2000 would have to be revised to 1,270m. from 1988 peasant couples were permitted a second child after four years if the first born was a girl, a measure to combat infanticide. in 1999 china started to implement a more widespread gradual relaxation of the one-child policy. in dec. 2013 the standing committee of the national people's congress (npc) approved a resolution allowing couples to have two children if either parent was an only child. the one-child policy was formally abandoned altogether from 1 jan. 2016. an estimated 50m. persons of chinese origin lived abroad in 2012. a number of widely divergent varieties of chinese are spoken. the official 'modern standard chinese' is based on the dialect of north china. mandarin in one form or another is spoken by 885m. people in china, or around 70% of the population of mainland china. the wu language and its dialects has some 77m. native speakers and cantonese 66m. around 400m. people in china cannot speak mandarin. the ideographic writing system of 'characters' is uniform throughout the country, and has undergone systematic simplification. in 1958 a phonetic alphabet (pinyin) was devised to transcribe the characters, and in 1979 this was officially adopted for use in all texts in the roman alphabet. the previous transcription scheme (wade) is still used in taiwan and hong kong. mainland china is administratively divided into 22 provinces, five autonomous regions (originally entirely or largely inhabited by ethnic minorities, though in some regions now outnumbered by han immigrants) and four government-controlled municipalities. these are in turn divided into 332 prefectures, 658 cities (of which 265 are at prefecture level and 393 at county level), 2,053 counties and 808 urban districts. tianjin, 9·29m.; dongguan, 7·27m.; wuhan, 6·84m.; foshan, 6·77m.; chengdu, 6·32m.; chongqing, 6·26m.; nanjing, 5·83m.; shenyang, 5·72m.; xian, 5·21m.; hangzhou, 5·16m.; haerbin, 4·60m.; suzhou, 4·08m.; dalian, 3·90m.; zhengzhou, 3·68m.; shantou, 3·64m.; jinan, 3·53m.; qingdao, 3·52m.; changchun, 3·41m.; kunming, 3·28m.; changsha, 3·19m.; taiyuan, 3·15m.; xiamen, 3·12m.; hefei, 3·10m.; urumqi (wulumuqi), 2·85m.; fuzhou, 2·82m.; shijiazhuang, 2·77m.; wuxi, 2·76m.; zhongshan, 2·74m.; wenzhou, 2·69m.; nanning, 2·66m.; ningbo, 2·58m.; guiyang, 2·52m.; lanzhou, 2·44m.; zibo, 2·26m.; changzhou, 2·26m.; nanchang, 2·22m.; xuzhou, 2·21m about 80% of the population is engaged in the dominant industries of farming and animal husbandry. in 2009 the total sown area was 240,610 ha. output in 2011: total grain crops, 937,300 tonnes; vegetables, 600,700 tonnes. in 2011 there were 14·59m. sheep and goats and 6·45m. cattle and yaks. tibet has over 2,000 mineral ore fields. mining, particularly of copper and gold, has expanded rapidly since 2006 when the railway came to tibet. cement production, 2011: 2·35m. tonnes. electricity consumption totalled 2·7bn. kwh in 2012. in 2011 there were 63,108 km of roads (21,842 km in 1990) . there are airports at lhasa, bangda and nyingchi providing external links. in 2011, 270,800 foreign tourists visited tibet. in july 2006 a 1,142-km railway linking lhasa with the town of golmud opened. it is the highest railway in the world. direct services have subsequently been introduced between lhasa and a number of major chinese cities, including beijing and shanghai. an extension from lhasa to shigatse, tibet's second largest city, became operational in aug. 2014. in 2011 tibet had 860 primary schools (with 294,725 pupils) and 123 secondary schools of which 22 were senior secondary schools (with 44,676 pupils), 93 junior secondary schools (with 136,371 pupils) and eight whole secondary schools. there were also six vocational secondary schools in 2011 (19,446 pupils). tibet has six higher education institutes (the largest of which is tibet university), with 33,198 enrolled students in total in 2011. the illiteracy rate of people aged 15 and above was 32·3% in 2011. in 2011 there were 10,797 medical personnel (including 4,175 doctors) and 1,378 medical institutions, with a total of 9,462 beds. births, 2012, 16,350,000; deaths, 9,660,000 . 2012 birth rate (per 1,000 population), 12·1; death rate, 7·2. in 2005 the birth rate rose for the first time since 1987. there were 13,235,900 marriages and 3,103,800 divorces in 2012. in 2011 the marriage rate was 9·7 per 1,000 population and the divorce rate a record high 2·1 per 1,000. the divorce rate has doubled since 2003. in april 2001 parliament passed revisions to the marriage law prohibiting bigamy and cohabitation outside marriage. the suicide rate in china in 2012 was 16·2 per 100,000 population. life expectancy at birth, 2015, was 73·6 years for men and 79·4 years for women. infant mortality, 2015, 9 per 1,000 live births. china has made some of the best progress in recent years in reducing child mortality. the number of deaths per 1,000 live births among children under five was reduced from 54 in 1990 to 14 in 2012. fertility rate, 2013, 1·7 births per woman (compared to over 6 in the mid-1960s). annual population growth rate, 2010-15, 0·5%. according to the world bank, the number of people living in poverty (less than us$1·25 a day) at purchasing power parity declined from 835m. in 1981 to 156m. in 2010. most of china has a temperate climate but, with such a large country, extending far inland and embracing a wide range of latitude as well as containing large areas at high altitude, many parts experience extremes of climate, especially in winter. most rain falls during the summer, from may to sept., though amounts decrease inland. monthly average temperatures and annual rainfall (2012): beijing (peking), jan. 25·5°f (-3·6°c), july 81·3°f (27·4°c). annual rainfall 28·9" (733 mm). chongqing, jan. 45·0°f (7·2°c), july 83·3°f (28·5°c). annual rainfall 43·5" (1,104 mm). shanghai, jan. 40·5°f (4·7°c), july 85·5°f (29·7°c). annual rainfall 43·5" (1,104 mm). tianjin, jan. 25·2°f (-3·8°c), july 81·0°f (27·2°c). annual rainfall 29·7" (755 mm). on 21 sept. 1949 the chinese people's political consultative conference met in beijing, convened by the chinese communist party. the conference adopted a 'common programme' of 60 articles and the 'organic law of the central people's government' (31 articles). both became the basis of the constitution adopted on 20 sept. 1954 by the 1st national people's congress, the supreme legislative body. the consultative conference continued to exist after 1954 as an advisory body. three further constitutions have been promulgated under communist rule-in 1975 communist rule-in , 1978 communist rule-in and 1982 . the latter was partially amended in 1988, 1993, 1999 and 2004, endorsing the principles of a socialist market economy and of private ownership. the unicameral national people's congress is the highest organ of state power. usually meeting for one session a year, it can amend the constitution and nominally elects and has power to remove from office the highest officers of state. there are a maximum of 3,000 members of the congress, who are elected to serve five-year terms by municipal, regional and provincial people's congresses. 2012, xi pursued a strong style of authoritarian rule at home and a proactive and muscular foreign policy in his first term. in oct. 2016 the ccp gave him the title of 'core' leader, a significant honorific bracketing him with mao zedong and deng xiaoping among previous party figures although conferring no absolute powers. then, at its five-yearly congress in oct. 2017, the party voted to enshrine his name and ideology in the chinese state constitution. he was subsequently re-elected in march 2018 and parliament also voted to abolish presidential term limits in a major shift from precedent. xi jinping was born on 15 june 1953 in beijing, the son of one of the first generation of communist leaders. he joined the ccp in 1974 and, after graduating from tsinghua university in 1979 with a degree in chemical engineering, he became secretary to the vice-premier and secretary-general of the central military commission. xi became the zhengding county committee deputy secretary in hebei province in 1982 and the following year was promoted to secretary. in 1985 he was made deputy mayor of xiamen city, fujian province. having undertaken various party roles in the province, he became deputy governor of fujian in 1999 and governor a year later. in 2002 he moved to zhejiang province and made his first inroads into national politics when he was named a member of the 16th central committee. from 2003-07 he was party secretary of fujian, overseeing economic growth averaging 14% a year and earning a reputation as an opponent of corruption. in march 2007 xi transferred to shanghai to take the role of party secretary following the dismissal of the incumbent on corruption charges. his appointment to such an important regional post was seen as a vote of confidence from the central government and he became a member of the politburo standing committee at the 17th party congress in oct. 2007. he was also made a high-ranking member of the central secretariat. on 15 march 2008 he was elected vice-president at the 11th national people's congress and took on a number of high profile portfolios including the presidency of the central party school. he was also beijing's senior representative for hong kong and ahead of his presidency, xi said little about his policy ambitions. there was hope abroad and at home that he would champion political and social reform and attempt to deal with corruption and a widening wealth gap between rich and poor and between urban and rural communities. he also faced the conundrum of how to provide adequate healthcare to a rapidly ageing population. in jan. 2014 the prospect of greater transparency and accountability under his leadership was undermined when the authorities began criminal proceedings against anti-corruption campaigners calling for public disclosure of officials' assets. this coincided with a report by a us investigative organization claiming that relatives of some of china's top political and military figures, including xi's brother-in-law, held secret offshore financial holdings. in other social and political affairs the ccp announced plans in nov. 2013 to ease china's one-child policy (which was subsequently abandoned following an announcement in oct. 2015, with effect from 2016) and to abolish the system of 'reeducation through labour' camps, while a party plenum calledfor the first time-for markets to play a 'decisive' role in the allocation of resources. meanwhile, in 2014 xi was confronted by domestic political opposition in the form of militant attacks by ethnic uighur separatists from xinjiang region and, from sept. that year, by widespread pro-democracy and autonomy protests in hong kong. on the economic front, china's previously frenetic annual rate of growth slowed markedly in 2015, reflecting a slump in factory production and concerns over depressed oil prices, and again in 2016 to its lowest since 1990. it also heralded severe stock market turbulence into 2016 despite emergency government measures, which had negative reverberations throughout the world economy. nevertheless, recognizing china's rise as a global economic power, the imf in nov. 2015 voted to add the yuan as the fifth member of its special drawing rights (sdr) currency basket alongside the us dollar, japanese yen, british pound and the euro. in foreign affairs, regional concerns over china's territorial and military intentions were raised in nov. 2013 by the government's declaration of a new 'air defence identification zone' over a swathe of the east china sea including disputed islands claimed by japan and south korea. there has also been friction, regionally and with the usa, over china's sovereignty claims and land reclamation operations on islands in the south china sea, although in july 2016 an international legal tribunal ruled in favour of a challenge by the philippines to china's sovereignty assertions-a verdict beijing vowed to ignore. further afield, xi has meanwhile undertaken numerous official visits abroad, as well as attending multilateral forums, for diplomatic, trading and investment purposes. and, while in singapore in nov. 2015, xi and president ma ying-jeou of taiwan held the first direct talks between leaders of the two estranged governments since their split in 1949. most recently, xi urged greater trade co-operation with the usa during his first encounter with the new us president, donald trump, in april 2017, while also increasing economic and military cooperation with russia. li keqiang took office as premier of the state council, a role equivalent to prime minister, in march 2013, succeeding wen jiabao. he was re-elected in march 2018. li keqiang was born on 1 july 1955 in dingyuan county, anhui province. following graduation from high school in 1974, he joined the ccp and in 1982 he graduated in law from peking university, serving as head of the students' federation from 1978-82. he went on to earn a master's degree and doctorate in economics and headed the university's communist youth league of china (cylc) committee. over the following two decades he rose through the cylc ranks, joining the secretariat of its central committee in the 1980s and serving as its first secretary in the 1990s. at this time he built up his power base and forged close ties with hu jintao, a fellow cylc committee member and future chinese president. in 1998 li became deputy party secretary for henan province and a year later was appointed henan's governor. in dec. 2004 he was named party secretary for liaoning province where he spearheaded a major coastal infrastructure project, the '5 points and one line' highway development. in 2009 this template was adopted at the national level to rejuvenate industrial northeast china. he also oversaw the rehousing of 1·5m. shanty-town residents into new apartment blocks over a three-year period. li advanced to national level politics when he was elected to the politburo standing committee in oct. 2007. he was appointed vice-premier of the state council in march 2008, leading a medical reform programme aimed at creating an accessible public healthcare service. he also chaired an affordable housing programme and introduced tax reform plans. in nov. 2012 li was re-elected as a member of the politburo standing committee and on 15 march 2013 became premier of the state council at the 12th national people's congress. regarded as the steward of the chinese economy, li was expected to focus on securing china's long-term expansion and on the further provision of basic national healthcare, affordable housing, employment growth, regional development and cleaner energy. however, global confidence in china's economy has been shaken since 2015 as the country's growth momentum has slowed amid apparent policy differences and blunders, prompting rumours that li was being increasingly sidelined in the governing hierarchy. he was nevertheless re-elected to the politburo standing committee in oct. 2017 and to the premiership in march 2018. the chinese president is chairman of the state and party's military commissions. china is divided into seven military regions. the military commander also commands the air, naval and civilian militia forces assigned to each region. china's armed forces (pla: 'people's liberation army'), totalling nearly 3·0m. in 2013 including the paramilitary people's armed police (pap) and 2·3m. excluding the pap, are the largest of any country. however, active armed personnel numbers have halved since 1980. moreover, in 2015 president xi laid out plans to reform the army structure-replacing an organization based on seven regions with one based on five 'theatre commands'-and reduce the number of military personnel by a further 300,000. conscription is compulsory, but for organizational reasons, is selective: only some 10% of potential recruits are called up. service is for two years. a military academy to train senior officers in modern warfare was established in 1985. defence expenditure in 2013 was us$112,173m. (equivalent to us$83 per capita). china's military spending more than trebled during the 2000s. defence spending in 2013 represented 1·2% of gdp. only the usa spent more on defence in 2013, but china's defence expenditure totalled around a fifth of that of the usa. in march 2014 it was announced that the defence budget would rise by 12·2% to us$132bn. following increases of 10·7%, 11·2% and 12·7% in the previous three years. china is the world's third largest exporter of arms after the usa and russia, with 6·2% of the global major weapons total over the period 2012-16. in the period 2004-08 it had only been the eighth largest exporter. as at 31 may 2016 china had 3,044 personnel serving in un peacekeeping operations (the largest contingent of any of the five permanent members of the un security council and more than the other four combined). having carried out its first test in 1964, there have been 45 tests in all at lop nur, in xinjiang (the last in 1996). the nuclear arsenal consisted of approximately 270 operational warheads in jan. 2017 according to the stockholm international peace research institute. china has been helping pakistan with its nuclear efforts. the army (pla: 'people's liberation army') is divided into main and local forces. main forces, administered by the seven military regions in which they are stationed, but commanded by the ministry of defence, are available for operation anywhere and are better equipped. local forces concentrate on the defence of their own regions. ground forces are divided into infantry, armour, artillery, air defence, aviation, engineering, chemical defence and communications service arms. there are also specialized units for electronic counter-measures, reconnaissance and mapping. in 2013 there were 18 group armies covering seven military regions. they included: 17 armoured divisions and brigades; 29 mechanized infantry divisions, brigades and regiments; 30 motorized infantry divisions and brigades; nine special operations units; 19 artillery divisions and brigades; 3 amphibious brigades and divisions; two mountain brigades; 14 aviation brigades and regiments; and two guard divisions. total strength in 2013 was 1·60m. including some 800,000 conscripts. reserve forces are undergoing major reorganization on a provincial basis but are estimated to number some 510,000. there is a paramilitary people's armed police force estimated at 660,000 under pla command. in nov. 2011 the naval arm of the pla included 71 submarines, of which three were strategic (two jin-class and one xia-class) and 68 tactical. by mid-2015 two more jin-class nuclear-powered ballistic missile submarines had entered service. surface combatant forces in nov. 2011 included 13 destroyers and 65 frigates. sea trials of china's first aircraft carrier, liaoning (a former soviet warship purchased from ukraine), began in aug. 2011. it entered service in sept. 2012 and was initially only used for training before being declared 'combat ready' in nov. 2016. work on china's first domestically-built aircraft carrier began in 2015. it was launched in april 2017 and is expected to be operational by 2020. there is a land-based naval air force of about 311 combatcapable aircraft, primarily for defensive and anti-submarine service. the force includes h-6 strategic bombers and jh-7 fighters. the naval arm is split into a north sea fleet, an east sea fleet and a south sea fleet. in 2013 naval personnel were estimated at 235,000, including 26,000 in the naval air force and 35,000 conscripts. the people's liberation army air force organizes its command through seven military region air forces. the air force has an estimated 1,700 combat-capable aircraft. equipment includes j-7 (mig-21) interceptors (known in the west as 'fishbed'), h-6 chinese-built copies of tu-16 strategic bombers, q-5 fighterbombers (evolved from the mig-19 and known in the west as 'fantan'), su-27 fighters supplied by russia (known in the west as 'flanker'), j-10 chinese-designed and produced fighters (known in the west as 'firebird') and j-8 locally-developed fighters (known in the west as 'finback'). total strength (2013) was 398,000. in 2014 agriculture accounted for 9·1% of gdp, industry 43·1% and services 47·8%. industry was the largest contributor until 2011, while services only overtook agriculture as the second largest sector in 1985. in the late 1960s agriculture was the largest contributor towards gdp. china's economic performance has been marked by high rates of growth for over three decades. annual gdp increases in the early 2000s consistently exceeded 10% until the global financial crisis. china also holds the world's largest foreign exchange reserves, at more than us$3·05trn. in april 2017, although they have been falling since 2014 as the central bank strives to boost the currency in the face of large capital outflows. it is among the top recipients of foreign direct investment (fdi) and is the world's largest producer and consumer of coal. in 2005 china made the transition from net receiver of foreign aid to net donor and has established itself as a key player in africa's economic development, becoming the largest export partner of sub-saharan africa in 2013. according to the world bank, china's cumulative fdi stock in africa totalled nearly us$34·7bn. in 2015, up from us$14·7bn. in 2011. in 2010 china overtook japan to become the world's second largest economy after the usa. the first steps from a centrally-planned towards a more market-oriented economy were taken by deng xiaoping in the late 1970s. he opened the economy to foreign trade and investment, decentralized industrial management and allowed private sector development. in 2001 china became a member of the world trade organization, establishing trade relations with many countries. private entrepreneurs and foreign investors have played an important role in developing the manufacturing sector, china's principal growth engine. even before 1978 the economy was heavily skewed towards manufacturing, but following the market-oriented transition output increased significantly. during this period there was a structural shift away from large state-owned enterprises (soes), although these still remain an important part of the economy. between 1997 and 2003 the government oversaw reform of soes, with many poorly performing businesses privatized or liquidated. stronger firms were restructured and often listed on the stock market. many more recent enterprises are labourintensive as distinct from the capital-intensive soes. growth has been fuelled by low added value and labour-intensive exports. however, chinese firms are predicted to become increasingly competitive with higher added value producers, such as south korea. although the global financial crisis reduced the rate of growth and inbound fdi, china's recovery was among the earliest. gdp growth averaged 7·9% in the second quarter of 2009, up from a two-decade low of 6·1% in the first quarter of that year. fdi also recovered rapidly, averaging 4·1% of gdp annually between 2009 and 2013. growth was rooted in a stimulus package of 4trn. yuan (us$586bn. or 13% of 2008 gdp), including fiscal spending and interest rate cuts, as well as an expansionary monetary policy. central government committed 1·18trn. yuan, with the rest coming from local government, banks and soes. although exports declined by around 17% in 2009, other countries fared worse and china's share of world exports increased to nearly 13·6% in 2016 (up from 3% in 1999), making it the world's largest merchandise provider. gdp growth in 2010 stood at more than 10% but moderated between 2011 and 2014, reflecting the global economic slowdown and diminishing dividends from past reforms. in aug. 2015 a devaluation of the yuan sent the shanghai stock exchange plummeting by nearly 40%, which was swiftly followed by a surge in capital outflows. the stock market meltdown lasted until feb. 2016, with trading halted altogether for two days in jan. that year. nonetheless, the shanghai exchange subsequently began a recovery and had stabilized (at around 3,000 points) by feb. 2017. despite stock market turbulence, the property market, which constitutes a quarter of china's gdp and is vital to the banking sector (as it accounts for a substantial amount of its collateral), remained buoyant. gdp growth declined to 6·9% in 2015 (the slowest rate in 25 years) and fell again to 6·7% in 2016 as china attempted to reduce its reliance on exports, increase domestic consumption and develop its service sector. the economy then grew by 6·9% in 2017. rapid economic advance has brought with it a number of challenges that threaten future growth. notably, china's cost advantage has been undermined in recent years by rising wages and transportation costs, as well as weak global demand. other concerns include rising property costs, high levels of local government debt, lack of enforcement of intellectual property rights, endemic corruption at government level and credit and investment dependence, while total social financing-a broad measure of total credit-increased by 77% of gdp between 2008 and early 2014. the stimulus package implemented by the government to boost growth increased total debt levels to more than double the value of gdp in 2016. according to the imf, an increase in consumer demand and a reduced dependence on exports and investment are keys to achieving stable long-term economic expansion. china's 13th five-year plan (covering 2016-20) aims to promote domestic consumption and to support innovation and entrepreneurship within a framework of balanced and sustainable development. efforts to promote domestic consumption have seen exports' share of gdp falling from 38% in 2007 to 19·6% in 2016 and a lower investment contribution to gdp. the continued decline in commodity prices coupled with china's economic slowdown has had knock-on effects for commodityexporting nations, such as brazil, indonesia and argentina, given that china consumes about half of the world's steel, aluminium and nickel. inefficient production and outmoded equipment have meanwhile led to significant environmental problems, especially in the north of the country. air pollution, soil erosion and a declining water table are of particular concern. china has become the world's largest consumer of coal and second largest consumer of oil after the usa. the government aims to diversify its energy sources, relying less on coal and more on nuclear and alternative energy sources. there has been heavy investment in hydro-power, including the three gorges dam. since 1980, 600m. people have been lifted out of poverty, yet china still has the second largest number of poor in the world after india. the world bank estimates that 98·9m. people lived below the national poverty line at the end of 2012 (equivalent to income less than us$1 per day), located mainly in remote and resource-poor regions and particularly in the west and the interior. nonetheless, some progress has been made, with 7·2% of the rural population living below the poverty line in 2014 compared to 8·5% in 2013. growing inequality between urban and rural regions, particularly in terms of educational opportunities, needs to be addressed, however. china also faces the growing burden of an ageing population. those aged 65 and over accounted for 10·1% of the total population in 2016, up from 6·9% in 2000. the currency is called renminbi (i.e. people's currency). the unit of currency is the yuan (cny) which is divided into ten jiao, the jiao being divided into ten fen. the yuan was floated to reflect market forces on 1 jan. 1994 while remaining state-controlled. for 11 years the people's bank of china maintained the yuan at about 8·28 to the us dollar, allowing it to fluctuate but only by a fraction of 1% in closely supervised trading. in july 2005 it was revalued and pegged against a 'market basket' of currencies the central parities of which were determined every night. in july 2008, after three years of sharp appreciation, it was repegged at around 6·83 yuan to the dollar, leading to claims from some international observers that it was being kept unfairly low to boost exports. in june 2010 the government announced that the yuan would be allowed to move freely against the dollar as long as a rise or fall does not exceed 0·5% within a single day. in aug. 2015 the yuan was devalued by a total of 4·65% on three consecutive days. in aug. 2009 total money supply was 20,039·5bn. yuan, gold reserves were 33·89m. troy oz and foreign exchange reserves us$2,210·8bn. (us$75·4bn. in 1995 of the total revenues in 2015 central government accounted for 6,926·7bn. yuan and local governments 8,300·2bn. yuan. tax revenues came to 12,492·2bn. yuan in 2015 (including domestic vat 3,110·9bn. yuan and corporate income tax 2,713·4bn. yuan) and non-tax revenues 2,734·7bn. yuan. of the total expenditure in 2015 central government accounted for 2,554·2bn. yuan and local governments 15,033·6bn. yuan. the leading items of expenditure in 2015 were education (2,627·2bn. yuan) and social safety net and employment effort (1,901·9bn. yuan). the standard rate of vat is 17%. savings deposits in various forms in all banking institutions totalled 40,370·4bn. yuan in 2012; loans amounted to 67,287·5bn. yuan. there are stock exchanges in the shenzhen special economic zone and in shanghai. a securities trading system linking six cities (securities automated quotations system) was inaugurated in 1990 for trading in government bonds. china received a record us$135·6bn. worth of foreign direct investment in 2015, up from us$128·5bn. in 2014. external debt totalled us$548,551m. in 2010 (up from us$145,339m. in 2000) and represented 9·3% of gni. china's carbon dioxide emissions from the consumption and flaring of fossil fuels in 2011 accounted for 25·3% of the world total (making it the biggest emissions producer, having overtaken the usa in 2007) and were equivalent to 6·1 tonnes per capita (up from 4·5 tonnes per capita in 2007). an environmental performance index compiled in 2016 ranked china 109th of 180 countries, with 65·1%. the index examined various factors in nine areas-agriculture, air quality, biodiversity and habitat, climate and energy, fisheries, forests, health impacts, water and sanitation, and water resources. pollution is estimated to cost china about 10% of gdp annually. installed generating capacity in 2011 was an estimated 1,006m. kw, compared with 299m. kw in 2000. in 2014 electricity output was 5,649,580 gwh, up from 1,355,600 gwh in 2000. consumption per capita was 3,927 kwh in 2014. rapidly increasing demand has meant that more than half of china's provinces have had to ration power. sources of electricity in 2014 as percentage of total production: thermal, 75·6%; hydro-electric power, 18·8%; wind. 2·8% (china is one of the world's largest producers of wind power); and nuclear, 2·3%. in 2016 there were 35 nuclear reactors in use and 20 under construction. generating electricity is not centralized; local units range between 30 and 60 mw of output. in dec. 2002 china formally broke up its state power monopoly, creating instead five generating and two transmission firms. the three gorges dam project on the yangtze river was launched in 1993 and is intended to produce abundant hydro-electricity (as well as helping flood control). the first three 700,000-kw generators in service at the project's hydro-power station began commercial operation in july 2003. the original specification was completed in oct. 2008, although six more generators have been added in the meantime (bringing the total to 32). the final two generators become operational in july 2012, giving the dam an overall capacity of 22·5 gw. china surpassed germany in terms of solar generating capacity in 2015, with 43·5 gw at the end of the year. on-shore oil reserves are found mainly in the northeast (particularly the daqing and liaohe fields) and northwest. there are off-shore fields in the continental shelves of east china. oil production was a record 211·4m. tonnes in 2014. china is the second largest consumer of oil after the usa. ever-growing demand has meant that increasing amounts of oil are having to be imported. a 964-km pipeline from skovorodino in russia to daqing in the northeast of china was inaugurated in jan. 2011, allowing china to increase significantly its imports of oil from the world's second largest producer. the 1,833-km turkmenistan-china gas pipeline, bringing natural gas to xinjiang in china via kazakhstan and uzbekistan, was inaugurated in dec. 2009. this connects with china's second west-east gas pipeline. only the usa imports more oil. domestic production now accounts for only 55% of consumption, compared to nearly 85% in 1998. proven reserves in 2013 were 18·1bn. bbls. the largest natural gas reserves are located in the western and north-central regions. production was a record 138·0bn. cu. metres in 2015-up from 71·6bn. cu. metres in 2007-with proven reserves of 3·3trn. cu. metres in 2013. china is the second largest producer of wind power after the usa, with 156·1bn. kwh in 2014. in 2015 total installed capacity amounted to 145,362 mw, the highest of any country and 33·6% of the world total. china is one of the world's leading mineral producing and consuming countries. recoverable deposits of coal in 2012 totalled 229·9bn. tonnes, mainly distributed in north china (particularly shanxi province and the inner mongolia autonomous region). coal production was 3,660m. tonnes in 2012. annual coal production has increased every year since 2000. growing domestic demand nonetheless meant that china became a net importer of coal in 2009. iron ore reserves were 19·5bn. tonnes in 2012. deposits are abundant in the anthracite field of shanxi, in hebei and in shandong, and are found in conjunction with coal and worked in the northeast. production in 2012 was 1,310m. tonnes, making china the world's largest iron ore producer. it is also the largest consumer, at around 55% of the global total in 2012. tin ore is plentiful in yunnan, where the tin-mining industry has long existed. tin production was 110,000 tonnes in 2012. china is a major producer of wolfram (tungsten ore). there is mining of wolfram in hunan, guangdong and yunnan. output of other minerals (in 1,000 tonnes) in 2012: salt, 69,100; bauxite, 47,000; aluminium, 37,700; zinc, 4,900; lead, 2,800; copper, 1,550. there are also reserves of diamond, nickel, barite, bismuth, graphite, gypsum, mercury, molybdenum, silver, salt, phosphate ore and sylvite. gold production, 2012: 403 tonnes. china surpassed south africa as the world's leading gold producer in 2007, since when its output has increased every year. agriculture accounted for approximately 10% of gdp in 2012, compared to over 50% in 1949 at the time of the birth of the people's republic of china and over 30% in 1980. in 2015 sown areas for major crops were (in 1m. ha.): corn, 38·12; rice, 30·22; wheat, 24·14; soybeans, 8·87; tubers, 8·84; rapeseed, 7·53. intensive agriculture and horticulture have been practised for millennia. present-day policy aims to avert the traditional threats from floods and droughts by soil conservancy, afforestation, irrigation and drainage projects, and to increase the 'high stable yields' areas by introducing fertilizers, pesticides and improved crops. in aug. 1998 more than 21m. ha., notably in the yangtze valley, were under water as china experienced its worst flooding since the 1950s. the 1998 flood season claimed over 4,100 lives. 'township and village enterprises' in agriculture comprise enterprises previously run by the communes of the maoist era, cooperatives run by rural labourers and individual firms of a certain size. there were 1,786 state farms in 2012 with 3·18m. employees. net per capita annual income of rural households, 2012: 7,917 yuan. in 2014 there were an estimated 106·3m. ha. of arable land and 16·2m. ha. of permanent cropland; 70·4m. ha. were equipped for irrigation. there were 4·85m. large/medium-sized tractors in 2012 and 17·97m. small tractors. china is the world's leading producer of a number of agricultural crops. production of major products (in 1m. , 1978-1990. 1992 forestry in 2015 the area under forests was 208·32m. ha., or 22% of the total land area. the average annual increase in forest cover of 1,542,000 ha. between 2010 and 2015 was the highest of any country in the world. total roundwood production in 2011 was 329·47m. cu. metres, making china the world's third largest timber producer (9·4% of the world total in 2011). it is the highest consumer of roundwood; timber consumption in 2011 totalled 375·71m. cu. metres. it is also the world's leading importer of roundwood, accounting for 35·9% of world timber imports in 2011. output of major products, 2015 unless otherwise indicated (in tonnes): cement, 2,359·2m.; rolled steel, 1,123·5m.; crude steel, 803·8m.; pig iron, 691·4m.; gas oil and diesel oil (2014), 176·4m.; gasoline, 121·0m.; paper and paperboard, 117·4m.; sulphuric acid, 89·8m.; chemical fertilizers, 74·3m.; fuel oil (2014), 35·4m.; yarn, 35·4m.; refined sugar, 14·7m. also produced in 2015: cloth, 89,260m. metres; beer, 47,156·0m. litres; 1,812·6m. mobile phones; 174·4m. notebook pcs; 144·8m. colour tv sets; 142·0m. air conditioners; 79·9m. home refrigerators; 72·7m. washing machines; 68·8m. bicycles; 28·5m. cameras; 25·0m. motorcycles. china is the world's leading cement, steel and pig iron manufacturer; since 2000 output of cement has doubled and production of crude steel and pig iron has quadrupled (although in 2015 both crude steel and pig iron production fell for the first time in 34 years). china overtook japan as the world's largest producer of motor vehicles in 2009, and in 2013 produced 18·1m. cars and 4·0m. commercial vehicles. the employed population at the 1990 census was 647·2m. (291·1m. female). by 2012 it had risen to 767·0m. (2·8m. more than in 2011), of whom 396·0m. worked in rural areas (9·0m. fewer than in 2011) and 371·0m. in urban areas (11·9m. more than in 2011). in 2015 china's registered urban jobless was 4·1%, with 9·66m. registered unemployed in the country's cities. with china's fast-growing ageing population, according to the united nations the working-age population began to decline in 2015. in 2012 china had 189,289 private industrial enterprises. it was not until the late 1970s that the private sector even came into existence in china. the average annual wage of people working in urban units in 2012 was 46,769 yuan. china's labour law stipulates a five-day working week with no more than eight hours a day and no more than 44 hours a week. minimum working age was fixed at 16 in 1991. strikes over pay have become ever more frequent in china, particularly at foreign-owned facilities. china had 2·95m. people living in slavery according to the walk free foundation's 2013 global slavery index, the second highest total of any country. there are five special economic zones at shenzhen, xiamen, zhuhai, shantou and hainan in which concessions are made to foreign businessmen. the pudong new area in shanghai is also designated a special development area. since 1979 joint ventures with foreign firms have been permitted. a law of april 1991 reduced taxation on joint ventures to 33%. there is no maximum limit on the foreign share of the holdings; the minimum limit is 25%. in china is the second largest trading nation in the world, accounting for 10·3% of global merchandise imports by value in 2014 and 12·3% of global merchandise exports (up from 4·3% when it joined the wto in 2001). it was the second largest importer in 2014 behind the usa and the largest exporter. as recently as 2004 the usa's total trade in goods was more than twice that of china. it overtook germany as the largest exporter of goods in 2009. its trade surplus in goods is the highest of any country. however, it has the world's highest trade deficit in services. in 2014 imports of services totalled us$382bn. but exports only us$232bn. main imports in 2015 (in us$1bn.): machinery and transport equipment, 682·4; non-edible raw materials, 209·7; mineral fuels, lubricants and related materials, 198·6; chemicals, 171·3. major exports in 2015 (in us$1bn.): machinery and transport equipment, 1,059·1; miscellaneous manufactured goods, 587·5; light textile industrial products, rubber products, minerals and metallurgical products, 391·0; chemicals, 129·6. the main trading partners were as follows in 2015 (in us$1m.): the total road length in 2012 was 4,237,500 km, including 96,200 km of expressways (of which there had not been any as recently as the mid-1980s); 31,885m. tonnes of freight and 35,570m. persons were transported by road that year. the number of civilian motor vehicles was 109·30m. in 2012, including 89·43m. passenger vehicles and 18·95m. trucks (more than double the number in 2008, when there were 51·00m. civilian vehicles overall including 38·39m. passenger vehicles and 11·26m. trucks). china is the world's fastest-growing car market. there were 204,196 traffic accidents in 2012, with 59,997 fatalities. in 2013 in jan. 2014 there were 2,577 ships of 300 gt or over registered, totalling 44·45m. gt. of the 2,577 vessels registered, 968 were bulk carriers, 583 general cargo ships, 545 oil tankers, 192 container ships, 189 passenger ships and 100 liquid gas tankers. mainland china's busiest port in 2012 was ningbo-zhoushan (handling 744·0m. tonnes of cargo), followed by shanghai (637·4m. tonnes), tianjin (477·0 tonnes), guangzhou (canton) (435·2m. tonnes) and qingdao (406·9m. tonnes). shanghai overtook singapore to become the world's busiest container port in 2010 and handled 33·6m. teus (twenty-foot equivalent units) in 2013. shenzhen, mainland china's second busiest port for container traffic and the world's fourth busiest in 2012, handled 22·9m. teus. hong kong handled 23·1m. teus in 2012. in jan. 2001 the first legal direct shipping links between the chinese mainland and taiwanese islands in more than 50 years were inaugurated. inland waterways totalled 125,000 km in 2012; 4,587·0m. tonnes of freight and 257·5m. passengers were carried. in june 2003 the three gorges reservoir on the chang jiang river, the largest water control project in the world, reached sufficient depth to support the resumption of passenger and cargo shipping. out of 178 countries analysed in the 2017 fragile states index-a list published jointly by the fund for peace and foreign policy magazine-china was ranked the 85th most vulnerable to conflict or collapse. the index is based on 12 indicators of state vulnerability across social, political and economic categories. six new codes of law (including criminal and electoral) came into force in 1980, to regularize the legal unorthodoxy of previous years. there is no provision for habeas corpus. as well as treason and murder the death penalty may be used for rape, embezzlement, smuggling, fraud, theft, drug-dealing, bribery and robbery with violence. amendments to the criminal law in 2011 and 2015 reduced the number of capital crimes-which include both violent and non-violent offences-from 68 to 55 and further to 46. china does not divulge figures on its use of the death penalty, but amnesty international reported that in 2017 china executed thousands of people and was the world's top executioner. nevertheless, western analysts believe that the number of executions now is around a fifth of the yearly total in the 1990s. 'people's courts' are divided into some 30 higher, 200 intermediate and 2,000 basic-level courts, and headed by the supreme people's court. the latter, the highest state judicial organ, tries cases, hears appeals and supervises the people's courts. it is responsible to the national people's congress and its standing committee. people's courts are composed of a president, vice-presidents, judges and 'people's assessors' who are the equivalent of jurors. 'people's conciliation committees' are charged with settling minor disputes. there are also special military courts. procuratorial powers and functions are exercised by the supreme people's procuracy and local procuracies. in march 2017 the national people's congress passed legislation developing aspects of the 1986 general principles of civil law, with effect from oct. 2017. among its provisions was the extension of legitimate rights and interests from chinese citizens only to anyone conducting civil activities in the country. in addition, the statute of limitation was increased from two to three years. the number of sentenced prisoners in mid-2015 was 1,649,804 (118 per 100,000 of national population). china was ranked 47th of 102 countries for criminal justice and 67th for civil justice in the 2015 world justice project rule of law index, which provides data on how the rule of law is experienced by the general public across eight categories. an educational reform of 1985 brought in compulsory nine-year education consisting of six years of primary schooling and three years of secondary schooling, to replace a previous five-year system. in mainland china the 2010 population census revealed the following levels of educational attainment: 119·63m. people had finished university education; 187·99m. had received senior secondary education; 519·66m. had received junior secondary education; and 358·76m. had had primary education. 54·66m. people over 15 years of age or 4·08% of the population were illiterate, although this compared favourably with a 15·88% rate of illiteracy in the 1990 census and a 6·72% rate in 2000. in 2010 adult literacy was estimated at 95·1%; youth literacy in 2010 was 99·6%. in 2012 there were 181,251 kindergartens with 36·86m. children and 1·48m. full-time teachers; 228,585 regular primary schools with 96·96m. pupils and 5·59m. full-time teachers; 81,662 secondary schools (including: 14,205 senior secondary; 53,216 junior secondary; 5,245 specialized; 4,517 vocational; and 2,901 technical) with 94·21m. pupils and 5·99m. full-time teachers. there were also 378,751 pupils at 1,853 special education schools. institutes of higher education, including universities, numbered 2,442 in 2012, with 23·91m. undergraduates and 1·72m. postgraduate level students, and 1·44m. full-time teaching staff. china has more than 600 private universities, almost all of which have been established since the mid-1990s. a national system of student loans was established in 1999. the number of chinese students studying abroad went up from 3,000 in 1990 to 39,000 in 2000; it rose above 100,000 in 2002 and 200,000 in 20009, and by 2015 exceeded 500,000, making china the largest source of overseas students in the world. chinese students account for a fifth of all international students in tertiary education in the oecd, but fewer than half return to china after finishing their studies. the number of chinese undergraduate students in american universities in 2013-14 was 11 times as many as in 2006-07, rising from 10,000 to 110,000 in the space of seven years. there is an academy of sciences with provincial branches. an academy of social sciences was established in 1977. in 2012 national government expenditure on education came to 2,124,210m. yuan and accounted for 16·9% of national government spending. medical treatment is free only for certain groups of employees, but where costs are incurred they are partly borne by the patient's employing organization. in 2012 there were 950,297 health institutions throughout china, including 23,170 hospitals, 912,620 local health centres, 3,490 centres for disease control and prevention, and 1,289 specialized prevention and treatment centres. china's first aids case was reported in 1985. at the end of 2014 there were 501,000 reported cases of people living with hiv/ aids. the number of deaths of people who had been living with hiv/aids in 2014 was 21,000. in the first half of 2003 china was struck by an epidemic of a pneumonia-type virus identified as sars (severe acute respiratory syndrome). the virus was first detected in southern china and was subsequently reported in over 30 other countries. according to the ministry of health, by the time the outbreak had been contained a total of 5,327 cases had been reported on the chinese mainland; 4,959 patients were cured and discharged from hospital, and 349 died. in water: at what cost? the state of the world's water 2016, wateraid reported that 4·5% of the population does not have access to safe water. china ranked as the country with the second largest number of people living without access to safe water (63·2m. in 2015). in 2015 an estimated 47·6% of adult males and 1·8% of adult females smoked in china. a study from the same year estimated that chinese males smoke one-third of all the world's cigarettes. in 2012 there were 48,078 social welfare enterprises with 4·49m. beds. numbers (in 1,000) of beneficiaries of relief funds in 2012: urban residents receiving minimum living allowance, 21,435; rural residents receiving minimum living allowance, 53,445; persons receiving traditional relief, 796; persons in rural households entitled to the 'five guarantees' (food, clothing, medical care, housing and burial expenses), 5,456. the official retirement age for men is 60 and for women 50 (or 55 in the case of civil servants and professionals). the government accords legality to five religions only: buddhism, islam, protestantism, roman catholicism and taoism. confucianism, buddhism and taoism have long been practised. confucianism has no ecclesiastical organization and appears rather as a philosophy of ethics and government. taoism-of chinese origin-copied buddhist ceremonial soon after the arrival of buddhism two millennia ago. buddhism in return adopted many taoist beliefs and practices. a more tolerant attitude towards religion had emerged by 1979, and the government's bureau of religious affairs (since renamed the state administration for religious affairs) was reactivated. ceremonies of reverence to ancestors have been observed by the whole population regardless of philosophical or religious beliefs. a new quasi-religious movement, falun gong, was founded in 1992, but has since been banned by the authorities. the movement has claimed some 100m. adherents, although the chinese government has disputed this. muslims are found in every province of china, being most numerous in the ningxia-hui autonomous region, yunnan, shaanxi, gansu, hebei, henan, shandong, sichuan, xinjiang and shanxi. roman catholicism has had a footing in china for more than three centuries. two christian organizations-the chinese patriotic catholic association, which declared its independence from rome in 1958, and the protestant three-self patriotic movement-are sanctioned by the chinese government. according to estimates (by the state-approved xinhua news agency, the chinese academy of social sciences and the state administration for religious affairs) there were 100m. buddhists (more than in any other country), 23m. christians and more than 21m. muslims in the country in 2009. other official figures indicate that there are 5·3m. catholics, although unofficial estimates are much higher. the number of christians in china is generally thought to be far higher than official numbers indicate, with socalled 'house churches' becoming ever more popular. some analysts estimate that there are as many as 100m. christians overall. legislation of 1994 prohibits foreign nationals from setting up religious organizations. in 2012, 7,920m. volumes of books were produced. in 2012 tourist numbers totalled 57·7m. the world tourism organization predicts that china will overtake france as the world's most visited destination by 2020. it was the third most visited destination in 2012 after france and the usa. income from tourists in 2012 was us$50·0bn., ranking it fourth behind the usa, spain and france. expenditure by chinese travellers outside of mainland china for 2013 was us$128·6bn., the most of any country. in 2011 both german and us travellers abroad had spent more than those from china. the lunar new year, also known as the 'spring festival', is a time of great excitement for the chinese people. constituencies encompassing all eligible persons in a workforce of 2·9m., and ten from an election committee formed by members of 18 district boards. a president was elected from and by the members. at the elections on 17 sept. 1995 turnout for the geographical seats was 35·79%, and for the functional seats (21 of which were contested), 40·42%. the democratic party and its allies gained 29 seats, the liberal party 10 and the pro-beijing democratic alliance 6. the remaining seats went to independents. on 21 dec. 1996 the selection committee selected a provisional legislature which began its activities in jan. 1997 while the legislative council was still functioning. in jan. 1997 the provisional legislature started its work by enacting legislation which would be applicable to the hong kong special administrative region and compatible with the basic law. constitutionally hong kong is a special administrative region of the people's republic of china. the basic law enables hong kong to retain a high degree of autonomy. it provides that the legislative, judicial and administrative systems which were previously in operation are to remain in place. the special administrative region government is also empowered to decide on hong kong's monetary and economic policies independent of china. in july 1997 the first-past-the-post system of returning members from geographical constituencies to the legislative council was replaced by proportional representation. there were 20 directly elected seats out of 60 for the first elections to the legislative council following hong kong's return to chinese sovereignty, increasing in accordance with the basic law to 24 for the 2000 election with 36 indirectly elected. in the sept. 2004 legislative council election (and that of sept. 2008) 30 of the 60 seats were directly elected. for the election in sept. 2012 the number of seats was increased to 70, with 35 directly elected and 30 indirectly elected by functional constituencies. there were also five new functional constituency seats nominated by elected district council members. the chief executive is chosen by a beijing-backed 1,200-member election committee (800 prior to the march 2012 election), although it has been stated that universal suffrage is the ultimate aim. in 2007 a timetable was announced for hong kong to directly elect its chief executive in 2017 and its legislative council in 2020. however, beijing insisted that only approved candidates would be allowed to stand in 2017, prompting mass pro-democracy rallies in the territory in 2014 and formal rejection of the plan by the legislative council in june 2015. beijing nevertheless refused to countenance amendments. in july 2002 a new accountability or 'ministerial' system was introduced, under which the chief executive nominates for appointment 14 policy secretaries, who report directly to the chief executive. the chief executive is aided by the executive council, consisting of the three senior secretaries of department (the chief secretary, the financial secretary and the secretary for justice) and eleven other secretaries plus five non-officials. according to the anti-corruption organization transparency international, hong kong ranked equal 13th in the world in a 2017 survey of the countries and regions with the least corruption in business and government. it received 77 out of 100 in the annual index. overview hong kong has one of the world's most open economies and is an internationally important financial centre. the territory's economic rise was founded on its role as an international trade emporium, acting as a conduit for china's burgeoning exports. mainland china, the usa and japan are hong kong's major export partners, accounting for 51·2%, 7·2% and 5·0% of exports respectively in 2015. the island is dependent on imports of food and other resources. in 2015 it imported 49% of goods from mainland china, 7% from taiwan and 6% from japan. in 2004 and 2005 the economy grew strongly on the back of a rise in chinese tourism, healthy global demand for exports and improving domestic consumer confidence. however, the global financial crisis saw the economy shrink by 2·5% in 2009 before rebounding with a 6·8% increase the following year. between 2010 and 2015 annual growth averaged 3·5%, supported by strong external demand. student-led pro-democracy protests in the latter months of 2014 caused major disruption in several key business districts and threatened to weaken the local economy in the short term. foreign direct investment levels have been high, averaging 39% of gdp between 2010 and 2015 according to world bank data, and the world economic forum ranked hong kong as the ninth most competitive economy in the world in its 2016 report. the government aims to tackle a housing shortage by providing 280,000 new housing units by the mid-2020s. the unit of currency is the hong kong dollar (hkd) of 100 cents. it has been pegged since 1983 at a rate of hk$7·8 to the us dollar. banknotes are issued by the hongkong and shanghai banking corporation and the standard chartered bank, and, from may 1994, the bank of china. total money supply was hk$529,161m. in july 2009. in aug. 2009 gold reserves were 67,000 troy oz and foreign exchange reserves were us$223,211m. inflation rates (based on imf statistics): in 2010-11 revenue totalled hk$376·5bn. and expenditure hk$323·8bn. earnings and profits taxes accounted for 38·0% of revenues in 2010-11 and indirect taxes 26·1%; education accounted for 19·1% of expenditures and social welfare 12·6%. hong kong's carbon dioxide emissions from the consumption of energy in 2011 were the equivalent of 13·2 tonnes per capita. installed capacity was 12·6m. kw in 2011. production in 2011 was 39·03bn. kwh. hong kong is a net importer of electricity. consumption in 2011 was 47·41bn. kwh. the local agricultural industry is directed towards the production of high quality fresh food through intensive land use and modern farming techniques. out of the territory's total land area of 1,103 sq. km, only 60 sq. km is currently farmed. in 2006 local production accounted for 55% of live poultry consumed, 23% of live pigs and 4% of fresh vegetables. the gross value of local agricultural production totalled hk$1,184m. in 2006, with pig production valued at hk$585m., poultry production (including eggs) at hk$340m., and vegetable and flower production at hk$254m. in 2015 the total catch was 145,193 tonnes, exclusively from marine waters. the leading companies by market capitalization in hong kong in may 2017 were: china mobile, a telecommunications company (us$225·3bn.); aia group, a life insurance company (us$77·1bn.); and cnooc, an integrated oil company (us$54·8bn.). industry is mainly service-oriented. in june 2013 there were 343,006 establishments employing 2,505,081 persons in service industries and 11,609 establishments employing 103,350 persons in manufacturing industries. establishment statistics by service type (and persons engaged) were mainly: import/export trade and wholesale, 116,335 (554,372); retail, 65,046 (264,805) ; social and personal services, 44,194 (460,973) ; professional and business services, 42,017 (344,544); financing and insurance, 21,683 (207,346); accommodation and food services, 17,201 (276,207); real estate, 15,071 (126,415) . in 2011 the size of the labour force (synonymous with the economically active population) was 3,703,100 (1,760,400 females). the persons engaged in june 2012 included 1,090,059 people in wholesale, retail and import/export trades, accommodation and food services, 664,652 in finance, insurance, real estate, professional and business services, 159,217 in the civil service, 107,637 in manufacturing and 71,721 in construction sites (manual workers only). a minimum wage of hk$28 per hour was introduced for the first time on 1 may 2011. unemployment stood at 3·1% in the period sept.-dec. 2011. in 2009 the total value of imports was hk$2,692,356m. and total exports hk$2,469,089m. the main suppliers of imports in 2009 were mainland china (46·4%), japan (8·8%), taiwan (6·5%), singapore (6·5%) and usa (5·3%). in 2009, 51·2% of total exports went to mainland china, 11·6% to the usa, 4·4% to japan, 3·2% to germany and 2·4% to the united kingdom. the chief import items in 2009 were: electrical machinery, apparatus and appliances, etc. (26·8%); telecommunications, sound recording and reproducing equipment (13·7%); office machines and automatic data processing machines (9·2%); articles of apparel and clothing accessories (4·5%). the main exports in 2009 were: electrical machinery, apparatus and appliances, etc. (26·4%); telecommunications, sound recording and reproducing equipment (16·8%); office machines and automatic data processing machines (10·1%); articles of apparel and clothing accessories (7·2%). in 2011 there were 2,086 km of roads, over 50% of which were in the new territories. there are 16 road tunnels, including three under victoria harbour. in 2011 there were 435,000 private cars, 111,000 goods vehicles, 20,000 buses and coaches, and 39,000 motorcycles and mopeds. there were 15,541 road accidents in 2011, of which 128 were fatal. a total of 26·7m. tonnes of cargo were transported by road in 2011. a 50-km bridge linking hong kong, zhuhai in guangdong province in mainland china and macao has been built and was scheduled to open in july 2018 following a number of delays. hong kong was ranked fourth for its road infrastructure in the world economic forum's global competitiveness report 2017-2018. hong kong's railways are run by the mtr corporation limited (mtrcl), a public listed company of which the government is the majority shareholder. the mtr system comprises nine railway lines serving hong kong island, kowloon and the new territories. its 175-km network has 82 stations and carries an average of 4·8m. passengers each day. mtr lines carried 1,545m. passengers in 2012. in addition, a light rail network (36·2 km and 68 stops) serves the local communities of tuen mun, yuen long and tin shui wai in the new territories; 464,000 passengers travel daily on the system. a high speed rail service between hong kong and guangzhou on the mainland is scheduled to open in late 2018. the electric tramway on the northern state of hong kong island commenced operating in 1904 and has a total track length of 16 km. the peak tram, a funicular railway connecting the peak district with the lower levels in victoria, has a track length of 1·4 km and two tramcars (each with a capacity of 120 passengers per trip). it carries an average of 16,200 passengers daily. the airport express line (35·2 km) opened in 1998 and is also operated by the mtrcl. it carried 12·7m. passengers in 2012. in june 2013 it was estimated that 12·2m. passenger journeys were made daily on public transport (including local railways, buses, etc.). in the world economic forum's global competitiveness report 2017-2018 hong kong ranked third for quality of rail infrastructure. the new hong kong international airport (generally known as chek lap kok), built on reclaimed land off lantau island to the west of hong kong, was opened on 6 july 1998 to replace the old hong kong international airport at kai tak, which was situated on the north shore of kowloon bay. more than 100 airlines now operate scheduled services to and from hong kong. in 2012 cathay pacific airways, the largest hong kong-based airline, operated approximately 105,000 passenger and cargo services to 172 destinations in 41 countries and territories around the world. cathay pacific carried 21,146,492 passengers and 1·4m. tonnes of cargo in 2012. dragonair, a cathay pacific subsidiary, provided scheduled services to 41 cities in mainland china and asia in 2012. in 2012 air hong kong, an all-cargo operator, provided scheduled services to bangkok, beijing, ho chi minh city, manila, nagoya, osaka, penang (via bangkok), seoul, shanghai, singapore, taipei and tokyo. hong kong international airport handled more international freight in 2011 than any other airport. in 2011, 334,000 aircraft arrived and departed and 54m. passengers and 3·94m. tonnes of freight were carried on aircraft. hong kong was second, behind only singapore, in the rankings for air transport infrastructure in the world economic forum's global competitiveness report 2017-2018. the port of hong kong handled 23·1m. teus (twenty-foot equivalent units) in 2012, making it the world's third busiest container port after shanghai and singapore. the kwai chung container port has 24 berths with 7,694 metres of quay backed by 275 ha. of cargo handling area. at the end of 2016 there were 2,513 ships (2,228 ocean-going) of 107,573,898 gt registered in hong kong. in 2016, 27,642 ocean-going vessels, 72 ,810 river cargo vessels and 84,559 river passenger vessels arrived at the port of hong kong. a total of 257m. tonnes of freight were handled in 2015. hong kong was ranked third in the world economic forum's global competitiveness report 2017-2018 for the quality of its port facilities. in 2013 there were 4,546,000 main (fixed) telephone lines (equivalent to 631·1 per 1,000 population). the local fixed telecommunications network services (ftns) market in hong kong was liberalized in 1995. there were 17,098,000 mobile phone subscriptions in 2013 (equivalent to 2,373·5 per 1,000 population), up from 11,580,000 in 2008 (1,661·9 per 1,000 population). the number of subscriptions doubled between 2006 and 2013. the internet market has also seen huge growth. in 2013 there were 6,892,000 wireless broadband subscriptions (956·7 per 1,000 population) and 2,220,000 fixed broadband subscriptions (308·2 per 1,000 population). the number of fixed broadband subscriptions has been declining since 2011 as more people have wireless subscriptions instead. in march 2012 there were 3·8m. facebook users. the external telecommunications services market has been fully liberalized since 1 jan. 1999, and the external telecommunications facilities market was also liberalized starting from 1 jan. 2000. the hong kong act of 1985 provided for hong kong ordinances to replace english laws in specified fields. the courts of justice comprise the court of final appeal (inaugurated 1 july 1997), which hears appeals on civil and criminal matters from the high court; the high court (consisting of the court of appeal and the court of first instance); the lands tribunal, which determines on statutory claims for compensation over land and certain landlord and tenant matters; the district court (which includes the family court); the magistracies (including the juvenile court); the coroner's court; the labour tribunal, which provides a quick and inexpensive method of settling disputes between employers and employees; the small claims tribunal, which deals with monetary claims involving amounts not exceeding hk$50,000; and the obscene articles tribunal. while the high court has unlimited jurisdiction in both civil and criminal matters, the district court has limited jurisdiction. the maximum term of imprisonment it may impose is seven years. magistracies exercise criminal jurisdiction over a wide range of offences, and the powers of punishment are generally restricted to a maximum of two years' imprisonment or a fine of hk$100,000. after being in abeyance for 25 years, the death penalty was abolished in 1992. 75,936 crimes were reported in 2011, of which 13,100 were violent crimes. 38,327 people were arrested in 2011, of whom 8,962 were for violent crimes. the population in penal institutions was 9,067 at 31 dec. 2011 (127 per 100,000 population). in 2010 the adult literacy rate was 94·6% (92·4% in 2000). universal basic education is available to all children aged from six to 15 years. in around three-quarters of the ordinary secondary day schools teaching has been in cantonese since 1998-99, with about a quarter of ordinary secondary day schools still using english. in 2010 there were 148,940 pupils in 951 kindergartens, 331,112 in 572 primary schools (including 40 international schools) and 458,131 in 565 secondary schools (including 27 international schools). the estimated total government expenditure on education in 2011-12 was hk$68·3bn. (18·6% of total government spending and 3·6% of gdp). in 2010-11: 20·1% of total government spending and 3·4% of gdp. according to the oecd's 2015 pisa (programme for international student assessment) study, 15-year-olds in hong kong rank second among oecd and other major countries and cities in mathematics and reading, and ninth in science. the three-yearly study compares educational achievement of pupils in over 70 countries. the department of health (dh) is the government's health adviser and regulatory authority. the hospital authority (ha) is an independent body responsible for the management of all public hospitals. in 2009 there were 12,424 registered doctors, equivalent to 1·8 doctors per 1,000 population. in 2009 there were 2,126 dentists, 38,641 nurses and 4,525 midwives. the total number of hospital beds in 2009 was 35,062, including 26,872 beds in 38 public hospitals under the ha and 3,818 beds in 13 private hospitals. the bed-population ratio was 5·0 beds per thousand population. the chinese medicine ordinance was passed by the legislative council in july 1999 to establish a statutory framework to accord a professional status for chinese medicine practitioners and ensure safety, quality and efficacy of chinese medicine. in 2009 there were 6,048 registered chinese medicine practitioners. total expenditure on health in 2009-10 amounted to hk$88,069m., an increase of 5·2% over that in 2008-09. social welfare programmes include social security, family services, child care, services for the elderly, medical social services, youth and community work, probation, and corrections and rehabilitation. 171 non-governmental organizations are subsidized by public funds. the government gives non-contributory cash assistance to needy families, unemployed able-bodied adults, the severely disabled and the elderly. caseload as at aug. 2011 totalled 280,358. victims of natural disasters, crimes of violence and traffic accidents are financially assisted. estimated recurrent government expenditure on social welfare for 2011-12 was hk$42·2bn. sub-tropical tending towards temperate, with an average temperature of 23·0°c. the number of rainy days is around a third of the year. average annual rainfall varies from 47-87" (1,200-2,200 mm) . it is very humid from may to sept. macao's constitution is the 'basic law', promulgated by china's national people's congress on 31 march 1993 and in effect since 20 dec. 1999. it is a special administrative region (sar) of the people's republic of china, and is directly under the central people's government while enjoying a high degree of autonomy. the legislative assembly has 33 seats of which 14 are directly elected, 12 indirectly elected by functional constituencies and seven appointed by the chief executive. at the elections held on 17 sept. 2017 the macau-guangdong union won two of 14 elected seats with 10·0% of votes cast and the union for development two with 9·7%. ten other parties won a single seat each. turnout was 57·2%. fernando chui sai-on was re-elected chief executive for a second term on 31 aug. 2014, receiving 380 out of 396 votes in the election committee. the economy grew by an average 7·7% per year from 2005-13, driven mainly by the gaming sector and the ongoing construction of a number of casino resorts. however, it went into recession from 2014 following china's crackdown on government corruption. macao's traditional manufacturing industries virtually disappeared following the transfer of much of the textile industry to the chinese mainland and, in 2005, the termination of the multifibre arrangement, which had governed international textile trade flows for three decades. the unit of currency is the pataca (mop) of 100 avos, which is tied to the hong kong dollar at parity. inflation was 8·6% in 2008 and 1·2% in 2009. foreign exchange reserves were us$18,350m. in 2009. total money supply was 30,608m. patacas in 2009. in 2014 revenues totalled 161,861m. patacas; expenditures, 67,078m. patacas. revenues from gaming tax accounted for 84·5% of total revenue in 2014; current expenditure accounted for 86·4% of expenditure. real gdp growth was just 1·7% in 2009 but then rose to 25·3% in 2010 and 21·7% in 2011. more recently the economy contracted by 0·9% in 2014 and then by 20·3% in 2015-the lowest rate for any advanced economy that year-owing to a decline in tourism and gaming revenues. total gdp in 2016 was us$44·8bn. there are two note-issuing banks in macao-the macao branch of the bank of china and the macao branch of the banco nacional ultramarino. the monetary authority of macao functions as a central bank (chairman, teng lin seng). commercial business is handled (2015) by 28 banks, nine of which are local and 19 foreign. total deposits, 2015 (including non-resident deposits), 728,785·9m. patacas. there are no foreign exchange controls within macao. macao's carbon dioxide emissions from the consumption of energy in 2011 were the equivalent of 2·8 tonnes per capita. installed capacity was 0·47m. kw in 2013; production, 0·41bn. kwh. macao imported 4,059m. kwh of electricity in 2013. oil and gas 202,688,000 litres of fuel oil were imported in 2009. the catch in 2015 was estimated at 1,500 tonnes. although the economy is based on gaming and tourism there is a light industrial base of textiles and garments. in 2014 the number of manufacturing establishments was 864 (food products and beverages, 284; textiles and wearing apparel, 160; publishing, printing and reproduction of recorded media, 153). in 2015 a total of 396,500 people were in employment, including 83,500 (21·1%) in gaming and junket activities (up from 12,500 in 1999); 55,000 (13·9%), hotels, restaurants and similar activities; 54,800 (13·8%), construction; 45,000 (11·4%), wholesale and retail trade, repair of motor vehicles, motorcycles and personal and household goods; 29,800 (7·5%), real estate and business activities; 29,400 (7·4%), public administration and social security. employment in 2015 was 98·2% of the labour force; unemployment rate stood at 1·8%. in 2009 imports (c.i.f.) were valued at us$4,750·9m., of which the main products were telecommunications, sound recording and reproducing equipment; petroleum and petroleum products; and gold, silverware, jewellery and articles of precious materials. in 2009 the chief import sources (in us$1m.) were: mainland china (1,451·6); hong kong (505·4); japan (381·9). 2009 exports (f.o.b.) were valued at us$960·7m., of which the leading products were articles of apparel and clothing accessories; gold, silverware, jewellery and articles of precious materials; and petroleum oils and oils obtained from bituminous minerals. in 2009 the main export markets (in us$1m.) were: hong kong (377·5); usa (163·8); mainland china (139·9). in 2013 there were 421 km of roads. in 2011 there were 165,500 landline telephone subscriptions (equivalent to 297·9 per 1,000 inhabitants) and 1,353,200 mobile phone subscriptions (or 2,435·0 per 1,000 inhabitants). in 2012, 82·5% of households had internet access. in march 2012 there were 205,000 facebook users. there are a judicial district court, a criminal court and an administrative court with 24 magistrates in all. in 2009 there were 12,406 crimes, of which 6,462 were against property. there were 930 persons in prison in dec. 2009. there are both public and private schools. in 2014-15 there were 95 schools and colleges. number of students in the 2014-15 academic year (with number of teachers): pre-primary, 14,552 (916); primary, 24,252 (1,722); secondary, 30,088 (2,629). in 2014-15 there were four special education schools with 624 pupils and 112 teachers. there were ten higher education institutions with student enrolment of 30,771. in 2014 there were 31 institutions offering vocational training courses, in which participants totalled 52,636. expenditure on education came to 1·8% of gdp in 2013 and 14·9% of total government spending in 2014. in 2009 there were 723 doctors, 108 dentists and 450 nurses working in primary health care, and 560 doctors, 14 dentists and 1,169 nurses working in hospitals. in 2009 there were 1,294 hospital beds; there were 2·4 doctors per 1,000 population. in 2010 there were an estimated 320,000 folk religionists and 90,000 buddhists according to the pew research center's forum on religion & public life. a further 80,000 people were religiously unaffiliated. there are also small numbers of catholics. the historic centre of macao was inscribed on the unesco world heritage list in 2005. in 2009 there were 14 daily newspapers (nine in chinese, three in portuguese and two in english) and 11 weekly newspapers (ten in chinese and one in portuguese). tourism is one of the mainstays of the economy. in 2014 there were 31·5m. tourists (of which 21·3m. were from mainland china, 6·4m. from hong kong and 1·0m. from taiwan), up from 29·3m. in 2013 and 28·1m. in 2012. visitor spending in 2014 totalled 61,749m. patacas. the government-run macao international music festival featuring a wide range of chinese and western music takes place in oct.-nov. in sept. 2009 chen shui-bian received a life sentence (later reduced to a 19-year term) after being found guilty of multiple counts of corruption. china and taiwan signed a free trade agreement in june 2010, which was considered a significant thawing of relations. nonetheless, tensions remained, particularly in relation to disputed sovereignty over several islands in the east china sea. in jan. 2012 ma ying-jeou was re-elected to the presidency but the election in jan. 2016 was won by tsai ing-wen, whose democratic progressive party won the most seats in legislative polls at the same time-the first occasion that the nationalist party has not been the largest party in government since 2004. beginning with the elections to the seventh legislative yuan held on 12 jan. 2008 the legislative yuan has 113 members (formerly 225). of the 113 members 73 are elected under the first-past-thepost system in single-member constituencies, 34 are filled by proportional representation in accordance with a nationwide party vote and six are reserved for aboriginal candidates. since 1996 the president has been directly elected. since 1997 a resolution on the impeachment of the president or vice president is no longer to be instituted by the control yuan but rather by the legislative yuan. the legislative yuan has the power to pass a no-confidence vote against the premier of the executive yuan, while the president of the republic has the power to dissolve the legislative yuan. the premier of the executive yuan is directly appointed by the president of the republic. in dec. 2003 a law came into effect allowing for referendums to be held. national anthem 'san min chu i' ('the three principles of the people'); words by dr sun yat-sen, tune by cheng mao-yun. conscription was reduced from 14 months to 12 months in 2009. the government has announced its intention to move towards a volunteer professional force-a process that was originally scheduled to start in 2011 and end in 2014 but was delayed owing to low recruitment levels. in dec. 2016 the defence minister announced that conscription would officially cease in 2018. defence expenditure in 2013 totalled us$10,316m. (us$443 per capita), representing 2·1% of gdp. the republic of china army conducts ground combat missions as well as air support and airborne special operations. it was estimated to number about 200,000 personnel in 2011, with reserves numbering 1·5m. its principal role is to defend against a possible amphibious assault from the chinese mainland by the people's liberation army. in addition there are paramilitary forces totalling 17,000 personnel. navy personnel in 2011 totalled 45,000, with 67,000 reservists. the forces consist of four submarines, four cruisers and 22 frigates. there are also 61 missile craft for patrol and coastal defence, 12 mine-laying vehicles and 290 amphibious landing craft. in 2011 the air force numbered 55,000 personnel with 90,000 reservists. there were 477 combat-capable aircraft in the same year including f-5es, f-16s and mirage 2000-5s. by a treaty of 2 dec. 1954 the usa pledged to defend taiwan, but this treaty lapsed one year after the usa established diplomatic relations with the people's republic of china on 1 jan. 1979. in april 1979 the taiwan relations act was passed by the us congress to maintain commercial, cultural and other relations between usa and taiwan through the american institute in taiwan and its taiwan counterpart, the co-ordination council for north american affairs in the usa, which were accorded quasi-diplomatic status in 1980. the people's republic took over the china seat in the un from taiwan on 25 oct. 1971. in may 1991 taiwan ended its formal state of war with the people's republic. taiwan became a member of the world trade organization on 1 jan. 2002. in feb. 2018 taiwan had formal diplomatic ties with 20 countries. in aug. 2007, 15 of the diplomatic allies sponsored an unsuccessful proposal for taiwan to join the un. taiwan has made a successful transition from an agricultural economy to one based on high-tech electronics. economic growth averaged 8% per year over three decades from the 1970s, driven primarily by high value-added manufacturing and exports, especially in electronics and computers. government-owned enterprises, including banks, have been privatized. though largely escaping the impact of the 1997 asian financial crisis, the economy went into recession in 2001 with the first year of negative growth ever recorded and unemployment reaching record highs. strong export performance stimulated a recovery, with annual gdp growth above 4% from 2002-08. inflation has been consistently low and unemployment, which fell below 3% in 1999, has averaged between 4 and 6% since the turn of the century. owing to its heavy dependence on exports, taiwan suffered a severe downturn as a result of the global financial crisis in 2008. major export industries such as semiconductors and memory chips declined, unemployment reached its highest levels since 2003 and, in 2009 , the economy again went into recession. a us$5·6bn. stimulus package boosted recovery and in 2010 the economy recorded its highest growth rate for nearly three decades, at 10·7%. however, growth subsequently cooled owing to lower demand from developed nations, averaging 1·9% per year between 2013 and 2016. tourism has grown in importance, with over 10·5m. visitors in 2016 constituting taiwan's highest annual number to date. an ageing population and high savings rates threaten to constrain domestic demand in the future. the unit of currency is the new taiwan dollar (twd) of 100 cents. gold reserves were 13·62m. oz in dec. 2010. there was inflation of 1·2% in 2014 but deflation of 0·3% in 2015. foreign exchange reserves were us$382·0bn. in dec. 2010. in 2006 general government revenues totalled nt$2,172,436m. and expenditures nt$2,261,958m. tax revenue accounted for 71·7% of revenues in 2006; education, science and culture accounted for 21·6% of expenditures, economic development 17·0% and general administration 15·3%. taiwan sustained rapid economic growth at an annual rate of 9·2% from 1960 up to 1990. the rate slipped to 6·4% in the 1990s and 5·9% in 2000; taiwan suffered from the asian financial crisis, though less than its neighbours. in 2001 global economic sluggishness and the events of 11 sept. in the usa severely affected taiwan's economy, which contracted by 2·2%. subsequent economic recovery led to growth of 5·4% in 2006 and 6·0% in 2007. there was negative growth of 1·6% in 2009 but again the economy bounced back, and grew by 2·2% in 2013, 3·9% in 2014 and 2·1% in 2015. the central bank of the republic of china (taiwan), reactivated in 1961, regulates the money supply, manages foreign exchange and issues currency. the governor is yang chin-long. the bank of taiwan is the largest commercial bank and the fiscal agent of the government. there are seven domestic banks, 38 commercial banks and 36 foreign banks. there are two stock exchanges in taipei. taiwan's carbon dioxide emissions from the consumption of energy in 2011 were the equivalent of 13·4 tonnes per capita. output of electricity in 2011 was 238·6m. mwh; total installed capacity was 41,401 mw. there were six units in three nuclear power stations in 2010. crude oil production in 2010 was 91,000 bbls; natural gas, 290m. cu. metres. taiwan imports most of the oil and natural gas that it consumes. in 2010 the cultivated area was 813,126 ha., of which 410,832 ha. were paddy fields. rice production totalled 1,451,011 tonnes. livestock production was valued at nt$144,614m., accounting for 34% of taiwan's total agricultural production value. forest area, 2010: 2,102,000 ha. forest reserves: trees, 357,492,000 cu. metres; bamboo, 1,109m. poles. timber production, 19,468 cu. metres. the catch in 2015 was 987,873 tonnes, almost exclusively from sea fishing. the first three are container centres, kaohsiung handling 9·98m. 20-ft equivalent units in 2013, making it the world's 13th busiest container port in terms of number of containers handled. suao port is an auxiliary port to keelung. in jan. 2001 the first legal direct shipping links between taiwanese islands and the chinese mainland in more than 50 years were inaugurated. in 2011 there were 16,907,300 landline telephone subscribers (726·8 per 1,000 inhabitants). taiwan's biggest telecommunications firm, the state-owned chunghwa telecom, lost its fixed-line monopoly in aug. 2001. in 2011 there were 28,861,800 mobile phone subscriptions, equivalent to 1,240·7 per 1,000 persons. in 2013 there were 57·1 mobile broadband subscriptions per 100 inhabitants and 24·2 fixed broadband subscriptions per 100 inhabitants. in march 2012 there were 11·9m. facebook users. the judicial yuan is the supreme judicial organ of state. comprising 15 grand justices, since 2003 these have been nominated and, with the consent of the legislative yuan, appointed by the president of the republic. the grand justices hold meetings to interpret the constitution and unify the interpretation of laws and orders. there are three levels of judiciary: district courts and their branches deal with civil and criminal cases in the first instance; high courts and their branches deal with appeals against judgments of district courts; the supreme court reviews judgments by the lower courts. there is also the supreme administrative court, high administrative courts and a commission on the disciplinary sanctions of public functionaries. criminal cases relating to rebellion, treason and offences against friendly relations with foreign states are handled by high courts as the courts of first instance. the death penalty is still in force. there was one execution in 2016 but none in 2017. the population in penal institutions in april 2013 was 65,288 (280 per 100,000 of national population). since 1968 there has been compulsory education for six to 15year-olds with free tuition. the illiteracy rate dropped from 7·1% in 1989 to 2·5% by 2006. there were 2,654 primary schools, 1,061 secondary schools and 156 vocational schools in 2008; and 102 universities, 45 colleges and 15 junior colleges. in 2005-06 there were 1,831,913 pupils with 101,682 teaching staff at elementary schools; 951,236 pupils and 48,816 teaching staff at junior high schools; 420,608 pupils and 34,112 teaching staff at senior high schools; and 331,604 students and 15,590 teaching staff at senior vocational schools. there were 1,259,490 students in universities and colleges in 2005-06 with 48,047 academic staff. in 2011 there were 40,002 physicians (one for every 510 persons), 5,570 doctors of chinese medicine, 133,336 nurses, 12,032 dentists and assistants, and 31,300 pharmacists and assistants. in 2010 there were 20,691 medical facilities serving 1,119 persons per facility; there were 158,922 beds and 68·6 beds per 10,000 persons. in 2010 cancers, heart diseases, cerebrovascular diseases, diabetes and accidents were the first five leading causes of death. a universal health insurance scheme came into force in 1995 as an extension to 13 social insurance plans that cover only 59% of taiwan's population. premium shares among the government, employer and insured are varied according to the insured statuses. by the end of 2010, 23·07m. people or 99% of the population were covered by the national health insurance programme. according to estimates by the pew research center's forum on religion & public life, 44·2% of the population in 2010 were folk religionists, 21·3% were buddhists and 5·5% christians. the remainder of the population was either religiously unaffiliated or followed other religions, including taoism. there were 23 daily newspapers in 2008 with a circulation of 4·2m. and 21 non-dailies with a circulation of 3·8m. the biggest circulation dailies are the liberty times and apple daily. in 2011 there were 6,087,000 international visitors. receipts totalled us$11,065m. the pop festival, spring scream, is held in april in kenting. china in world history chinese politics in the age of deng xiaoping china and the global political economy china: the rise of xi jinping the cambridge encyclopaedia of china the cambridge history of china. 14 vols the politics of hong kong's reversion to china the chinese economy under transition china this century the tragedy of liberation: a history of the chinese revolution china: a modern history china's deep reform: domestic politics in transition chinese capitalism deng xiaoping and the making of modern china the great chinese revolution 1800-1985 the politics of eu-china economic relations china's second continent: how a million migrants are building a new empire in africa china in transition: communism, capitalism and democracy sowing the seeds of democracy in china: political reform in the deng xiaoping era historical dictionary of the chinese cultural revolution the rise of modern china china: a macro history tombstone: the untold story of mao's great famine china's economy: what everyone needs to know all under heaven: a complete history of china chinese politics in the hu jintao era: new leaders, new challenges the people's republic of amnesia: tiananmen revisited chinese foreign policy in a changing world chinese economy in the 1990s the politics of china: sixty years of the people's republic of china the party: the secret world of china's communist rulers. 2010.-asia's reckoning: china, japan and the fate of us power in the pacific century china's war with japan, 1937-1945: the struggle for survival social and political development in post-reform china age of ambition: chasing fortune, truth and faith in the new china a revolutionary life at the crossroads of post-communist modernisation: russia and china in comparative perspective a history of china wealth and power: china's long march to the twenty-first century mao's road to power: revolutionary writings 1912-1949. 7 vols china goes global: the partial power the chinese century: the rising chinese economy and its impact on the global economy, the balance of power, and your job the china-pakistan axis: asia's new geopolitics the chan's great continent: china in western minds eldest son, zhou enlai and the making of modern china india's and china's recent experience with reform and growth critical issues in contemporary china making china strong other more specialized titles are listed under territory and population; tibet; agriculture further reading statistical information: the census and statistics department is responsible for the preparation and collation of government statistics. these statistics are published mainly in the hong kong monthly digest of statistics. the department also publishes monthly trade statistics, economic indicators and an annual review of overseas trade hong kong's transitions the politics of hong kong's reversion to china the end of hong kong: the secret diplomacy of imperial retreat the hong kong story the final years of british hong kong: the discourse of colonial withdrawal last post: the end of empire in the far east the politics of democratization in hong kong historical dictionary of hong kong and macau china: a political history of the british crown colony's transfer to chinese rule managing china's sovereignty in hong kong and taiwan the democratic progressive party won 68 seats (50 constituency and 18 proportional); the nationalist party, 35 (24 constituency and 11 proportional); the new power party, 5; the people first party, 3; the non-partisan solidarity union, 1; ind., 1. current government president: tsai ing-wen; b. 1956 (nationalist party/kuomintang foreign affairs; health and welfare; interior; justice; labour; national defence; science and technology national defence: yen de-fa. science and technology: chen liang-gee. transportation and communications: ho chen-tan tang feng; lo ping-cheng coast guard administration: lee chung-wei. environmental protection administration: lee ying-yuan. fair trade commission: huang mei-ying. financial supervisory commission: koo lihsiung. hakka affairs council: lee yung-te. council of indigenous peoples: icyang parod. mainland affairs council: chen ming-tong. national communications commission: chan ting-i. overseas community affairs council: wu hsin-hsing. directorate general of personnel administration: shih ning-jye. veterans' affairs council: lee shying-jow hon hai precision industry, an electronics manufacturer (us$43·0bn.); and chunghwa telecom (us$24·7bn metres; integrated circuit packages, 50·5trn. units; global positioning system (gps) sets, 20·9bn. units. labour in 2010 the average total labour force was 11·07m., of whom 10·49m. were employed. of the employed population, 27·3% worked in manufacturing 7·6% in construction; 6·9% in accommodation and food services 100 buses and coaches, 1·0m. lorries and vans, and 13·9m. motorcycles and mopeds were in use. 1,007m. passengers and 594m. tonnes of freight were transported in 2006. there were 3,140 fatalities in road accidents in 2006. rail in 2010 freight traffic amounted to 14·5m. tonnes and passenger traffic to 864m. total route length was 1,741 km. there are metro systems in taipei civil aviation there are currently two international airports: taiwan taoyuan international airport at taoyuan near taipei, and kaohsiung international in the south there were 140 ships of 300 gt or over registered, totalling 2·63m. gt. of the 140 vessels registered, 40 were general cargo ships, 38 bulk carriers, 27 container ships, 26 oil tankers and nine passenger ships. there are six international ports statistical yearbook of the republic of china. annual. the republic of china yearbook. annual. taiwan statistical data book. annual. annual review of government administration the other taiwan: 1945 to the present day historical dictionary of taiwan national identity and status in international society managing china's sovereignty in hong kong and taiwan the shadow of china: political developments in taiwan since 1949 national statistics website the climate is subtropical in the north and tropical in the south. the typhoon season extends from july to sept. the average monthly temperatures of jan. and july in taipei are 59·5°f (15·3°c) and 83·3°f (28·5°c) respectively, and average annual rainfall is 84·99" (2,158·8 mm). kaohsiung's average monthly temperatures of jan. and july are 65·66°f (18·9°c) and 83·3°f (28·5°c) respectively, and average annual rainfall is 69·65" (1,769·2 mm). the roc constitution is based on the principles of nationalism, democracy and social wellbeing formulated by dr sun yat-sen, the founding father of the republic of china. the roc government is divided into three main levels: central, provincial/ municipal and county/city, each of which has well-defined powers.the central government consists of the office of the president, the national assembly, which is specially elected only for constitutional amendment, and five governing branches called 'yuan', namely the executive yuan, the legislative yuan, the judicial yuan, the examination yuan and the control yuan. key: cord-295500-j84v1k1o authors: conway, j.; gould, a.; westley, r.; khan, s.; emmerton, d.; raju, s. a.; oklopcic, a.; broadbent, a.; abdelhafiz, a. h. title: chinese and british hospitalised patients with covid-19—a comparative case series analysis date: 2020-07-18 journal: sn compr clin med doi: 10.1007/s42399-020-00414-w sha: doc_id: 295500 cord_uid: j84v1k1o the covid-19 pandemic initially started in china then spread to europe. it is not known whether covid-19 affects patients differently across the two continents. we aimed to describe our cohort of patients admitted to a single british centre with covid-19 in comparison to a chinese cohort of similar size and admitted over a similar time period to chinese centres. we present a comparison of 62 chinese and 71 british cases hospitalised for covid-19. cases in both sites were confirmed by a positive rt-pcr of nasopharyngeal swabs. comparison analysis highlighted some differences between both populations. the most striking difference is the significantly older age of the british population (72% of the british ≥ 66 years compared to only 3% of the chinese patients, difference of 69%, 95% confidence interval (ci) 68.3% to 69.7%, respectively) and the associated significant premorbid conditions (85% of patients vs 32%, difference of 53%, 95% ci 52 to 54%, respectively). gastrointestinal and general symptoms were more common clinical presentation in the british while respiratory symptoms were more prominent in the chinese cohort. mortality was significantly higher in the british cohort 14% compared to none in the chinese cohort (difference of 14%, 95% ci 13.7 to 14.3%). we conclude that covid-19 does present differently in these two cohorts, but the apparent differences in the clinical presentations could be explained by the inherent differences in the demographics and case mix between both countries. in december 2019, a respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 covid-19 was initially reported in china. the disease later spread to europe to cause a global pandemic. affected patients usually present with respiratory, gastrointestinal or general and non-specific symptoms. mortality is high especially in those with premorbid chronic conditions. because the pandemic started first in china, most of the literature on covid-19 describes chinese populations. in this analysis, we aimed to describe a comparative analysis between a chinese and a british cohort to explore the differences of covid-19 patients across asia and europe. in this case series, we aimed to describe a comparative analysis between a chinese and a british cohort to explore the differences of covid-19 patients between the two countries. data were collected on patients admitted with covid-19 to a single district general hospital in the uk. for comparison, we used a published chinese case series of similar population size, similar methodology and similar data collection period [1] . cases on both sites were confirmed by a positive rt-pcr of nasopharyngeal swabs. british cohort included 71 patients (70 white british) and the chinese 62 patients (all chinese). the most striking difference was the significantly older age of the british population (72% of the british were ≥ 66 years old compared to only 3% of the chinese patients, difference of 69%, 95% confidence interval (ci) 68.3% to 69.7%, respectively). the pre-existing morbidities were also significantly higher in the british compared to the chinese cohort (85% of patients vs 32%, difference of 53%, 95% ci 52% to 54%, respectively). however, the only comorbidity which was higher in the chinese cohort was the chronic liver disease (11% vs 7% difference of 4%, 95% ci 3.5 to 4.5%). gastrointestinal and general symptoms were more common clinical presentations in the british while respiratory symptoms were more prominent in the chinese cohort (table 1) . mortality was significantly higher in the british cohort of 14% compared to none in the chinese cohort (difference of 14%, 95% ci 13.7 to 14.3%). the significant older age in the british cohort is likely due to the fact that the prevalence of older people (≥ 65 years) is higher in the uk than in china (18% vs 11%) [2] . similarly, the larger number of comorbidities in the british cohort is likely related to the higher prevalence of older age groups. the only comorbidity that was significantly more common in the chinese cohort was the chronic liver disease which reflects the higher prevalence of liver cirrhosis in asia than in europe [3] . respiratory symptoms were more prominent in the chinese cohort probably due to the fact that the chinese media and national advocacy have instructed patients with fever, cough, expectoration and other upper respiratory tract symptoms to go to the hospital at an early stage, while in uk, social distancing and self-isolation at home was more encouraged [1] . the british cohort presented with slightly more gastrointestinal symptoms such as diarrhoea and general symptoms such as myalgia and fatigue which may represent atypical clinical presentation of covid-19 infection in the elderly [4] . the mortality rate was significantly higher in the british cohort reflecting their older age and the associated higher comorbid conditions. older age was identified as a risk factor for mortality from covid-19 pneumonia in a previous study (odds ratio (or) 1.10, 95% ci 1.03 to1.17, p = 0·004) [5] . ageing appears to play a significant role in mortality rate differences between countries affected. for example, the overall case fatality rate in italy (7.2%) is substantially higher than that in china (2.3%) but when data are stratified by age groups, the case fatality rate in italy and china appear very similar up to the age of 69 years. individuals aged ≥ 70 years represent 37.6% of cases in italy and only 11.9% in china which may explain that the higher overall case fatality rate is due to the high prevalence of older age groups in italy compared to china [6] . also, in an initial british report of 20,133 patients with severe covid-19 who were hospitalised, median age was 73 years (iqr 58, 82). increased age was a strong predictor of in-hospital mortality after adjusting for comorbidity, reference age < 50 years, 50-69 years (hazard ratio (hr) 4.02, 95% ci 2.88 to 5.63, p < 0.001), 70-79 years hr 9.59 (6.89 to 13.34, p < 0.001), ≥ 80 years hr 13.59 (ci 9.79 to 18.85, p < 0.001) [7] . in a chinese nationwide analysis of 1590 hospitalised patients with covid-19, a minimum one comorbidity was present in only 25.1% of patients. two or more comorbidities were reported in 8.2% of patients, and the number of comorbidities proportionally increased the risk of adverse outcomes [8] . in europe, the prevalence of comorbidities was much higher. for example, early on of the outbreak in italy in february 2020, when most cases were in the northern region, case fatality rates were similar between italy and china of 2.3%. travel-related cases were the main source of covid-19 cases during that period of the epidemic in italy. in both countries, fatalities appear to affect mostly individuals with known comorbidities. however, case fatalities in italy were more common in older people. for example, 57% of people who died were ≥ 80 years old in italy compared to only 20% in china [9] . later on, a report for italy, published in april 2020, showed that mortality rate has risen to 12%, most cases that died were > 70 years old, a male to female ratio of 3:1 with at least 1 comorbidity and cardiovascular disease was the highest risk condition. these data were different from the epidemiologic results observed in other asian countries at that time where mortality rate ranged between 1 and 8% and a male/female ratio of 2:1. this variation can be explained by the difference in the local demography due to the higher prevalence of cardiovascular disease both in italy compared to china and in men compared to women [10] . a chart review of 355 patients who died with covid-19 in italy, the mean (sd) number of comorbidities was 2.7 (1.6). overall, 99.2% of patients had comorbidities, 25.1% had one comorbidity, 25.6% had 2 comorbidities and 48.5% had ≥ 3 comorbidities suggesting that mortality is proportional to the number of comorbidities [6] . similarly, in the british report of 20,133 patients hospitalised with severe covid-19, 77% of patients had a documented comorbidity which was associated with increased hospital mortality [7] . this suggests that older age and comorbidities were more common in european cohorts affected by covid-19 than in china, and they have a significant impact on mortality difference between the two continents. table 2 summarises age and comorbidities of covid-19 patients reported from china, uk and italy. the main difference in this comparison was the significantly older age of the british population and its associated significant premorbid conditions. this may reflect the fact that the prevalence of older people (≥ 65 years) is higher in the uk than in china (18% vs 11%) [2] . the larger number of comorbidities such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, cardiovascular disease and chronic kidney disease was much more common in the british cohort likely related to the higher prevalence of older age group. the only comorbidity that was significantly more common in the chinese cohort was the chronic liver disease which also reflects the higher prevalence of liver cirrhosis in asia than in europe [3] . respiratory symptoms dominated in the chinese cohort which may be due to the fact that chinese media and national advocacy have instructed patients with fever, cough, expectoration and other upper respiratory tract symptoms to go to the hospital at an early stage while in the uk, social distancing and self-isolation at home was encouraged [1] . the british cohort presented with slightly more gastrointestinal symptoms like diarrhoea and general symptoms like myalgia and fatigue which may represent atypical clinical presentation of covid-19 infection in older age groups [4] . the mortality was significantly higher in the british cohort which is likely related to old age and morbidities. older age was identified as a risk factor for mortality from covid-19 pneumonia in a previous study (odds ratio (or) 1.10, 95% confidence interval (ci) 1.03 to1.17, p = 0·004) [5] . we conclude that covid-19 clinical presentation of hospitalised patients across china and uk appears to be similar. the apparent differences in presentations are likely due to the inherent differences of the demographic features and case mix between the two countries. we conclude that covid-19 clinical presentation of hospitalised patients across china and uk appears to be slightly different; however, these apparent differences could be due to the inherent differences of demographic features and case mix between the two countries. literature review suggests that this demographic pattern may also extend to represent the difference between other european countries and china. the aged population is currently concentrated in the wealthier developed countries, which are able to absorb the financial impact of the pandemic and limit its spread to other countries. with the global demographic shift towards old age, the sector of older people will exponentially expand, especially in lowand middle-income countries where heath care resources to face a future pandemic are limited and thus increases the risk of uncontrollable global spread. therefore, who and governments around the world must consider this potential threat in health care planning. also, uncertainty about covid-19 trajectories remains substantial. comparative measures are still required, in addition to the traditional deaths per-capita method, to calculate covid-19 deaths and to compare progression of the disease across different countries. current projections seem to underestimate the eventual impact of covid-19 on the annual life expectancy at birth. indirect standardization as an alternative to death per capita has estimated that in the usa, the covid-19 impact would reach twice that of hiv infections or opioid overdoses, reducing the 2020 life expectancy to its lowest level since 2008 [11] . clinical findings in a group of patients infected with the 2019 novel coronavirus (sars-cov-2) outside of wuhan, china: retrospective case series liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis atypical presentation of covid-19 in a frail older person clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study italy and the uk country population main findings china [8] 1590 patients a. mean (sd) age was 48.9 years (16.3) b. 25.1% have ≥ 1 comorbidity c mortality risk increased by comorbidity (hr 1.79, 95% ci 1.16 to 2.77) for ≥ 1 comorbidity and 2.59 (1.61 to 4.17) for ≥ 2 comorbidities comorbidities were diabetes mellitus (35.5%), ischaemic heart disease (30%), atrial fibrillation (24.5%), active cancer (20.3%), stroke (9.6%) and dementia 133 patients a. median age 73 years (iqr 58, 82) b. 77% had documented comorbidity common comorbidities were cardiac disease (31%), uncomplicated diabetes (21%), non-asthmatic chronic respiratory disease (18%) and ckd (16%) mortality rate 26% increased age and morbidity predicted mortality ds standard deviation, hr hazard ratio, ci confidence interval, iqr interquartile range, ckd chronic kidney disease sn compr case-fatality rate and characteristics of patients dying in relation to covid-19 in italy features of 20 133 uk patients in hospital with covid-19 using the isaric who clinical characterisation protocol: prospective observational cohort study comorbidity and its impact on 1590 patients with covid-19 in china: a nationwide analysis similarity in case fatality rates (cfr) of covid-19/sars-cov-2 in italy and china mortality rate and gender differences in covid-19 patients dying in italy: a comparison with other countries beyond deaths per capita: three covid-19 mortality indicators for temporal and international comparisons. medrxiv publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations conflict of interest none.ethical approval approved by the rotherham hospital foundation trust research and development department. key: cord-018070-js9vvsud authors: hayes, anna marie title: human insecurity in the people’s republic of china: the vulnerability of chinese women to hiv/aids date: 2011-10-13 journal: human security doi: 10.1007/978-94-007-1799-2_2 sha: doc_id: 18070 cord_uid: js9vvsud hiv/aids has become one of the world’s leading causes of human insecurity for both men and women. in addition to physiological factors, women’s vulnerability to hiv transmission is primarily fuelled by gender inequality and gender-based discrimination and violence. therefore, women’s vulnerability to hiv transmission is closely linked to issues of empowerment and gender-based power relations. even with this realization however, women are still sometimes overlooked in many hiv/aids prevention and treatment campaigns, such as those in the people’s republic of china (prc), and responses to hiv/aids do not always actively seek to empower women. therefore, a deficiency in women’s human security increases their hiv/aids vulnerability. this chapter examines the intersection of gender inequality and hiv vulnerability as it applies to women in the prc. the unequal status of many women in china, and the privileged position accorded to chinese men, strongly indicates that chinese women face a heightened vulnerability to hiv transmission. while many of these vulnerabilities are similar to women elsewhere in the world and certainly are not unique to china, by overlooking the many social, cultural, economic and political factors that contribute to hiv/aids vulnerability and transmission of the virus, particularly those faced by women, china has a long way to go before chinese women are protected from hiv transmission. given that hiv/aids heightens human insecurity, the stage is set for chinese women (and men) to face an insecure future if the chinese government does not fully implement international best practice, meaning a gendered response, into its overall hiv/aids response. for the purposes of this chapter, the defi nition of human security is aligned closely with that of the united nations which states that human security is both 'freedom from fear' and 'freedom from want', incorporating components such as economic, food, health, environmental, personal, community and political security. this defi nition challenges the more restricted notions of human security and is centred on the principles that human security is a universal concern, its components are interdependent, that it is best achieved through prevention rather than intervention and that it is people-centred (undp 1995 : 232-34) . figures from the ministry of health (moh) show sexual transmission is now the main mode of hiv transmission in the prc, signalling that china has moved into the 'growth period' of its hiv/aids epidemic. at the close of 2009, it was reported that 59% of the total number of hiv/aids cases in china were caused by sexual transmission, with heterosexual transmission accounting for 44.3% of those infections and homosexual transmission accounting for 14.7% (ministry of health of the people's republic of china 2010 : 22) . of the total reported number of hiv/aids cases, 30.8% of plwha in the prc are women demonstrating the vulnerability of women to hiv transmission and increasing the concerns that the country is in a growth period (scawco and unaids 2007 : 4) . also concerning is that since 2005, sexual transmission has been the fastest growing mode of hiv transmission in china (hong et al. 2009 ) . further evidence of china's hiv epidemic moving into its growth period are the country's fi gures on mother-to-child-transmission (mtct). since 2005, it has estimated that mtct of hiv accounted for approximately 1.3-1.5% of the total number of new hiv cases (national center for aids/std prevention and control 2006 : 2; ministry of health of the people's republic of china 2010 : 23). according to the united nations joint program on hiv/aids (unaids) mtct rates in excess of 1% demonstrate that a hiv/aids epidemic meets the criteria for the categorization of a 'generalized epidemic' as mtct highlights rates of hiv among women in the general population who do not belong to any particular high-risk group (gill et al. 2007 ) . therefore, the above results are further evidence that china's overall hiv/aids epidemic has moved into its growth period . if effective prevention and control measures are not introduced prior to or during the growth period, and the country's hiv/ aids epidemic moves into the 'rampant prevalence period', large scale hiv transmission is inevitable. although rates of hiv among the general population remain low in the prc, with rates believed to be between 0.042% and 0.071% (ministry of health of the people's republic of china 2010 : 5), the spread of hiv through heterosexual intercourse among the general population is very much a warning that the numbers of plwha may soon explode across the country. if this occurs, it would make the epidemic very diffi cult to prevent and control and chinese women's vulnerability to hiv transmission will increase substantially, particularly because the prevalence rate of hiv among the general population would increase rapidly. physiologically, women are two to four times more vulnerable to hiv transmission than their male counterparts when engaging in unprotected vaginal intercourse (unaids 2002 : 57) . 2 in addition to physiological risks, women worldwide face a number of vulnerabilities to hiv/aids, deriving from a variety of social, cultural, economic and political factors. a society's gender roles have considerable infl uence on three main areas of hiv/aids vulnerability; accurate sexual and reproductive health knowledge, sexual passivity and aggression, and promiscuity. in addition, 'enabling environments' such as social, cultural, political and economic environments, can all fuel hiv vulnerability among women and these vulnerabilities are largely the result of gender inequality (feinstein and prentice 2000 ) . thus, in order for a state's hiv/aids response to be effective it must include gender-specifi c factors. therefore, women must be recognized as a vulnerable group. however, when asked whether she believed chinese women were particularly vulnerable to hiv transmission, interviewee d (2003, pers. comm., 27 august) , 3 who was the director of a government organization that played a key role in hiv/ aids prevention and treatment, responded that she believed 'women are less vulnerable [than men] to hiv/aids' and that women's vulnerability to hiv/aids largely depended on whether a woman was a sex worker, an intravenous drug user (idu), if she had donated her blood, had a blood transfusion or had used other blood products (interviewee d 2003, pers. comm., 27 august) . this point of view was supported by another interviewee, who was the national programme offi cer for an international non-governmental organization (ingo) responsible for hiv/aids prevention and treatment. in response to the same question, this interviewee stated that 'gender does not play any role [in its hiv/aids policies], and it is not part of mainstream discussions' (interviewee c 2003, pers. comm., 22 august) . these responses are alarming because they ignore the patterns of hiv transmission to women in much of the rest of the world, whereby women in the general population have been found to be extremely vulnerable to hiv transmission in areas with high rates of hiv/aids. 4 however, while interviewee c's organization did not incorporate a gendered response into its overall hiv prevention and treatment programs, her responses indicated that the intersection of gender and hiv vulnerability was being considered (2003, pers. comm., 22 august) . interviewee c believed that gender and economics were important issues in hiv/aids prevention and treatment, even though they were not yet widely recognized or were a part of china's offi cial hiv/aids response and policies. on the issue of what factors increased female vulnerability to hiv transmission, she said: women are vulnerable… for a number of reasons. these include the status of womenpolitical, economic and social status of women. also, the educational level of women is lower than their male counterparts, and unemployment rates are a great deal higher. this has a lot to do with remaining views on the role of women, which follow closely with the traditional stereotypes of women as wives, devoted to house and raising children. they are still seen in this caregiver role. women are also restricted in their access to information, so this also makes them vulnerable because they don't know what hiv/aids is or how to prevent it (interviewee c 2003, pers. comm., 22 august). responses from other interviewees also demonstrated that organizations were aware of the links between gender and hiv vulnerability. when asked what factors he believed increased chinese women's vulnerability to hiv/aids, interviewee e (2003, pers. comm., 27 august), a health specialist for an ingo that included hiv/ aids in its health framework, responded that he felt unemployment and low education levels were key factors because they led to economic insecurity that could lead women to prostitution. he stated that particularly in rural china, female school enrolments were much lower than those of males, and that this adversely affected women's employment opportunities. he also stated that women were further disadvantaged because they were not paid the same as men for equal work. also, because many women had been laid-off from their jobs in northeast china, due to factory closures and cutbacks, many of these women had been forced to enter the sex industry as a means of survival (interviewee e 2003, pers. comm., 27 august) . hence, while both interviewees c and e were aware of the effects gender has on hiv/aids vulnerability, neither their particular organizations, nor any other organizations responsible for hiv/aids prevention and treatment campaigns at the time, incorporated gender into their programmes or education campaigns. interviewee a, who was a senior programme offi cer for an overseas aid agency (2003, pers. comm., 21 august) , offered two possible reasons for this oversight. firstly, she believed a gendered response was not a major component of china's hiv/aids strategy because 'gender issues are generally addressed by the all china women's federation (acwf) or the regional women's commission (rwc)' (interviewee a 2003, pers. comm., 21 august) . secondly, at the time of fi eldwork, ordinary chinese women among the general population were not widely recognized or targeted as being vulnerable to hiv transmission (interviewee a 2003, pers. comm., 21 august). therefore, according to interviewee a, because women among the general population were not regarded as a vulnerable group it made little sense to organizations such as hers to engender their hiv/aids prevention strategies. however, if we consider interviewee a's fi rst response, it would appear that the acwf and rwc have unintentionally 'marginalized' women in discussions on hiv/aids vulnerability among organizations responsible for hiv/aids prevention and treatment campaigns because these organizations do not want to interfere with the role of the acwf and the rwc. this reluctance could in part be because of the historical background of the acwf. this organization was one of the fi rst mass organizations formed by the chinese communist party following the 1949 liberation and was the impetus for the social, legislative and policy changes aimed at improving the status of women in the 1950s. while it was temporarily disbanded during the cultural revolution , the organization was fully reformed in 1978 and since that time it has continued its earlier work on improving the status of women in china through legislative and social change (howell 2003 ) . therefore, the acwf has had a monopoly on women's issues in china for much of china's post-liberation period. while there has been an expansion of women's groups and organizations since the reform and opening of china in 1978, it is signifi cant to note that the acwf has remained an important ally for these groups (lee and regan 2009 ) , and the strongest women's organization in china due to its political legitimacy and sway in the political structure (howell 2003 ) . therefore, interviewee a's reasons for the lack of consideration of gender in offi cial responses to hiv/aids in china demonstrates that there are serious impediments which need to be addressed. it would seem there is a reluctance to either tackle gender issues by non-acwf organizations as they may perceive a turf war confl ict, or simply because they feel that such issues are best handled by the acwf. whatever the reason, because such organizations are reluctant to incorporate gendered responses into their hiv/aids prevention and treatment campaigns women have been marginalized in the mainstream responses to hiv/aids in china even though international experience has repeatedly demonstrated that if they are left unresolved, gender vulnerabilities to hiv transmission fuel hiv epidemics. however, interviewee a did state that should the epidemic move into the 'rampant prevalence' period, these groups (meaning women in the general population not belonging to any of the traditional 'high-risk' groups) would receive more attention from organizations like hers. thus, it would appear some organizations do believe gendered responses may be necessary in the future. nonetheless, the reluctance of international organizations like interviewee a's to incorporate gendered responses was concerning as in many aids-stricken countries, especially those in sub-saharan africa, women among the general population have been found to be at substantial risk of contracting hiv through non-commercial heterosexual intercourse (unaids, unfpa and unifem 2004 : 1-2). as stated above, much of this vulnerability stems from social, cultural, economic and political factors that often refl ect gender inequality and this chapter now turns to an examination of these in the context of women in the prc. accurate knowledge about hiv/aids, including the prevention and transmission of hiv, is an essential part of an adequate response to hiv/aids. however, surveys conducted by some ingos have revealed that as much as 20-40% of china's population has no knowledge of hiv/aids at all (park 2003 : 54; unaids 2002 : 43) . while recent fi gures suggest this has changed and that 'basic' 5 hiv/aids awareness is in the vicinity of between 74.5% and 85.1% for urban and rural residents and migrant workers, there still remain pockets of the population who lack accurate hiv/aids knowledge and awareness (ministry of health of the people's republic of china 2010 : 7). one of the reasons often cited for this lack of knowledge is that due to china's size and regional variances in language dialects, country-wide hiv/ aids education campaigns are diffi cult to conduct. interviewee f (2003, pers. comm., 9 september) , the division director of a government organization that examines hiv/aids related issues, confi rmed this when she stated 'because china is so large… not everyone knows about aids [and] the information has not spread to very remote areas, [therefore] more work will be done there'. these factors seriously complicate the dispersal of accurate hiv/aids knowledge, and are a key area that the chinese government must overcome to effectively respond to china's growing hiv/aids epidemic. however, there also exists a range of other reasons for the poor levels of hiv/aids knowledge in china. the reform and opening period , which began in the late 1970s, loosened societal attitudes and views on sexual issues in china, and this resulted in an increase in premarital sex and societal acceptance of premarital sex (qian et al. 2004 ; wu et al. 2007 ) . a study by the sex sociology institute of the people's university of china found that in people over 40 years of age, 45.7% of men and 24.1% of women reported they had engaged in premarital sex . however, for the 25-29 year old age bracket, rates were signifi cantly higher with 72.2% of men and 46.2% of women reporting they had engaged in premarital sex (xia 2004 : 14) . even though premarital sex is occurring, sex education and the supply of contraceptive devices to young, unmarried people remains a contentious issue. interviewee c (2003, pers. comm., 22 august) stated that sex education was an important topic in china and that there had been much debate over when young people should be taught about sexual health, with some sections of chinese society arguing that the university level was the most appropriate time for formalized sex education . there was also growing debate over abstinence-based sex education as opposed to sex education that promotes 'safer sex', such as using condoms, with the proponents of the abstinence-based sex education style hoping to see a return to 'traditional morality' (xia 2004 : 15) . in the meantime, no real steps have been made in implementing a comprehensive sex education curriculum into chinese schools. as a result, many university students in the prc have 'alarmingly low' levels of aids knowledge and self-perceived risk (wu et al. 2007 : 683) , refl ecting the need for a national sex education curriculum. this is concerning as hiv in china is most prevalent among people in the 20-29 year old age bracket, with this group accounting for 56% of china's overall hiv/aids cases (ma et al. 2009 : 249) . however, these rates of infection are unsurprising when one considers that surveys of university students have found that only 15% of those who were sexually active reported 100% condom use in their sexual encounters during the year prior to the study (ma et al. 2009 : 256) . for many young unmarried people in china, the lack of accurate knowledge on 'safer sex' has been a contributing factor in them engaging in unprotected sex, which easily facilitates the transmission of stis, including hiv, as well as increasing rates of unintended pregnancy. although young unmarried people can access contraceptive services in china, information and advice about contraception is somewhat limited. this is because the national family planning programme only targets married couples for the delivery of contraception information and devices. furthermore, studies conducted in rural and urban shanghai found that when premarital sex resulted in pregnancy, most pregnancies were unintended, and were usually because the couple had not used contraceptives (qian et al. 2004 ) . surveys conducted on confi dence levels when purchasing condoms found that only 44.3% of women compared to 85.5% of men felt confi dent buying condom s (ma et al. 2009 : 257) . clearly, even though premarital sex has become more commonplace and generally more acceptable, a comprehensive sex education programme and easy, more accepted access to reliable barrier methods of contraception are needed if optimum health outcomes are to be achieved. another key factor in this discussion is how condoms are perceived by chinese society. with the resurgence of stis in china, and the need to promote condoms effectively as a means of preventing stis, condoms have undergone a name change from bi yun tao , or 'avoid pregnancy sheath', to an quan tao , or 'safety sheath'. the change refl ects the dual role of condoms in preventing conception, but also as a means of preventing the transmission of stis/hiv (yuan et al. 2003 : 17) . interviewee f acknowledged this change, adding that her organization stressed '…using condoms is benefi cial for men and women, from the point of view of health, because men and women will both benefi t from the[ir] use ' (2003, pers. comm., 9 september) . however, a recent study has reinforced that condoms are still primarily perceived by some university students as pregnancy prevention rather than protection against stis/hiv. the study found that 95% of respondents identifi ed condoms as protection against pregnancy while only 30-41% regarded them as protection against stis/hiv (ma et al. 2009 : 256) . clearly, condoms are a necessary part of an effective hiv prevention strategy so it is imperative that their role in sti prevention is stressed and encouraged in the chinese situation. thus, even with the name change, condom use in china remains low. this is alarming to epidemiologists because of the role of condoms in preventing stis/hiv, particularly for women. a study by xia in 2002 found that 75.1% of male respondents were unwilling to use condoms in their sexual relations because they found them to be 'troublesome', to decrease male sexual pleasure, as well as too expensive. in addition, many unmarried men preferred not to use condoms because they felt their 'sexual and reproductive ability' was proven if their partners became pregnant ( 2004 : 22). furthermore, many men continue to view their sexual relationship with their wife as procreation, whereas sexual pleasure is derived from commercial sex workers. therefore, condoms within marriage are not considered appropriate and they are rarely used, regardless of some men having multiple sexual partners (chen 2008 ) . interviewee b (2003, pers. comm., 22 august), a programme offi cer for an overseas aid agency, believed that women could be vulnerable to stis from their partners because 'there is no such dialogue [safer sex] between husband and wife or partners'. furthermore, she concluded that in south-west china for instance, promotion of condom use in sexual relationships was absolutely necessary because the main route of hiv infection for men there has been idu and for women, it was through heterosexual intercourse 'within the family, within marriage, it's not through commercial sex workers' (interviewee b 2003, pers. comm., 22 august) . increasing condom usage rates among the general population is further complicated because many chinese women use intra-uterine devices (iuds) or have had surgeries such as tubal ligation or hysterectomies to avoid further pregnancies, causing condoms to be viewed as unnecessary. 6 therefore, interviewee b believed that it was imperative condoms be promoted as a sexual health device within marriage and committed relationships in addition to persons engaging in premarital sex or infi delity. while promoting condom use among the general population was also identifi ed as a necessity by interviewees d and c, work is needed on promoting 100% condom use among commercial sex worker s in both their commercial and noncommercial sexual relations. in china, condom use among sex workers is also extremely low with only 10% of sex workers surveyed at various locations reporting that they always used condoms, and close to 50% of sex workers reporting that they had never used a condom with a client (kanabus 2004 ) . this is not surprising considering many sex workers lack adequate hiv/aids information in the fi rst instance and secondly because condom use in sexual exchange generally involves a 'discount' due to both decreased sensitivity and male sexual pleasure. therefore, the economic burden faced when insisting on condom use in the commercial sex exchange means that for many sex workers condom use is not a viable or desirable economic option. in addition, low rates of hiv/aids and sti knowledge has meant that many sex workers do not believe they are at risk of contracting hiv. this clearly indicates a continuing lack of hiv prevention knowledge in an important 'high-risk' group, which increases the likelihood of the transmission of hiv among sex workers and their clients (kanabus 2004 ) . furthermore, other sex workers who wanted to use condoms in the commercial sexual exchange were prevented from doing so because they lacked 'the power to insist on the use of condom s with their clients' . in most instances, it is the client who decides whether or not a condom is used in commercial sexual exchange, again refl ecting the disempowered status sex workers face (kanabus 2004 ) . hence, poor hiv/aids awareness and female disempowerment facilitates such 'high-risk' behaviour, and this situation reinforces the need for widespread public education campaigns to better educate the entire chinese population on hiv/aids prevention and risk. this is particularly pressing considering that commercial sex is the leading contributing factor for the transmission of hiv through heterosexual intercourse (hong et al. 2009 ) . however, such an education campaign must contain accurate and appropriate messages about hiv/ aids and hiv prevention. early state media representations of hiv/aids negatively affected hiv/aids knowledge in china, and how plwha were received by society and by the medical profession. interviewee d (2003, pers. comm., 27 august) stated that when the state media initially discussed hiv/aids, it was portrayed as 'the enemy' and that media reports were largely focused on scaring people about the virus. furthermore, interviewee d believed that these early representations greatly contributed to the stigma and discrimination of plwha in china. this argument was reinforced by dikötter, who claimed that aids was initially described in offi cial discourse as an 'evil from abroad', and that it was widely believed that the 'superior immune system' of the chinese, combined with their 'neo-confucian values', would mean that hiv/aids would not infect the general population but would largely remain limited to homosexual men and sex workers who serviced foreign clients ( 1997 : 78-79). such beliefs became accepted by chinese society and have infl uenced how both the virus and plwha are perceived. in addition to stigma and discrimination , these early representations of hiv/ aids have also led to many people falsely believing that they are not at risk from contracting hiv if they do not belong to one of the above-mentioned groups. this false sense of security was refl ected in the section on 'self-perceived risk of contracting hiv/aids' in a study conducted by the futures group ( 2004 : 17) . this study explored the levels of hiv/aids knowledge among respondents and their attitudes and behaviours towards aids related issues. the study found that 78% of those surveyed believed themselves to be at 'low-risk' of contracting hiv/aids, and that the main reason for such a belief was because very few of the respondents (2%) reported that they knew of a plwha or a person who had died from aids. therefore, because they themselves had not known anyone affected by hiv/aids, their perception of the virus was that it is something that affects the 'other' or that it only affected 'degraded people' (futures group 2004 : 17) . consequently, because they did not fi t either category, they believed themselves to be of little risk of contracting hiv/aids. self-perceived risk has also been skewed by the government's hiv/aids prevention policies, which have long been focused on 'high-risk' groups. it can be argued that current prevention strategies actually put women at risk because they stress partner reduction over condom use as an effective way to avoid hiv transmission. the 'one partner' or 'faithfulness' prevention messages, which teach both men and women to protect themselves against hiv transmission by limiting the number of partners they have to one, has been described by unaids as lulling people into a 'false safety' (unaids 2002 : 44) . surveys that have been conducted in china among traditional 'low-risk' groups such as married women, who do not engage in any of the traditionally recognized 'risky practices' conducive to hiv transmission, have found that most women believe that limiting the number of partners they have to one is much better protection against hiv transmission than using condom s (unaids 2002 : 44) . however, such a measure is dependent upon their spouse having a negative status upon the commencement of the relationship, and not engaging in practices that may cause them to contract hiv for the duration of the sexual relationship. furthermore, the 'one partner' campaign ignores the fact that for many women in the developing world who have contracted hiv/aids through heterosexual intercourse, the source of their transmission was their only sexual partner, usually their husband. 7 often these women were unaware of their husband's hiv+ status, and in other cases, whereby they knew their husband was hiv+, they were unable to say no to sex or insist on condom use due to the unequal gender-based power relations within the relationship. in a study of chinese women who contracted hiv from their husbands, none of the women interviewed were aware of their husband's hiv+ status prior to their own diagnoses. in addition, one husband commented that he felt women 'had little choice if their husbands insisted they do so [have sex], inasmuch as the fact that "we are still married" legitimized their sex' (cited in zhou 2008 : 1119). therefore, the government sponsored campaigns in china that primarily focus on individuals reducing 'risky practices' or limiting the number of sexual partners they have to one, are out of step with reality. instead, hiv/aids prevention campaigns also need to focus on providing easily accessible sexual and reproductive health information for both men and women, and making condoms available and accessible to all sexually active persons. they should also aim to empower women and challenge the negative gender stereotypes and biases attributed to both men and women that heighten their vulnerability to hiv transmission. worldwide, women's vulnerability to hiv/aids is further heightened in societies where women are expected to be passive towards sex. while china was, traditionally, very much a society whereby passivity was expected of women in sexual matters, after 1949 this situation was widely believed to have altered because of mao's proclamations about female equality as well as the belief that the 'smashing' of class 7 surveys conducted in africa reveal that 60-80% of hiv positive women, who contracted hiv from sexual intercourse, reported that their only sexual partner was their husband. another study, which was conducted in india, another region where hiv/aids is growing at an alarming rate, reveals that 91% of hiv positive women surveyed, who had contracted hiv from sexual intercourse, also reported that their only sexual partner was their husband (feinstein and prentice 2000 : 22) . these fi ndings support the results of an earlier study conducted in 1989 which also found the majority of hiv positive women who had contracted hiv through heterosexual intercourse, had also contracted hiv/aids from their only sexual partner, their husband. the researchers in this instance concluded that often 'condom use was more effective in preventing hiv infection than was limiting the number of partners' (berger and vizgirda 1993 : 62). difference would lead to the eradication of outdated sexual stereotypes regarding men and women. however, patriarchal views still permeate chinese society and overall chinese men retain their position of gender privilege, often refl ected in the power dynamics of heterosexual relationships. the one child policy is one of the main factors in increasing female insecurity in contemporary china, particularly within the marital unit. since its introduction, there has been a strong resurgence in son preference , especially in the rural areas where sons play an important role in continuing the family lineage, contributing to the family labour force and their fi lial duty to provide for their parents in old age ( croll et al. 1985 ; croll 2000 ; chan et al. 2002 ) . in some areas of china, the reemergence of son preference has caused there to be strong pressure on women to give birth to a son and failure to do so can lead to domestic violence and even divorce. this is because women are wrongfully blamed over the sex of the child due to poor knowledge on the biological determinants of the sex of the fetus and also because it is believed to be 'the duty of a chinese wife to bear a son to continue the family name' (chan et al. 2002 : 427) . in her discussion of son preference and the resultant violence against women who give birth to daughters, croll provided several accounts of incidences whereby a husband committed acts of domestic violence against his wife after she bore a daughter ( 2000 : 78-80). the acwf has found that reported cases of domestic violence occur in approximately 30% of chinese families, with 32.5% of abused women being beaten around four times per month (xinhua 2000 ) . female suicide rates are also high in the prc, refl ecting female insecurity there. of the total number of female suicides worldwide, 56% occurred in china (renwick 2002 : 383) . in addition, while the urban rate of female suicide is estimated to be in the vicinity of 15.9 per 100,000 women, in rural areas the fi gures have reached 78.3 per 100,000 women, clearly demonstrating a rural/urban divide in female suicide rates in china (hric, cited in renwick 2002 : 383) . a report by the bbc echoed these fi ndings, and stated that many rural women are highly successful in their suicide attempts because they used pesticides and rat poisons to commit suicide (bbc 2002 ) . if gender-based violence such as domestic violence is viewed as an acceptable factor in preserving gender relations in the home, it can substantially increase women's vulnerability to hiv transmission. in societies where there exists 'a cultural ethos that violence is a valid means of solving inter-personal disputes' (whelan 1999 : 11) , such as in the domestic spheres, women may avoid discussing the use of condoms or fi delity issues with their partners for fear of violent response. the fear of violent retribution was identifi ed by women from a range of countries such as guatemala, jamaica and papua new guinea as being the reason why they did not try to negotiate condom usage with their sexual partners (feinstein and prentice 2000 : 24) . women's vulnerability to hiv/aids is heightened by male aggression because it can often be linked to the occurrence of sexual coercion, non-consensual sex and sexual violence against women. for many women, decisions about their sexual behaviour are denied to them because they are forced into sexual intercourse against their will. this is applicable both inside and outside of relationships. in such instances, condom usage is unlikely, so women's vulnerability to hiv transmission is increased (irwin et al. 2003 : 31) . therefore, the accounts given above of high rates of domestic violence and female suicide demonstrate that there are a great number of women in the general population who are facing increased hiv vulnerability due to their unhealthy domestic environment. the traffi c of women in china is also fuelling female vulnerability to hiv transmission, and is most prolifi c in sichuan and guizhou. interviewee a (2003, pers. comm., 21 august) attributed this to the fact that these two provinces 'have a high number of poor farmers and unemployed' so they sell women for fi nancial rewards. interviewee a also stated that the 'traffi c of women in china is generally restricted to marriage, whereas traffi cking outside of china is generally for prostitution'. in saying this, the interviewee believed that the traffi c of women , while bad, would not increase the likelihood of hiv transmission because the women were sold as 'brides', not sex workers (interviewee a 2003, pers. comm., 21 august) . the belief that traffi cked 'brides' are not particularly vulnerable to hiv transmission was also shared by interviewee e (2003, pers. comm., 27 august) . however, this belief demonstrates a serious lack of understanding of human traffi cking as members of the traffi cking gangs sometimes rape the women, regardless of them being traffi cked as 'brides' or as sex workers . furthermore, prospective husbands are sometimes allowed to have intercourse with the women before purchasing them, in order to decide which woman will become their 'bride' and also so that they can bargain the price of the woman ( south china morning post , cited in jaschok and miers 1994 : 264) . clearly, the rape of these women by numerous men, including their 'husband', increases their vulnerability to hiv transmission. in addition, the likelihood that their 'husband' will contract hiv from them or from other women he 'sampled' is also heightened if he does not already carry the virus. hence, it is a very serious misconception that the traffi c of women in china as 'brides' will have little impact on the hiv/aids epidemic there. equally alarming is the view held by some segments of chinese society that 'as long as they [men] have the money, buying a wife or child is their own affair' (li zhongxiu, cited in jaschok and miers 1994 : 265) . again, this kind of attitude illustrates the low status that many women (and children) continue to occupy in chinese society and the patriarchal factors that heighten their vulnerability to hiv/aids. in addition, it is widely predicted that the sale of women in china is set to continue to expand because from a purely economic standpoint, buying a traffi cked bride can be far cheaper than paying a dowry (song, cited in jaschok and miers 1994 : 265) . also, the skewed sex ratios that have resulted from the introduction of the one child policy and resultant resurgence of son preference have seen men far outnumber women in many areas of china (edwards 2000 : 75) . it has been estimated that by 2029, there will be 30 million more males than females in the 20-49 year age bracket due to sex selective abortion and the neglect of girl children in china (chan et al. 2002 : 429) . due to the gender imbalance it is unlikely that these men will be able to fi nd a bride to marry legally and they will increasingly turn to bride traffi cking as the solution, making it a crime that is likely to soar over the next few decades, alongside prostitution. while the chinese government has not ignored this situation, and the public security bureau often detects and arrests human traffi ckers , traffi cking is diffi cult to police as the number of women traffi cked yearly is believed to be in the vicinity of tens of thousands. they are primarily abducted from poor regions in guizhou, sichuan and yunnan provinces (woodman and ho, cited in hughes et al. 1999 ) . further complicating this issue is the fact that many women who have escaped their 'husbands' have not received assistance because some authorities also have sympathy toward men who have been unable to fi nd brides. as a result, women who escape their situation are often returned to their 'husbands' by authorities. villagers also assist in the traffi cking of women either by ignoring the problem, or by helping to buy women. in fact, it has been reported that one remote village collectively purchased women with the intention of soliciting them from their homes (woodman and ho, cited in hughes et al. 1999 ) . the traffi c of women constitutes a serious potential bridge for hiv transmission to the general population and again refl ects a heightened vulnerability, in terms of both hiv transmission and human insecurity, for chinese women. another factor identifi ed by interviewee c as compounding the situation of women's vulnerability to hiv transmission was the migration of rural workers to the cities for work. she stated that although many male migrant workers are married, they leave their wives behind and often engage in 'risky practices' in the cities, such as idu, procuring sex workers, and infi delity. generally, the men return to their homes once a year, during which they engage in sexual activity with their spouse, usually without using condoms. the interviewee further stated that even if the woman may suspect her spouse of having engaged in 'risky practices' while away, many women are unable to insist that their spouse use a condom (interviewee c 2003, pers. comm., 22 august) . in addition, for many rural women, labour migration can heighten their vulnerability to hiv transmission because it removes them from the economic support and protection nets that exist in their home villages, making them easy targets to be lured or forced into prostitution. in fact, a large number of china's sex workers are migrant women (thompson 2003 ) and they sometimes display higher risk behaviour than non-migrant sex workers, in part due to low education levels and poor hiv/aids awareness, which increases their likelihood of contracting hiv (hong et al. 2009 ) . many migrant women have also become the victims of sexual harassment and sexual violence, which also increases their vulnerability to hiv transmission. while conservative estimates suggest the number of sex workers in china is approximately three million to four million (harding 2000 ) , scholars such as professor pan of people's university of beijing believe the fi gure to be much higher when the numbers of women who engage in 'casual or infrequent transactional sex' are included (cited in . it has also been reported by unaids that the public security bureau estimates the number of sex workers in china could be as high as six million (unaids 2002 : 65) . jeffreys states that government authorities in china have called prostitution a 'widespread and growing problem ' ( 2004 : 83) . 8 thus, a conservative estimate of four million sex workers demonstrates that a considerable number of chinese women are vulnerable to hiv infection through prostitution. the illegal nature of prostitution in china is a major barrier to hiv/aids advocacy for sex workers and continues to exacerbate the vulnerable status of sex workers. interviewee d (2003, pers. comm., 27 august) stated that organizations like hers could give hiv prevention information to sex workers, without arresting them, because it was not a government organization. if workers from the government organizations identifi ed sex workers, she stated that they were required to report them because of the illegality of prostitution. after being reported, the identifi ed sex worker would then face detention in a rehabilitation centre. while there are debates in china as to whether or not prostitution should be decriminalized or legalized so as to allow ingos, ngos and government organizations to legally provide sti prevention knowledge and services to sex workers, the rehabilitation system does currently offer an opportunity to reach this vulnerable group with hiv/aids prevention information. however, interviewee d (2003, pers. comm., 27 august) stated that this was not occurring, even though the organization she worked for had been trying to launch programs that linked 'hiv/aids prevention education into the rehabilitation programs of these centres'. furthermore, without adequate help to overcome their economic insecurity, upon release from these centres many women actually returned to prostitution. thus, she stated, an important opportunity was being missed. there is concern however, over the contradiction in the government's response to prostitution, which sees sex workers targeted by interventionist programs, not those soliciting the prostitutes. this obvious gender bias is in part fuelled by the extant view in china that those selling sex always come before those buying sex. this view is problematic in that one could argue that it is demand that drives provision; however at a very basic level it punishes the sex worker as the guilty party in the commercial sex exchange and not the solicitor. it also means that many of the men who solicit prostitutes are left out of the targeted commercial sex hiv prevention strategies although they are clearly a 'high-risk' group (chen 2008 ) . if they are married or have other sexual encounters outside of the commercial sexual exchange, they are also a possible 'bridge' population who have the potential to transmit hiv into the general population. chen ( 2008 ) argues that the failure of the chinese government to adequately respond to this contradiction refl ects that there is an urgent need in china for recognition of the important role men play in safer sexual practice, a responsibility that is continually being thrust onto women. in fact, recent campaigns by the acwf reportedly 'exposed' 27.25 million women across china to hiv/aids prevention and awareness knowledge. however, there was no discussion of if/how men were also given this important knowledge or if they were made aware of how their actions can impact on the hiv vulnerability of their spouses (scawco and unaids 2007 ) . considering the unequal gender-based power relations discussed above, it is unlikely that these types of measures will have much success as men and women both need to be involved in such advocacy programs. to neglect the involvement and importance of men serves to increase women's vulnerability while at the same time proportioning responsibility to women for their own hiv safety, something that is simply unachievable for many women. the failure of the rural health system is also exacerbating the vulnerability of chinese women to hiv/aids. approximately 60% of rural women are now showing symptoms of having untreated rtis or stis (interviewee c 2003, pers. comm., 22 august), both of which increase their susceptibility to hiv through sexual transmission ( jolly and ying 2003 : 2) . the fi gures on stis clearly indicate that behaviours conducive to the transmission of hiv/aids, such as unprotected intercourse, are becoming more widespread. however, rural healthcare facilities continue to be inadequate, and therefore information on hiv/aids and prevention of the virus is not reaching rural men and women (interviewee c 2003, pers. comm., 22 august) . in addition, many rural women are not targeted for information dissemination due to the offi cial belief that these women fall into the 'low-risk' category due to their marital status and individual behaviour. in light of the discussion above, this overly simplistic classifi cation of who is or is not 'at risk' is substantially heightening women's vulnerability to hiv. considering the changing face of china's hiv/aids epidemic in the current era, the failure of the government to have a comprehensive gendered response to the burgeoning aids epidemic in the prc may result in the government ineffectively responding to hiv/aids. chen ( 2008 ) warns that this could lead to an increase in stigma and discrimination against women as their hiv+ rates increase and may further exacerbate women's insecurity. when critiquing the privatization of health care in china, interviewee d (2003, pers. comm., 27 august) stated that prior to the 1990s, the health system in rural china was much better because 'bare foot doctors and health workers were active in even the most remote areas'. however, after the dismantling of government sponsorship, the rural healthcare system was left in ruins, with only expensive private doctors available to meet the health care needs of the rural population. another problem with the provision of health care is that the government does not regulate sti facilities. in fact, some sti clinics are now being rented out to private practitioners. while this can benefi t plwha, because it reduces the possibility of their hiv+ status being leaked, 9 it also causes prices to rise and patient care tends to decline (interviewee c 2003, pers. comm., 22 august) . therefore, the privatization of essential services such as the health industry has seen medical services fall out of the economic reach of many poorer families or individuals. this compounds chinese women's vulnerability to hiv because it limits the ability of both men and women to manage their sexual and reproductive health. another diffi culty identifi ed by interviewee d (2003, pers. comm., 27 august) was that organizations like hers lacked adequate funding both to run programs as well as to support plwha. she stated that because most plwha in china are rural poor, education on lifestyle, proper diet and medication was in vain as 'many [patients] can't follow these instructions because they live in poor conditions in rural china, where their income is just enough to feed their families'. however, with better funding, hiv/aids prevention and treatment campaigns could help plwha with the costs of living and medications, making their lives better (interviewee d 2003 , pers. comm., 27 august). interviewee f (2003 also identifi ed funding as a problem for hiv/aids prevention and treatment. she stated that sometimes her organization wanted to carry out pilot projects, but because they were given insuffi cient funding they were unable to run the projects. clearly, without the funding to properly test pilot programmes or institute nation-wide campaigns, hiv/aids prevention in china will continue to be hindered. on the other hand, the introduction of the 'four frees and one care ' policy in 2003 has seen a positive change in the government's funding response to china's aids epidemic. the 'four frees' provided by the policy include government funded schooling for aids orphans, drug therapy for plwha, prevention of mtct and voluntary counseling and testing (vct). the 'one care' component refers to care and economic assistance for people affl icted with or affected by hiv/aids (cao et al. 2006 : 520) . however, by the government's own admission, the implementation of this policy has been uneven (national center for aids/std prevention and control 2006 : ii), so while it is certainly a step in the right direction, it is not fully operational as it will require a great deal of cooperation between all levels of government and assistance by civil society before it can really meet its objectives. it should be acknowledged that china has been injecting more funds into hiv/aids prevention and treatment strategies since 2003. the 2009 update by unaids and the world health organization reported that there had been a threefold increase in funding by china in the period between 2003 and 2006 demonstrating stronger commitment from the government (unaids and who 2009 ) . the incorporation of civil society into hiv/aids prevention was an issue also identifi ed by interviewee b (2003, pers. comm., 22 august) . she stated that the solitary nature of the moh in combating hiv/aids in china means that it is effectively tackling hiv/aids by itself. while the enabling environments for hiv transmission include diverse fi elds such as employment and public security, interviewee b stated that there was no cooperation between the ministry of public security (mps) and the moh, a point which chen believes has led to; tensions, and sometimes contradictions, between the goals of public policies and the methods of policy practice, such as the confl ict between public security (law enforcement) policies relating to sex work and public health policies for the prevention of hiv/aids ( 2008 : 185). furthermore, issues pertaining to commercial sex workers and idus, which were handled by the mps, also did not involve input from the moh. this is quite possibly the reason why hiv/aids prevention advocacy programs have still not been uniformly implemented in all rehabilitation centres for idus and sex workers . interviewees c and f both believed that education campaigns aimed at the general population could be a valuable way to disperse hiv/aids information. they stated that efforts like the severe acute respiratory syndrome (sars) mass media education campaigns would be a major step in changing people's beliefs about hiv/ aids and increasing knowledge and public awareness of the virus and how it is transmitted. after the cessation of sars, the chinese government did shift its focus to hiv/aids, and education campaigns on hiv/aids have been undertaken. therefore, unlike previous efforts, top leaders in government have demonstrated they are serious in their response to hiv/aids. while this signals a positive change, unfortunately the gender issues that contribute to hiv/aids vulnerability do not appear to be an integral component of these campaigns, so their overall effectiveness is doubtful. in addition, gender inclusive campaigns would also need to be supported with active steps at both the government and grassroots level to reverse the continuing unequal social, political and economic structures that disempowered chinese women, which have been shown to heighten their vulnerability to hiv/ aids. however, beijing's reluctance to support the development of an unrestrained civil society in china makes this unlikely. in the united nations report hiv/aids: china's titanic peril ( 2002 ) , china's political system was identifi ed as possibly the most sensitive obstacle to tackling hiv/aids in the prc. this was because the central government has long appeared uncomfortable with the emergence of organizations that are independent of the government and especially the free fl ow of information that such organizations may facilitate (unaids 2002 : 69-82 ). yet, while the central government may fear that the emergence of civil society could contribute to a breakdown in the chinese communist party's authority in china, civil society participation and the free fl ow of information are not only good governance when responding to hiv/ aids epidemics, but international experience has proven them to be essential elements in a state's response to hiv/aids. therefore, until the central government is willing to allow greater autonomy among the various ngos and ingos operating in china, it is unlikely that the chinese response to hiv/aids will make any real inroads in the prevention of hiv transmission -and even less so in terms of gender-specifi c issues such as the human insecurities that increase women's vulnerability to hiv/aids. when determining women's vulnerability to hiv transmission, female human security , or more aptly their 'insecurity', is an important factor. the status of many women in china, and the privileged position accorded to chinese men, strongly indicates that chinese women face a heightened vulnerability to hiv transmission. while many of these vulnerabilities are similar to women elsewhere in the world and certainly are not unique to china, they attest to the interplay of the unequal status accorded many chinese women due to their sex, their disempowered status within society, unequal gender-based power relations both within the domestic and public arenas, and the patriarchal norms and attitudes that infl uence all of the above. by overlooking the many social, cultural, economic and political factors that contribute to hiv/aids vulnerability and transmission of the virus, particularly those faced by women, china has a long way to go before chinese women are protected from hiv transmission. given that hiv/aids heightens human insecurity, the stage is set for chinese women (and men) to face an insecure future if the chinese government does not fully implement international best practice, meaning a gendered response, into its overall hiv/aids response. hiv hits women hardest prevention of hiv 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country women's organizations and civil society in china the factbook on global sexual exploitation global aids: myths and facts. tools for fi ghting the aids pandemic women and chinese patriarchy: submission, servitude and escape feminist prostitution debates: are there any sex workers in china? key issues on gender and hiv/aids in china hiv & aids in china why develop and support women's organizations in providing legal aid in china? women's rights, women's organization and legal aid in china behavioural and psychosocial predictors of condom use among university students in eastern china 2005 update on the hiv/aids epidemic and response in china china's secret plague: how one us scientist is struggling to help the government face up to an exploding aids crisis unintended pregnancy and induced abortion among unmarried women in china: a systematic review the 'nameless fever': the hiv/aids pandemic and china's women a joint assessment of hiv/aids prevention, treatment and care in china hiv/aids epidemic in china spreads into the general population china's growing aids epidemic increasingly affects women hiv/aids: china's titanic peril women and hiv/aids: confronting the crisis aids epidemic update redefi ning security: the human dimension gender and hiv/aids: taking stock of research and programmes evolution of china's response to hiv/aids hiv/aids in china ban on family violence urged in china modelling the impact of the legal and policy environment on hiv/aids in china quality of care of reproductive health in china today endangered womanhood: women's experiences with hiv/aids in china the author would like to thank professor donald mcmillen, dr rosemary roberts and an anonymous reviewer for their insightful comments and suggestions. key: cord-022467-j2trahab authors: loo, may title: select populations: children date: 2009-05-15 journal: complementary and alternative medicine doi: 10.1016/b978-0-323-02028-2.50015-2 sha: doc_id: 22467 cord_uid: j2trahab nan the majority, usually seeking cam therapy as an adjunctive management for pain and other discomforts related to the oncologic illness or to medications. 207 in the general pediatric population, chiropractic is the most common form of cam treatment used by children. reports indicate that children made up 1% of chiropractic patients in 1977 and 8% in 1985. 303 a survey of the boston metropolitan area revealed that an estimated 420,000 chiropractic visits were made by children in 1998. 237 childhood disorders being treated include pain, respiratory and gastrointestinal tract problems, ear infection, enuresis, and hyperactivity. 303 homeopathy was the second most popular form of cam therapy used by children in spiegelblatt's 1994 report. 386 in 2001, however, the university of pittsburgh found that homeopathy was the most common cam therapy used by children who visited an emergency department (ed). 329 also, in a 2000 survey of homeopathic practitioners in massachusetts, children constituted one third of patient visits. 236 homeopathic remedies are highly diluted substances that induce self-healing. these remedies are readily available from a variety of sources, including some grocery stores. although homeopathy may be safe and effective in many childhood conditions, many practitioners believe that homeopathic remedies are best used as adjunctive therapy to conventional medicine in chronic conditions and in acute disorders that respond poorly to conventional therapy. 197, 198 acupuncture is the third most common therapeutic method used in children 386 but has the largest body of scientific data compared with other cam therapies. 248 a harvard survey of 47 patients with a median age of 16 years who received acupuncture treatment, which included needle insertion, moxa/heat, cupping, and magnets, reported that 67% of patients rated the therapy as pleasant and 70% thought treatment helped their symptoms. 209 electrical stimulation, laser, heat, magnet methods, and acupressure or acumassage 324 are effective alternatives to needles for treating children with needle phobia. acupuncture and traditional chinese medicine (tcm) have been used in asia and europe to treat a wide spectrum of childhood illnesses. their use in the united states has been recent but is growing rapidly in popularity. naturopathy ranks with acupuncture as the third most common complementary therapy used by children, 385 although scientific data are sparse. currently, evidence-based information is limited about safety and efficacy of herbal remedies, especially in terms of dosage and application in infants and children, who may be more susceptible to some of the adverse effects and toxicities because of differences in physiology and immature metabolic enzyme systems. 293, 412 other cam treatments used in children include touch therapy (therapeutic touch), osteopathy, oligotherapy, and hypnosis. religious practices such as prayer have also become prevalent in the pediatric population. 22 children have reported the ability to readily feel energy field from touch therapy. 118 the increasing support for therapeutic touch (tt) 223, 226 has been anecdotal with little scientific data. approximately 9% of children receiving treatment with cam therapies seek osteopaths, 386 who claim success in treating many common childhood conditions, including colic and otitis. 19 approximately 4% of pediatric cam visits are to oligotherapists, 386 who administer poorly absorbed trace elements such as copper, manganese, and zinc to improve health. relaxation training and imagery are forms of hypnosis that have also been effective in children. 309 in fact, children seem to be able to learn relaxation training better and faster than adults. 122 table 11 -1 summarizes the cam therapies most often used to treat various pediatric conditions. box 11-1 lists additional and recent surveys and reviews of cam therapies used to treat pediatric conditions. vaccination is an essential component of pediatric well-child care and has both public health and educational ramifications because up-to-date vaccination is required for vaccine safety is monitored closely. adverse events are reported to the vaccine adverse event reporting system (vaers), administered by the centers for disease control and prevention (cdc) and the u.s. food and drug administration (fda). approximately 10,000 adverse cases are reported each year. data are shared internationally by independent scientific experts on the joint committee on vaccination and immunization and committees of the medicines control agency. surveillance results in product withdrawal when there is clear evidence of a safety issue. 300 currently, several serious pediatric conditions are controversially attributed to vaccination: immune compromise, 377 neurologic sequelae, autism, and crohn's disease. the medical community has expressed concern about the effects of vaccination on an immature immune system, especially in neonates. 419 controversial debates are ongoing regarding the possible connection between vaccination and autoimmune illnesses, such as the association between measles and anti-hepatitis b virus (hbv) vaccines with multiple sclerosis. tetanus toxoid, influenza vaccines, polio vaccine, and others have been related to autoimmune phenomena ranging from autoantibody production to full-blown illness, such as rheumatoid arthritis and guillain-barré syndrome. recent evidence suggests that autism may be related to the immune system. 273 the mechanism of autoimmune reactions after immunization has not yet been elucidated. one possibility is molecular similarity between some viral antigen (or other component of the vaccine) and a self-antigen. this similarity may be the trigger to the autoimmune reaction. 16, 374 before 1991, whole-cell pertussis vaccine was used, composed of a suspension of formalin-inactivated bordetella pertussis b cells. convulsions occurred in 1 case to 1750 doses administered, and acute encephalopathy occurred rarely, at 10.5 cases per million doses administered. sudden infant death syndrome (sids) and infantile spasms have also been suggested to be associated with diphtheria-pertussis-tetanus (dpt) vaccination. 103 in the 1970s, reports linking pertussis vaccine with infant brain damage attracted media attention, 227 which in turn caused great parental and professional anxiety; the immunization rate fell from 80% to 30%. between 1976 and 1988, three major pertussis epidemics occurred in the united states, resulting in more than 300,000 hospitalizations and at least 70 deaths. 300 in countries such as sweden, japan, united kingdom, ireland, italy, and australia, antivaccine movements targeted pertussis whole-cell vaccines. 129 opponents to the pertussis vaccine have argued that the risks of vaccination outweigh the benefits. 103 the largest study to date conducted by the national institute of child health and human development at the national institutes of health (nih) revealed that sids was actually less likely to occur in recently vaccinated infants. 165 another large study showed that the permanent neurologic sequelae due to pertussis vaccine are so rare as to be unquantifiable. 280 nevertheless, concerns about brain damage led to the development of acellular pertussis vaccine (dtap) that contains purified, inactivated components of b. pertussis cells. this form is associated with a lower frequency of adverse events and is more effective in preventing pertussis disease. dtap was first licensed for the fourth and fifth doses of the pertussis series in 1991 and for the primary series in 1996. several studies conducted in europe and africa revealed that u.s.-licensed dtap vaccines have efficacy ranging from 71% to 84%. currently, only acellular pertussis vaccine is used. 103 no encephalopathy has been reported. hypotonic hyporesponsive episode (hhe) is the sudden onset of hypotonia, hyporesponsiveness, and pallor or cyanosis that occurs within 48 hours of vaccination, usually after pertussis vaccine administered to children under 2 years of age. hhe occurred in approximately 1 of every 1750 dta vaccinations. the largest published report of 40,000 cases concluded that although hhe does occur after the administration of dtap and other non-pertussis-containing vaccines, it is generally benign, self-limited, and nonrecurrent. 92 the connection of encephalopathy with pertussis vaccine was biologically more plausible than the proposed link between pertussis, measles vaccines, and autism. 300 the incidence of autism has increased from 1 in 10,000 in 1978 to 1 in 300 in 1999 in some u.s. communities. a study of 60 autistic children suggests that autism may be caused by a pertussis toxin found in the dpt vaccine. the toxin separates the g-alpha protein from retinoid receptors, which are critical for vision, sensory perception, language processing, and attention-characteristic problems of autism. those children most at risk have at least one parent with a preexisting g-alpha protein defect, presenting clinically with night blindness, pseudohypoparathyroidism, or adenoma of the thyroid or pituitary gland. natural vitamin a may reconnect the retinoid receptors. 273 in recent years, discussion has increasingly centered on the controversy concerning the possible association of the measles-mumps-rubella (mmr) vaccine with autism and crohn's disease.* the chinese were among the first populations to vaccinate, beginning with smallpox vaccine, which was injected intranasally. tcm considers most childhood illnesses to occur at superficial levels, and vaccination actually introduces pathogens, still considered energetically active, into deeper blood levels of the body. in addition, tcm also posits that the body can usually effectively handle only one process at a given time. when two separate processes occur at the same time, the human system could become overwhelmed, especially the tender system of an infant or a young child. therefore, although multiple vaccines given at the same time are less traumatic for children and save nursing time, they can easily overwhelm an immature immune system and make the child weak and deficient. 352 although the fear of epidemics motivates the chinese to vaccinate all their children, tcm practitioners in the west often advise against immunization. 320 there is discrepancy among the homeopaths regarding recommendation of conventional vaccines. a german questionnaire survey reported that homeopathic physicians generally do not refuse vaccinations but show a preference for the dpt vaccines. 239 a british survey conducted between 1987 and 1993 reported that preference for homeopathic remedies for illnesses and religion were the most common reasons parents refused immunization; 21% believed the risk of diseases to be less than the risk of vaccination and would seek homeopathic treatment if any illness developed in their children, and 17% believed that children "are protected by god and not by vaccines." 379 a u.s. cross-sectional descriptive survey of 42 homeopathic practitioners and 23 naturopathic practitioners in massachusetts revealed that the majority of the practitioners did not actively recommend immunizations. 236 many homeopaths recommend homeopathic vaccines, which are not yet supported by scientific data. 399 a random sample survey by mail of 1% of american chiropractors revealed that one third believe there is no scientific proof that immunization prevents disease, that vaccinations cause more disease than they prevent, and that contracting an infectious disease is safer than immunization. 66 a reported 81% believed that immunization should be voluntary and that spinal adjustment is a viable alternative. a crosssectional, descriptive survey of 90 chiropractics in the boston metropolitan area reported that only 30% actively recommended childhood immunization. 237 the decision of whether or not to immunize a child is difficult for both parents and practitioners. the advantages of vaccination are difficult to refute, but the temporal relationship between immunization and side effects and the controversies surrounding potential risks are disconcerting. although data are insufficient on cam approaches to vaccination today, practitioners should be aware of the slow yet steady trend toward alternatives and should properly address parental concerns and questions regarding immunization. 348 each practitioner needs to inform parents of the most up-to-date pros and cons of vaccination, be as objective as possible, put aside personal belief systems, and be supportive and understanding of whichever decision the parents make. parents need to become as informed as possible, consider all the pros and cons, weigh the risks and benefits, and realize that ultimately they must live with the outcome of their decision. the common cold is the most frequent infection in children in the united states and throughout the industrialized world. 394 a preschool-aged child has an average of 4 to 10 colds per year. the clinical symptoms vary greatly without any correlation with specific viruses. 94, 121 the majority of the symptoms are mild, consisting of rhinorrhea, sneezing, nasal congestion and obstruction, postnasal drip, and cough. there may often be additional symptoms of low-grade fever, sore throat, clear eye discharge, digestive discomfort, and general malaise. 180, 213, 276 some common viruses that cause upper repiratory tract infections (uris) include rhinovirus, coronavirus, adenovirus, respiratory syncytial virus (rsv), influenza virus, and parainfluenza virus. 101, 121, 139 transmission varies with different viruses. for example, rsv spreads primarily through contact with symptomatic children and contaminated objects, whereas influenza spreads mainly through airborne droplets. the precise route of transmission for rhinovirus remains controversial. 139 the virulence of rhinovirus is maximum in infants before 1 year of age (median age 6.5 months) 327 and in immunocompromised children. 330 wheezing is associated with rsv in children younger than 2 years of age and with rhinovirus in those over age 2. 338 simultaneous infection by more than one virus, such as rsv and adenovirus together, can also occur frequently in the pediatric population. many children may also have associated bacterial infection, such as haemophilus influenzae conjunctivitis. 327 the viruses gain entry into host cells through specific viral surface proteins, which cause tissue injury and result in clinical disease. 432 recent studies suggest that the host's response to the virus, not the virus itself, determines the pathogenesis and severity of the common cold. proinflammatory mediators, especially the cytokines, appear to be the central component of the response by infected epithelial cells. 158, 417 specific viral diagnosis is not necessary because of the benign, self-limiting nature of the disease 294 and the prevalence of different viruses overlapping from fall to spring, which makes it difficult to determine precisely which virus or viruses are causing the symptoms. 121 current medical management of uri remains symptomatic, controversial, and in most cases, ineffective. fluid, rest, humidifier, and saline nose drops constitute the mainstay of nonpharmacologic treatment. topical adrenergic agents do not have systemic side effects, but overuse can result in rebound congestion. 84, 114 antihistamine and combinations of antihistamine with decongestants are the ingredients in at least 800 over-the-counter (otc) cold remedies. the majority of studies have concluded that antihistamines are of marginal or no benefit in treating cold symptoms. 47, 110, 153, 254, 383 dextromethorphan is an antitussive that is abundant in otc formulations. although this medication is reportedly safe when taken in the recommended dosages, there have been cases of "recreational" use by teenagers, and deaths by overdose have been reported. 291 codeine is ineffective in controlling uri cough. 95 medications are often overprescribed, leading to higher health care costs 102 and dangerous side effects, such as greater antibiotic resistance. 257 more steroids are prescribed, which leads to a myriad of complications. 274 although interferon has been shown to produce good protection against infection, the high doses necessary to produce a prophylactic effect are often associated with serious undesirable side effects, including nasal stuffiness, bloody mucus, and mucosal erosions, 213 and the trauma of daily intramuscular injection makes it an unlikely remedy for children. 169 research for new medical therapies for the common cold is directed toward increasing resistance to or immunity against the viruses. histamine antagonists are not indicated in the common cold. 369 antiinflammatory mediators 417 and specific antiviral agents 361 may be promising. development of an effective vaccine against the common cold is unlikely because of the large number of viral serotypes. 213 rhinovirus, for example, has at least 100 different immunotypes. 158 although viral uri is a benign illness of short duration, it can lead to bacterial complications such as otitis media, sinusitis, lower respiratory tract infections, mastoiditis, and even meningitis. 330 scientific data on cam treatment for the common cold are surprisingly sparse. in 1971, linus pauling carried out a meta-analysis of four placebo-controlled trials and concluded that vitamin c alleviates cold symptoms, but subsequent reviews indicated that the role of vitamin c in uri is still controversial. [146] [147] [148] 199 although breast-feeding has been believed to protect against infection in infants, studies have been inconsistent in demonstrating its efficacy. in a 4-year prospective study that actively tracked breast-feeding and respiratory illnesses in 1202 healthy infants, breast-feeding was found to reduce significantly the duration of respiratory illnesses during the first 6 months of life. 75 a retrospective review from saudi arabia of randomly selected charts revealed that a direct correlation exists between duration of breast-feeding and frequency of uri in the first 2 years of life. 1 a hospital-based descriptive recall study from sri lanka examined the relationship between breastfeeding and morbidity from respiratory illnesses in infants. of the 343 infants, 285 were admitted and 58 were controls. an inverse relationship was found between the length of breast-feeding and incidence of respiratory illnesses. 319 a nutritional study of 170 healthy newborns followed for 6 months demonstrated that breast-feeding lowers frequency and duration of acute respiratory tract infection compared with formula feeding. 251 a more recent japanese study examined the incidence of pathogenic bacteria isolated from the throat of 113 healthy infants fed with different methods. 166 no pathogens were detected in breast-fed and mixed-fed infants, while h. influenzae and moraxella catarrhalis were isolated from the oropharynx of formula-fed infants. the investigators suggest that breast milk may inhibit the colonization by respiratory bacterial pathogens of the throat of infants. the mechanism was thought to be enhancement of mucosal immunity against respiratory tract infection. in addition to the presence of secretory immunoglobulin a (iga), another mechanism may be the presence of complex carbohydrates in human milk. these glycoconjugates may exert various antipathogenic effects, such as inhibiting the binding of pathogens to the receptors and reducing the production of bacterial toxins. 299 however, a u.s. study that examined nasopharyngeal swabs from 211 infants at 1 month of age and swabs from 173 of these infants at 2 months of age (keeping environmental parameters similar, e.g., number of children in household, number of siblings in day care, proportion with recent uri) revealed that the exclusively breast-fed (n = 84) and exclusively formula-fed (n = 76) infants did not differ significantly in the number of pathogens. 196 a multicenter randomized trial was conducted in 31 hospitals in the republic of belarus. 228 evaluation within the first year revealed that breastfeeding had no significant reduction in respiratory tract infection compared with the control group. a survey from singapore of breast-feeding mothers at 6 months postpartum revealed no significant differences in the rates of uri between breast-fed and non-breast-fed infants. 64 data are sparse on acupuncture, herbal, and homeopathic remedies for treatment of uri, especially in children. most data are uncontrolled, clinical reports. current information on adults supports efficacy of acupuncture for treating the common cold. 172, 311, 454, 462 acupuncture has been shown to increase the velocity of the nasal mucociliary transport in chronic rhinitis patients. 454 one possible use of acupuncture in uri is its potential effect on the immune system. 322 when chinese herbs were pasted onto acupoints for treating rhinitis and bronchitis in infant, serum immunoglobulin m (igm), igg, complement c3, and especially iga levels increased. 461 acupuncture has also been shown to increase t lymphocytes. 404 even massaging local acupoints was effective in relieving symptoms and in enhancing immune functions, with increases in immune indices that persisted for at least 6 months. 466 one report of acu massage of only one point for just 30 seconds resulted in clinical relief from nasal congestion, even though there was no change in nasal airway resistance or airflow. 403 these reports are encouraging for parents because acupressure can be easily learned by nonprofessionals, is well tolerated by children of all ages (including infants), has no side effects, and costs nothing. a clinical trial administering a nontoxic chinese herbal mixture to 305 infants demonstrated more than 95.1% effectiveness in treatment of uri. 465 in a single-blind trial using a chinese herb for acute bronchiolitis with serologic evidence of rsv, 96 hospitalized children were randomized into three treatment groups: herbs, herbs with antibiotics, and antibiotics alone. herbal treatment was found to decrease symptoms and duration of illness without adverse effects. 218 in a randomized, controlled trial using an herbal mixture, 89 children in the treatment group demonstrated 92% efficacy versus 67% of 61 children in the control group. 255 there was no description in the abstract (original article in chinese) of what constituted control (e.g., placebo herb, no treatment, conventional drugs) or what constituted efficacy (e.g., improvement in symptoms, duration, of illness). further rigorous studies are needed to demonstrate safety and efficacy of herbal treatment. a recent clinical trial that included children over age 12 years and used a fixedcombination homeopathic remedy for a mean 4.1 days of treatment reported that 81.5% reported subjective feelings of being symptom free or significantly improved without complaint of any adverse side effects. 4 a randomized, double-blind, placebocontrolled study from great britain of 170 children with a starting median age of 4.2 years in the experimental group and 3.6 years in the placebo group concluded that individually prescribed homeopathic remedies seem to be ineffective in reducing symptoms or decreasing the use of antibiotics in pediatric patients with uri. 78 otitis media (om) represents a continuum of conditions that include acute om, chronic om with persistent effusion, chronic suppurative om, recurrent om, unresponsive om, and om with complications. 28 acute otitis media (aom) is most prevalent in young children 8 to 24 months of age. approximately two thirds of all children will have had at least one episode of aom before age 3 years, and half of them will have recurrences or chronic serous om with effusion into early elementary school years. 132 by the time the child reaches adolescence, aom occurs infrequently. 443 almost one third of pediatric office visits are for treatment of aom. 109 the most common etiologic factors are allergic rhinitis 72,336 and ascending bacterial or viral agents from the nasopharynx attributable to eustachian tube dysfunction. the most common viral culprits are rsv, 10 influenza virus, 153 and adenovirus. 108 two thirds of middle ear infections are caused by bacteria. 109 the predominant organisms are pneumococci, h. influenzae, m. catarrhalis, 53, 305, 358, 388 and group b streptococcus. 325 bacterial pathogens adhere to mucous membranes, and colonization ensues. the severity of infection or the response to the invading bacteria depends on the health of the child's immune system. 53 the humoral system is especially significant in protecting the middle ear cavity from disease, and the nasopharyngeal lymphoid tissues are the first line of defense against bacterial colonization. 335, 359 the sterility of the eustachian tube and tympanic cavity depends on the mucociliary system and on secretion of antimicrobial molecules, such as lysozyme, lactoferrin, and betadefensins. 313 evidence indicates that a number of children with recurrent episodes of aom have minor immunologic defects. 359 pneumococcus is by far the most virulent of aom bacteria. it causes approximately 6 million cases of om annually in the united states. 468 uncontrolled pneumococcal otitis can lead to meningitis. 416 the incidence of aom is higher in winter and early spring. clinically, the child with aom presents with earache and fever, usually accompanied by upper respiratory symptoms such as rhinorrhea. on otoscopic examination the tympanic membrane varies from hyperemia with preservation of landmarks to a bright-red, tense, bulging, distorted appearance. in advanced stages of suppuration the tympanic membrane ruptures with a gush of purulent or blood-tinged fluid from the ear. 108 because viral or bacterial om usually cannot be distinguished by otoscopic examination, aom is usually treated empirically, using antibiotics such as amoxicillin that have a high concentration in the middle ear fluid. 214, 224 however, the widespread use of antibiotics has resulted in increasing resistance to the more common medications. 53, 358 currently, 10% of children with aom are recalcitrant to antibiotic therapy. 277 the prevalence of resistant organisms tends to increase in the winter months. 43 economically, treatment failure due to drug resistance has been responsible for further escalating the billions of dollars spent treating aom. 287 in addition, antimicrobials suppress normal flora, which is beneficial to the host because the antibiotic can interfere with and therefore prevent pathogenic infections and may enhance recovery from uris. 43 on the other hand, since the advent of antibiotics, complications such as mastoiditis and intracranial infections have significantly decreased. 297 the current focus is on prevention of aom. breast-feeding confers lifesaving protection against infectious illness, including otitis. 134, 156 pneumococcal conjugate vaccine (pcv), approved in 2000 for use in the united states, covers the seven serotypes that account for about 80% of invasive infections in children younger than age 6 years. pcv was demonstrated to have more than 90% efficacy 468 and has resulted in a modest reduction of total episodes of aom. 317 the goal of pcv is to prevent symptomatic infections in the middle ear and prevent colonization of the pneumococci that can cause subsequent middle ear infections. 41 pcv may eliminate nasopharyngeal carriage of pneumococci. 235 however, because pcv only prevents disease caused by the most common serotypes, there is concern that the nonvaccine serotypes will become more common, especially in children less than 2 years of age. 317 an effective rsv vaccine for the infant and young child could greatly decrease om disease. 10 intranasal spray of attenuated viruses is currently under investigation, in the hope that early antiviral therapy would reduce the risk of om after uri. 137, 153 chronic otitis media with effusion (ome) is one of the most common diseases in childhood. 91 ome is associated with infection, eustachian tube obstruction, allergic or immunologic disorders, and enlarged adenoids. 108 the serous fluid still contains bacteria, such as h. influenzae and pneumococci. 48 ome has been implicated to be an immune-mediated disease 91 because immune complexes have been demonstrated in the middle ear effusion, 268 and highly organized lymphatic tissue has been found in the middle ear mucosa. 422 the rationale for treating ome is prevention of recurrence of aom. currently, a once-daily antibiotic regimen is the recommended prophylaxis. the benefit is also weighed against the increasing risk of emergence of resistant bacteria. 134 when antibiotics fail to control recurrent om, a short trial of prednisone may be prescribed. surgery is recommended when medical treatment fails, 277 especially when the child has hearing loss. 305 tympanostomy tubes appear to be beneficial in ome but are of less value in chronic suppurative otitis. 134 increase in hearing loss has been reported with insertion of ventilation tubes. 144 adenoidectomy is sometimes recommended, 193 especially after tympanostomy tube failure. 134 any safe and effective cam therapy for om would be an important contribution to the pediatric population. large-scale, randomized, controlled studies for cam treatment would need medical collaboration, especially for otoscopic examination and tympanometry. 366 in addition, since aom has a high rate of spontaneous resolution, any clinical study must also prove that treatment effect is faster than natural improvement. although breast-feeding has been found to reduce uri, data concerning its association with frequency or duration of om have been conflicting. epidemiologic reports consistently provide evidence of protection of young children from chronic otitis with prolonged breast-feeding. 138 a u.s. study that followed 306 infants at well-baby visits in two suburban pediatric practices reported that the cumulative incidence of first om episodes increased from 25% to 51% between 6 and 12 months of age in infants exclusively breast-fed versus 54% to 76% in infants formula-fed from birth. 89 there was a two-fold risk of first episodes of aom or ome in formulafed babies in the first 6 months. a danish study that evaluated 500 infants using monthly questionnaires reported no statistical difference in the breast-fed versus formula-fed infants in incidence of om. 355 an earlier jewish study comparing 480 infants visiting a pediatric ed with 502 healthy infants found that breast-feeding significantly reduced infectious diseases, including om in infants under 5 months of age. 76 a study from switzerland evaluated 230 children with aom by administering individualized homeopathic medicine in the pediatric office. 119 if there was insufficient pain reduction after 6 hours, a second (different) homeopathic medicine was given. antibiotics were given if there was lack of response to the second dose. pain control was achieved in 39% of the patients after 6 hours, with another 33% after 12 hours. the resolution rate was 2.4 times faster than in placebo controls. no complications were observed in the study group. 119 in a u.s. double-blind, placebo-controlled pilot study, 75 children ages 18 months to 6 years with ome and ear pain and/or fever for more than 36 hours were randomized into individualized homeopathic medicine or placebo group. 181 no statistically significant results were noted. a british nonblinded, randomized pilot study was done with 33 children ages 18 months to 8 years who had ome and hearing loss greater than 20 db and an abnormal tympanogram. 150 the results revealed that the homeopathy group had more children with a normal tympanogram, fewer referrals to specialists, lower antibiotic consumption, and a higher proportion with a hearing loss less than 20 db at follow-up. however, the differences were not statistically significant. further research with larger groups is needed for a definitive trial. in a prospective, observational study carried out by one homeopath and four conventional ear-nose-throat (ent) physicians, a single (nonindividualized) homeopathic remedy was compared with nasal drops, antibiotics, and antipyretics. 125 children between 6 months and 11 years of age were included in the study. homeopathic treatment was given to 103 children and conventional treatment to 28 children. homeopathic remedies were found to be significantly more effective in reducing duration of pain and in preventing relapses. because om tends to affect predominantly young children, it would be more appropriate for studies to compare results in children of similar age rather than a wide range of ages, from infancy to preadolescence. a retrospective, nonrandomized study of 46 children under 5 years of age receiving 3 weeks of treatment from a single chiropractor reported a decrease in om symptoms. the limitations to this study included retrospection and a lack of comparison with the natural course of ear infections. 124 an israeli controlled clinical trial examined the efficacy and tolerance of ear drops made with naturopathic extracts in the management of aom pain. 362 ranging in age from 6 to 18 years, 103 children were randomized into the treatment group and control group using a conventional anesthetic ear drop. there was statistically significant improvement in both groups, indicating that the naturopathic ear drops were as effective as the anesthetic ear drops. the university of arizona has initiated a study of the use of echinacea, a dietary supplement, in the prevention of recurrent om. 261 acupuncture data are lacking on treatment of om in children. 411 the theoretical potential benefit of acupuncture would appear to be its effect on the immune system, as discussed in the section on uri. allergic rhinitis affects 5% to 9% of children. 113 perennial rhinitis is related to allergens that children are exposed to continuously, such as animal dander, house dust mites, mold, and feathers. seasonal rhinitis is related to seasonal pollenosis and rarely affects children under age 4 or 5 years. 100 allergic diseases are major causes of morbidity in children of all ages, 437, 447, 448 and allergic rhinitis is a significant cause of middle ear effusions. 72, 267, 336, 452 conventional therapy usually consists of avoidance of allergens, use of air-clearing devices, desensitization shots, and medication with antihistamines and at times steroids, both of which are frequently abused. 179, 200 antihistamines may be beneficial when sneezing and itching are present. 114 cam therapy is common among children with allergic diseases in sweden 155 and is becoming more popular in the united states, although scientific data specifically on children are still lacking. physicians have become more aware of the importance of nutrition 384, 424 and environmental factors in the development of allergic symptomatology in childhood. 289, 396, 446 a prospective, longitudinal study of healthy infants followed from birth to 6 years of age concluded that recurrent wheezing is less common in nonatopic children who were breast-fed as infants. 450 hypnosis has been reported anecdotally to be effective in hay fever. 439 homeopathic efficacy has received increasing attention in recent years, 342 but data consist of adult studies. an international multicenter study involving 30 investigators in four countries and 500 patients with three diagnoses, including upper and lower respiratory tract allergies, concluded that homeopathy appeared to be at least as effective as conventional medicine. 345 another multicenter study using a randomized, double-blind, placebo-controlled parallel group design also demonstrated that homeopathic preparations differ from placebo for allergic rhinitis. 408 homeopathic remedies for allergic children are unsupported by scientific studies at this time. an adult study using changes in conductance of specific acupuncture points for diagnosis and treatment demonstrated statistically significant changes that correlated with clinical improvement. 195 in a randomized study of 143 patients that included older teenagers, desensitization was compared with specific acupuncture treatment for allergic asthma, allergic rhinitis, or chronic urticaria. the study was ridden with multiple, tedious variables. the conclusion that acupuncture was significantly more effective than desensitization in improving symptoms and in reducing recurrence in all three conditions did not give a breakdown in age groups. 228 in a clinical report of 75 chronic allergic rhinitis cases that included three cases in children 6 to 10 years of age and 17 cases in 11-to 20-year-olds, two different acupuncture treatments were administered according to tcm diagnoses. there was a cumulative 40% cure rate without age differentiation. 454 asthma is the most common cause of chronic illness in childhood, with approximately 10% of children in the united states carrying the diagnosis. 259, 297, 442 a significant number of school days are lost because of asthma. a wide variation of incidence is found in different countries, with the highest rates in the united kingdom, australia, and new zealand and the lowest rates in eastern europe, china, and india. 296, 442 in recent years, prevalence of asthma is increasing worldwide, especially in children under 12 years of age. 17, 382 although asthma can have onset at any age, 80% to 90% of asthmatic children have their first symptoms before 4 to 5 years of age. 297 children up to age 4 years have distinct symptoms and require special consideration. 36 they have increased health service utilization, including a higher annual rate of hospitalization, 298 which has almost doubled in the united states from 1980 to 1992 for children 1 to 4 years of age. 17 the same trend is observed by other nations worldwide. 9,18 among american children ages 5 to 14 years, asthma death rates almost doubled from 1980 to 1995. 17 new zealand and canada have observed a similar increase in severity and mortality. 73, 387 asthma is a diffuse, reversible, obstructive lung disease with three major features: bronchial smooth-muscle spasm, edema and inflammation of the mucous membrane lining the airways, and intraluminal mucus plugs. 442 during the last two decades, chronic airway inflammation, rather than smooth muscle contraction alone, has been recognized as playing the key role in the pathogenesis of asthma in adults. 63, 131 although this association is less well established in children, recent guidelines for managing asthma in the pediatric population still have emphasized that treatment be directed toward the inflammatory aspects of the disease. 206, 402, 440 chronic inflammation is caused by the local production of inflammatory mediators and an increase in recruitment of inflammatory cells, predominantly eosinophils and mast cells. studies in young adults suggest that the chronic inflammation may be responsible for longterm pulmonary changes, including bronchial hyperresponsiveness, airway remodeling, and irreversible airflow obstruction. because of difficulties in conducting studies in infants and young children, pediatric information is incomplete. 230 limited studies have detected increases in inflammatory cells and thickening of the lung basement membrane in infants and young children and have found that asthmatic children have significantly lower lung function at 6 years of age compared with nonwheezers when both groups of children began with the same baseline at age 6 months. these data support the possible presence of an asthmalike inflammation at a very early age that is associated with nonreversible impairment of lung function. 263 the excessive inflammatory changes indicate that asthma is caused by a poorly regulated "immunologic runaway response" that, instead of protecting the host, destroys normal structure. increased concentrations of proinflammatory mediators, such as histamine and leukotrienes, are found in the airways as well as the blood and urine of asthmatic patients 131 during an acute attack and after allergen and exercise challenge. 34 strong evidence correlates asthma with rsv infection; children who enter day nursery before age 12 months and who are exposed to viruses early in life have built up immunity, with decreased development of allergies. 88 in most children, whose asthma is triggered mainly by respiratory infections at a younger age, asthma symptoms appear to remit by the adolescent years. 263 in older children and teenagers, emotions play a significant role both as the cause of symptoms and as the result of interplay of a chronic illness affecting the child's self-image and family dynamics. 297 the latest asthma management guidelines classify pediatric asthma into four groups of severity: mild intermittent, mild persistent, moderate persistent, and severe. 206 mild intermittent asthma can be typified by exercise-induced asthma, a common pediatric condition. status asthmaticus, defined as progressive respiratory failure that does not respond to conventional management, is becoming more prevalent in american children. 442 conventional treatments for pediatric asthma vary from allergen avoidance to state-of-the-art biochemical therapy. avoiding allergens has been a successful management of asthma since the sixteenth century. asthma is a much more complex problem today because of the increasing number of pollutants and chemicals in the environment that are potential allergens for children. 157 parental education, especially in regard to smoking, can reduce hospital admissions. 449 because infections that trigger asthma attacks are mostly viral, 31 antibiotics are not routinely indicated. medication consists primarily of bronchodilators and inhaled steroids, which are now justified as first-line therapy, 191 both as long-term management 402 and for acute attacks. 231 because growth suppression due to inhaled corticosteroids has been well documented, 61 it is important to distinguish infants with early-onset asthma from those with transient wheezing. 469 recently, the fda has also approved leukotriene receptor antagonists for use in asthmatic children under 4 years of age. 380 these agents counteract the hyperimmune response, resulting in diminished airway inflammation and decreased eosinophilia in the airway mucosa and peripheral blood. 34 parents turn to cam for their asthmatic children because of drug side effects or fear of taking long-term medication, especially steroids. 11,62 a recent survey from texas of 48 multicultural parents of children with asthma reported the usage of a variety of cam therapies, including homeopathy, herbal therapy, vitamins, and massages. hispanic parents were more likely to use herbal and massage therapies, whereas african-american parents often turned to prayers. 269 the relatively abundant studies on cam therapy in asthma are on adults and often have flaws in methodology. significant improvement 15,308,310 and even complete cure 83 have been demonstrated with hypnosis, although most studies had weak designs. hypnosis was recommended for children because they were found to be more hypnotizable, 68 but it is unclear whether the efficacy of hypnosis in asthmatic children is a reflection of children's greater suggestibility or a result of a more reversible disease process. 439 in a recent preschool program, 25 children ages 2 to 5 years received treatment with seven hypnotherapy sessions. the number of physician visits was reduced, and parental confidence in self-management skills increased. 217 tcm has been used to treat asthma for centuries. asthma epitomizes the chinese medicine concept of "winter disease, summer cure," which means the best treatment for asthma should be given during the summer, when the child is symptom free. in china, many asthmatic children who were treated with herbal patches applied to acupoints during the summer had minimal or no symptoms during asthmatic seasons. 37, 58, 320 although several recent adult studies used herbs for asthma, 107 only two involved children. a controlled study comparing herbal treatment of 30 children with penicillin and aminophylline treatment of another 30 children revealed no significant difference in the response from the two groups. 242 a multicenter doubleblind, placebo-controlled clinical herbal study from taiwan evaluated 303 asthmatic children using tcm diagnoses. 170 the children were randomized into three different herbal and placebo groups. although both groups showed improvement, the herbal groups showed greater improvement in symptomatology and in biochemical changes, such as increase in total t cells and decrease in histamine. an animal experiment using a 13-herb concoction revealed 99.1% efficacy in easing bronchial spasm. 170 another animal study with an herbal preparation demonstrated strong smooth muscle relaxation through inhibition of histamine and acetylcholine. 242 from the pediatric standpoint, it would be worthwhile to follow the development of external tcm approaches and noninvasive acupuncture. one clinical obser-vation of pasting chinese herbs to acupuncture points in 72 infants with acute bronchitis showed high cure and improvement rate, especially in infants. 461 humoral immune substances, especially iga, were found to be increased after treatment. another clinical observation reported 78% efficacy in 46 children treated with external application of plasters made of herbal mixtures with antitussive and antiasthmatic properties and 88% efficacy in 17 children treated with antiasthmatic herbal patches. success was also reported with a different herbal patch for acute attacks. the patches were well received by the children. 401 improvement from acupuncture treatment has been reported in asthmatic adults. 392, 406, 428, 463 despite methodologic weaknesses, it still seems that acupuncture may help asthma, especially drug-induced or allergic asthma. 439 in some european countries, almost a fourth of general practitioners believe in the efficacy of acupuncture in the treatment of asthma. 216 its role in the united states is still controversial; some physicians accept acupuncture's effectiveness, 426 whereas others criticize data based on poorly conducted studies. 5 the few current studies and clinical reports on acupuncture treatment of children with asthma are generally favorable. 168, 457 a german practitioner reported good results treating asthmatic children using a simple acupuncture regimen in uncontrolled clinical experience. 145 one study demonstrated that although acupuncture did not affect the basal bronchomotor tone, when administered 20 minutes before exercise, acupuncture was shown to be effective in attenuating exercise-induced asthma, 128 which is common in children. one possible mechanism of acupuncture is in reducing the reflex component of bronchoconstriction, but not in influencing direct smooth muscle constriction caused by histamine. 460 for children who are fearful of or who cannot tolerate needles, safe and painless treatments such as cupping and auricular press pellets, 457 laser acupuncture, 288, 292 and massage of acupuncture points 168 have also been found to be effective. the most interesting future role for acupuncture in asthma lies in its potential both in stimulating an immune response and, more importantly, in regulating or modulating a hyperimmune response. at this time, ample biochemical data in the literature support the theory that acupuncture activates both the humoral and the cellular immune systems to protect the host.* studies have also demonstrated that acupuncture can modulate the synthesis and release of proinflammatory mediators. 192, 256, 458 current hypotheses suggest that this is most likely mediated through a common pathway connecting the immune system and the opioids, 30,321,363 which has been well known to be associated with analgesic effects of acupuncture. homeopathic remedies have been reported to be remarkably effective in asthma in adults, 120, 345, 427 and homeopathic doses of allergens have been shown to alleviate allergic symptoms and desensitize patients to allergens. 433 however, there is paucity of scientific data on homeopathy in both children and adults, as well as a lack of consensus among homeopaths as to the appropriate treatment, administration regimen, or potency for asthma. 439 homeopathic practitioners believe that in chronic conditions such as asthma, homeopathic remedies can stimulate the child's innate healing ability, thereby leading to improvement. 197, 198 two recent large reviews on the role of homeopathy in clinical medicine concluded that, except for the occasionally demonstrated benefit, little scientific evidence exists to support the use of homeopathy in most clinical settings. 159, 439 the availability of homeopathic, nutritional, and herbal remedies without a prescription is appealing to the asthmatic adolescent's desire for independence. 12 in a number of european countries, chiropractic is often used for treatment of asthma. 186 one of the many difficulties in evaluating chiropractic efficacy lies in the varying abilities of the manual therapy practitioners. natural human differences exist in manual applications and techniques. the practitioners have various training backgrounds, including physiotherapy, respiratory therapy, chiropractic, and osteopathy. a danish questionnaire survey of 115 families with children up to age 7 years reported that 92% of parents who sought chiropractic help considered the treatment beneficial for their children. 77, 423 an australian survey reported that the most common cam visits were to chiropractors. 87 a u.s. prospective, observer-blinded, clinical pilot evaluated 36 children from 6 to 17 years of age with mild to moderate persistent asthma for chiropractic treatment in addition to optimal medical management. 42 children were randomized into treatment and sham spinal manipulative therapy (smt) for 3 months. the children with combined smt and medical treatment rated their quality of life substantially higher and their asthma severity substantially lower, and their improvements were maintained at 1-year follow-up. however, there were no significant changes in lung function or hyperresponsiveness. further research is needed to determine which components of the chiropractic encounter are responsible for the improvements. a controlled, patient-blinded trial of chiropractic manipulation for 91 children with mild or moderate asthma randomized the children into an active or a simulated chiropractic manipulation for 4 months. 20 each subject was treated by 1 of 11 participating chiropractors, selected by the family according to location. no significant benefit was observed in the treatment group. a few studies in adults generated statistically insignificant data. 176 one study found subjective but not objective improvements in individuals with asthma who received treatment in a chiropractic clinic. 186 a 2001 systematic review revealed that the majority of the studies on smt had poor methodology; the two good studies did not demonstrate significant differences between chiropractic smt and sham maneuver. 167 the reviewers concluded that the evidence is still insufficient at this time to support the use of manual therapies for patients with asthma. a german pilot study of 15 children ages 5 to 11 years with bronchial asthma combined relaxation using various techniques, including progressive muscle relaxation, autogenic training, fantasy travels, mantras, and periodic music, and demonstrated significant improvement in a number of pulmonary function parameters. 142 however, it is difficult to interpret the results because of the variety of techniques used. 143 a u.s. review of anecdotal reports indicated that massage therapy can improve asthmatic symptoms. [110] [111] [112] diarrhea acute diarrhea is a common occurrence in the pediatric population and a significant cause of pediatric morbidity and mortality in both developed and underdeveloped countries. 79, 302, 354 each year an estimated 54,000 to 55,000 u.s. children are hospitalized for diarrhea, 136 and more than 4 million infants and young children worldwide die of acute infectious diarrhea. 354 infants under 3 months of age have the highest risk for hospitalization and mortality. 304 children under age 3 years have an average of approximately 2.5 episodes of gastroenteritis per year in the united states. 143, 302 internationally, the average is approximately 3.3 episodes annually. 354 both diagnosis and treatment continue to be problematic in the pediatric population. 260 the infectious pathogens that cause acute diarrheal episodes in children include viruses, bacteria, and parasites. 229 transmission is most likely through the fecal-oral route, from ingesting contaminated food or water, 434 or in infants and toddlers, by mouthing contaminated toys. the nature of food-borne diseases is changing as more mass-produced, minimally processed, and widely distributed foods result in nationwide and international outbreaks of diarrheal disease instead of just a few individuals who shared a meal. 143 a majority of the cases are caused by viral infections. rotavirus is the most prevalent, 264 and human astrovirus (hastv) is a significant cause of diarrheal outbreaks. 434 frequently, children are co-infected by several viruses. viral diarrhea tends to involve the small bowel, producing large, watery, but relatively infrequent stools. 82 these illnesses usually have short, self-limiting courses, 6 typically lasting 3 to 7 days. 264 however, the diarrheal bouts can be devastating to children with compromised immune systems or structural abnormalities of the gastrointestinal tract. 143 the most common bacterial agents are enteropathogenic escherichia coli, shigella/salmonella, and campylobacter. 82, 264 these are much more virulent pathogens that usually cause mucocal injury in the small and large intestines, producing frequent, often bloody stools containing leukocytes. 82 e. coli has become an important public health problem in recent years, causing more than 20,000 cases of infection and up to 250 deaths per year in the united states. 220, 381 transmission of infection is most often linked to consumption of contaminated meat, water, unpasteurized milk, leafy lettuce, alfalfa sprouts, and goat's milk, 220, 413 and exposure to contaminated water in recreational swimming sites. 413 the most common parasitic infection is giardia lamblia, which often causes secretory diarrhea without blood 264 and frequently leads to chronic diarrhea. 161 diagnosis and treatment are still inconsistent. because most acute diarrheal conditions are self-limited, physicians often do not obtain stool cultures or examination for ova and parasites because the results are not available sometimes for several days. stool culture can identify different types of bacteria, but detection of specific enteropathogenic strains of e. coli requires specific serotyping that is not performed in routine stool cultures. 220 it is expensive, time-consuming, and often not sufficiently specific or sensitive and therefore is not recommended for routine diagnosis. 151 the primary treatment focus is on correction of dehydration, 275 which is the most important cause of morbidity and mortality in acute diarrhea. 243 oral rehydration treatment (ort) with solutions containing appropriate concentrations of electrolytes and carbohydrates is recommended by the world health organization (who) and has significantly reduced mortality. 82, 140, 367 after rehydration, early refeeding with a lactose-free 82 or normal, age-appropriate diet 229 is important for reducing diarrheal duration, severity, and nutritional impact. supplementation with specific dietary ingredients that are lost in diarrhea, such as vitamin a, zinc, and folate, is also recommended. 140 because most of the acute infectious diarrheal conditions are viral, patients do not require antimicrobial therapy. 326, 333 the rotavirus vaccine was put on the market in the united states in october 1998. this vaccine, as the natural infection, decreases the risk of acute rotavirus diarrhea by 50% and the risk of severe diarrhea with dehydration by more than 70%. 367 improving hygiene such as handwashing is also important, especially in day care. breast-feeding is one of the most important preventive measures. 351 continuation of breast-feeding has been found to control acute diarrheal episodes 140 and lower the frequency and duration of acute diarrhea, especially in infants under 6 months of age. 251 a large-scale randomized trial was conducted in 31 hospitals in the republic of belarus. evaluation within the first year revealed that breast-feeding significantly reduced the risk of gastrointestinal tract infection compared with the control group. 228 however, a survey from singapore of breast-feeding mothers at 6 months postpartum revealed no significant differences in the rates of diarrheal diseases between breast-fed and non-breast-fed infants. 64 treatment with antimicrobial therapy must be instituted carefully and only with specific identification of pathogen and drug sensitivity. with the increasing frequency of antibiotic resistance, common antibiotics may be ineffective in patients with acute diarrhea. 143, 351, 367 treatment of salmonellosis with antibiotics can prolong the carrier state and lead to a higher clinical relapse rate. 143 injudicious antimicrobial therapy may also lead to susceptibility to other infections, enhance colonization of resistant organisms, 29, 143 and disrupt the normal intestinal flora, the body's natural defense against infection. 270 homeopathy has the most convincing evidence of efficacy in treating diarrhea in children. a randomized, double-blind clinical trial comparing homeopathic medicine with placebo in the treatment of acute childhood diarrhea was conducted in nicaragua in 1991. eighty-one children 6 months to 5 years of age were given treatment with individualized homeopathic medicine. standard ort was also given. there was a statistically significant decrease in the duration of diarrhea in the treatment group. 182 although criticisms of the study include homeopathic theory being inconsistent with scientific belief 378 and possible toxicity of the dilute homeopathic remedies, 210 the report was also praised for being an impressive, 54 well-designed 44 study that paves the way for future research into the efficacy of homeopathy and other cam therapies. 115 using the predefined measures based on the 1991 study, the same group of researchers more recently carried out a similar study and replicated the same findings of decrease in the duration of diar-rhea and number of stools in 126 children in nepal, ranging in age from 6 months to 5 years. 183 a few studies have demonstrated effectiveness of acupuncture in pediatric diarrhea. the treatment protocols in point selections generally depend on tcm diagnoses, with the majority of points chosen on the two major digestive channels. 109, 190, 245, 398, 455 acupuncture has also been shown to induce favorable anatomic and biochemical changes in improving intestinal peristaltic function and in enhancing both humoral and cellular immunity. 244 a randomized study comparing shallow acupuncture treatment (needles inserted superficially and withdrawn swiftly) with drugs in 761 children ages 1 to 35 months reported significantly higher therapeutic effect in the acupuncture group. 244 the diagnosis and subsequent choice of points were based on tcm principles, not on stool culture results. unlike the homeopathy study, this investigation grouped together patients with acute and chronic diarrhea. in a clinical trial using one chinese herbal formula for treatment of acute diarrhea, there was significant reduction of symptoms and duration of diarrhea. 38 a clinical report of 20 years' application of a seven-herb concoction in 419 children demonstrated 96.4% improvement and 90% cure rate. 241 this nonrandomized, nonblinded report used tcm diagnoses that encompassed a variety of diarrheal conditions, including acute, chronic, infectious, and noninfectious diarrhea. the mechanisms were hypothesized as eliminating pathogenicity, improving immunity, accelerating intestinal digestion, and inhibiting intestinal peristalsis. in a clinical report comparing chinese herbs to western medicine in 158 children with diarrhea due to rotavirus, the herbs were reported to be superior and had a viral inhibitory rate of 71.43%, but no mention was made of the efficacy of conventional medicine. 435 chronic nonspecific diarrhea of childhood differs from acute diarrhea in that it is not associated with significant morbidity. once potentially serious causes are excluded, appropriate diet can be instituted to minimize complications, and reasonable time is then allowed for spontaneous resolution. 414 in a nonrandomized clinical trial involving 30 children ages 3 months to 8 years with chronic diarrhea of 2 to 4 months' duration that was unresponsive to western medicine and tcm, individualized acupuncture treatment eliminated symptoms and normalized stools. 109 infantile colic is estimated to affect 20% to 30% of all infants under 4 months of age and remains a medical enigma of nature versus nurture. colic may represent a heterogeneous expression of developmental variance, unmet biologic needs, psychologic or emotional distress from poor parent-infant interaction, intrinsic temperamental predisposition, colonic hypermotility, 278 or milk allergy.* although colic is selflimiting by 3 to 4 months of age, treatment is mandated because the psychologic consequences may result in a disturbed mother-infant relationship. 174, 355 evidence suggests that uncontrollable crying is the precipitating factor in many cases of infant abuse. 178, 441 because the precise etiology is not understood, the therapeutic goal of western medicine is not aimed at "curing" colic but at containment of the crying. 328 removing cow's milk protein from the mother's diet, changing formula, and prescribing antispasmodic medications are the mainstays of conventional treatment and may be helpful. 69 treatment is often directed toward behavioral changes in mothers. parents may be referred for therapy to learn parenting and coping skills. cam treatments yield inconsistent results. herbs have not yet been proven to be efficacious, 265 although a survey of 51 hispanic mothers in an urban neighborhood in texas revealed that herbal teas were commonly used for colic. 346 evidence is controversial for chiropractic treatment of colic. a multicenter prospective, uncontrolled study of 316 colicky infants involving 73 chiropractors in 50 clinics in the united kingdom for 3 months demonstrated efficacy with chiropractic smt in controlling colic, as reported by mothers in 94% of cases. 215 a retrospective questionnaire study in 1985 revealed satisfactory results of chiropractic treatment in 90% of infants. 301 a randomized, blinded, placebo-controlled clinical trial of 100 infants with typical colic reported that chiropractic manipulation was no more effective than placebo. 307 however, a randomized, controlled, 2-week trial comparing smt with the drug dimethicone demonstrated significantly better results in the chiropractic treatment group. 444 craniosacral therapists empirically claim success in treatment of colic. 19 massage therapists have also found empirically that touch therapy can decrease severity of colic. 111 in a finnish clinical trial, 58 infants less than 7 weeks of age perceived as colicky by their parents were randomized into an infant massage group (n = 28) and a crib vibrator group (n = 30). 173 over 4 weeks there was no difference in the reduction of colicky crying between infants receiving massage and those with a crib vibrator, leading the investigators to conclude that the decrease of crying reflects more the natural course of early infant crying and colic than a specific effect of intervention. therefore infant massage is not recommended as treatment for colic. enuresis is defined as inappropriate or involuntary voiding during the night at an age when urinary control should be achieved. 7 enuresis is a complex disorder with poorly understood pathogenicity and pathophysiology. it affects children worldwide, 297 with about 5 to 7 million children affected in the united states 281 and as many as 30% of school-age children in italy. 48 the condition is classified as primary nocturnal enuresis (pne) when the child has never been dry at night or secondary nocturnal enuresis (sne) when wetting follows a dry period, usually after an identifiable stress. 203, 297 by age 8 years, 87% to 90% of children should have nighttime dryness. 65 in 85% of pne patients, bedwetting is monosymptomatic, with a spontaneous remission rate of 15% per year of age. both the etiology and the pathophysiology of enuresis are still not well understood. multiple factors may interplay: genetic and psychologic predispositions, delayed maturation of the central nervous system, sleep disorders, urinary reservoir abnormalities, detrusor-sphincter incoordination, and urine production disorders. 48 although enuresis is benign, treatment is warranted because of adverse personal, family, and psychosocial effects. 281, 282 nocturnal enuresis delays early autonomy and socialization because of a decrease in self-esteem and self-confidence and a fear of detection by peers. the child may be at increased risk for emotional or even physical abuse from family members. 368, 438 the conventional treatment modalities are still controversial. because the vast majority of pne cases resolve spontaneously with time, treatment should carry minimal or no risk. the moisture alarm is both safe and inexpensive and should be the treatment of choice in most cases 65, 286, 357 but is often the one least prescribed. 15, 258 the medications imipramine and ddavp were frequently chosen as first-line treatment choices. adjunctive therapy may include bladder-stretching exercises, which have a success rate of 30%, and behavioral conditioning. 357 numerous cam therapies are available for childhood enuresis; the most common are hypnosis, acupuncture, and biofeedback. less common cam therapies are chiropractic and nutrition management. hypnotherapy has been recognized by conventional practitioners as a potentially effective therapy. 262, 286 uncontrolled studies have reported high rates of success. 24, 67, 74, 308, 310 in one comparative study of imipramine and direct hypnotic suggestion with imagery for functional nocturnal enuresis in 5-to 16-year-old patients, 76% of the imipramine group and 72% of the hypnosis group had positive response. 21 after termination of treatment, the hypnosis group continued practicing self-hypnosis. at 9-month follow-up, 64% of the hypnosis group maintained dryness compared with only 24% of the imipramine group. hypnosis and self-hypnosis were found to be less effective in younger children (ages 5 to 7 years) compared with imipramine treatment. hypnotherapy has the added advantage that nonphysician health care professionals, such as nurse practitioners, can easily learn the technique to help children. 163 a recent review of controlled studies reported promising findings for hypnosis in children with enuresis, but none of the interventions can currently qualify as efficacious. a major limitation is the lack of treatment specification via a manual of its equivalent. 283 the requirement that the child practice the self-hypnosis technique several times a day limits compliance with the program. 286 acupuncture has been used as an effective treatment for enuresis since at least the 1950s. 459 current worldwide literature in general demonstrates its viability as either a primary or an adjunctive therapy for the enuretic child.* a turkish clinical study on 162 subjects treated with electroacupuncture therapy reported a success rate of 98.2%. 418 acupuncture has been found to be successful both in decreasing the occurrence of enuresis during treatment and in exerting a long-term effect after treatment. 35, 48, 370 parents also report a decrease in sleep arousal threshold. 35 although the precise mechanism of acupuncture is still unknown, a multidisciplinary approach that included acupuncture demonstrated on electroencephalography (eeg) that treatment normalized activities of the cerebral cortex. 415 data from china usually consist of clinical reports of large sample populations. results in one study of 500 patients treated with acupuncture on only two body points demonstrated cure in 476 patients (98%), improvement in 14, and no response in 10 patients. 459 number of treatments ranged from one to three in 453 patients and four to six in 23. another study of 302 enuretic children ages 3 to 15 years (10 over 15 years; oldest 23 years) used tcm diagnosis of organ imbalance and different combinations of acupuncture points, with 10 treatments constituting one course. 453 the results showed that 221 patients were cured, 71 showed marked improvement, and 10 were "effectively" treated. treatment using scalp acupuncture has also been reported to be successful. in one clinical study, 59 children ages 4 to 17 years were treated for 10 to 15 sessions, and some needed a second course. 61 cure was obtained in 9 children, marked improvement in 27, improvement in 19, and no response in 4 children. in all these clinical reports, subjects of a wide range of ages were included in the same study; the discussions were short and generalized, giving very few or no details about the children (e.g., types of enuresis, duration of enuresis, number of wet nights, types of improvement); the methods of treatment were laden with numerous variables (e.g., number of points, treatment courses). a clinical study from italy of 20 children with bladder instability due to uninhibited contractions of the detrusor muscle reported that acupuncture treatment was successful in gradual elimination of enuresis in 11 and improvement of symptoms in 7 children. the mechanism was not clarified. 284 a russian clinical trial of using acupuncture specifically for enuresis due to neurogenic bladder dysfunction demonstrated that acupuncture was beneficial in 17 of 25 children. 194 in a clinical report of 54 enuretic children, short-term success in reducing wet nights was 55% with acupuncture versus 79% with ddavp, whereas long-term success rates were 40% and 50%, respectively. 48 a zagreb report of a clinical trial of acupuncture treatment on 37 children with mean age of 8 years who failed psychotherapy demonstrated a statistically significant decrease in enuresis even at 6 months after treatment. 350 a self-controlled regulating device operating on the principles of acupuncture was found to be effective in the treatment of nocturnal enuresis attributable to neurogenic bladder dysfunction. 233 a controlled clinical study of 40 children between 5 and 14 years of age randomly selected into four groups of 10: treatment with ddavp alone, acupuncture alone, combined ddavp with acupuncture, and placebo. efficacy of treatment, expressed as a percentage of dry nights, was high in both ddavp and acupuncture groups, but the combined-treatment group had the best results. 52 a scandinavian clinical trial used traditional chinese acupuncture for treatment of primary persistent pne in 50 children ranging in age from 9 to 18 years. the response rate was monitored at 2-week, 4-week, and 3-month intervals. 370 within 6 months, 43 (86%) of children were completely dry and 2 (10%) were dry on at least 80% of nights, leading the clinicians to conclude that acupuncture is effective, with stable results. another scandinavian study investigated the efficacy of electroacupuncture in treating 25 children ranging in age from 7 to 16 years. 35 twenty treatments were administered over 8 weeks. the number of dry nights consistently increased when the children were reevaluated at 3 weeks, 3 months, and 6 months after treatment. five children had more than 90% reduction of wet nights at 6 months, and 65% had more dry nights at the 6-month follow-up. a recent teaching round at the china academy of traditional chinese medicine in beijing discussed successful acupuncture treatment of a complicated case of enuresis in a 16-year-old student who had previously failed both western and chinese medicines for his physical and emotional sequelae. 171 using tcm diagnosis of organ imbalances, the treatment combined body acupuncture, scalp acupuncture, and auricular acupressure seed. the patient began improving after three treatments in the first week. he received 3 more weeks of treatment, with no recurrence of enuresis at 6month follow-up. children are often unwilling to undergo needle acupuncture because of fear of pain, 61 prompting researchers to use noninvasive forms of acupuncture. simple acumassage has been previously reported to be beneficial to the enuretic child. 21 an austrian prospective, randomized trial evaluated efficacy of laser acupuncture versus desmopressin in 40 children over age 5 years with pne. 337 at 6-month follow-up, the desmopressin-treated group had 75% success rate with complete resolution of symptoms, an additional 10% had a more than 50% reduction in wet nights, and 20% did not respond. the laser acupuncture group had 65%, 10%, and 15% rates, respectively. the results were not statistically significant. therefore laser acupuncture should be considered as an alternative, noninvasive, painless, cost-effective, and short-term therapy in children with normal bladder function and high nighttime urine production. worldwide reports have demonstrated efficacy in treating enuresis with biofeedback, 164, 250, 318, 332 which aims at learning or relearning of influence of involuntary functions. 266 a clinical study from italy treated 16 boys and 27 girls ages 4 to 14 years with detrusor-sphincter dyssynergy. biofeedback was successful in all the children, with sne resolving significantly sooner than pne and girls responding better than boys. two-year follow-up still revealed an 87.18% success rate, with 80% at 4 years. 332 in a french study, 120 children with three predominant urinary disorders that included nocturnal enuresis were treated with biofeedback. detrusor-sphincter discoordination was diagnosed in 33 children. pelvic floor biofeedback produced excellent results in these children. 323 belgian investigators reported a clinical biofeedback study of 24 children with median age of 10.4 years who did not respond to anticholinergics. 164 seventeen subjects had complete resolution of enuresis, six had a decrease in symptoms, and one child did not respond. at 6-month follow-up, two children in the cured group had recurrence of enuresis. another study from belgium also reported success in using biofeedback in 26 children with pseudo-detrusor-sphincter dyssynergy; 17 were completely cured, and 5 improved considerably. 266 a spanish study used biofeedback to treat unstable detrusor in 65 enuretic children; complete disappearance of symptoms was seen in 70.5%, with improvement in 78.2%. 318 in a u.s. report of 8 boys and 33 girls ages 5 to 11 years who underwent an average of 6 hours of biofeedback for nocturnal and diurnal enuresis, improvement was noted in 90% of nocturnal enuresis and 89% of diurnal enuresis. 272 another u.s. clinical study used biofeedback for 21 children with dysfunctional voiding; 17 (81%) had an excellent response, 3 (14%) had a fair response, and 1 (5%) was too inconsistent to rate. 70 the average number of sessions to achieve a consistent urodynamic response was 3.7 (range 2 to 14). average follow-up was 34 months (range 14 to 51 months). the investigators recommended biofeedback as an effective method that requires only a short period for treating dysfunctional voiding. 70 all these worldwide studies were clinical reports, not randomized, controlled, blinded studies. the efficacy of chiropractic manipulation in enuresis has been inconsistent. one clinical report identified an 8-year-old boy with functional enuresis who had successful treatment with manipulation. 37 in an uncontrolled study of 175 children ages 4 to 15 years, with responses monitored by parents, chiropractic manipulation resulted in only 15.5% success. 234 however, a randomized, controlled clinical trial of 57 children demonstrated that 25% of the treatment group had 50% or more reduction in enuretic symptoms, although the pretreatment to posttreatment change in wet night frequency was not statistically significant, and there was no long-term follow-up. 341 a comprehensive review of the literature revealed that smt was no more effective than the natural regression of enuresis with age. 225 food allergy as a cause of enuresis has been in the literature for several decades. 106 a recent study of children with severe migraine or attention deficit disorder (add) included 21 children with enuresis. oligoantigenic diets were successful in curing 12 children and improving enuresis in 4 other children. relapse of wetting occurred when foods were reintroduced; the substances implicated most often were chocolate, citrus, fruits, and milk from cows. 281 although no studies are available on naturopathic approaches, which focus on natural remedies (e.g., corn silk and tea, tea and honey), physicians should not dismiss parental opinion that these remedies may be safe and effective. the future of treatment for enuresis should combine various methods to increase the probability of treatment success and minimize risk to the child. 281 atopic dermatitis affects almost 10% of all children 56 and 20% of children ages 3 to 11 years. 201, 202 it accounts for more than 30% of outpatient pediatric visits. 95 most children with atopic dermatitis typically come to medical attention with cradle cap and facial and extremity rashes by age 2 to 3 months. 95 despite considerable research, the etiology of allergic disease remains poorly understood. 16 allergic dermatitis can be thought of as an inherited skin "sensitivity" that reacts to various external allergens and changes in psychologic states. 357 food causes atopic dermatitis in 50% of infants, 20% to 30% of young children, and 10% to 15% of children after puberty. 395 topical steroids remain the main therapeutic method. dermatologists tend to prescribe antibiotics and use potent topical steroids, 343 which are more readily absorbed in children and can result in hypothalamic-pituitary-adrenal axis suppression. 179 new immune modulators have shown promise in severe atopic dermatitis. 149, 212 cam therapies are increasingly used for dermatitis, 127 although most of the information is in clinical reports, and research data are limited. a database review of 272 randomized clinical trials of atopic eczema covering at least 47 different interventions revealed that evidence is still insufficient to make recommendations on maternal allergen avoidance for disease prevention, herbs, dietary restrictions, homeopathy, massage therapy, hypnotherapy, or various topical cam therapies. 162 a multicenter randomized clinical trial conducted in 31 hospitals in the republic of belarus reported that breast-feeding significantly reduced the risk of atopic eczema compared with the control group in the first year of life. 228 psoriasis was found to worsen with cam treatments such as herbs, dietary manipulation, and vitamins. 116 dietary management with evening primrose oil, rich in gamma-linolenic acid, has been found to be inconsistently effective in small studies. fish oil supplements (enriched in n-3 polyunsaturated fatty acids) have also been used. 357 various herbs offer relief for eczema. 127 a placebo-controlled, double-blind trial used a chinese herbal prescription specifically formulated for widespread nonexudative atopic eczema. thirty-seven children were randomly assigned to 8-week active treatment and placebo, with an intervening 4-week "washout" period. the response to active treatment was significantly superior to placebo, without evidence of hematologic, renal, or hepatic toxicity. 373 the same investigators monitored the children over the following 12 months. eighteen children had at least a 90% reduction in eczema, and five showed lesser degrees of improvement. 374 two randomized, double-blind placebo-controlled trials from singapore revealed that a concoction of 10 chinese herbs was efficacious in the treatment of atopic dermatitis in both children and adults, and that the mechanism may be through the beneficial immunosuppressive effects. toxicity is a concern, however, because exact dosing of the active derivatives is difficult to achieve. 339 acupuncture treatment of acne has been reported to be successful 247 in as many as 91.3% of adolescents given treatment. 456 other tcm techniques have also been reported to be helpful. 57 a clinical trial treated 20 children with severe, resistant atopic dermatitis with hypnosis. 393 nineteen showed immediate improvement, 10 maintained improvement in itching, and 9 maintained improvement in sleep disturbance 18 months after treatment. homeopathy is frequently used to treat dermatitis. in one homeopathic clinic in israel, more than 80% of the patients expressed satisfaction with treatment. however, the authors of the survey believed that homeopathic medicine complements conventional medicine and is not an alternative. 316 chiropractic treatment has also been sought by children for allergic problems. 303 a small british study tested the hypothesis that massage with essential oils (aromatherapy) used as a complementary therapy in conjunction with normal medical treatment would help to alleviate the symptoms of childhood atopic eczema. 9 eight children were randomized into the treatment group, who were massaged with oil, and the control group, massaged without essential oil. no significant difference was found between the two groups. there was a later deterioration of eczema in the oil massage group, suggesting allergic contact dermatitis provoked by the essential oils themselves. attention deficit-hyperactivity disorder (adhd) is the most common neurodevelopmental disorder of childhood, with a prevalence rate between 2% and 11%, 373 averaging about 5%. 14, 371, 405 the road constellation of hyperactive, inattentive, and impulsive symptoms combined with the multiple comorbid conditions makes the definition and adhd controversial and the diagnosis flawed. 405 adhd is a chronic, heterogeneous condition with academic, social, and emotional ramifications for the school-age child. 371 the disabling symptoms persist into adolescence in approximately 85% of children and into adulthood in approximately 50%. 14, 32 there is a developmental pattern in the primary symptoms of the disorder; hyperactivity diminishes while attentional deficits persist or increase with age. 371 the precise etiology of adhd is still unknown, and assessment and management remain diverse. medication continues to be the mainstay of treatment, with methylphenidate (ritalin) the treatment of choice. 141 the tricyclic antidepressants were added as an alternative medication in the 1970s, 32 with clonidine, buspirone (buspar), and other antidepressants and neuroleptics added to the list in the 1980s. 55, 60 although it is generally agreed that drugs are beneficial on a short-term basis, there is a paucity of data on the long-term efficacy and safety of medications, especially in children younger than 3 years of age. these drugs have not been shown to produce long-term gains academically or socially. 90 besides pharmacotherapy, a multimodal approach using a combination of drugs and other methods, such as cognitive-behavioral therapy (cbt), psychotherapy, social skills training, and school interventions, is frequently prescribed for adhd. cbt represents the most widely used alternative to pharmacotherapy, although previous studies have shown disappointing results. 2, 3, 45, 177 in 1992 the national institutes of mental health (nimh) began a 14-month, multisite clinical trial, the multimodal treatment study of adhd (mta). 160, 189 the results indicated that high-quality medication management (with careful titration and follow-up) and a combination of medication and intensive behavioral therapy were substantially superior to behavioral therapy and community medication management. there is slight advantage of combination of medication and behavioral therapy over medication alone. psychotherapy can be an effective adjunct to medication 364,365 but usually requires a long-term commitment to several years of treatment. concerns about side effects of medication, 232,391 treatment acceptability, 27,334 and compliance are additional factors that complicate management of the adhd child. clearly, there is room to explore safe, acceptable, and relatively easy alternatives. interest is increasing in more natural, holistic integrative approaches to adhd. studies using cam therapy for treating adhd encompass more than the usual research difficulties because of the complexity and heterogeneity of the disorder, as well as subjective evaluation by parents and teachers of a wide range of 18 characteristics that may qualify for several different diagnoses. a majority of the cam therapies to date continue to have mostly anecdotal and empiric evidence. the few welldesigned studies include biofeedback, herbal medicines, dietary modifications or supplements, and acupuncture. 46 studies have demonstrated that there is a significant difference in baseline eeg measurements in children with attention deficit disorder (add) compared with normal-achieving preadolescent males. these differences occur mainly in the parietal region for on-task conditions 187 and in the cortex and corticothalamic excitatory and inhibitory interactions. 252, 255 biofeedback or neurofeedback is a technique for modifying neurophysiology for learning. 252 in 1991 a critical review of 36 studies in which biofeedback was used as a treatment for hyperactivity indicated that biofeedback alone had not been effectively evaluated, and methodologic problems limit generalizations that it may be applicable to the entire hyperactive population. 238 a 2001 review continues to indicate that although anecdotal and case reports cite promising evidence, methodologic problems coupled with a paucity of research preclude any definitive conclusions as to the efficacy of enhanced alpha and hemisphere-specific eeg biofeedback training. 340 some recent studies using more sophisticated technology claim that neurofeedback can improve attention, behavior, and intellectual function in the child with add, 49, 246, 253 with measurable eeg improvement in the frontal/central cortex. 295 its stabilizing effect has also been found to last as long as 10 years after treatment. 407 hypnotherapy and biofeedback do not appear to alter the core symptoms of adhd but may be helpful in controlling secondary symptoms. these methods allow children to become active agents of their own coping strategies. 26 a mailed questionnaire survey of 381 children with adhd with a 76% response rate reported that 69% were using stimulant medication and that 64% of the respondents used or were using a nonprescription therapy. diet therapies constitute the most common cam therapy (60%). 397 one review of cam therapy lends support to individualized dietary management and specific trace element supplementation in some children with adhd. 26 nutritional management of add includes elimination diet, megavitamins, 26,372 supplements, and trace element replacement. simple sugar restriction seems ineffective. 14 the well-known feingold diet eliminates natural salicylates, food colors, and artificial flavors. studies have demonstrated mixed results. 211 megavitamins were demonstrated to be ineffective in the management of add in a two-stage study with clinical trial and double-blind crossover. potential hepatotoxicity is a major concern with use of megavitamins. 152 in a recent longitudinal, nonrandomized clinical trial, 17 adhd children were given a glyconutritional product containing saccharides known to be important in healthy functioning and a phytonutritional product containing flash-dried fruits and vegetables. 93 five children were not receiving methylphenidate (ritalin), six children were taking prescribed doses of methylphenidate, and the remaining six children had their medications reduced by half after 2 weeks. the glyconutritional supplement was administered for the entire 6 weeks, and the phytonutritional supplement was added after 3 weeks. the teachers and parents rated behavioral items for adhd, oppositional defiant disorder, and conduct disorder. the conclusion was that the glyconutritional supplement decreased the number and severity of adhd, associated odd and cd symptoms, and side effects of medications during the first 2 weeks of the study; there was little further reduction with the addition of the phytonutritional supplement. the three groups did not differ statistically in degree or reduction of symptoms. 93 this 6-week study had too many variables and too few subjects without control for a definitive conclusion, although the concept of simple nutritional supplement is important to explore. there is increasing interest in abnormality of fatty acid metabolism as the etiology of at least some features of adhd. 344 these abnormalities can range from genetic abnormalities in the enzymes involved in phospholipid metabolism to symptoms that were reportedly improved after dietary supplementation with long-chain fatty acids. 436 in a randomized, double-blind, placebo-controlled trial of docosahexaenoic acid (dha) supplementation, 63 children ages 6 to 12 years receiving stimulant medication were randomly assigned to receive dha supplementation or placebo for 4 months. there was no significant improvement in the treatment group. 429 oligotherapy focuses on deficiency of trace elements in children with add. 221, 389 in a polish controlled clinical trial, magnesium deficiency was found in blood and in hair of hyperactive children. 390 fifty 7-to 12-year-old add children were given a magnesium supplement of 200 mg/day for 6 months while the control group of 25 children continued on their medical regimen. increase in magnesium contents in hair correlated with a significant decrease of hyperactivity in the treatment group, whereas hyperactivity actually intensified in the control group. the same investigators also found deficiencies of copper, zinc, calcium, and iron, with magnesium being the most common deficiency, in 116 children with adhd. 389 a thorough literature review of alternative treatments for adhd identified 24 cam therapies and reported that chinese herbal treatment has promising pilot data. 14 a clinical trial using chinese herbs in the treatment of 66 children with a diagnosis of hyperkinesia based on the american psychiatric association's diagnostic and statistical manual of mental disorders, ed 3 revised (dsm-iiir) criteria demonstrated 84.8% effectiveness in ameliorating hyperactivity and improved attention and school performance. 401 the herbal remedy was prepared according to the tcm diagnosis of common energetic (qi) imbalance found in these children. clinical observations were substantiated by laboratory findings of significant increase in urinary content of norepinephrine, dopamine, dihydroxyphenylacetic acid, cyclic adenosine monophosphate, and creatinine. 401 in a randomized study, chinese herbal treatment was found to be comparable to methylphenidate but had fewer side effects. 464 research is currently being conducted to investigate the efficacy of herbal and homeopathic remedies because current evidence is inconsistent or lacking. 26 in a prospective, randomized, double-blind pilot study funded by nih that integrated dsm-iv diagnostic criteria, conventional theories of frontal lobe dysfunction, and neurotransmitter abnormalities with traditional chinese theories of energetic imbalances, laser acupuncture was used in the treatment of adhd in 7-to 9-year-old children. 249 preliminary data on the six children in the treatment group showed promise in reducing signs and symptoms of adhd. using conners scale as a weekly follow-up measure, improvement in classroom behavior was reflected by substantial drops in the teachers' scores before and after treatment in five of six children. the parents' scores dropped in three children but did not change in the other three children (figures 11-1 and 11 -2). one child was promoted to the gifted program, and another demonstrated marked improvement in learning disabilities. there are no data at this time on homeopathic or chiropractic treatment of adhd, although many practitioners claim anecdotal success with the use of homeopathic desipramine (norpramin) and manipulation. pediatric use of cam therapies continues to increase. 385 it is therefore advisable for physicians who treat children to take a thorough history of cam use, especially in those with chronic disorders, to become knowledgeable about the various alternative therapies that can complement conventional care. this allows practitioners to consider possible adverse effects or interactions of cam with conventional therapy, to open lines of communication with cam providers, and even to consider integrating effective cam therapy into their medical regimen. although cam therapy is in general considered safe, there have been a few reports of significant side effects. 219, 271 continuous research is needed to investigate the safety and efficacy of cam therapies for children; to address explicitly the tremendous heterogeneity between and among the practices, beliefs, and providers of professional and lay services; and to study how cam may enhance the quality of mainstream health services. 208 although children are entitled to new therapies, pediatric research in cam is further complicated by children's vulnerability to violation of their personal rights and to risk exposure. 420 in children of the same age, varying cognitive capacity can be required for informed consent. 315, 353 differences in physiologic maturation can change the kinetics, end-organ responses, and toxicity of therapy, so data from adult studies cannot be extrapolated for children. 240 even in conventional medicine, children are often rendered "therapeutic orphans" 376 because of history of abuses in pediatric research, a heightened sensitivity to risks in children-especially since the thalidomide disaster-and a limited market potential. 353 in the united states, 80% of drugs have age limits or contain disclaimers for pediatric use. 135 therefore protecting children by giving them only scientifically proven therapies is counterbalanced by denying them access to possible safe and effective treatment that may not be proven for many years to come. a frequently expressed concern is that visits to cam practitioners may cause delay in diagnosis. 467 a more serious concern is the lack of formal pediatric training in many cam therapists so that they may fail to recognize potentially serious illnesses, especially in infants. 236 conventional medicine is endowed with superb technologic support for making physical diagnoses, whereas some cam practitioners may claim the ability to diagnose a discomfort on an "energetic level" that is not yet defined biomedically. an integration of these disciplines should provide a better understanding of human health and disease. currently, many medical 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potential role of fatty acids in attention-deficit/hyperactivity disorder homeopathy and conventional medicine: an outcomes study comparing effectiveness in a primary care setting use of folk remedies in a hispanic population controversies in measles immunization recommendations childhood immunization, homeopathy and community nurses acupuncture for immune-mediated disorders: literature review and clinical applications the treatment of nocturnal enuresis by acupuncture lectures and personal communications: immunizations, pacific college of oriental medicine the ethical boundaries of drug research in pediatrics pediatric clinical gastroenterology relationship between infant feeding and infectious illness: a prospective study of infants during the first year of life infantile colic: incidence and treatment in a norfolk community rudolph am: rudolph's pediatrics upper respiratory tract infections in family practice the nasopharynx and the middle ear: inflammatory reactions in middle ear disease electro-acupuncture modifies humoral immune response in the rat common colds: causes, potential cures, and treatment efficacy of naturopathic extracts in the management of ear pain associated with acute otitis media acupuncture stimulation enhances splenic natural killer cell cytotoxicity in rats multimodality treatment: a two year evaluation of 61 hyperactive boys three year multimodality treatment study of 100 hyperactive boys a feasibility study of chiropractic spinal manipulation versus sham spinal manipulation for chronic otitis media with effusion in children effectiveness of treatments for nocturnal enuresis in a heterogeneous population acupuncture therapy in the management of persistent primary nocturnal enuresis: preliminary results attention deficit hyperactivity disorder megavitamins for minimal brain dysfunction: a potentially dangerous therapy a controlled trial of traditional chinese medicinal plants in widespread non-exudative atopic eczema one-year follow up of 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vaccination ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive developmental disorder in children viral respiratory infections the homeopathic treatment of asthma and allergies role of astroviruses in childhood diarrhea clinical therapy and etiology of viral diarrhea in children potential diagnostic aids for abnormal fatty acid metabolism in a range of neurodevelopmental disorders worldwide variations in the prevalence of atopic symptoms: what does it all mean? psychosocial implications of nocturnal enuresis the role of alternative therapies in the treatment of allergic diseases pharmacotherapy of asthma in children, with special reference to leukotriene receptor antagonists treatment of infantile colic with diclyclomine hydrochloride status asthmaticus in children : a review upper respiratory tract infections in adolescents the short-term effect of spinal manipulation in the treatment of infantile colic: a randomized controlled clinical trial with a blinded observer alternative/complementary medicine: wider usage than generally appreciated environmental control in the prevention and treatment of pediatric allergic diseases prospects for the prevention of allergy in children atopic disease, rhinitis and conjunctivitis, and upper respiratory infections allergen avoidance: does it work surveys of complementary and alternative medicine. i. general trends and demographic groups relationship of infant feeding to recurrent wheezing at age 6 years current treatment of allergic rhinitis and sinusitis 302 cases of enuresis treated with acupuncture treatment of acne with ear acupuncture-a clinical observation of 80 cases 14 cases of child bronchial asthma treated by auricular plaster and meridian instrument acupuncture of guanyuan (ren 4) and baihui (du 20) in the treatment of 500 cases of enuresis effect of acupuncture on bronchial asthma acupuncture treatment of chronic rhinitis in 75 cases immediate antiasthmatic effect of acupuncture in 192 cases of bronchial asthma preliminary study of traditional chinese medicine treatment of minimal brain dysfunction: analysis of 100 cases clinical and experimental study on yifei jianshen mixture in preventing and treating infantile repetitive respiratory infection clinical investigation on massage for prevention and treatment of recurrent respiratory tract infection in children pneumococcal conjugate vaccine for young children prevention of asthma morbidity: recent advances key: cord-019032-vdiaexbw authors: kshetri, nir title: china date: 2020 journal: the statesman&#x02019;s yearbook 2020 doi: 10.1057/978-1-349-95940-2_49 sha: doc_id: 19032 cord_uid: vdiaexbw nan upon soviet assistance for economic development. a soviet-style five-year plan was put into action in 1953, but the relationship with moscow was already showing signs of strain. by the end of the 1950s the soviet union and china were rivals, spurring the chinese arms race. chinese research into atomic weapons culminated in the testing of the first chinese atomic bomb in 1964. mao introduced rapid collectivization of farms in 1955. the plan was not met with universal approval in the communist party but its implementation demonstrated mao's authority over the fortunes of the nation. in 1956 he launched the doctrine of letting a 'hundred flowers bloom', encouraging intellectual debate. however, the new freedoms took a turn mao did not expect and led to the questioning of the role of the party. strict controls were reimposed and free-thinkers were sent to work in the countryside to be 're-educated'. in may 1958 mao launched another ill-fated policy, the great leap forward. to promote rapid industrialization and socialism, the collectives were reorganized into larger units. neither the resources nor trained personnel were available for this huge task. backyard blast furnaces were set up to increase production of iron and steel. the great leap forward was a disaster. it is believed that 30m. died from famine. soviet advice against the project was ignored and a breakdown in relations with moscow came in 1963, when soviet assistance was withdrawn. a rapprochement with the united states was achieved in the early 1970s. having published his 'thoughts' in the 'little red book' (as it is known in the west) in 1964, mao set the cultural revolution in motion. militant students were organized into groups of red guards to attack the party hierarchy. anyone perceived to lack enthusiasm for mao zedong thought was denounced. thousands died as the students lost control and the army was eventually called in to restore order. after mao's death in 1976 the gang of four, led by mao's widow jiang qing, attempted to seize power. these hard-liners were denounced and arrested. china effectively came under the control of deng xiaoping. deng pursued economic reform. the country was opened to western investment. special economic zones and 'open cities' were designated and private enterprise gradually returned. improved standards of living and a thriving economy increased expectations for civil liberties. the demand for political change climaxed in demonstrations by workers and students in april 1989, following the funeral of communist party leader hu yaobang. in beijing where demonstrators peacefully occupied tiananmen square, they were evicted by the military who opened fire, killing more than 1,500. hard-liners took control of the government, and martial law was imposed from may 1989 to jan. 1990 . since 1989 the leadership has concentrated on economic development. hong kong was returned to china from british rule in 1997 (for the background, see page 330) and macao from portuguese rule in 1999. the late 1990s saw a cautious extension of civil liberties but chinese citizens are still denied most basic political rights. beijing was chosen for the 2008 olympic games. china's treatment of tibet came under the international spotlight in the build-up to the games, following violent protests in tibet's capital city, lhasa. the arrest by japan of a chinese trawler in disputed waters in 2010 marked the beginning of heightened tensions between the two nations in the east and south china seas. in 2011 china became the world's second largest national economy. in nov. 2012 the communist party congress selected xi jinping to succeed hu jintao as president from march 2013. in sept. that year, former leadership hopeful bo xilai received a life sentence for corruption in one of china's highest-profile trials in decades. in oct. 2015 the government announced the end of the country's one-child policy. a month later, the presidents of china and taiwan met for talks-the first time that leaders from the respective territories had met since 1949. on the economic front, gdp growth in 2015 was at its lowest level for a quarter of a century. china is bounded in the north by russia and mongolia; east by north korea, the yellow sea and the east china sea, with hong kong and macao as enclaves on the southeast coast; south by vietnam, laos, myanmar, india, bhutan and nepal; west by india, pakistan, afghanistan, tajikistan, kyrgyzstan and kazakhstan. the total area (including taiwan, hong kong and macao) is estimated at 9,572,900 sq. km (3,696,100 sq. miles). a law of feb. 1992 claimed the spratly, paracel and diaoyutasi islands. an agreement of 7 sept. 1993 at prime ministerial level settled sino-indian border disputes which had first emerged in the war of 1962. china's sixth national census was held on 1 nov. 2010. the total population of the 31 provinces, autonomous regions and municipalities and of servicemen on the mainland was 1, 339,724,852 (652,872,280 females, representing 48á73%); density, 140 per sq. km. china's population in 2010 represented 19% of the world's total population. the population rose by 73,899,804 (or 5á84%) since the census in 2000. there were 665,575,306 urban residents, accounting for 49á68% of the population; compared to the 2000 census, the proportion of urban residents rose by 13á46% (reflecting the increasing migration from the countryside to towns and cities since the economy was opened up in the late 1970s). population estimate, dec. 2016: 1,382,710,000. china has a fast-growing ageing population. whereas in 1980 only 5á2% of the population was aged 65 or over and by 2010 this had increased to 8á2%, by 2030 it is expected to rise to 17á2%. long-term projections suggest that in 2050 as much as 27á6% of the population will be 65 or older. the population is expected to peak at 1á42m. around 2028 and then begin to decline to such an extent that by around 2050 it will be back to the 2011 level. china is set to lose its status as the world's most populous country to india in about 2022. the un gives a projected population for 2020 of 1,424á55m. 1979 regulations restricting married couples to a single child, a policy enforced by compulsory abortions and economic sanctions, were widely ignored, and it was admitted in 1988 that the population target of 1,200m. by 2000 would have to be revised to 1,270m. from 1988 peasant couples were permitted a second child after four years if the first born was a girl, a measure to combat infanticide. in 1999 china started to implement a more widespread gradual relaxation of the one-child policy. in dec. 2013 the standing committee of the national people's congress (npc) approved a resolution allowing couples to have two children if either parent was an only child. the one-child policy was formally abandoned altogether from 1 jan. 2016. an estimated 50m. persons of chinese origin lived abroad in 2012. a number of widely divergent varieties of chinese are spoken. the official 'modern standard chinese' is based on the dialect of north china. mandarin in one form or another is spoken by 885m. people in china, or around 70% of the population of mainland china. the wu language and its dialects has some 77m. native speakers and cantonese 66m. around 400m. people in china cannot speak mandarin. the ideographic writing system of 'characters' is uniform throughout the country, and has undergone systematic simplification. in 1958 a phonetic alphabet (pinyin) was devised to transcribe the characters, and in 1979 this was officially adopted for use in all texts in the roman alphabet. the previous transcription scheme (wade) is still used in taiwan and hong kong. mainland china is administratively divided into 22 provinces, five autonomous regions (originally entirely or largely inhabited by ethnic minorities, though in some regions now outnumbered by han immigrants) and four government-controlled municipalities. these are in turn divided into 332 prefectures, 658 cities (of which 265 are at prefecture level and 393 at county level), 2,053 counties and 808 urban districts. population of largest cities in 2010: shanghai, 20á22m.; beijing (peking), 16á45m.; shenzhen, 10á36m.; guangzhou (canton), 9á70m.; tianjin, 9á29m.; dongguan, 7á27m.; wuhan, 6á84m.; foshan, 6á77m.; chengdu, 6á32m.; chongqing, 6á26m.; nanjing, 5á83m.; shenyang, 5á72m.; xian, 5á21m.; hangzhou, 5á16m.; haerbin, 4á60m.; suzhou, 4á08m.; dalian, 3á90m.; zhengzhou, 3á68m.; shantou, 3á64m.; jinan, 3á53m.; qingdao, 3á52m.; changchun, 3á41m.; kunming, 3á28m.; changsha, 3á19m.; taiyuan, 3á15m.; xiamen, 3á12m.; hefei, 3á10m.; urumqi (wulumuqi), 2á85m.; fuzhou, 2á82m.; shijiazhuang, 2á77m.; wuxi, 2á76m.; zhongshan, 2á74m.; wenzhou, 2á69m.; nanning, 2á66m.; ningbo, 2á58m.; guiyang, 2á52m.; lanzhou, 2á44m.; zibo, 2á26m.; changzhou, 2á26m.; nanchang, 2á22m.; xuzhou, 2á21m.; tangshan, 2á13m. china has 56 ethnic groups. according to the 2010 census 1,225,932,641 people (91á51%) were of han nationality and 113,792,211 (8á49%) were from national minorities (including zhuang, manchu, hui, miao, uighur, yi, tujia, mongolian and tibetan) . compared with the 2000 census, the han population increased by 66,537,177 (5á74%), while the ethnic minorities increased by 7,362,627 (6á92%). non-han populations predominate in the autonomous regions, most notably in tibet where tibetans account for around 95% of the population. chang tibet relations between tibet and china's central government have fluctuated over the question of tibetan independence. the borders were opened for trade with neighbouring countries in 1980. in 1984 a buddhist seminary opened in lhasa, the regional capital, with 200 students, and monasteries and shrines have since been renovated and reopened. there were some 46,000 monks and nuns in 2013. in 1988 tibetan was reinstated as a 'major official language', competence in which is required of all administrative officials. in 1998 the then chinese president, jiang zemin, said he was prepared to meet the dalai lama provided he acknowledged chinese sovereignty over tibet and taiwan. in sept. 2002 direct contact between the exiled government and china was re-established after a nine-year gap. however, in march 2008 anti-chinese protests in lhasa ended in violence, with dozens reportedly killed by the chinese authorities, and in oct. that year the dalai lama stated he had lost hope of reaching agreement with china on tibet's status. in april 2011 he announced his retirement from active politics in favour of lobsang sangay, who had been elected to lead the tibetan government-in-exile. in july 2011, shortly after us president obama had received the dalai lama in washington, china's soon-to-be president, xi jinping, pledged to 'smash' attempts to destabilize tibet. by feb. 2013 there had been over 100 reported cases of self-immolation by tibetans protesting against chinese rule. the estimated population of tibet at the end of 2012 had risen to 3á08m. from 3á00m. at the 2010 census. the average population density was 2á26 persons per sq. km in 2008, although the majority of residents live in the southern and eastern parts of the region. birth rate (per 1,000), 2012, 15á5; death rate, 5á2. population of lhasa, the capital, in 2010 was 199,159. about 80% of the population is engaged in the dominant industries of farming and animal husbandry. in 2009 the total sown area was 240,610 ha. output in 2011: total grain crops, 937,300 tonnes; vegetables, 600,700 tonnes. in 2011 there were 14á59m. sheep and goats and 6á45m. cattle and yaks. tibet has over 2,000 mineral ore fields. mining, particularly of copper and gold, has expanded rapidly since 2006 when the railway came to tibet. cement production, 2011: 2á35m. tonnes. electricity consumption totalled 2á7bn. kwh in 2012. in 2011 there were 63,108 km of roads (21,842 km in 1990 most of china has a temperate climate but, with such a large country, extending far inland and embracing a wide range of latitude as well as containing large areas at high altitude, many parts experience extremes of climate, especially in winter. most rain falls during the summer, from may to sept., though amounts decrease inland. monthly average temperatures and annual rainfall (2012): beijing (peking), jan. 25á5 f (-3á6 c), july 81á3 f (27á4 c). annual rainfall 28á9" (733 mm). chongqing, jan. 45á0 f (7á2 c), july 83á3 f (28á5 c). annual rainfall 43á5" (1,104 mm). shanghai, jan. 40á5 f (4á7 c), july 85á5 f (29á7 c). annual rainfall 43á5" (1,104 mm). tianjin, jan. 25á2 f (-3á8 c), july 81á0 f (27á2 c). annual rainfall 29á7" (755 mm). on 21 -in 1975, 1978 and 1982 (currently in force) . the latter was partially amended in 1988, 1993, 1999, 2004 and 2014 , endorsing the principles of a socialist market economy and of private ownership. the unicameral national people's congress is the highest organ of state power. usually meeting for one session a year, it can amend the constitution and nominally elects and has power to remove from office the highest officers of state. there are a maximum of 3,000 members of the congress, who are elected to serve five-year terms by municipal, regional and provincial people's congresses. 1988 -93 yang shangkun 1993 -2003 jiang zemin 2003 -13 hu jintao 2013 -xi jinping prime ministers since 1949 . 1949 -76 zhou enlai 1976 -80 hua guofeng 1980 -87 zhao ziyang 1987 -98 li peng 1998 -2003 zhu rongji 2003 wen jiabao 2013-li keqiang elections of delegates to the 13th national people's congress were held between oct. 2017 and feb. 2018 by municipal, regional and provincial people's congresses. at its annual session in march 2018 the congress re-elected xi jinping as president and elected wang qishan as vice-president. president xi jinping succeeded hu jintao as president in march 2013 at the 12th national people's congress. tipped for the role since his appointment as secretary general of the chinese communist party (ccp) and chairman of the central military commission in nov. 2012, xi pursued a strong style of authoritarian rule at home and a proactive and muscular foreign policy in his first term. in oct. 2016 the ccp gave him the title of 'core' leader, a significant honorific bracketing him with mao zedong and deng xiaoping among previous party figures although conferring no absolute powers. then, at its five-yearly congress in oct. 2017, the party voted to enshrine his name and ideology in the chinese state constitution. he was subsequently re-elected in march 2018 and parliament also voted to abolish presidential term limits in a major shift from precedent. xi jinping was born on 15 june 1953 in beijing, the son of one of the first generation of communist leaders. he joined the ccp in 1974 and, after graduating from tsinghua university in 1979 with a degree in chemical engineering, he became secretary to the vice-premier and secretary-general of the central military commission. xi became the zhengding county committee deputy secretary in hebei province in 1982 and the following year was promoted to secretary. in 1985 he was made deputy mayor of xiamen city, fujian province. having undertaken various party roles in the province, he became deputy governor of fujian in 1999 and governor a year later. in 2002 he moved to zhejiang province and made his first inroads into national politics when he was named a member of the 16th central committee. from 2003-07 he was party secretary of fujian, overseeing economic growth averaging 14% a year and earning a reputation as an opponent of corruption. in march 2007 xi transferred to shanghai to take the role of party secretary following the dismissal of the incumbent on corruption charges. his appointment to such an important regional post was seen as a vote of confidence from the central government and he became a member of the politburo standing committee at the 17th party congress in oct. 2007. he was also made a high-ranking member of the central secretariat. on 15 march 2008 he was elected vice-president at the 11th national people's congress and took on a number of high profile portfolios including the presidency of the central party school. he was also beijing's senior representative for hong kong and ahead of his presidency, xi said little about his policy ambitions. there was hope abroad and at home that he would champion political and social reform and attempt to deal with corruption and a widening wealth gap between rich and poor and between urban and rural communities. he also faced the conundrum of how to provide adequate health care to a rapidly ageing population. in jan. 2014 the prospect of greater transparency and accountability under his leadership was undermined when the authorities began criminal proceedings against anti-corruption campaigners calling for public disclosure of officials' assets. this coincided with a report by a us investigative organization claiming that relatives of some of china's top political and military figures, including xi's brother-in-law, held secret offshore financial holdings. in other social and political affairs the ccp announced plans in nov. 2013 to ease china's one-child policy (which was subsequently abandoned following an announcement in oct. 2015, with effect from 2016) and to abolish the system of 're-education through labour' camps, while a party plenum called-for the first time-for markets to play a 'decisive' role in the allocation of resources. meanwhile, in 2014 xi was confronted by domestic political opposition in the form of militant attacks by ethnic uighur separatists from xinjiang region and, from sept. that year, by widespread pro-democracy and autonomy protests in hong kong. on the economic front, china's previously frenetic annual rate of growth slowed markedly in 2015, reflecting a slump in factory production and concerns over depressed oil prices, and again in 2016 to its lowest since 1990. it also heralded severe stock market turbulence into 2016 despite emergency government measures, which had negative reverberations throughout the world economy. nevertheless, recognizing china's rise as a global economic power, the imf in nov. 2015 voted to add the yuan as the fifth member of its special drawing rights (sdr) currency basket alongside the us dollar, japanese yen, british pound and the euro. in foreign affairs, regional concerns over china's territorial and military intentions were raised in nov. 2013 by the government's declaration of a new 'air defence identification zone' over a swathe of the east china sea including disputed islands claimed by japan and south korea. there has also been friction, regionally and with the usa, over china's sovereignty claims and land reclamation operations on islands in the south china sea, although in july 2016 an international legal tribunal ruled in favour of a challenge by the philippines to china's sovereignty assertions-a verdict beijing vowed to ignore. further afield, xi has meanwhile undertaken numerous official visits abroad, as well as attending multilateral forums, for diplomatic, trading and investment purposes. and, while in singapore in nov. 2015, xi and president ma ying-jeou of taiwan held the first direct talks between leaders of the two estranged governments since their split in 1949. more recently, in 2018 xi aimed to extend china's economic and military co-operation with russia and also sought to defuse tensions with india over a simmering border dispute at an informal summit with prime minister narendra modi. meanwhile, friction with the usa escalated markedly over disputed trading and commercial practices, with both countries imposing punitive trade tariffs. li keqiang took office as premier of the state council, a role equivalent to prime minister, in march 2013, succeeding wen jiabao. he was re-elected in march 2018. li keqiang was born on 1 july 1955 in dingyuan county, anhui province. following graduation from high school in 1974, he joined the ccp and in 1982 he graduated in law from peking university, serving as head of the students' federation from 1978-82. he went on to earn a master's degree and doctorate in economics and headed the university's communist youth league of china (cylc) committee. over the following two decades he rose through the cylc ranks, joining the secretariat of its central committee in the 1980s and serving as its first secretary in the 1990s. at this time he built up his power base and forged close ties with hu jintao, a fellow cylc committee member and future chinese president. in 1998 li became deputy party secretary for henan province and a year later was appointed henan's governor. in dec. 2004 he was named party secretary for liaoning province where he spearheaded a major coastal infrastructure project, the '5 points and one line' highway development. in 2009 this template was adopted at the national level to rejuvenate industrial northeast china. he also oversaw the rehousing of 1á5m. shanty-town residents into new apartment blocks over a three-year period. li advanced to national level politics when he was elected to the politburo standing committee in oct. 2007. he was appointed vice-premier of the state council in march 2008, leading a medical reform programme aimed at creating an accessible public health care service. he also chaired an affordable housing programme and introduced tax reform plans. in nov. 2012 li was re-elected as a member of the politburo standing committee and on 15 march 2013 became premier of the state council at the 12th national people's congress. regarded as the steward of the chinese economy, li has aimed to focus on securing china's long-term expansion and on the further provision of basic national health care, affordable housing, employment growth, regional development and cleaner energy. however, global confidence in china's economy has been shaken since 2015 as the country's growth momentum has slowed amid apparent policy differences and blunders, prompting rumours that li was being increasingly sidelined in the governing hierarchy. he was nevertheless re-elected to the politburo standing committee in oct. 2017 and to the premiership in march 2018. having sought assurances that a recently revised us-mexico-canada trade agreement would not stop canada from signing deals with other countries, li met with canadian prime minister justin trudeau in nov. 2018 at an international summit in singapore with the aim of pursuing negotiations on a bilateral free trade pact. the chinese president is chairman of the state and party's military commissions. china is divided into seven military regions. the military commander also commands the air, naval and civilian militia forces assigned to each region. china's armed forces (pla: 'people's liberation army'), totalling nearly 3á0m. in 2013 including the paramilitary people's armed police (pap) and 2á3m. excluding the pap, are the largest of any country. however, active armed personnel numbers have halved since 1980. moreover, in 2015 president xi laid out plans to reform the army structure-replacing an organization based on seven regions with one based on five 'theatre commands'-and reduce the number of military personnel by a further 300,000. conscription is compulsory, but for organizational reasons, is selective: only some 10% of potential recruits are called up. service is for two years. a military academy to train senior officers in modern warfare was established in 1985. defence expenditure in 2013 was us$112,173m. (equivalent to us$83 per capita). china's military spending more than trebled between 2007 and 2015. defence spending in 2013 represented 1á2% of gdp, although the share has actually declined since 1990. only the usa spent more on defence in 2013, but china's defence expenditure totalled around a fifth of that of the usa. in march 2014 it was announced that the defence budget would rise by 12á2% to us$132bn. following increases of 10á7%, 11á2% and 12á7% in the previous three years. china is the world's third largest exporter of arms after the usa and russia, with 6á2% of the global major weapons total over the period 2012-16. in the period 2004-08 it had only been the eighth largest exporter. as at 31 may 2016 china had 3,044 personnel serving in un peacekeeping operations (the largest contingent of any of the five permanent members of the un security council and more than the other four combined). having carried out its first test in 1964, there have been 45 tests in all at lop nur, in xinjiang (the last in 1996). the nuclear arsenal consisted of approximately 270 operational warheads in jan. 2017 according to the stockholm international peace research institute. china has been helping pakistan with its nuclear efforts. the army (the pla groundforce) is divided into main and local forces. main forces, administered by the seven military regions in which they are stationed, but commanded by the ministry of defence, are available for operation anywhere and are better equipped. local forces concentrate on the defence of their own regions. ground forces are divided into infantry, armour, artillery, air defence, aviation, engineering, chemical defence and communications service arms. there are also specialized units for electronic counter-measures, reconnaissance and mapping. in 2013 there were 18 group armies covering seven military regions. they included: 17 armoured divisions and brigades; 29 mechanized infantry divisions, brigades and regiments; 30 motorized infantry divisions and brigades; nine special operations units; 19 artillery divisions and brigades; 3 amphibious brigades and divisions; two mountain brigades; 14 aviation brigades and regiments; and two guard divisions. total strength in 2013 was 1á60m. including some 800,000 conscripts. reserve forces are undergoing major reorganization on a provincial basis but are estimated to number some 510,000. there is a paramilitary people's armed police force estimated at 660,000 under pla command. in nov. 2011 the naval arm of the pla included 71 submarines, of which three were strategic (two jin-class and one xia-class) and 68 tactical. by mid-2015 two more jin-class nuclear-powered ballistic missile submarines had entered service. surface combatant forces in nov. 2011 included 13 destroyers and 65 frigates. sea trials of china's first aircraft carrier, liaoning (a former soviet warship purchased from ukraine), began in aug. 2011. it entered service in sept. 2012 and was initially only used for training before being declared 'combat ready' in nov. 2016. work on china's first domestically-built aircraft carrier began in 2015. it was launched in april 2017 and is expected to be operational by 2020. there is a land-based naval air force of about 311 combat-capable aircraft, primarily for defensive and anti-submarine service. the force includes h-6 strategic bombers and jh-7 fighters. the naval arm is split into a north sea fleet, an east sea fleet and a south sea fleet. in 2013 naval personnel were estimated at 235,000, including 26,000 in the naval air force and 35,000 conscripts. the pla air force organizes its command through seven military region air forces. the air force has an estimated 1,700 combat-capable aircraft. equipment includes j-7 (mig-21) interceptors (known in the west as 'fishbed'), h-6 chinese-built copies of tu-16 strategic bombers, q-5 fighter-bombers (evolved from the mig-19 and known in the west as 'fantan'), su-27 fighters supplied by russia (known in the west as 'flanker'), j-10 chinese-designed and produced fighters (known in the west as 'firebird') and j-8 locally-developed fighters (known in the west as 'finback'). total strength (2013) was 398,000. in 2014 agriculture accounted for 9á1% of gdp, industry 43á1% and services 47á8%. industry was the largest contributor until 2011, while services only overtook agriculture as the second largest sector in 1985. in the late 1960s agriculture was the largest contributor towards gdp. china's economic performance has been marked by high rates of growth for over three decades. annual gdp increases in the early 2000s consistently exceeded 10% until the global financial crisis. china also holds the world's largest foreign exchange reserves, at more than us$3á05trn. in april 2017, although they have been falling since 2014 as the central bank strives to boost the currency in the face of large capital outflows. it is among the top recipients of foreign direct investment (fdi) and is the world's largest producer and consumer of coal. in 2005 china made the transition from net receiver of foreign aid to net donor and has established itself as a key player in africa's economic development, becoming the largest export partner of sub-saharan africa in 2013. according to the world bank, china's cumulative fdi stock in africa totalled nearly us$34á7bn. in 2015, up from us$14á7bn. in 2011. in 2010 china overtook japan to become the world's second largest economy after the usa. new sectors like e-commerce and online financial services are gaining momentum in an economy long dominated by export-oriented sectors. rising trade tensions between the usa and china, however, pose a threat to longer-term prospects. the first steps from a centrally-planned towards a more market-oriented economy were taken by deng xiaoping in the late 1970s. he opened the economy to foreign trade and investment, decentralized industrial management and allowed private sector development. in 2001 china became a member of the world trade organization, establishing trade relations with many countries. private entrepreneurs and foreign investors have played an important role in developing the manufacturing sector, china's principal growth engine. even before 1978 the economy was heavily skewed towards manufacturing, but following the market-oriented transition output increased significantly. during this period there was a structural shift away from large state-owned enterprises (soes), although these still remain an important part of the economy. between 1997 and 2003 the government oversaw reform of soes, with many poorly performing businesses privatized or liquidated. stronger firms were restructured and often listed on the stock market. many more recent enterprises are labour-intensive as distinct from the capitalintensive soes. growth has been fuelled by low added value and labourintensive exports. however, chinese firms are predicted to become increasingly competitive with higher added value producers, such as south korea. although the global financial crisis reduced the rate of growth and inbound fdi, china's recovery was among the earliest. gdp growth averaged 7á9% in the second quarter of 2009, up from a two-decade low of 6á1% in the first quarter of that year. fdi also recovered rapidly, averaging 4á1% of gdp annually between 2009 and 2013. growth was rooted in a stimulus package of 4trn. yuan (us$586bn. or 13% of 2008 gdp), including fiscal spending and interest rate cuts, as well as an expansionary monetary policy. central government committed 1á18trn. yuan, with the rest coming from local government, banks and soes. although exports declined by around 17% in 2009, other countries fared worse and china's share of world exports increased to nearly 13á6% in 2016 (up from 3% in 1999), making it the world's largest merchandise provider. gdp growth in 2010 stood at more than 10% but moderated between 2011 and 2014, reflecting the global economic slowdown and diminishing dividends from past reforms. in aug. 2015 a devaluation of the yuan sent the shanghai stock exchange plummeting by nearly 40%, which was swiftly followed by a surge in capital outflows. the stock market meltdown lasted until feb. 2016, with trading halted altogether for two days in jan. that year. nonetheless, the shanghai exchange subsequently began a recovery and had stabilized (at around 3,000 points) by feb. 2017. despite stock market turbulence, the property market, which constitutes a quarter of china's gdp and is vital to the banking sector (as it accounts for a substantial amount of its collateral), remained buoyant. gdp growth declined to 6á9% in 2015 (the slowest rate in 25 years) and fell again to 6á7% in 2016 as china attempted to reduce its reliance on exports, increase domestic consumption and develop its service sector. however, china remains one of the fastest growing major economies in the world, recording expansions of 6á9% and 6á6% in 2017 and 2018, respectively, driven by exports and robust domestic household consumption. in may 2017, for the first time since 1998, the credit rating agency moody's downgraded china's sovereign rating. inflation was 2á2% in 2018, up from 1á6% in 2017, while public debt was measured by the government at 50á1% of gdp (although there is wide-held suspicion that the real figure is significantly higher). corporate debt reached 165% of gdp in 2018, with household debt-although still low-rising by 15% of gdp over the preceding five years. president xi jinping has targeted spending cuts and aims to curb loans to bloated soes. rapid economic advance has brought with it a number of challenges that threaten future growth. notably, china's cost advantage has been undermined in recent years by rising wages and transportation costs, as well as weak global demand. other concerns include rising property costs, high levels of local government debt, lack of enforcement of intellectual property rights, endemic corruption at government level and credit and investment dependence, while total social financing-a broad measure of total credit-increased by 77% of gdp between 2008 and early 2014. the stimulus package implemented by the government to boost growth increased total debt levels to more than double the value of gdp in 2016. according to the imf, an increase in consumer demand and a reduced dependence on exports and investment are keys to achieving stable long-term economic expansion. china's 13th five-year plan (covering 2016-20) aims to promote domestic consumption and to support innovation and entrepreneurship within a framework of balanced and sustainable development. efforts to promote domestic consumption have seen exports' share of gdp falling from 38% in 2007 to 19á6% in 2016 and a lower investment contribution to gdp. trade frictions are predicted to disproportionately affect smaller firms that are less able to squeeze profit margins to accommodate tariff hikes, as well as those geographical regions most reliant on exports. the continued decline in commodity prices coupled with china's economic slowdown has had knock-on effects for commodity-exporting nations, such as brazil, indonesia and argentina, given that china consumes about half of the world's steel, aluminium and nickel. inefficient production and outmoded equipment have meanwhile led to significant environmental problems, especially in the north of the country. air pollution, soil erosion and a declining water table are of particular concern. china has become the world's largest consumer of coal and second largest consumer of oil after the usa. the government aims to diversify its energy sources, relying less on coal and more on nuclear and alternative energy sources. there has been heavy investment in hydro-power, including the three gorges dam. since 1980, 600m. people have been lifted out of poverty, yet china still has the second largest number of poor in the world after india. the world bank estimates that 98á9m. people lived below the national poverty line at the end of 2012 (equivalent to income less than us$1 per day), located mainly in remote and resource-poor regions and particularly in the west and the interior. nonetheless, some progress has been made, with 7á2% of the rural population living below the poverty line in 2014 compared to 8á5% in 2013. a large gap remains between living standards of the urban and rural communities, between urban zones on the chinese coast and the interior and western parts of the country, and between the urban middle classes and those who have not been able to profit from the growth of recent decades. china also faces the growing burden of an ageing population. those aged 65 and over accounted for 10á1% of the total population in 2016, up from 6á9% in 2000. the currency is called renminbi (i.e. people's currency). the unit of currency is the yuan (cny) which is divided into ten jiao, the jiao being divided into ten fen. the yuan was floated to reflect market forces on 1 jan. 1994 while remaining state-controlled. for 11 years the people's bank of china maintained the yuan at about 8á28 to the us dollar, allowing it to fluctuate but only by a fraction of 1% in closely supervised trading. in july 2005 it was revalued and pegged against a 'market basket' of currencies the central parities of which were determined every night. in july 2008, after three years of sharp appreciation, it was repegged at around 6á83 yuan to the dollar, leading to claims from some international observers that it was being kept unfairly low to boost exports. in june 2010 the government announced that the yuan would be allowed to move freely against the dollar as long as a rise or fall does not exceed 0á5% within a single day. in aug. 2015 the yuan was devalued by a total of 4á65% on three consecutive days. in aug. 2009 total money supply was 20,039á5bn. yuan, gold reserves were 33á89m. troy oz and foreign exchange reserves us$2,210á8bn. (us$75á4bn. in 1995). china's reserves are the highest of any country, having overtaken those of japan in 2006. inflation rates (based on imf statistics): 5á9% -0á7% 3á3% 5á4% 2á6% 2á6% 2á0% 1á4% 2á0% 1á6% china's economy overheated in the early 1990s, leading to inflation rates of 14á7% in 1993, 24á1% in 1994 and 17á1% in 1995 of the total revenues in 2015 central government accounted for 6,926á7bn. yuan and local governments 8,300á2bn. yuan. tax revenues came to 12,492á2bn. yuan in 2015 (including domestic vat 3,110á9bn. yuan and corporate income tax 2,713á4bn. yuan) and non-tax revenues 2,734á7bn. yuan. of the total expenditure in 2015 central government accounted for 2,554á2bn. yuan and local governments 15,033á6bn. yuan. the leading items of expenditure in 2015 were education (2,627á2bn. yuan) and social safety net and employment effort (1,901á9bn. yuan). the standard rate of vat is 16%. performance gdp totalled us$12,237á7bn. in 2017, the second highest behind the usa. china's share of world gdp has risen from 4% in 2000 to 15% in 2016. it replaced japan as the second largest economy in 2010. it is forecast that around 2020 china will overtake the usa to become the world's largest economy. as recently as 2000 the us economy was around eight times larger than china's. real gdp growth rates (based on imf statistics): supervising the country's banks and other deposit-taking financial institutions from the central bank. legislation in 1995 permitted the establishment of commercial banks; credit co-operatives may be transformed into banks, mainly to provide credit to small businesses. there were 1,927 rural credit co-operatives at the end of 2012. insurance is handled by the people's insurance company. the industrial and commercial bank of china is the world's largest bank by assets (us$3,743bn. as at 31 dec. 2016). savings deposits in various forms in all banking institutions totalled 40,370á4bn. yuan in 2012; loans amounted to 67,287á5bn. yuan. there are stock exchanges in the shenzhen special economic zone and in shanghai. a securities trading system linking six cities (securities automated quotations system) was inaugurated in 1990 for trading in government bonds. china received a record us$136á3bn. worth of foreign direct investment in 2017, up from us$133á7bn. in 2016. external debt totalled us$548,551m. in 2010 (up from us$145,339m. in 2000) and represented 9á3% of gni. china's carbon dioxide emissions from the consumption of energy in 2011 accounted for 25á3% of the world total (making it the biggest emissions producer, having overtaken the usa in 2007) and were equivalent to 6á1 tonnes per capita (up from 4á5 tonnes per capita in 2007). carbon dioxide emissions have more than doubled since 2000. an environmental performance index compiled in 2016 ranked china 109th of 180 countries, with 65á1%. the index examined various factors in nine areas-agriculture, air quality, biodiversity and habitat, climate and energy, fisheries, forests, health impacts, water and sanitation, and water resources. pollution is estimated to cost china about 10% of gdp annually. installed generating capacity in 2011 was an estimated 1,006m. kw, compared with 299m. kw in 2000. in 2014 electricity output was 5,649,580 gwh, up from 1,355,600 gwh in 2000. consumption per capita was 3,927 kwh in 2014. rapidly increasing demand has meant that more than half of china's provinces have had to ration power. sources of electricity in 2014 as percentage of total production: thermal, 75á6%; hydro-electric power, 18á8%; wind. 2á8% (china is one of the world's largest producers of wind power); and nuclear, 2á3%. in 2016 there were 35 nuclear reactors in use and 20 under construction. generating electricity is not centralized; local units range between 30 and 60 mw of output. in dec. 2002 china formally broke up its state power monopoly, creating instead five generating and two transmission firms. the three gorges dam project on the yangtze river was launched in 1993 and is intended to produce abundant hydro-electricity (as well as helping flood control). the first three 700,000-kw generators in service at the project's hydro-power station began commercial operation in july 2003. the original specification was completed in oct. 2008, although six more generators have been added in the meantime (bringing the total to 32). the final two generators become operational in july 2012, giving the dam an overall capacity of 22á5 gw. china surpassed germany in terms of solar generating capacity in 2015, with 43á5 gw at the end of the year. on-shore oil reserves are found mainly in the northeast (particularly the daqing and liaohe fields) and northwest. there are off-shore fields in the continental shelves of east china. oil production was a record 211á4m. tonnes in 2014 and was 191á5m. tonnes in 2017. china is the second largest consumer of oil after the usa. ever-growing demand has meant that increasing amounts of oil are having to be imported. a 964-km pipeline from skovorodino in russia to daqing in the northeast of china was inaugurated in jan. 2011, allowing china to increase significantly its imports of oil from the world's second largest producer. the 1,833-km turkmenistan-china gas pipeline, bringing natural gas to xinjiang in china via kazakhstan and uzbekistan, was inaugurated in dec. 2009. this connects with china's second west-east gas pipeline. only the usa imports more oil. domestic production now accounts for only 55% of consumption, compared to nearly 85% in 1998. proven reserves in 2017 were 25á7bn. bbls. the largest natural gas reserves are located in the western and northcentral regions. production was a record 149á2bn. cu. metres in 2017-up from 138á0bn. cu. metres in 2015-with proven reserves of 5á5trn. cu. metres in 2017. china is the second largest producer of wind power after the usa, with 156á1bn. kwh in 2014. in 2015 total installed capacity amounted to 145,362 mw, the highest of any country and 33á6% of the world total. china is one of the world's leading mineral producing and consuming countries. recoverable deposits of coal in 2012 totalled 229á9bn. tonnes, mainly distributed in north china (particularly shanxi province and the inner mongolia autonomous region). coal production was 3,660m. tonnes in 2012. annual coal production has increased every year since 2000. growing domestic demand nonetheless meant that china became a net importer of coal in 2009. iron ore reserves were 19á5bn. tonnes in 2012. deposits are abundant in the anthracite field of shanxi, in hebei and in shandong, and are found in conjunction with coal and worked in the northeast. production in 2012 was 1,310m. tonnes, making china the world's largest iron ore producer. it is also the largest consumer, at around 55% of the global total in 2012. tin ore is plentiful in yunnan, where the tin-mining industry has long existed. tin production was 110,000 tonnes in 2012. china is a major producer of wolfram (tungsten ore). there is mining of wolfram in hunan, guangdong and yunnan. output of other minerals (in 1,000 tonnes) in 2012: salt, 69,100; bauxite, 47,000; aluminium, 37,700; zinc, 4,900; lead, 2,800; copper, 1,550. there are also reserves of diamond, nickel, barite, bismuth, graphite, gypsum, mercury, molybdenum, silver, salt, phosphate ore and sylvite. gold production, 2012: 403 tonnes. china surpassed south africa as the world's leading gold producer in 2007, since when its output has increased every year. agriculture accounted for approximately 10% of gdp in 2012, compared to over 50% in 1949 at the time of the birth of the people's republic of china and over 30% in 1980. in 2015 sown areas for major crops were (in 1m. ha.): corn, 38á12; rice, 30á22; wheat, 24á14; soybeans, 8á87; tubers, 8á84; rapeseed, 7á53. intensive agriculture and horticulture have been practised for millennia. present-day policy aims to avert the traditional threats from floods and droughts by soil conservancy, afforestation, irrigation and drainage projects, and to increase the 'high stable yields' areas by introducing fertilizers, pesticides and improved crops. in aug. 1998 more than 21m. ha., notably in the yangtze valley, were under water as china experienced its worst flooding since the 1950s. the 1998 flood season claimed over 4,100 lives. 'township and village enterprises' in agriculture comprise enterprises previously run by the communes of the maoist era, co-operatives run by rural labourers and individual firms of a certain size. there were 1,786 state farms in 2012 with 3á18m. employees. net per capita annual income of rural households, 2012: 7,917 yuan. in 2014 there were an estimated 106á3m. ha. of arable land and 16á2m. ha. of permanent cropland; 70á4m. ha. were equipped for irrigation. there were 4á85m. large/medium-sized tractors in 2012 and 17á97m. small tractors. china is the world's leading producer of a number of agricultural crops. production of major products (in 1m. tonnes), 2015 (unless otherwise indicated): corn, 224á63; rice, 208á23; wheat, 130á19; sugarcane, 116á97; potatoes (2014 estimate livestock, 2015 (unless otherwise indicated): pigs, 451,125,000; sheep, 162,062,000; goats, 148,934,000; cattle and buffaloes, 108,173,000; horses, 5,908,000; chickens (2014 estimate), 4á63bn.; ducks (2014 estimate), 665m. china has more pigs, goats, sheep, horses and chickens than any other country. it is also home to nearly two-thirds of the world's ducks. meat production in 2015 was estimated at 86á25m. tonnes; milk, 38á70m. tonnes; eggs, 29á99m. tonnes; honey, 477,000 tonnes. china is the world's leading producer of meat, eggs and honey. gale, fred, (ed.) china's food and agriculture: issues for the 21st century. 2012 powell, s. g., agricultural reform in china: from communes to commodity economy, 1978 -1990 . 1992 forestry in 2015 the area under forests was 208á32m. ha., or 22% of the total land area. the average annual increase in forest cover of 1,542,000 ha. between 2010 and 2015 was the highest of any country in the world. total roundwood production in 2011 was 329á47m. cu. metres, making china the world's third largest timber producer (9á4% of the world total in 2011). it is the highest consumer of roundwood; timber consumption in 2011 totalled 375á71m. cu. metres. it is also the world's leading importer of roundwood, accounting for 35á9% of world timber imports in 2011. total catch, 2012: 16,167,443 tonnes, of which 13,869,604 tonnes were from marine waters. china's annual catch is the largest in the world, and currently accounts for approximately 18% of the world total. in 1989 the annual catch had been just 5á3m. tonnes. china's aquaculture production is also the largest in the world, at 45,468,960 tonnes in 2014. imports of fishery commodities in 2012 were valued at us$7,441m. (the third highest behind japan and the usa); exports were the most of any country, at us$18,211m. china's fishery commodities exports in 2012 represented approximately 13% of the global total. in 2013, the first phase of the south-to-north water diversion project opened, with a second phase opening a year later. the scheme, which by 2018 provided beijing with a third of its total supply, was estimated to have cost almost us$50bn., with a third phase still to be completed. the leading companies by market capitalization in china in march 2019 were alibaba, an e-commerce and data company (us$499á4bn.); tencent holdings, an investment holding company (us$491á3bn.); and icbc, the world's largest commercial bank (us$311á0bn.). in nov. 2007 petrochina was briefly the world's largest company after its flotation on the shanghai stock market, with a market capitalization in excess of us$1trn., although its rank has since fallen considerably. industry accounted for 43á1% of gdp in 2015. cottage industries persist into the 21st century. industrial output grew by 15á7% in 2010. modern industrial development began with the manufacture of cotton textiles and the establishment of silk filatures, steel plants, flour mills and match factories. in 2012 there were 343,769 industrial enterprises with an annual revenue of more than 20m. yuan. of these enterprises, 286,861 were domestically funded, 30,973 were foreign funded and 25,935 were dependent on funds from hong kong, macao and taiwan. there were 17,851 state-owned industrial enterprises in total. output of major products, 2015 unless otherwise indicated (in tonnes): cement, 2,359á2m.; rolled steel, 1,123á5m.; crude steel, 803á8m.; pig iron, 691á4m.; gas oil and diesel oil (2014), 176á4m.; gasoline, 121á0m.; paper and paperboard, 117á4m.; sulphuric acid, 89á8m.; chemical fertilizers, 74á3m.; fuel oil (2014), 35á4m.; yarn, 35á4m.; refined sugar, 14á7m. also produced in 2015: cloth, 89,260m. metres; beer, 47,156á0m. litres; 1,812á6m. mobile phones; 174á4m. notebook pcs; 144á8m. colour tv sets; 142á0m. air conditioners; 79á9m. home refrigerators; 72á7m. washing machines; 68á8m. bicycles; 28á5m. cameras; 25á0m. motorcycles. china is the world's leading cement, steel and pig iron manufacturer; since 2000 output of cement has trebled, and production of crude steel has increased sixfold and of pig iron fivefold (although in 2014 pig iron production fell for the first time in more than 30 years, as did crude steel production in 2015). china overtook japan as the world's largest producer of motor vehicles in 2009, and in 2013 produced 18á1m. cars and 4á0m. commercial vehicles. the employed population at the 1990 census was 647á2m. (291á1m. female). by 2012 it had risen to 767á0m. (2á8m. more than in 2011), of whom 396á0m. worked in rural areas (9á0m. fewer than in 2011) and 371á0m. in urban areas (11á9m. more than in 2011). in 2015 china's registered urban jobless was 4á1%, with 9á66m. registered unemployed in the country's cities. with china's fast-growing ageing population, according to the united nations the working-age population began to decline in 2015. in 2012 china had 189,289 private industrial enterprises. it was not until the late 1970s that the private sector even came into existence in china. the average annual wage of people working in urban units in 2012 was 46,769 yuan. china's labour law stipulates a five-day working week with no more than eight hours a day and no more than 44 hours a week. minimum working age was fixed at 16 in 1991. strikes over pay have become ever more frequent in china, particularly at foreign-owned facilities. china had 2á95m. people living in slavery according to the walk free foundation's 2013 global slavery index, the second highest total of any country. there are five special economic zones at shenzhen, xiamen, zhuhai, shantou and hainan in which concessions are made to foreign businessmen. the pudong new area in shanghai is also designated a special development area. since 1979 joint ventures with foreign firms have been permitted. a law of april 1991 reduced taxation on joint ventures to 33%. there is no maximum limit on the foreign share of the holdings; the minimum limit is 25%. in china is the second largest trading nation in the world, accounting for 10á3% of global merchandise imports by value in 2014 and 12á3% of global merchandise exports (up from 4á3% when it joined the wto in 2001). it was the second largest importer in 2014 behind the usa and the largest exporter. as recently as 2004 the usa's total trade in goods was more than twice that of china. it overtook germany as the largest exporter of goods in 2009. its trade surplus in goods is the highest of any country. however, it has the world's highest trade deficit in services. in 2014 imports of services totalled us$382bn. but exports only us$232bn. main imports in 2015 (in us$1bn.): machinery and transport equipment, 682á4; non-edible raw materials, 209á7; mineral fuels, lubricants and related materials, 198á6; chemicals, 171á3. major exports in 2015 (in us$1bn.): machinery and transport equipment, 1,059á1; miscellaneous manufactured goods, 587á5; light textile industrial products, rubber products, minerals and metallurgical products, 391á0; chemicals, 129á6. the main trading partners were as follows in 2015 (in us$1m.): the total road length in 2012 was 4,237,500 km, including 96,200 km of expressways (of which there had not been any as recently as the mid-1980s); 31,885m. tonnes of freight and 35,570m. persons were transported by road that year. the number of civilian motor vehicles was 109á30m. in 2012, including 89á43m. passenger vehicles and 18á95m. trucks (more than double the number in 2008, when there were 51á00m. civilian vehicles overall including 38á39m. passenger vehicles and 11á26m. trucks). china is the world's fastest-growing car market. there were 204,196 traffic accidents in 2012, with 59,997 fatalities. in 2013 in jan. 2014 there were 2,577 ships of 300 gt or over registered, totalling 44á45m. gt. of the 2,577 vessels registered, 968 were bulk carriers, 583 general cargo ships, 545 oil tankers, 192 container ships, 189 passenger ships and 100 liquid gas tankers. mainland china's busiest port in 2012 was ningbo-zhoushan (handling 744á0m. tonnes of cargo), followed by shanghai (637á4m. tonnes), tianjin (477á0 tonnes), guangzhou (canton) (435á2m. tonnes) and qingdao (406á9m. tonnes). shanghai overtook singapore to become the world's busiest container port in 2010 and handled 33á6m. teus (twenty-foot equivalent units) in 2013. shenzhen, mainland china's second busiest port for container traffic and the world's fourth busiest in 2012, handled 22á9m. teus. hong kong handled 23á1m. teus in 2012. in jan. 2001 the first legal direct shipping links between the chinese mainland and taiwanese islands in more than 50 years were inaugurated. inland waterways totalled 125,000 km in 2012; 4,587á0m. tonnes of freight and 257á5m. passengers were carried. in june 2003 the three gorges reservoir on the chang jiang river, the largest water control project in the world, reached sufficient depth to support the resumption of passenger and cargo shipping. in 2013 out of 178 countries analysed in the 2017 fragile states index-a list published jointly by the fund for peace and foreign policy magazine-china was ranked the 85th most vulnerable to conflict or collapse. the index is based on 12 indicators of state vulnerability across social, political and economic categories. six new codes of law (including criminal and electoral) came into force in 1980, to regularize the legal unorthodoxy of previous years. there is no provision for habeas corpus. as well as treason and murder the death penalty may be used for rape, embezzlement, smuggling, fraud, theft, drug-dealing, bribery and robbery with violence. amendments to the criminal law in 2011 and 2015 reduced the number of capital crimes-which include both violent and non-violent offences-from 68 to 55 and further to 46. china does not divulge figures on its use of the death penalty, but amnesty international reports that china executes thousands of people annually and is the world's top executioner. nevertheless, western analysts believe that the number of executions now is around a fifth of the yearly total in the 1990s. 'people's courts' are divided into some 30 higher, 200 intermediate and 2,000 basiclevel courts, and headed by the supreme people's court. the latter, the highest state judicial organ, tries cases, hears appeals and supervises the people's courts. it is responsible to the national people's congress and its standing committee. people's courts are composed of a president, vicepresidents, judges and 'people's assessors' who are the equivalent of jurors. 'people's conciliation committees' are charged with settling minor disputes. there are also special military courts. procuratorial powers and functions are exercised by the supreme people's procuracy and local procuracies. in march 2017 the national people's congress passed legislation developing aspects of the 1986 general principles of civil law, with effect from oct. 2017. among its provisions was the extension of legitimate rights and interests from chinese citizens only to anyone conducting civil activities in the country. in addition, the statute of limitation was increased from two to three years. the number of sentenced prisoners in mid-2015 was 1,649,804 (118 per 100,000 of national population). china was ranked 47th of 102 countries for criminal justice and 67th for civil justice in the 2015 world justice project rule of law index, which provides data on how the rule of law is experienced by the general public across eight categories. an educational reform of 1985 brought in compulsory nine-year education consisting of six years of primary schooling and three years of secondary schooling, to replace a previous five-year system. in mainland china the 2010 population census revealed the following levels of educational attainment: 119á63m. people had finished university education; 187á99m. had received senior secondary education; 519á66m. had received junior secondary education; and 358á76m. had had primary education. 54á66m. people over 15 years of age or 4á08% of the population were illiterate, although this compared favourably with a 15á88% rate of illiteracy in the 1990 census and a 6á72% rate in 2000. in 2010 adult literacy was estimated at 95á1%; youth literacy in 2010 was 99á6%. in 2012 there were 181,251 kindergartens with 36á86m. children and 1á48m. full-time teachers; 228,585 regular primary schools with 96á96m. pupils and 5á59m. full-time teachers; 81,662 secondary schools (including: 14,205 senior secondary; 53,216 junior secondary; 5,245 specialized; 4,517 vocational; and 2,901 technical) with 94á21m. pupils and 5á99m. full-time teachers. there were also 378,751 pupils at 1,853 special education schools. institutes of higher education, including universities, numbered 2,442 in 2012, with 23á91m. undergraduates and 1á72m. postgraduate level students, and 1á44m. full-time teaching staff. china has more than 600 private universities, almost all of which have been established since the mid-1990s. a national system of student loans was established in 1999. the number of chinese students studying abroad went up from 3,000 in 1990 to 39,000 in 2000; it rose above 100,000 in 2002 and 200,000 in 20009, and by 2015 exceeded 500,000, making china the largest source of overseas students in the world. chinese students account for a fifth of all international students in tertiary education in the oecd, but fewer than half return to china after finishing their studies. the number of chinese undergraduate students in american universities in 2013-14 was 11 times as many as in 2006-07, rising from 10,000 to 110,000 in the space of seven years. there is an academy of sciences with provincial branches. an academy of social sciences was established in 1977. in 2012 national government expenditure on education came to 2,124,210m. yuan and accounted for 16á9% of national government spending. medical treatment is free only for certain groups of employees, but where costs are incurred they are partly borne by the patient's employing organization. in 2012 there were 950,297 health institutions throughout china, including 23,170 hospitals, 912,620 local health centres, 3,490 centres for disease control and prevention, and 1,289 specialized prevention and treatment centres. china's first aids case was reported in 1985. at the end of 2014 there were 501,000 reported cases of people living with hiv/aids. the number of deaths of people who had been living with hiv/aids in 2014 was 21,000. in the first half of 2003 china was struck by an epidemic of a pneumoniatype virus identified as sars (severe acute respiratory syndrome). the virus was first detected in southern china and was subsequently reported in over 30 other countries. according to the ministry of health, by the time the outbreak had been contained a total of 5,327 cases had been reported on the chinese mainland; 4,959 patients were cured and discharged from hospital, and 349 died. in water: at what cost? the state of the world's water 2016, wateraid reported that 4á5% of the population does not have access to safe water. china ranked as the country with the second largest number of people living without access to safe water (63á2m. in 2015). in 2015 an estimated 47á6% of adult males and 1á8% of adult females smoked in china. a study from the same year estimated that chinese males smoke one-third of all the world's cigarettes. in 2012 there were 48,078 social welfare enterprises with 4á49m. beds. numbers (in 1,000) of beneficiaries of relief funds in 2012: urban residents receiving minimum living allowance, 21,435; rural residents receiving minimum living allowance, 53,445; persons receiving traditional relief, 796; persons in rural households entitled to the 'five guarantees' (food, clothing, medical care, housing and burial expenses), 5,456. the official retirement age for men is 60 and for women 50 (or 55 in the case of civil servants and professionals). the government accords legality to five religions only: buddhism, islam, protestantism, roman catholicism and taoism. confucianism, buddhism and taoism have long been practised. confucianism has no ecclesiastical organization and appears rather as a philosophy of ethics and government. taoism-of chinese origin-copied buddhist ceremonial soon after the arrival of buddhism two millennia ago. buddhism in return adopted many taoist beliefs and practices. a more tolerant attitude towards religion had emerged by 1979, and the government's bureau of religious affairs (since renamed the state administration for religious affairs) was reactivated. ceremonies of reverence to ancestors have been observed by the whole population regardless of philosophical or religious beliefs. a new quasi-religious movement, falun gong, was founded in 1992, but has since been banned by the authorities. the movement has claimed some 100m. adherents, although the chinese government has disputed this. muslims are found in every province of china, being most numerous in the ningxia-hui autonomous region, yunnan, shaanxi, gansu, hebei, henan, shandong, sichuan, xinjiang and shanxi. roman catholicism has had a footing in china for more than three centuries. two christian organizations-the chinese patriotic catholic association, which declared its independence from rome in 1958, and the protestant three-self patriotic movement-are sanctioned by the chinese government. according to estimates (by the state-approved xinhua news agency, the chinese academy of social sciences and the state administration for religious affairs) there were 100m. buddhists (more than in any other country), 23m. christians and more than 21m. muslims in the country in 2009. other official figures indicate that there are 5á3m. catholics, although unofficial estimates are much higher. the number of christians in china is generally thought to be far higher than official numbers indicate, with so-called 'house churches' becoming ever more popular. some analysts estimate that there are as many as 100m. christians overall. legislation of 1994 prohibits foreign nationals from setting up religious organizations. johnson, ian, the souls of china: the return of religion after mao. 2017 china and provides habitat for a number of rare animal species, kulangsu, a historic international settlement (2017), a tiny island located on the estuary of the chiu-lung river, qinghai hoh xil (2017), the largest and highest plateau in the world, and fanjingshan (2018), an island of metamorphic rock in guizhou province. shared with kazakhstan and kyrgyzstan, silk roads: the routes network of chang'an-tianshan corridor (2014) is a 5,000-km section of the extensive silk roads network stretching from chang'an/ luoyang to the zhetysu region in present-day kazakhstan. china has two news agencies: xinhua (new china) news agency (the nation's official agency) and china news service. in 2012 there were 1,918 newspapers and 9,867 magazines; 48,230m. copies of newspapers and 3,350m. copies of magazines were published. in 1980 there were fewer than 200 newspapers. the communist party newspaper, renmin ribao (people's daily), had an average daily circulation of 2á6m. in 2012. the most widely read newspaper is cankao xiaoxi, with an average daily circulation of 3á1m. in 2012. china has the second highest circulation of daily newspapers after india, with an estimated average daily total of 137á8m. in 2014. as of sept. 2014 it was also home to the world's two most visited online news sites: xinhua news agency (90á2m. unique desktop users per month) and people's daily online (89á1m.). in the 2013 world press freedom index compiled by reporters without borders, china ranked 173rd out of 179 countries. in 2012, 7,920m. volumes of books were produced. in 2015 tourist numbers totalled 56á9m. china was the fourth most visited destination in 2015 after france, the usa and spain. income from tourists in 2015 was us$45á0bn., ranking it third behind the usa and spain. expenditure by chinese travellers outside of mainland china for 2015 was us$249á8bn., the most of any country and more than double the next largest expenditure (that of us tourists). in 2011 both german and us travellers abroad had spent more than those from china. the lunar new year, also known as the 'spring festival', is a time of great excitement for the chinese people. the climate is sub-tropical, tending towards temperate for nearly half the year, the winter being cool and dry and the summer hot and humid, may to sept. being the wettest months. normal temperatures are jan. 60 f (15á8 c), july 84 f (28á8 c). annual rainfall 87" (2,214á3 mm). hong kong used to be administered by the hong kong government. the governor was the head of government and presided over the executive council, which advised the governor on all important matters. the last british governor was chris patten. in oct. 1996 the executive council consisted of three ex officio members and ten appointed members, of whom one was an official member. the chief functions of the legislative council were to enact laws, control public expenditure and put questions to the administration on matters of public interest. the legislative council elected in sept. 1995 was, for the first time, constituted solely by election. it comprised 60 members, of whom 20 were elected from geographical constituencies, 30 from functional constituencies encompassing all eligible persons in a workforce of 2á9m., and ten from an election committee formed by members of 18 district boards. a president was elected from and by the members. at the elections on 17 sept. 1995 turnout for the geographical seats was 35á79%, and for the functional seats (21 of which were contested), 40á42%. the democratic party and its allies gained 29 seats, the liberal party 10 and the pro-beijing democratic alliance 6. the remaining seats went to independents. on 21 dec. 1996 the selection committee selected a provisional legislature which began its activities in jan. 1997 while the legislative council was still functioning. in jan. 1997 the provisional legislature started its work by enacting legislation which would be applicable to the hong kong special administrative region and compatible with the basic law. constitutionally hong kong is a special administrative region of the people's republic of china. the basic law enables hong kong to retain a high degree of autonomy. it provides that the legislative, judicial and administrative systems which were previously in operation are to remain in place. the special administrative region government is also empowered to decide on hong kong's monetary and economic policies independent of china. in july 1997 the first-past-the-post system of returning members from geographical constituencies to the legislative council was replaced by proportional representation. there were 20 directly elected seats out of 60 for the first elections to the legislative council following hong kong's return to chinese sovereignty, increasing in accordance with the basic law to 24 for the 2000 election with 36 indirectly elected. in the sept. 2004 legislative council election (and that of sept. 2008) 30 of the 60 seats were directly elected. for the election in sept. 2012 the number of seats was increased to 70, with 35 directly elected and 30 indirectly elected by functional constituencies. there were also five new functional constituency seats nominated by elected district council members. the chief executive is chosen by a beijing-backed 1,200-member election committee (800 prior to the march 2012 election), although it has been stated that universal suffrage is the ultimate aim. in 2007 a timetable was announced for hong kong to directly elect its chief executive in 2017 and its legislative council in 2020. however, beijing insisted that only approved candidates would be allowed to stand in 2017, prompting mass pro-democracy rallies in the territory in 2014 and formal rejection of the plan by the legislative council in june 2015. beijing nevertheless refused to countenance amendments. in july 2002 a new accountability or 'ministerial' system was introduced, under which the chief executive nominates for appointment 14 policy secretaries, who report directly to the chief executive. the chief executive is aided by the executive council, consisting of the three senior secretaries of department (the chief secretary, the financial secretary and the secretary for justice) and eleven other secretaries plus five non-officials. hong kong used to be administered by the hong kong government. the governor was the head of government and presided over the executive council, which advised the governor on all important matters. the last british governor was chris patten. in oct. 1996 the executive council consisted of three ex officio members and ten appointed members, of whom one was an official member. the chief functions of the legislative council were to enact laws, control public expenditure and put questions to the administration on matters of public interest. the legislative council elected in sept. 1995 was, for the first time, constituted solely by election. it comprised 60 members, of whom 20 were elected from geographical constituencies, 30 from functional constituencies encompassing all eligible persons in a workforce of 2á9m., and ten from an election committee formed by members of 18 district boards. a president was elected from and by the members. at the elections on 17 sept. 1995 turnout for the geographical seats was 35á79%, and for the functional seats (21 of which were contested), 40á42%. the democratic party and its allies gained 29 seats, the liberal party 10 and the pro-beijing democratic alliance 6. the remaining seats went to independents. overview hong kong has one of the world's most open economies and is an internationally important financial centre. the territory's economic rise was founded on its role as an international trade emporium, acting as a conduit for china's burgeoning exports. mainland china, the usa and japan are hong kong's major export partners, accounting for 51á2%, 7á2% and 5á0% of exports respectively in 2015. the island is dependent on imports of food and other resources. in 2015 it imported 49% of goods from mainland china, 7% from taiwan and 6% from japan. in 2004 and 2005 the economy grew strongly on the back of a rise in chinese tourism, healthy global demand for exports and improving domestic consumer confidence. however, the global financial crisis saw the economy shrink by 2á5% in 2009 before rebounding with a 6á8% increase the following year. between 2010 and 2015 annual growth averaged 3á6%, supported by strong external demand. student-led pro-democracy protests in the latter months of 2014 caused major disruption in several key business districts and threatened to weaken the local economy in the short term. foreign direct investment levels have been high, averaging 39% of gdp between 2010 and 2015 according to world bank data, and the world economic forum ranked hong kong as the ninth most competitive economy in the world in its 2016 report. the government aims to tackle a housing shortage by providing 280,000 new housing units by the mid-2020s. the unit of currency is the hong kong dollar (hkd) of 100 cents. it has been pegged since 1983 at a rate of hk$7á8 to the us dollar. banknotes are issued by the hongkong and shanghai banking corporation and the standard chartered bank, and, from may 1994, the bank of china. total money supply was hk$529,161m. in july 2009. in aug. 2009 gold reserves were 67,000 troy oz and foreign exchange reserves were us$223,211m. inflation rates (based on imf statistics): environment hong kong's carbon dioxide emissions from the consumption of energy in 2011 were the equivalent of 13á2 tonnes per capita. installed capacity was 12á6m. kw in 2011. production in 2011 was 39á03bn. kwh. hong kong is a net importer of electricity. consumption in 2011 was 47á41bn. kwh. the local agricultural industry is directed towards the production of high quality fresh food through intensive land use and modern farming techniques. out of the territory's total land area of 1,103 sq. km, only 60 sq. km is currently farmed. in 2006 local production accounted for 55% of live poultry consumed, 23% of live pigs and 4% of fresh vegetables. the gross value of local agricultural production totalled hk$1,184m. in 2006, with pig production valued at hk$585m., poultry production (including eggs) at hk$340m., and vegetable and flower production at hk$254m. in 2015 the total catch was 145,193 tonnes, exclusively from marine waters. the leading companies by market capitalization in hong kong in march 2019 were: china mobile, a telecommunications company (us$192á6bn.); aia group, a life insurance company (us$111á4bn.); and cnooc, an integrated oil company (us$78á8bn.). industry is mainly service-oriented. in june 2013 there were 343,006 establishments employing 2,505,081 persons in service industries and 11,609 establishments employing 103,350 persons in manufacturing industries. establishment statistics by service type (and persons engaged) were mainly: import/export trade and wholesale, 116,335 (554,372); retail, 65,046 (264,805); social and personal services, 44,194 (460,973) ; professional and business services, 42,017 (344,544); financing and insurance, 21,683 (207,346); accommodation and food services, 17,201 (276,207); real estate, 15,071 (126,415) . in 2011 the size of the labour force (synonymous with the economically active population) was 3,703,100 (1,760,400 females). the persons engaged in june 2012 included 1,090,059 people in wholesale, retail and import/ export trades, accommodation and food services, 664,652 in finance, insurance, real estate, professional and business services, 159,217 in the civil service, 107,637 in manufacturing and 71,721 in construction sites (manual workers only). a minimum wage of hk$28 per hour was introduced for the first time on 1 may 2011. unemployment stood at 3á1% in the period sept.-dec. 2011. in 2009 the total value of imports was hk$2,692,356m. and total exports hk$2,469,089m. the main suppliers of imports in 2009 were mainland china (46á4%), japan (8á8%), taiwan (6á5%), singapore (6á5%) and usa (5á3%). in 2009, 51á2% of total exports went to mainland china, 11á6% to the usa, 4á4% to japan, 3á2% to germany and 2á4% to the united kingdom. the chief import items in 2009 were: electrical machinery, apparatus and appliances, etc. (26á8%); telecommunications, sound recording and reproducing equipment (13á7%); office machines and automatic data processing machines (9á2%); articles of apparel and clothing accessories (4á5%). the main exports in 2009 were: electrical machinery, apparatus and appliances, etc. (26á4%); telecommunications, sound recording and reproducing equipment (16á8%); office machines and automatic data processing machines (10á1%); articles of apparel and clothing accessories (7á2%). in 2011 there were 2,086 km of roads, over 50% of which were in the new territories. there are 16 road tunnels, including three under victoria harbour. in 2011 there were 435,000 private cars, 111,000 goods vehicles, 20,000 buses and coaches, and 39,000 motorcycles and mopeds. there were 15,541 road accidents in 2011, of which 128 were fatal. a total of 26á7m. tonnes of cargo were transported by road in 2011. a 55 km bridge (the world's longest sea bridge) linking hong kong, zhuhai in guangdong province in mainland china and macao opened in oct. 2018 following a number of delays. hong kong was ranked fourth for its road infrastructure in the world economic forum's global competitiveness report 2017-2018. hong kong's railways are run by the mtr corporation limited (mtrcl), a public listed company of which the government is the majority shareholder. the mtr system comprises nine railway lines serving hong kong island, kowloon and the new territories. its 175 km network has 82 stations and carries an average of 4á8m. passengers each day. mtr lines carried 1,545m. passengers in 2012. in addition, a light rail network (36á2 km and 68 stops) serves the local communities of tuen mun, yuen long and tin shui wai in the new territories; 464,000 passengers travel daily on the system. a high speed rail service between hong kong and guangzhou on the mainland opened in sept. 2018. the electric tramway on the northern state of hong kong island commenced operating in 1904 and has a total track length of 16 km. the peak tram, a funicular railway connecting the peak district with the lower levels in victoria, has a track length of 1á4 km and two tramcars (each with a capacity of 120 passengers per trip). it carries an average of 16,200 passengers daily. the airport express line (35á2 km) opened in 1998 and is also operated by the mtrcl. it carried 12á7m. passengers in 2012. in june 2013 it was estimated that 12á2m. passenger journeys were made daily on public transport (including local railways, buses, etc.). in the world economic forum's global competitiveness report 2017-2018 hong kong ranked third for quality of rail infrastructure. the new hong kong international airport (generally known as chek lap kok), built on reclaimed land off lantau island to the west of hong kong, was opened on 6 july 1998 to replace the old hong kong international airport at kai tak, which was situated on the north shore of kowloon bay. more than 100 airlines now operate scheduled services to and from hong kong. in 2012 cathay pacific airways, the largest hong kong-based airline, operated approximately 105,000 passenger and cargo services to 172 destinations in 41 countries and territories around the world. cathay pacific carried 21,146,492 passengers and 1á4m. tonnes of cargo in 2012. dragonair, a cathay pacific subsidiary, provided scheduled services to 41 cities in mainland china and asia in 2012. in 2012 air hong kong, an all-cargo operator, provided scheduled services to bangkok, beijing, ho chi minh city, manila, nagoya, osaka, penang (via bangkok), seoul, shanghai, singapore, taipei and tokyo. hong kong international airport handled more international freight in 2011 than any other airport. in 2011, 334,000 aircraft arrived and departed and 54m. passengers and 3á94m. tonnes of freight were carried on aircraft. hong kong was second, behind only singapore, in the rankings for air transport infrastructure in the world economic forum's global competitiveness report 2017-2018. the port of hong kong handled 23á1m. teus (twenty-foot equivalent units) in 2012, making it the world's third busiest container port after shanghai and singapore. the kwai chung container port has 24 berths with 7,694 metres of quay backed by 275 ha. of cargo handling area. at the end of 2016 there were 2,513 ships (2,228 ocean-going) of 107,573,898 gt registered in hong kong. in 2016, 27 ,642 ocean-going vessels, 72,810 river cargo vessels and 84,559 river passenger vessels arrived at the port of hong kong. a total of 257m. tonnes of freight were handled in 2015. hong kong was ranked third in the world economic forum's global competitiveness report 2017-2018 for the quality of its port facilities. in 2013 there were 4,546,000 main (fixed) telephone lines (equivalent to 631á1 per 1,000 population). the local fixed telecommunications network services (ftns) market in hong kong was liberalized in 1995. there were 17,098,000 mobile phone subscriptions in 2013 (equivalent to 2,373á5 per 1,000 population), up from 11,580,000 in 2008 (1,661á9 per 1,000 population). the number of subscriptions doubled between 2006 and 2013. the internet market has also seen huge growth. in 2013 there were 6,892,000 wireless broadband subscriptions (956á7 per 1,000 population) and 2,220,000 fixed broadband subscriptions (308á2 per 1,000 population). the number of fixed broadband subscriptions has been declining since 2011 as more people have wireless subscriptions instead. in march 2012 there were 3á8m. facebook users. the external telecommunications services market has been fully liberalized since 1 jan. 1999, and the external telecommunications facilities market was also liberalized starting from 1 jan. 2000. in 2010 the adult literacy rate was 94á6% (92á4% in 2000). universal basic education is available to all children aged from six to 15 years. in around three-quarters of the ordinary secondary day schools teaching has been in cantonese since 1998-99, with about a quarter of ordinary secondary day schools still using english. in 2010 there were 148,940 pupils in 951 kindergartens, 331,112 in 572 primary schools (including 40 international schools) and 458,131 in 565 secondary schools (including 27 international schools). the estimated total government expenditure on education in 2011-12 was hk$68á3bn. (18á6% of total government spending and 3á6% of gdp). in 2010-11: 20á1% of total government spending and 3á4% of gdp. according to the oecd's 2015 pisa (programme for international student assessment) study, 15-year-olds in hong kong rank second among oecd and other major countries and cities in mathematics and reading, and ninth in science. the three-yearly study compares educational achievement of pupils in over 70 countries. the department of health (dh) is the government's health adviser and regulatory authority. the hospital authority (ha) is an independent body responsible for the management of all public hospitals. in 2009 there were 12,424 registered doctors, equivalent to 1á8 doctors per 1,000 population. in 2009 there were 2,126 dentists, 38,641 nurses and 4,525 midwives. the total number of hospital beds in 2009 was 35,062, including 26,872 beds in 38 public hospitals under the ha and 3,818 beds in 13 private hospitals. the bed-population ratio was 5á0 beds per thousand population. the chinese medicine ordinance was passed by the legislative council in july 1999 to establish a statutory framework to accord a professional status for chinese medicine practitioners and ensure safety, quality and efficacy of chinese medicine. in 2009 there were 6,048 registered chinese medicine practitioners. total expenditure on health in 2009-10 amounted to hk$88,069m., an increase of 5á2% over that in 2008-09. the hong kong act of 1985 provided for hong kong ordinances to replace english laws in specified fields. the courts of justice comprise the court of final appeal (inaugurated 1 july 1997), which hears appeals on civil and criminal matters from the high court; the high court (consisting of the court of appeal and the court of first instance); the lands tribunal, which determines on statutory claims for compensation over land and certain landlord and tenant matters; the district court (which includes the family court); the magistracies (including the juvenile court); the coroner's court; the labour tribunal, which provides a quick and inexpensive method of settling disputes between employers and employees; the small claims tribunal, which deals with monetary claims involving amounts not exceeding hk$50,000; and the obscene articles tribunal. while the high court has unlimited jurisdiction in both civil and criminal matters, the district court has limited jurisdiction. the maximum term of imprisonment it may impose is seven years. magistracies exercise criminal jurisdiction over a wide range of offences, and the powers of punishment are generally restricted to a maximum of two years' imprisonment or a fine of hk$100,000. after being in abeyance for 25 years, the death penalty was abolished in 1992. 75,936 crimes were reported in 2011, of which 13,100 were violent crimes. 38,327 people were arrested in 2011, of whom 8,962 were for violent crimes. the population in penal institutions was 9,067 at 31 dec. 2011 (127 per 100,000 population). social welfare programmes include social security, family services, child care, services for the elderly, medical social services, youth and community work, probation, and corrections and rehabilitation. 171 non-governmental organizations are subsidized by public funds. the government gives non-contributory cash assistance to needy families, unemployed able-bodied adults, the severely disabled and the elderly. caseload as at aug. 2011 totalled 280,358. victims of natural disasters, crimes of violence and traffic accidents are financially assisted. estimated recurrent government expenditure on social welfare for 2011-12 was hk$42á2bn. in 2008 there were 54 daily newspapers, of which 50 were paid-for and four free. the newspapers with the highest circulation figures are all chinese-language papers-oriental daily news, apple daily and the sun. the english-language paper with the highest circulation is the south china morning post. circulation of dailies (including free papers) in 2008 was 3á6m. (2á0m. paid-for and 1á6m. free). there were a record 36,030,300 visitor arrivals in 2010. expenditure associated to inbound tourism totalled hk$209,983á0m. in 2010. the macao special administrative region, which lies at the mouth of the pearl river, comprises a peninsula (9á3 sq. km) connected by a narrow isthmus to the people's republic of china, on which is built the city of santa nome de deus de macao, the islands of taipa (7á6 sq. km), linked to macao by three bridges, colôane (7á6 sq. km) linked to taipa by a 2-km causeway, and cotai, a strip of reclaimed land between colôane and taipa (6á0 km). the total area of macao in 2016 was 30á5 sq. km. additional land continues to be reclaimed from the sea. the population at the 2016 census was 650,834 (336,816 females); density, 21,339 people per sq. km. according to un estimates, the entire population lived in urban areas in 2011. the official languages are chinese and portuguese, with the majority speaking the cantonese dialect. only about 4,000 people speak portuguese as their first language. the un gives a projected population for 2020 of 652,000. in 2015, 1,784 foreigners were legally registered for residency in macao. there were 8,468 legal immigrants from mainland china. social statistics 2014: births, 7,360 (11á8 per 1,000 population); deaths, 1,939 (3á1); marriages, 4,085 (6á6); divorces, 1,308 (2á1). infant mortality, 2014, 2á0 per 1,000 live births. life expectancy at birth , 82á9 years. sub-tropical tending towards temperate, with an average temperature of 23á0 c. the number of rainy days is around a third of the year. average annual rainfall varies from 47-87" (1,200-2,200 mm) . it is very humid from may to sept. macao's constitution is the 'basic law', promulgated by china's national people's congress on 31 march 1993 and in effect since 20 dec. 1999. it is a special administrative region (sar) of the people's republic of china, and is directly under the central people's government while enjoying a high degree of autonomy. the legislative assembly has 33 seats of which 14 are directly elected, 12 indirectly elected by functional constituencies and seven appointed by the chief executive. at the elections held on 17 sept. 2017 the macau-guangdong union won two of 14 elected seats with 10á0% of votes cast and the union for development two with 9á7%. ten other parties won a single seat each. turnout was 57á2%. fernando chui sai-on was re-elected chief executive for a second term on 31 aug. 2014, receiving 380 out of 396 votes in the election committee. chief executive: fernando chui sai-on; b. 1957 (sworn in 20 dec. 2009 and re-elected in aug. 2014 . government website: http://www.gov.mo the gaming sector is of major importance to the economy of macao. it accounted for 46á1% of total gdp in 2013 and provides billions of dollars in taxes. in 2014, 21á5% of the workforce was employed in gaming. in 2014 gross gaming revenue totalled us$43,307m. (nearly double the 2010 figure) . however, 2014 revenues were down slightly on the 2013 total. macao overtook nevada as the world's largest gaming market in 2008. macao's traditional manufacturing industries virtually disappeared following the transfer of much of the textile industry to the chinese mainland and, in 2005, the termination of the multifibre arrangement, which had governed international textile trade flows for three decades. the unit of currency is the pataca (mop) of 100 avos, which is tied to the hong kong dollar at parity. inflation was 2á4% in 2016 and 1á2% in 2017. foreign exchange reserves were us$18,350m. in 2009. total money supply was 30,608m. patacas in 2009. in 2014 revenues totalled 161,861m. patacas; expenditures, 67,078m. patacas. revenues from gaming tax accounted for 84á5% of total revenue in 2014; current expenditure accounted for 86á4% of expenditure. real gdp growth was just 1á7% in 2009 but then rose to 25á3% in 2010 and 21á7% in 2011. more recently the economy contracted by 0á9% in 2016 before growing by 9á1% in 2017. total gdp in 2017 was us$50á4bn. environment macao's carbon dioxide emissions from the consumption of energy in 2011 were the equivalent of 2á8 tonnes per capita. installed capacity was 0á47m. kw in 2013; production, 0á41bn. kwh. macao imported 4,059m. kwh of electricity in 2013. oil and gas 202,688,000 litres of fuel oil were imported in 2009. the catch in 2015 was estimated at 1,500 tonnes. although the economy is based on gaming and tourism there is a light industrial base of textiles and garments. in 2014 the number of manufacturing establishments was 864 (food products and beverages, 284; textiles and wearing apparel, 160; publishing, printing and reproduction of recorded media, 153). in 2015 a total of 396,500 people were in employment, including 83,500 (21á1%) in gaming and junket activities (up from 12,500 in 1999); 55,000 (13á9%), hotels, restaurants and similar activities; 54,800 (13á8%), construction; 45,000 (11á4%), wholesale and retail trade, repair of motor vehicles, motorcycles and personal and household goods; 29,800 (7á5%), real estate and business activities; 29,400 (7á4%), public administration and social security. employment in 2015 was 98á2% of the labour force; unemployment rate stood at 1á8%. in 2009 imports (c.i.f.) were valued at us$4,750á9m., of which the main products were telecommunications, sound recording and reproducing equipment; petroleum and petroleum products; and gold, silverware, jewellery and articles of precious materials. in 2009 the chief import sources (in us$1m.) were: mainland china (1,451á6); hong kong (505á4); japan (381á9). 2009 exports (f.o.b.) were valued at us$960á7m., of which the leading products were articles of apparel and clothing accessories; gold, silverware, jewellery and articles of precious materials; and petroleum oils and oils obtained from bituminous minerals. in 2009 the main export markets (in us$1m.) were: hong kong (377á5); usa (163á8); mainland china (139á9). in 2013 there were 421 km of roads. in 2013 there were 97,721 passenger cars in use (179 cars per 1,000 inhabitants), 3,723 buses and coaches, 5,114 trucks and 119,453 motorcycles. there were 19 fatalities in road accidents in 2013. a 55 km bridge (the world's longest sea bridge) linking macao, zhuhai in guangdong province in mainland china and hong kong opened in oct. 2018 following a number of delays. an international airport opened in dec. 1995. in 2009 macau international airport handled 3,643,970 passengers and 52,464 tonnes of freight (including transit cargo). in 2013 air macau flew to bangkok, beijing, changsha, chengdu, chongqing, da nang, hangzhou, hefei, kaohsiung, nanjing, nanning, ningbo, osaka, quanzhou, seoul, shanghai, shenyang, taipei, taiyuan, tokyo, wenzhou, xiamen and zhengzhou. regular services connect macao with hong kong, 65 km to the northeast. in 2011 there were 165,500 landline telephone subscriptions (equivalent to 297á9 per 1,000 inhabitants) and 1,353,200 mobile phone subscriptions (or 2,435á0 per 1,000 inhabitants). in 2012, 82á5% of households had internet access. in march 2012 there were 205,000 facebook users. there are a judicial district court, a criminal court and an administrative court with 24 magistrates in all. in 2009 there were 12,406 crimes, of which 6,462 were against property. there were 930 persons in prison in dec. 2009 . there are both public and private schools. in 2014-15 there were 95 schools and colleges. number of students in the 2014-15 academic year (with number of teachers): pre-primary, 14,552 (916); primary, 24,252 (1,722); secondary, 30,088 (2,629). in 2014-15 there were four special education schools with 624 pupils and 112 teachers. there were ten higher education institutions with student enrolment of 30,771. in 2014 there were 31 institutions offering vocational training courses, in which participants totalled 52,636. expenditure on education came to 1á8% of gdp in 2013 and 14á9% of total government spending in 2014. in 2009 there were 723 doctors, 108 dentists and 450 nurses working in primary health care, and 560 doctors, 14 dentists and 1,169 nurses working in hospitals. in 2009 there were 1,294 hospital beds; there were 2á4 doctors per 1,000 population. in 2010 there were an estimated 320,000 folk religionists and 90,000 buddhists according to the pew research center's forum on religion & public life. a further 80,000 people were religiously unaffiliated. there are also small numbers of catholics. the historic centre of macao was inscribed on the unesco world heritage list in 2005. in 2009 there were 14 daily newspapers (nine in chinese, three in portuguese and two in english) and 11 weekly newspapers (ten in chinese and one in portuguese). tourism is one of the mainstays of the economy. in 2014 there were 31á5m. tourists (of which 21á3m. were from mainland china, 6á4m. from hong kong and 1á0m. from taiwan), up from 29á3m. in 2013 and 28á1m. in 2012. visitor spending in 2014 totalled 61,749m. patacas. the government-run macao international music festival featuring a wide range of chinese and western music takes place in oct.-nov. in july 1999 president lee teng-hui repudiated taiwan's 50-year-old 'one china' policy-the pretence of a common goal of unification-arguing that taiwan and china should maintain equal 'state to state' relations. this was a rejection of beijing's view that taiwan is no more than a renegade chinese province which must be reunited with the mainland, by force if necessary. in the presidential election of 18 march 2000 chen shui-bian, leader of the democratic progressive party, was elected, together with annette lu hsiu-lien as his vice president. both supported independence although chen shui-bian made friendly gestures towards china and distanced himself from colleagues who wanted an immediate declaration of independence. following his wife's indictment on embezzlement charges in nov. 2006, president chen survived three parliamentary attempts to impeach him. he was succeeded as president in 2008 by ma ying-jeou of the nationalist party. in sept. 2009 chen shui-bian received a life sentence (later reduced to a 19-year term) after being found guilty of multiple counts of corruption. china and taiwan signed a free trade agreement in june 2010, which was considered a significant thawing of relations. nonetheless, tensions remained, particularly in relation to disputed sovereignty over several islands in the east china sea. in jan. 2012 ma ying-jeou was re-elected to the presidency but the election in jan. 2016 was won by tsai ing-wen, whose democratic progressive party won the most seats in legislative polls at the same timethe first occasion that the nationalist party has not been the largest party in government since 2004. the climate is subtropical in the north and tropical in the south. the typhoon season extends from july to sept. the average monthly temperatures of jan. and july in taipei are 59á5 f (15á3 c) and 83á3 f (28á5 c) respectively, and average annual rainfall is 84á99" (2,158á8 mm). kaohsiung's average monthly temperatures of jan. and july are 65á66 f (18á9 c) and 83á3 f (28á5 c) respectively, and average annual rainfall is 69á65" (1,769á2 mm). the roc constitution is based on the principles of nationalism, democracy and social wellbeing formulated by dr sun yat-sen, the founding father of the republic of china. the roc government is divided into three main levels: central, provincial/municipal and county/city, each of which has welldefined powers. the central government consists of the office of the president, the national assembly, which is specially elected only for constitutional amendment, and five governing branches called 'yuan', namely the executive yuan, the legislative yuan, the judicial yuan, the examination yuan and the control yuan. beginning with the elections to the seventh legislative yuan held on 12 jan. 2008 the legislative yuan has 113 members (formerly 225). of the 113 members 73 are elected under the first-past-the-post system in singlemember constituencies, 34 are filled by proportional representation in accordance with a nationwide party vote and six are reserved for aboriginal candidates. since 1996 the president has been directly elected. since 1997 a resolution on the impeachment of the president or vice president is no longer to be instituted by the control yuan but rather by the legislative yuan. the legislative yuan has the power to pass a no-confidence vote against the premier of the executive yuan, while the president of the republic has the power to dissolve the legislative yuan. the premier of the executive yuan is directly appointed by the president of the republic. in dec. 2003 a law came into effect allowing for referendums to be held. professional force-a process that was originally scheduled to start in 2011 and end in 2014 but has been delayed owing to low recruitment levels. defence expenditure in 2013 totalled us$10,316m. (us$443 per capita), representing 2á1% of gdp. the republic of china army conducts ground combat missions as well as air support and airborne special operations. it was estimated to number about 200,000 personnel in 2011, with reserves numbering 1á5m. its principal role is to defend against a possible amphibious assault from the chinese mainland by the people's liberation army. in addition there are paramilitary forces totalling 17,000 personnel. navy personnel in 2011 totalled 45,000, with 67,000 reservists. the forces consist of four submarines, four cruisers and 22 frigates. there are also 61 missile craft for patrol and coastal defence, 12 mine-laying vehicles and 290 amphibious landing craft. in 2011 the air force numbered 55,000 personnel with 90,000 reservists. there were 477 combat-capable aircraft in the same year including f-5es, f-16s and mirage 2000-5s. taiwan has made a successful transition from an agricultural economy to one based on high-tech electronics. economic growth averaged 8% per year over three decades from the 1970s, driven primarily by high value-added manufacturing and exports, especially in electronics and computers. government-owned enterprises, including banks, have been privatized. though largely escaping the impact of the 1997 asian financial crisis, the economy went into recession in 2001 with the first year of negative growth ever recorded and unemployment reaching record highs. strong export performance stimulated a recovery, with annual gdp growth above 4% from 2002-08. inflation has been consistently low and unemployment, which fell below 3% in 1999, has averaged between 4 and 6% since the turn of the century. owing to its heavy dependence on exports, taiwan suffered a severe downturn as a result of the global financial crisis in 2008. major export industries such as semiconductors and memory chips declined, unemployment reached its highest levels since 2003 and, in 2009, the economy again went into recession. a us$5á6bn. stimulus package boosted recovery and in 2010 the economy recorded its highest growth rate for nearly three decades, at 10á7%. however, growth subsequently cooled owing to lower demand from developed nations, averaging 1á9% per year between 2013 and 2016. tourism has grown in importance, with over 10á5m. visitors in 2016 constituting taiwan's highest annual number to date. an ageing population and high savings rates threaten to constrain domestic demand in the future. the unit of currency is the new taiwan dollar (twd) of 100 cents. gold reserves were 13á62m. oz in dec. 2010. there was inflation of 1á0% in 2016 and 1á1% in 2017. foreign exchange reserves were us$382á0bn. in dec. 2010. in 2006 general government revenues totalled nt$2,172,436m. and expenditures nt$2,261,958m. tax revenue accounted for 71á7% of revenues in 2006; education, science and culture accounted for 21á6% of expenditures, economic development 17á0% and general administration 15á3%. vat is 5%. taiwan sustained rapid economic growth at an annual rate of 9á2% from 1960 up to 1990. the rate slipped to 6á4% in the 1990s and 5á9% in 2000; taiwan suffered from the asian financial crisis, though less than its neighbours. in 2001 global economic sluggishness and the events of 11 sept. in the usa severely affected taiwan's economy, which contracted by 2á2%. subsequent economic recovery led to growth of 5á4% in 2006 and 6á0% in 2007. there was negative growth of 1á6% in 2009 but again the economy bounced back, and grew by 1á4% in 2016 and 2á9% in 2017. the central bank of the republic of china (taiwan), reactivated in 1961, regulates the money supply, manages foreign exchange and issues currency. the governor is yang chin-long. the bank of taiwan is the largest commercial bank and the fiscal agent of the government. there are seven domestic banks, 38 commercial banks and 36 foreign banks. there are two stock exchanges in taipei. taiwan's carbon dioxide emissions from the consumption of energy in 2011 were the equivalent of 13á4 tonnes per capita. output of electricity in 2011 was 238á6m. mwh; total installed capacity was 41,401 mw. there were six units in three nuclear power stations in 2010. crude oil production in 2010 was 91,000 bbls; natural gas, 290m. cu. metres. taiwan imports most of the oil and natural gas that it consumes. in 2010 the cultivated area was 813,126 ha., of which 410,832 ha. were paddy fields. rice production totalled 1,451,011 tonnes. livestock production was valued at nt$144,614m., accounting for 34% of taiwan's total agricultural production value. forest area, 2010: 2,102,000 ha. forest reserves: trees, 357,492,000 cu. metres; bamboo, 1,109m. poles. timber production, 19,468 cu. metres. the catch in 2015 was 987,873 tonnes, almost exclusively from sea fishing. the largest companies in taiwan by market capitalization in march 2015 were: taiwan semiconductor manufacturing (us$120á6bn.); hon hai precision industry, an electronics manufacturer (us$43á0bn.); and chunghwa telecom (us$24á7bn.). output (in tonnes) in 2010: crude steel; 20á5m.; cement, 16á3m.; cotton fabrics, 270á5m. sq. metres; integrated circuit packages, 50á5trn. units; global positioning system (gps) sets, 20á9bn. units. in 2010 the average total labour force was 11á07m., of whom 10á49m. were employed. of the employed population, 27á3% worked in manufacturing; 16á6% in wholesale and retail trade; 7á6% in construction; 6á9% in accommodation and food services; 5á9% in education; 5á2% in agriculture, forestry and fisheries. the unemployment rate was 5á2%. in 2006 there were 39,286 km of roads. in 2007, 5á7m. passenger cars, 117,100 buses and coaches, 1á0m. lorries and vans, and 13á9m. motorcycles and mopeds were in use. 1,007m. passengers and 594m. tonnes of freight were transported in 2006. there were 3,140 fatalities in road accidents in 2006. in 2010 freight traffic amounted to 14á5m. tonnes and passenger traffic to 864m. total route length was 1,741 km. there are metro systems in taipei (opened in 1996) , kaohsiung (opened in 2008) and taoyuan (opened in 2017). there are currently two international airports: taiwan taoyuan international airport at taoyuan near taipei, maritime transportation is vital to the trade-oriented economy of taiwan. in jan. 2014 there were 140 ships of 300 gt or over registered, totalling 2á63m. gt. of the 140 vessels registered, 40 were general cargo ships, 38 bulk carriers, 27 container ships, 26 oil tankers and nine passenger ships. there are six international ports: kaohsiung, keelung, taichung, hualien, anping and suao. the first three are container centres, kaohsiung handling 9á98m. 20-ft equivalent units in 2013, making it the world's 13th busiest container port in terms of number of containers handled. suao port is an auxiliary port to keelung. in jan. 2001 the first legal direct shipping links between taiwanese islands and the chinese mainland in more than 50 years were inaugurated. in 2011 there were 16,907,300 landline telephone subscribers (726á8 per 1,000 inhabitants). taiwan's biggest telecommunications firm, the stateowned chunghwa telecom, lost its fixed-line monopoly in aug. 2001. in 2011 there were 28,861,800 mobile phone subscriptions, equivalent to 1,240á7 per 1,000 persons. in 2013 there were 57á1 mobile broadband subscriptions per 100 inhabitants and 24á2 fixed broadband subscriptions per 100 inhabitants. in march 2012 there were 11á9m. facebook users. the judicial yuan is the supreme judicial organ of state. comprising 15 grand justices, since 2003 these have been nominated and, with the consent of the legislative yuan, appointed by the president of the republic. the grand justices hold meetings to interpret the constitution and unify the interpretation of laws and orders. there are three levels of judiciary: district courts and their branches deal with civil and criminal cases in the first instance; high courts and their branches deal with appeals against judgments of district courts; the supreme court reviews judgments by the lower courts. there is also the supreme administrative court, high administrative courts and a commission on the disciplinary sanctions of public functionaries. criminal cases relating to rebellion, treason and offences against friendly relations with foreign states are handled by high courts as the courts of first instance. the death penalty is still in force. there were no executions in 2017 but there was one in 2018. the population in penal institutions in april 2013 was 65,288 (280 per 100,000 of national population). since 1968 there has been compulsory education for six to 15-year-olds with free tuition. the illiteracy rate dropped from 7á1% in 1989 to 2á5% by 2006. there were 2,654 primary schools, 1,061 secondary schools and 156 vocational schools in 2008; and 102 universities, 45 colleges and 15 junior colleges. in 2005-06 there were 1,831,913 pupils with 101,682 teaching staff at elementary schools; 951,236 pupils and 48,816 teaching staff at junior high schools; 420,608 pupils and 34,112 teaching staff at senior high schools; and 331,604 students and 15,590 teaching staff at senior vocational schools. there were 1,259,490 students in universities and colleges in 2005-06 with 48,047 academic staff. in 2011 there were 40,002 physicians (one for every 510 persons), 5,570 doctors of chinese medicine, 133,336 nurses, 12,032 dentists and assistants, and 31,300 pharmacists and assistants. in 2010 there were 20,691 medical facilities serving 1,119 persons per facility; there were 158,922 beds and 68á6 beds per 10,000 persons. in 2010 cancers, heart diseases, cerebrovascular diseases, diabetes and accidents were the first five leading causes of death. a universal health insurance scheme came into force in 1995 as an extension to 13 social insurance plans that cover only 59% of taiwan's population. premium shares among the government, employer and insured are varied according to the insured statuses. by the end of 2010, 23á07m. people or 99% of the population were covered by the national health insurance programme. according to estimates by the pew research center's forum on religion & public life, 44á2% of the population in 2010 were folk religionists, 21á3% were buddhists and 5á5% christians. the remainder of the population was either religiously unaffiliated or followed other religions, including taoism. there were 23 daily newspapers in 2008 with a circulation of 4á2m. and 21 non-dailies with a circulation of 3á8m. the biggest circulation dailies are the liberty times and apple daily. in 2011 there were 6,087,000 international visitors. receipts totalled us$11,065m. the pop festival, spring scream, is held in april in kenting. xinjiang tianshan (2013), a mountainous site comprising four components covering 606,833 ha. and an important habitat for endemic and relic flora species, the grand canal (2014), a vast waterway system running from beijing to zhejiang, tusi sites (2015), the remains of tribal domains whose leaders were appointed by the central government as 'tusi', hereditary rulers of their regions from the 13th to the early 20th century, located in southwest china prime minister and president of the executive yuan: su tseng-chang vice premier: chen chi-mai. there are 12 ministries under the executive yuan: culture; economic affairs; education; finance; foreign affairs; health and welfare; interior; justice; labour; national defence; science and technology minister of culture: cheng li-chiun examples include the mongolian and tibetan affairs commission; the mainland affairs council; the fair trade commission; the public construction commission; and the financial supervisory commission. some of these are headed by ministers without portfolio (see above). other commissions, councils and agencies are headed by: council of agriculture: chen chi-chung mainland affairs council: chen ming-tong. national communications commission: chan ting-i. ocean affairs council: lee chung-wei. overseas community affairs council: wu hsin-hsing. directorate general of personnel administration: shih ning-jye. transitional justice commission (acting): yang tsui. veterans' affairs council: chiu kuo-cheng china in world history chinese politics in the age of deng xiaoping china and the global political economy china: the rise of xi jinping the cambridge encyclopaedia of china the cambridge history of china. 14 vols the politics of hong kong's reversion to china the european union and china the chinese economy under transition china this century the tragedy of liberation: a history of the chinese revolution china: a modern history china's deep reform: domestic politics in transition chinese capitalism deng xiaoping and the making of modern china the great chinese revolution 1800-1985 the politics of eu-china economic relations china's second continent: how a million migrants are building a new empire in africa china in transition: communism, capitalism and democracy sowing the seeds of democracy in china: political reform in the deng xiaoping era historical dictionary of the chinese cultural revolution how the chinese economy works the rise of modern china china: a macro history tombstone: the untold story of mao's great famine china's economy: what everyone needs to know all under heaven: a complete history of china chinese politics in the hu jintao era: new leaders, new challenges the people's republic of amnesia: tiananmen revisited chinese foreign policy in a changing world chinese economy in the 1990s the politics of china: sixty years of the people's republic of china the party: the secret world of china's communist rulers. 2010.-asia's reckoning: china, japan and the fate of us power in the pacific century china's war with japan, 1937-1945: the struggle for survival social and political development in post-reform china age of ambition: chasing fortune, truth and faith in the new china a revolutionary life at the crossroads of post-communist modernisation: russia and china in comparative perspective a history of china wealth and power: china's long march to the twenty-first century mao's road to power: revolutionary writings 1912-1949. 7 vols china goes global: the partial power the chinese century: the rising chinese economy and its impact on the global economy, the balance of power, and your job the china-pakistan axis: asia's new geopolitics the chan's great continent: china in western minds eldest son, zhou enlai and the making of modern china china in the xi jinping era india's and china's recent experience with reform and growth critical issues in contemporary china making china strong tide players: the movers and shakers of a rising china other more specialized titles are listed under territory and popula-tion; tibet; agriculture 100826. commissioner: ning jizhe information: the census and statistics department is responsible for the preparation and collation of government statistics. these statistics are published mainly in the hong kong monthly digest of statistics. the department also publishes monthly trade statistics, economic indicators and an annual review of overseas trade hong kong's transitions the politics of hong kong's reversion to china the end of hong kong: the secret diplomacy of imperial retreat the hong kong story the final years of british hong kong: the discourse of colonial withdrawal last post: the end of empire in the far east the politics of democratization in hong kong historical dictionary of hong kong and macau china: a political history of the british crown colony's transfer to chinese rule managing china's sovereignty in hong kong and taiwan macau, the imaginary city: culture and society, 1557 to the present taiwan statistical yearbook of the republic of china. annual. the republic of china yearbook. annual. taiwan statistical data book. annual. annual review of government administration the other taiwan: 1945 to the present day historical dictionary of taiwan national identity and status in international society taiwan's political re-alignment and diplomatic challenges managing china's sovereignty in hong kong and taiwan the shadow of china: political developments in taiwan since 1949. 1994 national library: national central library key: cord-300838-43spq01m authors: zhang, g.-x.; sanabria, c.; martinez, d.; zhang, w.-t.; gao, s.-s.; alemán, a.; granja, a.; páramo, c.; borges, m.; izquierdo, g. title: social and professional consequences of covid-19 lockdown in patients with multiple sclerosis from 2 very different populations date: 2020-10-29 journal: nan doi: 10.1016/j.nrleng.2020.08.007 sha: doc_id: 300838 cord_uid: 43spq01m the confinement due to the global covid-19 pandemic has almost had negative consequences in patients with multiple sclerosis (ms). objective we wanted to compare the socio-labor effect of confinement in two populations as different as spain and china, in patients with ms. method questionnaires were applied to a group of ms patients who have been reviewed in the ms unit of the vithas hospital (dinac foundation) in seville, and ms patients attended in various provinces of china during the month of april 2020, with the aim of analyzing the differences and similarities of the socio-labor effect between both populations. to carry out this analysis, a database was created and subsequently analyzed. results the chinese population has a higher proportion of younger patients and there is no difference regarding gender. most of the variables studied behaved the same way in both spanish and chinese ms patients. spanish patients had less impact (30.7%) on their socio-economic situation than chinese (44%), p < 0.05. there were no important differences in the rest of the variables between the two populations. social networks were widely used in the majority of patients in both populations. conclusions ms patients suffer in a very similar way from the consequences of the pandemic on their socio-labor situation and similarly use social networks and family support. spanish patients seem to have more economic stability, which may be due to social economic support. m étodo：se elaboraron unos cuestionarios a lo que respondieron un grupo de pacientes de em que son revisado en la unidad de em del hospital vithas(fundación dinac) en sevilla, y pacientes con em atendidos en varias provincias de china durante el mes de abril del 2020 , con el objetivo de analizar las diferencias y similitudes del efecto socio-laboral entre ambos poblaciones. para llevar a cabo este análisis, se creó una base de datos que se analizaron posteriormente. the chinese population has a higher proportion of younger patients and there is no difference regarding gender. most of the variables studied behaved the same way in both spanish and chinese ms patients. spanish patients had less impact (30.7%) on their socio-economic situation than chinese (44%), p since november 2019, covid-19 has become a public health emergency with enormous consequences across the globe. 1 in december 2019, the world health organization was informed by the healthcare authorities of wuhan, china, of a novel virus (sars-cov-2) that caused a severe respiratory syndrome (covid-19). the disease was declared a pandemic on 11 march 2020. covid-19 can present with a wide range of clinical manifestations, including fever, dry cough, and fatigue, which are frequently accompanied by pulmonary infection. sars-cov-2 is highly contagious, and most of the population is very susceptible to infection. it has been understood from the beginning of the pandemic that non-domestic animals, such as bats, and infected individuals were the main source of transmission of the disease, which is spread through respiratory droplets and direct contact with patients with sars-cov-2 infection. 2 the chinese government and the scientific community acted swiftly to identify the pathogen, to share viral genome sequencing data, and to implement measures to contain the epidemic. china established restrictions that were unprecedented in the history of public health. 3 wuhan and several other chinese cities were placed under lockdown between 23 january and 8 april 2020. during this period, the chinese population overcame all manner of difficulties and came together to fight the spread of the disease. the restrictive measures taken in china seemed effective in controlling the spread of sars-cov-2 and were praised by the world health organization. 4 however, they have had an enormous impact on the economy and the social and family lives of the populations under lockdown, and may have a considerable impact on their health. the scientific community soon began to consider the possibility that covid-19 may present with neurological manifestations, although some symptoms were non-specific (tinnitus, headache, olfactory disorders). 5 supporting this hypothesis, the virus was detected in the csf of a patient with encephalitis. 6 in spain, the epidemic started on 31 january 2020 on the island of la gomera, and the first known death due to covid-19 occurred on 13 february 2020 in valencia. in march 2020, the epidemic began spreading throughout spain. 7 for several weeks, torrejón de ardoz (madrid) became the first hotspot. due to the rapid spread of the virus, numerous decisions had to be taken by the regional governments of the areas affected. on 14 march 2020, the spanish national government declared a state of alarm for 15 days. 8 this measure limited the movement of the population, with the public confined to their homes and only permitted to leave for essential activities (grocery shopping, going to the pharmacy, medical appointments, etc). the state of alarm was extended 3 times, finally concluding on 9 may 2020. it considerably lowered the incidence of sars-cov-2 infection, with the numbers of new infections and deaths decreasing significantly. after that, spain started a lockdown de-escalation plan, approved on 28 april 2020, with adaptations for each region. the process involved 4 phases:  phase 0. elderly individuals and children could take walks, and all citizens could exercise individually in public spaces; timetables were established for these activities to prevent overcrowding.  phase 1. social gatherings were allowed outside and at home, with precautions in place (physical distancing, proper handwashing, and restricted occupant capacity of indoor and outdoor spaces). could open; social gatherings with more individuals.  phase 3 (advanced). the government gradually eased restrictions on other economic and sociocultural activities, with efforts to prevent overcrowding. these measures have had an enormous impact at all levels (education, healthcare, trade, tourism), freezing the economy and increasing unemployment rates; the economy is slowly recovering as we transition into the so-called "new normal." however, lockdown has had a patent, sustained negative impact on employment and lifestyles. 9 mass quarantine is an unprecedented event than will very likely have a considerable impact on the population's physical and psychological well-being. economic slowdown, school closure, and prolonged confinement of the entire population involves multiple stressful stimuli. 10 the pandemic has increased psychological pressure on the population, and its general and individual economic consequences persist. fear of infection and boredom due to prolonged confinement lead to anxiety and depression. lack of information, economic losses, and stigma have been identified as stressors that may have exacerbated the situation. the perceived level of stress may vary between countries, and is partly dependent on the measures taken in each region. 11 stress may therefore have considerable implications for the physical and mental health of the general population, and particularly for patients with multiple sclerosis (ms) worldwide. we compared the social and employment consequences of lockdown on patients with ms in spain and in china. we designed a questionnaire and sent it to patients with ms attended at the ms unit of hospital vithas (dinac foundation) in seville and to patients with ms from different chinese provinces in april 2020. we compared the impact of lockdown on social life and employment between the 2 populations. data were entered into a database and subsequently analysed using plots and statistical methods. we collected basic demographic data (age and sex) from our sample (fig. 1 ). the questionnaire contained closed-ended questions divided into 5 sections. the questions focused on the effects and consequences of lockdown due to the covid-19 pandemic. the questionnaire gathered the following data: a) f a m i l y r e l a t i o n s h i p s a n d s u p p o r t n e t w o r k two questions evaluated the closeness and importance of relationships. both spanish and chinese participants considered their relationships with family and friends to be a very important factor in their well-being ( fig. 2 and 3) . b ) e c o n o m y a n d e m p l o ym e n t in spain, 69.3% of patients reported little or no impact on their economic or employment status, while 30.7% reported a considerable impact. this may reflect the medium-high socioeconomic level of many patients with ms, many of whom receive economic support (benefits). these findings may be explained by 2 factors.  patients with ms in active employment have stable, solid positions.  the spanish social security system provides economic support to a considerable proportion of patients with ms due to the disability caused by the disease. in china, there was not a considerable difference in the number of patients reporting little or no impact on their economic and employment status (55.6%) and those reporting a substantial impact (44.4%) ( fig. 4 and 5) . the same trend is observed for economic status: spain showed marked differences, whereas china presented a homogeneous distribution (fig. 6 ). both populations showed similar results, with 84% of chinese patients and 79.8% of spanish patients indicating that the pandemic has had little or no impact on their physical health, suggesting that the effects of lockdown on these patients were similar to the effect on individuals without ms (fig. 7) . we observed similar results in chinese and spanish patients: both patient groups reported that lockdown had had little or no impact on their cognitive status (72% and 79.7%, respectively). we may conclude that lockdown has not significantly altered cognitive function in these patients. however, this should be evaluated in the medium and long term, since it is reasonable to expect that cognitive problems may be detected no sooner than 6 months after the end of lockdown (fig. 8 ). similar percentages of both spanish and chinese patients reported using social media a lot or quite a lot (68% and 66%, respectively). this shows that social media have become a hub for information and a means of communicating and sharing one's thoughts and mood, particularly during lockdown; this may have helped mitigate the feeling of loneliness during this period (fig. 9 ). this study has several limitations. firstly, the questionnaire was completed during lockdown in spain, but after confinement was lifted in china. we needed to collect data from the 2 populations simultaneously, but circumstances were different in each country. secondly, most spanish participants were from the south of spain, whereas the other population included individuals from every chinese region. therefore, the local severity of covid-19, the economic situation, and the healthcare resources available will differ between participants. this may have had an impact on our results. located in east asia, china is a large (9 600 000 km 2 ), highly populated country (1400 million inhabitants) with great social, cultural, and linguistic diversity between regions. the economy of eastern china is the strongest, whereas western regions are the poorest, with the centre of the country standing between the 2. chinese patients with ms are younger than spanish patients and have lower incomes. the pandemic had a greater impact on younger individuals , which explains why chinese patients reported more severe economic consequences than spanish patients. the prevalence of ms in china is low and research into the disease is limited, 12 although interest has grown in recent years. 13 diagnostic rates have increased, and chinese patients diagnosed with ms are younger. the social and economic consequences of the disease constitute the main source of concern for these patients. however, we cannot rule out the influence of such other factors as healthcare services and medical insurance. some studies suggest that students and younger individuals are more likely to present psychological sequelae after the pandemic, with age acting as a protective factor: older individuals seem to be less vulnerable to the psychological consequences of this health crisis. 14 enforced confinement dramatically decreases opportunities to socialise with relatives and friends, which may have a considerable impact on physical and mental health; as a result, most people used social media and online platforms to obtain social support and reinforce their sense of belonging. this may explain why our participants reported no impact on their relationships with family and friends. our results demonstrate the importance of family and friends in an individual's well-being, both in china and in spain. the widespread use of social media during lockdown may also be related to remote work, 15 which may explain why most participants reported no impact on their employment status. therefore, both in china and in spain, people used social media and online platforms more frequently than before the pandemic. however, usage may decrease as the de-escalation process progresses. 16 during lockdown, some hospitals have postponed treatment for some chronic neurological diseases, such as ms. although the consequences of covid-19 were initially thought to be more severe, the results from our questionnaire, both in spain and in china, suggest that the disease has had no significant impact on ms and that these patients present a similar risk to that of individuals without ms. 17 our results show that the impact of lockdown on the social and employment status of patients with ms is not significantly different from that of the general population. furthermore, there is no evidence that the incidence of covid-19 is higher among patients with ms. china and spain present considerable differences in terms of culture, education, training, and traditions, but patients have similar values, placing much emphasis on family, friendship, and the need to socialise. in both countries, social media and online platforms have partially fulfilled the basic human need for physical contact during lockdown. in conclusion, china and spain present more similarities than differences in terms of the social and employment consequences of lockdown on patients with ms. this study was partially funded by the dinac foundation. figure 1 age distribution in our sample, by country. ¿se ha visto afectada su relación con las personas que ha convivido? figure 3 responses to the question "were you able to rely on your support network during lockdown? (family, friends, neighbours, etc)," by country. figure 5 responses to the question "has the employment status of any of your relatives changed?," by country. figure 6 responses to the question "has your economic situation worsened?," by country. figure 7 responses to the question "has your physical health worsened?," by country. figure 8 responses to the question "have you noticed more severe cognitive alterations? (memory or concentration problems, difficulty concentrating)," by country. figure 9 responses to the question "have you actively used social media or online platforms during lockdown?," by country. world health organization. www.who.int date last accessed an overview of covid-19 wuhan lockdown 'unprecedented', shows commitment to contain virus: who representative in china chinese officials note serious problems in coronavirus response. the world health organization keeps praising them neurologic manifestations of hospitalized patients with coronavirus disease a first case of meningitis/ encephalitis associated with sars-coronavirus-2 anxiety and depression levels in the initial stage of the covid-19outbreal in a population sample in the northern spain the emotional impact of coronavirus 2019-ncov (new coronavirus disease) immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china the psychological impact of quarantine and how to reduce it: rapid review of the evidence multiple sclerosis in china-history an future incidencia y prevalencia de la esclerosis múltiple en china y países asiáticos covid-19: factores asociados al malestar emocional y morbilidad psíquica en población española covid-19 confinement and health risk behaviors in spain covid-19 and the consequence of isolating the elderly covid-19 and ms diseasemodifying therapies we thank the multiple sclerosis unit at hospital vithas, in seville, for the support given. this study was supported by the multiple sclerosis unit, neurology service, vithas nisa hospital, seville, spain. funding:this research did not receive any specific grant from funding agencies in the public,commercial,or not-for-profit sectors. authors declare no conflict of interests. key: cord-257749-eyhsc8q8 authors: koul, bhupendra; taak, pooja; kumar, arvind; kumar, anil; sanyal, indraneel title: genus psoralea: a review of the traditional and modern uses, phytochemistry and pharmacology date: 2019-03-25 journal: j ethnopharmacol doi: 10.1016/j.jep.2018.11.036 sha: doc_id: 257749 cord_uid: eyhsc8q8 ethnopharmacological relevance: the genus psoralea (fabaceae) harbours 105 accepted species that are extensively used by local peoples and medicinal practitioners of china, india, and other countries for treatment of tooth decay, psoriasis, leucoderma, leprosy, kidney problems, tuberculosis, indigestion, constipation and impotence. presently, pharmacological research reports are available on only few species namely bituminaria bituminosa (syn: p. bituminosa), p. canescens, p. corylifolia, p. esculenta, p. plicata and p. glandulosa which are valued for their chemical constituents and traditional uses. aim of the review: this review article provides explicit information on traditional uses, phytochemistry, and pharmacological activities of selected psoralea species. the possible trends and perspectives for future research on these plants are also discussed. materials and methods: an extensive and systematic review of the extant literature was carried out, and the data under various sections were identified using a computerized bibliographic search via the pubmed, web of science and google scholar, cab abstracts, medline, embase, inmedplan, natts as well as several websites. key findings: a total of 291 bioactive compounds from 06 species of genus psoralea have been isolated and characterized. however, p. bituminosa alone possess nearly 150 compounds. these bioactive compounds belong to different chemical classes, including flavonoids, coumarins, furanocoumarins, chalcones, quinines, terpenoids and some others due to which these species exhibit significant anti-oxidant, anti-bacterial, anti-fungal, anti-viral, anti-helmintic, anti-diabetic, diuretic, hepatoprotective, anti-cancer and anti-tumor activities. p. corylifolia l. (babchi), a chinese traditional medicinal plant has been used in traditional medicine for many decades for its healing properties against numerous skin diseases such as leprosy, psoriasis and leucoderma. conclusions: the in vitro studies and in vivo models have provided a simple bio-scientific justification for various ethnopharmacological uses of psoralea species. from the toxicological perspective, the root, leaf, and seed extracts and their preparations have been proven to be safe when consumed in the recommended doses. but, meticulous studies on the pharmaceutical standardization, mode of action of the active constituents, and sustainable conservation of psoralea species are needed, to meet the growing demands of the pharmaceutical industries, and to fully exploit their preventive and therapeutic potentials. the medicinal herbs have been a major source of biodynamic compounds of therapeutic value in ayurveda, unani, homeopathy, traditional chinese medicine (tcm) and other traditional system of medicines. several dreadful diseases including cancer, aids, kidney psoralea species have been used in folklore and indigenous system of medicine for a long time. several psoralea products are successfully commercialized and available in the markets (supplemental information 2, table s2 ). the roots of p. argophylla pursh (silver leaf scurf pea, silver leaf indian breadroot) are eaten raw or cooked (tanaka, 1976; yanovsky, 1936) . the dried roots may be ground into a powder and used an ingredient of soups and bread (yanovsky, 1936) . a tea prepared from the leaf and stem powder possess anti-pyretic properties (weiner, 1990) . a decoction of the plant is used as a wash for wounds (moerman, 1998) . the root extract is used as a remedy for chronic constipation (moerman, 1998) . bituminaria bituminosa (l.) c.h.stirt. (arabian pea or pitch trefoil) is used as a forage crop. psoralea canescens michx. (buckroot) roots are eaten raw or cooked (hedrick, 1972; tanaka, 1976; yanovsky, 1936) . the powdered roots are used in preparation of soups or breads (yanovsky, 1936) . as the plant has analgesic properties, a poultice prepared from roots is applied on painful areas of the body (moerman, 1998 ). an infusion of the roots and its steam is used for the treatment of cold, cough, headache and sore throat (moerman, 1998) . psoralea castorea s. watson (beaver indian breadroot) roots are also eaten raw or cooked and the root-powder can be used in soups or breads (hedrick, 1972; tanaka, 1976; uphof, 1968; yanovsky, 1936) . psoralea corylifolia l. (bu gu zhi) is revered in chinese traditional medicine as a tonic to improve general vitality. the name 'buguzhi' (fructus psoraleae) actually comprises of three chinese words: 'bu' means 'to invigorate'; 'gu' means 'bone' and the third word 'zhi' means 'fat'. the chinese name of the herb suggests the function of the herb to provide fat for the invigorating bones. one of the most important features of p. corylifolia is that each and every part of the plant is beneficial which includes roots, stems, leaves, seeds and even blooms (hodges, 2015) . since p. corylifolia is a leprosy destroyer it is revered to as "kushtanashini" in sanskrit. moreove, it is an ancient remedy for leucoderma among the traditional system of medicines in india and china and also among the people in the west (chopra and chopra, 1958 ). in unani system, the plant has been effective against fever, skin diseases and internal ulcers (chopra and chatterjee, 1927) . it is also found to be an effective antihelmintic and sedative (nadkarni, 1976) . for treating leprosy and leucoderma the leaves are consumed as powder and also apllied on skin in the form of paste (anon, 1998; nadkarni, 1976; panda, 2000) . however, some precaution should be taken when applying the herbalpaste externally, since it can cause a skin-allergic reaction when exposed to sunlight (anderson and voorhees, 1980) . the leaves are also used to treat dermatitis, inflammation, mucomembranous disorders, oedematous conditions of the skin and to alleviate diarrhea (rajpal, 2005; sharma et al., 2001; krishnamurthi et al., 1969) . the plant possesses blood purifying properties and therefore used to treat boils, itching eruptions or red papules, ringworm-infection, extensive eczema, rough and discolored dermatosis with fissures, and scabies (khare, 2004) . the essential oil from plant is reported to have a strong effect on streptococcal infection of the skin (rajpal, 2005) . moreover, it is known to improve the color of skin, hair and nails. seeds are sweet, bitter, acrid, and astringent. the seeds are anti-pyretic and also possess alexiteric properties and therefore are given in scorpion-sting or snake bite and in bilious disorders (agharkar, 1991; kapoor and boca, 2001; nadkarni, 1976; panda, 2000) . both the seeds and fruits contain psoralen (furocoumarin), known to regulate pigmentation (rashid and agarwala, 1965; sebastian, 2006) . p. corylifolia seed extracts have been reported to possess anti-hyperglycemic, antidepressant, anti-tumor, anti-bacterial and anti-oxidant property (steven and russell, 2007; wang et al., 1990) . seed extract and powder are beneficial as anti-helmintic, laxative, diuretic, and for healing wounds (rajpal, 2005) . they are used as stomachic, diaphoretic and aphrodisiac . the major components psoralen (92) and isopsoralen (2) are known to possess anti-bacterial, anti-viral and antitumor properties (liu et al., 2004) . therefore, the seeds are used for curing various disorders such as cough, asthma, nephritis, alopecia areata, menstruation, uterine disorders and haemorrhages (qiao et al., 2007; ruan et al., 2007) . the crude extracts of seeds are used in the treatment of febrile diseases, impotence, spermatorrhea, premature ejaculation, lower back pains, incontinence, enuresis, pollakiuria, and cold symptoms in the waist and knees (chopra et al., 1956; lin et al., 2007; zhao et al., 2005a zhao et al., , 2005b . it also possesses coronary vasodilatory activity . the seeds act as deobstruent and heal ulcers, heart troubles, cure blood disorders and elephantiasis (anonymous, 1969; drury, 1873) . the extracts also possess cytotoxic, anti-mutagenic and anti-repellant properties . the seeds are also used to make perfumed oil (gupta et al., 1979; nadkarni, 1976) . in japan, the ethanol extract of the seeds has been used as a preservative for pickles and some processed foods (qiao et al., 2007) . the seed cake is rich in nitrogen and minerals and is used as cattle feed or manure . the fruits of the p. corylifolia also have valuable medicinal uses. the seeds or the seed with the seed pod, possess high aphrodisiac properties allo-aromadendrene (1) u (azzouzi et al., 2014a (azzouzi et al., , 2014b bertoli et al., 2004; innocenti et al., 1998; khatune et al., 2004; pazos-navarro et al., 2011; pistelli et al., 2003; tava et al., 2007) [ reference(s) psoralea canescensmichx. angelicin (isopsoralen) (2) n (innocenti et al., 1997) [ and bhakuni, 2010; wang et al., 2014; won et al., 2015; wu et al., 2007 a, b; wu et al., 2008; xiao et al., 2012; xu et al., 2012; yadava and verma, 2003; yadava and verma, 2005; yang et al., 2006; yang et al., 2009; yin et al., 2004; yu et al., 2005; zhang et al., 2016; zhao et al., 2005a) bakuchicin ( xanthoangelol ( (christensen et al., 2008; kaye and moodie, 1978; perara, reese, 2002; stahnke et al., 2008) [ leaf, flower, seed angelicin (isopsoralen) (2) n (arfaoui et al., 2013; cheikh et al., 2015; el-abgy et al., 2012; hamed et al., 1997 hamed et al., , 1999 khatune et al., 2004; menon et al., 1999; rasool et al., 1989 rasool et al., , 1990 1991; youssef et al., 2013) [ (backhouse et al., 2001; labbe et al., 1996; li et al., 2016; madrid et al., 2012 madrid et al., , 2013 madrid et al., , 2015a madrid et al., , 2015b bakuchiol ( psoralen ( and are used as a tonic to strengthen the genital organs (ven, 1987) . the fruits are bitter in taste, can prevent vomiting, cure difficulty in micturition, cure piles, bronchitis and anaemia and are known to improve complexion (joshi, 2000) . moreover, fruit extract inhibits the growth of mycobacterium tuberculosis (yeung, 1985) . the roots and seeds of p. corylifolia are used for preventing tooth decay (duke, 2009 ). they also promote bone calcification, and hence are beneficial for treating bone fractures and osteoporosis (joshi, 2000; krishnamurthi et al., 1969; rabie, 2010a, 2010b) . psoralea esculenta pursh. (breadroot, large indian breadroot) roots are starchy (70% starch), glutinous (9% protein) with a sweetish turniplike taste (5% sugars) and are eaten raw or cooked (hedrick, 1972; saunders, 2011; tanaka, 1976; uphof, 1968; yanovsky, 1936) . the dried roots are pulverized and used with cereals in making cakes and porridge (facciola, 1983) . a poultice prepared from the crushed roots is applied to sprains and fractures. an infusion of the dried roots is used in the treatment of sore throats, gastro-enteritis and chest problems. the roots are chewed by children as a treatment for bowel complaints (moerman, 1998) . psoralea glandulosa l. is cultivated in chile for its leaves and young shoots, which are used to make a refreshing cold drink. the leaves are anti-helmintic. psoralea hypogaea torr. & a. gray (small indian breadroot) roots are eaten raw or cooked (elias and dykeman, 2009; harrington, 1974; hedrick, 1972; moerman, 1998; yanovsky, 1936) . the roots are rich in starch and can be ground into a powder and used in soups or with cereals for making bread (yanovsky, 1936) . the roots were used an important source of food for the native north american indians (diggs et al., 1999) . psoralea macrostachya dc. (large leather root) roots are eaten raw or cooked and may be dried for winter use. moreover, the plant has been used in the treatment of ulcers and sores (moerman, 1998) . a strong fibre is obtained from the inner bark of the stem (saunders, 2011; usher, 1974) . a fibre is also obtained from the roots, which is used to make ropes and bags (moerman, 1998; uphof, 1968) . roots are aromatic and the perfume persists for several months (saunders, 2011) . a yellow dye is also obtained from the roots (moerman, 1998) . psoralea orbicularis lindl. (roundleaf leather root) leaves are cooked and eaten (moerman, 1998; tanaka, 1976; yanovsky, 1936) . a decoction of the root is used to purify blood and to treat prexia (moerman, 1998) . the plant is a good soil stabilizer (huxley, 1992) . psoralea pedunculata (mill.) vail (sampson's snakeroot) is used as a bitter tonic. psoralea species have been investigated since 1890s (dymock et al., 1893) . leaf, rhizome, root, seeds, fruit and resinous extracts of psoralea species have been subjected to hplc and hptlc followed by pharmacological analyses (pandey et al., 2012; shailajan et al., 2012; uikey et al., 2010; won et al., 2015; yin et al., 2015; zhao et al., 2005a) . detailed and extensive chemical investigation of six psoralea species viz: p. bituminosa l. (syn: bituminaria bituminosa), p. canescens michx., p. corylifolia l., p. esculenta pursh, p. plicata delile and p. glandulosa l. led to the characterization of a large number of bioactive constituents. review of literature reveals the presence of altogether 291 chemical constituents including volatile compounds in the aforementioned species (table 1) . these chemical compounds have been categorized into coumarins, furanocoumarins, flavonoids (polyphenols), isoflavones, meroterpenes, chalcones, phenols, phenolic cinnamates, phenylpropene, sterols, terpenes, tocopherols, benzofurans, sesquiterpenes, acids, fatty acids, alkyl aldehydes, alcohols and esters (agarwal et al., 2006; bertoli et al., 2004; hsu et al., 2001; qiao et al., 2006; ruan et al., 2007; tava et al., 2007; yin et al., 2006 yin et al., , 2007 yu et al., 2005) . the chemical structures of 1-291 compounds are shown in the supplemental information (supplemental information 3, fig. s1 ). their chemical names, chemical class and the corresponding plant sources are compiled in table 1 . the structures of those bioactive compounds which are representative of the genus and with reported pharmacological activities are presented in the main text (fig. 2) . recently, an isoflavone synthase (ifs) gene has been isolated and functionally characterized from p. corylifolia (misra et al., 2010) . the active principle found in p. corylifolia is bakuchiol (155) and psoralen (92) (dev, 1999; wang et al., 2009) . psoralen is linear in structure and may be called as a derivative of umbelliferone (jois et al., 1933; rangari and agrawal, 1992) . the production of psoralen enhances when the plant is exposed low dose of gamma radiation (jan et al., 2011) . isopsoralen (2) is a structural isomer of psoralen (92), and it was found to be identical to angelicin (2) (jois et al., 1933; jois and manjunath, 1934; seshadri and venkata rao, 1937) . angelicin (isopsoralen) (2) is a photosensitizing agent and used for determination of dna and rna structures in cells and microorganisms (kittler et al., 1980) . angelicin (2) and its derivatives occur in a number of plants belonging to the family umbelliferae. the active compound, bakuchiol (155) is a monoterpene phenol, has been obtained in a pure state and named after sanskrit name of the plant (mehta et al., 1973) and possess the potent anti-bacterial property (satyavati et al., 1987) . the seed contains volatile oils, monoterpenes, flavones, coumarins, stigmasteroids, resins, lipid compounds and phenols. the volatile oils include limonene (64), linalool (65), β-caryophyllene (126), geranyl acetate (199) and terpinen-4-ol (97), coumarin derivatives include psoralen (92), isopsoralen (2), isopsoralidin (209), corylidin (179) (211). lipids include triglycerides, diglycerides and monoglycerides. monoterpene phenol includes bakuchiol (155). others include free fatty acids, stigmasterol (232), triacontane (233), daucosterol (192), glucose and saponin. the fatty acids obtained from oil were found to be primarily palmitic acid (86) and linoleic acid (66) together with small fraction of linolenic acid (67). the pharmacologically active oil is identical with the unsaponifiable oil isolated by earlier workers (gaind et al., 1965; gupta et al., 1962) . more that 188 chemical constituents (belonging to furanocoumarins, coumestrol group, chalcones and flavones) have been reported from the seeds chakrovarti et al., 1948; chen et al., 2005; satyavati et al., 1987; tsai et al., 1996) . psoralea species have received tremendous attention because of their bioactive principles possessing remarkable pharmaceutical properties ( fig. 3 ; supplemental information 4, table s3 ). several protocols have been followed to analyse the anti-oxidant property of seeds and leaf extracts of p. bituminosa, p. glandulosa, p. corylifolia, p. plicata, p. esculenta and p. glandulosa. the phenolic compounds obtained from different extracts were found to protect the biological membranes from oxidative stresses (haraguchi et al., 2002; guo et al., 2005; borchardt et al., 2008; kim et al., 2013; madrid et al., 2013; huang et al., 2014) . the antioxidant activity of fruit extracts of psoralea plicata was evaluated by dpph assay. the study indicated that the methanol extract shows an anti-oxidant activity (288.32 micromol trolox equivalent/100 g dry material) which is slightly higher as compare to aqueous extract (258,65μmol trolox equivalent/100 g dry material) (cheikh et al., 2015) . in a study on p. corylifolia, several bioactive compounds such as bakuchiol (155), psoralen (92), isopsoralen (2), corylin (187), corylifolin (185) and psoralidin (228) were screened for their anti-oxidant potential. their antioxidant activities were investigated individually and compared with butylated hydroxytoluene (bht) and α-tocopherol by the oxidative stability instrument (osi) at 100ºc among these compounds psoralidin exhibited highest anti-oxidant activity (5.23) than that of standard compounds (psoralidin > bht > α-tocopherol > bakuchiol > corylifolin > corylin > isopsoralen~psoralen) (jiangning et al., 2005) . however, antioxidant activity alone cannot be of any pharmacological significance. it is accompanied by other specific pharmacological activities to claim any therapeutic benefit. there are several reports on the anti-bacterial activitiy of p. bituminosa and p. corylifolia. the ethanol and methanol extracts obtained from the aerial parts of p. bituminosa contain flavones and isoflavones, while the seed extracts of p. corylifolia contain psoralidin (228), bakuchicin (154), psoralen (92) and angelicin (2), which have shown significant anti-bacterial activities. techniques such as disc-diffusion method, uv (ultraviolet), h nmr (proton nuclear magnetic resonance), c nmr (carbon nuclear magnetic resonance), anti-bacterial assay, broth-dilution method, column chromatography, hplc (high performance liquid chromatography) and tlc (thin layer chromatography) were used to quantitate and analyse the anti-bacterial property of these natural compounds (azzouzi et al., 2014a (azzouzi et al., , 2014b bhawna et al., 2013; cui et al., 2015) . bakuchiol obtained from seed extract of p. corylifolia has been reported to inhibit the growth of staphylococcus mutans and actinomycess viscosus and hence possess strong anti-bacterial activity and mic value of bakuchiol was found to be 9.76-19.5 µg/ml (khushboo et al., 2010; rao et al., 2011) . in a study, the compounds psoralidin (228), bakuchicin (154), psoralen (92) and angelicin (2) obtained from different extracts of the plant were found to show antibacterial activity against different gram-positive and gram-negative bacteria. among them, psoralidin (228) showed highest anti-bacterial activity against shigella sonnei and s. flexneri as depicted by disc diffusion assay . 6.3. anti-fungal activity p. corylifolia and p. glandulosa are known to possess significant antifungal activity. aqueous and methanol extract of seeds and petroleum ether extract of the aerial parts p. corylifolia have been tested against various seed borne fungi such as (alternaria, cladosporium, dreschslera and rhizophus spp.) of maize. in aqueous extract, maximum inhibition (95.4% inhibition at 50% concentration) was observed against a. alternata followed by c. lunata (86.0%), rhizopus sp. (82.3%), d. halodes (68.0%) and c. cladosporioides (57.7%). among the solvents used for the preparation of extracts, maximum inhibition was observed with petroleum ether extract and moderate activity was observed with methanol extract (kiran et al., 2011) . in an anti-fungal assay, the essential oil extracted from p. corylifolia, was studied against three dermatophytic fungi microsporum canis, trichophyton rubrum and trichophyton mentagrophytes. the zone of inhibition (by disc-diffusion assay) for m. canis, t. rubrum and t. mentagrophytes was found to be 20, 35 and 37 mm respectively, while the minimum inhibitory concentration was reported to be 1.4, 0.4 and 0.5 μl/ml, respectively (sharma and tiwari, 2012) . in another study, methanol extract of p. corylifolia seeds was found to be most effective against tomato late blight (phytophthora infestans) and wheat leaf rust (puccinia recondite) (shim et al., 2009) . the crude extract of p. corylifolia exhibited significant antifungal activity against candida albicans . in a study by borate et al. (2014) , methanol extract of p. corylifolia seeds was reported to exhibit a maximum zone of inhibition against c. albicans the crude ethanol extract of the seeds of p. corylifolia exhibited significant anti-viral activity against the severe acute respiratory syndrome corona virus (sars-cov) papain-like protease (plpro). the ic50 value for the same was 15 μg/ml. sars-cov-plpro is the enzyme that is crucial for replication of sars virus . in a recent study, it was reported that bakuchiol (155) present in seeds of p. corylifolia inhibited the influenza a viral infection and growth and activated the nuclear factor erythroid 2-related factor (nrf2) pathway. this pathway is responsible for cellular defense against electrophilic or oxidative stress (shoji et al., 2015) . bakuchiol (155) extracted (petroleum ether extract, dichloromethane extract, and methanol extract) from the aerial parts of p. glandulosa inhibits degranulation in human neutrophils and decreases the cell migration, eicosanoid levels and myeloperoxidase activity in mice thus, confirming its anti-inflammatory potential (ferrándiz et al., 1996; backhouse et al., 2001) . in another study, bakuchiol (155) from p. corylifolia was reported to inhibit the expression of inducible nitric oxide synthase (nos) gene through the inactivation of nuclear transcription factor-b in raw 264.7 macrophages (pae et al., 2001) . the bioactive compounds obtained from leaves, fruits and seeds of p. corylifolia inhibit the functioning of tumor necrosis factor-alpha (tnf-α) and exhibt anti-inflammatory activity (mueller et al., 2010) . the production of inflammatory mediators such as, reactive oxygen species (ros), reactive nitrogen species (rns), and cytokines such as il-1β, il-6 and tnf-α (tumor necrosis factor) in pma (phorbol 12-myristate 13acetate)/lps (lipopolysaccharide), in ifn-stimulated murine peritoneal macrophage cell line (raw 264.7) was inhibited by neobavaisoflavone (212) (szliszka et al., 2011a) . cytotoxicity of neobavaisoflavone (212) was tested by using ldh assay (lactate dehydrogenase assay). psoralidin (228) suppresses the activity of pro-inflammatory cytokines which regulate pulmonary inflammation in human lung-fibroblasts and in mice, by ionizing radiation, has been reported (yang et al., 2011) . in a recent study the activity of il-6-induced stat3 (signal transducer and activator of transcription 3) was found to be inhibited by bavachin (159), bakuchiol, bavachinin (160), corylin (187), corylifol a (180), neobavaisoflavone (212), and isobavachalcone (203). hence, these bioactive compounds hold promise to cure inflammatory diseases . in a study by newton et al. (2002) , forty-three plant species were screened for their anti-mycobacterial activities. among them, bakuchiol (155) extracted from p. corylifolia hexane seed-extract exhibited significant anti-bacterial activity (mic = 31.25 g/ml) against mycobacterium aurum and m. smegmatis thus, confirming its potential for treatment of leprosy. however, these studies further require in vitro and in vivo analyses for their large-scale utilization . in a study by dwarampudi et al. (2012) , the ethanolic seed extract of p. corylifolia showed an ic50 value of 255 μg/ml and a considerable anti-psoriatic activity (75.87%), using the mouse tail model. the seed extract converted parakeratosis stage (keratinization) to orthokeratosis (formation of anuclear keratin layer) stage of the cell, thus confirming its anti-psoriatic potential (dwarampudi et al., 2012) . in a recent report, different micro-emulsions containing single and both commiphora mukul powder and babchi-oil from p. corylifolia were used to assess the anti-psoriatic efficacy on diseased rat paw. the synergistic effect of both the natural products gave better results, hence this herbal combination could be a cheap and effective source of anti-psoriatic agent (marwaha, 2013) . in a study involving human subjects, p. corylifolia hexane-seeds extract was prepared into a cream using stearic acid followed by an open clinical trial on thirty patients suffering from eczema, for a period of one month. the placebo preparation, for this experiment contained all the ingredients except the seed extract. the parameters studied were length of the lesion, exudation rate and rate of itching. the symptoms score reduced after two weeks of cream application. finally, the length of the lesion reduced from 6.367 ± 1.098-0.333 ± .279, exudation rate reduced from 1.333 ± .994-0.165 ± .087 and the rate of itching reduced from 2.567 ± .504-0.165 ± .132. this study concluded that p. corylifolia seed extracts could be used effectively used for the treatment of eczema (gidwani et al., 2010a). the compounds obtained from the p. corylifolia extract have played an influential role for the treatment of vitiligo. the furocoumarins, psoralen (92) and isopsoralen (2) present in psoralea species assists the skin to produce new pigment. they initiate the transformation of dihydroxyphenylalanine (dopa) to melanin when exposed to sunlight and are therefore being used for treating vitiligo, psoriasis and leprosy (fitzpatrick and pathak, 1959; hussain et al., 2016; song et al., 2004; yin et al., 2004) . psoralen (92) alone can effectively treat psoriasis and alopecia areata (ji and xu, 1995; wang and wang, 2007) . in a report by abu tahir et al. (2010), human melanocytes were used to test the antivitiligo activity of the oleo-resinous extracts of the seeds. the seed extract acted as an effective anti-vitiligo agent by restoring the melanocytes of the affected area (abu tahir et al., 2010). ethanol seed extract of p. corylifolia when administrated orally to streptozotocin-nicotinamide (stz) induced diabetic rats lead to an increase in glycogen content of liver and insulin level in plasma with a decrease in plasma cholesterol and blood glucose level (kamboj et al., 2011) . in a report by bera et al. (2013) , the aqueous seed extract of p. corylifolia was found to regulate the functioning of insulin sensitive enzyme activities in wistar strain male albino rats. the seed extract tends to increase the activity of liver hexokinase, glucose-6-phosphate and decrease the level of glucose-6-phosphatase (bera et al., 2013) . the furanocoumarins psoralen (92) and isopsoralen (2) obtained from the seed extract of p. corylifolia have showed anti-depressant activity in mice by hindering the mao (monoamine oxidase) activity, hypothalamic-pituitary-adrenal axis action and oxidative stress . another compound, psoralidin (228) inhibits the transcription of crf (corticotrophin releasing factor) gene, which is responsible for stress response . the anti-depressant activity of psoralidin (228) was evaluated by applying the forced swimming test on rats . psoralen was reported to successfully change the level of 5-hydroxyindoleacetic acid (5-hiaa) and serotonin (5-ht) in hippocampus and frontal cortex of mice . bakuchiol (155) decreases the immobilization time in behavioral despair mouse and plasma epinephrine and norepinephrine (neurotransmitter) levels in bovine adrenal medullary cells hence, exhibits anti-depressant activity . these results depict the anti-depressant activity of psoralen and bakuchiol. psoralea species possess unique bioactive compounds with anticancer properties. p. corylifolia leaves contain remarkably high concentrations (more than 2 g per kg dry weight) of genistein (198), the anti-cancer metabolite. bioactivity of two furocoumarins psoralen (92) and isopsoralen (2) was determined for their cytotoxicity on carcinoma lines kb, kbv200 (vincristine resistance subline of kb), human erythroleukemia cell k562 and k562/adm (doxorubicin resistance subline of k562). both the compounds induced apoptosis in these cells thus, confirming their anti-cancer potential. the ic50 values of psoralen were 88.1, 86.6, 24.4 and 62.6, which of isopsoralen were 61.9, 49.4, 49.6 and 72.0, respectively (wang et al., 2011) . psolaren (92) when subjected to human hepatocarcinoma cells, showed its inhibitory activity by inducing the mechanism of apoptosis. psoralen (92) was able to inhibit the growth of smmc-7721 cells in a dose-and timedependent manner and had a strong proapoptotic effect on these cells (jiang and xiong, 2014; khan et al., 2015) . the bioactive compounds 7,2 ' ,4 ' -trihydroxy-3-arylcoumarin (263), psoracoumestan (224) and corylifol c (182) from p. corylifolia showed strong anti-cancer potential by inhibiting the enzyme mapk/erk kinase phosphorylation and inducing aptotic cell death . in a study, psoralidin (228) showed its activity in mcf-7 cancer cells (isolated from human breast) by induction of ps2 gene activity, with an ec50 value of ere-reporter gene transcription activity of 1.85 μm . the seed extract of p. corylifolia induced apoptosis in the human breast cancer (mcf-7) cells followed by mitochondrial cell death (rajan et al., 2014) . in another study, psoralidin (228) was reported to generate reactive oxygen species and also inhibited a549 cell proliferation. the method adopted was mtt assay and the ic50 values obtained after 24-, 48-and 72-h treatment were 19.2, 15.4, and 11.8 μm, respectively . psoralidin (228) and neobavaisoflavone (212) in combination with trail (tumor necrosis factor-related apoptosis-inducing ligand) have showed their anti-cancer property by inducing apoptosis in lncap (human adinocarcinoma prostate cancer cells) (szliszka et al., 2011a) . in another report, psoralidin (228) in combination with trail influenced apoptosis in hela cells by increasing the expression of death receptor (trail-r2) (bronikowska et al., 2012) . in a similar report, psoralidin (228) compound obtained from different extracts of p. corylifolia exhibited the anti-cancer activitiy against human lung cancer (a549) cells. psoralidin dramatically decreased the cell viabilities in dose and time-dependent manner . psoralea fructus suppressed the proliferation of human colorectal cancer cell lines, such as lovo (ic50: 23.3 ± 1.9 μg/ml), sw480 (ic50: 37.9 ± 1.6 μg/ml), ht-29 (ic50 value: 40.7 ± 1.5 μg/ml), and hct116 (ic50: 45.3 ± 1.2 μg/ml) by decreasing the protein expression of cyclin d1 and cdk4. succeeding experiments with many kinase inhibitors revealed that p. fructus-mediated degradation of cyclin d1 and cdk4 is dependent on gsk3β and/or erk1/2 (park et al., 2016) . psoralen (92), isoporalen (2) and bakuchiol (155) identified in p. corylifolia extracts (chloroform and ethanol) have shown their cytotoxic property against hep-2 cell line (whelan and ryan, 2003) , bgc-823 cancer cell (guo et al., 2003) and cultured human cancer cells (sk-ov-3, a549, xf498 and sk-mel-2hct15) (ryu et al., 1992) . bakuchiol (155) is one of the active ingredients of the dried ripe fruit of p. corylifolia. in a study by miao et al., 2013, bakuchiol (155) suppressed the testosterone induced cell proliferation and gene expression in androgen-dependent prostate cancer (pca) cell line (lncap). the ic50 of bakuchiol (155) to androgen receptor was 8.87 × 10 4 , which was similar to the standard flutamide (10.00 × 10 4 ). bakuchiol (155) has also showed a strong anti-cancer action against human lung adenocarcinoma cell line a549 and showed better results than its analogue resveratrol. ic50 of bakuchiol (155) at 72 h was 9.58 ± 1.12 μmol/l, much lower than that of resveratrol (33.02 ± 2.35 μmol/l). compared to resveratrol, bakuchiol (155) triggered the process of apoptosis to a higher level. it was also observed that oxygen species mediated apoptosis contributes to the cytotoxic properties of bakuchiol (155) and can therefore be used against non-small-cell lung cancer . invitro experiments with a2058 melanoma cells using p. glandulosa resinous exudates revealed that it can inhibit the growth of cancer cells after 48 h of treatment. these experiments confirmed the anti-cancer potential of p. glandulosa which can be attributed to the presence of bakuchiol, 3-hydroxy-bakuchiol and 12-hydroxy-isobakuchiol (madrid et al., 2015b) . ethanol, methanol, chloroform and aqueous seed extracts of p. corylifolia were tested against the tumor cells of mice and were found to stimulate the antibody complement-mediated cytotoxicity during tumor development (latha et al., 2000) . anti-tumor property of bakuchiol (155) was also compared with resveratrol and it was observed that bakuchiol was more efficient in inhibiting the growth of tumor cells, when tested against human lung adeno-carcinoma a549 cell line . in a similar study on tumor cells of murine origin, radioiodinated bakuchiol showed greater cytotoxic effect than bakuchiol (bapat et al., 2005) . bakuchiol (155) also induced erβ expression and suppressed the erα expression in mcf-7 cells (breast cancer cells). it also caused the arrest of s-phase in mcf-7 and mda-mb 231 cells and showed a stronger anti-proliferative effect than resveratrol. additionally, bakuchiol (155) caused the apoptotic cell induction and interrupted membrane potential in mitochondria of mcf-7 cells via an intrinsic apoptotic pathway. the same compound when tested for in vivo anti-breast cancer effect in zebrafish xenografts showed a significant reduction in mcf-7 cell mass (li et al., 2017) . similarly, two more compounds from the same species identified as isobavachalcone (203) and bavachinin (160) attenuate aβ42-induced cell toxicity. the investigation was carried out on yeast two-hybrid system. during this study, eight compounds were tested, and among them ibc (3 μm) and bcn (30 μm) proved to be active at non-toxic concentrations . this is a significant property which is associated with the p. corylifolia fruit extract, the osteoblastic proliferation in cultured umr106 (osteosarcoma) cell line and enhancing the formation of bones . in several studies, p. corylifolia extracts showed significant inhibitory effect on osteoclasts (yang et al., 2007; zhang et al., 1995) . corylin (187) and bavachin/coryfilolin (159) were reported to promote the proliferation of osteoblasts and inhibit bone resorption . bakuchiol (155) compound in the extracts showed inhibitory effect on osteoporosis, mediated through estrogen deficiency (lim et al., 2009; tsai et al., 2007) . in a report by tsai et al. (2007) , it was observed that p. corylifolia extract lead to a decrease in calcium and osteocalcin through urinary excretion in ovariectomized (ovx) rat model and thus, maintained the bone density (tsai et al., 2007) . in a similar report, ethanolic bakuchiol present in seed extract of p. corylifolia reduced the bone loss in ovx rat model thus, showed promising anti-osteoporosis activity (lim et al., 2009 ). the ethanolic fruit extract of p. corylifolia showed estrogenic activity, which was demonstrated by transcription of lacz in recombinant yeast system . in another report by zhao et al. (2007) , proliferation rates of mcf-7 cells increased significantly when treated with the p. corylifolia extract (zhao et al., 2007) . in a study by lim et al. (2011) bakuchiol (155) showed a higher estrogenic activity and estrogen receptor (er) binding affinity than genistein, both in vitro and in vivo (lim et al., 2009 . among the seven bioactive components of p. corylifolia extract exhibited isobavachalcone (203), bavachin (159), corylifol a (180), neobavaisoflavone (212), bakuchiol (155), and two coumarins psoralen (92) and isopsoralen (2) compounds selectively activated er-α while the other compounds activated both er-α and er-β (xin et al., 2010) . park et al. (2012) , reported that bavachin (159) could bind and activate the estrogen receptor . in addition to it, psoralidin (228) was reported as aganist for both er-α and er-β . in a similar study by xin et al. (2010) , seed extract of p. corylifolia containing psoralen (92) and isopsoralen (2) enhanced the mcf7 cell prolification by enhancing the activity of erα (estrogen receptors), hence showed significant estrogenic activity. 6.14. hepatoprotective activity p. corylifolia is revered for its hepatoprotective potential (dai et al., 2009; ye et al., 1999) . three compounds psoralen (92), bakuchicin (153) and bakuchiol (155) (ec50 values of 1.0, 47.0, and 50.0 μg/ml, respectively) have shown hepatoprotective activity towards the liver cells (hep g2 cells) in which the cytotoxicity was induced by tacrine (cholinesterase inhibitor) . in a similar study, bakuchiol (155) reduced the toxic activity of carbon tetrachloride (ccl 4 ), d-galactosamine (d-gain), and tert-butylhydroperoxide (tbh) in primary rat hepatocytes (park et al., 2005) . the activity of hepatic stellate cells (involved in liver fibrosis) was reduced by bakuchiol in liver injured rats thus, confirming its hepatoprotective activity (park et al., 2007) . in a recent report, bakuchiol (155) obtained from the seed extract of the p. corylifolia exhibited hepatoprotective activity by inhibiting the production of reactive oxygen species (ros) and malfunctioning of the mitochondria in human diploid fibroblast (hdf) (seo et al., 2013) . in a study, the cultured rat pheochromocytoma (pc12) cells pretreated with p. corylifolia l. seed extract significantly attenuated 3-np induced cell death, reduced atp levels, and lowered the mitochondrial membrane potential. thus, p. corylifolia seed extract has the potential to treat neurodegenerative diseases (im et al., 2014) . in another study, it was revealed that isobavachalcone, a flavonoid from p. corylifolia, has the ability to ameliorate the neuronal injury in brain diseases related to inflammation, and this was accomplished through inhibition of the expression of lipopolysaccharide induced intercellular adhesion molecule-1 and leukocyte adhesion to brain endothelial cell, by blocking toll-like receptor 4 signaling . 6.16. immunomodulatory activity p. corylifolia extract effectively increased the proliferation rate of diploid fibroblasts (in mice) and increased the ability of non-specific immunity (wang et al., 1990) . in the study, a mixture of fruit extracts of p. corylifolia and brucea javanica improved the immunological regulation in rats that were infected with pneumocystis carinii pneumonia. as a result of the treatment, gain in body weight, decline in the number of cysts produced in the lungs and the level of t cells (cd4 + and cd8 + ) and tnf-alpha in the serum also increased considerably in the immunosuppressed rats (qin et al., 2006) . in another study, the ethanol seed-extracts of p. corylifolia stimulated the immune system in mice by increasing both cell-mediated and humoral immune responses in mice (latha et al., 2000) . 6.17. anti-asthma activity p. corylifolia has long been used for its anti-asthmatic properties. experiments have shown that coumarins isolated from p. corylifolia exhibits anti-asthmatic activity by markedly increasing the level of serum camp (deng et al., 2001; yu et al., 2006) . in another study, a chinese herbal decoction, which contained six herbs, along with p. corylifolia seeds, could prompt treatment for asthma in the convalescent stage, to prevent emphysema (fu, 1989) . in a study by hongfen (2007) , the preparations obtained from the p. corylifolia showed high antiasthma activity by stabilization of mast cells and inhibition of histamine release. thus, the natural compounds obtained from p. corylifolia can act as promising molecules to cure asthma. several studies on animal models showed that a trihydroxyflavone, genistein (198) has the potential to decrease body weight by decreasing the food intake. one such study was conducted on ovariectomised mice wherein, it reduced the fat pad weight and enhanced the apoptosis of adipose tissues. genistein (198) isolated from p. corylifolia, exhibited a potential anti-obesity and ant-diabetic activity through multiple mechanisms and cell signaling pathways by the action on adipocyte life cycle, obesity-related low-grade inflammation, and oxidative stress . in a report, the aqueous and alcohol extracts of the leaves and seeds of p. corylifolia showed significant anti-filarial activity against setaria cervi. alcohol extracts of both leaves and seeds caused death of microfilariae in vitro. the lc50 and lc90 for alcohol extract of leaves and seed was 15, 25 ng/ml and 12, 18 ng/ml respectively (qamaruddin et al., 2002) . the extracts also caused the inhibition of spontaneous movements of the whole worm and the nerve muscle preparation of s. cervi (qamaruddin et al., 2002) . the methanolic p. corylifolia seed extracts was observed to inhibit the aggregation of rabbit platelets induced by arachidonic acid, collagen, and platelet activating factors. the anti-platelet aggregation activity of isobavachalcone was found to be most effective against aggregation induced by arachidonic acid, with a 50% inhibitory concentration (ic50) of about 0.5 µm (tsai et al., 1996) . using rabbit as an animal model, and escherichia coli endotoxin (13 ng/kg) as a pyrogen, the petroleum ether, dichloromethane, and methanol extracts of the aerial parts of p. glandulosa have been reported to possess anti-pyretic activity. the anti-pyretic effect (21.7%) of the petroleum ether extract was reported because of bakuchiol compound present in the extract. maximum anti-pyretic effect (68%) was observed at the dose of 17 mg/kg (backhouse et al., 2001) . isobavachalcone (203) and bavachinin (160) from psoralea modulate amyloid β (aβ) peptides, especially the peptides with 40 (aβ40) or 42 (aβ42) residues, which are believed to be responsible for the development of amyloid plaques in alzheimer's disease. isobavachalcone significantly inhibits both oligomerization and fibrillarization of aβ42, whereas, bavachinin converts aβ42 into large unstructured aggregates in neuroblastoma cells . psoralen (92) isolated from p. corylifolia fruits was investigated as an inhibitor of ache enzyme in an attempt to explore its potential for the management of alzheimer's disease. the concentration of psoralen used was 25-400 μg/ml. it inhibited the ache in a dose-dependent manner in animal models. adult male wistar rats, weighing 180-250 g, were used in the study. while molecular docking study was also carried out, which showed that psoralen (92) binds well within the binding site of the enzyme showing interactions such as hydrogen bonding and π-π stacking . these findings may provide valuable information for the synthesis of new drugs or for the treatment of alzheimer's disease. although having excellent bioactivities, excess intake or use of psoralea is not free from side-effects. p. fascicularis (synonym: psoralea tenuifolia thunb.) has been reported to be toxic to horses, cattle and therefore is not recommended as a fodder. there have been reports on skin allergic reactions after the oral and injected preparations of psoralea (bensky et al., 2004) . in over-dose, psoralea has been associated with dizziness, general weakness, blurred vision, rapid breathing, and vomiting. severe cases of overdose have been associated with vomiting of blood, loss of consciousness, and coma (bensky et al., 2004; chen and chen, 2004) . psoralen plus uva (puva) therapy has been used to treat skin diseases, such as vitiligo and psoriasis. the reported side-effects include dermatitis, blistering, edema, renal complications, loose-motions, biliousness, malaise, sleeplessness, annoyance and mental depression. prolonged therapy has reported to affect liver, eyes, and the immune system (rajpal, 2005) . the psoralen (92) treatment along with uva can cumulatively cause extensive chromosome damage to mammalian cells and could lead to malignancy. a mixture of psoralen (92), isopsoralen (2), and imperatorin caused hypertrophy of liver, kidney, and spleen in rats at a daily dose of 2.5 mg/75 g for 60 days (sharma, 2001) . in a similar study, different concentrations of p. corylifolia extracts were administered to the rats for 90 days. the treatment decreased the body weight and gonad weight (testes and ovaries) thus indicating psoraleninduced reproductive toxicity (takizawa et al., 2002) . there are several reports on hepatotoxicity symptoms in mice and rats after long-term usage of psoralen or isopsoralen (khushboo et al., 2010; totonchy and chiu, 2014; wang et al., 2012) . in an investigation, p. corylifolia and its natural compounds (bavachin, corylifol a, neobavaisoflavone, ibc, and bcn) were evaluated for their potential toxicity, and the results showed it had a potent inhibitory effect against human udp-glucuronosyltransferase 1a1 (ugt1a1) which is considered a stimulant for p. corylifolia related toxicity, including hepatic injury and raised bilirubin levels . in another study, p. corylifolia extract and fractionated compounds such as psoralen (92) and isopsoralen (2) were incubated with the recombinant cyp3a4 enzyme or differentiated huh-7 and heparg cells. p. corylifolia extract, psoralen, and isopsoralen caused the inhibition of concentration cyp3a4 activity in a dose dependent manner with different potency in vitro. it was also noted that none of the sample tested showed any toxicity (liu and flynn, 2015) . three cases of liver injury have been reported in chinese population associated with consumption of p. corylifolia dried seeds (fructus psoraleae) (cheung et al., 2009) . pregnant women are discouraged from consuming p. corylifolia (bensky et al., 2004; chen et al., 2007) . in a case study, a 44-year-old female ingested p. corylifolia seeds every 1 h for seven weeks for treating osteoporosis but, developed acute cholestatic hepatitis (nam et al., 2005) . in another case study, a 64year-old female developed severe hepatotoxicity after administration for nine months of three kinds of herbal tablets and herbal tea for treating vitiligo. tablets made from p. corylifolia leaves were identified as the most probable cause of the hepatotoxicity (teschke and bahre, 2009; teschke et al., 2014) . however, the underlying hepatotoxic mechanisms of p. corylifolia and its major components are not well elucidated. a text on traditional chinese medicine reports that no adverse effects of psoralea occur when a normal dose range (decoction of 4.5-9.0 g) is consumed (bensky et al., 2004) . in all the case-studies/ experiments on psoralea induced toxicity one thing was found common and that is purposeful/deliberate and continuous/prolonged intake/ application of a high dose. going through the available literature we can conclude that there are mixed opinions about the psoralea induced toxicity and therefore there is still a research gap with regard to its mode of action and its pharmaceutical standardization. as already mentioned the genus psoralea has immense potential to cure various diseases and the most important among these are psoriasis, leprosy and vitiligo. although pre-clinical studies have shown promising results, further studies are required to explore the in-depth molecular mechanisms responsible for the afore-mentioned pharmacological activities and to test the efficacy of isolated compounds, in properly designed experiments. in addition, long term toxicity studies and data on interaction with other drugs are also required to establish the safety profile of extracts before the commencement of clinical trials. the efficiency and efficacy of the bioactive compounds present in the psoralea species has been evaluated from time to time. now, since there is awareness complemented with scientific proof regarding the medicinal benefits, their mass cultivation/propagation and extraction of bioactive compounds should also be the objective of further research. the commercialization of pharmaceutical drugs containing psoralea as a sole or a part of the ingredients shall bring relief to millions of people suffering from psoriasis, leprosy and vitiligo, in a natural way. looking into the available literature on the genus psoralea, including the discovery of the number of bioactive compounds from each species (as mentioned in table 1 ) it is very clear that p. corylifolia is an important member of the genus from ethnobotanical, ethnopharmacological, biological, and phytochemical point of view. several bioactive compounds isolated from psoralea are commercially available. the compounds such as daidzin (cas 552-66-9) is a potent inhibitor of human mitochondrial aldehyde dehydrogenase that indicates it chemopreventive property (keung and vallee, 1993) ; angelicin (cas 523-50-2) is an antifungal compound (sardari et al., 2000) ; 8-methoxypsoralen (cas 298-81-7) has been known as a potent suicide inhibitor of cytochrome p-450 (tinel et al., 1987) ; corylifol c and xanthoangelol are potent protein kinase inhibitors and induce apoptotic cell death therefore, possess anti-cancer property ; bakuchiol (cas 10309-37-2) is a ptp1b and dna polymerase inhibitor (choi et al., 2015) ; genistein (cas 446-72-0) is a highly specific inhibitor of protein tyrosine kinase (zarmouh et al., 2016) ; psoralen has been used as photochemical probe in dna mutation and repair studies (gasparro, 1988) ; and bavachin (cas 19879-32-4) stimulates bone formation (anti-osteoporotic activity) xin et al., 2010) . these examples indicate the utility of bioactive compounds isolated from psoralea species. psoralea species are difficult to propagate because of poor seed-germination and high seedling-mortality (mitter et al., 1993; saxena et al., 1997; siva et al., 2014) . to ensure sustained production and benefits of psoralea products we must aim at its mass cultivation through conventional approaches as well as micropropagation (koul and chase, 2015) . psoralea guenzii harv. has become extinct while species like p. asarina (p.j.bergius) t.m.salter, p. fascicularis dc. and p. glaucina harv. are vulnerable to extinction. their bioactive principles and mode of action has not been explored yet. their conservation would also ensure an alternative source of continuous and sustainable supply of elite bioactive compounds such as bakuchiol, psoralen, angelicin and psoralidin, for the pharmaceutical industry (supplemental information 5, table s4 ). although, reproducible or rapid regeneration protocols for all the psoralea species are not yet developed, but the same can ensure the enhancement of bioactive compound(s) production in near future, through suspension culture or transgenic technology (arya and gothalwal, 2015) . these techniques may also streamline the path for further research on the bioactive principles and for the discovery of new compounds with novel properties in future. this is the first report wherein a detailed botanical description, traditional uses, phytochemistry and conservation of psoralea species has been discussed. to conclude, psoralea species have immense potential to act as panacea to several health-related maladies and so its conservation before excessive exploitation should be a prerequisite. current remedies for vitiligo isolation of chalcones from the seeds of psoralea corylifolia linn medicinal plants of bombay presidency psoralea corylifolia l: ethnobotanical, biological, and chemical aspects: a review antipsoriatic microemulsion gel formulations for topical drug delivery of babchi oil (psoralea corylifolia) psoralen photochemotherapy of cutaneous disorders the wealth of india, a dictionary of indian raw materials and industrial products. csir phytopharmacological assessment of medicinal properties of psoralea corylifolia. afr experimental and density functional theory study of a new dimer with tetra-substituted cyclobutane ring system isolated from psoralea plicata seeds phytochemical and biological activities of bituminaria bituminosa l (fabaceae). asian pac anti-oxidant potential of n-buoh extract was evaluated through two methods, dpph and cupric ion reducing anti-oxidant capacity assay. asian pac active constituents isolated from psoralea glandulosa l. with anti-inflammatory and anti-pyretic activities a new chromenochalcone bavachromene from the seeds of psoralea corylifolia preparation and in vitro evaluation of radio iodinated bakuchiol as an anti-tumor agent genistein: a promising therapeutic agent for obesity and diabetes treatment chinese herbal medicine: materia medica protective effect of aqueous extract of seed of psoralea corylifolia (somraji) and seed of trigonella foenum-graecum l (methi) in streptozotocin-induced diabetic rat, comparative evaluation volatile constituents of different organs of psoralea bituminosa l some new flavonoids from psoralea corylifolia antimicrobial activity of psoralea corylifolia linn. 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effects of total coumarin on cgmp/cgmp of asthmatic rats evaluation of the isoflavone genistein as reversible human monoamine oxidase-a and-b inhibitor in vitro estrogenic activities of chinese medicinal plants traditionally used for the management of menopausal symptoms the effect of psoralea corylifolia on isolated osteoclasts cells the chemical constituents and bioactivities of psoralea corylifolia linn. a review fingerprint analysis of psoralea corylifolia l.by hplc and lc-ms analysis of psoralea corylifolia l. fruits in different regions evaluation on phytoestrogen effects of ten kinds of chinese medicine including flos carthami the authors are thankful to lovely professional university (lpu), punjab, india for the infrastructural support. the authors are also thankful to the center for chromatography and mass spectrometry, industrial university of santander, columbia for awarding the postkey: cord-276976-ybsk1r79 authors: jiang, qinxu; yuen, mantak; horta, hugo title: factors influencing life satisfaction of international students in mainland china date: 2020-08-04 journal: int j adv couns doi: 10.1007/s10447-020-09409-7 sha: doc_id: 276976 cord_uid: ybsk1r79 china is advancing in its bid to internationalize higher education, but little is known to date about the life satisfaction of overseas students in that country. life satisfaction can be understood as the extent to which individuals’ experiences in a host country help them achieve their personal goals and satisfy their expectations regarding acculturation. this paper examines past research, especially international literature, to provide an overview of factors that may influence the life satisfaction of international students in countries other than their own, and looks particularly at those matters that may also affect overseas students in china. comparisons are made between variables identified in general and those in asia, and specifically china. the findings have implications for policy-makers and university practitioners seeking to improve educational quality and counseling support services for international students. in recent years, china has grown in prominence on the world stage. this includes its position as an emergent educational hub for international students (wen and hu 2019) . although many chinese students undertake studies in north america, western europe and oceania, china has also begun attracting increasing numbers of students from overseas. this phenomenon can be traced to the development of higher education in the country, with several chinese universities now placing highly in world rankings, and to the country's growing economic prominence (jiani 2017) . data attract international students, and government initiatives around these matters. following this section, the international literature on matters related to life satisfaction among overseas students in western contexts and in other emerging asian countries is reviewed. similarities and differences are identified between observations in other countries and those in china. factors that might predict the life satisfaction of international students in china are discussed. in this context, a general description of counseling services available in higher education institutions in china is provided, followed by suggestions for developing such services that address the specific needs of international students. in the final section, future possible research directions are proposed. the ease of mobility of international students across borders has many advantages to both host countries and international students. the internationalization of higher education also yields appreciable economic benefits for host institutions, and this in turn can support research and increase resources and staffing (horta 2009) . a less tangible but no less valuable benefit is the positive interaction and cultural exchange that typically occurs between international students and domestic students (ammigan 2019) . a deeper understanding of different cultures can facilitate cooperation, tolerance and international peace (gebregergis et al. 2019; sam 2001; taušová et al. 2019) . residing and studying in a foreign country enables international students to have rewarding experiences that contribute to increased confidence and self-growth (taušová et al. 2019) , although the mobility of international students tends to be motivated more by financial goals than by deliberate cultural exchange (feng and horta 2020 ). an international student may acquire foreign language competency, multicultural experiences and enriched cultural literacy, thereby increasing their human capital of knowledge and skills (wen and hu 2019) , as well as the scope of their employability (nerlich et al. 2018 ). however, overseas students also face numerous adaptation challenges related to their social, cultural, and learning experiences, and not all their experiences are necessarily positive (bamber 2014) . china entered the globalization movement of higher education at a later stage than the west, and although the country is increasingly attracting international students, it faces stiff competition from more established host countries such as the u.s., the u.k., australia and new zealand, as well as from neighboring countries like south korea, japan and singapore. china's success in attracting overseas students can be attributed in major part to its affordable tuition fees and living expenses, which are lower than those in most western countries (dervin et al. 2018) . china also has accessible scholarships, government grants and supportive policies for employment opportunities after graduation (dervin et al. 2018) . the opportunity to acquire chinese language competence is also an attraction because of its value in the global business world (ding 2016) . other factors that potential students take into account include china's political stability, its less strict admission policies, the economic boom and their own interest in chinese culture and history (jiani 2017; liu et al. 2013; wen and hu 2019) . the internationalization of higher education and the recruitment of overseas students has been high on the chinese government's agenda. the moe formulated its program for study in china to strengthen educational exchange and cooperation between china and other countries. it aimed to develop study opportunities that would be accessible by international students. the plan set a target for china to become the asian country with the largest number of foreign students by 2020; this number is anticipated to reach 500,000. 3 this was reinforced by the launching in 2013 of the one belt one road initiative (obor, centered on a silk road economic belt and a maritime silk road), which further opened china up to the rest of the world. critical importance was attached to strengthening educational cooperation and exchange with several countries in asia and in central and eastern europe (lu and tian 2018) . the obor initiative is suggestive of how international education development can be seen as an exercise of soft power: it does not focus on revenue benefits (although it may generate a revenue stream), but rather is part of china's global strategy to influence attitudes overseas and increase awareness of china's culture and its economic and creative growth (wen and hu 2019; yang 2015) . in this context, it is relevant to note that international recruitment mostly targets students in developing countries. these students will likely become part of the governing elite in their countries and will potentially be more sensitive to chinese viewpoints and interests after their stay in china, given their acquired knowledge of the chinese language and china's society, culture, history and politics (yang 2015, p. 25) . by april 2017, china had signed 45 cooperation agreements with countries along the "belt and road" and had signed mutual recognition agreements for academic degrees with 24 countries (china youth network 2017). although these initiatives are important, future growth in the number of international students in china is bound to be more dependent on growing a reputation for the quality of the education and student experiences provided by chinese universities. the fact that such students have to pay fees for their studies means they will always weigh whether they are getting value for money. host nations must therefore be mindful of the need to meet their expectations (karaman and watson 2017) . life satisfaction is defined as "a global assessment of a person's quality of life according to his [or her] chosen criteria" (shin & johnson, 1978 , cited in diener et al. 1985 . it is also considered to be "a generic concept representing an individual's contentment with his or her life"-that is, the level of an individual's subjective appraisal as to whether his or her aspirations and goals have been achieved (jacobsson & lexell, 2013 , cited in nilsson 2015 . the life satisfaction of international students can be understood as the extent to which their experiences in the host country satisfy their expectations in terms of personal goals being realized and appropriate acculturation taking place. in other words, it is a subjective evaluation of a student's perceived level of satisfaction and adjustment to a new sociocultural environment. throughout the literature, international students' assessment of life satisfaction is closely linked to their acculturation experiences in the host country (zhang and goodson 2011) . for example, they may encounter unexpected challenges and adjustment problems in an unfamiliar culture, and may experience mental or psychological stress as a consequence. acculturation is defined as "the dual process of cultural and psychological change that takes place as a result of contact between two or more cultural groups and their individual members" (berry 2005, p. 698) . international students and members of the host culture they connect with undergo acculturative changes through contact, adaptation and accommodation (smith and khawaja 2011; zhang and goodson 2011) . psychological adaptation refers to affective responses (sense of well-being, confidence and self-esteem) as well as physical well-being (ward et al., 2001 , cited in smith & khawaja, 2011 . sociocultural adaptation is "based on behavioral responses related to how effectively an individual links in to the new society" (ward et al., 2001 , cited in smith & khawaja, 2011 . having a clear understanding of international students' acculturation processes is helpful for understanding the factors that may predict their degree of life satisfaction in a new environment. a number of quantitative and qualitative studies have examined acculturation among international students. in their review of 94 studies on acculturation that had been published before 2011, smith and khawaja (2011) thoroughly investigated the acculturation experiences of international students, although almost all the studies they included were from western countries. they identified five of the most common stressors facing such students: (i) language difficulties, (ii) educational factors, (iii) sociocultural differences, (iv) discrimination, and (v) practical problems, such as financial difficulties and accommodation or transportation issues. in western host nations where english is the native language, a low level of english proficiency naturally affects international students' academic performance and social adjustment (smith and khawaja 2011) . it can be deduced from their review that any similar setting in which a student has to cope with a language other than their first language is challenging. the mental strain brought about by unsatisfactory educational experiences or difficulties socializing and making friends can add to the stress. a mismatch between a student's expectations regarding the ease or difficulty of academic courses and the reality of such contributes significantly to stress no matter the circumstances, but this stress can be compounded when it happens in a foreign country (smith and khawaja 2011) . access to counseling services can be important in helping students handle these stressors, but the problem can be exacerbated if the quality of the counseling and support services offered by the host educational institution is poor (smith and khawaja 2011) . in such circumstances, acculturative stress can become debilitating and can significantly undermine a student's level of life satisfaction. in their review, smith and khawaja (2011) identified sociocultural stressors associated with overseas students' attempts to build new social networks in their host country. they found that international students' individual characteristics, such as their personality or attachment style, affected their psychosocial adaptation (smith and khawaja 2011) . a possible example of this finding is that asian students from a collectivist culture may find it hard to accept western social norms and attitudes that seem to conflict with their own. the same kinds of difficulties can occur in reverse, where a student from an individualized culture must cope in a collectivist society. this can be an obstacle to forming friendships, and if friendships are less accessible in the host community, loneliness may occur and be a negative predictor for life satisfaction (salimi 2011; yalçin 2011) . discrimination against international students, sometimes evident through prejudice, verbal insults, physical assault or hostility, has also been recognized to be a significant acculturative stressor. international students were found to be more vulnerable to discrimination, in both covert and overt forms, on and off campus (smith and khawaja 2011) . discrimination not only discourages international students from making friends with local people but can also affect their mental health and wellbeing. in extreme cases, this can also cause a student to withdraw from study and return home. other practical stressors that international students were found to be at risk of experiencing included financial, accommodation and transportation issues (smith and khawaja 2011) . naturally, however, data on the relevance and severity of these more practical factors may vary from country to country depending on conditions in different settings. zhang and goodson (2011) reviewed 64 peer-reviewed american journal articles published between 1990 and 2009 to investigate predictors of international students' psychological adjustment to life in the u.s. consistent with smith and khawaja's (2011) findings, factors such as general stress, social support, language proficiency, the characteristics of the origin country, social connectedness with locals, gender, self-efficacy, personality and length of stay in the host location were most frequently reported as influences on adjustment. it should be noted that the reviews by smith and khawaja and by zhang and goodson were published in 2011, so more recent data are needed, as the past nine years have seen rapid growth in international student mobility. mesidor and sly (2016) contributed a more recent review (albeit drawing also only on u.s. sources) on the variables that contribute to international students' adjustment. unsurprisingly, factors enumerated in their review overlapped with those identified by smith and khawaja (2011) and zhang and goodson (2011) . they identified factors associated with academic issues, language barriers, sociocultural issues, financial problems, and lack of social support, but mesidor and sly (2016) also added more personal factors: emotional intelligence, resilience, locus of control, self-efficacy, coping styles and engagement in leisure activities. an investigation of international students' satisfaction in life and its predictors was carried out by sam (2001) at the university of bergen, norway, where universities widely use english as the medium of instruction. his paper provided a comprehensive review of earlier findings that focused on seven aspects that contribute to satisfaction in life: language proficiency, demographic characteristics, financial situations, academic standards, social activities and social relationships, and the clarity of information received prior to enrollment. in addition, in sam's (2001) study, students from europe and north america studying in norway appeared to have a higher level of satisfaction than their counterparts from asia and africa. this may have been a reflection of students' english language proficiency and the tendency of asian and african students on campus to experience more obvious discrimination and to have fewer friends. in addition, some of the latter students may have received inadequate information about courses prior to enrolment, leading to stress when faced with the reality of study demands. sam (2001) recognized that, overall, the factors identified, together with difficult financial situations, seriously influenced the life satisfaction of the international students involved. in the same study, there were also apparent differences between international students from developing countries and those from developed countries (sam 2001) . for example, interestingly, financial issues appeared to be of greater concern to students from developed countries than to those from developing countries. one possible reason for this difference, according to the researcher, may be that the latter group were typically recipients of financial support from their governments, while the others were not. these differences highlight the fact that influences on the life satisfaction of international students may vary considerably from one geographical, economic, or cultural setting to another. studies since 2011 in both western and non-western contexts have tended to confirm the influence of all the factors previously identified. language, educational experience, financial insecurity, discrimination, social integration, stress, living expenses, and accommodation continue to be common influential factors. for example, ammigan (2019) pointed out that the main factors that predict international students' institutional satisfaction in the u.s., australia, and the u.k. include social networking, work opportunities, suitable accommodation, and compatibility with local culture. more recently, the following influences have gained attention in the literature, with seemingly more sophisticated variables being given attention: cultural distance/proximity, individual coping competence, campus support services, prior sojourn experience, and predeparture preparedness all seem to be particularly important for international students' adjustments (alemu and cordier 2017; ammigan and jones 2018; hennings and tanabe 2018; kosheleva et al. 2015; taušová et al. 2019 ). taušová et al. (2019), in their netherlands-based study of psychological adjustment among international students from 62 countries, investigated four factors of perceived cultural distance: (i) "subjectively perceived discrepancy between cultures in areas such as values, habits, norms, religion and leisure" (p. 13), (ii) perceived growth initiative, which refers to "striving to grow and achieve positive changes in personally important life domains" (p. 13), (iii) english and dutch language proficiency, and (iv) length of residence. as with norway, english rather than dutch is the language most used both in academic and social spheres in the netherlands. another study focused on singapore (nasirudeen et al. 2014 ), a multicultural society where the main language spoken is english. international students from neighboring malaysia were found to have less stress and to experience less discrimination than students from china and myanmar. this was mainly because the students from malaysia had better english competence and shared similar cultural norms to the host nation. this finding reinforces the importance of having adequate proficiency in the language used in the higher education institution of any host country. language proficiency is clearly a major influence on how quickly a foreign student is likely to become acculturated and to achieve a positive level of life satisfaction (nasirudeen et al. 2014) . in a large-scale study of 45,701 international students from 96 universities in australia, the u.k. and the u.s. undertaken by ammigan (2019), the english proficiency of the lecturers was found to be very important for overcoming students' stress associated with the demands of study. in their study of international students in korean universities, alemu and cordier (2017) found that international students from east asian countries tended to be more satisfied with their experiences than other international students, largely because of their greater cultural proximity to the host nation. based on this research, it can be deduced that foreign students who decide to study overseas are likely to encounter the most difficulties if they opt for a country with a different language and very different cultural norms from their home country. research studies have paid less attention to students' coping competence as a factor influencing how they adapt to a new environment. smith and khawaja (2011) acknowledged that most acculturation models recognize that an individual's coping mechanisms play a key role in how they adjust to and integrate into an unfamiliar host culture. a comparative study of determinants of life satisfaction among chinese students in finland and russia indicated that those who were more able to cope with change and were open to new experiences tended to fit into the new culture faster, and with greater confidence and satisfaction (svergun 2016) . saha and karpinski (2016) found that international students who coped by using social media platforms such as facebook, linkedin, twitter, qq, or skype to seek social support from families and friends at home also tended to have higher levels of life satisfaction, which contributed to their overall academic performance. it also appears that marital status can influence how easily a foreign student adjusts to a new country. for example, bhandari (2012) found that married nepalese participants who lived with their spouse in south korea experienced less acculturative stress than did single students. obviously, having such close support and shared experiences is helpful psychologically for international students, and it can also be claimed that couples might be more likely to become engaged with locals through social invitations extended to them as a couple. it is not yet clear whether students' age, gender, and length of residence are linked to acculturative stress, so more research is merited in this area. for example, sam (2001) found that female international students were less adaptive than males and that age and length of stay were positively correlated with students' adaptation abroad. other studies have shown conflicting results in regard to the impact of these factors (nasirudeen et al. 2014; salimi 2011; yalçin 2011) . the degree and quality of campus support services have been recognized in several studies to influence the life satisfaction of international students; these services can determine how well students cope while studying abroad. a quantitative study of the experiences of more than 45,000 international students from 96 institutions across australia, the u.k. and the u.s. revealed that support from the international office, services from the financial department, and assistance from tutoring services had a significant influence on international students' levels of satisfaction (ammigan and jones 2018) . similarly, in their study involving international students at an american university, cho and yu (2015) found a positive relationship between university support, a reduction of psychological stress, and an increase in life satisfaction. the large-scale survey of 45,000 international students from 96 different institutions in australia, the u.s. and the u.k. by ammigan (2019) also revealed that international students' satisfaction with the level of support services (especially related to learning) influenced the decisions of prospective applicants. effective advising (e.g., personal counseling and preparing potential students for their choice of overseas institution) was also found to be important for international students' satisfaction, engagement, persistence, retention, and academic performance (bista 2015; mamiseishvili 2012; zhang 2018) . it is clear that counselors also play an integral role in supporting international students' academic success and well-being (arthur 2017) . counseling can help international students address their immediate concerns, overcome problems, and thus strengthen their adjustment and decision-making abilities (arthur 2017 ). banjong's (2015) u.s. study found that amid the challenges of language, loneliness and financial difficulties, seeking help from a counseling center helped improve international students' academic success. one aspect of "fitting in" to a new educational environment is being able to use all available resources that are provided. library services, for example, are a core resource used by international students upon arrival to transition into the new academic realm, with libraries being critical for engaging with academic content, which is central to the purpose of students being in the host nation. it should be standard procedure for host universities to help international students develop required scholastic skills, such as searching for information online and in print (hughes et al. 2018; toner 2019) . students' prior sojourn experiences and pre-departure preparedness have been found to positively relate to adjustment and acculturation (alemu and cordier 2017; gebregergis et al. 2019; morrell et al. 2013; park and rubin 2012) . international students who have traveled or worked in other foreign countries are likely to have more realistic expectations about the challenges and difficulties they might experience. typically, they are better able to activate adaptation skills readily and experience less stress within a new environment than those with no previous international experience. pre-departure preparedness in terms of information provided by the host institution has also been found to influence how easily an international student adapts to a new study environment (madden-dent and laden 2016) . this pre-preparation information from host country settings typically includes not only important educational details about academic matters but also information about social life, accommodation, financial budgeting, and the availability of counseling and learning support services (alemu and cordier 2017) . the provision of these resources by the educational institution conveys a sensitivity to the challenges that the incoming international students will be facing, and reassures students that such support will be available to them. in summary, the above review of mainly western research identifies several important factors that affect the life satisfaction of international students in general. the review also reveals that there may be differences in the relative importance of these factors according to the characteristics of the host countries and the students' countries of origin. specific regional elements, therefore, have to be taken into account to avoid the risk of overgeneralizing the set of influences that determine international students' life satisfaction in any new study environment. ding (2016) has pointed out that western countries such as germany, new zealand, the u.k. and australia have conducted surveys of international students to better understand their experiences of living and studying in the host country concerned. the results obtained have then been analyzed with the aim of improving educational services and the experiences of the students. in contrast, fewer studies have investigated the life satisfaction of international students in china, where these types of surveys have not yet been a major priority. instead, the work of attracting students has been emphasized over the evaluation of course quality, support services, and levels of student satisfaction. the available survey research of this type in china is four large-scale questionnaire surveys conducted in shanghai (ding 2010 (ding , 2016 and beijing (wen et al. 2013 (wen et al. , 2018 about international students' experiences and levels of satisfaction. these studies identified several factors that were closely related to the life satisfaction of international students studying in mainland china. one limitation is that these investigations were carried out at universities in the two biggest and most metropolitan cities in china, where education and support services are believed to be more advanced than in other chinese cities. in addition, the reality is that there are many more international students studying in china at educational institutions in what can be regarded as second-tier or third-tier cities. therefore, to obtain more in-depth information about life satisfaction of international students, it is also necessary to review studies conducted in these smaller cities. in larger cities, the questionable quality of education seems to be the most frequently raised factor contributing to international students' dissatisfaction (ding 2010 (ding , 2016 sun et al. 2009; tian and lowe 2018; wen et al. 2013 wen et al. , 2018 . according to ding (2010) , only 32.3% of 457 international students felt "satisfied" or "very satisfied" with the teaching quality they experienced, 25.0% felt "unsatisfied" or "very unsatisfied," and 42.8% perceived the teaching quality to be "average." the explanations given for these ratings were largely associated with instructors' teaching methods, which were perceived to be rigid spoon-feeding that required too much rote learning and lacked interactions between teachers and students. these perceptions often led to low class attendance rates among international students. it is possible that international students' levels of satisfaction could have been even lower if not for the fact that most international students in china originate from asia, where similar types of learning (e.g., rote learning) are also prevalent. this potentially explains why the greater proportion of international students chose the option "average" in regard to teaching quality. in a more recent study, ding (2016) conducted a mixed-methods study involving a question-based survey and individual interviews with international students studying in universities in shanghai. the survey found that 67.1% of 1,892 international students at 28 universities in shanghai reported they were satisfied with studying and living in shanghai, and 59.2% of them were willing to recommend studying in china to their social network. however, less than half of the students reported being satisfied with the education they received. class sizes, outdated teaching materials, limited interaction with teachers in class, and unsatisfactory teaching methods were the most frequent targets of their complaints (ding 2016) . for instance, comments were made that teachers were more inclined to lecture and have students memorize material than to encourage self-motivated learning. wen et al. (2013) found that international students complained most about unreasonable curricula and obsolete teaching methods. for example, some courses were too researchoriented to be useful for practical work, or were arranged and structured only to comply with graduation requirements. limited teacher-student interaction was another target of complaint, as were the lack of english used in teaching processes and the limited provision of technical support. for instance, most of the postgraduate seminars and tutorials were conducted in chinese, barring international students with limited chinese proficiency from participating. in a more recent study, wen et al. (2018) conducted a large-scale survey among 1,674 international students enrolled in universities in beijing to investigate the quality of their educational experience. the results indicated that, overall, the international students were satisfied with their learning experience in china, with 83% of them feeling "very satisfied" or "satisfied." yet the researchers also received reports from international students studying in english-medium programs that faculty members teaching the courses were not sufficiently proficient in english. students opined that these teachers were not motivated to invest their time in improving their english because of the greater value given at their university to research rather than to teaching and learning (wen et al. 2018) . similarly, tian and lowe (2018) also found that international medical students thought their teachers had expertise in subject knowledge but were weak in english language proficiency, hindering them from giving clear explanations and answering questions. their teaching style typically involved simply reading slides from overhead projectors. international students considered this ineffective, and this led to dissatisfaction and frustration (and even at times protest) among them. overall, regarding program quality, yang (2018) suggested that chinese institutions were often attracted to the prestige of "internationalization" without the level of commitment and resources needed to strengthen their programs. the second domain about which international students in china tended to report less satisfaction was campus support services. to begin with, international students noted a scarcity of adequate and transparent information (ding 2010; tian and lowe 2018) . they complained, for instance, that the english websites of institutions often failed to reasonably meet students' information needs, and that administrative services sometimes failed to promptly inform them of changes to arrangements, preventing them from making adequate preparations. similarly, tian and lowe (2018) found that international students thought that information on university websites was insufficiently clear. some students also reported that their local agencies at home had provided them with inaccurate information before they reached their host university in xi'an. apart from perceived problems with information and communication, other support services were also perceived to be inadequate for international students' actual needs (ding 2016; tian and lowe 2018; wen et al. 2013; zhou et al. 2018) . in one study, more than 30% of international students reported that they did not receive assistance with airport pick-ups, opening a bank account, or finding an apartment to rent (ding 2016) . many international students reported feeling disappointed by the lack of activities on campus because their desire to interact socially with chinese students could not be fulfilled (tian and lowe 2018) . in terms of guidance for seeking employment, there was a lack of information specifically for international students who desired to work in china after graduation (wen et al. 2013) . in one study, most students found that the career planning help from the campus employment guidance office was not open to international students (wen et al. 2013) . zhou et al. (2018) undertook a focused investigation on the extension of university library services to meet the needs of international students in china. in-depth interviews with 23 international students at a wuhan university revealed their dissatisfaction with the library services. five recommendations emerged from the interviews. first, it was thought to be essential to build a "bilingual library environment" with regard to library signage, management regulations, rules and restrictions, and website design. next, it was recommended that high priority be given to increasing librarians' english skills and cultural sensitivity. third, it was recommended that collaborative relationships be established between the library and the school of international education. fourth, it was considered necessary to improve library space allocation. finally, there was seen a need to develop diversified library collections. from this study, it can be inferred that tailoring library services to international students in mainland china still has a long way to go. accommodation appears to be another salient issue among international students studying in china (tian and lowe 2018; wen et al. 2013) . in beijing, survey results indicated a relatively high percentage (77%) of international students feeling "satisfied" with or "very satisfied" with accommodation, but this figure was below an international standard of 86% (wen et al. 2013) . international students complained about a wide range of problems, such as slow internet speed, a hot water supply shortage, old dormitory facilities, limited visitor time, unprofessional attitudes of dormitory staff, a shortage of single rooms, fees for internet and electricity use, and the separation of international students' accommodation from that of local students (tian and lowe 2018; wen et al. 2013) . international students also expressed dismay with the quality and efficiency of administrators, with some administrators appearing to them to be unfriendly and unhelpful. there also seemed to be a lack of collaboration between departments, with international students finding it difficult to find help solving their problems, which often cut across several areas of responsibility (ding 2010) . international students in china usually have separate coursework and accommodation from chinese peers. in the research, this separation was found to hinder international students from connecting with and getting to know chinese students, thus limiting their studies and quality of life (ding 2016; tian and lowe 2018; wen et al. 2013) . interestingly, chinese students were at times perceived by international students to be unfriendly (ding 2016) . this observation might be attributed to the degree to which chinese students are typically preoccupied with their own studies and their lack of motivation for befriending foreigners. ding (2010) found that international students often wished to do part-time jobs to support themselves because most were relying on parents or relatives for their expenses. even students on scholarship sometimes found their funding insufficient to cover both study and living expenses. sun et al. (2009) noted that some international students grappled with tuition and accommodation fees and tended to experience more anxiety and insecurity when a part-time work permit could not be obtained, with this often being restricted by chinese law. wen et al. (2013) found that international students were more satisfied with tuition fees, living expenses and scholarships in beijing because the municipal government there had invested more funding to support international student education. acculturation sun et al. (2009) surveyed 450 international students from 13 universities in the cities of kunming, beijing, guangzhou and shanghai on the three dimensions of (i) social adaptation, (ii) psychological adaptation, and (iii) cultural adaptation. the findings indicated that the students' social adaptation was satisfactory on the whole, but they at times reported unsatisfactory encounters with, and poor services from, people from government departments (sun et al. 2009 ). they felt most comfortable making friends and going shopping, and they expressed satisfaction with their accommodation. the study also found that the majority of the students had positive experiences of psychological adaptation, but there were some students who felt lonely, sad and disappointed. more women than men reported negative emotional experiences. the findings also showed that international students who lacked social support had the lowest levels of adaptability, while those who experienced social support, mainly from co-nationals and chinese people, had the best levels of adaptability (sun et al. 2009 ). regarding cultural adaptation, sun et al. (2009) noted that international students often found some chinese traditions and rituals hard to understand. according to the researchers, the adaptability of european and american students studying abroad was higher than that of asian students. they attributed four possible reasons for this: (i) foreign students' intrinsic motivation to study in china vs. the pressure of asian parents' expectations, (ii) more adequate psychological preparedness of european and american students for adaptation vs. inadequate preparedness among asians, (iii) individualistic cultures in the west vs. collectivist cultures, and (iv) strong financial background vs. weaker financial status. it should be noted that the study by sun et al. was undertaken a decade ago in 2009, and it provided a broad understanding of international students' acculturation and satisfaction with life and learning in china at that time. it is hoped that the situations they described have improved since then, as indications are that china has progressed considerably in terms of public services and the quality of higher education. however, it is important for topical research to be undertaken to determine whether such changes are reflected in the experiences and perceptions of international students studying in mainland china at present. tan (2013) addressed the adaptability of foreign students to studying in china and suggested that it was natural for international students who had lived in china for longer periods to be better adapted than new arrivals. the latter faced difficulties with social integration, a lack of orientation or counseling services, and communication with chinese staff and classmates; with these factors being confirmed as having an impact on acculturation (li 2007; tan 2013) . gebregergis et al. (2019) addressed the issue of acculturation in their study. they explored the correlation of the three variables of prior travel experience, age, and cultural intelligence (understanding a culture that is not your own and the ability to relate effectively across cultures). they then related these to acculturative stress and depression among international students studying in wuhan. their findings showed that students with prior international experience had lower acculturative stress and were prone to less depression than those without such prior travel experience. age had a negative correlation with acculturative stress and depression in the study, with younger students demonstrating more openness to new experiences and more flexibility in their coping strategies. cultural intelligence was found to be negatively correlated with acculturative stress and depression. international students with more multicultural awareness or experience were less prone to acculturative stress and depression. findings from an empirical study by li et al. (2015) revealed that students from china's neighboring asian countries found it less difficult to integrate into chinese society than international students with more cultural distance from china. nonetheless, the chinese language proved to be a major barrier for them, hindering them from communicating easily with chinese people. for example, even in beijing, a cosmopolitan city where english is more commonly used, international students who lacked either chinese or english language proficiency tended to experience more communication obstacles (wen et al. 2018 ). it was not surprising to find that international students who had good proficiency in a local dialect spoken in the city where they studied, or who spoke chinese more in daily life, were more likely to have adapted well and to express higher levels of satisfaction (sun et al. 2009 ). tian and lowe (2018) found that the perceived wealth of international students' countries of origin seemed to influence administrators' attitudes toward the students. it was also reported that black students were more vulnerable to racist attitudes, although this was not widespread (tian and lowe 2018) . there is a need to research more deeply the issues of discrimination and racism that seem to occur (although they are often hidden) when international students of different backgrounds interact with peers and staff in host educational institutions. because of the deeply personal impact of such attitudes and behaviors, such experiences inevitably have a major effect on life satisfaction and adaptation. international students committed to a religion that they openly practiced tended to encounter more difficulties making friends and maintaining religious activities, and this was a potential source of considerable stress (bin et al. 2014) . for example, muslim international students reported that they were not allowed to pray in public, but only in their dormitory corridors (tian and lowe 2018) . furthermore, muslim and hindu students who had food restrictions found it difficult to eat with chinese students, and those who could not find food that tasted familiar expressed higher levels of homesickness (li et al. 2015) . this review of the literature on international students attending universities in mainland china seems to suggest that factors contributing to life satisfaction and adjustment are similar to those found in other countries. these factors include language barriers, issues with acculturation, financial hardship, cultural proximity/distance, perceived discrimination, campus support services, age, gender, marital status, length of residence, prior sojourn experience, predeparture preparedness, and individual coping skills. yet studying in china seems to pose particular challenges in the form of language barriers and the limited availability of campus support services. the language barrier is especially significant because international students have to speak chinese for everyday tasks, such as shopping, renting an apartment, seeing a doctor, traveling, using banking services, consuming entertainment, and eating in a restaurant, apart from tasks within the crucial educational context. those who are unable to speak chinese adequately tend to be constantly challenged and typically struggle more with life satisfaction and adaptation. ding (2016) and wen et al. (2013) have pointed out that the overall satisfaction level of international students in china is lower than that recorded in other host countries, especially compared with countries like the u.s., the u.k., australia and new zealand. there seem to be four possible reasons for this situation: (i) educational institutions in other settings may be more revenue-driven and thus may attach more importance to maintaining international students' satisfaction; (ii) the universities in these other host countries may have developed better styles of teaching; (iii) the settings mentioned use english as the mode of instruction; and (iv) the settings mentioned have better curricula and well-designed course materials. their years of experience as providers of courses to an international market have taught them the importance of support service systems for student applications, student orientations, and counseling services (smith & khawaja, 2011) . in comparison, china seems at this stage to fall short in these aspects, and chinese universities seem to rely too heavily on outside agencies to recruit, inform, and prepare potential students. it seems evident from the studies reviewed here that chinese institutions may be unaware of the need to improve their services, are resistant to change, or are in the process of adapting but are still in the early stages of doing so. china has created a number of favorable policies designed to attract international students, and chinese universities have made considerable efforts to increase enrollments, but it is important to ensure that current practices and offerings are valued by international students and are sustainable in the long term. china's eagerness to build a reputation as a world-class provider of university education is undermined by international students' perceptions of the quality of experience currently provided. too little attention has been given to researching and addressing the needs of foreign students. china has not actively evaluated its higher education practices, so improvements have been slow to eventuate. with the global advancement of higher education, competition for enticing students at home and abroad will become even more fierce. because hosting international students is crucial to china's soft power strategy, it is important for the chinese government and higher education institutions to more successfully meet the expectations of overseas students, and to ensure that their life satisfaction is strengthened rather than undermined by their experiences in china. the life satisfaction of international students studying in china is clearly influenced by multiple factors. to increase the satisfaction of international students, efforts should be made to improve four main domains: (i) the quality of the courses offered, (ii) the greater use of english language to communicate at all levels, (iii) support services development, and (iv) counseling services. first and foremost is the need to improve the quality of education provided in chinese universities, particularly in terms of teaching style, curriculum content, and study materials. research has confirmed that to ensure ongoing recruitment and retention, high-quality education must be provided that meets the needs and expectations of international students (alemu and cordier 2017; ammigan and jones 2018; ding 2016; jiani 2017; tian and lowe 2018; wen and hu 2019) . it is imperative that regular surveys of international students' evaluation of teaching and support services be conducted, and any deficiencies detected should be addressed at both government and institution levels. second, it is clearly essential that lecturers and teaching assistants in china receive adequate training in english proficiency and oral presentation skills. they need to observe examples of interactive teaching methods that engage students more effectively and establish good teacher-student rapport. this can be achieved through international teacher-exchange programs and video viewings of good practice. the lecturers also need to acquire better cultural knowledge of international students' backgrounds and their expectations. course textbooks and materials should be updated regularly, and full use should be made of e-learning and related technology. thirdly, support services should be developed and extended to meet international students' needs. areas most in need of strengthening include better website pre-enrollment information, better orientation programs for new students, ongoing counseling services, and employment guidance. international students are now used to accessing information and services online, so chinese universities should make full use of the internet to provide fast and convenient communication channels between lecturers and students and between students themselves. it is also recommended that policies be formulated and funding provided to improve accommodation and strengthen logistical services appropriate for international students. international students' social interactions with chinese students can be enhanced in all chinese universities through activities such as cultural exchange programs and chinese language courses. improved chinese language skills help overseas students function more effectively in the local community and within the institution. developing friendships with chinese students and fellow international peers is important for international students to reduce their loneliness and help them feel more engaged (hendrickson et al. 2011; smith and khawaja 2011) . fourthly, strengthening counseling services would greatly assist international students (yalçin 2011) . counselors can help to improve students' level of optimism and motivation through professional work and the establishment of a social support network. counseling support services are a basic necessity in chinese universities, but currently they are very inadequate compared to services in western settings. at present, student counseling services at china's higher education institutions are mostly limited to employment guidance and psychological counseling for local students (li 2010) . however, chinese colleges and universities have begun to attach greater importance to psychological counseling for all students. most of these institutions are establishing centers equipped with facilities (both rooms and resources) for individual counseling and group sessions. counselors are allocated a certain number of students each year, and telephone counseling, online counseling, peer counseling, and other methods are being used (su and wang 2015) . to meet the needs of students, some colleges have administered vocational ability tests to assist with career planning and provided psychological counseling for job candidates. each institution has specific counseling services tailored to their student population. overall, multiple counseling methods are being developed, and they should take full account of students' feedback, as has been made evident in this paper (su and wang 2015) . issues facing counseling services in chinese universities merit particular attention. first, chinese students tend to have misconceptions about counseling, associating it with mental illness or psychological abnormalities. for this reason, they fear that they may be stigmatized by their classmates or teachers if they seek counseling (su and wang 2015) . their reluctance may also be fed by the collectivist cultural influence that constrains help seeking (raunic and xenos 2008) . another possible explanation for students' reluctance is that counseling services at this point seem to fall short of achieving their aims on campus. students doubt whether counselors are able to communicate with them and really understand their worries or problems (sun 2019) . thereupon, eliminating students' misconceptions and mistrust of counseling may be an ice-breaking step towards addressing their needs. secondly, there is a shortage of professional counselors with appropriate skills, training and experience, with this causing counseling-type duties to fall upon other staff members. often, these personnel are student affairs professionals who take general care of a large number of students for such matters as studies, extra-curricular activities, dormitory checks, management matters, and discipline. the shortage of professional counselors, if not addressed, may add more work burden to student affair professionals and deter from achieving the objective of professional counseling in a real sense. third, the emergence of counseling services for international students has been slow at some universities in china, and services for career planning or employment guidance for such students are barely visible. the counseling and consulting services that are available tend to focus on providing the general student population with socialist political guidance, life values, and education about vocational ideals, rather than on providing guidance to individual students for their problems and stress management needs (li 2010) . additionally, students perceive the counseling environment to be insufficiently private, which greatly affects their levels of openness in psychological counseling communication. english language proficiency is also a challenge for counselors, and speaking only in chinese with foreign students who have limited chinese language skills can hardly achieve desired outcomes (xu et al. 2016) . the most important goal for the immediate future is for chinese higher education institutions to acknowledge international students' counseling needs. resources should be invested to build professional counselor teams to serve this increasingly large group of students if chinese universities and colleges are to continue to attract overseas enrolments. multicultural awareness training and language training are essential for all lecturers and counselors because international students comprise a heterogeneous group with unique cultures, religions, traditions, values, expectations, and ways of thinking (arthur 2017) . intercultural competencies for counselors could help them better understand students' perspectives when they are involved in cross-cultural counseling (pattison and robson 2013) . more counseling services are expected to be provided in future, including academic advising, language tutoring, career planning, and employment guidance. modes of online and offline counseling can be combined flexibly and innovatively (sun 2019) . this should help to enhance students' quality of life and levels of satisfaction. for instance, during the current situation of the covid-19 pandemic, in which face-to-face counseling is not feasible, online counseling should be offered to mitigate international students' anxiety and distress. although knowledge of the influences that affect international students studying abroad is significant, several areas would benefit from further empirical research in the chinese context. 4 first, it would be valuable to explore precisely what matters most to international students when they study in the chinese context and which services should be provided or improvedfor example, academic and career counseling, psychological counseling, and career guidance. second, studies should investigate how international students' academic success is affected by the very formal teaching methods traditionally used in china. does this approach hinder them from achieving their goals and expectations? a third important issue to investigate is how individual students differ in the way they cope with the challenges they face. such information would help those who counsel and support international students. it could lead to the development of powerful ways of assisting students in developing coping strategies and resilience. in addition, in the context of the covid-19 global pandemic, it is important to study the 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the planned reverse mobility work? the emergence of a regional education hub: rationales of international students' choice of china as the study destination a research on practices of mental health service for overseas students social support and optimism as predictors of life satisfaction of college students commentary: international students in china-what we know, what we don't, and what next china's strategy for the internationalization of higher education: an overview. frontiers of education in china china's soft power projection in higher education state formation and higher education (he) policy: an analytical review of policy shifts and the internationalization of higher education (ihe) in china between 1949 and 2019. higher education predictors of international students' psychosocial adjustment to life in the united states: a systematic review home away from home: extending library services for international students in china's universities using bronfenbrenner's ecological approach to understand academic advising with international community college students publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgements the paper is based on qinxu jiang's doctoral research under the supervision of hugo horta and mantak yuen at the university of hong kong faculty of education. conflict of interest the authors declared that they have no conflict of interest. key: cord-031840-k9l91unc authors: lu, li; lankala, srinivas; gong, yuan; feng, xuefeng; chang, briankle g. title: forum: covid-19 dispatches date: 2020-09-11 journal: cult stud crit methodol doi: 10.1177/1532708620953190 sha: doc_id: 31840 cord_uid: k9l91unc covid-19 pandemic is the first truly global crisis in the digital age. with death count worldwide reaching 586,000 merely 7 months after its first outbreak in china in late december 2019 and 13.6 million cases reported in 188 countries and territories as of july 2020, this ongoing pandemic has spread far beyond domain of world health problem to become an unprecedented challenge facing humanity at every level. in addition to causing social and economic disruptions on a scale unseen before, it has turned the world into a site of biopolitical agon where science and reason are forced to betray their impotence against cultish thinking in the planetary endgame depicted in so many dystopian science fictions. it is in this context that this forum offers a set of modest reflections on the current impacts incurred by the covid-19 virus. blending ethnographic observations with theory-driven reflections, the five authors address issues made manifest by the crisis across different regions, while keeping their sight on the sociopolitical problems plaguing our life both individually and collectively. taken together, they provide a grounded documentary for the archive that the covid-19 virus is making us to construct. the apparition of these faces in the crowd. -ezra pound, "in a station of the metro" the french word envoi is polysemic, defined as dispatch, the action of sending, something that is sent, a poetic dedication or dedication of a literary work, and the marking of the beginning of a process. this article is a dispatch from hubei, china, based on the author's 4-month stay in his hometown qianjiang, a small city in the middle of hubei, during the coronavirus pandemic. firsthand observations sent from the epicenter give us a clear picture of what the coronavirus has done. moreover, this article argues that the coronavirus marks a spectral moment in which a repressed trauma returns. there have been fierce debates on the origins of the coronavirus and the political, economic, and social significances of the pandemic. popular representations of the coronavirus which isolate, stigmatize, and terrify the other are symptoms of a returning trauma, which is caused by bodily memories of being victims in past disasters. a derridean reading of the envoi highlights the inherent failure of sending: what is sent can always be held up by a malfunctioning in the process of the sending or postal system, and the meaning of the trauma is lost. this traumatic failure results in a repetition in representation and the return of what is sent to the writer/sender. proposing a supplement, this article foregrounds bodily knowledge acquired through social and political trauma by virtue of fear of the coronavirus. this fear of what is familiar reminds us of the feeling of the uncanny. according to freud and derrida, the uncanny is related to the spectral working of a hidden desire that repeatedly returns as a haunting body, representation, and history. this line of thinking helps us to better understand conflicting representations of the coronavirus. the coronavirus is a ghost. this is not merely a metaphorical proposition; this is accurate in the sense that the coronavirus instantiates our phantasms, fears, and desires toward ghosts. in this regard, derrida's specters of marx provides us with a basic framework for understanding the coronavirus as a ghost. the first teaching of derrida is that ghosts do not come at just any time but in spectral moments that do not belong to time. by pointing precisely to the 953190c scxxx10.1177/1532708620953190cultural studies <span class="symbol" cstyle="symbol">↔</span> critical methodologiesli et al. present or now-time, derrida (2006) regards spectral time as "a disjointed now that always risks maintaining nothing together in the assured conjunction of some context whose border would still be determinable" (p. 1). second, a ghost is a phenomenon in the game of repetition and difference. neither exclusively situated in life nor in death, neither visible nor invisible, a ghost is "the frequency of a certain visibility. but the visibility of the invisible. and visibility, by its essence, is not seen, which is why it remains epekeina tes ousias, beyond the phenomenon or beyond being" (derrida, 2006, p. 125) . third, to "make oneself fear" is essentially ineluctable in the experience of a ghost. one becomes frightened of a ghost "on the condition that one can never distinguish between the future-to-come and the comingback of a specter" (derrida, 2006, p. 46) . in other words, what one fears is not the ghost, but the fear, imagination, and one's subject inspired by the ghost. finally, "a ghost never dies, it remains always to come and to come-back" (derrida, 2006, p. 123) . whatever repression the dead may suffer, the return of the dead is anticipated, and "this being-with specters would also be, not only but also, a politics of memory, of inheritance, and of generations" (derrida, 2006, p. xviii) . in light of derrida's framework on specters, once the coronavirus finds a host, it starts to live a ghostly life. the coronavirus pandemic irrupted during a time of turmoil. as the chinese president xi jinping has expressed, the world is experiencing profound shifts unseen in a century. while the trend of globalization is markedly receding, nationalism, popularism, and isolationism are on the rise. the eulogic discussions of "chimerica," a popular term coined by the british epidemiologist neil ferguson in 2007, are being replaced by the theories and practices of the china-u.s. decoupling. the trade dispute between china and the united states puts an end to the chinese ideal of great harmony in the world. in addition, as his campaign slogan "america first" shows, donald trump epitomizes the idea of american exceptionalism. in traditional chinese thinking, famine, natural disasters, and plague happen when the political order or legitimacy are out of joint. during this disjointed moment, a plague was anticipated, even fabricated before it came. according to a widely circulated story in the we-media during the height of the coronavirus, wang yongyan, an academician specializing in chinese medicine at the chinese academy of engineering, predicted half a year ago that a plague would come after the dongzhi (winter solstice), one of the 24 chinese solar periods. in addition, he predicted that the plague would last until next spring. in hindsight, rumors about a new virus were spreading right after the dongzhi. or, simply put, divination went hand in hand with the plague during a time of disjointing, disjunction, or disproportion. while scientists are still trying to track down patient zero, conspiracy theories about the origins of coronavirus have been spreading. bat soup and biological warfare are on the top of the list of suspected criminals. like ghosts, the coronavirus takes shape in the game of visibility and invisibility. in this game, ways of seeing determine how a virus can be understood. approximately made up of 0.125 microns, the coronavirus can only be seen under an electron microscope, made visible with the help of scientific equipment and representations. in contrast, a poet like ezra pound sees the invisible through his gifted imagination. his imaginative inspiration and aesthetic reflection allow his keen observation to become a line of poetic beauty and philosophical complexity. through this form of observation, an invisible apparition becomes visible in the faces of the crowd. similarly, the depiction of a fictional killer-virus called wuhan-400 in dean koontz's 1981 novel the eyes of darkness, re-gained popularity among those who regard it as an imaginative depiction of the coronavirus. in line with this imaginative depiction, mr. wang, well-trained in traditional chinese medicine, claimed that his prediction was based on his reading of the xiang (image) of the sky, earth, plants, animals, and human beings. visible to the naked eye, xiang functions as the visible traces from which an invisible plague becomes visible to an expert in traditional chinese medicine. in other words, with scientific support, talent, and training, people are able "to see this invisibility, to see without seeing, thus to think the body without body of this invisible visibility" (derrida, 2006, p. 187) . in this way, the ghostly nature of the coronavirus lies in the different frequencies of its visibility. however, despite our faith in being able to depict, and make distinctions between, the invisible and the visible, the way of seeing the coronavirus, especially in this time of turmoil, is politically conditioned and manipulated. when i took a night bullet train to wuhan with my family for vacation, it felt like an ordinary chinese family reunion trip during the spring festival: carriages packed with passengers, luggage, excitement, anxiety, and weariness in the air. one of the reasons for the peaceful atmosphere was that china and the united states had signed a trade agreement a few days before, sending a false message to the world that rationality and peace would return. one thing was markedly noticeable on the train: most passengers wore a facial mask for fear of an officially unidentified but unofficially sarslike virus. to my surprise, a line of masked faces was greeted at the exit by the smiling faces of relatives or friends, the indifferent faces of railroad workers, and the shrewd faces of barkers at the hankou railway station. this lack of consistency indicates that aspects of the coronavirus were kept secret. furthermore, this scenario at the station reminded me of a horrifying scene in the film the cassandra crossing, an eye-opening disaster thriller for my generation directed by george p. cosmatos. in this harrowing film, an international express carrying a virus-infected terrorist approaches a station at night. when the train reached the station, the passengers, who were kept from the truth, were confronted with members of the u.s. army in white biological hazard protective suits lined up on both sides of the platform. in both cases, the dynamic of the visibility and the invisibility of a virus was of political significance. the facial masks and the protective suits were used not only to protect people from a virus but also to make the secret of the virus both visible and invisible. in other words, political manipulation complicates the ways that a virus is seen and how the coronavirus, in particular, is seen as a political ghost. the coronavirus pandemic frightened people because it looked like the return of a specter, namely sars. because of its fatality and residua, sars remains an unresolved trauma for many chinese. at the early stages of the coronavirus pandemic, what was most frightening was its assumed high fatality rate. similarly, the short notice given for the lockdown of wuhan, a huge city of more than 10 million residents, sent a clear message to everyone that the novel coronavirus was the grim reaper. corona, the brand of the first car i owned and of the beer i had on my first visit to a mexican restaurant, was colored by images of a fearful virus, deserted streets, calm officials on tv news channels, and panicking crowds in wuhan hospitals caught on video by the we-media. unlike the countries who proposed or actually enacted herd immunity, the chinese authorities imposed very tough immunity measures, a lesson learned from the 2003 sars pandemic, when highways, the railway station, and docks in my hometown were closed overnight. nursing homes were under quarantine; no visitors were allowed in. local authorities advised avoiding public gatherings, including public square dancing and playing majiang. the most popular forms of social activity, especially for retired people, were no longer available. after the initial panic, it was discovered that the fatality rate of the coronavirus was much lower than sars. according to the world health organization, the sars mortality rate worldwide was about 11%. in early february, the chinese authorities claimed that the coronavirus mortality rate in wuhan was about 5%. subsequently, what elicited fear in the population was the future-to-come, particularly in the form of social unrest. on one hand, stricter quarantine measures were implemented: all roads were quickly blocked with cranes or tankers or stones; vehicles' use was not allowed, unless a special permit was issued; all grocery shops, markets, restaurants, and hotels were shut down; residents were not allowed to exit their residential areas except for grocery shopping at an arranged supermarket. in addition, central and local authorities watched closely for other concerns, such as food shortages and the inflation of prices. thanks partly to its rich agricultural products in a land of fish and rice, the impact of the coronavirus on food supply and prices did not affect my hometown. however, under the restrictions put in place, my hometown looked like a ghost town, and the uncertainty of the future frightened people of all social strata. in fact, what people fear most is that the coronavirus will never die and will come back again and again, either in the form of a future-to-come or a return of the dead. regardless, despite the medical or political ambition to eradicate the coronavirus, we might have to accept the fact that the virus will co-exist with us forever. for instance, the coronavirus has been mutating, and the way the coronavirus replicates itself in the cells of other organisms is ubiquitous. this mechanism of repetition and difference functions both literally and metaphorically. on one hand, the coronavirus reproduces itself through difference. merely a collection of genetic materials that seems to think with/like a human once it infects its host, the virus induces a feeling of the uncanny, a topic to which i will return later. in addition, news sources reported that infected patients tested positive again after they had been released from the hospital. robert redfield, director of the u.s. centers for disease control and prevention, admitted that some deaths from coronavirus have been discovered posthumously (cnn, 2020) . in other cases, the coronavirus acted like a whimsical tyrant who inadvertently signed a death sentence. for example, the only cases of death in my residential area was an old couple who lived in an apartment very close to that of my parents. they got infected by their son and daughter who came back from wuhan. what remained a mystery was that the son and the daughter had stayed with their parents for more than 20 days, much longer than the latent period of coronavirus. days after they were hospitalized, they died one after another. on the other hand, the coronavirus reproduces difference in its host organisms. the neighborhood my mother lives in is an acquittance community and an aging society. cadres and volunteers from the neighborhood committee have diligently attended to the needs of the old. aware of the higher fatality rate of the old, an ageist exhortation to quarantine was broadcast repeatedly through a portable loudspeaker placed at the gate of the neighborhood committee building. as stigmatized targets, senior residents were susceptible to the emotion of shame and, for this reason, chose to stay at home. the use of broadcasts and the instigation of shame illustrates how the coronavirus (re)produces, moderates, and polices the line between the public and private spheres. the coronavirus also changed the affective, moral, and power economy of the family. the spring festival is supposed to be the perfect time for a temporary family reunion of joy and harmony. when the lockdown continued longer than everyone expected, generational conflicts broke out. in extreme cases, the political infected families while they were trying to contend with the coronavirus during quarantine. for example, fang fang, a veteran chinese writer who lived in wuhan, posted her thoughts on life in quarantine on her or her friend's weibo account. those posts were later collected and published under the title wuhan diaries. public opinion on those posts varied and eventually led to a political debate between left-wing and right-wing netizens, eventually affecting family members who conflicted in their attitudes toward the wuhan diaries. along with the coronavirus, the memory of personal, generational, and political traumas returned. sars, the cultural revolution, natural disasters, and national humilities were recurring themes in representations of the coronavirus. the suffering and trauma in the epicenter deserve an envoi/dedication, and efforts have been made to achieve this goal, such as daily national and international coverage, fang fang's wuhan diaries, and we-media postings. in these kinds of representation, a rhetoric of "suffering as sublime" is usually at play. in addition, stigmatizing the suffering of others, or blaming the other for one's suffering, is another kind of dedication. both kinds of representations of the coronavirus attempt to take the moral higher ground by attempting to fix the coronavirus as a mere object awaiting to be represented. no matter what position the representation takes toward the coronavirus and its significances, the will to truth turns a dedication quickly into a testimony and even a perjury. a virus is an infectious agent that replicates only within a host organism. for the host, a coronavirus is a deadly stranger and an intimate family member at the same time. familiar, frightening, and secretive, the coronavirus reminds us of the uncanny, as discussed by freud. in his pioneering study, freud focused on the unsettling psychological state of the uncanny. distinct from the feeling of fear, the uncanny is a kind of terrifying feeling that is associated with something known and familiar. after an etymological investigation of the german words heimliche/unheimliche, and a close reading of hoffmann's story "the sand-man," freud (1964) unearthed the origins of the uncanny: "it may be true that the uncanny [unheimlich] is something which is secretly familiar [heimlich-heimisch], which has undergone repression and then returned from it, and that everything that is uncanny fulfills this condition" (p. 245). he also associates the feeling of the uncanny "with the omnipotence of thoughts, with the prompt fulfillment of wishes, with secret injurious powers and with the return of the dead" (freud, 1964, p. 247) . following the lead of freud, derrida worked on the concept of the uncanny to engage with marx's concepts of repetition, specter, and fear. refuting the claims that the tenants of marxism have died, derrida emphasizes the strange familiarity of the specter of marxism in the age of advanced capitalism. as derrida insists, the specter of marxism will continue to return from the future to visit us, to live with us, and to alert us. similarly, derrida (2006) interprets the uncanny through the concept of absolute hospitality, in which "one may deem strange, strangely familiar and inhospitable at the same time (unheimlich, uncanny)" (p. 212). remaining structurally open to future interpretation, the uncanny in derrida's account presupposes a materialism without substance, a messianic without messianism. derrida's understanding of the uncanny is critical to my reading of the coronavirus as a ghostwriter of envoi. as a ghostwriter, the coronavirus is a ghost who writes from the future. as a stranger and a family member, it writes with and in the place of the host. by writing an envoi, a kind of writing haunted by failure and repetition, the coronavirus makes itself visible and frightening in a spectral moment. however, the envoi is not exclusively governed by a ghostly logic that is followed by and instantiated through the coronavirus. in critiquing the tendency to unearth an ultimate truth, eve kosofsky sedgwick & frank (2003) regard affects as a possible way out of the binary opposition of truth and falsehood in representation. by invoking the power of the performativity of shame, they highlight the negative affects neglected by identity politics, dismissed and stigmatized: without positive affect, there can be no shame: only a scene that offers you enjoyment or engages your interest can make you blush. similarly, only something you thought might delight or satisfy can disgust. both these affects produce bodily knowledges. (sedgwick & frank, 2003, p. 116) in their view, shame is neither subversive nor mandatory; it works with other affects, drives, and representations to adapt the body to its situation. foregrounding bodily knowledge acquired through trauma commits us to thinking differently about representation and the envoi in question. fear of the coronavirus is not only the fear of a returning trauma as a ghostly logic in representation. more importantly, the coronavirus writes itself and writes about bodily memories of trauma in a constant play of materialization: inscribing fear in itself and on the body of the host permanently. with the end of the lockdown in hubei, the coronavirus pandemic is almost over in china. however, the coronavirus has been sending, and will keep sending, its fearful envoi. the enduring sign of the coronavirus pandemic for indians was not related to medicine or public health. it was the unprecedented exodus of migrant workers from metropolitan centers to their native rural districts, sometimes hundreds of miles away (mukhopadhyay & naik, 2020; petersen & chaurasia, 2020) . the scale of this migration was vast and is still being understood. it certainly provokes disturbing questions about urbanity and the fragility of a political compact that kept people in their place through calibrated deprivation (dahdah et al., 2020) . but for our purposes here, i will explore the ways in which it underscores the varying effects of the pandemic on different classes of people and the diversity of its signification. the virus in india is both a medical event to be dealt with through appropriate public health measures and a mediated discourse that has developed its own ramifications and responses. i argue that both forms of the virus have had tragic and miserable consequences, but on different classes and groups of people. like the televised persian gulf war of 1991 that jean baudrillard found to be a distinct and distorted signifier of the actual fighting on the ground, 1 the virus itself is not the same phenomenon once it is transformed into a signifier for other meanings and purposes. the novel coronavirus later named covid-19 emerged in the public consciousness as a distinct problem with the rapid rise in infections in several indian states by february 2020. in march, the government of india mandated an immediate "lockdown" of the entire country. this new term burned itself into the national consciousness and its many vernaculars almost instantly, as its meaning became physically apparent. it involved the physical arrest of people wherever they happened to be at the moment, and the prohibition of all commerce, traffic, and circulation. it was announced with a 4-day notice period by the prime minister, in an eerie echo of a similar announcement in 2016 of the withdrawal of paper currency. 2 that tragic farce had laid a historical precedent for this second tragedy to come. as a deeply iniquitous society and economy were forced to a halt, the effect was expectedly unequal. metropolitan indian citizens soon learned to cope with the new hardships of "work-from-home," homeschooling, online classes and meetings, and such social-media-driven innovations as cooking and cleaning without domestic servants and entertaining themselves in their houses and apartments. the government also encouraged the adoption of derivative coping mechanisms as soon as they were observed in other countries: applauding medical workers from the safe confines of apartment balconies and terraces; singing, chanting and clanging metal plates and dishes with utensils in cacophonous, solidarity of the gated classes; lighting lamps and candles; and waving mobile phone flashlights at appointed times (krishnan, 2020) . however, the actual effect of the virus became inseparable from the effect of the "lockdown." the sudden impoverishment of the majority of the country's population led to starvation, medical neglect, and a national panic. while invisible to the citizens in its first few weeks, it became impossible to ignore, when workers across indian cities started to simply walk back to their native villages. their exit from cities also emphasized the fragility of urban belonging: that in a crisis, indian cities were fundamentally empty shells, drawing people not through cosmopolitan attractions or civic rewards but by rural misery. 3 at this point, the virus was still largely a media phenomenon, while the "lockdown" was what had directly affected most indians: the sudden disappearance of work, wages, commerce, and circulation magnified the precarity of urban existence. the largely informal national economy quickly unraveled in a crisis. this crisis was exacerbated by the role of the virus in continuing the ideological and political discourses of the chaotic period immediately preceding the lockdown. the use of the virus to carry out "politics by other means" can be seen in other polities as well, but its entanglement with indian politics is particularly useful as a means to understand the virus as a set of signifying practices. the context of this political use of the virus as a signifier is also inseparable from the highly mediatized nature of indian politics and society. 4 the virus emerged as a discursive phenomenon in india at a crucial juncture in a national conflict over changes to the country's citizenship laws. with the rise to national power of the ruling rashtriya swayamsevak sangh (rss, or the national volunteers organization-a fascist group founded in 1922), india's national government had been attempting since 2014 to achieve its political goal of abolishing its secular and liberal constitution through a steady dismantling of public institutions (roy, 2020) . this conflict worsened in 2019 with the re-election of the rss-controlled government headed by the current prime minister, and the consequent repeal of laws that had hitherto guaranteed the autonomy of the occupied territory of kashmir. this was followed by a critical change to citizenship laws to specifically exclude muslims from gaining indian citizenship and institute a new "citizens' register" to determine afresh the legal status of all residents. 5 with reports of the parallel construction of detention camps outside major cities, the fascist inspiration and ominous intent of the new laws became clearer and more immediate. 6 protests and political resistance to the new measures emerged across the country, and were met with violent responses from the police and rss groups. matters had reached a head when the nationwide lockdown was suddenly imposed. except in a few indian states such as kerala, with still functioning local health systems, the lockdown did not involve any public initiative to test or prevent the spread of the virus. instead, in keeping with the ruling ideology of our time, citizens were mandated to protect themselves, on pain of being brutalized by the police if they failed. in this chaotic sauve qui peut scenario, the rhetoric of basic preventive measures took on ominous ideological connotations depending on who you were and where you lived. as it became clear that only access to clean running water, adequate space, and a home to live in would guarantee the efficacy of the public health guidelines, medical advice became meaningless for much of the country's population, especially the inhabitants of vast informal urban settlements in the metropolitan cities. in effect, a dual situation emerged: a parallel virus had infected the classes who lived in gated urban communities and formal neighborhoods and who followed its progress in daily primetime news trackers. positive cases, testing ratios, death rates, and other numbers soon flew across television and website screens in macabre charts, graphs, and complex animations, as breathless studio anchors enthusiastically tracked the competitive fatalities across states, regions, cities, and countries. as the formal state and civil society response to the virus grew more and more into a media discourse, its actual effect on the population was determined by existing social conditions and ideological practices than by the ideals of public health. 7 in the early period of its spread, the illusion of its control was maintained through the interpellation of the mass television audience as ideal national subjects. in a series of televised speeches, the prime minister exhorted citizens to planned acts of mass discipline, such as the applause, noise-making, and lamp-lighting exercises mentioned earlier. it took several costly weeks for the citizens to realize that this national son-et-lumière had only served to deafen and obscure a different and more real virus that had silently spread illness and death among urban populations who did not have houses or apartments with balconies. a starved public health system soon proved inadequate and unprepared. because this real crisis was not mediated or televised, there was no appropriate or meaningful response to it. the easy congruity of the eagerly adopted virus prevention measures with the practice of caste-based rituals of discrimination was not lost on most indians (george, 2020) . this fortunate coincidence enabled the easy normalization of virus prevention as a legitimization of existing hierarchical practices. the convenient prescription of social distancing appeared to keep the privileged class of wealthy and respectably middle-class white-collar workers as far away as possible from the physical contact or proximity of their social inferiors. the pandemic thus seemed tailor-made for defenders of hindu caste hierarchies, a righteous and suitably scientific legitimation of social discrimination. the fantasy of caste purity would have remained an abhorrent social remnant if it had not become part of state policy in the last few years. but in the context of the stateled legitimation of religious hierarchies and the consequent onslaught on emancipatory laws, this entanglement of the virus with caste and with the violent hate crimes against muslims acquired a dangerous dimension. it is this distrust of and disgust with a compromised public health system that drove so many indians streaming out of cities and into the relative safety of their impoverished rural communities. the alienation of muslims as a national other has been a part of the basic doctrine of india's current ruling group ever since its founders, awed by the nazi policy of extermination, adopted a similar goal for the erasure of non-hindu communities in india. the mass protests and popular uprising against the rss's attempts to irrevocably alter the basic structure of the country's republican constitution had reached a tipping point when the covid-19 epidemic was suddenly deemed emergent enough to impose an unprecedented "lockdown," in effect a de facto police state across the country. the imposition of the lockdown allowed police to destroy protest sites, detain protestors, and unleash a reign of terror across indian cities. caught in the initial crossfire were members of an apolitical muslim religious group, the tablighi jamaat, whose convention in delhi had been interrupted by the lockdown. jamaat members trapped in the organization's premises by the curfew were found to be infected with the virus. the consequent media narrative of the discovery of the infection among the jamaatis veered into the fantastical, with nightly news anchors debating the strategies of a "corona jihad" that was to be waged by militant muslims using the virus as a weapon (perrigo, 2020) . this dog-whistle narrative of muslim bodies as unclean spreaders of a foreign disease dovetails with similar narrative frames used to portray hindus from laboring and working castes as well. the manufacture of conspiracies surrounding the coronavirus can be seen across the world and is not unique to india. a disturbingly large proportion of americans, for example, appear to believe that the virus has been manufactured to enable mind-control through vaccination and 5g cellular signals by a ruling elite (fisher, 2020) . on rare occasions, these conspiracies do spiral out into real effects such as the bombing of cellular towers in britain and the anti-vaccination movement in the united states. in india, however, the covert encouragement of such theories by the state itself, to legitimize the hatred toward muslims, exacerbates and normalizes the rumors as mainstream prime time news which is then amplified and shared through an organized social media campaign (ellispetersen & rahman, 2020) . the vilification of the muslim other serves two purposes, one of furthering the state's broader agenda of religious and caste purity, and the other more immediate goal of providing a scapegoat for the inescapable rise in infections and deaths due to the virus and the inability of the state and society to understand the crisis. the brutal police crackdown that accompanied the lockdown and the violence of its imposition across the country were a small reminder of the routinization of the "lockdown" as a way of life in the occupied valley of kashmir, part of the only muslim-majority state in the indian union. the effects of the police state as a normalized entity have been multiplied since the abrogation in 2019 of constitutional laws guaranteeing the region's autonomy, even if such laws were honored more in the breach in preceding decades (zia, 2020) . the uncanny resemblance of a public health curfew to a military occupation is not coincidental, but the result of the colonial origins of both, and of the state institutions they represent. the symbiotic existence of caste-based discrimination, the extermination of a religious minority, and the colonial occupation of an entire province within the same body politic is made possible by the continuous interpellation of the mass of people to become national citizen-subjects. this call to obedience, broadcast daily through primetime television and magnified through the near-mandatory use of mobile phones, 8 is the only sign of a nation-state that is otherwise absent in the real world. the failure to stop the spread of the real virus is obscured as the interpellated citizen is urged, cajoled, and threatened to participate in the simulacral fight against a mediated virus in a purely semiotic realm. the washing of hands without the precious reality of running water, the maintenance of "social distance" in the absence of space, the exhortation to "work from home" for a population that is not housed, and the discourses of online socialization and commerce are all much more than signs of mere denial: they are the components of this new semiotic space, enabling the call to national belonging in a new domain, bereft of its mooring in the world. from a broader historical perspective, the coronavirus epidemic does not appear to have affected indians as much as the far greater fatalities caused by more prosaic diseases, hunger, and the increasingly toxic air and water (rukmini, 2020) . what has caused the greatest pain and panic is the response to the epidemic. this response has been not to the virus itself, but to a simulacral virus that appears to occupy the same space and shares the same name as covid-19, but which is a mere signifier, pointing to other, older evils. like baudrillard's hyperreal war, it has surpassed the real virus itself and has come to occupy its place. it cannot be wished away or prevented with a vaccine, it needs a response in kind: of new counter-signs and counter-discourses. a catastrophic pandemic unseen in a century, the current raging of covid-19 around the globe has undoubtedly produced a unique symbolic site for global, regional, and national imaginations. as the earliest epicenter of this infectious illness, china has witnessed the proliferation of discourses about the evolution of the pandemic on various media platforms, through which the chinese public has the rare chance to reflect on important issues regarding identity construction, social reformation, and nation building. while much attention has been paid to the stigmatization of china in euro-american politics, media, and everyday whisper that label the natural coronavirus as a cultural and ethnic fault (fu, 2020) , what has been overlooked is how china has portrayed other countries in this global health crisis, especially those surrounding nation-states in the same geopolitical area. east asia, or the sinosphere in the broader sense, with the collective memory of fighting sars in 2003, is thought to have responded to covid-19 more efficiently than many western countries (salmon, 2020) . how, then, is the east asian encounter with covid-19 depicted in the chinese public discourse? how does such depiction envisage china's relations with neighboring countries and its position in the area? in this essay, i discuss the ways in which the coronavirus pandemic has been appropriated by the chinese public for a (re)imagination of east asia. by exploring the evolving representations of its neighboring countries throughout the epidemic on chinese media platforms including weibo, wechat, and zhihu, i argue that the talk of the regional responses to covid-19 envisions a china-centered union of selected east asian countries in parallel with the historical tributary system of the sinosphere. through the expression of the nostalgia for imperial china, the discursive reconstruction of the east asian identity is a ratification of china's contemporary ambition to reclaim its geopolitical dominance. synchronized with the rapid transmission of the coronavirus in china and east asia between january and march 2020, the chinese public in this early phase drew close attention to the unfolding of the epidemic in its nearby countries, and japan and south korea in particular. with the disease breakout involving diamond princess (japan) and shincheonji church of jesus (south korea) frequently making news headlines, the discussions of how those countries responded to covid-19 flourished online, which, in combination with the continuous debates over china's own pandemic threat management, contributed to the imagination of the covid-19 rampancy as a regional challenge that china and its neighbors faced together. central to the discursive formation of this imagined community was the celebration of the incessant interaction and cooperation between china and some east asian countries to combat the virus collectively. in the wake of the outbreak when china was threatened by the crumbling of its health care system, the countries under the spotlight-japan and south korea-were widely appraised for the sympathetic and supportive approaches they took to help china overcome the severe shortage of medical resources. the media reports of japanese and south korean governments leading the international aids to china (gong, 2020) were echoed by numerous warm anecdotes on social media championing the heartfelt support from their people. perhaps the most well-known story of this kind, a japanese institution wrote a chinese-language verse on the boxes of masks it donated to the province of hubei: "rivers low, mountains high; the same moon in the sky" (trans. zhao, 2020) ("山川异域，风 月同天"), which immediately went viral online because of its signification of the long-lasting friendship between china and japan. according to account of the expedition to the east by the great master (唐大和上东征传) written by omi no mifune (淡海三船) (see wong, 2018) , this sentence was from an ancient poem written on the edges of the buddhist robes japanese missions (遣唐使) brought to tang china as the tribute from prince nagaya (長屋王). given its profound roots in the history of japanese envoys to imperial china learning from the chinese culture and civilization, this verse went beyond re-fostering the traditional sino-japanese solidarity. analogizing japan's mask donation with ancient japanese envoys' gifts, it also evoked the retrospective commemoration of the hierarchy between china and japan in history which almost vanishes in the modern era. therefore, the popularity of this verse may indicate the aspiration for the reoccurrence of such bi-lateral relations. indeed, this was only one example of the ubiquitous imaginary of the pan-east asian cooperation and exchange of goods and information as a modern emulation of the tributary system through which imperial china maintained its diplomatic and trade relations to neighboring countries and consolidated its dominance in the region for over a millennium. after china started to keep the pandemic under control and resume the production of medical supplies, this metaphor was further perpetuated in an attempt to accentuate that china's supplies of medical goods and anti-epidemic lessons to nearby countries drastically outnumbered what it was initially given. on weibo, china's return of masks and respirators to its neighbors was often explicitly compared with the "vassals' gifts" chinese emperors assigned to tributary states in posts like this: tribute is both the highest form of alliance and an advanced way of investment, but (this time) it is based on masks! recently, xinwu district in wuxi, jiangsu province donated 50,000 to toyokawa, aichi prefecture in japan in return for the 4,500 masks, protective clothing and other anti-epidemic materials toyokawa donated to xinwu district in february. (weibo source, march 25, 2020) this nostalgic use of metaphor implies a crucial undertone of sinocentrism of the public imagination of the community comprising china and bordering countries fighting against the coronavirus. the tracing of the origin of east asian solidarity to the past is suggestive of the ambition of the present. the chinese public not only fantasizes about a reunion of china, japan, and south korea for covid-19 but more importantly yearns for the recovery of their nation's leadership and centrality in this battle. as the coronavirus expands rampantly to the rest of the world from march 2020 onward, chinese media coverage quickly catches up with the shift of the epicenters from east asia to europe and north america and reformulates the pandemic as a global health crisis. against the depiction of how covid-19 created chaos, helplessness, and dysfunction in western societies stands the stark contrast of east asia as a safer zone where the outbreaks have been largely contained with success. with the similar control of cases less than 20,000, japan and south korea remain at the heart of this imagined safe zone in company with china even though the reality has seen even fewer confirmed cases in other parts of asia as well as the recent resurgence of virus spreading in all these three countries. this rhetoric is in concert with the prevalence of online deliberations about why east asia as an area has performed better than other parts of the globe in the containment of the virus. at the core of these discourses lies the construction of an east/west binary which frames the global responses to the pandemic into a competition in which "we" (the east/ east asia) have triumphed "them" (the west/euro-america). although china and neighboring countries diverge in the official approaches to handle the pandemic, their relative efficiency in virus containment in comparison with the west is considered to be guided uniformly by the cultural values they share as part of the "confucius east." in particular, collectivism-the principles of prioritizing community interests to personal interests, pursuing social harmony, compliance to authority, avoid causing inconvenience to others-has been glorified as the main drive for the people in east asia to more effectively cope with the governmental strategies in contact tracing, testing, social distancing, and mask wearing. similarly, the regional cooperation in the pandemic management is regarded as a manifestation of these values. for example, the reflections on how south korea has set a model of disease control using mass tracing and testing tend to recognize the smooth uptake of this procedure facilitated by koreans' collectivist mind-set that downplays individual privacy and complies with the data-mining measures to track and publicize their locations, activities, and close contacts. meanwhile, other popular discussions blame the religiosity of the shincheonji church members whose gatherings caused the initial covid outbreak in south korea, which is reflected from the titles of zhihu posts that describe the diffusion of the virus through "hallelujah" such as "the occupation of south korea by covid-19, everything has to start from 'hallealia'" and "south korean cult hallelujah devastated the country." apparently, these titles have no intention to mask the underlying tone mocking at the role of christianity in the acceleration, not mitigation, of disease spreading, which further serves as a foil to the power of confucianism to help south korea navigate away from the disaster. in fact, satire targeting at christianity represents the broader criticism of western cultural values in hindering the efficacious enforcement of restrictive and surveilling measures against the coronavirus. the east asian identity is thus reaffirmed through the clashes between the eastern and western civilizations. however, it is worth noting that the narratives about the east asian conquest of covid-19 are again permeated with the metaphor of the tributary system delineating china as the leader and role model in this imagined "safe zone." not only does the attribution of the regional success to confucianism call up the historical chinese centrality in the sinosphere but the emphasis on china's ability to offer lessons and instructions from its early experience for its neighbors to benefit from also ratifies the restoration of the "teacher/student" relation between imperial china and pre-modern japan and korea. far from a total reenactment of the historical sinosphere, this chinese imaginary of east asia engages with a purposeful selective process that amplifies china's solidarity with some east asian countries but simultaneously mutes others in the same region. as remarked earlier, a majority of the online narratives about the cooperative responses to covid-19 in east asia revolves around china, japan, and south korea, with less frequent inclusion of singapore as well as occasional reference to such countries as mongolia and myanmar. this emphasis on forming a coalition with japan and south korea is compatible with china's longterm agenda of promoting and dominating the china-japan-south korea union (中日韩一体化), which was recently reiterated by the three governments' consensus to speed up the negotiation of the free trade zone (中日韩自贸 区) (wang, 2019) . in this sense, the covid-19 crisis has offered a discursive site for the chinese state to rebuild this trilateral bond and remodel its significant neighbors whose national images, due to the respective disputes around diaoyu islands and thaad (terminal high altitude area defense), have been negative in china for almost a decade. while the china-japan-south korea triangle is romanticized in connection with other small countries, the alienation of some confucius societies from this imagined "cooperative" east asia is quite striking, especially given the outstanding results some of them have produced in the prevention of disease transmission. the first excluded category includes taiwan, hong kong, and macau-the territories outside the mainland in the great china area. whereas macau is often forgotten by the media as it has always been, both taiwan and hong kong are widely criticized and mocked for their attempt to politicize the pandemic as a weapon to confront beijing and increase international recognition. the second group pertains to north korea and vietnam-the authoritarian states that have close political and ideological bonds with china. for instance, north korea has been constantly questioned and satirized because of the lack of transparency in the disclosure of its epidemic circumstances. vietnam's outstanding handling of the virus which led to only 334 confirmed cases and 0 death was nearly silenced in the mainstream media coverage. in the unusual reference to vietnam in some zhihu conversations, vietnam's success was rarely celebrated but considered as a "threat" to china's leadership in containing the pandemic in the area. the trivialization and exclusion of these countries/ regions from the chinese imagination of east asia as a collective force fighting against covid-19 is not unexpected. in the first place, the negative attitudes toward them (except macau) reflects a backlash against the restrictive, noncooperative methods those governments have enforced to block the virus from mainland china (e.g., full border closure; ban on exports of medical supplies), which signifies their resistance to be incorporated into the modern tributary system chinese people have aspired. yet for taiwan and hong kong, this exclusion repeats the endeavor of chinese official propaganda to erase the distinction between them and the mainland and disavow their political autonomy. instead of being completely out of the picture, their responses to the coronavirus are mainly discussed as part of the chinese experience to consolidate the national identity. for north korea and vietnam, the negative impression may partly result from china's ongoing diplomatic conflicts with them in recent years regarding the south china sea and denuclearization, respectively. nevertheless, the shaking of the "socialist brotherhood" on the matter of covid-19 also implies the reluctance of the chinese public to articulate a regional identity around the axis of a shared political regime. in fact, assimilating itself with ideological and political allies is likely to obscure the focus of this imaginary on china's historical and cultural alignment with japan and south korea. as covid-19 begins to shift both the scholarly and media focus on an international scale to reconsidering the dark sides of globalization (chan & haines, 2020) and mourning for the disruption of european union (trofimov & pancevski, 2020) , china's reversed agenda of imagining a regional union is stunningly intriguing. on one hand, the eagerness to build solidarity with east asian countries represented by japan and south korea might be a strategy to react to the racialization of covid-19 as a "chinese virus" and the demonization of china as a "public enemy" and "trouble maker" in the euro-american political and media agenda (viala-gaudefroy & lindaman, 2020). by articulating china's resemblance (and collaboration) with the bordering democratic capitalist states (rather than the "socialist brothers") in the "confucius-inspired" success of halting the virus, the public discourse strives to construct a collective identity of the east so as to brush off china's label of the other imposed by the western imagination. ironically, this consolidation of the eastern identity also serves as a repercussion to otherize the west as the loser to the coronavirus. on the other hand, the rise of this east asian imaginary centering around china's historical and cultural bonds with japan and south korea has far-reaching implications for china's geopolitical strategies beyond the covid-19 pandemic and the realm of public health. rested upon the trope of the imperial tributary system, this imagination reflects how the chinese public discourse echoes the state ambition to recuperate the historical dominance of china in the sinosphere, which is part of chinese communist party's long-term project of "the great revival of the chinese nation" (中华民族伟大复兴), or in xi jinping's term, the "chinese dream" (中国梦). incorporating japan and south koreathe most important american allies in east asia-into the imagined tributary network might serve the specific purpose of weakening the u.s. hegemony in the region (see ikenberry, 2004) , whereas the tactic exclusion of north korea and vietnam indicates the indifference of many chinese to the state's political and ideological "comrades" (whose traditional alliance with china has often proven itself unstable and delusionary in the changeable economic and political dynamics in east asia). more importantly, this selective reimagination of the eastern union expresses the chinese public's nostalgic ideal of the nation's revival, which dreams of a return to the middle kingdom, the empire that reunites and leads east asia through culture and history. during the year 2020, which is anticipated to be the warmest year in human history, we failed to stop the rampant spread of a coronavirus called covid-19 and its disastrous impact on societies and individual lives. unlike its "cousin" sars, which broke out in early 2003 and vanished into thin air largely because of rising temperatures, the current respiratory epidemic has yet to show any sign of amelioration with the arrival of summer. news photos have shown audiences an incredibly bleak, bizarre, and somewhat surreal picture of life during the pandemic. streets are evacuated. stores are closed. public services are paralyzed. modernized cities have become empty and ghostly quiet. only scattered people equipped with medical face masks walk anxiously in this futurist, apocalyptic scene. to use timothy morton's concept, the covid-19 pandemic has become a "hyperobject," a phenomenon that possesses an ahuman time scale and an extremely diffused quality in occupying space. in such a space-time reconfiguration, or, in plain language, during this type of disaster, humankind becomes an obsolete idea, as humans no longer play a meaningful role in the space-times created by and for "hyperobjects." unfortunately, such a concept bares relevance in light of the uncontrollable proliferation of the coronavirus across the globe at this juncture. worse still, some epidemiologists warn that a new round of outbreak will likely occur soon in the coming fall. a possible scenario could repeat the conditions after the 3/11 fukushima daiichi nuclear disaster, when breathing with face masks, people eventually became accustomed to a state of emergency as the conditions for living and dying in the anthropocene. "[p]oison has become a normal feature of daily life, the second nature we have to inhabit" (berardi, 2012, p. 12) . while one can attribute the deterioration of nature to neoliberalism and its disastrous governance, this essay, rather, speculates on what foregrounds the involutional relationship between humans and the earth beyond the "nature-culture" divide. whether one is willing to admit or not, viruses are neither creation ex nihilo nor culturally and politically constructed representation. instead, they are beings that have always been part of earth's composition. in a prophetic book, the natural contract, the late philosopher michel serres (1995) describes the evolution of the earth's composition. in ancient law and modern science, nature was treated as an objective reference point, because it had no subject. existing objectively "out there," the earth was a space that did not depend on humans but only acted passively in relation to causality. yet, witnessing the ecological crisis arising in the 20th century, humans realized that the earth has been affected by our behavior and is now behaving like an aberrant subject! in recent scholarship, this subject has been referred to as gaia, the capricious goddess of the earth (see latour, 2014, p. 3) . the earth is full of action and so is covid-19. as described in news reports, the coronavirus looks for and hijacks its hosts; it finds easy purchase on, and takes control of, human bodies; it kills many, but not all, of its hosts so as to keep moving, spreading, replicating, and surviving. it would be impossible to talk about the virus without referring to those actions. cited by the washington post, a virologist came up with a vivid analogy for viruses by comparing them with destructive burglars. "they break into your home, eat your food, use your furniture and have 10,000 babies" (kaplan et al., 2020) . as the word "object" refers to entities that are inanimate and subject to chains of causality, viruses, in this sense, hardly fit into this definition. for instance, covid-19 remains mostly enigmatic, not least because it is considered strikingly sneaky-"the virus doesn't really want to kill us. it's good for them, good for their population, if you're walking around being perfectly healthy," said another virologist in the same washington post article (kaplan et al., 2020) . besides doing things such as breaking-into, eating, and having-babies, the virus is further endowed with intentions-it does not want to kill us! however, the coronavirus should not be mistaken for a subject, especially a subject-agent, which is historically associated with liberal humanism since the enlightenment and which is deeply rooted in the "nature-culture" divide, an ontological regime referred to by latour as "the modern constitution" (see latour, 1993b) . the idea of the subject as a product of euro-american modernity is indivisible from its aim to achieve individual sovereignty and autonomy. in a politico-legal sense, bounded individualism is the most evolved form of this idea in the wake of the global expansion of capitalism. faced with an unprecedentedly active earth in the late 20th century, nonetheless, this anthropocentric conception of the subject-agent has been confronting exponential challenges, among which the current coronavirus pandemic constitutes the latest one. to be clear, the term "subject" is a mismatch for covid-19, not because it is agentless and incapable of doing the same things that humankind does. the contrary is true: the state of being of the virus-what it is-can unfold only through its actions and long after its performances. at stake for the virus and humans is that there are "no pre-constituted subjects and objects, and no single sources, unitary actors, or final ends" (haraway, 2003, p. 6 ) far from being a de-animated object, or an anthropomorphized subject, gaia, the increasingly "rioting" earth, is a collective of actions that distributes agency in heterogeneous and surprising ways. as a result, "we must not believe in advance that we know whether we are talking about subjects or objects, men or gods, animals, atoms, or texts" (latour, 1993a, p. 167) , and also viruses until their actions are captured, and rendered into shapeswhether the shape of a human or of a virus. the story of the human-centered history is being replaced by an explosion of narratives about the increasingly animated and animating earth. however, the dualism of the subject versus the object, unfortunately, is still perniciously conserved in the mainstream reaction to the covid-19 pandemic. when societies are forced to act on the pandemic, the virus is almost exclusively treated as an object subject to the chain of causality. this tendency is clearly reflected in the mobilization of wartime rhetoric and discourses in conjunction with governments' anti-epidemic measures. for instance, when visiting wuhan right after its lockdown, sun chunlan, china's vice premier, warned that the country was facing "wartime conditions." likewise, only 1 month later, president donald trump declared a national state of emergency over the coronavirus outbreak in the united states. in this antagonistic discourse, contending with the virus, a not-yet-tamed and potentially threatening other, is framed as a relationship between humans and their enemies. for those who believe humans and only humans make history, a self-proclaimed war on the virus is unavoidable! peace, accordingly, is only imaginable to be reached, or more precisely restored, to an already existing order, established primarily for humans. mobilized to describe the relationship between covid-19 and humans, "war" is a terrible and even dangerous choice in terminology, due to its undertone of human exceptionalism. in fact, nearly 90% of the cells in a human body is "part of a vast community of companion species, particularly bacteria and viruses" (smart & smart, 2017, kindle 72) . unfortunately, most humans have yet to learn the meaning of living and becoming-with these beings who are made by and making humans at the same time. in her book staying with the trouble: making kin in the chthulucene, donna haraway (2016) invites readers to contemplate our troubling present, the chthulucene, an emerging regime of naturecultures, as opposed to the "nature-culture" divide. contrasting to the discourse of the anthropocene and the capitalocene, both of which are conceived as human-induced condition, the "chthulucene" is, first and foremost, concerned with earth beings who live in "manifold forms and manifold names in all the airs, waters, and places of earth"-they are monsters which "demonstrate and perform the material meaningfulness of earth processes" (haraway, 2016, p. 2) . the vicious coronavirus is evidently one of these monsters. despite the havoc it is creating in the present, the epidemic is a manifestation of the biotic and abiotic powers inherent in earthly actors and is part of "ongoing multispecies stories . . . in times that remain at stake" (haraway, 2016, p. 55) . as implied by the title, one of the valuable lessons of haraway's book is that, for humans in particular, there might be no better option other than to stay with troubles, of which humans are never innocent. staying with the troubles demands caring for all the threads that bind us together and make our existence possible in the first place-humans are made by countless earth beings and vice versa. it also means that we are required to weave unexpected and even dangerous connections with others, in haraway's (2016) words, making kin as oddkin "in unexpected collaborations and combinations . . . we become-with each other or not at all" (p. 4). this insight is particularly useful for thinking about viruses. because viruses have "no cellular machinery of their own, they become intertwined with ours. their proteins are our proteins" (kaplan et al., 2020) . in this sense, the evolution of humans and viruses is inseparable from the process of involution of the two into one. in other words, becomingwith means that, by definition, a "we" always precedes an "i," a "you," or a "they." the so-called "asymptomatics" provide an excellent example of this point. asymptomatics refer to those who test positive for covid-19 but, confusingly, do not suffer from illness or show any symptom of the disease. asymptomatic infections or carriers are possibly greater in number than those with symptoms. at this point, it is impossible to decide which of the two types is more typical of covid-19 infections, because, as a researcher at the university of oxford says, "there is not a single reliable study to determine the number of asymptomatics" (shukman, 2020) . in the same news report, neil hall, a biomedical expert, suggests considering asymptomatic cases of the coronavirus as the "dark matter" of the epidemic, as invisible and not-yet identified dark matter is believed to make up most of the matter in the universe. despite the fact that no conclusion has been reached about the enigmatic phenomenon of asymptomatics, the differences that manifest among patients reveal that the virus, and the particular cases of infection, should be examined as specific units. in other words, between the virus and humans, the specificity of an encounter matters. unlikely to be autopoietic systems that reproduce autonomous units, the virus and an infected body constitute a collectively produced, sympoietic system that does not have self-defined spatial or temporal boundaries. in these cases, and from a non-anthropocentric, philosophical point of view, the idea of bounded individualism has to be discarded for good. beyond the divide between the subject and the object, what emerges are ontologically heterogeneous practitioners who are involved in each other's lives. besides evolution, living also relies on involution. without any intention of "romanticizing" covid-19 and the current pandemic, staying with the trouble, as articulated by haraway (2016) , is "to make kin in lines of inventive connection as a practice of learning to live and die well with each other in a thick present" (p. 1). the coronavirus does not happen as a matter of fact, which "passively" waits to be discovered, investigated, tamed, or neutralized by "active" humans. what we call the covid-19 pandemic manifests itself as a differentiating and relational effect because it matters by bringing into being various relations between humans, and between humans and their oddkin. in this view, science is only one practice among many others to capture the efficacy of its mattering. in addition to biomedical measures, a more critical question for the coronavirus crisis is "what method does the matter demand" (thompson, 2018, p. 13) ? proposed by haraway for living in the chthulucene, the string figure might also serve as an appropriate method and image for the pandemic, characterized by its exceptional contagiousness and interactivity. consisting of "passing on and receiving, making and unmaking, picking up threads and dropping them," the string figure is all about "becoming-with each other in surprising relays" (haraway, 2016, p. 3) . crucial to this method is that it does not guarantee what is obtained turns out to be good in the end, because living itself has become so dangerous in this very thick present-agencies are distributed, conflicting, and entangled in a myriad of practitioners, human and non-human alike. in this pandemic, we are all playing the game of string figures with our oddkin. it is not beneficial to judge in advance who is a subject and who is an object, or which one is active and which one passive, as all participants might be capable of something that matters in one way or another. for example, one thing that the respiratory disease teaches us is that not only breathing matters but also the manner how one breathes matters to others. life and death happen inside specific connections and their mattering in mundane, and even fleeting, encounters. making covid-19 matter requires us to reanimate "what is coming into states of matter and mattering in bodies, stories, acts, and events" (stewart, 2018, p. 24) , in other words, in the vicissitudes of our ordinary lives. for the future of this thick present, one key is to stop imagining the crisis of the coronavirus as something wholly predicated on effective vaccines and scientific solutions. instead, humans must learn to connect and also care for threads, some of which are obvious, some elusive, some vicious and dangerous, and some fictional. we may need to discard terms such as "overcoming" or "solution," and turn to terms like "participation" concerning all that we are uncertain of but have to live and become with, together, in the "metamorphic zone" called the earth (latour, 2014, p. 13 ). what does it mean, the plague? it is life, that is all. the most abundant biological entities on earth, viruses are forever and everywhere. suspended between living and being dead, they are simply there, a slimy strip of ribonucleic acid (rna), as biologists tell us. poorer in life than tardigrades, incapable of movement, and having no logistic of their own, they ride on and feed off others to replicate themselves, to become the viruses that they are. as smart schoolchildren know, they are transmissible and must be so transmitted as to go viral, to become the viruses as we know them. dependent entirely on carriers, that is, exploiting others' hospitality, without which they have no life (but also no death either), viruses exemplify transmissibility. they live and thrive, as it were, only if their hosts are susceptible, in motion, and in contact and they die or die down when susceptible hosts are either unavailable or no longer hospitable. defined, that is, made finite, by transmissibility, and yet transcending its barren finitude through parasitism, viruses exist and operate like pure media, self-generating and selfgenerated by being entirely coterminous with the channel through which they flow and multiply. interpolating and encoding themselves in the metabolic cycle of others, thereby reproducing themselves passive-actively, they mediate by colonizing others and, in so doing, mediate themselves by proxy, going about so energetically and indiscriminately as to cause the demise and thus thwarting unwittingly their own propagation. if viruses communicate anything, if their shadowy occupation of host bodies sends any message, it is their very own communicability, their ability to disseminate themselves over a large population with effort less than minimal. although all over creation and in abundance, most of the viruses cause us no harm and we pay them little attention, even though they populate our body and capitalize on its resources. they become a matter of grave concern when they infect us, when they not only put themselves inside (in-ficere) our body and stain its normal functioning, but also threaten to afflict as many people as their "infectivity" attacks. more dangerous and less tamable than most microbes, viruses invade our body and compromise it at the cellular level. they do not just make us sick; they bring about plague. once seen as a cause of infection, viruses accrue significance and take on the label "pathogens." to refer to viruses as pathogens implies that they are "medicalized," that they not only enter into a relation with humans who regard them as toxic and virulent, but are also seen as a problem to be addressed in a methodical, systematic, that is, "scientific," manner. it is through this medicalization that viruses are individuated and identified as a distinct biological entity and, having been so captured and given a name-for example, h1n1, mers-cov, sars-cov-2, covid-19, and the like-by what might be called the "clinical gaze" and its taxonomic procedures, they enter into sciences and become a focus of medical research, made all the more pressing if and when they create public health crisis. more than one hundred years after martinus beijerinck gave the name contagium virum fluidum (contagious living fluid) to the incitant of tobacco mosaic first discovered by adolf mayer and dimitri ivanovsky, viruses are now actively collected, classified, and manipulated by scientists in highly restricted spaces called laboratories, most of which, like the viruses housed carefully therein, are hidden from public eyes. while slimy poisons were once thought to be sent down by god to punish us for our sins, we now see viruses not only as an object of scientific investigation but also as a medical challenge that nature poses to us as biological creatures on earth. like birds, bats, and rats, we are all equal opportunity hosts to killer germs. not all viruses are fully pathogenic, but pathogenic viruses are ever ready to go viral when the conditions are ripe. however, although viral infection may break out and spill over, it does not mean that there is a pandemic. "pandemics," as virologists tell us, "begin when a brandnew virus infects a human who also at that point is able to transmit the virus to other humans" (buettner, 2020) . two points should be noted without delay. first, pandemics are not created by transmission of viruses from some source to humans, but from humans to humans. breakouts of viral infections among members of a primate community deep in the amazon rainforests, for example, may be large scale and may disturb ecological balance alarming to conservationists, but they do not for all that count as pandemics in the sense that the term is properly used. viruses might infect one or more individuals, but humans are responsible for creating the conditions that transform infections to outbreaks and outbreaks into pandemics. pandemics, in other words, are not natural or biological phenomena; they name a human crisis, a contagious malady plaguing humans who are both agents and patients at the same time. contagious diseases are disastrous to all, locked, as we are, in the same bubble in which microbes live and grow, but pandemics are decidedly more pernicious in that we become, often unknowingly, the source and the cause of our own infestation. second, pandemics are "declared." as is the case with catastrophic events in history, like wars, famines, or mass cultural anomaly as bizarre as the chinese sorcery scare of 1768, whose duration and identity result from an act of punctuation and sense-making entirely sociopolitical in nature, pandemics too begins with a performative act that announces their beginning and, having made them to begin in this way, determines when they reach their end, even though the viruses and their carriers may still be with(in) us (see kuhn, 1992) . naming not microbial activities in nature but a crisis for humans, pandemics are events made real, public, and urgent, as just said, by a performative-a speech act, to be exact-whose authority in pronouncing their beginning and end depends on the very force that makes the declaration authoritative and forceful in the first place. brought into being by discourse and public communications, pandemics are social constructions; they signal a state of emergency-appearing, first, as physical ailments on the part of individuals, subsequently identified and ratified by medical and scientific community as a real health problem, and finally materialized by authoritative broadcast and public acknowledgment, thereupon becoming a public policy issue to be addressed by political leadership, all these over a determinate territory. once established as such, a pandemic individualizes a collective paroxysm, making it a public enemy by giving it a face, a name, a certain life span in the social calendar, without which the havocs wreaked by the virus would not be the crisis its name designates and invokes. it is in this declarative nature of pandemics that we can see how viruses, once medicalized and publicly acknowledged, are inevitably entangled with science, history, culture, and politics. socially constructed by a decision, by a cut or break into regular time, they mark a "zone of exception," a temporal heterotopic, as it were, where we, individually and collectively, stand to one another as equal subjects to illness, unfreedom, and death in the unending drama of man against nature and its hostile elements. viruses are viruses are viruses. they have no political content; operating according to the laws of physics, chemistry, and biology, they come and go on their own rules and on their own times, as nature dictates. in sharp contrast, pandemics are biopolitical phenomena; they are moments of discontinuity or rupture in social order, shot through from start to finish with forces and factors that shape culture, history, and economy, which in turn determine what they mean and how they come about and come to pass. moreover, and importantly, a pandemic is not a single, monolithic event; it is a series of localized epidemics, each with its own point of origin, its own history, its own epidemiological pattern and impacts. further still, all these factors crisscross one another in a complex, nonlinear fashion, amassing multiple agents and stakeholders in such a critical fashion that the language of war is often used by the authority in charge to quell the infectious assault. 9 pandemics force social changes precisely because the changes they incur invite resistance. it is for this reason, perhaps for this reason alone, that pandemics inevitably appear as a site of social contestations, politicizing and politicized by the heterogeneous constructions barely betrayed by the name of a single virus. 10 it is for this reason too that pandemics assert themselves as a sign of generalized cultural and economic strife, a symptom of social struggle underlying the health terror that a viral breakout unfailingly induces. covid-19 is a novel virus, novel in that scientists do not fully understand how it afflicts the body and therefore cannot predict its epidemiological paths. to control its spread, we have no choice but to employ methods developed from past experiences, such as quarantine/isolation, social distancing, face coverings, and contact tracing, to name a few now well-known. because viruses are infectious, to control its spread is, understandably, to separate and to isolate. this means that people be kept away from one another. instead of gathering or being together, we make ourselves scare; better yet, we isolate ourselves, even if begrudgingly. more than that, the injunction of isolation leads straightaway to insulation in that the ultimate, foolproof means of isolation is to literally atomize ourselves, to turn ourselves into windowless monads. indeed, all the mitigation measures we hear about of late-quarantine, mask wearing, hand washing, and social distancing-are in reality anti-social measures. don't reach out and don't touch anyone! cover up your face! just as social distancing-a contradiction in terms of sorts-means keeping physical distance, and just as mask wearing reduces mutual recognition based on simple vision to its unnatural minimum, (self-)isolation and quarantine all but eliminate human contact of all kinds. when the plagues struck, we were all lepers; when covid-19 strikes, we are all windowless monads. pandemics are born of communicable diseases, yet for this reason, they force us to be incommunicable. flattening individuals and bringing to a halt exchange and commerce of every kind, they turn a society into one that is against society. if there is a history of pandemics, it is a history of anti-social history. neither alive nor dead, neither this nor that, viruses are by nature improper. never proper, that is, never being (of) themselves, they appropriate-always ready to make others their own. they are pure media, as suggested earlier. viruses are pure because they mediate unconditionally. however, inasmuch as unconditional mediation performed by viruses leads to the demise of their host, upon whom they depend for their parasitic reproduction, viruses end up annihilating themselves by their very nature; they are always already their own collateral casualties. rendering themselves nil by simply being and subsisting as themselves, pure media are no (longer) media. unconditional mediation ends all mediations. by bringing society to go against itself, viruses commit suicide, so to speak, by killing their host, by the unconditional abuse of others' hospitality. and, alas, weat least some of us-are spared. covid-19 is a new virus. but, unlike the known flu viruses, or h1n1, sars, and the like, covid-19 is considered "novel," not the least because, as indicated earlier, it frustrates scientists' understanding. "it has been like nothing else on earth," says an infectious-disease expert, who falls victim to the virus; "i knew i had the disease; it couldn't have been anything else," but "i don't understand what's happening in my body" (yong, 2020) . there are many things, inanimate or living, on earth that are like nothing we know so far, and there are many things happing in our body that we do not understand at all. covid-19 can justifiably be called "novel," but isn't every virus novel in its own way and at some moment in time? isn't being novel the normal course of event in life and in life sciences as well? "there is novelty here," remarks a prominent epidemiologist karl friston upon leaving a lab meeting about covid-19, but he quickly adds, "so this, from my point of view, is just an average day" (kosner, 2020) . being novel is the very characteristic of all viruses and many other things in nature as well. the novelty of covid-19 may not be as novel as we think. what is possibly novel about covid-19 is the fact that it gives us the first pandemic in our truly globalized age. the global village, in which we now live, is so hyper-connected-not only by technology but also through affluence, commerce, and global travel-that an infectant can travel from one city to another as fast as jet streams flow. connectivity translates qualitative diversity into measurable multiplicity, reducing distance and difference for the formation of the common, which in turn strengthens connectivity. to be alive, as few would disagree, is to be connected, literally and in every other sense. but this means that we must live in and with the risks that global connectivity brings to us. to be connected brings with it the possibility of being stranded in harm's way. as covid-19 makes clear, "connectivity is the killer" (kosner, 2020) . after all, life depends on maintaining boundaries and keeping differences. deadly viruses are deadly because they breach them. as infection rate rises, so does anxiety. and bleak scenes spread as wide as the virus goes. deserted streets, boardedup stores, closed factories, shot-down public transportations; remote learning, work-from-home; stock markets crashed . . . and, worse yet, "i just lost my job." individual solation leads quickly to desolation across the board. and economy bears the brunt of a colossal coronal attack. shortly after covid-19 spread out of wuhan, china, to europe in january 2020, stories about the economic plight began to top the list of topics in public forums and news media. the future we face seems to lie in one of the two choices: to die from hunger or to die from the disease (餓死 或病死), as the expressions go in chinese media. it is not for no reason that a policy brief released in june 2020 by the united nations on the impact of the pandemic is given the title "the world of work cannot and should not look the same after this crisis" (guterres, 2020) . the address on the launch of this brief, given by the secretary-general antónio guterres (2020) , begins as follows: the covid-19 pandemic has turned the world of work upside down. every worker, every business and every corner of the globe has been affected. hundreds of millions of jobs have been lost . . . many small and medium-sized enterprises-the engine of the global economy-may not survive. after painting a depressing picture of the future and explaining how difficult it will be for the world economy to return to "normal," guterres's (2020) address makes a hardly perceptible turn when he says "let's not forgot the pre-covid-19 world was far from normal." it seems then that, rather than shattering the world of work as we know it, the covid-19 pandemic simply exposes in higher resolution the "tremendous shortcomings, fragilities and fault lines" that have been eroding society and economy from the bottom-up for decades. the pre-covid-19 world, in which we thought we lived a normal life, is not as normal as we think (see guterres, 2020) . to save the economy under siege is to "return to normal" as soon as possible, so cry the bureaucrats and journalists alike. but what is "normal" in this case? what does "being normal" mean exactly? is the world, old or new, ever normal? there are norms regulating life, but has there ever been a "normal life" as such? the so-called normal life, a life before covid-19, to which we pray to return, is in truth one of recollection, a romantic one at that, as the un policy brief readily admits. just as a viral infection may display more than one symptom on the part of its victims, embody more than one single illness, and create more than one single public health challenge, life, as it is actually lived, is hardly reducible to one normal life. in fact, the socalled normal life is the one that brought us the pandemic in the first place. to live is to live normally; to return to normal is what living is all about. the so-called new normal is both new and not so new, which is to say, it is neither really new nor really normal. perhaps the world has never been and will never be normal, whatever our idea of "being normal" means. if a pandemic can turn the world upside down, it is because life has been turning and turning again. and anything that returns cannot be entirely new. humans have been haunted by viruses since time immemorial. from the prehistoric pandemics in northeastern china 5,000 years ago, uncovered at sites now called hamin mangha and miaozigou, to the justinian plague (541-549 ad) that may have helped to bring down feudalism, or the small pox outbreak that finally toppled the aztec empire before hernán cortés returned to the region in the spring of 1521, viral infections have tormented the lands and their people over millennia. traveling with host animals and humans, viruses had gone global long before globalization became a fact. there are 10 known pandemics in the last 250 years, all displaying the same pattern of spiking in seasonal waves after the initial attacks. covid-19, and some of its coronal cousins, will undoubtedly expand the list. to those who are living through its assault, the impacts brought about by covid-19 are more or less clear and more or less measurable. but what is the meaning of covid-19 when the current pandemic is over? will it be remembered? if so, in what way and to what extent? if the history of pandemics has taught us anything, it is that history tends to repeat itself, that viral outbreaks are an ineliminable part of the natural history, in which humans are a part and in which no "zone of being" is free from viral infection. recall the spanish flu of 1918, the worst pandemic during the last two centuries. it is estimated to have wiped out 50 million people worldwide, meanwhile infecting 500 million, a third of the world's population at the time. however, despite its short distance of mere one hundred years from us, few people today know much about it, and still fewer are able to understand or feel the impact it had at that time. its centenary a short time ago passed noiselessly, certainly not for lack of stories or records. like the many plagues before it, the spanish flu, it seems, never quite made itself into what reinhart koselleck (2018) calls the "the space of experience" (p. 34). failing to make its way into collective memory, it is also helpless in figuring into our "horizon of expectation" (koselleck, 2018, p. 14) . if the spanish flu faded largely from memory, all the woes caused by covid-19 are, likewise, likely to dissipate in time, regardless of how we feel and say about it now. there was a pre-coronavirus world, and there will be a post-coronavirus world, but viruses, known or novel, will outlast our worlds. viruses are everywhere and forever. so, plagues will never disappear for good (camus, 1991, p. 307) . but what then does it mean, the pandemic? it is life, that is all. a troubled memory, fading, under the vast indifference of the sky. until the gate of oran closes again. assembled in this forum, the five short essays provide some modest reflections on the coronavirus pandemic and its still unfolding consequences. committed to a variety of disciplinary perspectives and interests, the authors did not set out by pursuing any preset direction or common agenda supposedly carried out collectively in our intellectual labor. rather, what unifies the diverse inquiries in these essays is the shared awareness about the confusion in the public discourse that constantly fails to distinguish a coronavirus called covid-19 from the covid-19 pandemic, or as briankle reminds us in his essay, from "a series of localized epidemics." this alertness constitutes a common ground in addressing specific issues or phenomena in these essays. this forum is anything but comprehensive. if it can contribute to the discussion of the crisis, it is most likely because all the essays refuse to bind the pandemic exclusively with the coronavirus and to position the virus and humanity in rigid opposition to each other. in her multispecies ethnography, anna tsing tells a marvelous story about matsutake mushrooms. "when hiroshima was destroyed by an atomic bomb in 1945," says she, "it is said, the first living thing to emerge from the blasted landscape was a matsutake mushroom" (tsing, 2015, p. 3) . when human history temporarily comes to a halt in disasters, matsutake, and also viruses in our case, may well survive and continue to thrive with their own stories. histories are being made every day by humans and non-humans alike; however, the future for those histories to converge has still yet to come. as demonstrated in the essays gathered here, while governments and the public are desperate to frame the virus in their own social and political narratives, the virus also works hard to inscribe its historicity on the earth and humans too. if a message must be dispatched out to all at this juncture, it is that for a future of collaborative survival, the stake of living together has nothing to do with harmony and conquest, but is derived from "disturbance-based ecologies" (tsing, 2015, p. 5) , that is, plagues. plagues are life, that is all. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) received no financial support for the research, authorship, and/or publication of this article. gong yuan https://orcid.org/0000-0001-8352-3541 xuefeng feng https://orcid.org/0000-0002-7692-052x notes 1. in a trilogy of contemporary essays, baudrillard (1995) argued that the war in the desert was a new phenomenon, because it was defined and shaped by its discursive aspect as a form of television programming, regardless of what happened on the ground. 2. that earlier announcement called "demonetisation" led to a vast contraction of commerce and an immiseration of a majority of the population which has still not recovered, and is now widely considered an unnecessary exercise of personal whimsy. for an analysis of the economic consequences, see ghosh et al. (2017) . 3. the decline of indian agriculture is not adequately discussed in the celebration of urban growth. its effects are however inescapable and directly lead to the growth of informal settlements in cities (balakrishnan, 2020; jaffrelot & thakker, 2020) . 4. mediatization, or the analysis of events with their mediated construction as the starting point, is a phenomenon that has grown in importance across cultural contexts, as media theorists attempt to understand the increasing influence of media forms on culture, especially with the virtualization of human interaction and the redefinition of community through the use of social media and mobile communication. for a fuller discussion, see couldry and hepp (2013) . discontents: an indian history (2013), jayal (2019) traces the current shift in the discourse of indian citizenship from an egalitarian rights-based model to a new regime predicated on religious and cultural identity, given shape through the concomitant technocratic frames of transactional welfare and biometric identity. 6. four short essays provide further context and narrate the response: shankar et al. (2020) . 7. partha chatterjee's (2004 chatterjee's ( , 2011 insightful categorization of indian society separates the distinct ontological domain of a small formal "civil society" that includes rights-bearing citizens, from the vast undifferentiated mass of the population that constitutes "political society" and which forms the actual locus of democratic practice. 8. the current indian government has dramatically increased the acquisition and use of big data in governance, including a reliance on biometric identification for access to welfare programs and the use of mobile phones for access to services: part of the government's covid-19 response was in the form of a mandatory mobile application that purported to use location tracking to show active virus infections in the user's vicinity. an analysis of its invasive nature can be found in a working paper by deb (2020). 9. societies always declared war on problems they cannot solve: war on drugs, war on poverty, and the like. it is no surprise to see donald trump refers to covid-19 as an "invisible enemy" and calls himself a war-time president in his speeches on the covid-19 pandemic. similar examples abound across the board throughout history. it is widely recognized by epidemiologists today that the model developed by john snow based on the cholera outbreaks between 1831 and 1853 in england is too linear to be of any use in contemporary pandemics. like the global climate instability or financial market volatility, pandemics are nonlinear phenomena, displaying a high degree of uncertainty that defies simple causal explanation. on this, see kosner (2020) . 10. it is therefore not surprising that we observe donald trump repeatedly refers to covid-19 as wuhan virus or kung flu in reaction to his rise and fall in poll and public opinion as he tries to find scapegoat, in this case, china, for his sorry failure in handling the crisis. a virus is always more than a virus when it enters the body politic. india's brutally uneven development patterns are mapped in routes migrant workers are taking home. scroll the gulf war did not take place bifo covid-19: straight answers from top epidemiologist who predicted the pandemic the plague. vintage diseasescape: coping with coronavirus, mobility, and politics. global-e the politics of the governed: reflections on popular politics in most of the world lineages of political society: studies in postcolonial democracy cdc director says some coronavirus-related deaths have been found posthumously conceptualizing mediatization: contexts, traditions, arguments the covid-19 crisis in india: a nascent humanitarian tragedy. books & ideas public policy imperatives for contact tracing in india specters of marx: the state of the debt, the work of mourning and the new international coronavirus conspiracy theories targeting muslims spread in india. the guardian why coronavirus conspiracy theories flourish, and why it matters. the new york times the standard edition of the complete psychological works of sigmund freud as coronavirus spreads, so does racism and xenophobia covid-19 lockdown and the pandemic of caste demonetisation decoded: a critique of india's currency experiment chinese-japanese-s. korean relations evolve to meet the challenge of covid-19. global times the world of work cannot and should not look the same after this crisis the companion species manifesto staying with the trouble: making kin in the chthulucene american hegemony and east asian order by revealing magnitude of migrant worker phenomenon, covid-19 points to rural distress. the indian express reconfiguring citizenship in contemporary india the coronavirus isn't alive. that's why it's so hard to kill sediments of time: on possible histories karl friston takes on the pandemic with the brain's arsenal high on talk, low on substance: modi's speech showed india is ill-prepared for covid. the caravan soulstealers: the chinese sorcery scare of 1768 the pasteurization of france we have never been modern agency at the time of the anthropocene migrant workers distrust a state that does not take them into account it was already dangerous to be muslim in india. then came the coronavirus india racked by greatest exodus since partition due to coronavirus. the guardian india: portents of an ending: modi, the rss and the rise of the hindu far right. the nation how covid-19 compares against other killer diseases in india why east beat west on covid-19: east asia has handled and contained the pandemic far better than the west on nearly all metrics shame in the cybernetic fold: reading silvan tomkins the natural contract the demagogue and his labyrinth. the baffler coronavirus: the mystery of asymptomatic "silent spreaders posthumanism: anthropological insights mattering compositions labyrinth of linkages: cinema, anthropology, and the essayistic impulse coronavirus crisis threatens to split an already fractured eu the mushroom at the end of the world: on the possibility of life in capitalist ruins donald trump's "chinese virus south korea agree to continue push for free-trade deal despite ongoing tensions across region. south china morning post buddhist pilgrim-monks as agents of cultural and artistic transmission: the international buddhist art style in east asia, ca covid-19 can last several months the popularity of "rivers low, mountains high; the same moon in the sky" and its english translation the hindu rashtra comes of age. contending modernities li lu is an associate professor of literary theory at the school of chinese language and literature and a research associate at the center for literary theory at beijing normal university. he teaches courses on marxian aesthetics, critical theory, and translation theories.srinivas lankala teaches in the department of communication at the english and foreign languages university, hyderabad. he works in the areas of semiotics and critical theory, and engages with questions of politics, history, and nationalism. key: cord-293126-6ae1p15w authors: liu, yu; saltman, richard b. title: establishing appropriate agency relationships for providers in china date: 2019-08-27 journal: inquiry doi: 10.1177/0046958019872348 sha: doc_id: 293126 cord_uid: 6ae1p15w physicians play multiple roles in a health system. they typically serve simultaneously as the agent for patients, for insurers, for their own medical practices, and for the hospital facilities where they practice. theoretical and empirical results have demonstrated that financial relations among these different stakeholders can affect clinical outcomes as well as the efficiency and quality of care. what are the physicians’ roles as the agents of chinese patients? the marketization approach of china’s economic reforms since 1978 has made hospitals and physicians profit-driven. such profit-driven behavior and the financial tie between hospitals and physicians have in turn made physicians more the agents of hospitals rather than of their patients. while this commentary acknowledges physicians’ ethics and their dedication to their patients, it argues that the current physician agency relation in china has created barriers to achieving some of the central goals of current provider-side health care reform efforts. in addition to eliminating existing perverse financial incentives for both hospitals and physicians, the need for which is already agreed upon by numerous scholars, we argue that the success of the ongoing chinese public hospital reform and of overall health care reform also relies on establishing appropriate physician-hospital agency relations. this commentary proposes 2 essential steps to establish such physician-hospital agency relations: (1) minimize financial ties between senior physicians and tertiary-level public hospitals by establishing a separate reimbursement system for senior physicians, and (2) establishing a comprehensive physician professionalism system underwritten by the chinese government, professional physician associations, and major health care facilities as well as by physician leadership representatives. neither of these suggestions is addressed adequately in current health care reform activities. chinese health system development and economic reforms in the past 70 years have nurtured the current unique physician agency relations in china. between 1949 and 1978, the chinese health care system was designed with the objective to provide "equal access for all regardless of ability to pay," an ideology championed by the chinese communist party under mao zedong. 1 to achieve this goal, the chinese government inquiry assumed control of all aspects of health care and delivery-it provided funding for the construction of hospitals and clinics, paid health workers a fixed salary, and set the prices for medicines and services. 2 at that time, all physicians became employees of public hospitals, establishing the foundation of the current dominating role of public hospitals, especially tertiary-level public hospitals in china. 3 while the post-1978 economic reforms and the marketoriented approach have helped develop the chinese health care system (eg, the number of hospitals in china has increased from 9902 to 20 918 between 1980 and 2010), 4 new challenges have also emerged. first, governmental subsidies to public health care facilities declined dramatically after 1978. the government's subsidies to public hospitals fell to merely 10% of their total expenditures by the 1990s, 5 and 90% or more of chinese public hospitals' revenue continued to depend on drug sales and services in 2010. 6 while chinese public hospitals continued to have a bureaucratic and complex government-run regulation and management system, 3 they also were expected to behave like for-profit entities to earn profit to survive and to continue being competitive in the health care market. 7 second, because laborrelated medical services remained underpriced, 8 the chinese government set a higher margin rate for high-technology procedures and diagnostic tests, and hospitals are allowed to charge a 15% to 25% mark-up on drug sales (15% for western medicine and 25% for traditional chinese medicine). 9 such policies provided financial incentives for hospitals to begin a "medical arms race" to scale up their provision of high-technology diagnostics and interventions, as well as to overprescribe drugs. [10] [11] [12] third, most of senior physicians' income from hospitals is still a combination of basic salary and bonus, 13 with the bonus coming from hospitals' financial profit. 14 to increase their hospital's profit, hospital management tied the physicians' bonus to their contribution to hospital profits, which has intensified the overprescription of drugs and overuse of diagnostic tests. 5, 7, 8, [10] [11] [12] [15] [16] [17] such an extrinsic bonus incentive method may also "crowd-out" physicians' intrinsic concerns for other important aspects of health care, for example, the health care quality and population health. 18 some scholars have commented that these financial incentives even may have directly eroded physicians' ethics. 17, 19 because of this strong alignment of financial incentives, senior physicians in effect can become more the agents for public hospitals rather than for their patients. there has been concern in the past that the rise of china's promarket health care delivery system between 1978 and 2002 had sown the seed for a major public health breakout, sars (severe acute respiratory syndrome), in 2003 in china. 20 the sars epidemic combined with other health services issues, for example, increasing out-of-pocket health care expenditures and insurmountable access barriers to health care (in a popular chinese proverb: kanbingnan, kanbinggui), led to a comprehensive health care reform in 2008. 20 although some researchers may not completely agree, 21 by 2012, this chinese health care reform has achieved significant progress toward the first 4 goals set in 2008, including expanding social insurance coverage and public health services, improving the primary care delivery system, and establishing an essential medicines system. 20 however, by 2012, the pilot public hospital reforms in 17 cities had failed to deliver meaningful results, 20 and the progress of public hospital reforms had been slow. 6 currently, public hospital reform remains one of the major issues on the chinese health care reform agenda. the number of public hospital reform piloting cities expanded to 100 in 2015, and all the city-level public hospitals and hospitals above this grade were expected to be undergoing reform by 2017. 22 the chinese government believed that health care reform had already entered the "deep water zone" in that public hospital reform was the most difficult component. 23 in the chinese state council's "the thirteenth five-year plan for deepening healthcare system reform," the government listed several aspects of public hospital reform as one of the most important tasks. 24 in addition to the general public hospital reform challenges shared with other countries (eg, the 3 structural sources and the 3 contextual sources summarized by edwards and saltman), 25 china's current public hospital reform confronts several unique challenges. among these unique challenges is the lack of appropriate and clear physician agency relations caused by the combination of the dominating role of tertiary-level public hospitals, public hospitals' profitdriven behaviors, the existing strong financial ties between physicians and public hospitals, and the lack of a comprehensive physician professionalism system. chinese hospitals can be categorized as "public" and "nonpublic" by registration status, or "government owned," "social enterprise owned," and "investor owned" by ownership status. 4 in this commentary, we use "private hospitals" as a general category for the "non-public hospitals." since 1989, the former chinese ministry of health established a hospital accreditation system to categorize hospitals into 3 grades (3, 2, and 1), as well as 3 within-grade levels (a, b, and c), mainly based on size (20-99 beds for primary hospital, 100-499 for secondary hospital, and above 500 for tertiary hospital), and other factors including service, technology, and quality. 9 almost all the tertiary-level hospitals are public hospitals. public hospitals hold a dominate position in terms of patient volume, medical technology, and high-quality practitioners. the percentage of total inpatient admissions made by public hospitals was about 90% by 2012, the percentage of inpatient admissions by government-owned hospitals remained about 84% between 2005 and 2012, and the percentage of inpatient admissions at tertiary-level hospitals during this latter period actually increased from 28% to 37% (see table 1 ). 4 the dominating role of public hospitals also can be observed in variation of occupancy rates: in 2012, the bed occupancy rate was 94.2% for public hospitals, 104.5% for tertiary-level public hospitals, as against 63.2% for private hospitals. 4 public hospitals accounted for 88.15% of the inpatient surgeries as of 2012. 4 public hospitals also are the employers of most high-quality practitioners, for example, 82.07% of practicing physicians worked at public hospitals and 86.33% of registered nurses worked at public hospitals as of 2012. 4 the public data from china health statistical yearbook are available up to 2012; however, based on the trend between 2005 and 2012, the dominating role of tertiarylevel public hospitals has not changed much since 2012. for example, china's public hospitals accounted for more than 85% of both inpatient and outpatient care as of 2015. 26 for most tertiary-level public hospitals, senior physicians are the attending physicians who control and manage a number of hospital beds, serving also as leader of a group of junior physicians and residents. attending or senior physicians have a significant role in generating hospitals' revenue, and such revenue is tied to his or her own income as mentioned above. therefore, even though physician-agency relation issues exist at all levels of public hospitals as well as private hospitals, the financial relation between specifically tertiary-level public hospitals and senior physicians remains a major barrier for the recent provider-related health care reform activities discussed below, reflecting the dominating medical role of tertiary-level public hospitals in china's health care system. as part of its new round of health care reform in 2013, the chinese government tried to improve the overall efficiency, access, and quality of care with a series of provider-related policies. these policies include (1) promoting private hospitals owned by domestic social capital and foreign investors, (2) further establishing physicians' multilocation practice systems, and (3) eliminating the drug mark-up for public hospitals. however, the current unbalanced set of physicianagency relationships has become one of the major barriers to the success of these reform measures. since 2013, a new round of health care reform returned to a market-oriented direction for provider-related reforms, with promoting private hospitals as a major policy. 20 the chinese government hopes to create competition among current lowefficiency public hospitals with newly established private hospitals, to improve the overall efficiency and quality of the entire health care system. 7 the "national planning guideline for the healthcare service system (2015-2020)" released in 2015 reemphasized "strongly develop non-public healthcare facilities" as one of the 5 concrete tasks, 27 though the government's goal of treating 20% of the patient population in private hospitals by 2015 seems not to have been reached. 28 the policy of promoting private hospitals has faced a number of barriers due to current physician-agency relationships. in particular, recruiting physicians to new private hospitals, especially senior physicians, has been a significant challenge. 29 senior physicians prefer to remain at tertiarylevel public hospitals for professional as well as financial reasons, where senior physician resources and service volume remain concentrated 30 and where service volume is reinforced by the existing pattern of greater trust among patients in large public hospitals compared with other health care facilities. 3 if new private hospitals are to emerge and establish themselves, the relationship between senior and/or more highly respected physicians and tertiary-level public hospitals will have to give way to a more balanced public/private set of physician relationships. second, the emerging private hospitals owned by social enterprise or investors are more likely to be for-profit, and such profit-driven nature will make the physicians practicing at their facilities profit-making agents as well. strengthened physicians' professionalism will be even more important in an environment where physicians are practicing at explicitly for-profit facilities. given that a central challenge for private hospitals' development has been the difficulty of recruiting senior physicians, an almost hand-in-hand reform initiative alongside promoting private hospitals was to allow physicians to practice in more than one hospital: for example, to enable physician multilocation practice. this multilocation practice policy also sought to redistribute patient flow to lower level health care facilities by better distributing more senior physician resources who previously had practiced only in tertiary-level public hospitals. 30 on january 2015, the chinese national health and family planning committee, the national development and reform commission, and 3 other chinese national commissions under the state council released the newest regulation for the promotion of physician multilocation practice, further reducing the regulatory and administrative barriers for senior physicians to practice in other health institutes. 31 by transforming currently employed physicians into "free agents" in the medical marketplace, the multilocation practice policy seeks to break the domination of physician resources by tertiary-level public hospitals. however, critical barriers still exist, and the establishment of multilocation practice will itself create new challenges. first, even though the chinese government seeks to promote physicians' mobility, it is not surprising that such policies have had little success due to resistance from the tertiary-level public hospitals. as described above, with physicians' income and hospitals' profit so strongly tied together in the existing tertiary-level public hospital arrangement, physicians have become in effect the agents of their hospital. in addition, the nature of uncertainty of medical services and the asymmetry of information 32,33 demonstrate the difficulty of evaluating physicians' performance at their own employer hospital. holmstrom and milgrom pointed out that a firm should restrict its agents from conducting outside activities if it is difficult to measure the performance of the agent's "inside firm activity." 34 as a result, while physicians are still agents and employees of tertiary-level public hospitals, it will be difficult to design an appropriate profit/cost sharing mechanism between physicians' current employer hospitals and the facilities they choose for multilocation practice. in all these respects, the tertiary-level public hospitals become a natural barrier to the development of multilocation practices. second, the implementation of physician multilocation practice policy may itself create new problems, including health service quality and increased patient risk. to practice in additional health care facilities, some chinese physicians are establishing private physician-group companies. 35 however, government regulations on physicians' groups or physicians practicing in other health care facilities are still vague and insufficient. 36 even though the current regulations and code of conduct for chinese physicians may not be ideal, physicians are at least under the regulation and supervision of their employers: public hospitals. if physicians can practice at other health care facilities freely or as an employee of loosely regulated physician-group companies, the current immature physician professionalism system does not have the capability to substitute for the current regulatory role served by employer hospitals in terms of ensuring appropriate procedures, care quality, and risk control. to eliminate the perverse financial incentives related to drug mark-up policies described above, from 2015, the chinese government began to eliminate the 15% drug cost markup for public hospitals (eg, zero mark-up drug policy). by september 30, 2017, all public hospitals should have eliminated the drug markup (except for traditional chinese medicine). 37 to compensate for the loss of revenue to public hospitals, most labor-related services such as physician service fees, inpatient bed fees, nursing fees, surgery fees, and traditional medicine rehabilitation fees have all been increased. the comprehensive payment structure reform required that, on average, the increased fee schedule will compensate 90% of the drug mark-up profit loss for countylevel hospitals and above. 38 the goal of this policy is to eliminate the incentive for physicians to overprescribe expensive drugs and high-technology diagnostics tests. however, if physicians' incomes are still tied to public hospitals' profit, hospitals can design other financial incentive systems to reward physicians who help hospitals to increase profit. multiple studies have already reported that hospitals and physicians responded by increasing physician and other service charges. [38] [39] [40] [41] [42] one recent study on a well-recognized reform model, "sanming," 26, 43 also showed the zero mark-up drug policy's effect on reducing expenditure faded over the long term. 44 lack of a proper professional code for chinese physicians could make physicians' and hospitals' fee response behaviors even more extensive. in summary, the post-1978 chinese health care system's development has had the overall effect of making chinese physicians more the agents of hospitals rather than of their patients. substantial evidence has shown that the financial tie between physicians and tertiary-level public hospitals is a critical reason for much of existing inefficiency or even misuse of health care resources. 11, 12, 16 more recently, the existing strong financial relation between senior physicians and tertiary public hospitals also has jeopardized efforts to create competition from emerging private hospitals as well as reform measures that allow physicians to practice among multiple health care facilities. the eventual goal of current chinese health care reforms is to create a market with providers of numerous ownership, including public and forprofit private hospitals, and to redistribute physician resources from currently dominating public hospitals to other settings. to achieve this long-term goal with sustainable physician-patient and physician-hospital agency relations, a systematically well-developed physician professionalism system will also be necessary. the chinese government has implemented policies to reduce overprescribing behaviors; however, more needs to be done to align physicians' incentives with the patient population. 17 an important next step is to disconnect the close financial relationship between senior physicians and the profit earned by tertiary-level public hospitals. an existing tool the chinese government may consider is the us resource based relative value scale (rbrvs), 45 which could be modified so as to represent chinese physicians' workload and value in a scientifically valid manner. the chinese version of an rbrvs system to pay physicians directly based on workload, specialty, length of training, risk, quality of care, service location, and so on would support both private hospital development and multilocation physician practice by cutting the current tight financial relationship between senior physicians and the currently dominating tertiary-level public hospitals. the chinese version of rbrvs could also increase physicians' current income by properly reflecting physicians' value, solving the issue of underpaid physician services, 8 so that physicians will not rely on drug sales, inducement of services, or other financial incentive systems designed by hospitals. the chinese version of rbrvs could also incorporate health care outcome, patient satisfaction, population health, and other qualityrelated measures based on specialty, to create positive incentives on physicians' behaviors that align with the overall chinese health care reform goals of 2030. of course, to design and implement an independent physician reimbursement system would require a substantial administrative and legal framework, for example, establishing billing and collection processes, and comprehensive malpractice insurance for physicians if they are practicing independently, all of which are public hospitals' responsibility in the current situation. we recognize the significant investment of time and funding necessary to implement an independent physician reimbursement system for senior physicians at tertiary public hospital level; however, given the current situation in china, the advantages of such a major reform outweigh the disadvantages, especially considering the expected long-term effects on efficiency and quality of service within the health care delivery system. in addition, as the function, goal, and financial sources for health care facilities in rural areas, and also for secondary level and community-based primary care systems in urban settings, are very different than those of tertiary-level public hospitals, 17 physicians practicing at these lower intensity health care facilities should be paid using the current approach until the chinese version of rbrvs is operating and mature. changing financial relations will increase physicians' mobility; however, changing only the physician-hospital financial relationship will be insufficient to adequately regulate physicians' behavior, especially given the chinese government's expectation that the physician will increasingly practice in multiple locations. this observation leads to the conclusion that a comprehensive physician professionalism system will also be necessary to serve as the foundation for a long-term solution for the recently introduced provider-related health care reforms. as the base of a health care system, a physician's professionalism can be traced to the oath of hippocrates. 46 in the united states, the flexner report in 1910 was an important landmark in the development of a modern medical profession, and some scholars further defined its physician professionalism framework based on flexner's perspectives. 47 in an increasing complex health care delivery system, physician professionalism may be defined in various frameworks with multiple ways. to be sure, physicians in china with their confucian-based culture may not interpret or fully practice exactly the western standard of physician professionalism. 48 however, china's health system development has demonstrated that market mechanisms alone do not have the capability to create a high-functioning professionalism structure for physicians. 8 a comprehensive physician professionalism system tailored to chinese culture and social background may need the engagement and collaboration of government, professional physician associations, health care facilities, and physician leadership representatives. however, almost no efforts for physician professionalism have been implemented as part of the newest round of health care reform. 49 the development of a comprehensive physician professionalism system should be implemented at macro, meso, and micro levels, a multipronged approach which has proved to be an effective health care reform strategy in a number of countries. 50 at the macro level, the chinese government should design a high-level legal framework and regulation to prohibit hospitals using measures related to volume or contribution of profit to incentivize physicians. the us stark law and anti-kickback statute provide examples of how western legal systems keep the autonomy and professionalism of practitioners separate from health care facilities. a professional physician association, for example, the chinese medical association, should assume a larger role in developing, monitoring, and supervising high-level physicians' professional values and behaviors. such professional values and behaviors should also be incorporated into the competencies of physician accreditation. the chinese medical association may consider some of the standards designed by its western counterparts. 51 in addition, physician professionalism will require broader social awareness, support, and an alliance between society and the medicine profession. 52 (see table 2 for summary of "stakeholder," "major responsibilities and goal," and "example," for the 3 levels.) at the meso level, a physician governance body, either independent physician group companies or the physician governance body within a health care facility, should design, to be a role model for young physicians • • role modeling is a crucial area for physician professionalism development and mutually beneficial for both educator and learner 59 monitor and evaluate physicians' professional behavior as part of the physicians' key performance review. 53 health care facilities should seek to create a clear culture to support physician professionalism and to align their internal culture with an overall physician professionalism framework. 54 physician leaders' roles in nurturing this new environment and to be a liaison between physicians and health care facilities are also important. 55 at the micro level, physician professionalism is a lifelearning experience, 60 and needs to be reinforced during already challenging daily practice. 61 the establishment of physician personal professionalism requires a combination of medical school and graduate medical education, 56,57 self and peer assessment, 58 role model of attending physicians, 59 and specific values and behaviors to interact with patients, health care team, and health care facilities. 55 a combination approach. we recognize that every reimbursement structure has its caveats, either in efficiency, quality, or cost control. 62 however, in any reimbursement structure, a strong financial relationship between physicians and health care facilities can always enable health care facilities to design mechanisms to benefit their own financial goals. 63 the current most important barrier for the chinese public hospital reform is the lack of competition caused by the existing financial relations between public hospitals and senior physicians. the chinese government has tried to leverage private hospital investment, use policy to promote physicians' mobility, and change reimbursement policy, to overcome these barriers. however, the financial relations between large public hospitals and senior physicians still allow public hospitals to design mechanisms to maintain their dominating positions. a rbrvs system reimbursing senior physicians directly will be able to eliminate such financial ties. separating senior physicians from public hospitals as "free-agents" will promote the current provider-side reform, even though this strategy may also create other issues, such as the need to more closely monitor and supervise physician behavior. therefore, a well-designed comprehensive physician professionalism system can serve as the foundation for a long-term solution that can promote provider-related reform activities. health systems in different countries have their own historical background and limitations, and even health systems in developed countries such as europe 64 and the united states 65 currently confront significant challenges. the chinese health system has gone through its own developmental phases and is facing unique challenges. we recognize that simply copying the health care reimbursement and managerial system from another country is unlikely to be successful in the chinese context, and that any health system reform needs to be aligned with a country's unique background and current stage of health system development. at the current health system reform stage in china, the physician agency issue has become a central operational factor, one that can systematically jeopardize other essential provider-side reform measures. physicians are multitasking agents in health care services, and some outcomes of their tasks are more difficult to evaluate than others. 34 even in the united states and other western developed countries, establishing provider payment systems that create effective incentives for both cost control and quality improvement is difficult. 62 the chinese health care system is moving toward case-based or diagnosis-related group-based reimbursement approach for hospitals. 66 under such a prospective payment system, how physicians balance hospital interests, their own income, and patients' benefits is a crucial measure of the physicians' care decisions. 67 if physicians' personal income is still tied to their employer hospitals' profit and hospitaldesigned financial incentives, however, it may be more likely that physicians will continue to prioritize hospital's or their own profit rather than patients' interest. a study on the impact of reimbursement method change from fee-for-service to per-diem for a chinese public psychiatric hospital illustrated that the payment policy had not achieved its anticipated goals because physicians' behaviors were still tied to the original financial incentives the hospital had designed. 68 chinese health care professionals have demonstrated a strong commitment to society, especially during natural disasters. 69 however, providers' behaviors in terms of health care service quality and quantity are associated with physicians' remuneration approach. 70 in this commentary, we contend that a major barrier to achieving the government's prospective goals for its health care delivery reform in china is the lack of an appropriate physician-agency relationship. as a central strategy to overcome this barrier, we suggest reducing the direct financial tie between tertiary-level public hospitals and physicians, and establishing a comprehensive system of physician professionalism in china. to be sure, provide-side reform in china is more complex than only the 2 issues described here. other factors will also influence the efficiency and effectiveness of health care reform efforts, for example, public funding to public hospitals, 14 public hospital governance, 71 resource allocation between rural and urban areas, 72,73 health care professional workforce development, 74 patients' experience, 75 community-based primary care, 76 and associated referral system. 7 however, as yip, wagstaff, and hsiao 77 summarized earlier, more in-depth understanding of physicians' incentives are necessary, and as la forgia and yip pointed out subsequently, 28 the critical reform direction for providers is the alignment of providers' interests with the general social welfare rather than their individual income. all of these directions require the 2 aspects we propose: minimizing the inquiry financial tie between tertiary-level public hospitals and physicians, and establishing a high-standard physician professionalism system in china. the author(s) declared no potential conflicts of 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of the information revolution on tax-funded european health systems and some potential policy responses increasing value: a research agenda for addressing the managerial and organizational challenges facing health care delivery in the united states provider behavior under prospective reimbursement does per-diem reimbursement necessarily increase length of stay? the case of a public psychiatric hospital white coat sodiers touch china handbook of health economics research on chinas public hospital governance: from perspective of implementation issues equity in health and health care: the chinese experience health insurance benefit design and healthcare utilization in northern rural china health system reform in china 5 4 china's human resources for health: quantity, quality, and distribution patient experiences with inpatient care in rural china evolution of primary care in china economic analysis of china's health care system: turning a new page key: cord-303581-wowtg63z authors: gao, grace; sai, linna title: opposing the toxic apartheid: the painted veil of covid‐19 pandemic, race and racism date: 2020-08-08 journal: gend work organ doi: 10.1111/gwao.12523 sha: doc_id: 303581 cord_uid: wowtg63z this article is a personal reflection of how the coronavirus exposes ‘shocking’ levels of racism against us, and our vulnerability as chinese women living in britain. by reflecting our experiences of verbal and physical race‐based violence connected to coronavirus, we explore the fluidity of our racial identities, the taken‐for‐granted racial stereotypes and white privilege, and everyday racism in the uk. can the vulnerable use vulnerability as an agent to shift the moment of helplessness? we contribute to the uncomfortable yet important debate on racism against chinese women living in the uk through voicing up our embodied vulnerability as invisible and disempowered subjects to this viral anti‐chinese racism. this is a form of resistance where we care for the racialised and marginalised others. in doing so, we lift the painted veil of pandemic, race and racism to collectively combat racial inequalities. this article is protected by copyright. all rights reserved. we are 'sitting ducks' during this global health crisis. an increased tide of race-based violence and animosity toward chinese are flashing up, in the aftermath of the coronavirus outbreak. we were told to go home. it tortures us. whilst we are hesitant to risk our bodies being assaulted physically and verbally, it takes courage to unveil our vulnerabilities as the 'targets' of this viral racist attack associated with 'chinese virus' and 'kung flu'racist terms publicly promoted by politicians such as u.s. president trump (guardian, 2020a) . the term 'kung fu' represents time-honoured tradition grounded in fortitude and courage, extracted from chinese traditional martial arts (yam, 2020) . overtime, it has been frequently used as an expression in honour of any discipline or skill that is achieved by constant hard working and practice. but now it has become a racist joke. the reason for us being attacked is simply because of our race and skin tone. it is appalling for us to be seen as unhygienic, filthy and unsanitary, and being accused of carriers of the deadly virus; some people even connected us to the 'yellow peril' theme which portrays us as an image of 'evil' and 'aliens'. by reflecting the ample manifestations of maskaphobia, prejudice and racial discrimination connected to the coronavirus against chinese in britain, we break our silence and speak up against the increasing anti-chinese rhetoric, with whom we are in solidarity and to whom we offer our labour, time and support as a driver of resistance. since the outbreak of the novel coronavirus, anti-chinese sentiment has been spreading around the world. in the uk, incidents of xenophobia and racist harassment against chinese have significantly increased. a recent poll into racism suggests that 76% ethnic chinese have experienced a direct racial slur (at least once), making us the most common victims of racism in the uk (cgtn, 2020). a chinese postgraduate student was reported being verbally and physically abused for wearing a face mask when she was walking alone in sheffield (jones, this article is protected by copyright. all rights reserved. 2020). in leicestershire, another two asian students who were mistakenly thought to be chinese, were pelted with eggs on the street (guardian, 2020b) . in the schools, racists have also targeted chinese kids by expressing slogans such as 'keep away, they are all poisoned' that defame our community. however, this is not the end. since the initial case was confirmed in the uk on january 31 st , 2020, the city where i live has been fuelled with a surging increase of race-based violence. i have been warned by other fellow chinese in the local community who have been spat at on the street, been shouted at as a liar. soon i become very cautious when walking out. i avoided the narrow alleys even during the daytime and i kept my head down, lay low and walked fast. such risks of being physically abused are interwoven with the mainstream media and we are becoming the target for cyber racist violence. a danish newspaper, jyllands-posten, published a satirical cartoon of chinese national flag, replacing the five gold stars by the deadly virus, which implies that chinese should be blamed for this outbreak -an insult to china (bbc, 2020). in the past, chinese groups have been depicted as intelligent, hardworking and compliant as part of a diaspora (e.g., archer, francis & mau, 2010; costigan, hua, & su, 2010) . a discourse of 'model minority' was also observed in britain (yeh, 2014) . however, under the current pandemic, the public perception of chinese as 'model minority' has been shifted to the 'yellow perils' (lee, 2020) . i was shocked by the idiocy of anti-china sentiment and racist memes based on ignorance such as 'chinese eat bats' 'chinese eat dogs'. chinese is seen as the source and carrier of this deadly virus. i felt very disgusted. i soon learned that the aggressive comments i received on my social media account comes from a 'bat soup' video that purported bat as a chinese dish. and i was even being asked if that is true by a person this article is protected by copyright. all rights reserved. who has known me for at least two years, asking if i do eat these things. i responded that chinese only eat what everyone else eats and muted the person since then. ironically, only certain epidemic virus outbreaks such as sars originated from china and ebola from africa have led to a racial backlash. however, neither the swine flu (h1n1) epidemic which originated from the united states nor the mad cow disease from britain has been racialised in the past. prejudice and ethnocentrism toward us, deliberately dehumanise chinese people and imply that it is our fault. such prejudice also carries to our offline interactions and behaviours. before the national lockdown, i had dinner in london's chinatown. it was unusually quiet. i entered one restaurant which is apparently less busy than usual. i had a chat with the manager, and believed that western people were misled by the false news of 'chinese eat bats' and scared of eating chinese food. however, there is no evidence that eating chinese food will cause people to get infected, supported by the world health organization's (who) claim -that people will be likely to get infected by close contact/interaction with people who might have been exposed to the virus. our captured moments continue to unravel the ample manifestations of maskaphobia associated with behavioural changes in response to the yellow attacks. in early february, few weeks before the national lockdown, i had been shoved and shouted at, calling me 'virus' while walking on the street. i become more cautious afterwards by walking faster and avoiding contact with other people. at the time, i did not wear a mask because i was afraid of being physically assaulted over maskaphobia. but i was also afraid of being infected through droplets. this article is protected by copyright. all rights reserved. when i started to wear a mask, it felt like i become a target of public criticism, even though it was common to wear a mask in italy -the europe epicentre. i have learnt from other countries where the local authorities have advised citizens to wear face masks to protect ourselves and others. but the unwanted attention made me feel uncomfortable. i then stopped wearing a mask until the government's announcement on 4th june 2020 that it is compulsory to wear face coverings on public transports and advised to wear face coverings at places where social distancing is difficult to maintain. after that i feel safe to wear a mask. how can we mobilise our vulnerability (butler, 2016 )? gender theorist judith butler's keynote speech at the international conference of 'how to act together: from collective engagement to protest' in belgrade, serbia reminded us to reconsider and rethink the relationship between vulnerability and resistance that 'we may think that either we are vulnerable or we resist, and that resistance consists of overcoming vulnerability, [but] the short version of my argument is that resistance can be a way of mobilising vulnerability, and that even fighting back or triumphing in a fight does not negate vulnerability'. what is at stake under the current pandemic, is that we, as human beings, seek to become secure, yet our embodied vulnerabilities are emerging. vulnerability as resistance matters (ahonen et al., 2020; gilmore, harding, helin & pullen, 2019; helin, 2019) , because it has become our only choice of seeking to foreground and oppose the increased condition of precariousness. in resonating with simone de beauvoir's feelings of 'irritation' and 'hesitation' before writing the second sex, where she described her long-time hesitation of writing a book on women -a subject that is irritating especially to women and is not new, we find ourselves choked with emotions to write this piece. we are provoked by kyoo lee's self-question and reflection upon herself 'feeling being a problem [as an asian female], [here], not feeling or being a problem but "feeling being" one' (lee, 2013, p. 87) . women of asian origins have this article is protected by copyright. all rights reserved. been depicted as exotic, submissive sex objects and invisible (e.g., mukkamala & suyemoto, 2018) . these stereotypes constructed by the dominant society group 'legitimise' us as controllable and deferential -we are expected to be "ok with anything", be quiet and not speak up for ourselves. the reflection of feeling being a problem originated from embodied vulnerability is further exaggerated when framed, targeted and staged by unexpected and uncontrollable forces in the workplace. concerns about job security in white institutions have exacerbated our irritation in challenging the normalised practices in the neoliberal academia. however, due to precarious positioning, we are forced to navigate ourselves strategically with the whiteness to survive. people from chinese backgrounds have been constructed as 'different', 'aliens' and 'foreigners' by the hegemonic perpetuation of dominant ethnic (white) groups (cheng, 2013; liu, 2017a; liu, 2017b) . despite us being assimilated to the british society, we are still 'outsiders' and being excluded from the mainstream narratives depicted by the dominant societal groups. this article is protected by copyright. all rights reserved. in response to the increased racist attacks, i received a message circulated from the top level, urging staff to support their chinese colleagues and students. yet one of our students was involved in posting offensive materials that may constitute a hate crime. in the footage, the student said, 'i am rich, white, privileged, and tanned … and got good teeth'. this was reported immediately to the police and is now the subject of a police investigation. white power constantly 'passes' through our bodies as people of colour, who have been instrumentalised into everyday white supremacist practices (bonilla-silva, 2012). a burgeoning racial discrimination and injustice are manifested under the white supremacist ideology (e.g., burnett, 2017 ). the entrenched system of government authorities constantly reinforces the racialised climate injustice and a bespoke antagonistic 'global policing' for immigration control at the expense of the 'others' (bowling & westenra, 2018; sealey-huggins, 2018) . ironically, as chinese, i have not been considered as a 'minority' from the eyes of other groups. i always hear 'oh, china grows fast and is rich'. i remembered my recent conversation with a black colleague about chinese ability in building an instahospital in 10 days to battle the coronavirus. and he didn't think people who come from such a nation with great strength and wealth could have faced social inequality and inequity like they have faced. likewise, white british also don't believe that chinese would experience racism or simply deny it. we stuck in the middle of white and black, west and east -always as the 'betweeners'. admittedly, the visibility of chinatowns along with chinese workers' high income, a group who earn about thirty percentage higher than their white british counterparts (office for national statistics, 2019); and the boosting numbers of chinese students studying across british institutions contribute to the discourse of race, racism and inequality overlooks this article is protected by copyright. all rights reserved. chinese. yet chinese are at the bottom line of 'displays of power' manifested in both social and business settings, where a society perpetuated by white supremacist ideologies (dar, liu, dy, & brewis, 2020) . following the shocking news of the killing of george floyd, an initiative in establishing bame staff network was circulated in my school. these 'anti-racist' messages were sent by white people from the top level to promote equality and equity policies for the sake of charters. for example, promoting athena swan related projects for materialist ranking purposes. but i know nothing will actually change, so i keep silent. such paradoxical feelings present a continued hesitation to stand up against how the dominant white constructs whiteness as moral authority to 'correct' the underrepresented minorities. white supremacy is frequently cited to describe the centuries-old racialised social system (feagin, 2013 ) that consists 'totality of the social relations and practices that reinforce white privilege' (bonilla-silva, 2006, p. 9) . it manifests in the compliance of reproducing and reinforcing white solidarity and white social capitalist and thereby excluding women and people of colour. as such, management and organisational scholars call for rethinking racial capitalism and redefining differences by claiming that capitalism is racist and advocating for acting up for resistance (e.g., bhattacharyya, 2018; dar et al., 2020; lorde, 2017) . bronwyn fredericks also writes on the different ways that a marginalised other can resist white dominance, saying that "there are those who are undertaking [resistance] through the legal and political rights arenas both nationally and internationally, those who write about it through analytically researched academic papers challenging the status quo, and others who do so through creative narrative prose and pieces of art" (fredericks, 2010, p. 548) . it becomes clear that there are no right or wrong ways of doing resistance as long as we are resisting. we stand together, write together, and resist together. this article is protected by copyright. all rights reserved. it is struggling to express the inexpressible 'true' stories and feelings when writing this paper. chinese, and other east asians as a whole, have long been criticised in their proximity to white privilege and thereby benefiting from white supremacy (young, 2015) . this is a big lie. as female academics of chinese origins, choices have to be made between 'authenticity' and 'appropriateness' to fit in the dominant white scholarly community, due to fear of being harshly criticised. few weeks ago, when i finally completed the marking and moderation process, i received a message from a white senior colleague in a night, implying to raise marks for a student from her class. she explained that the student is a non-native english speaker from europe, and markers should be more 'sympathetic'. i understand her intention, but i believe that i should not lower down the academic bargain simply based on whether english is the student's native language or not. i have provided enough justification to make sense of my scoring, but eventually 'surrendered', to stay in the loop and avoid being seen as a 'troublemaker'. the paradox pushes us to relate to others for the benefits of being included in a group. there is a need to perform different facets to different audiences, but at times, we are distanced from the 'authentic self'. the contradictory effect on (re)constructing our identities can be further reflected through the fluid racial identity process (helm, 1995) . since the pandemic, i started to rethink the idea of racism in the context of my experience. i realised that i have been constantly conforming to the white culture while trivialising the significance of race and racism. i was 'colour-blinded' because i have been trained to learn and express how to speak and think in the 'language' of this article is protected by copyright. all rights reserved. whiteness. the sudden realisation of some racist practices resulting from the pandemic marked my dissonance with an ongoing suspicious mind and anxiety. the instabilities of racial identity are presented in the moments of transitioning, where 'the collective and individual, the past and present, and the central and marginalised identities are spheres and overlap' (shirazi, 2018, p.16) . our changes embedded in these short narratives are juxtaposed within a new cultural, political and economic environment. looking back, the recognised race-based oppressions have been constantly (re)structuring our lives and livelihoods as chinese women living in the uk. those neglected attributes and vulnerabilities in the past have been amplified amid this global health crisis. our account is not just a personal diary. it 'pushes' us to rethink and reflect sensitive subjectsrace and racism, which might be uncomfortable for the dominance yet have constantly affected our choices for practising silence and/or taking the initiative to voice up as members of ethnic minorities. by writing this piece collectively, it extends beyond the sum of our embodied oppressions and voices seeking to alleviate problematic racism issues, which grounded in british history, for a better and equitable society. it is time to be bold and brave. having been rolled with the punches for a long time to survive in the neoliberal capitalist society, this article contributes to the burgeoning discussion on race, racism and writing differently as a form of resistance. writing through vulnerability liberates us to heal, to calm down and to find meanings in our lived experiences. moving beyond the movement of #blacklivematters, we recognise those disempowered and invisible others alike, in everyday racism; and opening up a new dialogue of the toxic racial apartheid amplified during covid-19 pandemic in the uk. after all, the subject of race and racism will never fade away. writing resistance together the culture project: diasporic negotiations of ethnicity, identity and culture among teachers, pupils and parents in chinese language schools coronavirus: denmark in cartoon bust-up with china over flag rethinking racial capitalism: questions of reproduction and survival racism without racists: colour-blind racism and the persistence of racial inequality in the united states the invisible weight of whiteness: the racial grammar of everyday life in contemporary america a really hostile environment: adiaphorization, global policing and the crimmigration control system racial violence and the brexit state vulnerability in resistance ethnic chinese are the most common victims of racism in the uk according to a yougov poll strategic orientalism: racial capitalism and the problem of 'asianness'. african identities living up to expectations: the strength and challenges experienced by chinese canadian students the business school is racist: act up! organization the white racial frame: centuries of racial framing and counterframing empowering ourselves: australian aboriginal women writing differently. management learning donald trump calls covid-19 'kung flu' at tulsa rally chinese in the uk report 'shocking' levels of racism after coronavirus outbreak dream writing: writing through vulnerability. qualitative inquiry an update of helm's white and people of color racial identity models chinese student attacked in sheffield over coronavirus. the stars why asian female stereotypes matter to all: beyond black and white, east and west corona virus fears show how 'model minority' asian american become the 'yellow peril undoing whiteness: the dao of anti-racist diversity practice. gender, work and organization beneath the white gaze: strategic self-orientalism among chinese australians women in culture: an intersectional anthology for gender and women's studies racialized sexism/sexualized racism: a multimethod study of intersectional experiences of discrimination for asian american women the climate crisis is a racist crisis: structural racism, inequality and climate change ambivalent identity and liminal spaces: reconfiguration of national and diasporic identity in mohsin hamid's the reluctant fundamentalist ethnicity pay gaps in great britain bruce lee's daughter on 'kung flu': 'my father fought against racism in his movies contesting the 'model minority': racialization, youth culture and 'british chinese'/ 'oriental' nights it's not just black and white key: cord-021375-lca26xum authors: voelkner, nadine title: riding the shi: from infection barriers to the microbial city date: 2019-08-23 journal: nan doi: 10.1093/ips/olz016 sha: doc_id: 21375 cord_uid: lca26xum how can a microbial approach to global health security protect life? contemporary infection control mechanisms set the human and the pathogenic microbe against each other, as the victim versus the menace. this biomedical polarization persistently runs through the contemporary dominant mode of thinking about public health and infectious disease governance. taking its cue from the currently accepted germ theory of disease, such mechanisms render a global city like hong kong not only pervasively “on alert” and under threat of unpredictable and pathogenic viruses and other microbes, it also gives rise to a hygiene and antimicrobial politics that is never entirely able to control pathogenic circulation. the article draws on recent advances in medical microbiology, which depart from germ theory, to invoke an ecological understanding of the human-microbe relation. here, while a small number of viruses are pathogenic, the majority are benign; some are even essential to human life. disease is not just the outcome of a pathogenic microbe infecting a human host but emerges from socioeconomic relations, which exacerbate human-animal-microbial interactions. in a final step, the article draws on daoist thought to reflect on the ways that such a microbial understanding translates into life and city dwelling. any visitor to hong kong will realize that disinfection is an urgent and pervasive imperative in contemporary everyday life in this global city. in late 2016, hong kong was on the way to fashioning itself an antimicrobial global city. public signs on multiple surfaces including elevator buttons, escalator handrails, and floor mats duly inform the passer-by of hourly or daily sanitation. at various busy urban spaces, including mtr (metro) stations, walkways, libraries, and office and housing complex receptions, free hand sanitizer dispensers compel the passer-by to engage regularly in the act of public cleansing of the body. similarly, handbag-sized instant hand sanitizer bottles, readily available at every corner store or supermarket, with promises of killing "99.99 percent of germs"; notices of hand-washing rituals; and the donning of masks by individual city dwellers, remind residents of the private acts of virus and bacteria control. all these practices of cleansing nourish an insidious sanitizing imperative in the defense against epidemic infections deeply enmeshed with the pulsating energies of an ambitious global city. it is the experience and fear of infection and death that accompanied the recent experience of the sars (severe acute respiratory syndrome) outbreak in 2003, which precipitated this aggressive stance to potential contagions emerging in hong kong. 1 li (2014) , a scholar of asian architecture, suggests that infection control in the form of public hygiene in contemporary postcolonial hong kong manifests itself in what he has termed "infection barriers." these antimicrobial-like-that is, antibiotic-and antiviral-like-physical and mental barriers aim to prevent the virus and other microbes from settling in the city. basing his interpretation on the traditional conception of the chinese city, "infection barriers" help him to analyze the historico-aesthetics of the city's contemporary urban defense against infectious diseases. li succinctly demonstrates how public hygiene is not only governed through overt public health programs but is affectively knit into both the fabric of the urban architecture and the tissue of the city population. infection barriers take the form of structures and widespread cleansing practices, which in li's eyes render hong kong a hospital disguised as a city. like other modern infection control mechanisms, the story of infection barriers in hong kong is one of setting the human and the virus against each other, as the victim versus the menace. this biomedical polarization, in which an external pathogen threatens the healthy human body, persistently runs through the contemporary dominant mode of thinking about public health and infectious disease governance (macphail 2002 (macphail , 2014 fishel 2015; white 2015; du plessis 2017) , which is rooted in the currently accepted germ theory of disease. it renders a city like hong kong pervasively "on alert"-albeit with chinese characteristics, as will be shown below. indeed, the polarization between the human body and the virus in global health constitutes "a world on alert" (weir and mykhalovskiy 2010; lee and mcinnes 2012) . "global public health vigilance," bolstered by an extensive transnational surveillance apparatus led by the world health organization (who), caters to a world under threat of unpredictable and pathogenic microorganisms and diseases. over the past two decades, a range of global health issues have reached the highest levels of political concern, prompting states and international organizations to respond to such threats in the language, and with the arsenal, of security (rushton and youde 2015) . worryingly, it has been suggested that these security practices render citizens as patients and states as megahospitals (elbe 2010) , as is also the argument in li's description of hong kong. in her excellent "pathography" of global public health's experience with the 2009 h1n1 pandemic, macphail (2014) examines our collective fear of viruses by tracing the h1n1 influenza virus through history and sites of public health activity, particularly in hong kong. the picture she paints is also of anxiety fueling an influenza pandemic narrative in which not only is the virus misunderstood but archaic truths of influenza research dominate (cf. webster 1993) and infection control stifles the development of necessary, novel ideas of infection control (schiffman 2014; lee 2015) . the fallacy of the influenza pandemic narrative lies in it largely misunderstanding the virus and bacteria and their relation to the human. recent advances in medical microbiology have found that the human-virus relationship is not one of opposition per se but of profound entanglement. one cannot be thought without the other, leading some to theorize the figure of homo microbis (helmreich 2014) . in this understanding, few microbes are pathogenic; most are benign, some even essential to human life. indeed, viruses have been and are a vital source of new genetic information, horizontal gene transfer, and genetic diversity in the evolution of life. zoonotic viruses' ability to continuously mutate as they go about infecting hosts and exchanging genetic information renders global health strategies largely obsolete. moreover, there is an increasing realization that antimicrobial interventions such as antivirals and antibiotics are accelerating antimicrobial resistance, making infection control strategies not just obsolete but also counterproductive. thus, a rethinking of the human-virus relationship in (urban) politics and security in hong kong and global health more generally is timely. the article begins by tracing the way the global city of hong kong has been constituted as an antimicrobial city since the sars outbreak in 2003. the antimicrobial stance takes its cue from the scientifically accepted germ theory of disease. in a second step, the article explores the recent claims of medical microbiology, which profoundly depart from the germ theory to invoke an ecological or configurational understanding of the human-microbe relation. here, disease is not just the outcome of a pathogenic microbe infecting a human host but emerges from socioeconomic relations, which intensify human-animal-microbial interactions, thereby leading to pathogenesis-that is, the diseased state (lorimer 2017) . in a final step, the article draws on daoist thought and traditional chinese medicine to reflect on the ways that such an ecological understanding translates into life and city dwelling. sporadic outbreaks of h5n1 in the live bird markets; the spectre of sars whenever someone with an acute, unexplained upper respiratory tract infection is hospitalized; the occasional case of japanese encephalitis; thick, humid air that feels pregnant with microbes; the soundless, nearly invisible mosquitos ubiquitous in the lush, dense patches of forest that cover the territory. contagions seem to originate both from within and from without. (macphail 2014, 79) in early 2003, after having treated patients with atypical pneumonia in a guangzhou hospital, a medical professor arrived in hong kong from guangzhou carrying sars coronaviruses. the arrival of the coronaviruses led to the volatile outbreak of sars in hong kong. hitching a ride on the chinese professor, the pathogenic microbe family began infecting and reproducing among the large pool of hosts-that is, the hospital staff and medical students whom the chinese professor was visiting. during the professor's short stay at the metropole hotel in kowloon, before he himself fatally succumbed to sars, the viruses continued infecting seven other hotel guests, who traveled elsewhere in hong kong, singapore, vietnam, and canada. the viruses moved into the prince of wales hospital while journeying on a local hotel guest who was admitted in early march. there, they moved through the hospital, infecting over one hundred medical and nursing personnel. by early april, coronaviruses entered the housing estate "amoy gardens," where they infected and reproduced among the large pool of hosts living in and beyond this estate (lee 2003) . only a month later, coronavirus activities finally began to slow down and decrease-however, not before having also spread to a number of global cities including beijing, guangzhou, singapore, and hanoi in east asia as well as toronto. as hardy has aptly noted, "the history of the infectious diseases in modern times remains inextricably intertwined with the history of the cities that spawned them" (hardy 1993, 293; see also mcneill 1976) . this can be said too of hong kong. with the social and environmental conditions of a global city, the densely populated city is argued to have provided the necessary breeding and circulation ground for a fast-emerging disease such as sars to spread rapidly in the network of connecting global cities. 2 cities afford microbes a large pool of closely connected human hosts by which a "sustainable chain of transmission" is ensured (harris ali and keil 2008, 4) . "the city is a playground for parasites," notes guardian writer kira cochrane and adds, quoting historian of science barnett (cochrane 2014 ), there are a lot more exciting human beings they can jump on to, . . . lots more opportunities for vectoring and transmission. it's all about movement. parasites love movement. so in that sense the city is an absolutely fantastic place for them. indeed, in hong kong, according to li shiqao, the sars outbreak brought into painful realization the problem with the city's characteristically chinese urban architecture of abundance or "maximum quantities," expressed through the functional building of ever-higher skyscrapers to house more and more people within ever smaller spaces (li 2014, 28-30; also roloff 2007) . this specific urbanity of hong kong emerged with the unique political and economic circumstances that came with the arrival of large waves of mainland chinese refugees after the creation of the people's republic of china in 1949. until the 1960s, an estimated one million people were homeless in hong kong. before they were resettled in tiny spaces in public housing estates by the colonial authority, mainland chinese refugees lived in squalid squatter-settlements, which gave rise to the circulation of diseases and criminality (roloff 2007, 112) . throughout history, cities have responded in different ways to infectious diseases-from the traditional quarantine, to the development of urban hygiene infrastructure through sanitation and waste management systems (loos 1987, 45-49; melosi 1999) , to the more recent establishment of public health systems. "the whole history of urban life," argues medical historian richard barnett, "is of living with parasites and trying to get rid of them" (as quoted in cochrane 2014) . indeed, in the modernization of cities in the late nineteenth century, gandy emphasized the way technopolitical discourses became entangled with advances in the medical sciences such as disease epidemiology to influence developments in civil engineering and planning, as well as public health (gandy 2006, 15) . 3 writing about the inclusion of public hygiene in urban design and architecture, li shiqiao has spoken of "an architecture of bacteria and virus control" emerging in europe during this time (li 2014, 117-18) . this found its expression especially in urban architectural designs of whiteness (which expresses the visual act of bleaching and antisepsis) and homogenous surfaces (which express the medical practice of disinfection) (li 2014, 117-18) . 4 thus, the concern for public hygiene and microbial control has shaped (particularly western) urban architecture since the turn of the twentieth century. chinese cities, on the other hand, first encountered the late nineteenth century european discourse of urban hygiene 5 through "treaty-port cities" such as hong kong, shanghai, and tianjin, which were established to ensure the trading interests of western powers in china (rogaski 2004, 141) . 6 cities like hong kong were to participate in late nineteenth century global trade, at a time when a bubonic plague was also spreading globally. hong kong's crowded architecture rendered it a 3 gandy (2006) referred to this as the emergence of the "bacteriological city," to highlight the complex interactions between disease, water, and urban infrastructure. similar to concepts such as the "sanitary city" and the "hydraulic city" in analyzing the relationship between water and cities in the modernization of cities in late nineteenth century europe, gandy's "bacteriological city" nevertheless goes further in emphasizing the role of scientific advances such as disease epidemiology. 4 according to li (2014, 188) , whiteness symbolizes "the visual act of bleaching, the physical and metaphorical removal of dirt as an antiseptic practice." it is reflective of ventilation and light in hospital design. "shine" is produced of homogenous surfaces that find their cue from the medical practice of disinfection. 5 health strategies in china have traditionally focused on preserving the body. urban hygiene as a rationale was officially incorporated into the qing imperial administration in the early twentieth century and subsequently adopted by the communist government in 1949. urban hygiene was linked to the nationalist project of the mao regime and launched in mass campaigns to eliminate disease and pest (li 2014, 119) . 6 hong kong was created in the mid-nineteenth century as a result of the opium war between the british empire and the qing empire in china. having lost the war, the chinese emperor ceded hong kong in perpetuity to britain in 1842. under british rule, the city was a free trade center with low taxation, a character it still holds today. its british heritage is an intensely neoliberal mentality reflected in a minimum government, few controls on imports and exports, and the lack of a military arm, which laid the ground for its eventual integration into the global economy and evolution into a global city. hygienically challenged city that was particularly vulnerable to infectious diseases, leading to urban hygiene becoming a fundamental feature in governing the colonial, and eventually postcolonial, city (li 2014, 118-19) . historically, hong kong is considered a "naturally diseased space," where new influenzas emerge. with its "year-round humidity and swampy, tropical marshland," from the early times of british colonization hong kong was "seen as a reservoir-pit-of disease" (macphail 2014, 80) . a series of deadly outbreaks in the newly acquired colony led the british to set up hospitals and bring in western medical authorities to ensure there was little disruption to economic flow. the port of hong kong had become indispensable to the british economy and thus necessitated a strategic eye to controlling disease circulation (macphail 2014, 82) . in 1894, hong kong experienced a plague outbreak which led to the establishment in 1906 of what would eventually become the bacteriological institute, its first modern microbiological research center (macphail 2014, 83) . while until the 1890s hong kong's medical officials followed the widely accepted miasma theory in explaining infectious disease circulation, by the early nineteenth century, and with the establishment of the institute, the shift to germ theory in european medical circles had resolutely arrived in hong kong. using the new technology of the microscope, germ theory established that infectious diseases were not caused by atmosphericmiasma or "bad air" but by pathogenic microorganisms such as bacteria, protozoa, fungi, and viruses in the body. microbiologists proved that specific microbes, which spread from person to person, caused infectious diseases. germ theory radically changed the practice of medicine. it influenced how hospital space in hong kong and elsewhere had to be rethought toward including microbiological laboratories and isolation wards (sihn 2017). more importantly, as the accepted scientific theory of disease, which still underlies contemporary biomedicine, germ theory to this day influences and dominates modern sanitary practices and public health. the battle against sars, occurring only five years after hong kong's handover to china in 1997, revealed considerable problems both with the sino-british political arrangement of "one country, two systems" and with the city's public health governance system. sars "can be understood epidemiologically as a virus that tested hong kong's healthcare system and governance to the maximum" (baehr 2008, 147) . while a number of stringent but important measures to control the spread of infections-including isolation and home confinement, regular health checks at the border, and public information sharing-were introduced during the outbreak, the hong kong government's response was widely considered to have been severely delayed and inadequate (ng 2008, 71-73) . 7 in fact, the change in political rule and the insufficient governmental response provoked a distinct cultural reaction to sars by the hong kong people who mistrusted mainland chinese and associated hong kong officials. culturally, baehr found the "mask culture," which arose during this time, a sign of an emerging social solidarity among hong kong people in which they paid tribute to a common good by meeting one's duty not to endanger the wider hong kong community. the plague, or any other pandemic in chinese culture, is traditionally seen as a sign of evil: it "summons up the possibility of a collective death: the extirpation of the social itself" (baehr 2008, 147) . mask-wearing thus "became the quickly improvised, if obligatory, social ritual: failing to don one was met with righteous indignation, a clear sign of ritual violation" (baehr 2008, 150) . in the immediate sars aftermath, partly to be seen to regain control of the battle against infectious diseases and partly to defend its beleaguered image as "asia's world city," the hong kong government aggressively promoted a new culture of urban hygiene (roloff 2007, 74) . building on the "positive hygiene spirit" and mask-culture during the sars outbreak, the city government began working to normalize a mentality of urban hygiene in the hong kong community. shortly after the sars outbreak, it established the governmental organization team clean. its role was to regain hong kong's status as a world-class city by instituting high hygiene standards throughout the city. former chief secretary for administration, donald tsang, declared on may 28, 2003: there are problems emanating from personal hygienic habits, household hygiene unsatisfactory conditions and some environmental unhygienic problems relating to building maintenance and so on. . . . it is a monumental task but it is an important step that hong kong must go through if we aspire to be a city of the first rank and not only as a very successful international financial centre, but in fact a "clean room" in asia. (tsang 2003) the work of team clean began by identifying, defining, and clearing "hygiene blackspots" in nearly one hundred public housing estates. but the city's hygiene efforts extended not only to cleaning up buildings and surrounding infrastructure, it crucially involved changing the behavior of the people of hong kong: we believe that all efforts must begin with the self, extend to the family and the immediate neighbourhood, and then radiate throughout the entire community of hong kong before we can claim a place as a world-class city. (team clean report as quoated in roloff 2007, 97) by orchestrating mass campaigns of hygiene habits through posters, audio announcements, television broadcasts on public transportation, and the display of disinfection stations, public notices of disinfection routines, etc. and by incorporating regular and mandatory hand washing in schools, hong kong actively worked to induce an antimicrobial (sanitizing) imperative in the hong kong people. its stringent urban hygiene regime is creating hygienic world-class citizens who are to carry hong kong back into the top ranks of global cities (roloff 2007, 91) . in li's reading of the post-sars climate in hong kong, an architecture of bacteria and virus control was manifesting in distinctly chinese-style "infection barriers" in the city. historically, the chinese city is "conceived as a set of concentric corporeal defenses of the body, the family, the village, the work unit, and the state family" (li 2014, 133) . the preferred method of defense in traditional cities in china was walls. infection barriers in chinese cities like hong kong, li claims, take on some of the characteristics of the traditional walls in their concentric forms. unlike city walls or gated communities, however, infection barriers manifest according to the principles of antimicrobials. as such, in reproducing the chinese imperative of prudence in preserving the body, they defend the body by "fighting bacteria and viruses from within the tissues of architecture" (li 2014, 130) . in this way, the "monumental task" of transforming hong kong into an antimicrobial global city was underway. li concludes, "in hong kong, the hospital is poised to take over the entire city, spreading its standard practices of hand-washing, maskwearing, and temperature-taking" (li 2014, 130-31) . building on germ theorywhich posits that pathogenic microorganisms such as bacteria, protozoa, fungi, and viruses residing in human bodies spread from person to person to cause infectious diseases-an extreme urban hygiene culture emerged in this global city to prevent germs from spreading. this is not only fueling and normalizing anxieties of infection and disease as i experienced when visiting hong kong in late 2016, it may also not be achieving what it set out to do, namely, securing human life. considering recent advances in gene sequencing in microbiology, through which a "vast diversity of microbial life in, on and around the human body" (lorimer 2017, 544) has been identified as residing in complex relationality with one another, how befitting is it to fight infectious diseases by indiscriminately eliminating microbes through the use of antimicrobials and practicing urban hygiene as in the case of hong kong? what happens when the enemy is not the virus or other microbes but us (methot and alizon 2014, 778) ? like many others caught up in the emerging-disease narrative, which is based on the tenets of germ theory, the story of infection barriers is one of setting the human and the nonhuman virus against each other, as the victim versus the menace. viruses are commonly understood to be "'bad matter' to be prepared for, brought under control, and ultimately eradicated or rendered impotent" (white 2015, 145-46) . unlike the germ theory of disease, which makes a specific microbe responsible for a specific disease (e.g., the coronavirus is responsible for sars), an ecological perspective holds that microbes are not essentially pathogenic (methot and alizon 2014) . rather, as hinchliffe et al. (2016) have argued, disease emerges from the complex entanglement between the immune system of a host and the microbial milieu in and outside of the host. various scholars have noted how, much like hong kong in the face of sars, global public health programs adopt an antimicrobial stance to the control and/or elimination of infectious diseases, however, which might prove to be counterproductive in securing human life (macphail 2014; methot and alizon 2014; fishel 2015 fishel , 2017 white 2015; hinchliffe et al. 2016; du plessis 2017; lorimer 2017, 545) . at the microbial level, ecological microbiologists understand most viruses and bacteria are not pathological; they are benign and even indispensable to human life. scientists are understanding better the causes of infectious diseases, but they also "increasingly hear about beneficial microbes and the consequences of their decline or absence" (lorimer 2017, 544) . 8 causal links remain unclear and contested, however; as lorimer finds, there is "a widespread reappraisal underway in modern medicine of the salutary potential of the microbiome and the therapeutic use of microbes" (lorimer 2017, 544) . humans and microbes seem deeply and irrevocably entangled. this has led anthropologist stefan helmreich to consider the figure of homo microbis, made up of bacteria, viruses, fungi, and protozoa (helmreich 2014 (helmreich , 2015 . what are the implications of this understanding of the human body as mostly microbial to the way we fight infectious diseases in global cities and elsewhere? microbes are everywhere. apart from the ocean floors (helmreich 2009 ), soil, and deep forests, they inhabit nearly all of living matter, including mammals. humans are colonized by many viruses. this collection of viruses found in or on humans is known as the human virome, which is the viral component of the human microbiome-the assemblage of microorganisms including bacteria, fungi, protists, archaea, and viruses residing in/on the human body. only a minority of viruses infect human cells and can cause "acute, persistent, or latent infection"; some viruses are even "integrated into the human genome such as endogenous retroviruses" (wylie, weinstock, and storch 2012) , which are essential to human reproduction. 9 8 "missing microbes" have arguably been linked to several metabolic, immunological, and mental health conditions, such as allergies, obesity, inflammatory bowel disease, and depression. see velasquez-manoff 2012; blaser 2014; and lorimer 2017. 9 endogenous retroviruses are fossil viruses which "began to be integrated into the human genome some 30-40 million years ago and now make up 8% of the genome" (tugnet et al. 2013) . they may be associated with autoimmune diseases such as rheumatoid arthritis, though evidence is still limited. yet, while many mammalian viruses, such as the endogenous retrovirus, picked up mammalian genes during their evolution by subverting these "to provide a selective advantage to the virus," an opposite story can be told too. an endogenous defective retrovirus "has been sequestered to serve an important function in the physiology of a mammalian host" by encoding a protein call syncytin. syncytin has been found to be vital in placenta production, a necessary prerequisite to human reproduction (mi et al. 2000; zimmer 2012 ). there is no scientific consensus on whether viruses are living matter. 10 this is because viruses cannot live without a host cell: "they must invade and 'hijack' a cell's mechanism" so that they can produce the proteins needed for their own reproduction (macphail 2014, 8) . it is in this sense that van regenmortel and mahy (2008) have noted, viruses lead "a kind of borrowed life." their capacity to produce an effect-that is, their efficacy-, like other nonhuman matter, is "not only to impede or block the will and designs of humans but also to act as quasi agents or forces with trajectories, propensities, or tendencies of their own" (bennett 2010, viii) . by not taking seriously their efficacy to alter the course of events, however, their animating role in evolution has until very recently been overlooked. viruses have been and are a vital source of new genetic information, horizontal gene transfer, and genetic diversity in the evolution of life, including increasing and decreasing immunity to certain viruses or bacteria. 11 they have effected change on the direction of human evolution and were involved in the making of human history, most visibly in the form of plagues and diseases (mcneill 1976) . they are essential to sustaining the environment, including sea and freshwater regulation, as well as human reproduction; humans are deeply involved with viruses, in the positive and negative sense (fishel 2015, 158) . the vital role of viruses in human evolution necessitates an epistemological rethinking of evolution, as melissa a. white has noted, "from darwinian models of the 'survival of the fittest' to the phenomenon of emergent life" (white 2015, 146-47) . viruses are able to evolve very quickly, reinventing themselves by mutation and adaptation, thereby "evading immune systems and other means of eradicating them" and "surviving under conditions that would cripple or kill other organisms" (macphail 2014, 9) . essentially, viruses are "packets of pure information" in that they are protein encasements of genetic material in the form of either dna or rna. rna viruses such as influenza a (responsible, for example, for avian flu in 2003, the 1918 flu, and swine flu in 2010) evolve by engaging in "antigenetic drift" when mutating while replicating. zoonotic viruses that are able to jump species also evolve by engaging in "antigenetic shift" during which they exchange "entire genetic segments with other viruses inside a host" (macphail 2014, 9) . it is in this capacity that viruses ought to be recognized as "bioinformatic transport machines." indeed, white argues, "they ought to be considered active participants in creating the potentiality of new conditions of life through their capacity to assemble novel coalitions of genes" (white 2015, 147) . antigenetic shifts can change the surface proteins of the virus (the antigens), which are then no longer recognizable by the host's immune system, thus provoking a slower or no response to fend off the virus. virologists studying influenza a tend to focus on any incremental changes or dramatic shifts in genetic makeup to the viral antigens hemagglutinin (ha) and neuraminidase (na). it is after these specific antigens that influenza a viruses are named by their h and n numbers 10 generally, scientists apply a list of a priori criteria to decide on life. following this, according to virologists van regenmortel and mahy (2008) , viruses today are considered somewhere in-between living and nonliving. similarly, theresa macphail (2104) argues, while viruses ought to be considered to have a "certain type of nontrivial agency," they are usually seen as "liminal objects" "with some of the properties of life, yet they cannot be considered fully 'alive' while outside of a permissive host." they are "organisms at the edge of life" (rybicki 1990) . 11 in fact, historical viral traces in human dna were, until recently, controversially referred to as "junk dna." this noncoding dna makes up a greater portion of the human genome than "segments of dna that actively code for genes" (macphail 2014) . the human genome effectively consists of only two to three percent of coding dna, while the remaining ninety seven to ninety eight percent was thought to be just a "sea of genetic gibberish" with no biological function, hence "junk dna" (hall 2012) . this idea was debunked in 2012 by the encode group, which revealed that "junk dna" was in fact brimming with important genetic information. the encode group produced "a stunning inventory of previously hidden switches, signals and sign posts embedded like runes throughout the entire length of human dna." this essential noncoding dna, as macphail (2014) has noted, is evidence of past infections or "of a long-standing symbiotic partnership" with viruses. viral "junk" may even be responsible for creating new genes and for enabling the immune system to adapt to emerging infections (macphail 2002). (macphail 2014, 10). the pathogenicity of influenza a viruses is established both by their molecular makeup and their ability to cause serious illness in their host species, birds or other. a highly pathogenic virus causes severe or lethal illness in bird or other species populations. it is possible for a virus to "jump" from its host species into a human host, resulting in an usually severe and lethal infection. yet, viruses do not have "motives, or thoughts, or diabolical plans to wreak havoc to our cities"; "their function and purpose (if we can even say that they have one) is to replicate, to evolve, to survive" (macphail 2014, 11) . 12 most viruses, however, infect microorganisms including bacteria in the human microbiome (edwards and rohwer 2005) . these prokaryotic viruses "affect human health by impacting bacterial community structure and function" (relman 2015; also wylie et al. 2012) . because viruses evolve very quickly, the human virome (and thus also the microbiome) is changing all the time. each human virome is different and unique as it evolves and is formed both by preexisting immunity and viral and human genetics as well as by human lifestyle, age, geographic location, and susceptibility to disease, all of which affect individual exposure to viruses (delwart 2013) . from this perspective, diseases are not the outcome of a virus or other microbe infecting a human, as germ theory holds, but emerge from the unique constellation of political and ecological relations that affect the biological interactions of the human, the animal, and the microbe and lead to the potential development of a diseased state-that is, pathogenesis. hinchliffe et al. usefully speak of disease as "multispecies conditions configured by specific socio-ecological 'situations'" (hinchliffe et al. 2016; lorimer 2017, 545) . some scientists already seek a shift toward this ecological or configurational thinking. the emerging diseases and global health security narrative runs on the notion that the bacteria or virus is the enemy against which the global surveillance / health security apparatus must operate (weir and mykhalovskiy 2010) . this narrative rests on the germ theory of disease currently dominating microbiology/bacteriology. in her pathography of the h1n1 influenza pandemic in hong kong in 2009, macphail finds that a few "heretic" microbiologists are challenging the dominant emerging infectious diseases narrative, calling for a new epistemology in which microbes are understood not as enemies but as coinhabitants of the world (macphail 2014, 17) . hong kong biologist frederick c. leung suggests that the problem with the alarmist influenza pandemic discourse lies partly in the way viral genetic data revealed through "signature sequences" has been interpreted by leading influenza scientists such as the virologist robert webster (webster 1993) . speaking against the central focus on the h and n proteins as the key to what makes an influenza virus deadly or not in the dominant influenza surveillance and research discourse, leung and others believe that "the public health orthodoxy has become too ready to see what it has already been prepared to look for and to fear" (macphail 2014, 190) . evolutionary biologist paul w. ewald suggests that although the h and n proteins are most visible to our immune system, it is not certain that they are the reason for a strain's pathogenicity or severity (macphail 2014, 190) . ewald believes that scientists tend to confuse "sources of variation-the mutation and recombination of genes-with the process of evolution by natural selection" (ewald 2000, 22-23) . 12 hong kong biologist frederick c. leung suggests that the problem with the alarmist influenza pandemic discourse lies partly in the way viral genetic data, revealed through "signature sequences," has been interpreted by leading influenza scientists such as the virologist robert webster (1993) . speaking against the central focus on the h and n proteins as the key to what makes an influenza virus deadly or not in the dominant influenza surveillance and research discourse, leung and others believe that "the public health orthodoxy has become too ready to see what it has already been prepared to look for and to fear" (macphail 2014) . evolutionary biologist paul w. ewald (2000) suggests that although the h and n proteins are most visible to our immune system, it is not certain that they are the reason for a strain's pathogenicity or severity. ewald believes that scientists tend to confuse "sources of variation-the mutation and recombination of genes-with the process of evolution by natural selection." to date, our understanding of the human virome, benign viruses, and the virushuman relation remains limited. yet, viruses may not simply be bits of "bad matter" that slow down, disassemble, and debilitate complex systems. rather, viruses might well be approached from another vantage point altogether, as vitalizing forces in complex ecological systems in which humans are not the center. (white 2015, 149) the relation between the human and microbial communities is not antagonistic but symbiotic. while the rapid emergence of infectious diseases is creating a "world on alert," as weir and mykhalovskiy (2010) have observed, it demonstrates the frail character of the ecological balance of this vital symbiosis between humanity and their vital environment (methot and alizon 2014, 782) . the study of the biology and ecology of viruses forces us to appreciate our mostly symbiotic relationship with viruses and other microbes. it compels us to rethink how (human) life has come to be. it is not the darwinian paradigm of "the survival of the fittest" but rather an emerging paradigm revolving around a microbiological understanding of "emergent life" that explains our evolution. it also necessitates that we understand and respond to disease not as the invasion of enemy microbes but as the pathogenesis, that biological mechanism, of a unique constellation of politico-ecological relations and human-animal-microbial interactions, which gives rise to a malady. how can this emerging ontological and epistemological understanding of human life inform the governance of disease? the best defence we have against microbes is our brains, which can surely work out how to live in harmony with the microbes we know, and find non-disruptive ways of combating those that emerge in the future. (crawford 2007, 213) how do we live in harmony with the microbial world but still prevent infectious diseases from developing? how do we move from a potentially destructive antimicrobial perspective such as is embodied in hong kong to a microbial perspective in which we take responsibility for our vital relation with the microbial world? new materialist thinking (cf. hinchliffe 2007; coole and frost 2010; dolphijn and tuin 2012), which takes seriously the efficacy and ecology of human bodies and nonhuman bodies such as the virus and other microbes, invites us to examine how the human-microbe relationship can be rethought in politics. while a number of theorists have begun to conceptualize a new materialist politics and ethics within modern political theory (bennett 2010; connolly 2013; mitchell 2014) , others have looked to indigenous cosmologies, which take into account the world we share with other kinds of beings, to formulate a postanthropocentric politics (kohn 2013; tsing 2015; du plessis 2017) . the daoist cosmology underlying chinese medicine and chinese strategic thought and practices provides a first step to think in distinctly chinese ethical terms about how public health strategies in hong kong and beyond can begin to direct a human-microbial ecology to the advantage of protecting all life. daoist thought takes reality as dynamic, and the regulation of this changing reality is immanent to the interaction of the heterogeneous factors involved, thus emerging spontaneously (jullien 2004 ). sunzi's philosophy strategizes how best to direct a heterogeneous ensemble of human and nonhuman (virus, bacteria, and other nonhuman) bodies, by shifting the inherent potential, the shi, of this ecology to our advantage. in the art of war (515-512 bce), success in war was achieved not through the courage, activity, and talent of any individual fighter but through careful planning instead of actual combat. in fact, combat in chinese thought is not violence; violence is to be avoided. in medicine too, defending the body from danger demanded care for the body manifested in preservation regimes instead of reactive "western drug-and surgery-based medical practice" (li 2014, 83) . chinese medicine is about preserving rather than curing. this can be seen in its guise as a conception of food: it demands specific diet regimes developed from "observations of the characteristics of the vegetation and animals in the season." over time, it came to incorporate a puzzling spectrum of diet-based caring regimes that are still widely practiced today (li 2014, 83) . reflecting on this, medical anthropologist judith farquhar has noted of chinese medicine that it "heals in a world of unceasing transformation." this a priori dynamism in chinese medicine contrasts sharply with the modern western "world of discrete entities characterized by fixed essences, which seem to be exhaustively describable in structural terms." since motion and change are a given, they rarely require explanation with reference to their causes. according to farquhar, "one consequence of this dynamic bias in chinese medicine is that the body and its organs (i.e., anatomical structure) appear as merely contingent effects or by-products of physiological processes" (farquhar 1994 as quoted in needham 2000) . in a comparable vein, methot and alizon (2014) and others (hinchliffe and bingham 2008; lorimer 2017) have argued that pathogenesis results not from any single pathogenic microbe but from the configuration of socio-ecological relations and human-animal-microbe interactions. chinese thought, francois jullien explains, takes reality as an immanently "regulated and continuous process that stems purely from the interaction of the factors in play (which are at once opposed and complementary: the yin and yang)" (jullien 2004, 15) . reality is dynamic, and the regulation of this transformative reality-that is, the order of reality-emerges spontaneously. it is not achieved through external intervention but is "entirely contained within the course of reality, which it directs in an (inherent) fashion, ensuring its viability" (jullien 2004, 15) . two notions are central to this ancient chinese strategy: (a) the notion of a situation or configuration (xing)-that is, as a relation of forces such as are immanent to an ecology-and (b) the notion of the potential (shi) of a situation/configuration. this is commonly illustrated by "a mountain stream that, as it rushes along, is strong enough to carry boulders with it" (jullien 2004, 17) . the configuration (xing) of the mountain consists of a downward-sloping course and narrow channel, while this configuration itself gives rise to the potential (shi) for the rushing stream to carry boulders with it. thus, it is not "what we ourselves personally invest in the situation" that counts so much but rather "the objective conditioning that results from the situation" (jullien 2004, 17) . 13 jullien has argued that shi helps to "illuminate something that is usually difficult to capture in discourse: namely, the kind of potential that originates not in human initiative but instead results from the very disposition of things" (jullien 1995, 13) . bennett (2005, 461) usefully elaborates on this by explaining that "shi is the style, energy, propensity, trajectory, or élan inherent to a specific arrangement of things." for bennett, "shi names the dynamic force emanating from a spatiotemporal configuration rather than from any particular element within it." as "both the membership (of a configuration or assemblage) changes over time and the members themselves undergo internal alteration," as bennett points out, the shi or mood of a configuration also changes (bennett 2005, 461) . in margaret archer's words, everyone in the configuration "possesses autonomous emergent properties which are thus capable of independent variation and therefore of being out of phase with one another in time" (archer 1995, 66) . it is possible that an individual element such 13 biophilosophers deleuze and guattari (2004) describe something comparable when they discuss the milieu as a force field composed of nonhuman and human things (xing). not only do these heterogeneous elements constituting a milieu each entail some form of efficacy, but the milieu as a whole gives rise to a potential to effect (shi). jane bennett (2005) likewise argues that there is an agency that attaches to assemblages of human and nonhuman entities. she contends that this agency of an assemblage is comparable to the chinese strategic notion, shi. as a virus, in an antigenic shift, "becomes out of sync with its (previous) self" and forms new relations within an assemblage, "leaning towards a different set of allies" (bennett 2005, 462) . as such, the members of an assemblage "maintain an energy potentially at odds with the shi" (bennett 2005, 462) . it is for this vibrancy, according to bennett, that the agency of assemblages cannot be understood in terms of passive social structures. crucially, in chinese strategic thought, it is the shi that "can be made to play in one's favour" (jullien 2004, 17) . it is because of their variability that circumstances or ecologies can little by little be turned advantageously by the propensity or efficacy immanent to a situation. a chinese sage, according to jullien, "is inclined to concentrate his attention on the course of things in which he finds himself involved in order to deter their coherence and profit from the way that they evolve" (jullien 2004, 16) . a good general, in turn, "must be able to read and then ride the shi of a configuration of moods, winds, historical trends, and armaments" (bennett 2005, 461) . this "logic of regulated evolution" allows the potential of a situation "to develop of its own accord and to 'carry' us with it" (jullien 2004, 17) . jullien illustrates this by drawing on an old chinese proverb that captures the core idea of this thinking (mencius as quoted in jullien 2004, 16) : "even with a mattock and a hoe to hand, it is better to wait for the moment of ripening." unlike the western tradition of establishing a model that is projected onto a variable reality, according to jullien, chinese thought will concentrate on understanding how things unfold so as to discover their configuration (relationality) in order to come up with alternative ways to effect a more advantageous outcome. thus, instead of constructing an ideal form that we then project on to things, we could try to detect the factors whose configuration is favourable to the task at hand; instead of setting up a goal, we could allow ourselves to be carried by the propensity of things. (jullien 2004, 16) to ride the shi-in other words, to live harmoniously alongside and with the microbial word-we need to identity those factors whose configuration is favorable to human life. daoist ethics and chinese strategic thought lead us to embed homo microbis in an environment that is favorable to all life. as hong kong biologist frederik leung points out, the problem not only lies in the prevailing dominance of germ theory in science, it also lies in the way we relate to the animal and nonhuman world at large with which humans are so deeply entangled. he speaks against the culling of birds and animals as a response to an emerging influenza pandemic (macphail 2014, 192) . in fact, the flu is argued to be unpredictable only because influenza experts "don't understand the basic science" (leung, as quoted in macphail 2014, 193) . viruses naturally undergo constant mutation. in the case of cross-species transmission, such as the sars coronavirus which crossed over from civet cats to humans in 2003, it became clear that "highly pathogenic influenza viruses naturally burn themselves out, . . . they pose no greater risk to humanity than 'normal' influenza viruses" (macphail 2014, 193) . in fact, "the more virulent the virus, the faster the virus dies out. by evolutionary principle" (leung, as quoted in macphail 2014, 194) . leung laments the current focus on the development of influenza vaccines, since intervention through the vaccine encourages further mutation, whereas allowing the virus to take its natural course leads to its natural burn out (macphail 2014, 194) . leung's call for rethinking how we relate to the animal world echoes the recent effort to do just that in the one world one health initiative of scientists, physicians, and veterinarians worldwide to collaborate across disciplines in addressing emerging diseases. in part, this effort came about due to concerns for shared risks across human, animal, and environmental health. the focus, however, has tended to lie on the contamination and transmission of pathogens rather than on the socioeconomic relations underlying disease and health. it has been criticized for reducing diversity and for underappreciating the local, contingent, and practical engagements that first make health possible (hinchliffe 2015) . yet, it is not just how we relate to the animal world that matters. it is also about how we think about life in cities, especially as sars in hong kong in 2003 revealed, a set of absent actors-animals, microbes, airplanes, sewage systems, respiratorsthat had been banished to the margins of our conceptions of urban life, even as they actively contributed to how urban lives were composed and lived. (braun 2008, 251) the sars encounter and the post-sars politics force us to think about the microbes, animals, and many other organisms living amongst us and influencing the "social" collectives of humans. that social collective, the city, needs to be rethought on microbial terms. at the turn of the twentieth century, cities thrived on "bacteriological" (gandy 2006) and "epidemiological" conceptions of urban spaces in europe and north america. they aimed to transform urban spaces and the behavior of city people accordingly (braun 2008, 3) . in his exploration of the chinese city, li shiqiao highlights the key imperative of prudence, understood in terms of "the principle of endurance and an unknown future reward," which firmly runs through chinese conceptual thought (li 2014, 81) . he interpreted this in the post-sars situation of hong kong to be the donning of masks and ultimately striving to become hygienic subjects. yet, it seems prudent to build a microbial instead of an antimicrobial city, to rethink space and the behavior of the city people in hong kong and other (global) cities in ecological and sustainable terms, and to take into account the social-economic relations that intensify human-animal-microbial interactions. this article set out to show how a better understanding of the microbe and its deeply entangled existence with humans is crucial to conceptualizing a better approach to health and life. specifically, it argued for an inclusive approach to the virus and other microbes with which we share the world we live in over an exclusively oppositional approach to eradicating pathogenic circulation, which also eliminates or mutates benign viruses essential to human life. the article began by looking at the antimicrobial politics in chinese postcolonial hong kong since the turn of the century. it particularly focused on the notion of "infection barriers" advanced by li (2014) . li bases his analysis on the traditional conception of the chinese city and the practice of defense in walling the city off against danger. by arguing that, in the struggle against infectious diseases, contemporary practices of urban defense have taken on another guise, namely infection barriers, li is able to demonstrate how the politics of public hygiene operates not only through overt public programs but through infection barriers that are affectively knit into the fabric of the urban architecture and tissue of city dwellers. although his lens on chinese urban defenses takes seriously ancient chinese thought in the making of urban spaces, nonetheless, the politics of infectious disease remains caught up in the prevalent and dominant oppositional narrative of the human against the microbe. infection barriers set up the human and the nonhuman virus against each other, as the victim versus the menace. like antivirals and antibiotics, urban hygiene practices are never entirely able to control pathogenic circulation. this is because urban hygiene proceeds on the basis of a very narrow conception of disease, namely the widely accepted germ theory of disease. by studying the biology of microbes, it becomes possible to grasp more what the virus and other microbes are and do but particularly how they relate to the human. first, the activities of the virus escape the political designs, regimes, and practices because the virus and other microbes are forever in transformation. how then can human efforts be conceived to control pathogenic, while fostering benign, viral circulation? second, viruses play a large and essential part in making up the human. while a small number of viruses are pathogenic, the majority are benign, and some are even essential to human life. strategies to eliminate them may kill pathogenic viruses but essential viruses might also be killed off in the process. as the human cannot be thought without the virus, and attempts to alter or eliminate it (in)directly also affect the human, how might we think differently about urban spaces and public health if we consider the human and the virus not as opposed but as fundamentally interrelated? finally, the article considered daoist thought, to begin to reflect on the governance of microbes, which takes seriously their efficacy, dynamism, and deeply historical relationality with humans. from the biological vantage point of ecologies in which the virus, the human, and many other organisms are fundamentally interconnected forms that vitally depend on, but can also harm, each other, all interventions to control viruses will affect all involved, including the virus as well as the human. thus, it is in the interest of human beings to proceed with interventions to control viruses that cause the least direct or indirect harm to humans. daoist thought offers some ideas for how to strategize public health schemes, which take due consideration of this deep involvement of viruses and humans. public health schemes that develop defenses against pathogenic viral circulations, especially in a densely populated global city such as hong kong, remain important. however, there is also a need to consider and adapt the human practices that both create(d) the easy passages for viral circulation as well as forced viral mutations through the overuse of antiviral (and antibiotic) agents or vaccine development which is thought to have led to antiviral resistance. most of all, rather than fostering an oppositional relation between the human and the virus, there is a need for an appreciation of the vital role of the virus in human lives as well as of how deeply we are entangled with the virus. instead of only arming against pathogenic viral circulation by sanitizing both the urban environment and the minds of city dwellers, as in the case of hong kong, such circulation might be more usefully countered by championing an approach that proceeds on the understanding that the human irrevocably inhabits an ecosystem in which the multiplicity of life forms are deeply interrelated and dependent on each other. much like the chinese general evaluating the course of things immanent to a situation, since humans thrive on a range of other beings doing well, "an interest in human security becomes an interest in biodiversity: thriving is not a zero-sum game between different species, in fact, quite the opposite" (du plessis 2017, 18). global health projects ignore this and are struggling to deliver what they aim to do. modernity at large: cultural dimensions in globalization. public worlds realist social theory: the morphogenetic approach city under siege: authoritarian toleration, mask culture, and the sars crisis in hong kong the agency of assemblage and the north american blackout vibrant matter: a political ecology of things missing microbes: how killing bacteria creates modern plagues thinking the city through sars: bodies, topologies, politics the rise of the network society sick cities: why urban life is breeding new illness fears the fragility of things: self-organizing processes, neoliberal fantasies, and democratic activism new materialisms: ontology, agency, and politics deadly companions: how microbes shaped our history a thousand plateaus: capitalism and schizophrenia a roadmap to the human virome new materialisms: interviews and cartographies when pathogens determine the territory: toward a concept of non-human borders viral metagenomics security and global health: towards the medicalization of security plague time: how stealth infections cause cancers, heart disease, and other deadly ailments microbes the bacteriological city and its discontents journey to the genetic interior the epidemic streets: infectious diseases and the rise of preventive medicine 1865-1900 networked disease: emerging infections in the global city homo microbis: the human microbiome, figural, literal, political more than one world, more than one health: re-configuring interspecies health mapping the multiplicities of biosecurity pathological lives: disease, space and biopolitics the propensity of things: towards a history of efficacy in china how forests think: toward an anthropology beyond the human revealing power in truth global health and international relations. cambridge: polity. lee, shi hung understanding the chinese city. theory, culture and society. london: sage. loos, adolf. 1987. "plumbers parasites, ghosts and mutualists: a relational geography of microbes for global health the viral gene: an undead metaphor recoding life the viral network: a pathography of the h1n1 influenza pandemic. expertise: cultures and technologies of knowledge plagues and people the sanitary city: urban infrastructure in america from colonial times to the present. creating the north american landscape what is a pathogen? toward a process view of host-parasite interactions syncytin is a captive retroviral envelope protein involved in human placental morphogenesis only human? a worldly approach to security part vi: medicine. science and civilisation in china: biology and biological technology globalization of sars and health governance in hong kong under "one country, two systems are viruses alive? the human microbiome and the future practice of medicine hygienic modernity: meanings of health and disease in treaty-port china die sars-krise in hong kong: zur regierung von sicherheit in der global city routledge handbook of global health security the classification of organisms at the edge of life, or problems with virus systematics the global city reorganizing hospital space: the 1894 plague epidemic in hong kong and the germ theory transcript of the press conference with the chief secretary for administration in the conference hall of the central government offices new annexe on may the mushroom at the end of the world: on the possibility of life in capitalist ruins human endogenous retroviruses (hervs) and autoimmune rheumatic disease: is there a link? an epidemic of absence: a new way of understanding allergies and autoimmune diseases influenza global public health vigilance: creating a world on alert. routledge studies in science virus emerging view of the human virome mammals made by viruses i thank the anonymous reviewers and the editors of ips for their generous comments. i am also grateful for insightful comments on earlier versions of the article presented at the eisa convention 2017, ewis 2018, and before the irss research group, university of groningen. i am especially thankful to gitte du plessis, luis lobo-guerrero, and christopher long for thought-provoking nudges. this paper was produced under the aegis of the groningen centre for health and humanities and the aletta jacobs school of public health, university of groningen. key: cord-017225-6ofi6mg5 authors: wei, yuwa title: human rights issues date: 2018-12-10 journal: issues decisive for china&#x02019;s rise or fall doi: 10.1007/978-981-13-3699-7_8 sha: doc_id: 17225 cord_uid: 6ofi6mg5 contemporary china is plagued by a wide range of human rights related issues and problems. in addition to those arising in the areas of religious toleration, judicial practice, treatment of labor and forced abortion, which were extensively reported by the media in the past, some newly emerged problems concerning human rights violation are much more alarming, due to the size of population affected and the degree of challenge caused to the public’s psychological endurance and confidence in the social ethnics and administration of the nation. most of all, these problems concern nearly every chinese citizen’s well-being and impact on their personal prosperity, as well as the prosperity of the nation as a whole. these problems are mainly associated with failures in environmental protection, food safety, and medical security. first white paper on human rights being released in 1991, the white papers of the following years were arranged as a series sequentially informing the progress made and the actions taken in human rights promotion in each year. 7 nevertheless, it is an undeniable fact that contemporary china is plagued by a wide range of human rights related issues and problems. in addition to those arising in the areas of religious toleration, judicial practice, treatment of labor and forced abortion, which were extensively reported by the media in the past, some newly emerged problems concerning human rights violation are much more alarming, due to the size of population affected and the degree of challenge caused to the public's psychological endurance and confidence in the social ethnics and administration of the nation. most of all, these problems concern nearly every chinese citizen's wellbeing and impact on their personal prosperity, as well as the prosperity of the nation as a whole. these problems are mainly associated with failures in environmental protection, food safety, and medical security. achieving modernization has been the core economic objective and a solemn promise of the chinese government. 9 urbanization has been a major means of reaching this goal. this course has been accelerated since the 1990s with an average urban population growth rate of more than 3.4%. 10 nowadays, the number of urban population has reached 7711.6 million, account for 56.1% of the total population of the nation. 11 in the meantime, china has scored an extraordinary gdp growth rate ranging from the lowest 6.8% to the highest 13% between 1991 and 2014. 12 if these are to be seen as modernization or development, the modernization or development droughts and storms, deforestation, desertification, etc., affected more than two billion people and the economic toll multiplied compared with the previous decades. 17 this trend has an even acuter presentation in china. in the past three decades, china experienced extraordinary economic growth, accompanied by rapid industrialization and urbanization. the emergence of many city clusters has resulted in centralized and condensed population in urban areas. the economic development, together with urbanization, has generated substantial environmental problems. nowadays, china is facing nearly all of the world's ecological challenges including climate change, desertification, deforestation, declining water resources, acid rain, soil erosion, air and water pollution and biodiversity loss. 18 apart from increasingly frequent natural disasters caused by climate change, air and water pollution has become a paramount concern to the general public, which is acutely perceived in their daily life. as mentioned in the beginning of this section, the cost of environmental degradation in china is massive and profound, from people's lifespan to economic toll. the link between environment and human rights can be established on basis that physical environment is a precondition for living a life of dignity and worth. good environment is a pre-requisite for the enjoyment of fundamental human rights. 19 in china, for a long time, human rights violations and environmental degradation have not been treated by central and local governments as related issues and addressed in a coherent and integrated way. it has become evident that environmental protection and human rights are prima facie interrelated, interconnected, and mutually responsive, since they both serve the purpose of improving and sustaining the well-being of humanity. 20 human well-being has a basic requirement for safe food, clean air and drinking water, safe shelter and protection from diseases. 21 human activities such as rapid industrialization and urbanization result in environmental degradation 17 including rising of sea levels, air and water pollution, drought, flooding, which in turn, affects people at a large number. at the international law level, the vital role that environment plays in guaranteeing individuals' fundamental human rights has been recognized at a much earlier time. the stockholm declaration of 1972, nairobi declaration of 1982, world charter for nature of 1980, earth summit of 1992, johannesburg conference on sustainable development of 2002, un conference on sustainable development of 2012 have all acknowledged the interdependence between environment and human rights by conveying the message that environment may lead to long term impact on humanity and violation of human rights. 22 the human rights council in its resolution 7/23 of march 2008 and resolution 10/4 of march 2009 focused specifically on human rights and climate change, pointing out that environment change impairs and undermines directly and indirectly the effective enjoyment of human rights. 23 traditional international environmental laws commonly address environmental issues through creating and determining rights and obligations between states. human rights laws, on the other hand, place individuals' rights at the center of the focus. the establishment of the linkage between human rights and environment enables individuals victimized by environmental degradation to seek remedy on human rights violation ground, which traditional environmental laws gives little focus. it is unfortunate that in china's priority agenda, both human rights protection and environment protection have given way to economic development for quite a while. the link between environmental damage and human rights violation has not been articulately addressed either. indeed, it is a high time for china to adopt a comprehensive, human rights based approach to formulate environmental policies for clarifying human rights obligation in environment protection and for identifying and promoting good practice in environment management. there are signs that current central government shows the interest in considering human rights law enforcement as a means of achieving the purpose of environment protection. "environment protection" have become hot words in china's political life since the 18th national congress of the communist party of china (nov. 8-14, 2012) . in his keynote report in the opening ceremony, hu jin tao, the president of china by then, emphasized the term "ecological civilization" for fifteen times. his successor, the current president xi jin ping, in his speeches at the national people's congress 2015 and at the chinese people's political consultative conference 2015, called for environment protection and pointed out that protecting environment is as important as protecting productive forces. 24 with the initiative from top leaders, the governments of all levels have become more and more mobilized to change their focus and give particular importance to environment protection. although the areas like beijing, hebei and shanxi are still frequently blanketed by hazardous smog and problems caused by environmental degradation and climate change are still acute, people are more willingly to adopt an optimistic attitude when speaking likely environmental improvement in the coming decades. nowadays, with the growth of economic prosperity, common chinese people enjoy an ever-abundant supply of food products and are keen to broaden their dining experiences. in today's china, eating occupies nearly all occasions and businesses. visitors to china are likely to find that eating is arranged as a highlight for them by the hosts. some research suggests that the current food consumption pattern in china even poses as an exception to engel's law, that is: as the income of an average chinese family rises, the proportion of income spent on food increases, rather than decreases. 25 some other research finds that in fact, the share of chinese households' income spent on food fell from over half in the 1970s to about one-third nowadays. 26 nevertheless, one-third of household income being spent on food is still spectacularly excessive, compared with 6.7% in the u.s., 9.3% in the u.k., and 6.7% in singapore. 27 while all levels of the population take any possible opportunities to indulge with feasts, disturbing facts concerning food safety emerge. this article concerns itself with some of the most severe problems associated with food safety in china, which mainly refer to the cases involving deliberate contamination of food for profits. these include problems such as manufacturing and trading imitation food (e.g., selling pork as beef), processing and selling contaminated food, adding chemical additives into food products for improving visual appeal, taste, or simply for falsely 24 increasing nutritional value (e.g., adding melamine into baby formula to inflate the protein levels), and producing and trading tainted food (e.g., profiting from recycled oil mainly dredged up from restaurant gutters). 28 worst of all, the above problems are not sporadic but are widespread and rampant, and in some cases, systematic. it needs to be borne in mind that the above issues are the most severe ones and only account for a small part of the avalanche of food scandals. here, incidents relating to sanitation or foodborne illness outbreaks caused by negligence in manufacture and service processes are not taken into account, though they are also serious problems. the right to safe food is a basic human right for all individuals. 29 in addition, safe food should be regarded as an issue of national security for the reason that toxic food poses a serious threat to public health, which in turn leads to destructive social and economic consequences, and eventually has an adverse impact on the national interests of a country. it is high time for the chinese to review their policies and strategies in dealing with social issues, including social justice, equal distribution, anticorruption and clean governments, social ethics and public morality, and public psychology. regulation is surely a necessary instrument to control illegal conduct. however, given the fact that policies and laws are always watered down or compromised in implementation, it is thus particularly important for policy makers to take all the above issues into consideration when shaping the nation's regulatory infrastructure for food safety. when serious food problems have a devastating impact on a large proportion of the population, it is necessary to assess the situation from a human rights perspective while searching for solutions. this section examines china's food safety issues in connection with human rights awareness in the country. it investigates the social, political and cultural causations of the food scandals, and explores possible solutions. before the 1980s, under the planned economy, food problems that arose from manufacturing were extremely rare and the regulatory focus was on sanitation occurring in the service and consumption processes, where the food safety administration was part of the duties of the sanitation and anti-epidemic departments. 31 although it appeared that a legal framework was largely put into place, the food industry was, in fact, less effectively regulated, due to the loose context of the laws and the gaps between the laws and their practice. 32 the situation has deteriorated since the beginning of the new millennium with the introduction of the practice of quality inspection exemption or the regime of self-inspection by enterprises themselves, an initiative launched to reduce the operational costs of food enterprises. 33 the self-inspection regime was a result of the administrative authorities exercising their supervisory powers in an abusive manner while in the discharge of their quality control duties concluding with the imposition of unnecessary and excessive burdens on food producers. 34 however, instead of disciplining administrative conduct, the policy makers opted for a compromise by abolishing food quality inspection. research has shown that the managerial costs in chinese firms are chiefly caused by defects inherent in the governance of these firms. 35 without fundamental improvements in the corporate governance system, 30 34 xu, supra note 32. 35 see, for detailed discussions on managerial costs and corporate governance in chinese firms, yuwa wei, "directors' duties under chinese law -a comparative review", 3(1) university of the costs are likely to continue to inflate. later instances of food safety crises have proven that those who maintain the argument that relaxation in quality control can reduce food companies' operational costs are simply barking up the wrong tree, where the most likely result is noncompliance. it took the government 8 years to realize that giving enterprises free rein in regards to food quality control was an unwise decision. it was at least partly responsible for the current culpable culture in the food industry. in the aftermath of a series of food scandals, policy and regulatory mechanisms have been introduced as the main crisis control efforts. on the current law imposes full responsibility on food producers and manufacturers to ensure that their products meet safety standards throughout each process, including purchase of raw materials, production, storage, package, transport and delivery. 37 in addition, they need to faithfully record the safety management throughout the whole course. however, china's experiences reveal that without fierce scrutiny, the industry is unlikely to comply with such requirements. under the current regime, the supervision and administration are given to local governments at or above the county level, who formulate annual plans for food safety and undertake food sampling inspection. 38 specific branches of government, including the departments of agriculture administration, quality supervision, industrial and commerce administration, and the food and drug administration carry out the routine work of food sampling inspection. 39 (2006) china, § 3 (2009) , an english version is available at <www.fdi.gov.cn/1800000121_39_4037_0_7.html>. the section states: "the food producers and traders shall, in accordance with laws, regulations and food safety standards, carry out productive and operational activities, establish and improve the food safety management system and adopt efficient management measures to ensure food safety. the food producers and traders shall be responsible for the safety of produced and trade food themselves as well as society and the public, and also bear social responsibility." 38 ibid, at § 47. 39 ibid, at § 48. persons with direct responsibility in the above mentioned governments are subject to disciplinary punishment comprising of the recording of serious demerits, demotion, dismissal or expulsion, in the event of a failure to perform their supervisory and administrative duties, particularly where the failure causes a serious social effect. 40 the same penalties are imposed directly on persons responsible for the above mentioned government branches, in the case where negligence is committed, daily supervision and inspection of food samples are omitted, abuse of power occurs, or favouritism is shown in the supervisory and administrative processes. 41 from the above overview of the new regulatory regime, a few inadequacies can be identified. first, the legal (regulatory) framework is far from comprehensive. the supervisory model of food safety mapped out in the new laws can be summarized as: relying mainly on the segment-based approach, supplemented by a categorybased approach. 42 in other words, the administration of food quality is undertaken by multiple inspection and administrative agencies, exercising their authorities in different stages of food production and services and targeting different types of foods. 43 such an arrangement poses a potential risk in regards to conflict of powers, though the new laws allude to the benefits of efficient coordination among these agencies by identifying their authorities and duties in different stages of production and services. 44 given the gaps in the existing laws, it is very likely that china will encounter further challenges in food supervision caused by its inefficient administrative system. speaking from a broader perspective, china is not the only country that has applied a multi-agency approach to food supervision and administration. the united states and japan have also adopted a scheme of assigning duties of food administration to multiple governmental agencies and departments. 45 however, their comprehensive and detailed stipulations on division of responsibilities, quality standards, transparency and public scrutiny have ensured effectiveness of the system and smooth coordination among the agencies. moreover, it is noteworthy that even in countries such as the united states, there are increasing calls for combining their multiple agencies into a single agency to further the operational efficiency. 46 it is therefore necessary for china to improve its food safety administration system to further enhance its regulatory regime on the one hand, and to rationalize the administrative chains and procedures in food supervision on the other. second, the current legal regime does not provide sufficient remedies for victims of food safety, nor does it effectively encourage consumer and community participation in food safety control. the laws have introduced monetary remedies for consumers consisting of damages and a fine of ten times that of the commodity's value. however, the accused are liable for the fine only where evidence shows that they have produced defective products and are at fault. 47 what is more outrageous is that the onus of proof is on the consumers in such cases. 48 the amount of ten times the value of the goods has already been criticized as being too insignificant to be a deterrent. 49 the requirement that consumers need to prove the culpability of producers in making defective foods renders it nearly impossible for the consumers to benefit from the fine, not to mention the conceivable negligible impact that the provision has on food producers. third, the regulatory regime has loopholes and demonstrates too much leniency towards liable producers and traders, as well as those administrative personnel who fail to discharge their duties or show favoritism. among government staff of relevant departments, only those directly responsible for administrative negligence or abuse of powers that result in serious social impact may face disciplinary action. 50 criminal penalties imposed on food producers for breaches of the law are also weak. moreover, no single criminal penalty is available to penalize delinquent public servants. the criminal law of china only punishes the conduct of producing 45 for instance, in the u.s., the powers of food administration are divided amongst the u.s. department of agriculture, the food and drug administration and the environmental protection agency. 46 see chamus burnside-savazzini, "training in an integrated food safety system: focus on food protection officials", food safety magazine (april/may 2011), <www.foodsafetymagazine.com/ article.asp?id=4018&sub=sub1>. 47 the people's congress of the people's republic of china, supra note 36, § 96. 48 the food safety law does not address the issue of burden of proof. hence, the rules of general law apply, rendering that the burden of proof lies upon he who brings the claim. 49 see tonghai liu, "on the shortcomings of the foot safety law and some suggestions on improvement", blog of tonghai liu on legal study net (october 10, 2011), <http://wq.zfwlxt.com/ newlawyersite/blogshow.aspx?itemtypeid=fdf950ea-312b-4519-91ea-9bfb01037315&itemid= de914f78-54bd-4f50-9bdc-9f80015e3473&user=9947>. 50 the people's congress of the people's republic of china, supra note 36, § 61. and selling foods causing serious food poisoning and diseases, and the conduct of producing and selling foods mixed with toxic or harmful non-food substances. 51 it can thus be observed that the scope of application of the criminal law provisions is limited to offences occurring in food production and sale. this leaves the conduct of processing, packaging, storing and transporting defective or harmful foods unpunished. 52 furthermore, the amounts of the penal fines provided in the criminal law are even less than those stipulated in the food safety law, and are subject to a higher threshold in application. 53 finally, the most essential issue to be addressed by the chinese is the enforcement of the laws. according to a survey carried out by the national survey research center at renmin university of china in 2011, 68% of people interviewed attributed the cause of food scandals to administrative inefficiency and supervisory failure. 54 in the meantime, judicial failure to rigorously implement food laws has cast a further shadow over effective law enforcement in the future. it is reported that courts are reluctant to support consumers' claims for damages up to 2 or 10 times the amount of the commodity price provided for in the law of the people's republic of china on the protection of consumer rights and interests 1993 and the food safety law of the people's republic of china 2009. 55 many manufacturers also promise 51 the criminal code of china states: "whoever produces or sells food that does not confirm to hygiene standards in a manner that is sufficient to cause a serious food-poisoning accident or any serious disease caused by foodborne bacteria shall be sentenced to fixed-term imprisonment of not more than 3 years or criminal detention, and concurrently or independently be sentenced to a fine of not less than half of the sum obtained through sale and not more than twice of that. if the offence causes serious harm to human health, the offender shall be sentenced to fixed-term imprisonment of not less than 3 years and not more than 7 years, and concurrently be sentenced to a fine of not less half of the sum obtained through sale and not more than twice of that. if the consequences are especially serious, the offender shall be sentenced to fixed-term imprisonment of not less 7 years or life imprisonment, and concurrently be sentenced to a fine of not less than half of the sum obtained through sale and not more than twice of that or confiscation of property." a person who knowingly mixes the food to be produced or sold with toxic and harmful non-food stuffs is subject to the same penalties. : "when any manufacturer produces any food not conforming to the food safety standards or sells any food knowing its nonconformity with the food safety standards, the customer can demand the manufacturer or the seller to pay a penalty 10 times of the paid amount, in addition to the compensation for the loss thereof." the amount of the compensation provided for in article 49 of the law of the people's republic of china on the protection of consumer rights and interests 1993 is up to two times upon occurrence of fraud. junhai liu, the deputy president of china consumer association pointed out that due to judges' misunderstanding of legal reasoning, consumers' that an amount of compensation of up to 10 times the amount of the commodity price will be paid to consumers upon violation of food safety. however, such claims are likely to be rejected by courts. some judges insist that such an amount appears to be punitive and thus does not have legal basis in contractual relations. the stance of courts in such cases renewed the public's suspicion of judicial corruption. the worst scenario concerns events involving arrest and conviction of consumer advocates. the zhao lianhai case is a typical example. zhao lianhai was a man who became an activist after his son experienced kidney problems linked to contaminated baby formula. he was convicted of inciting public disorder by setting up a web site to help other parents with sick children share information, seek compensation, and organize protests. 56 it is clear that despite legislative efforts, tackling the food safety problem is an overwhelming challenge. compared to assessing legislative improvements, evaluating law enforcement in china presents a far more demanding task and is entangled with a number of social, political, economic and cultural issues. more discussions on enforcing food safety law in china will be carried out in section iii of this article. in summary, much work needs to be done to develop an efficient and effective food safety regulatory regime. this is not a mere legal task, but a social project involving reform of the administrative culture, a change in the business environment and transformation of the perception of the right to safe food for the public. human rights are rights inherent to all human beings, and they are inalienable and fundamental. 57 the international community has reached a common understanding on the universality of human rights. for promoting and protecting human rights and fundamental freedoms of individuals, governments are obliged to act in certain ways or to refrain from specific acts. 58 the most common universal human rights claims for compensation provided in the above provisions are rarely supported by courts in the past. see social and cultural rights 1966 , the right to food is recognized as part of the right to an adequate standard of living. 63 the rome declaration on world food security and world food summit plan of action 1996 reaffirms everyone's right to "have access to safe and nutritious food, consistent with the right to adequate food and the fundamental right of everyone to be free from hunger" and describes food security as: "[w]hen all people, at all times, have physical and economic access to sufficient, safe and nutritious food to meet their dietary needs and food preferences for an active and healthy life." 64 it is therefore clear that as a part of human rights, the right to food is inalienable and indivisible from other fundamental rights including the right to life, the right to health, the right to know, 65 (13-17 nov. 1996, rome) . 65 here, "right to know" is a term used in environmental law, referring to the legal principle that the individual has the right to know the chemicals to which they may be exposed in their daily living. it comprises two aspects -community right to know (environmental hazard information) and workplace right to know (workplace hazard information). nowadays, the term is used in the field of human rights in reference to the right of access to information concerning citizens' human rights, or their rights under freedom of information laws. for instance see sandra coliver, the justifiable to say that the right to food incorporates at least the following dimensions: availability, accessibility and adequacy. 66 in other words, food must not only be available as a resource and affordable in order for people to be able to satisfy their dietary needs, but must also be safe for human consumption and free from contaminants. everyone must have access to food that is not only nutritionally adequate, but also free from harmful substances, so that it does not endanger people's lives or health. the states parties to the international covenant on economic, social and cultural rights 1966 have agreed to assume the obligation to progressively realize the right to adequate food. the responsibility is interpreted by the committee on economic, social and cultural rights as comprising three types of obligations: respect, protect and fulfil/facilitate. 67 a state government must not interfere with individuals' efforts to access food. 68 it must also protect its people from infringement of their right to adequate food by others. the government should help those who do not already enjoy the right to food by creating opportunities for them to provide for themselves. in the case where people are unable to enjoy the right to food due to events out of the individuals' control (natural disaster for example), the government ought to provide food to them directly. 69 china is a signatory of the universal declaration of human rights and a contracting party of the international covenant on economic, social and cultural rights 1966, the convention on the elimination of all forms of discrimination against women 1979 and the united nations convention on the rights of the child 1989. china also signed the international covenant on civil and political rights 1966 but has yet to ratify it. 70 the government of china is under international obligation to facilitate a pre-warning system regarding threats to the right to adequate food, and to improve coordination between different government and food safety agencies, as well as improve their accountability. violation of the right to food refers right to know: human rights and access to reproductive health information (article 19 -university of pennsylvania press, london-philadelphia, 1995) ; and jacqueline klosek, the right to know (praeger, westport, 2009) . article 19 of the universal declaration of human rights states: "everyone has the right to freedom of opinion and expression; this right includes freedom to hold opinions without interference and to seek, receive and impart information and ideas through any media and regardless of frontiers." 66 jean ziegler, "what is the right to food?", right to food (august 6, 2012) <www.webcitation. org/68cmsst1c>. 67 not only to shortage of food, lack of infrastructure, mal-distribution and inadequate access to food, but also to protection from contaminated and harmful food. most of the recent food scandals in china involve rampant violations of the right to food in the dimension of adequacy -provision of food for safe consumption. while immoral and illegal conduct of individuals and enterprises is ultimately responsible for the outbreak of food safety crises, the government is accountable for inefficiencies in monitoring the enterprises and disciplining personnel in charge of administrating the food industry. as the most populated country on the earth, the chinese government has always paid great attention to food issues and regarded provision of enough food to the people as the first priority. after decades of effort, china has mostly solved the problem of feeding its people. 71 however, new problems associated with agriculture and food have arisen since the commencement of market oriented reforms. it is reported that due to accelerated industrialization and urbanization, arable land has been shrinking and farmland capacity has declined. 72 this constitutes a threat to china's future food security. the government has introduced the national land consolidation plan (2011) (2012) (2013) (2014) (2015) that aims to increase the effective area of arable land by 1.6 million hectares before 2015, though the enforcement of the plan faces challenges such as lack of mechanisms for protection of cultivated land and inefficiencies in the management of land tenure rights. it appears that china has made a significant effort to achieve food sufficiency in the country. food availability and accessibility have been a top agenda item for the government in the past and will continue to remain a central issue in the future. the adequacy aspect received far less attention. the recent outbreak of food scandals is chiefly a result of a lack of oversight within the food industry. this can be partly attributed to the understaffing of supervisory authorities, partly to the misfeasance, malfeasance, nonfeasance and unprofessionalism of administrative officers. it is noteworthy that administrative personnel's unsupportive attitude and behavior towards businesses has been the cause of changes in inspective practice, resulting in a switch of models from official inspection to enterprise self-inspection. 73 under the enterprise self-inspection regime, the working manner of administration is even more unprofessional. for instance, in the recycled buns case, when doing their sample inspection, the governmental inspectors, once arriving at a food factory or workshop, would only come into the administrative office and wait for the factory managerial staff to provide the samples to be examined. it is no surprise that they did not get any clues over the years. 74 in one of the clenbuterol contaminated pork 71 s z gu and y j zhang, "food security in china", in sun honglie and shidong zhao (eds.), area studies -china: regional sustainable development review (vol. 1, 2009) incidents, the problematic pigs were sold from henan pig farms to jiangsu province and had to go through several checkpoints conducted by the trade bureau, health inspection station, veterinary station, etc. however, some inspectors acted as middlemen between pig sellers and slaughterhouses for a commission of rmb10 yuan per pig, which caused wide dissemination of the contaminated pork and pork products. 75 the recycled buns case showed workers in a filthy workshop "recycling" buns by throwing the stale buns into a vat, adding water and flour, and repackaging them to be sold anew. the clenbuterol contaminated pork case involves pig farmers feeding pigs with pig feed mixed with clenbuterol used to make the pigs have leaner bodies, which sell for a higher price. other food scandals involve melamine-contaminated baby milk; pork sold as beef after it was soaked in borax; rice contaminated with cadmium, arsenic-laced soy sauce; popcorn and mushrooms treated with fluorescent bleach; bean sprouts tainted with an animal antibiotic; and wine diluted with sugared water and chemicals. 76 the alarming fact is that most of the food related offences were first discovered and disclosed by journalists, and not the personnel in charge of the surveillance authorities, or even the police or national security authority. it is inexcusable for administrative agencies to claim that ill-training, poor quality equipment and understaffing are the main causes for such an appalling incidence of food scandals in the country, since journalists are by no means in a position to be better trained and better equipped than food inspection agencies or police. as a matter of fact, detection and disclosure of food safety problems is not the expertise of journalists, nor their major business. respect for human rights is becoming a universal principle of good government. 77 this is because many human rights require activity on behalf of government. these activities relate to the duties to respect, protect and fulfil human rights in order to provide the conditions necessary for prosperity and well being of individuals. 78 a good government is committed to protection of the rule of law. 79 hence, it is the state government's responsibility to make good laws and to establish able, professional and corruption-free administrative institutions, with a public service team to guarantee the implementation of the laws. although china's government is quick in making legislative efforts to curtail misconduct in the food industry, it needs to demonstrate its determination and capability of ensuring that the laws are fully abided by and it is accountable for building a law enforcement agency comprised of highly motivated, dedicated, well-trained law enforcers. a typical national food control system comprises the following components: food law and regulation, food control management, inspection services, laboratory services and information, education, communication and training. 80 the capacity of food safety control in a nation is demonstrated by effectiveness, efficiency and sustainability. in china's case, apart from legislative efforts, much needs to be done in the following aspects: law enforcement involves certain members of society acting in an organized manner to promote adherence to the law by investigating and punishing persons who violate the rules and norms governing that society. the enforcement of the law consists of a system comprised of the courts and procuratorates, the judicial and public security agencies, and the administrative agencies, with their descending hierarchy of departments, bureaus, sub-bureaus, and stations. with regard to enforcement of food laws and regulations, administrative mechanisms play a more substantial role, compared with other enforcement instruments. the key is to enhance food control management. this involves development of food control strategies, implementation of risk analysis, operation of a food control program, securing funds and allocating resources, and development of emergency response procedures. 81 development and implementation of food control strategy is concerned with defining food control objectives, identifying priorities of competing interests relating to public investment, state economic interest, food import and export, farmers and producers. 82 an integral, effective food control strategy is particularly important to china, since it will improve the coherence of multiple existing administrative agencies in the country and reduce confusion, duplications of effort, inefficiencies in performance and waste of resources. for the time being, a crucial task china 80 food and agriculture organization of the united nations and world health organization, assuring food safety and quality: guidelines for strengthening national food control systems (joint fao/who publication) 6-9 (rome 2003), <ftp://ftp.fao.org/docrep/fao/006/y8705e/ y8705e00.pdf>. 81 see food and agriculture organization of the united nations and world health organization, supra note 62, at 7. 82 ibid. faces is to consolidate its food control policy at the macro-level by standardizing food quality certification, management, and rating, and in the meantime, to improve the market price system. a market entry certification system should also be put in place. another important task to deal with is to establish a uniform food safety risk analysis scheme to ensure compliance with food regulations and standards. 83 unlike developed countries, the food safety problems in china occur in every stage from food production to service, typically consisting of contamination of raw food materials, cross contamination in manufacture, improper storage and preservation, and unhygienic practices in services. 84 this requires a wide-ranging risk analysis system capable of identifying risk factors at every stage and of providing solutions. in doing so, there is the need to coordinate the risk assessment activities currently exercised by different administrative agencies and to develop a comprehensive scheme for food safety risk assessment, in which a professional team comprising food researchers, toxicological analyzers, pathological analyzers and inspectors play an essential role. attention should also be paid to food safety risk communication improvement. insufficient food risk communication in the past was chiefly responsible for a crisis in customer confidence with china's food industry. 85 until this point, no substantial improvement has been made in this regard. in summary, the flaws of this situation can be attributed to a lack of government guidance, silence on the part of scientific academia, and unreliability of entrepreneurs. 86 addressing this issue, the minister of health recently announced that a plan for food safety risk communication was in development and the press was expected to continue to play a leading role in this aspect. 87 however, without access to channels for obtaining scientific information, the press's capacity for publishing fair and accurate reports is considerably undermined. it is therefore necessary to base risk communication on a system of interactive exchange of information and opinions among all stakeholders, including risk assessors, risk managers, consumers, industries, the academic community and other interested parties. this requires the government to allocate sufficient funds to finance and staff risk communication institutions of various specialities. china has more than 200 million farmers and more than 500,000 food production companies. 88 hence, to some, the food production system seems too vast to 83 see world health organization/food and agriculture organization of the united nations, "about risk analysis in food", <www.who.int/foodsafety/micro/riskanalysis/en/>. 84 allow for meaningful inspection at all stages of the food production process. 89 however, the establishment of a national database for food supervision and inspection and a platform for food safety risk assessment enabling all interested parties to follow the development of food safety will absolutely make a difference to china's food industry. by the end of 2009, the ministry of health formed the expert committee for national food safety risk assessment, which was a significant step toward improvement of china's food safety control. 90 it is also reported that the state council of china has revealed its intention to establish a database of food companies' safety records. 91 according to the plan, companies with poor safety records will be blacklisted and publicized, and will be subject to punishment. 92 better regulation mechanisms, legal and standard systems, as well as technical support systems will also be introduced to improve the overall food safety management level. 93 now, the world is waiting to see how well the plan will be realized. improving inspection services for food safety control is another key element for enhancing the food safety control system in china. food inspection service is a means of ensuring that the food supply is safe for consumers and meets legislative requirements. it is also an instrument for decreasing hazardous intoxicants in foods, including pathogenic bacteria, viruses and parasites, chemical contaminants and mycotoxins. the primary duty of the food safety inspection service is to inspect food manufacturing, processing and handling facilities, importing/exporting of foods and the monitoring of a company's facilities for compliance with the national legal and regulatory requirements. 94 in some countries, the food inspectorate also conducts the functions of investigating food poisoning and injury cases and fraudulent marketing practices, as well as handling consumer complaints. 95 of individual inspectors and the quality of their work. it is thus important to make sure that inspectors have detailed guidance and rules to follow when discharging their responsibilities. their powers and the procedures to be followed should be well defined. inspectors should receive up-to-date training in the new technologies used in processing and manufacturing, including what is required for the control of these technologies in order for them to function at maximum effectiveness and to assure proper performance. they must also be able to evaluate the performance of equipment and instruments used in production to guarantee that they are appropriately controlled and monitored. 96 the impotence of china's food safety inspectorate has been widely reported and acutely recognized by consumers. it is officially perceived that the food safety inspection administration suffers from insufficient resources, a lack of qualified personnel, and deficient coordination among layers of governments and among various institutions, particularly among those administrative agencies at the provincial level and below. 97 apart from the above-mentioned vices, three more factors must be taken into account: corruption, shirking and laziness. china's public services have long suffered from a number of bureaucratic problems such as authoritarianism, routinism, elitism, corruption, shirking of responsibility, deceit, laziness, formalism, red tape, nepotism, seeking special privilege, overstaffing, duplication, ineffectiveness, and over-centralization. 98 upon close study, one can discern that corruption, shirking and laziness are the most prominent problems that induce or exacerbate the other problems. these deep-rooted problems penetrate the food safety inspection system and eventually take their toll on public confidence in the food industry. the government of china has pledged to enhance the ability of the inspectorate. in its food safety decision june 23, 2012, the state council announced that it planned to take 5 years to improve the nation's food safety and food control management. 99 according to the state council's statement, food safety will become a measure of local governments' performance in their annual assessments, in the hope that incorporating food safety as one of the evaluation criteria will make local governments and officials aware of their responsibilities. 100 however, given the institutional decline, erosion of authority of the central government, and loss of control over local agencies and agents in the era of the market economy, effectively rooting out corruption in the food safety administration will certainly demand much 96 greater efforts based on resolute determination. to a certain extent, it represents a social problem and needs to be tackled on a broader scale. to curtail food safety problems on a broader scale, it is necessary to promote general respect for universal human rights in the society. from this point of view, improvement of food safety can be seen as a social project. in the past three decades, in making the transition from a planned economy to a market economy, china placed much emphasis on economic gains and profitability. 101 along with gdp growth, extreme utilitarianism, fickleness and mammonism have become more and more evident and have turned into a driving force in chinese people's daily life. 102 the food safety outbreaks are merely typical consequences of the erosion of social morality and business ethics. food safety outrages spark a new round of calls to promote public morality and human rights. 103 many chinese have come to realize that without a morally healthy social environment, mere economic prosperity does not guarantee a successful society and true advancement. in contrast, it may only carry with it the seeds of corruption and decay. to bring changes to the broader system, the general public needs to step out from their family-centred tradition and self-interested sphere, and endeavor to shape a society where individual equality is upheld, respect for others' human rights is generally aware of, and public interests are greatly valued. the construction of such a society requires the combined efforts of the government, private sectors and the community. while the government is accountable for formulating policies and initiatives, facilitating state agencies and mechanisms, and allocating resources, the business sector and the community are expected to participate in shaping a good society by promoting sustainable business practices, interacting with the government and influencing the policies of governance. it is worth noting that the constitution of china only implicitly addresses citizens' rights to safe food. article 21 provides that "the state . . . promotes health and sanitation activities of a mass character, all for the protection of the people's health"; and article 45 states: "citizens of the people's republic of china have the right to material assistance from the state and society when they are old, ill or disabled." 104 compared with some nations that incorporate the right to healthy food into their constitutions, china is much behind in providing constitutional safeguards for food security. 105 given the challenge of tackling food problems, it may be necessary for china to introduce provisions to protect food safety in the constitution. in the case of combating food safety problems, the food industry shares responsibility with governmental agencies in achieving the objectives of a national food control strategy. involving the industry in national food control activities might be instrumental in overcoming potential problems. the food industry is responsible for the implementation of rules regulating agriculture, food manufacturing and processing practices, as well as a food quality and safety system. 106 the industry should also be obliged to educate and train all employees in food handling and make sure that they understand general food quality and safety system. it can also provide information to consumers through food labeling and advertising. 107 in china's case, the food industry may need to go through a long journey to correct its practices which may also involve a change in the business culture. as members of the community, consumers have a right to quality and safe food and also have responsibilities to prevent food related health hazards. consumers need to understand there is no such thing as an absolutely safe food supply. 108 the right to food for consumers also requires a responsibility to play a role in food control. consumers can actively contribute to food safety control by providing valuable information to the authorities, usually by complaining about product deception and poor quality and by reporting injury and illness caused by food. 109 the authority then needs to provide them with a channel to let their dissatisfaction be known. consumer organizations are expected to play an important role in representing the consumer in the development of a national food control strategy and also in bringing the concerns of consumers to the attention of policy makers and the industry. 110 the chinese government needs to take proactive action in order to ensure that consumers are heard and taken into account. in summary, combating food safety problems depends on a combination of mechanisms including training, business ethics education, administration and supervision, public scrutiny, civil litigation and penal punishment. in other words, combating the food safety problem require a collective effort from the entire nation. the government is certainly accountable for all mandatory activities necessary to ensure the quality and safety of food, including enacting food regulations, operating food inspectorates, organizing analytical services, and enforcing rules. the participation of other stakeholders and interested parties including the industry, consumers, communities and even the society as a whole, is equally crucial. the battle will happen across a gamut of fields involving governmental conduct, social ethics, public relations, business practice, and consumer culture. the medical insurance system of a state directly affects its people's key human rights, namely the right to life and the right to health. the notion of modern medical insurance can be traced back to the introduction of the sickness insurance program in 1883 in germany. the antecedents of similar kinds existed in the form of charity or welfare in some civilizations, such as friendly societies organized by european trade guilds, fraternal organizations, the english poor law 1601, the prussian common law 1974, and the civil war pension program 1862. the sickness insurance program in germany came as a result of the medical reform movement 1848 and a series of political debates and compromises afterwards. 111 the sickness insurance act was enacted in 1883 to facilitate the program. the law allowed the largest segment of workers to benefit from access to public health care through insurance funds. in the event of accidental injury, illness or old age, workers were entitled for minimum indemnity for medical treatment and sick pay for up to 13 weeks. this initial system was financed by workers and employers, with the employers contributed one third, while the workers contributed two thirds to insurance funds. in 1884 germany passed the accident insurance act covering serious and fatal accidents occurring on the job in certain industries. the 1884 act went a step further by placing the entire cost of the liability on the employers. the significance of the german health insurance program introduced in the 1880s lay in that it was for the first time in history that a national health insurance system was institutionalized. 112 following the german practice, industrialized countries commonly introduced social security programs in the following decades, i.g., the uk 111 114 the medical insurance program as an indispensable part of the modern social security system has carried human societies into a new era where the government of a country provides economic assistance to persons faced with unemployment, disability, or agedness for the purpose of advancing the benefits of the members of the community as a whole. 115 the key feature of the scheme is: it is imposed and controlled by the government. before the introduction of social security schemes, the dominant mode of support for people unable to provide for themselves was charitable relief proffered by benevolent societies, sometimes with financial help from the authorities. social security comprises two arms: social assistance and social insurance. 116 the rationale behind modern social security programs is the necessity to maintain social and economic justice. with industrialization, social security has gone through a change from charity to a state responsibility. guaranteeing a certain amount of social well-being and economic security to every individual member in the community has become a duty of a modern state. 117 nowadays, social security has emerged as a human right enshrined in the universal declaration of human rights, which states: after the establishment of the socialist state in 1949, as part of the social welfare or security package china introduced a state funded, central planned health care system, which provided a universal coverage of health care to the chinese population. an innovative feature of the system was the operation of the so call barefoot doctors at health clinics at the village and township level, which served the mass rural citizens accounting for three quarters of the total population. 119 this system was held up as a model for providing universal health care in the developing world in the 1970s by the world health organization (who) and inspired who to launch the "health for all by 2000 a.d." program. 120 under this scheme, public health in china improved dramatically, with the citizens' life expectancy increasing from 35 to 68 years, infant mortality decreasing from 200 to 34 per 1000 live births. 121 the system operated in china for nearly 40 years until the market oriented medical reform took place in the 1980s. as a result, china's health care program has experienced a change from a scheme performing universal social welfare function to a model that is a mixture of free market and medical insurance. however, the reform turns to be a failure which makes china's health care scheme one of the least equitable systems in the world. 122 care reforms ciency and abuse. its sustainability posed a challenge to the leadership in the post-mao era, which had an economic reform scheme at the top of the agenda. by the 1980s, the administrative and financial support for the health care was removed from the national agenda through decentralization before a nationwide health insurance system was provided. 125 with local governments having little incentive to promote local healthcare, individuals of rural areas and urban non-salaried residents primarily relied on out-of-pocket spending for medical and health services. in the meantime, prices for provision of medicines, diagnostic tests, surgical implants, and specialized care were deregulated. as a direct impact, many chinese were in short of medical services and supplies since they simply resolved to not seeking medical help. it was reported in 2003, about 50% of the chinese people refused to see a doctor when ill and 30% of those refused to go to hospital, mainly out of financial concerns. 126 there was still worse to come. after the collapse of the previous model, no strategy was adopted to mitigate the lack of integration and coordination in the later medical system. due to a lack of reliable local clinics, people had to wait in long queues for basic health care, with no scheduled appointments and little privacy. after all the inconvenience, what they could receive was usual a very brief face to face consultation of a few sentences or a couple of minutes. 127 during this period, health care was seen "as a consumption activity rather than a fundamental right of the people or a responsibility of the state". 128 indeed, this unsustainable, reactionary approach had to be subject to review and amendment. 129 as a result, in 2003, the new cooperative medical scheme (ncms) for rural population, mainly funded by the government, was launched. 130 since 2007, a health insurance scheme for urban non-salaried residents, especially for children and old people has been implemented. 131 although china's health care system has appeared to get back on the track of government subsidy since the mid-2000, it is far from offering accessible, affordable, equitable and quality health care services with a universal coverage. some believe that the current health care reform is unlikely to solve the fundamental problems of accessibility, affordability, equity and quality. as long as the buck-passing polity does not fully change and the health policy process is still influenced by interested groups, the problem of dis-125 see jason shafrin, "an olympic post: the history of the chinese healthcare system", healthcare economist (august, 2008), available at <http://healthcare-economist.com/2008/08/ page/3/>. 126 parity inherent in china's health care system will continue to affect the country's social environment. 132 the worst part of china's health care system is the rampant medical corruption stemming from the medical reform over the past decades, particularly in the period between the mid-1980s and the mid-2000s. the usual scenario is that doctors and other staff expect to be paid extra fees (usually in the form of "red envelops" 133 ) to perform operations and take kickbacks from pharmaceutical firms and medicalequipment suppliers. the practice is so prevalent that an unsullied doctor nearly does not exist. 134 almost all practitioners and medical staff tell the same story as the defence of their unclean hands -low salary or underpayment. whistle blowers also tell that doctors have economic income targets allocated by hospitals and hospital administrators for them to meet and exceed. only upon completion of their quotes, they are paid benefit bonuses which can be much higher than their basic salaries. 135 in other words, they are under pressure to charge patients extra fees and to recommend patients to go through unnecessary but expensive tests and procedures as well as purchase expensive medicines. nonetheless, such excuses are not sound enough to defeat professionalism and patients' human rights. besides, on many occasions, they are free to make a choice. for instance, a surgeon or a nurse can always hold up professional dignity by declining a red envelop because it is commonly given privately. moreover, nothing can justify their procurement of briberies and kickbacks from pharmaceutical companies or health care companies. facing a choice between campaigning for improving income or work environment and becoming corrupt, chinese doctors have had less difficulty in choosing to compromise their professional morality in the first place. moreover, nothing can defend the corruptive and negligent conduct of the personnel in governments and the health care system, which have caused further spread of epidemics such as aids. 136 a nation has every reason to become alarmed when seeing medical profession to be infested by the epidemic of corruption. the governments and citizens all have a responsibility to trace the deep root of the phenomenon in their society, culture, policy and ethics in order to find the cures. access to quality health care services is a basic right in a civilized society. it is essential to one of the core human rights -human right to health. 137 the human right to health care means that hospitals, clinics, medicines, and doctors' services must be accessible, available, acceptable, and of good quality for everyone, on an equitable basis, where and when needed. hence, universal access, availability, acceptability, dignity, non-discrimination, accountability, and transparency should be the fundamental principles upon which a health care system is built. many countries have upheld health care as a basic human right in their laws. 138 unfortunately, the failure of the health care scheme has deprived many chinese citizens this right for more than two decades after the medical reform. this renders china's medical reform a truly disgraceful story. when people are deprived their access to hospital and health care services, their human rights, including their rights to health, life and information are potentially compromised and threatened. china is a contracting party to the international covenant on economic, social and cultural rights (icescr) and the united nations convention against corruption (uncac), a signatory of the international covenant on civil and political rights (iccpr). it is thus under treaty obligation to protect individuals against corrupt acts of third parties. though corruption and abuse of the health care scheme committed by practitioners and professionals in hospitals, insurance companies and suppliers of medical and health care goods and services impact on patients' human rights, the guilty individuals are not in direct breach of the uncac. instead, the uncac is directed primarily at member states rather than non-state actors. hence, it is the obligation of the chinese government to prevent corruption involving governments, industries, companies and individuals in fight against corruption and to raise public awareness of the matter. 139 due to the fact that corruption has invaded into every corner of the chinese society, citizens have faced an unfavorable physical and social environment. fraud in project approvals and failure to apply emission control measures are responsible for 137 the human right to health means that everyone has the right to the highest attainable standard of physical and mental health, which includes access to all medical services, sanitation, adequate food, decent housing, healthy working conditions, and a clean environment. 138 xiangming zhou, a study of the health care right (phd thesis, jilin university, 2006) 1. 139 see part ii -articles 12 and 13 uncac. rising pollution in the country. some professions including teachers, doctors, lawyers and those safeguarding consumptive goods are not only important to people's lifestyle and well-being and society's progress, but also play a social role in which trustworthiness is an expectation in every tradition. 140 in china, these professions, because of the rampage of the unethical performance conducted by a majority of the people in the trades, have definitely failed to honor their part of social compact with society, which in turn exacerbates human rights related problems. it is a high time for china to review the ethical conduct of these key professions. the chinese government has an obligation to protect citizens' human rights to health, access to healthy food, safe drinking water, clean air, and a healthy environment. in discharging this obligation, effective mechanisms combating corruption in various forms need to be established in order to sustain the country's social stability and economic prosperity. china -pig farmers told to drug livestock china, fear of fake eggs and 'recycled' buns history of universal human rights -up to ww2 sourcebook: human rights & good governance (asialink project on education in good governance and human rights office of the united 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of human rights international covenant on economic, social and cultural rights united nations general assembly (1966b) international covenant on civil and political rights convention on the elimination of all forms of discrimination against women draft world charter for nature convention on the rights of the child what are human rights? www.ohchr.org/en/issues/pages/whatarehumanrights.aspx usda -economic research service (2014) percent of consumer expenditures spent on food, alcoholic beverages and tobacco that were consumer at home, by selected countries three prescriptions for treating the symptoms of the medical reform directors' duties under chinese law -a comparative review world meteorological organization, timely access and response to accurate early warnings are crucial for minimizing impacts of natural disasters johannesburg declaration on sustainable development and plan of implementation of the world summit on sustainable development: the final text of agreements negotiated by governments at the world summit on sustainable development a study of china's legal system for food safety a study of the health care right chinese vs. western perspectives: understanding contemporary china food safety becomes national priority, china daily what is the right to food? right to food key: cord-293372-saqoft9p authors: heffner, kelley; hizal, deniz baycin; majewska, natalia i.; kumar, swetha; dhara, venkata gayatri; zhu, jie; bowen, michael; hatton, diane; yerganian, george; yerganian, athena; o’meally, robert; cole, robert; betenbaugh, michael title: expanded chinese hamster organ and cell line proteomics profiling reveals tissue-specific functionalities date: 2020-09-28 journal: sci rep doi: 10.1038/s41598-020-72959-8 sha: doc_id: 293372 cord_uid: saqoft9p chinese hamster ovary (cho) cells are the predominant production vehicle for biotherapeutics. quantitative proteomics data were obtained from two cho cell lines (cho-s and cho dg44) and compared with seven chinese hamster (cricetulus griseus) tissues (brain, heart, kidney, liver, lung, ovary and spleen) by tandem mass tag (tmt) labeling followed by mass spectrometry, providing a comprehensive hamster tissue and cell line proteomics atlas. of the 8470 unique proteins identified, high similarity was observed between cho-s and cho dg44 and included increases in proteins involved in dna replication, cell cycle, rna processing, and chromosome processing. alternatively, gene ontology and pathway analysis in tissues indicated increased protein intensities related to important tissue functionalities. proteins enriched in the brain included those involved in acidic amino acid metabolism, golgi apparatus, and ion and phospholipid transport. the lung showed enrichment in proteins involved in bcaa catabolism, ros metabolism, vesicle trafficking, and lipid synthesis while the ovary exhibited enrichments in extracellular matrix and adhesion proteins. the heart proteome included vasoconstriction, complement activation, and lipoprotein metabolism enrichments. these detailed comparisons of cho cell lines and hamster tissues will enhance understanding of the relationship between proteins and tissue function and pinpoint potential pathways of biotechnological relevance for future cell engineering. proteomics sample preparation. samples for proteomics were thawed on ice and lysed in a solution of 2% sodium dodecyl sulfate (sds) in 500 µl of cell lysis buffer supplemented with 0.1 mm phenylmethylsulfonyl fluoride (pmsf) and 1 mm ethylenediaminetetraacetic acid (edta), ph 7-8. lysates were sonicated x3 times for 60 s at 20% amplitude followed by a 90 s pause. protein concentration was measured by a bicinchoninic acid (bca) protein assay. one hundred micrograms of each sample were reduced in 10 mm tris(2-carboxyethyl) phosphine (tcep), ph 7-8, at 60 °c for 1 h on a shaking platform. iodoacetamide was added to alkylate the sample to a final concentration of approximately 17 mm and incubated for 30 min in the dark. next, samples were passed through 10 kda filters to reduce the sds concentration as described in the filter-aided sample preparation (fasp) method 23 . during the fasp method, tetra-butyl ammonium bicarbonate (teabc) was added after the urea washes to increase protein recoverability from the filters. the samples were finally digested using trypsin/lysc enzyme mix (promega v507a) at an enzyme to substrate ratio of 1:10, overnight at 37 °c on a scientific reports | (2020) 10:15841 | https://doi.org/10.1038/s41598-020-72959-8 www.nature.com/scientificreports/ shaking platform. after digestion, peptides were cleaned up by c18 cartridges and labeled with tmt reagents. all tmt labeled samples were combined and vacuum centrifuged to dryness removing the entire liquid. labeling. in order to compare protein expression, samples were labeled in duplicate (biological replicates) using two tmt-10plex labeling kits (thermofisher scientific, waltham, ma, usa). triplicates were used for ovary tissue and cho-s. each of the 10 reagents has the same nominal mass and chemical structure, so that for each sample a unique reporter mass (126-131 da) was used to relate protein expression levels. specifically, we included technical and biological replicates of cho-s (two samples in tmt 1 and one sample in tmt 2) to aid in comparisons between and within the tmt experiments. all other samples contained only biological replicates, which were randomly assigned to one of the tmt-10plex kits. the tmt labeling design is provided in table 1 . following protein digestion, tmt reagents were thawed, and acetonitrile was used to dissolve the reagents. one reagent tube was added to each sample and then incubated at room temperature for 1 h. hydroxylamine was subsequently added to quench the reaction before the tubes were combined. all tmt labeled samples were combined and vacuum centrifuged to dryness, removing the entire liquid. each tmt-10plex was subjected to analysis by two-dimensional liquid chromatography tandem ms (2d lc/ms/ms). protein identifications were made using proteome discoverer software with a high confidence cutoff [< 1% false discovery rate (fdr)]. the protein intensities were evaluated by fold change, using the cho-s cell line technical replicate in each tmt as the basis. protein accession numbers were mapped to gene symbols using the biological database network (https ://biodb net-abcc.ncicr f.gov) for functional analysis by gene ontology (go). for go annotation, gene symbols were mapped to biological processes, using the go-cho platform (https ://ebdru p.biosu stain .dtu.dk/gocho ). all programming for the hypergeometric test were calculated in matlab version 2015vb (https ://www.mathw orks.com/produ cts/matla b) and rstudio (https ://www.rstud io.com). enrichment and depletion p-values were calculated using the hygecdf and hygepdf functions in matlab. these values were this study was undertaken to compare protein expression of various cho cell lines and hamster tissues, resulting in the most comprehensive multi-tissue analysis of the cricetulus griseus proteome (fig. 1a) . this multi-tissue and multi-cell line analysis aims to improve our understanding of the chinese hamster as the original tissue www.nature.com/scientificreports/ source for cho cell lines. additionally, since cho is the dominant biopharmaceutical production host in biotechnology, this comparison elucidates similarities and differences across cells and tissues. an overview of the proteomics workflow is shown in fig. 1b . following ms identification, the protein accession numbers were determined using the annotated chinese hamster genome 25 . protein accession numbers were converted to gene symbols for functional analysis 26 . for missing gene symbols, the accession numbers were searched against mouse and human databases using the online database, biodbnet 26 . in this study, gene ontology (go) and ingenuity pathway analysis (ipa) were used for functional analyses of the differentially expressed proteins. go analysis converts gene symbols to their molecular function, cellular component, and biological processes in order to evaluate the relationship between the molecular activities of gene products, location of activity, and pathways comprising the activity of multiple gene products, respectively 27 . in another functional analysis, each gene symbol was mapped to the relevant ipa pathways 28 , suggesting enriched and depleted pathways for comparisons between different tissues and cells. for both go and ipa, the enrichment and depletion values were determined based on p-values that were calculated via the hypergeometric distribution, with p < 0.05 set for evaluating significance. protein identification and total protein intensity differences. pca comparison. for each sample, the number of unique proteins and peptides identified are listed in table 2 along with the number of spectra obtained. the complete list of identified proteins and fold change ratios are listed in supplementary table 1 and are searchable online through the nist database (https ://pepti de.nist.gov). over 6000 proteins were identified in each sample with at least two unique peptides per protein; this corresponded to a total of 8470 unique proteins containing a false discovery rate (fdr) of 1% for protein identification when the tmt samples were combined and the duplicates were removed ( table 2) . between the two tmt experiments, there were 4430 common proteins identified in both sets ( fig. 2a) . a total of 2244 proteins were unique to tmt1 and 1796 proteins were unique to tmt2 ( fig. 2a) . protein intensity fold change ratios were initially evaluated through principal component analysis (pca) of proteins identified in all samples, as shown in fig. 2b 29 . the pca distribution represents differences in protein expression for those proteins identified in all samples and is influenced by proteins highly expressed in one tissue versus another. not surprisingly, as shown by pca, the cell samples clustered together and were distinct from all the tissues. for the tissue samples, the expression of proteins in spleen, liver, and heart clustered together. similarly, protein expression in the lung and kidney clustered together. interestingly, the first cluster (spleen, liver and heart) comprises tissues with dense connective tissue and capillary systems 30 . in contrast, the second cluster (lung and kidney) is specialized for transport, with tubular systems and thin insterstitium [30] [31] [32] [33] . ovary and brain were clustered separately from the other organs. next, the two replicates from the same tissue were plotted to examine their consistency. fitting a curve to the scatter plot and calculating the r 2 value assessed the linearity of the two replicates. shown in fig. 2c -f are the plots for the tissue replicates with the highest r 2 value for each cluster, specifically lung (from the lung/kidney cluster) and heart (from the heart/kidney/spleen cluster), plus brain and ovary. for the following analyses, we studied these representatives from each of the clusters; additional data on all proteins is provided in supplementary table 1 . to compare between cell lines and tissues, protein intensity was averaged between replicates and plotted in fig. 3 . the data was log2 transformed in order to ensure a normal distribution for each sample. a student's t-test was performed to determine the likelihood of significant differences between samples from cells and tissues. a summary of the statistical analysis, performed using student's t-test as a means comparison, is shown in table 3 . when comparing the cell lines to each other, no significant differences were observed between the cho-s and cho dg44 cell lines (table 2 and fig. 3a ) at a p-value of 0.05. we identified 178 proteins with significantly higher expression in cho-s relative to cho-dg44 and 155 proteins with significantly higher expression in cho dg44 relative to cho-s, representing the lowest number of total outliers for any comparison. a comparison between cells and tissues is shown in fig. 3b through i. for these comparisons, the total number of proteins with low and high expression (fold change < 0.5 or > 2.0, respectively) is approximately 50%. for the cell to tissue comparison, all tissues show a statistically significant difference as compared to either the cho-s or cho dg44 cell lines. the proteins expressed at significantly higher levels in cells over tissues include proteins related to dna replication, transcription, translation, and controlling cell apoptosis as expected to maintain rapid cell growth in exponential culture. among the most highly expressed proteins in cho-s and cho dg44 are dna-directed rna polymerase ii, eukaryotic translation initiation factor, histone h3.1t, general transcription factor 3c, 60s ribosomal protein, and apoptosis inhibitor 5. www.nature.com/scientificreports/ in comparison to ovary tissue (fig. 3e ,i respectively, p < 0.01), cho-s and cho dg44 cells exhibited differences in expression patterns. this is somewhat surprising considering that cho cells were derived from a mixture of ovary and the surrounding connective tissue. in fig. 3e ,i, the proteins colored blue and yellow represent those with higher expression in ovary or cho cells, respectively. in addition to ovary, statistical differences in protein expression were observed for cho-s and cho dg44 cells and to lung tissue (fig. 3d,h, p < 0.01) . similar to the comparison against ovary, an increase in upregulated proteins with higher expression was observed in the lung tissue in comparison to the cell lines. this suggests that tissue-specific functions may contribute to differences in expression patterns with cells regardless of the type of tissue. next, both cho cell lines show statistically significant differences in outliers as compared against heart tissue (fig. 3c ,g, p < 0.01). similar to the ovary and lung comparison, there are a greater number of proteins with higher expression in the heart tissue when compared to cell lines. over 50% of the cells in the heart are cardiac fibroblasts, which contributes to the specificity of this organ 34 . in addition, the heart has endothelial, smooth muscle, and pacemaker cells. this high degree of specialization is likely influential for the differences in proteins between cho and heart. finally, both cho-s and cho dg44 also show a difference in expression www.nature.com/scientificreports/ when compared to the brain, which is also likely related to the high degree of specialization required for brain cells such as neurons and glia (fig. 3b ,f, p < 0.01). amongst the tissues, wide differential regulation, both upregulation and downregulation, can be observed when comparing tissues against each other (fig. 3j-o) . there is a greater difference in terms of the total percentage of outliers in the brain versus heart comparison (~ 62% total outliers for brain and ~ 51% total outliers for heart). interestingly, only brain and heart tissues were found to have a statistically significant difference between each other (table 3 ). all other tissue to tissue comparisons were found to have insignificant differences in the percentage of outliers. one reason for the relatively high number of outliers in brain tissue may be attributed to the distinct separation in terms of embryonic development from the other organs. the brain originates from the ectoderm whereas the circulatory system (heart), epithelial layer of the lungs, and ovary develop from the table 2 ) are provided in the appendix. we also examined some of the top upregulated proteins in each tissue. hierarchical clustering of protein expression is depicted in the center plot of fig. 4 in which the color pink represents highly expressed proteins table 3 . means comparison using student's t-test for total percentage of outliers. *p-value < 0.05 indicates that the outlier comparison is statistically significant. coloring is shown from low (green) to high (pink) abundance. distinct clusters are shown for brain, lung, heart, and ovary tissues. from top to bottom: the protein functions exhibiting high expression for each tissue are shown relative to other tissues for ovary (a), brain (b), heart (c), and lung (d) plotted using genesis software. www.nature.com/scientificreports/ for each specific tissue. for each sample, the top 200 upregulated proteins, corresponding to approximately 3% of the total proteins in a tissue, were identified in order to highlight tissue specificity (supplementary table 3 ). for example, disintegrin and metalloproteinase domain-containing proteins (adam7, 10, 15) were highly upregulated in hamster ovary (supplementary table 3 ). indeed, adam 10 can control follicle formation by regulating the recruitment of ovarian follicle supporting cells 36 . disintegrin would be useful for control of the extracellular matrix as agrees with results from the human ovary-specific proteome 37 . similarly, highly upregulated brain proteins include amyloid beta a4 protein, neuron navigator 1 (nav1), calcium and integrin binding protein, and serine/threonine protein kinase (supplementary table 3 ). nav1 is specifically targeted to the nervous system 38 . in contrast, the heart is a strong muscle that must contract continually and is predominantly composed of cardiomyocytes and fibroblasts. the human heart tissue proteome was found to have 201 upregulated proteins 37 , including retinol dehydrogenase (rdh1) which was also significantly upregulated in our hamster heart proteome (supplementary table 3 ). previous studies have indicated that the knock-down of rdh1 led to abnormal neural crest cell migration and an abnormal heart loop in mutant embryos, signaling its importance in heart tissue 39 . we also observed high expression of proteins including pleckstrin homology domain-containing family f member 1-like, actin-related protein, glutathione s-transferase, protein o-glycosyltransferase, and ras gtpase-activating protein (supplementary table 3) . we also identified the top 200 upregulated proteins in hamster lung tissue (supplementary table 3 ). examples include branched chain aminotransferase, glycine n-methyltransferase, integrin alpha-6, and vesicle-associated membrane protein, indicating the importance in the lung of key metabolic and membrane process. as a comparison, the human proteome identified 183 genes highly expressed in the lung including similar membrane and secretory proteins 37 . indeed, the lung is particularly adept at expressing membrane and secreted proteins such as surfactants and solute carrier proteins 40 . analysis of the most abundant proteins for each tissue or cell line can, at least in some cases, relate to key function and roles of specific tissues and provide targets of opportunity for genetic engineering of cho cell lines. ipa pathway analyses. next, the proteins were annotated with gene symbols in order to perform pathway analysis. proteins with fold change values of less than 0.5 or greater than 2.0 were used for each comparison in order to determine downregulation and upregulation of pathways in the ipa software. as shown in fig. 4 , protein intensity hierarchical clustering was used to identify proteins with significantly higher expression in a specific tissue. protein functions identified in ipa that are enriched in the brain include g1/s phase arrest, metabolism of acidic amino acids, and organization of the golgi apparatus, and transport of phospholipids (fig. 4b) . the golgi plays a central role in cholesterol and other lipid metabolism; almost 25% of the human body's unesterified cholesterol is present in the brain 41 . additionally, glycosphingolipids are abundant in the nervous system, and are synthesized in the endoplasmic reticulum and completed in the golgi apparatus 42 . acidic amino acids, including glutamate and aspartate, serve important signaling functions in the brain, so an increase in their metabolic activity would be expected, especially since these metabolites are not readily obtained from the diet 43, 44 . pathways enriched in the lung include catabolism of branched chain amino acids (bcaas), metabolism of reactive oxygen species (ros), trafficking of vesicles, and synthesis of lipids (fig. 4d) . the lung shows high secretory capacity and thus trafficking of the secretory products through vesicles is important 45 . furthermore, the lung is the source of surfactants, composed of 90% lipids; thus, lipid synthesis will be an important component of its function 46, 47 . the lungs are also particularly sensitive to hypoxia occurring at high altitude. the lung responds to these hypoxic conditions through signaling, including the release of ros species to trigger hypoxia-inducible factor (hif) 48 . thus, the capacity for ros metabolism may be critical for lung function and adaptation to changes in oxygen levels in different environments. similarly, in the heart, enriched pathways include metabolism of alpha-amino acid, sorting of protein, and translation (fig. 4c ). amino acid metabolism was studied in rat heart with amino acid levels rising up to fivefold higher than plasma levels 49 , accompanied by increases in ribosome activity and translation 50 . finally, protein functions enriched in the ovary include development of extracellular matrix, docking of vesicles, and exocytosis (fig. 4a) . the matrix of ovary tissue is important for numerous physiological activities, including growth, migration, and differentiation, and the composition changes during ovulation 31 , critical to the fertility process 51 . further, malfunctions of the matrix are observed during ovarian cancer 52 . high levels of extracellular matrix components in chinese hamster ovaries are in agreement with our previous research examining the hamster ovary tissue proteome using label-free proteomics approaches 12 . for go functional analysis, gene symbols were annotated for biological processes in order to group proteins with similar biological relevance. the biological process go category was analyzed to determine enrichment and depletion p-values for the cell-to-tissue and tissue-to-tissue comparisons. the appendix lists the top 10 most enriched biological processes for cho-s (supplementary table 4 ) and cho dg44 (supplementary table 5 ) comparisons with tissue. enrichment is determined by hypergeometric distribution, with a p-value of < 0.05 used for significance. biological processes, representing a biological function involving the gene product, complements the pathway analysis in "ipa pathway analyses" shown above 27 . in both cho-s and cho dg44, the most common biological processes enriched involve dna and mrna processing, and metabolism. some of the most common enriched processes in cho-s include mrna processing and splicing, dna replication and repair, transcription, cell cycle, chromatin modification, and chromosome condensation. in comparison, signaling, transport, and adhesion were significantly enriched across the different hamster tissues. enriched brain biological processes relative to the cho cell lines include ion transport, axon guidance, www.nature.com/scientificreports/ synaptic transmission, and metabolic process, among others 27 . ion transport helps to maintain the stability of cerebral function due to the key roles that ions play in currents and synaptic transmission 53 . abnormal distributions of ions in the brain can lead to defects in neuronal function including seizures and depression. enriched biological processes in the heart compared to the cho cell lines show functions related to circulation and heart function such as vasoconstriction, sodium-independent organic ion transport, complement activation, blood coagulation, and lipoprotein metabolism. for example, complement activation involves mannosebinding lectin and complement components, c3, c5, and cd59. the complement cascade can be activated during heart disease or failure, especially in cases of myocardial ischemia and reperfusion 54, 55 . biological processes that are enriched in the lung as compared to the cho cell lines include g-protein coupled receptor signaling pathway, innate immune response, vesicle-mediated and transmembrane transport, and signal transduction. indeed, vesicle transport is an important component of secretory pathway machinery. unraveling the complexities of lung secretions may yield new insights into ways by which secretion differs in tissues and cell lines. signaling through g-protein coupled receptors and other pathways is an important proinflammatory response in lungs, which can undergo modifications leading to lung cancers 56, 57 . not surprisingly, protection of the lungs using the host innate immune response is critical as this organ is exposed to a variety of pathogens including bacterial, fungal, and viral, during breathing 58, 59 . finally, enriched biological processes in the ovary highlight differences between the cells and tissue around the region from which cho cells were derived. enriched ovarian biological processes include transmembrane transport, protein transport, vesicle-mediated transport, cell adhesion, and cell death. when vesicle production rate was quantified in the ovary, the turnover indicated high vesicle recycling across the endomembrane system 59 , which is consistent with these proteomic results. cell adhesion is also important to ovary function and follicle maturation through interactions with the extracellular matrix and direct cell-cell contacts. mutation of the ovarian surface is causative of approximately 90% of malignant ovarian tumors 60,61 . the results from the chinese hamster proteome provide new insights into global protein expression across a wide variety of tissues and multiple cell lines. these differences highlight the role of tissues in executing key organ functions which require a specific metabolic processes, such as transport and communication, in comparison to cho cells, which are focused on replication and gene expression, characteristics useful for rapid growth and the production of biologics. because of their relevance to biomedicine and the biotechnology industry, we compared the tissue proteome to cho cell lines and each other in order to identify functional differences in expression across tissues and cell lines. specifically, we observed enrichment of many physiological pathways in tissues that were not enriched in cells, such as ion, protein, and vesicle transport, signal transduction, and cell adhesion. often, these differences correlated with specific tissue functions while the activities in cell lines were often correlated with dna replication, cell cycle, or rna processing. furthermore, some of the proteins with high expression in lung, ovary, or other tissues versus cho, such as vesicle-mediated and protein transport, provide significant opportunities for cho cell engineering going forward. in this way, the study expands on our cho and chinese hamster tissue knowledge base by virtue of establishing an atlas to differentiate proteins across cells and tissue for this critically important biotechnological and biomedical host species. indeed, this comparison has enabled us to appreciate the changing proteomic landscape across cells and tissues and furthermore to recognize how the expressed proteins from different cell types can represent signatures for some of their key physiological or biotechnological functions. the complete list of identified proteins and fold change ratios are listed in supplementary table 1 life cycle analysis of mammalian cells: ii. cells from the chinese hamster ovary grown in suspension culture cho quasispecies-implications for manufacturing processes recombinant antibody production in cho and ns0 cells: differences and similarities isolation of chinese hamster cell mutants deficient in dihydrofolate reductase activity deletion of the diploid dihydrofolate reductase locus from cultured mammalian cells the genomic sequence of the chinese hamster ovary (cho)-k1 cell line genomic landscapes of chinese hamster ovary cell lines as revealed by the cricetulus griseus draft genome sequencing the cho dxb11 genome reveals regional variations in genomic stability and haploidy construction of bac-based physical map and analysis of chromosome rearrangement in chinese hamster ovary cell lines a reference genome of the chinese hamster based on a hybrid assembly strategy proteomic analysis of chinese hamster ovary cells lessons from the hamster: cricetulus griseus tissue and cho cell line proteome comparison elucidation of the cho super-ome (cho-so) by proteoinformatics animal cell culture integrated mirna, mrna and protein expression analysis reveals the role of post-transcriptional regulation in controlling cho cell growth rate a deep proteome and transcriptome abundance atlas of 29 healthy human tissues initial quantitative proteomic map of 28 mouse tissues using the silac mouse the chinese hamster as a model for the study of diabetes mellitus insulin and glucagon response of the diabetic chinese hamster in the asahikawa colony effects of neonatal ovarian x-irradiation in the chinese hamster. i. correlation between the age of irradiation and the fertility span specific aneusomies in chinese hamster cells at different stages of neoplastic transformation, initiated by nitrosomethylurea mice, hamsters, ferrets, monkeys. which lab animals can help defeat the new coronavirus universal sample preparation method for proteome analysis genesis: cluster analysis of microarray data an evaluation of public genomic references for mapping rna-seq data from chinese hamster ovary cells the biological database network gene ontology: tool for the unification of biology causal analysis approaches in ingenuity pathway analysis principal component analysis of proteomics (pcap) as a tool to direct metabolic engineering extracellular matrix of the developing ovarian follicle decidual cells in the human ovary at term. i. incidence, gross anatomy and ultrastructural features of merocrine secretion extracellular matrix of ovarian tumors mending broken hearts: cardiac development as a basis for adult heart regeneration and repair differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers adam10-notch signaling governs the recruitment of ovarian pregranulosa cells and controls folliculogenesis in mice tissue-based map of the human proteome mouse neuron navigator 1, a novel microtubule-associated protein involved in neuronal migration retinol dehydrogenase, rdh1l, is essential for the heart development and cardiac performance in zebrafish site-specific differences in gene expression of secreted proteins in the mouse lung: comparison of methods to show differences by location cholesterol metabolism in the brain the role of glycosphingolipid metabolism in the developing brain dietary amino acids and brain function amino acid precursors of monoamine neurotransmitters and some factors influencing their supply to the brain mass spectrometry-based secretome analysis of non-small cell lung cancer cell lines intermediary metabolism of the lung the role of lipids in pulmonary surfactant lung cell hypoxia: role of mitochondrial reactive oxygen species signaling in triggering responses regulation of protein synthesis in heart muscle. i. effect of amino acid levels on protein synthesis characterization of the human heart mitochondrial proteome the roles of the ovarian extracellular matrix in fertility alterations of the extracellular matrix in ovarian cancer studied by second harmonic generation imaging microscopy ion regulation in the brain: implications for pathophysiology complement activation in heart diseases. role of oxidants effects of complement activation in the isolated heart. role of the terminal complement components common pathways for activation of proinflammatory gene expression by g protein-coupled receptors in primary lung epithelial and endothelial cells pathogenesis of lung cancer signalling pathways: roadmap for therapies innate immunity in the lungs estimation of golgi membrane flow rates in ovary glands of aptenia cordifolia using cytochalasin b cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule cell biology of human ovarian surface epithelial cells and ovarian carcinogenesis the authors acknowledge the financial support of astrazeneca for funding this project. in addition, this material is based upon work supported by the national science foundation graduate research fellowship program under grant no. dge-1232825 and grant no. dge-1746891. any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the national science foundation. the authors declare no competing interests. supplementary information is available for this paper at https ://doi.org/10.1038/s4159 8-020-72959 -8.correspondence and requests for materials should be addressed to m.b.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. key: cord-311353-ozqfsuh8 authors: sun, chun-yang; sun, ya-lei; li, xin-min title: the role of chinese medicine in covid-19 pneumonia: a systematic review and meta-analysis date: 2020-07-08 journal: am j emerg med doi: 10.1016/j.ajem.2020.06.069 sha: doc_id: 311353 cord_uid: ozqfsuh8 introduction: chinese medicine (cm) has been used to treat novel coronavirus 2019 (covid-19) pneumonia in china. this meta-analysis was conducted to evaluate the clinical efficacy and safety of cm in the treatment of covid-19 pneumonia. methods: randomized controlled trials (rcts) involving cm in the treatment of covid-19 pneumonia were identified from cochrane central register of controlled trials, pubmed, embase, chinese national knowledge infrastructure, chinese biomedical database, wanfang database and vip information database. the methodological quality of trials was evaluated with cochrane hanadbook criteria, and the cochrane collaboration's review manager 5.3 software was used for meta-analysis. results: a total of 7 valid studies involving 681 patients were included. the meta-analysis exhibited in comparison to conventional treatment, cm combined with conventional treatment significantly improved clinical efficacy (rr = 1.21, 95% ci [1.08,1.36]), and significantly increased viral nucleic acid negative conversion rate (rr = 1.49, 95% ci [1.13,1.97]). cm also prominently reduced pulmonary inflammation (rr = 1.27, 95% ci [1.12,1.44]), and improved host immune function (wbc, md = 0.92, 95% ci [0.07,1.76]; lym, md = 0.33, 95% ci [0.08,0.57]; lym%, md = 2.90, 95% ci [2.09,3.71]; crp, md = −12.66, 95% ci [−24.40, −0.92]). meanwhile, cm did not increase the incidence of adverse reactions (rr = 1.17, 95% ci [0.39,3.52]). conclusion: according to the allocated data, cm has demonstrated clinical efficacy and safety on covid-19 pneumonia, which need to be confirmed by high quality, multiple-center, large sample randomized controlled trials. novel coronavirus disease 2019 pneumonia is caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which firstly appeared in wuhan, china [1] [2] . it is highly infectious and spreads through respiratory droplets and contact [3] . it is characterized by acute onset, severe symptoms, such as dyspnea and multi-organ dysfunction [4] . the world health organization listed this pneumonia epidemic of wuhan, china, as a public health emergency of international concern [5] . the world is now facing a pandemic of covid-19, for which no proven specific therapies are available, other than supportive care. on january 20, 2020, national health commission of the people's republic of china announced that covid-19 would be classified as category a infectious disease [6] . at the same time, chinese medicine experts quickly reached a consensus on chinese medicine (cm) therapy. as medical therapy, cm treatment was written in "diagnosis and treatment of pneumonia infected by 2019-ncov (trial implementation 7th edition)" published by national health commission of the people's republic of china [7] . however, compared with conventional treatment, there is no high-level evidence to support the effectiveness of cm treatment. therefore, the meta-analysis method will be used to systematically review the clinical efficacy and safety of cm for covid-19 pneumonia. this analysis is expected to obtain meaningful conclusions and provide a high level of evidence-based medicine evidence. studies meeting the following criteria were included: (1) randomized controlled trials (rcts) using cm (including chinese herbal medicine, chinese patent medicine and chinese medicine injections) to treat covid-19 pneumonia regardless of j o u r n a l p r e -p r o o f meta-analysis. if two or more homogeneous studies are available, we will use aggregated data for meta-analysis. if the data are not available for quantitative analysis, we will report result by qualitative description. for dichotomous outcomes, we calculated the risk ratio (rr), 95% confidence intervals (ci) and p values. for continuous variable, we calculated the mean difference (md), 95% ci and p values. we used the inverse variance method to calculate pooled md values and the mantel-haenszel estimator to calculate rr. studies will be evaluated for heterogeneity using i squared and chi-squared test. if i 2 >50%, or p0.05, the studies will be considered heterogeneous, and the pooling model will choose a random effects model, otherwise fixed effects model will be used. the funnel plot will be used to evaluate publication bias. 716 unique citations were identified from electronic database. after duplicates removed, 697 literature remained. by reading titles and abstracts, 42 articles were downloaded. a total of 42 articles were retrieved for further assessment, among which 35 were further excluded, for the reasons: wrong patient population; self-control; retrospective studies. in total, seven [9] [10] [11] [12] [13] [14] [15] rcts met the inclusion criteria and were subjected to data extraction ( figure 1 ). all studies included involved seven rcts with 681 patients. of the seven rcts, two rcts [9, 13] reported clinical effective rate, seven rcts [9] [10] [11] [12] [13] [14] [15] recorded incidence of adverse reactions, three rcts [10, 11, 14] reported viral nucleic acid negative conversion rate, four rcts [10, [12] [13] [14] recorded remission rate of pulmonary inflammation (chest ct). there were three rcts [9, 13, 14] reported white blood cell count (wbc), three rcts [9, 10, 14] reported lymphocyte count (lym), two rcts [9, 13] reported lymphocyte ratio (lym%), four rcts [9, 10, 12, 14] reported c-reactive proteins, and two rcts [12, 14] reported interleukin-6. the comparison of baseline characteristics showed there were no significant differences in gender, age, or disease duration between the treatment and control groups (p>0.05). the characteristics of the studies are illustrated in table 1 j o u r n a l p r e -p r o o f for the eligible studies, three studies [9, 12, 15] the clinical effective rate was tested in two rcts involved 273 patients. the efficacy criteria were predominantly based on reduction of clinical symptoms and could be divided into three grades: cured, remarkable recovery, unrecovered. the rate calculated by this formula: (number of cured patients+number of remarkable recovery patients)/total number×100% [16] . heterogeneity test results(p=0.39, i 2 =0%) indicated that there were no statistical significant difference between the studies, and the fixed effect model was selected for meta-analysis. as can be observes in figure taking incidence of adverse reactions into consideration (including seven rcts, 681patients), we noted there is high heterogeneity between studies(p=0.03, i 2 =62%). therefore, it was decided to choose the random effect model for meta-analysis. the chest ct findings were typical of findings for covid-19 pneumonia [17, 18] . figure 6 ). the results indicated that, compared with conventional treatment alone, combined therapy with cm can significantly reduce pulmonary inflammation (chest ct). [27] [28] [29] . these immunological markers may be of importance due to their correlation with disease severity in covid-19. there are no specific pharmacological interventions discovered for treatment of covid-19 pneumonia so far. the world health organization recommended that potential antiviral medicines should be developed [30] . however, the development of potential antiviral medicines may take months, even years. in consideration of these limitations, the application of chinese medicine could be promoted. showed that cm has excellent outcomes in the treatment of covid-19, bringing new hope for the control of covid-19 pneumonia [9] [10] [11] [12] [13] [14] [15] . the results of this meta-analysis are encouraging. in terms of clinical effective rate, viral nucleic acid negative conversion rate, remission rate of pulmonary inflammation, and biochemical markers, cm exhibited superior performance. meanwhile, cm has therapeutic safety. as the first meta-analysis evaluating the efficacy and safety of cm for the treatment of covid-19 pneumonia, the wide extent of literature screening and the introduction of statistical analysis methods have ensured the validity of this review, as well as providing a rational conclusion. it is critical for clinicians to accurately determine the severity of a patients condition. at the same time, clinicians follow the theory of chinese medicine, and determine the appropriate prescription to ensure effective treatment. especially, in the absence of chinese herbal medicine, a variety of a review of coronavirus disease-2019 (covid-19) the transmission and diagnosis of 2019 novel coronavirus infection disease (covid-19): a chinese perspective clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan world health organization. who director-general's statement on ihr emergency committee on novel coronavirus national health commission of the people's republic of china. pneumonia infected by covid-19 included in the management of legal infectious diseases updated guidance for trusted systematic reviews: a new edition of the cochrane handbook for systematic reviews of interventions clinical study on 37 case of covid-19 treated with integrated traditional chinese and western medicine multi-center clinical observation of reyanning mixture in treatment of novel coronavirus pneumonia observation on clinical effect of shufeng jiedu capsule combined with arbidol hydrochloride capsule in treatment of covid-19 analysis of the value of shufeng jiedu capsules combined with abidol in the treatment of mild novel coronavirus pneumonia treatment of covid-19 by pneumonia no.1 prescription and pneumonia no.2 prescription clinical observation of jinhua qinggan granule in treating pneumonia infected by novel coronavirus guiding principles for clinical research of new chinese medicines. 1 th ed. beijing, china: china medical science and technology press use of chest ct in combination with negative rt-pcr assay for the 2019 novel coronavirus but high clinical suspicion correlation of chest ct and rt-pcr testing in coronavirus disease 2019 (covid-19) in china: a report of 1014 cases a novel coronavirus from patients with pneumonia in china genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding world health organization chest ct for typical 2019-ncov pneumonia: relationship to negative rt-pcr testing a rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-ncov) infected pneumonia (standard version) clinical, laboratory and imaging features of covid-19: a systematic review and meta-analysis characteristics of peripheral blood leukocyte differential counts in patients with covid-19 clinical and immunologic features in severe and moderate coronavirus disease anti covid-19 drugs: need for more clinical evidence and global action key: cord-273388-615acz0l authors: he, miao; wang, jingxing; chen, limin; liu, jing; zeng, peibin title: the impact of emerging infectious diseases on chinese blood safety() date: 2016-11-04 journal: transfus med rev doi: 10.1016/j.tmrv.2016.10.002 sha: doc_id: 273388 cord_uid: 615acz0l emerging infectious diseases (eids) have always been one of the major threats to public health. although the implementation of mandatory testing for 4 classical transfusion-transmitted infectious—human immunodeficiency virus, hepatitis b virus, hepatitis c virus, and syphilis—has reduced the transfusion risk of these pathogens, the potential threat of various eid agents and their constantly evolving variants to blood safety in china is not fully understood. this review presents 9 representative eid agents that are autochthonous and epidemic nationally or regionally in china. the epidemiologic status and distribution of these eid agents among donors and/or healthy populations are summarized. the potential risks of these eid agents to blood safety are discussed. the review also explores strategies to strengthen hemovigilance systems and studies to further evaluate the impact of eid agents on blood safety. emerging infectious diseases (eid) agents are considered as major threats to transfusion safety. the most notorious eid agent that sabotaged blood safety during 1980s was human immunodeficiency virus (hiv). it raised global concerns of eids and triggered organized activity to systematically prevent eid agents from threatening transfusion safety. nowadays, blood donations are screened for various infectious agents in developed countries or regions where eid agents have been well studied. in the united states, the blood supply is routinely screened for human t-lymphocyte virus (htlv). west nile virus (wnv); trypanosoma cruzi [1] [2] [3] and babesia spp. [4] [5] [6] [7] have been systematically scrutinized to evaluate the value of donor screening [8] ; and zika virus has recently emerged as an eid threat [9] . in china, however, many of the eid agents are rarely investigated among blood donor and evidence for their impact on blood safety is absent. in 2009, the american association of blood banks published a catalog of pathogens relevant to blood transfusion medicine reviews j o u r n a l h o m e p a g e : w w w . t m r e v i e w s . c o m safety in which 68 eid agents were listed as confirmed or suspected to be associated with transfusion transmissible infection (tti) [10] . the threat of these eid agents to blood safety varies, due to different spreading patterns, transmission routes, epidemiologic characteristics, and endemic status; therefore, they need to be specifically evaluated in each country or area. in china, blood donors are routinely tested for only 4 pathogens: hiv-1/2, hepatitis b virus (hbv), hepatitis c virus (hcv), and syphilis [11] . with the broad implementation of nucleic acid testing (nat), the improvement in performance of enzyme immunoassay assays, and the more rigorous policies for donor recruitment and testing, the transfusion risks of the conventional ttis have been largely reduced in china [11, 12] . however, many of the diversely distributed eid agents still pose potential threats to blood safety, yet their risks have never been fully evaluated. nevertheless, china has witnessed recurrent outbreaks of highly virulent eids including severe acute respiratory syndrome (sars), highly pathogenic avian influenza (h5n1) and streptococcus suis, a zoonotic bacterium mostly carried by pigs or pork products which causes syndromes of streptococcal toxic shock, sepsis and meningitis. [13] . for example, outbreaks of human streptococcus suis infection in china were reported in sichuan province, resulting in 66 laboratory confirmed cases and 39 deaths from mid-july to the end of august 2005 [14] . some eid agents with asymptomatic distribution among chinese general population, such as malaria, hepatitis e virus, and dengue virus may emerge as greater threats to chinese blood safety and require interventions. in this review, we highlight 9 representative, autochthonous eids agents that are nationwide or regionally epidemic. the epidemiology of these eid agents and the investigations among blood donors and/or the general population are reviewed. the geographic distribution for eid agents that are regionally epidemic is summarized, and the prevalence of these eid agents among chinese donors is summarized. human parvovirus b19 (b19v) is a small, non-enveloped, singlestrand dna virus [15] , causing various clinical manifestations such as chronic anemia, aplastic crises and arthropathies, and a variety of other syndromes among immune-compromised or immunosuppressed patients [16] [17] [18] [19] . b19v has been confirmed to be one of the ttis transmitted through blood or blood products [20] . the us food and drug administration (fda) and european pharmacopeia have proposed a limit of 1 × 10 4 geq/ml for pooled-plasma in order to reduce the potential risk of transmission [21, 22] . there is limited data on b19v prevalence among blood donors or the general population in china. according to several reports, the estimated prevalence rate could be as high as 3.5% in the general chinese population [23] and 4.5% in hiv co-infected individuals [24] . in the tibetan area, the b19v dna positivity rate was 4.8% among the general population [23] . among chinese blood donors, the b19v dna prevalence rate was 0.58%, which is much lower than that in the general population [25] . the same study also reported that different geographic locations demonstrated different prevalence rates for b19v, and that the dna sequences in xinjiang province showed a different genetic lineage than in other places of china [25] . in another study, b19v dna was detected in 54.2% (77/142) of plasma pools from 2 chinese blood product manufacturers of intravenous immunoglobulin (ivig), factor viii, fibrinogen and prothrombin complex concentrates, with levels of b19v-dna varying from 1 × 10 2 geq/ml to 1 × 10 7 geq/ml [26] . the viral load in one donation sample was 1.09 × 10 10 geq/ml, which was significantly higher than the threshold recommended by the us fda and european pharmacopeia (1 × 10 4 geq/ml). while further investigation is necessary to determine whether b19v nat screening should be implemented as a routine in chinese blood centers, the current b19v contamination in plasma products is a serious concern. malaria malaria is caused by infection with the parasites of plasmodia spp. and the current distribution covers the tropics and large parts of the subtropics [27] . infection with plasmodia spp. often resembles a common viral infection which may lead to a delay in diagnosis [28] . malaria is considered a transfusion risk since asymptomatic immigrants who reside in and travelers who visit endemic areas might import malaria to non-endemic areas [10] . therefore, us fda has initiated a donor deferral policy that temporarily defers donors who travel to endemic areas. as a result, about 1% of us donors are deferred for that reason [29] . malaria was once highly endemic in china with an estimated 30 million cases per year [30] . the chinese government began a tremendous effort to eliminate malaria in 1955 when the national malaria control program was launched [31] . the main species that causes malaria in china is p vivax and has been found in many regions; however, other species of plasmodia have also been reported [32] . although malaria has been well controlled in the last 2 decades, sporadic outbreaks are frequently reported [31] , and malaria remains a reportable infectious disease in china [13] . several cases of malaria transmission by transfusion were recently reported ( table 1 ) [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] . meanwhile, the dna of p knowlesi was also found in pooled plasma from a manufacturer in guizhou [50] . however, currently chinese blood centers do not have a policy to defer donors who have traveled to malaria endemic areas or malaria infected countries during epidemic seasons. the actual prevalence of malaria and its residual risks among voluntary blood donors is unknown. further studies on malaria infected blood donors in china, such as a survey on the risks of infection and demographic characteristics of plasmodium infected donors, are crucial to better understand the transfusion risks of malaria in china. hepatitis e virus (hev) is an enterically transmitted, positive-sense, single-stranded non-enveloped rna icosahedral virus [51] . it usually causes an acute and self-limiting infection. hev has a worldwide distribution and substantial morbidity and mortality in some developing countries [52] . many cases of hev transmission by blood transfusion have been documented all over the world [53] [54] [55] [56] [57] [58] [59] . routine screening of donors for hev rna was suggested by some studies [60] . in china, the anti-hev seroprevalence is about 40% in the general population and increases with age by 1% per year [61] . approximately 2.7% of individuals are igm positive (indicating acute infection) and 0.3% are asymptomatic with viremia [62] . in the early 1990s, due to the frequent occurrence of illegal blood donation in central china, the anti-hev igg prevalence spiked to 22.7% and anti-hev igm prevalence was 1.8% among illegal blood donors [63] . in a recent study using test results from routine donations collected at 6 urban blood centers, investigators reported a prevalence of 32.6% for anti-hev igg, 0.94% for anti-hev igm, and 0.07% for hev rna among 44 816 donations. in addition, they found that prevalence rates varied by blood center locations [64] . in a comparative study [63] , where samples from both qualified blood donors and donors deferred due to elevation of alanine aminotransferase (alt) were examined, the prevalence rates of anti-hev igm and anti-hev igg in alt-elevated donors (2.76% and 40.02%, respectively) were significantly higher than those in qualified donors (1.02% and 27.42%, respectively). meanwhile, the prevalence of hev antigen among the alt-elevated donors (0.25%) was also higher than that among qualified donors (0.06%), but not at a statistically significant level. these data suggest that routine pre-screening and post-donation alt tests can reduce, but not eliminate the potential risks of hev infection from otherwise qualified donations in china. dengue viruses (denv) denv causes dengue fever, dengue hemorrhagic fever (dhf), and dengue shock syndrome. denv is a life-threatening mosquito-borne disease with global spread [65] . denv was shown to be capable of transmission by transfusion [66] . transfusion of red blood cells which tested denv seronegative but were rna positive with high viral load (n10 7 copies/ml) can lead to denv infections in transfusion recipients [67] . several countries and regions with a high prevalence of denv have investigated denv among blood donors and recipients to evaluate its impact on blood safety, as well as to develop a proper donor enrollment strategy to reduce the transfusion-transmission risk [68] [69] [70] . in china, early outbreaks of dhf in 1980s were reported mostly in guangdong, guangxi, yunnan, hainan, fujian, and zhejiang provinces located in the southeast coastal regions or border areas next to southeast asia [71] . more than 80% of the documented dhf cases were from guangdong province, one of the most developed provinces located in the south coastal area [72] . since dengue fever first reemerged in guangdong province in 1978 [73] , the epidemic of denv spread to 26 chinese provinces by 2014 [74] . from 1990 to 2013, the epidemic status of dhf gradually changed from sporadic imported to autochthonous endemic cases [75] . in 2013, there was a large dhf outbreak from july to november in foshan city, guangdong province with 5173 suspected febrile cases [76] . among them, 641 denv infections were confirmed by laboratory testing (436 rna positive and 205 igm positive) [76] . the following year, the third historically largest dhf outbreak spread throughout guangdong province (20 of 21 cities with reported cases) with 45 236 febrile cases (6024 denv infections confirmed) resulting in 6 deaths [77] . partly in response to the outbreaks in 2013 and 2014, the chinese center for disease control and prevention (cdc) amended the guidelines for dhf prevention and control to strengthen the implementation of mosquito control [78] . in 2015, the dhf cases in guangdong province dropped sharply to 739 cases by the end of september [79] , reflecting the effectiveness of denv control measures in this area. denv sentinel monitoring by sero-surveillance has been in operation in dhf epidemic regions in china since 1990s. the denv seroprevalence rate varied (igg: 0.25%-14.49%; igm: 0.56%-5.2%) in the denv endemic areas in guangdong [80, 81] , guangxi [82] , yunnan [83, 84] , hainan [85] , and fujian [86] provinces. a pilot study of denv serology and viremia among asymptomatic donors in guangzhou city (guangdong province) in september and october 2014 found that the denv igm prevalence rate was 2.4% (n = 3000). the study also identified one denv rna positive donor with viral load of 944 copies/ml [87] . another post-outbreak serological investigation among healthy populations in foshan city (next to guangzhou city) found significantly higher denv seroprevalence rates in the 4 towns that experienced dhf outbreaks in 2013 (igg rate: 2.7%, n = 817) compared with the 2 towns without autochthonous cases (igg rate: 0.6%) [76] . a blood product with denv rna viremia can potentially lead to transfusion-transmitted infection. however, to date, there are no published studies on denv transmission via transfusion in china. human brucellosis caused by brucella spp. is one of the most severe zoonotic diseases worldwide [88] . transfusion-transmitted brucellosis cases have been reported since the 1950s [89] [90] [91] [92] , and brucella spp. are considered a potential risk for blood safety [10] . human brucellosis is one of the leading threats to public health in farming areas with livestock in china [93] . more than 90% of brucellosis cases in china were found in north china and were concentrated in inner mongolia, shaanxi, heilongjiang, jilin, and hebei provinces [94] . a total of 141 604 brucellosis cases were confirmed in these areas. in addition, a rapidly increasing trend was observed in brucellosis incidence, from 0.92 cases per 100 000 people in 2004 to 2.62 clinical cases per 100 000 people in 2010 [94, 95] . an epidemiological investigation in inner mongolia reported the incidence rate as high as 12.94% among people who had close contact with livestock [96] . in china, most of brucella surveillance has focused on risk factors for infections [97, 98] , prevalence in dairy cattle [99] and local animals [100, 101] with the goal of providing information for brucellosis prevention and control. the dna prevalence rate of brucella in raw whole milk samples was found to be 1.07% in 15 provinces [102] . the low-risk population in urban areas is at increasing risk of brucellosis from contaminated milk or raw meat [103] . limited data showed the seroprevalence rate of brucella among the healthy human population to be 9.82% in endemic areas [104] . recently, a brucella spp. investigation based on enzyme immunoassay testing among blood donors in an endemic area (kashi, xinjiang province) showed that the reactive rate was 1% (39/3896), in which 0.64% (25/3896) samples were further confirmed by western blot (wb) testing, and the brucella dna prevalence rate was 0.39% (15/3896) [105] . although no infection cases transmitted by transfusion have been reported, the existence of brucella dna in donors' plasma samples indicates potential risk of transfusion-transmitted brucellosis in endemic areas and warrants future investigation. as the first retrovirus discovered in humans [106] , htlv is one of the important ttis that may lead to various human diseases such as adult t-cell leukemia/lymphoma, myelopathy/tropical spastic paraparesis, opportunistic infections, and inflammatory disorders [107] . the implementation of mandatory testing on donors has been in effect since mid-1980s in many countries to reduce the risk of transfusion transmission. [43] in china, sero-surveillance of htlv among the general population started in 1980s when an early study in beijing and other 28 provinces found a 0.08% positive rate in 9303 samples-all connected to the endemic country japan [108] . in 2005 and 2012, 2 nationwide investigations reported the prevalence of htlv among blood donors to be 0.05% (n = 145 293) [109] and 0.03% (n = 122 468) [110] respectively. a meta-analysis of 40 studies among 458 525 donors in 21 provinces and regions found that the pooled estimates of htlv-1 prevalence in fujian and guangdong were 9.9/10 000 (95% ci, 4.4/10 000-22.2/10 000) and 2.9/10 000 (95% ci: 1.7/10 000-4.8/10 000), respectively. most isolates belonged to the transcontinental subgroup a whereas only 2 cases of htlv-1 infection were found among 204 763 donors in other provinces and regions [111] . data from these studies indicate that while htlv prevalence is low in china, the infection has expanded from concentrated coastal regions in fujian and guangdong to the neighboring provinces where seroprevalence remains low (ranging from 0.02% in shanghai and 0.12% in jiangxi) [108, 110] . although no transfusion-transmitted htlv infections have been reported, the surveillance of htlv among blood donors and the evaluation of its impact on blood safety continue to be studied in china. severe fever with thrombocytopenia syndrome virus (sftsv), a novel tick-borne bunyavirus, was first identified in china to be the etiologic agent of severe fever with thrombocytopenia syndromes (sfts) with initial fatality rates between 12% and 30% in 2009 [112] . sftsv is concentrated in the mountainous rural areas in central and eastern china [112] [113] [114] . the epidemic seasons of sfts are mainly from spring to autumn and peak in may to july [113] . farmers are at high risk for sfts due to more exposure to ticks [115] . the molecular characteristics, epidemiologic distribution, risk factors and clinical symptoms have been well summarized in several reviews [116, 117] . by the end of 2013, sftsv had spread from 6 provinces in 2009 [113] to 14 provinces with a growing incidence but a decreasing fatality rate [118] . the increasing epidemic of sfts was reported and annual incidence was estimated to be 3 cases per 100 000 populations in autochthonous endemic area [118] . meanwhile, increasing numbers of sfts cases were reported in japan [119] [120] [121] and south korea [122, 123] . migratory birds are suspected to have played an important role in promoting the spread of sftsv in east asia [124] . although there is no recorded transfusion-transmitted sfts case at present, sftsv has the potential to become a transfusion-transmitted infectious agent due to several considerations: (1) nosocomial transmissions caused by direct exposure to sfts patients' blood have demonstrated that sftsv is a blood-borne pathogen [125] [126] [127] [128] . (2) the incubation period from infection to onset of the disease is one or 2 weeks on average [129] , and in some cases up to thirty days [130] . viremic asymptomatic blood donors within the incubation period may therefore potentially transmit sftsv to recipients leading to sfts. in a study launched by the national heart, lung, and blood institute, johns hopkins university, the chinese institute of blood transfusion, and 3 chinese blood centers (one located in an endemic and 2 in nonendemic regions), antibody screening and follow-up sftsv rna detections were performed on 17 208 blood donor plasma samples collected between april and october 2012. the seroprevalence rates were 0.54% (80/14 752), 0.27% (3/1130) and 0.28% (3/1326) in an endemic area (xinyang) and non-endemic regions (mianyang and luoyang) respectively, with no significant difference observed (p n .1). among 9964 donors screened by 4-sample minipool sftsv rna testing, 2 suspected viremic samples were detected each with a viral load less than 20 plaque-forming units (pfu)/ml [131] . other regional sftsv among the healthy individuals reported seroprevalence rates varying between 0.44% and 7.2% [132] [133] [134] in epidemic areas, with finding asymptomatic viremic cases. continued investigation is needed to evaluate whether sftsv presents a risk to transfusion recipients in china. leishmania infection is responsible for cutaneous and visceral leishmaniasis (kala-azar). leishmania spp. are usually transmitted to people through the phlebotomine sandfly [135] . the infected individual may harbor a persistent infection up to 30 years before recovery [136] . the transmissibility of leishmania infection via blood has been demonstrated in animals [137, 138] as well as human beings [139] [140] [141] [142] . leishmania in human red blood cells (rbcs) can survive for as long as 15 days under blood bank storage conditions [143] . it has been reported to cause cutaneous or visceral leishmaniasis in infants and immunocompromised patients [139] [140] [141] [142] . asymptomatic infections are usually found in healthy blood donors from endemic areas [144] [145] [146] [147] [148] . us military blood banks enforce permanent deferral for individuals with any history of leishmaniasis, but there is no existing regulation or standard for leishmania testing in civilian donor screening [10] . during the 1950s, there were more than 500 000 documented kalaazar cases in china, mainly in rural areas in the north [149] . with the efforts of a national control program, kala-azar was almost eliminated in 1960s [150] . currently, more than 300 cases of kala-azar are reported each year, mainly from xinjiang province and other provinces in western china [150] . recently, a retrospective study of visceral leishmaniasis by the chinese cdc reported an increase in the number of visceral leishmaniasis cases in endemic areas between 2005 and 2010 [149] , indicating that prevention and control strategies must be taken to restrain the increasing incidence and spread of leishmaniasis. otherwise, frequent population migration, tourism, and a rapidly growing public transportation may lead to further spread of the infection and push it up on the list of transfusion-transmitted infectious diseases in china. to date, there are still no survey studies of infection among donors and no documented transfusion-transmitted cases for leishmania infection in china. q fever is a zoonosis due to coxiella burnetii infection. c burnetii usually causes asymptomatic clinical manifestations such as a flu-like disease or atypical pneumonia in humans [151] ; however, acute [152, 153] and fatal chronic infections [154] [155] [156] [157] have been reported. in 2007, there was a large outbreak of q fever in the netherlands [158] . hogema et al initiated a surveillance of c burnetii dna and antibodies in local blood donations and found that the c burnetii dna positive rate was 0.3%, while the igg seropositive rate was 12.2% [159] . furthermore, 10 seroconversions were detected in donors with an incidence rate of 5.7% per year during the outbreaks from 2007 to 2009 [159] . after the great outbreaks of q fever, slot et al. started to investigate if chronically infected donors posed a threat to blood safety in the netherlands. the serological results from 2490 serum samples collected in the most affected area during august 2012 to january 2013 showed that chronic c burnetii infection was absent in the epidemic blood donors, which led to the donor re-entry policy that had already been initiated elsewhere in europe [160] . in china, most c burnetii infections have been observed in tibet, yunnan, xinjiang and inner mongolia [161] . the c burnetii dna positivity rate was about 10% in ticks and 7% in humans in western china [162] . as q fever is mainly an airborne disease, the individuals with exposure to livestock bear a higher risk. some epidemiological studies show that more than 50% of rural farmers had antibodies to c burnetii [163, 164] . although blood donor screening of c burnetii has not been initiated in china, the dna of c burnetii was found in pooled plasma from a manufacturer in guizhou [50] . a cross-sectional study of the seroprevalence and viremia status of c burnetii among blood donors, especially in nomadic herding and livestock regions, would provide a more comprehensive assessment of its impact on blood safety in china. due to its biological and geographic diversity, china will always be at high risk for various eid agents. as a populous country, a dramatic ramp-up in the number of blood donations was reported recently, with more than 21 million donations collected in 2012 at the donation index of 8.5 donations per 1000 people [165] . however, monitoring of the classical ttis such as hiv, hbv, hcv and syphilis, as well as eid agents has only been implemented by the chinese cdc and mostly based on sentinel investigations and clinical case report systems. the monitoring systems have demonstrated effectiveness in establishing proper guidelines for disease prevention and control based on epidemiological analysis of transmission routes and infection risk factors. the fatality rates and clinical symptoms from the documented cases are periodically summarized and analyzed to help with diagnosis and therapy of these pathogens, as well as with the development and improvement of laboratory diagnostic assays. effort towards disease control has benefitted from the system in the face of several outbreaks of eid epidemics, such as: sars [166] , h5n1 [167] , sftsv [113] , and denv [76] . the regional spread of infection is an important aspect to consider when evaluating the transfusion risk for eid agents. among the 9 eid agents listed above, all of them have been proven to result in pathological and autochthonous epidemics in china. b19v, hev and plasmodium spp. have nationwide distribution. three insect-borne eid agents (denv, sftsv, and leishmania spp.) and 2 zoonoses (brucella spp. and c burnetii) display significant geographic diversity due to their patterns of transmission. htlv is clustered in one coastal region. the regional distribution of 6 eid agents is shown in fig. 1 . not surprisingly, the regional distribution of insect-borne pathogens matches that of disease vectors (mosquitos, sand-flies and ticks). denv, a well-described mosquito-borne virus, has a global distribution in tropical and subtropical areas, the location of recent outbreaks of dhf. the infections of sftsv, the novel tick-borne bunyavirus, were identified from sfts patients in rural mountainous areas in central and eastern china, mainly because of the higher risk of tick exposure. in a similar way, most of the infections of zoonotic diseases (q-fever and brucellosis) were found in rural livestock farming areas in northern and western china. by compiling the distribution of reported clinical cases and the prevalence of eid agents in donors and/or general population, we provide estimates of the frequency of eid agents among chinese blood donor populations. see fig. 2 . hev and b19v are estimated to have national distribution among donors and general population in china based on previous cross-sectional studies. spread of brucella spp. depends on transmission routes from contaminated milk and raw meat produced from endemic regions. considering the current dna prevalence rate (0.39%) of brucella spp. among blood donors in endemic regions and its potential high frequency in the general donor population, this eid is a matter for concern. in the shadows of recent global outbreaks and the fast expanding trends of dhf, denv should also be highlighted for its potential risks in endemic areas in china. the other 3 regionally concentrated eid agents: qfever, leishmania spp., and sftsv are estimated to have moderate or low frequency among the blood donor population. however, ongoing surveillance on these eid agents in donors is prudent in order to provide sound evidence regarding their impact on blood safety in china. in order to evaluate the impact of eids on blood safety, a practical and feasible approach is to monitor the existence of eid agents among asymptomatic blood donors and obtain direct evidence from transfusion-transmitted cases confirmed by molecular analysis. firstly, the surveillance among blood donors through sero-markers and nucleic acid of pathogens provides data for estimating transfusion risk. among the 9 eids discussed in this review, only htlv has been continuously investigated at blood centers since 1980s. there are a few investigations and case reports on b19v, hev and plasmodium spp. among blood donors, but no systematic and continuous investigation on these eids. data on sftsv, denv and brucella spp. in china are very limited with only one documented donor surveillance study available for each agent. c burnetii (q fever) and leishmania spp. have not been investigated. in addition, well-organized and appropriately designed donorrecipient linkage studies may directly confirm transmission by transfusion, facilitate further evaluation of the post-transfusion outcomes, and yield more convincing evidence to support strategies for screening donors for eid agents. although china has not performed such linkage studies, brazil examined donor-recipient linkage for dengue virus using a large, nationally representative database [168] . this study may serve as an example to follow in order to evaluate transfusion risk of eids in china. collaborative efforts from global surveillance programs may prove useful to mitigate the transfusion risk of eids. although most eid agents in china were historically imported, some agents, such as sars and sftsv, originated in china and are expanding to other adjacent countries. also, non-endemic eid agents such as west nile virus (wnv), chikungunya virus, variant creutzfeldt-jacob disease (vcjd) and zika virus (zikv) should be immediately addressed due to their worldwide distribution and severity of clinical outcomes. recently, transfusiontransmitted zikv has been documented [169] [170] . several cases of zikv infection among travelers from epidemic areas have been reported in china [171] [172] . currently immigration authorities recommend oral fig. 1 . the distribution of 6 major regional eid agents in china. declaration of infection at entry-exit inspection and quarantine of symptomatic travelers from zikv epidemic areas upon entry into china. travelers from countries epidemic for vcjd are deferred from donation by health questionnaire in chinese blood centers. however, whether wnv, chikungunya virus and zikv should also be added to the deferral list remains a matter of controversy that needs evidence from further investigation. pathogen reduction of blood products is an alternative defense against eid agents. several studies described effective inactivation of eid agents such as denv [173] and wnv [174] . currently the only pathogen reduction technology in use in china is the methylene bluephotochemical technology applied to plasma products [175] . the technology is not mandatory and only performed at a few blood centers. more efforts should be made to evaluate whether and how pathogen reduction can be used to safeguard the blood supply in china. the costeffectiveness of screening strategies is a key factor to consider. currently there is a lack of cost-effectiveness studies on the existing screening strategies for the 4 classical ttis in china. such studies are needed to enhance the development and improvement of additional eid screening strategies in blood donations. in conclusion, the threats to blood safety posed by eid agents in china require further evaluation. with the support of the substantial evidence from such studies, china can implement more effective blood screening strategies on eid agents and further reduce transfusion risk to patients. antibody levels correlate with detection of trypanosoma cruzi 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methylene blue and white light treatment in four chinese blood centers the authors acknowledge dr hua shan and dr ling shi for their careful review of the paper. key: cord-310210-f2wb3er0 authors: xie, runsheng; xia, yun; chen, yaolong; li, hui; shang, hongcai; kuang, xinying; xia, linjun; guo, yi title: the right extension statement for traditional chinese medicine: development, recommendations, and explanation date: 2020-09-02 journal: pharmacol res doi: 10.1016/j.phrs.2020.105178 sha: doc_id: 310210 cord_uid: f2wb3er0 nowadays, the number of traditional chinese medicine (tcm) guidelines is constantly increasing, but its reporting quality is still disappointing. one of the main reasons is that there is a lack of suitable reporting standard to guide it. low-quality reports impede the presentation of the guidelines’ content even if the guidelines are well projected and developed, thereby hindering the user’s integration and evaluation of guidelines and even misleading clinical decisions [1,2]. in response to this long-standing problem, the reporting items for practice guidelines in healthcare (right) working group has organized a group of tcm clinical experts, methodologists, and epidemiology, through a multi-staged development process, including systematic review, reporting quality evaluation and online delphi expert consensus, developed the right extension statement for tcm (right-tcm). the right-tcm extends two sections of the right statement, includes basic information and recommendations section. seven strong recommendation sub-items were added on the basis of right statement and formed the right-tcm finally. the group hopes that the right-tcm can assist tcm guideline developers in reporting guidelines, support journal editors and peer reviewers when considering tcm guideline reports, and help health care practitioners understand and implement a tcm guideline. this article will introduce its background, development, recommendations and explanation as follows. nowadays, the number of traditional chinese medicine (tcm) guidelines is constantly increasing, but its reporting quality is still disappointing. one of the main reasons is that there is a lack of suitable reporting standard to guide it. low-quality reports impede the presentation of the guidelines' content even if the guidelines are well projected and developed, thereby hindering the user's integration and evaluation of guidelines and even misleading clinical decisions [1, 2] . in response to this long-standing problem, the reporting items for practice guidelines in healthcare reporting quality is a significant part of the study of clinical guidelines. high-quality reports can fully explain the guideline development process and provide useful and clear recommendations for readers. to solve the reporting problem of guidelines, researchers from different countries studied extensively and presented relevant reporting standards. in 1993, a nine-item reporting standard was developed for the summary of clinical practice guidelines (cpgs), which is the first time to provide a template and basis for how to systematically and normatively report the information about the development and content of guidelines [3] . in 2003, the conference on guideline standardization (cogs) working group was established to develop a reporting standard for cpgs [4] . the cogs standard consists of 18 items that cover the entire process of guideline development, but it is limited to the clinical field and has not been updated since 2003. since the launch of appraisal of guidelines j o u r n a l p r e -p r o o f for research and evaluation ii (agree ii) in 2009, agree ii has been widely used in the quality evaluation of guidelines [5] [6] [7] . although it is stated in the statement that it can also be used as a reporting standard, researchers still generally use it as a quality evaluation tool. in 2016, the international right working group developed the right statement as a reporting tool for practice guidelines [8] . based on the world health organization guidelines and the items of the cogs and agree ii, this international reporting tool was developed in strict accordance with existing framework and the enhancing the quality and transparency of health research (equator) network approach. consisting of 22 items across 7 domains, the right statement has been widely applied to clinical practice, public health and health policy guidelines [9] [10] [11] . however, we found the right statement checklist does not fully applicable to the traditional chinese medicine guidelines and hard to reflect its major characteristics [12] . tcm is one of the oldest medical systems in the world and its theoretical system has unique characteristics of chinese culture and philosophy and has accumulated rich clinical experience [13] . for example, tcm is characterized by the concept of organic wholeness and treatment based on syndrome differentiation. its guidelines also reflect its distinctive characteristics and chinese traditional cultural characteristics. these factors may be ignored in the process of developing and reporting guidelines [14] . the reporting standard of the tcm guidelines should reflect the characteristics of chinese medicine itself. this idea was also endorsed by the right working group, and a multidisciplinary expert was organized to develop the extended version. the equator network approach was used as the methodological guidance for this research [15] , which included in the following three steps: (1) establishment of research working group, (2) systematic review of the literature and items establishment, (3) expert consensus and items selection. the grading of recommendations assessment, development and evaluation (grade) grid rules were used to reach decisions when the consensus is elusive (additional file 4) [16, 17] . more details of material and methods is presented in additional file 5. literature search and reporting quality evaluation. the diagram of the screening process is shown in fig. 1 . after screened for potentially eligible cpgs, a total of 539 tcm cpgs were eventually included (additional file 6). our previous research results showed that the reporting quality of these 539 tcm cpgs was improving, but the overall quality remained suboptimal [12] . there were some difficulties we encountered during the evaluation of the tcm guidelines when using the right statement. for example, in the background section, tcm have their own unique historical evolution. in terms of epidemiology, there is a lack of statistics on the basic epidemiology of the health problem of tcm. in terms of recommendations, there is a lack of reporting content concerning principle-method-recipe-medicines of tcm. in terms of evidence, there is no uniform reporting standard for the quality of evidence of ancient classic theoretical chinese medical case and famous experts experience. for these aspects, the existing right statement items are not well applicable for tcm. after extracting the information of these 539 tcm guidelines, the contents of 10 items were found not included in the right statement checklist. these items are reported to varying degrees in the tcm guidelines (fig. 2) . among of them, items 8, 9 and 10 j o u r n a l p r e -p r o o f (traditional chinese medicine decoction, traditional chinese patent medicine and acupuncture) are the contents often mentioned in interventions section of tcm guidelines. as shown in fig. 3 , the specific reporting content of these three items were further analyzed. after discussion in the face-to-face meeting, the core working group determined 24 initial sub-items based on the results of describe the acupuncture points, major points, matching points, and their addition and subtraction information. besides, other 16 weak recommendation sub-items were not included, but these items could be served as a reference for future research (table 1) . the present paper describes a multi-staged development process of the right-tcm, including one of the purposes of a systematic evaluation is to reduce random errors and systematic errors as much as possible through comprehensive searches and rigorous review and to provide near-real scientific evidence for decision makers [18, 19] . we have comprehensively collected the published cpgs for tcm and tried to use existing tools for evaluation. to begin with, we evaluated the reporting quality of tcm guidelines. the results show that the reporting quality of the tcm guidelines is poor, and the existing right statement cannot be fully suitable for the tcm guidelines. there is a requirement to develop an extension of the right statement to reflect the unique characteristics of tcm. in addition, we conducted a comprehensive analysis of the data from the tcm guidelines and condensed the data into initial items. we also used a brainstorming method to supplement the initial items, and we supplemented new items with such discussions to prevent omissions. moreover, we used the delphi method and grade grid rules in the consensus process. all the participating experts did not know each other, and they answered the questions raised without meeting each other and without discussion. this back-to-back anonymity has advantages and can avoid other influencing factors [20, 21] . finally, a total of 7 strongly recommended sub-items are determined as extension items into the right-tcm. for item 1 (s1 in the checklist of the right-tcm), it is recommended that a clinical guideline for tcm could be identified by the title. this item is useful for rapid judgment, screening and classification for the tcm guidelines. for item 6 (s2 in the checklist of the right-tcm), it is recommended to describe the principle and method of tcm treatment in the recommendations section. these general principles and basic methods for treating diseases are based on the unique concept of holism and syndrome differentiation and have guiding significance for the specific j o u r n a l p r e -p r o o f treatment measures in traditional chinese medicine [22] . for item 7 (s3 in the checklist of the right-tcm), it is recommended to describe whether to treat disease based on the syndrome differentiation of tcm. syndrome differentiation is an important basic concept of tcm [23] [24] [25] . it is the process of applying "principle-method-recipe-medicines" to clinical practice. for item 8 (s4 in the checklist of the right-tcm), it is recommended to provide clear and accurate description of tcm decoction in the intervention. tcm decoction refers to a method consisting of herbs with relatively specific processing methods and usage. the decoction is the main prescription of tcm, so it is necessary to make a detailed report on the tcm decoction [26, 27] . for item 8-5 (s4-1 in the checklist of the right-tcm), it is recommended to describe the administration route and frequency of tcm decoction. the administration route and frequency are also one of the ways to influence the efficacy of the medicine. the traditional administration route of tcm is mainly based on internal and external use (oral and dermatological drugs) [28, 29] . in addition, there are many administration routes such as inhalation, sublingual administration, mucosal surface administration, rectal administration [30] . currently, only 4% and 0.3% of the guidelines describe the route and frequency of administration, respectively. for item 10 (s5 in the checklist of the right-tcm), it is recommended to provide clear and accurate description of the acupuncture in the intervention. acupuncture is an important component of tcm interventions. acupuncture has been increasingly used as an integrative or complementary therapy and it is well-tolerated with little risk of serious adverse effects [31] [32] [33] [34] . for item 10-1 (s5-1in the checklist of the right-tcm), it is recommended to describe the acupuncture points, major points, matching points, and their addition and subtraction information. the acupoint is the area that the qi in meridian flows into the body surface and is the area where the needle is stabbed [35] . with the rapid development in recent years, tcm has been widely used in different area, and its guidelines and handbooks have also played an important role in public health emergency of international concern (pheic) [36] . such as part of "tcm classification therapy to improve curative efficacy" in the "handbook of covid-19 prevention and treatment" [37] . for pheic, the procedures and methodological requirements of the rapid advice guideline should be adopted [38] [39] [40] . however, the current right-tcm reporting items for the rapid advice guideline has yet to be developed, which may be a possible research direction in the future. although this study reflects the scalability of the right statement, there are some limitations need to attention. in the current study, we only study the standardized reports of the most commonly tcm interventions, such as tcm decoction, traditional chinese patent medicine and acupuncture. interventions of tcm also included moxibustion, massage and cupping, etc. therefore, we will revise the checklist in the future based on user feedback and evaluation results. in summary, seven strong recommendation sub-items were added on the basis of right statement and formed the right-tcm finally. we hope that the right-tcm can assist tcm guideline developers in reporting guidelines and improving the reporting quality, help the target audience understand and implement a guideline. fig. 1 the diagram of the screening process excluded practice guidelines developed by specialty societies: the need for a critical appraisal the scandal of poor epidemiological research more informative abstracts of articles describing clinical practice guidelines standardized reporting of clinical practice guidelines: a proposal from the conference on guideline standardization agree ii: advancing guideline development, reporting and evaluation in health care quality and reporting of guidelines on the diagnosis and management of dystonia development and validation of a tool to assess the quality of clinical practice guideline recommendations a reporting tool for practice guidelines in health care: the right statement reporting quality evaluation of clinical practice guidelines published in journals of mainland china in 2016 practice guidelines on migrants' health: assessment of their quality and reporting a quality evaluation of guidelines on five different viruses causing public health emergencies of international concern using the right statement to evaluate the reporting quality of clinical practice guidelines in traditional chinese medicine consort extension for chinese herbal medicine formulas 2017: recommendations, explanation, and elaboration (traditional chinese version) clinical practice guidelines in china guidance for developers of health research reporting guidelines grade guidelines: a new series of the journal of clinical epidemiology use of grade grid to reach decisions on clinical practice guidelines when consensus is elusive cochrane handbook for systematic reviews of interventions version 5.1.0. the cochrane collaboration david sackett and the birth of evidence based medicine: how to practice and teach ebm a delphi study to identify performance indicators for emergency medicine essential key messages about diagnosis, imaging, and self-care for people with low back pain: a modified delphi study of consumer and expert opinions a research on syndrome element differentiation based on phenomenology and mathematical method the basic theory, diagnostic, and therapeutic system of traditional chinese medicine and the challenges they bring to statistics study on tcm syndrome differentiation of primary liver cancer based on the analysis of latent structural model a large-scale, multi-center urine biomarkers identification of coronary heart disease in tcm syndrome differentiation application evaluation of clinical practice guidelines for traditional chinese medicine: a clinical analysis based on the analytic hierarchy process wendan decoction (traditional chinese medicine) for schizophrenia gut microbiota, a new frontier to understand traditional chinese medicines the rise of traditional chinese medicine and its materia medica: a comparison of the frequency and safety of materials and species used in europe and china inhaled insulin-intrapulmonary, intranasal, and other routes of administration: mechanisms of action non-pharmacological treatments for pain relief: tens and acupuncture acupuncture in hospice settings: a qualitative exploration of patients' experiences clinical efficacy of acupuncture on rheumatoid arthritis and associated mechanisms: a systemic review acupuncture for pain observation on clinical therapeutic effect of acupuncture treatment on functional dyspepsia based on syndrome differentiation the clinical benefits of chinese patent medicines the authors wish to express their gratitude to the following people who participated in the research and consensus process of the report specification: hao chen (nanjing university of chinese medicine theory. background section 3 describe the basis for diagnosing the disease based on biomedical theory and/or traditional chinese medicine theory.weak recommendation 4 describe the knowledge of disease pathogenesis in traditional chinese medicine theory.weak recommendation 5describe the specific reasons for using traditional chinese medicine to treat the disease.weak recommendation 6describe the principle and method of treatment for traditional chinese medicine in the recommendations. extension of right 13a item (recommendation section) 7describe whether to treat disease based on the syndrome differentiation of traditional chinese medicine. 8provide clear and accurate description of traditional chinese medicine decoction in the intervention. describe the name and provenance of traditional chinese medicine decoction. describe the herbal names, herbal addition and subtraction, dosage of traditional chinese medicine decoction.weak recommendation describe the composition principle, basis and interpretation of traditional chinese medicine decoction.no recommendation describe the decocting method of traditional chinese medicine decoction.weak recommendation describe the administration route (e.g., oral, topical), frequency of traditional chinese medicine decoction. describe the duration of treatment of traditional chinese medicine decoction.weak recommendation 9provide clear and accurate description of traditional chinese patent medicine in interventions.weak recommendation 9-1describe the product name (e.g., the trade name), provenance and manufacturer of traditional chinese patent medicine.no recommendation 9-2 describe the dosage of traditional chinese patent medicine.weak recommendation 9-3describe the administration route (e.g., oral, topical), frequency of traditional chinese patent medicine.weak recommendation 9-4describe the duration of treatment of traditional chinese patent medicines.weak recommendation provide clear and accurate description of the acupuncture in the intervention. describe the acupuncture points, major points, matching points, and their addition and subtraction information. 10-2 describe the specific information of the needling instrument used in the acupuncture process.weak recommendation 10-3describe the needling manipulation, needling depth and needling retention time of treatment required for acupuncture.weak recommendation describe the frequency of treatment required for acupuncture.weak recommendation describe the duration of treatment required for acupuncture.weak recommendation key: cord-285567-glm49rr4 authors: zeng, pengjiao; li, juan; chen, yulong; zhang, lijuan title: the structures and biological functions of polysaccharides from traditional chinese herbs date: 2019-03-25 journal: prog mol biol transl sci doi: 10.1016/bs.pmbts.2019.03.003 sha: doc_id: 285567 cord_uid: glm49rr4 most of traditional chinese medicine substances come from herbal plants. the medicinal quality of herbal plants varies with the locations of cultivation, the parts of the herb collected, the season of the herb collected, and the herb processing method. polysaccharides are major components of the herb plants and their biosynthesis is partly controlled by the genes but mostly influenced by the availability of the nutrition and determined by the various environmental factors. in recent decades, polysaccharides isolated from different kinds of chinese herbs have received much attention due to their important biological activities, such as anti-tumor, anti-oxidant, anti-diabetic, radiation protecting, antiviral, hypolipidemic, and immunomodulatory activities. interestingly, different batches of the same herb can obtain different polysaccharide fractions with subtle differences in molecular weight, monosaccharide compositions, glycosidic linkages, and biological functions. even with these variations, a large number of bioactive polysaccharides from different kinds of traditional chinese herbs have been purified, characterized, and reported. this review provides a comprehensive summary of the latest polysaccharide extraction methods and the strategies used for monosaccharide compositional analysis plus polysaccharide structural characterization. most importantly, the reported chemical characteristics and biological activities of the polysaccharides from the famous traditional chinese herbs including astragalus membranaceus, ginseng, lycium barbarum, angelica sinensis, cordyceps sinensis, and ophiopogon japonicus will be reviewed and discussed. the published studies provide evidence that polysaccharides from traditional chinese herbs play an important role in their medical applications, which forms the basis for future research, development, and application of these polysaccharides as functional foods and therapeutics in modern medicine. the biological information flows from dna to rna to protein with template-based precision. 1 however, thorough understanding the information residing in dnas, rnas, and proteins cannot explain the makeup of cells, tissues, and organs as well as the pathophysiological and physiological processes because the environment is in charge of both the building materials and waste management to keep the organisms alive. moreover, polysaccharides/glycans and lipids are constantly synthesized and metabolized by concerted effort of at least hundreds of proteins from inorganic elements and small organic molecules without a template in living organisms. furthermore, polysaccharides are heterogeneous biomolecules containing far more structural information than that are carried by protein-, nucleic acid-, and lipid-combined. 2, 3 such paradigm is applicable to all living systems including animals, plants, fungi, and microbes. [4] [5] [6] [7] thus, polysaccharides are positioned to serve important energy, structural, and biological functions in all living organisms. traditional chinese medicine is one of the oldest medical systems in the world. most traditional chinese medicine substances come from herbal plants. the individual plant cell makes a cell wall enriched in cellulose, non-cellulosic polysaccharides and lignin. the non-cellulosic polysaccharides are heterogeneous. 4 spatially and temporally controlled heterogeneity in the physicochemical properties of cell wall non-cellulosic polysaccharides is observed at the tissue and individual cell levels, which plays important role in defensing and survival of the plants. it has been found that the herb polysaccharides have important biological activities such as anti-tumor, antioxidant, anti-diabetic, radiation protecting, antiviral, hypolipidemic, immunomodulatory, and other activities [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] with lower toxicity and side effects. therefore, the isolation, characterization, and biological activity testing of polysaccharides in herbs have become a hot research field in china. 20 this review provides a comprehensive summary of the extraction, isolation, identification, structural analysis and biological activity from many important traditional chinese herbs, such as astragalus membranaceus, ginseng, lycium barbarum, angelica sinensis, cordyceps sinensis, and ophiopogon japonicus. the published studies provide solid evidence that polysaccharides from traditional chinese herbs play an important role in their medical applications, which forms the basis for future research, development, and application of these polysaccharides as functional foods and therapeutics in modern medicine. the most common method for preparing herbal medicine is to boil the herb in hot water and the liquid is then taken as the medicine. most of the non-cellulosic polysaccharides are polar macromolecules that are readily soluble in water. thus, the traditional polysaccharide extraction method is a water leaching extraction method, which is usually extracted by hot water leaching, and the polar macromolecular compound polysaccharide is dissolved in a polar solvent such as water to extract by using the principle of "similar compatibility." in addition, according to the structure and properties of polysaccharides, some auxiliary means are introduced. 20 on the basis of traditional water extraction, acid-base extraction method, enzymatic extraction method, microwave-assisted extraction method, ultrasonic assisted extraction method and ultrahigh-pressure extraction method have been developed. [20] [21] [22] [23] [24] [25] [26] [27] [28] then the separation and purification process of the polysaccharide is generally carried out from the water extracted materials by removing the non-polysaccharide components first. common methods for polysaccharide purification include precipitation, gel chromatography, anion exchange chromatography, macro porous resin column chromatography, ultrafiltration, and other methods alike. [29] [30] [31] [32] [33] [34] most of the polysaccharides obtained by the extraction, separation and purification techniques at this stage are still crude products because the quality of polysaccharides is difficult to control. first, the medicinal quality of herbal plants varies with the locations of cultivation, the parts of the herb collected, the season of the herb collected, and the herb processing method. second, the extraction methods used vary from lab to lab. third, unlike dna, rna, and proteins, the non-template synthesized polysaccharides are never pure compounds no matter how many procedures have been used for purification. the obtained polysaccharides are always associated with either narrow or wide molecular weight ranges. the biological activities of the polysaccharides purified by the same starting materials vary as well. therefore, special attention has to be paid during the extraction, separation and purification of herb polysaccharides. [35] [36] [37] [38] the advantages and disadvantages of each method are shown in table 1 . the structure of polysaccharides is more complex than that of proteins and dnas. from a chemical point of view, the complexity of the polysaccharides undoubtedly brings great difficulties to its structural analysis. the structural classification of polysaccharides follows the suit of proteins and dnas, i.e., the structure of polysaccharides can be divided into primary, secondary, tertiary and quaternary structures. 39 like other biomolecules, the higher structure of the polysaccharide chain is based on its primary structure. the difference is that primary structure of the polysaccharide chain having much more "meaning" than the protein or dnas. to determine the primary structure of a polysaccharide chain, the following problems have to be solved: (1) relative molecular mass; (2) monosaccharide compositions of the polysaccharide chain; (3) presence or absence of uronic acid and specific uronic acid type and ratio; (4) d-or l-configuration of each monosaccharide residue, pyran ring or furan ring form; (5) sequence of linkage between individual monosaccharide residues; the αor β-anomeric form of each glycosidic bond; (7) the substitution of a hydroxyl group on each monosaccharide residue; (8) the attachment of a polysaccharide chain to a non-polysaccharide moiety; (9) the backbone of the polysaccharide chain and the branch linkage site; and (10) a polysaccharide residue may be modified by a sulfate group, an acetyl group, a phosphate group, a methyl group, or the like. there are many analytical methods for polysaccharide structural characterization, 40, 41 not only instrumental analysis methods such as infrared, nuclear magnetic resonance, mass spectrometry, etc., but also chemical methods such as partial acid hydrolysis, complete acid hydrolysis, periodic acid oxidation, smith degradation, etc., as well as biological methods such as specific glycosidase digestion, immunological methods, etc. polysaccharide extraction, separation and purification methods from traditional chinese herbs are shown in table 1 . 39 3. overview of biological activities of polysaccharides purified from traditional chinese herbs astragalus membranaceus (a. membranaceus) ( table 3) belongs to the family leguminosae and is widely distributed in asia, europe and north america. 43, 79 according to reports, there are >3000 different types of a. membranaceus, and the roots are collected and dried for use. it has been known for centuries as a treatment for various diseases in traditional chinese medicine. such as in wound healing, diabetes, leukemia, hypertension, eye disease, nephritis, cirrhosis, uterine cancer. 80 in recent years, many phytochemistry and pharmacological studies show that the polysaccharide part is one of the major bioactive components of a. membranaceus. it has a variety of health benefits, including immune regulation, anti-inflammatory, anti-oxidation, anti-glomerulonephritis, anti-atherosclerosis, anti-diabetes and anti-tumor ability. 42 a number of polysaccharides are isolated from the roots and aerial parts of a. membranaceus. jin et al. listed 24 polysaccharides isolated from the roots of a. membranaceus, and most of them are heteropolysaccharides. 42 these heteropolysaccharides have molecular weights ranging from 8.7 to 4800 kda, with different proportions of the monosaccharides, including arabinose, fructose, fucose, galactose, glucose, mannose, rhamnose, ribose and xylose. kiyohara et al. separated 13 different types of polysaccharides from the aerial part of a. membranaceus, 9 of which consist of arabinogalactans and pectic acid arabinogalactan or pectin. 44 structural analysis of the water-soluble heteropolysaccharide (apsid3) isolated from a. membranaceus showed that the minimal repeat unit consists of one terminal arabinose, one 1,5-linked arabinose, one 1,3-linked rhamnose, one 1,3,4-linked rhamnose, six 1,4-linked glcuronic acid and five 1,4linked galacturonic acid residues, with the backbone of which consists of 1,4-linked galacturonic acid, 1,4-linked glcuronic acid and a small amount of 1,3-linked rhamnose is attached and the side chain consists of a 1,5-linked arabinose on the c-4 of the 1,3-linked rhamnose. 45 the immunomodulatory activity of the aps polysaccharide has been extensively studied both in vitro and in vivo. aps has been reported to improve the function of t cells, b cells, macrophages, lymphocytes and dendritic cells 42 (fig. 1 ). abuelsaad 46 studied the immunomodulatory effects of aps treatment on mice infected with aeromonas hydrophila and found that aps treatment reduces ros production, downregulates neutrophil activity and the proportion of cd4+/cd8 + t cells is increased. yang et al. 47 reported the immunomodulatory activity of aps in experimental rat model of colitis induced by trinitrobenzene sulfonic acid. it is reported that aps can significantly improve experiment rat tnbs-induced colitis by regulating the expression of tnf-α, il-1β and nfatc4. 47 ginseng (table 3 ) has a long history of use as a traditional herb in many eastern countries including korea, china and japan. there are two main types of ginseng: panax ginseng and panax quinquefolius. the common medicinal "ginseng" is mainly derived from the roots. it has been found to play a role in the improvement of various injuries and diseases from the central nervous system, the cardiovascular system to endocrine secretion and the reproductive and immune systems. 52 the main active compound ginseng is ginsenoside, which is a steroidal saponin conjugated to different sugar moieties and polysaccharides (10-20% by weight). to date, several components of ginseng polysaccharides have been identified and studied, including arabinogalactan, pectin and acidic polysaccharides, which are mainly composed of monosaccharides such as l-arabinose, d-galactose, l-rhamnose, d-galacturonic acid and d-glucuronic acid. 53 molecular weights are ranged from 3.2 to 1900 kda. 48 however, there is a lack of detailed information on the actual structural characteristics and heterogeneity of these polysaccharide components. many studies have shown that ginseng polysaccharides have antibacterial, anti-oxidant, anti-inflammatory, anti-depressant, anti-tumor and immunomodulatory properties both in vitro and in vivo. 48 anti-tumor and chemical protective effects of ginseng polysaccharide have received a lot of attention in the past decade. in a tumor-bearing mouse model, a sublethal dose of cyclophosphamide (cp) after treatment with 100 mg/kg ganshan injection significantly reduced mortality and promoted recovery. 49 ginseng polysaccharide is also found to inhibit cell proliferation and to induce apoptosis in hct116 human colon cancer cells through the cyclin inhibitor protein p21. 50 and in both sexes of mice, a 100 mg/kg dose of ginsan (the polysaccharide fraction of ginseng) significantly enhances liver endogenous anti-oxidant levels with no significant hepatotoxicity. 51 in a mouse model of γ-radiation-induced spleen injury, ginsan (100 mg/kg) can be used to restore endogenous anti-oxidant enzymes heme oxygenase-1 (ho-1), sod and gpx by the action of cytokines. 54,81 lycium barbarum (table 3 ) polysaccharide (lbp) is derived from the lycium barbarum (wolfberry) fruit in the solanaceae family. lbp is a well-known traditional chinese herbal formula that has been used in china for >2300 years. 55 the chinese believe that it can nourish the eyes, liver and kidneys, and balance the "yin" and "yang" in the human body. 56 today, it has become a popular food or food supplement in east and west. recent studies have confirmed the beneficial effects of wolfberry on human health, including anti-oxidative stress, anti-tumor, anti-radiation, anti-fatigue, antiaging, anti-inflammatory and immunomodulatory properties. 57 under optimized extraction conditions, the polysaccharide component is 23% of the cognac mass. 58 up to 95% of the lbp consists of glycans including glucose, arabinose, galactose, mannose, xylose, rhamnose, and fucose. 59 recent studies have found that water-soluble polysaccharides derived from hydrazine have an average molecular weight of 49.1 kda and an average protein content of 3.75%. the molar ratio of arabinose to galactose is 5.6:1. in addition, lbp is a highly branched polysaccharide with a backbone of (1 ! 6) galp linked galactose replaced by galactosyl or arabinose at o-3. 82 studies have confirmed lbp's beneficial effects on various diseases such as acute liver injury, 60 alcoholic liver injury, 83 and nonalcoholic fatty liver disease, 60,84 performance impairment, 85 brain i/r injury, 86 retinal degeneration, 82 stroke 87 and alzheimer's disease. 55,88 angelica sinensis (a. sinensis) ( table 3) is a well-known chinese herbal medicine that has been used as a nourishing and hematopoietic agent for the treatment of gynecological diseases 61 for thousands of years. recent studies have shown that polysaccharides in a. sinensis (aps) are the main bioactive components with various biological activities. 62 many asp polysaccharides have been identified from the roots of a. sinensis. their main structural features such as the monosaccharide compositions and molecular weight ranges have been summarized. 62 several components of asp are mainly composed of monosaccharides such as glucose, mannose, galactose, rhamnose, arabinose, and xylose. molecular weights range from 5.1 to 2300 kda. most of the polysaccharides isolated from a. sinensis reported in the literature are heteropolysaccharides. cao et al. 63 studied the structural characteristics of an anti-tumor polysaccharide named aps-1d isolated from a. sinensis. it was found that the backbone of aps-1d consists of α (1,4)-d-glucopyranosyl residues. branches consist of α (1,6)-d-glcp residues and terminating with β-larabinofuranose residues. in addition, some glucans are isolated and purified from a. sinensis. as-iiia with a m w of 850 kda from a. sinensis consists of α-(1 ! 3)-glucan. 64 it is also reported that a glucan from a. sinensis has an m w of 100 kda and consists of α-(1 ! 6)-linked glucose. 65 cao et al. 63 47 the immunomodulatory activity of asp has been extensively studied both in vitro and in vivo. it has been found that asp increases the proliferation of total spleen cells, macrophages, and t cells by primary activation of non-specific immunity and secondary activation of helper t cells. asp also enhances the gene expressions of il-2 and ifn-γ. 89 the anti-tumor activity of asp is revealed in that asp can significantly inhibit the proliferation of hela cells and lung cancer cells. asp also inhibits the growth of transplanted sarcoma-180 tumors in mice. 63 other biological activities have also been found in asp, such as hematopoietic activity, anti-oxidant activity, hepatoprotective activity, anti-osteoarthritis activity, 60 gastrointestinal protection 66, 90 and anti-diabetic activity. 47,66 cordyceps sinensis (table 3) , the chinese caterpillar fungus or dong-chongxiacao (winter worm-summer grass) in chinese or tochukaso in japanese, is a valuable traditional chinese medicine. c. sinensis has been used in china for >700 years, mainly as a tonic for nourishing the lungs and nourishing the kidneys. 91 modern pharmacological studies have shown that it has a therapeutic effect on a variety of diseases and conditions such as the respiratory system, kidneys, liver, nervous system and cardiovascular diseases, as well as tumors, aging, hyposexuality, and hyperlipidemia. [92] [93] [94] [95] [96] [97] [98] [99] since 1964, c. sinensis has been listed as the official pharmacopeia of the chinese ministry of health by the pharmacopeia and the chinese ministry of education's committee of herbs in the severe acute respiratory syndrome (sars) outbreak in china in 2003, with a significant increase in the use of c. sinensis. 100, 101 polysaccharides have become the target of the development and quality control of c. sinensis. and they can be classified into two types according to their position in fungal cells, intracellular polysaccharides (ipss) and extracellular polysaccharides (extracellular polysaccharides, eps). 68, [101] [102] [103] [104] [105] the monosaccharide composition is usually glucose, mannose and galactose in different molar ratios. different molecular weights have been found under various source materials and experimental conditions of c. sinensis, ranging from 1 to 1000 kda. 68, 100, [106] [107] [108] [109] [110] [111] recently, some water-soluble ipss isolated from cultured c. sinensis are identified as glucomannan, whose backbone is mainly composed of (1 ! 2) and (1 ! 4)-mannose, (1 ! 3)-galactose, (1!) and (1 ! 3,6)-the linkage of glucose. 100, 112 wang et al. 30 reported that the chemical structure of the isolated water-soluble polysaccharide (cps-2) is derived from cultured c. sinensis, which is mainly composed of α-(1 ! 4)-d-glucose and α-(1 ! 3)-d-mannose branched with (1 ! 4,6)-d-glucose every 12 residues on averages. 101 we found that salinity-induced antiangiogenesis activities and structural changes of the polysaccharides from cultured cordyceps militaris. 113, 114 based on the theory of traditional chinese medicine, the main role of c. sinensis is to "enrich lung yin and yang." its uses include treatment of chronic low back pain, colds, excessive mucus and tears, chronic cough and wheezing, and sputum caused by kidney yang (shenyangqu). according to western medicine, c. sinensis also has antibacterial activity, which reduces asthma, lowers blood pressure and enhances heartbeat. according to a large number of animal and clinical studies, polysaccharides represent a large class of biologically active components of c. sinensis, contributing to its health and pharmacological activity. the various biological activities and health benefits of ips and eps are summarized in table 3 . both ips and eps obtained from wild or cultured c. sinensis show immunomodulation, anti-tumor, anti-oxidant and hypoglycemic effects, as well as other important biological activities, including anti-fibrosis, anti-fatigue, kidney protection, increasing plasma testosterone levels, and radiation protection. 30, [69] [70] [71] [72] [73] 111, 113 ophiopogon japonicus (maidong in chinese) (table 3) , is a widely used traditional chinese herbal medicine (chinese pharmacopeia commission, 2015). according to traditional chinese medicine theory, o. japonicas can nourish yin deficiency, promote body fluid production, nourish the lungs, relieve the mind, and eliminate heart fire. o. japonicas is listed as an edible chinese medicine by the ministry of public health of china because of its high efficiency, high availability and safety. 112 to date, china food and drug administration (cfda) has approved patent drugs namely shen mai injection/granule, xuan mai gan jie capsule/granule, etc., which contain o. japonicas as the main medicinal ingredient. 74, 115 the polysaccharides, the main composition of o. japonicas with an extraction rate up to 35%. 75 the molecular weights of o. japonicas polysaccharides are inconsistent, ranging from 2.74 to 325 kda. in general, o. japonicus polysaccharide are mainly composed of β-fructose and a small amount of α-glucose. the backbone of ojp is formed by fru-β(2 !,!2)-fru-β(6 !,!6)-glc-α(1 ! and ! 1,2)-fru-β(6 !), and the molar ratios were 6.8:15.8:1.0:5.8. 75 o. japonicus is rich in polysaccharides, which are possibly responsible for its biological activities, such as anti-diabetic activity, cardiovascular protection, immunomodulatory activity, anti-oxidant activity, anti-obesity activity, therapeutic effect on sjogren's syndrome, etc. 74, [76] [77] [78] [116] [117] [118] [119] [120] bioactive polysaccharides from traditional chinese herbal medicines are well known. during the past few decades, considerable efforts have been dedicated to the development of bioactive polysaccharides from the traditional chinese herbs. the main focus of these studies has been the purification of the polysaccharides from the traditional chinese herbs, which are followed by monosaccharide compositional analysis, structural characterization and biological activity studies ( fig. 1 and tables 1-3 ). the polysaccharides from astragalus membranaceus, ginseng, lycium barbarum, angelica sinensis, cordyceps sinensis, ophiopogon japonicus have been systematically studied by many different research groups. both structural and biological information obtained are plentiful and accountable. the unique and distinctive monosaccharide compositions, structural diversity, and remarkable biological activities of polysaccharides from the traditional chinese herbs represent rich natural sources for drug development. the information reviewed here may be helpful in the definition of structure and function relationships necessary to design biological active polysaccharides with potential for the therapeutical use or to be used as ingredients in functional foods. both advantages and disadvantages of polysaccharides as drugs rely on its complicated molecular structures, multiple biological functions, and multiple molecular targets. thus, there is a great need for further clarifying the active ingredients in the polysaccharides and its molecular targets responsible for the observed drug effects. in addition, how to comprehend the pharmacodynamics of these polysaccharides, how to standardize the quality of polysaccharides, and how to perform reliable pharmacokinetic studies 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structure features and bioactivities a review on the isolation and structure of tea polysaccharides and their bioactivities salinity-induced anti-angiogenesis activities and structural changes of the polysaccharides from cultured cordyceps militaris polysaccharides purified from wild cordyceps activate fgf2/fgfr1c signaling antimicrobial activities of endophytic fungi isolated from ophiopogon japonicus (liliaceae) preventive effect of ophiopogon japonicus polysaccharides on an autoallergic mouse model for sjogren's syndrome by regulating the th1/th2 cytokine imbalance mdg-1, induces s1p1 and bfgf expression and augments survival and angiogenesis in the ischemic heart influence of sulfation on anti-myocardial ischemic activity of ophiopogon japonicus polysaccharide structure and antioxidant activity of polysaccharide poj-u1a extracted by ultrasound from ophiopogon japonicus preventive effects of ophiopogon-polysaccharide on apiponectin in gestational diabetes mellitus rat lentinan as an immunotherapeutic for treating lung cancer: a review of 12 years clinical studies in china chemical, biochemical, preclinical and clinical studies of ganoderma lucidum polysaccharide as an approved drug for treating myopathy and other diseases in china molecular basis for poria cocos mushroom polysaccharide used as an antitumour drug in china overview of ganoderma sinense polysaccharide-an adjunctive drug used during concurrent chemo/radiation therapy for cancer treatment in china grifola frondosa polysaccharide: a review of antitumor and other biological activity studies in china preclinical and clinical studies of coriolus versicolor polysaccharopeptide as an immunotherapeutic in china the authors declare no conflict of interest. key: cord-021179-sctzn7i7 authors: zhao, kejin title: china’s rise and its discursive power strategy date: 2016-07-04 journal: nan doi: 10.1007/s41111-016-0037-8 sha: doc_id: 21179 cord_uid: sctzn7i7 it is increasingly evident that china has attached more attention to discursive power in foreign policy since the early 21st century. both top leaders and government agencies have been active in advocating for a new discourse on various international occasions. previously, china has been reluctant to join the debate in international affairs, and been instead preoccupied with domestic affairs since the late 1970s. the situation has changed since 2009 because of china’s rapid rise to become the world’s second largest economy. with regard to the motivations behind the chinese government’s support for discursive power, the dominant explanation is based on the “rise of china” argument. however, this argument does not explain the causal relationship between china’s rise and its discursive power strategy. so, this paper aims to clarify the motivation behind china’s discursive power strategy through document reviews and interviews with mainstream scholars. it concludes that a discursive power strategy has been the fundamental principle of the communist party of china since its establishment in 1921. since china’s adoption of an opening-up policy in 1978, this tradition has been suppressed but not eliminated entirely by top leaders. as china continues to rise on the world stage, the principle will drive china to create a new political model rather than be a mere follower of the established political order. the politics of discourse is one of the most recent topics of debate among scholars of international relations, with increasing numbers of scholars around the world beginning to conduct international relations studies from a discursive perspective. in fact, discourse studies has been a very important part of the ir academic community since 1980, previously emerging from post-colonialism, and before that from postmodernism, all of which highlight discursive elements, such as culture, ideology and other norms, as a special kind of social power resource. these perspectives hold different views on power than established mainstream theory (foucault 1972b) . in western liberal societies, discourses of power are almost exclusively adversarial and based on social competition. power tends to be associated with competition at best or coercion and domination at worst. these alternative perspectives, however, suggest that the way we act in relation to a subject is not the most important thing, but rather it is how we think and talk about it, and who thinks and talks about it. regardless of other ideas about discourse, the idea of discursive power has already been popularized inside the academic community. nearly all powers, not only established powers such as the united states, but also emerging powers such as china, brazil and india, increasingly seek discursive power advantages through various means. in reality, china places more emphasis on discursive power than other states. as a rising world power, chinese leaders have paid much more attention to discursive power in international affairs. in particular, china frequently proposes international initiatives under the rhetoric of supporting the discursive power of developing countries. what is more, china takes seriously the reform of the imf, wto, world bank, etc., strongly challenging the so-called unfair international system dominated by western powers. 1 so, as a still-rising power, how china expresses itself will definitely determine its relationship with the established powers. although this paper focuses solely on china's perspective of discursive power, it remains relevant to the potential new international order (which will be determined by many players), because china, as a newcomer, believes that the established order was solely drafted by western powers. how china imagines the future and how it shapes the discourse of the future international order will absolutely impact the nature of its future interactions. based on these considerations, this paper focuses on china's discursive strategy and tries to explain briefly why china has such strong incentives to focus on this topic. this paper will ask how china understands discursive power, why china has placed it as one of its most important strategic pillars in the coming decades, and what china hopes to gain by doing so. in particular, the paper will challenge the dominant explanation of power transition theory, which sets out that china's discursive power strategy is just the result of china's rising power. on the contrary, its discursive power strategy is determined by china's new discourse domestically, rather than the new power structure internationally. the communist party of china has placed emphasis on international discursive power since its establishment. particularly for top leaders, discursive power is regarded as a significant factor in determining their political power distribution in the party. and chairman mao zedong pointed out that, ''he who is inferior to marx is not a marxist; he who is equal to marx is also not a marxist; only he who is better than marx is a real marxist'' (wang 1979) . keen to pursue discursive power, the cpc central committee established the principle of independence at the zunyi conference in january 1935, and decided to maintain a level of freedom of discursive power in the comintern. to dispel skepticism within the party about whether ''the people living in the mountain valley can produce marxism'', after the rectification movement in yan'an in 1941 the chinese communists took maoism as their guiding position and stood up to the soviet union, further pursuing discursive power. after the people's republic of china was founded, from december 1959 to february 1960 conversation to political economics of soviet union (excerpt), mao zedong pointed out more clearly that, ''the communist party of any country and the thinkers of any country must create new theories, write new books and have their own theorists'' (mao 1999) . to defend china's discursive power, china launched great debates with the soviet union around the principles of leadership of the proletariat, marxism, revisionism, etc., some of which contributed to some extent to the ultimate breakdown of the sino-soviet alliance. from the late 1970s, although china tried to maintain a low profile attitude of noninterference overseas, it still endeavored to develop discursive power domestically, and made efforts to improve its ideology and system of discursive power. after the great debate on ''standards for judging the truth'' in the 1970s, the overthrow of the ''two whatevers'', and the development of the idea of ''socialism with chinese characteristics'' (media research center of xinhua news agency 2008); additional systems of discursive power have been proposed and established, including the important thought of the ''three represents'', the ''scientific outlook on development'', ''harmonious society and harmonious world'', and the ''chinese dream'', each of which has furthered the domestic discursive power of marxism in china. in recent years, chinese leaders have increasingly emphasized discursive power at home and overseas. president xi jinping coined the chinese dream in late 2012 and launched a strong wave of campaigns for a new political discourse domestically and internationally. under the umbrella of the chinese dream, xi has also proposed multiple international initiatives, such as the one belt one road program and the concept of comprehensive security, a new type of international relations based on win-win cooperation and upholding justice while pursuing shared interests, since he came to power in 2012 (yang 2013) . all these initiatives can be regarded as china's endeavors for new discursive power domestically and internationally. china hopes to expand the influence of ''socialism with chinese characteristics'' abroad through strategic efforts to build discursive power, especially in order to delegitimize the ''china threat'' theory overseas, dispel the doubts of other countries caused by the rapid increase in china's economic capabilities, and fully integrate into the international community. however, there remain some inaccurate views about how to understand china's discursive power, and opinions are not entirely uniform. not only is the chinese leadership's description of discursive power vague, but there are also many differences between decision makers in diplomacy, propaganda, and foreign affairs, and between groups of scholars, especially since coordination and consultation mechanisms between various departments are not perfect. this produces a lot of paradoxical behavior on the issue of discursive power, causing confusion in the international community. specifically, there are currently five views about china's international discursive power: first, some regard discursive power as the ''right to speak'', deeming that as long as one has the right to speak, he will have discursive power. some articles interpret the so-called right to speak as the right to speak without real understanding, or even think that the ''right to speak'' is the right to be heard and ''have a say''. 2 these scholars, mostly from marxism studies within china, believe that the capitalist system dominates the international system and blocks opportunities for discourse for developing countries. so, china can upgrade its discursive power through consolidating its ideological domination around the world, 3 or through upholding a high level of confidence in its values, advancing its foreign language capacity, enhancing its international communication ability, explaining clearly the true meaning of the success of the chinese road to the world, enhancing the discourse around socialist core values at the international level, and demonstrating the true appeal of chinese values (yu and su 2015) . this opinion is flawed, as the moral critique of the western discourse is inappropriate because the discursive power of western countries is not only dependent on holding the monopoly right to speak. the core of discursive power consists of power relations, and the nature of discursive power is not related to any ''right'', but rather to ''power''. second, some equate discursive power with the ''power discourse'', deeming that as long as national strength increases, discursive power grows accordingly. considering modern china's experience of international political humiliation, most scholars of international relations adhere to the idea that backward nations tend to be disadvantaged at the hands of other states, and are unable to obtain significant discursive power (zhang 2009 ). such an opinion is common among chinese people. it inappropriately equates discursive power with the ''power to speak'', and deems that the key to china's discursive power is to enhance china's national strength, and that discourse is only the expression of power 4 (meng 2015) . in fact, there does not exist a correlation between discourse and economic or military strength. the militarily weaker party may have more ''right to speak'' than the militarily stronger party. the vatican, for example, is a ''state within a country'', surrounded by italy, but nobody will deny that it has more international discursive power than italy (knopp 1997) . third, some regard discursive power as the ''power of the media'', deeming that once you have the power of the media, you will master the ''right to speak''. a large number of scholars in journalism and communication believe that the ''right to speak'' is determined by whoever controls the media, and that china can obtain discursive power by strengthening the internationalization of chinese media 5 (bai 2015) . the group to whom the media belongs will naturally spread their discourse in the media. the most fundamental reason why china lacks international discursive power is because it does not control the media well enough (wang 2009; liu 2010; liang 2009; hu 2014) . however, discursive power does not depend on the media. a persuasive example is that despite the fact that the united states holds the world's largest media machine, and has significantly increased its output of media broadcasts to the middle east-persian gulf region since 2001, anti-american sentiment has risen rapidly in the middle east since 2001, and the ''right to speak'' of the united states in the region has been seriously damaged. 6 fourth, some regard discursive power as ''soft power'', deeming that discursive power depends on moral standards and cultural strength, and that as long as the country's culture and values are propagated, discursive power will be expanded. since joseph nye of harvard university first proposed the concept of ''soft power'', attention has turned from the tangible ''hard power'' of territory, armaments, military, scientific and technological progress, economic development, geographic expansion, military combat, etc., to the more intangible ''soft power'' of culture, values, influence power, ethics, cultural inspiration, etc. (nye 2004 (nye , 2008 . some scholars assume that there is a link between discursive power and soft power. they deem that as a country's moral standards rise, its ability to formulate discourse will also expand (gao 2007; tang 2008; zhao 2015; dai 2015) . needless to say, a country's cultural and moral level is an important component in international discourse, but cultural and moral development does not necessarily lead to the enhancement of a country's discourse. familiarity with a country's culture and history will not automatically translate into international discourse. transformation of a country's cultural soft power to discourse also needs a ''strategic pivot''. through diplomacy, trade, propaganda, international non-governmental exchanges and many other channels, and the integration of all aspects of cross-cultural and cross-border exchanges and the coordination of all resources, cultural soft power advantages could be translated into increased discursive power. fifth, some regard discursive power as ''diplomatic skill'', deeming that discursive power depends largely on political operations and idea contributions, and as long as a country enhances its diplomatic ability, discursive power can also be strengthened. some researchers of international relations and foreign affairs regard discourse as an important indicator of national diplomatic skills, analyzing the discourse issue under the backdrop of the rise of modern china, and considering it an integral part of its national grand strategy (d ' hooghe 2007 ' hooghe , 2010 ' hooghe , 2014 tan 2013) . 7 from this point of view, the core of china's discourse consists of political power, and, as china grows, it should be prepared to assume more international responsibility, adopt a more transparent foreign policy, focus more on relations with neighboring and european countries, and when strategic reputation and economic interests are in conflict, adopt the principle that economic interests are subordinate to strategic prestige (yan 2014) . 8 china only has two choices: china could become part of the western ''kingship'', but that means that it must change its political system and become a democratic country. another choice is to establish china's own system which appears to be the current direction of china's foreign strategy (yan and jin 2009 ). scholars make clear that china should be brave enough to challenge the universal values of the west and establish china's own discourse. 9 there are scholars who believe that international discourse reflects a country's ability to operate politically and contribute ideas. the ability to operate politically is mainly embodied in agenda-setting, rule-making capacity and international mobilization ability, while the ability to contribute ideas is mainly embodied in the ability to propose and promote new ideas and new concepts. to enhance china's international discursive power, we must greatly improve china's ability to operate politically and contribute ideas (xu 2009 ). this opinion captures the key point that the clearer the political goals, and the more mature the entire system, the greater the international discourse will be. however, limiting the scope of discourse to political and diplomatic factors may bring short-term enhancement of the discourse, but, in the long-term, leave it unable to be consolidated entirely. china does not only need to establish its discourse politically, but also economically, socially, and culturally, in order to consolidate its material foundation and social infrastructure. all of these misunderstandings are not only very common among the leaders but also among the public. the main problem is that understanding of china's discourse comes mainly from just a few considerations and does not convey the real meaning of the discourse, limiting the discourse's strategy and its implementation. the reasons why such cognitive confusions exist are mainly related to china's longstanding weak position in modern history and traditional chinese culture. its longterm weak position caused china to mistakenly believe that only as a country becomes strong will it have discursive power, regardless of whether or not it proposes a new discourse and whether the discourse itself is rational and legitimate. in addition, traditional chinese culture regards discourse as the monopoly of knowledge, morals and status, standards, and differences in science and technology levels and approaches to ethics between china and the west also limit the chinese understanding of the nature of discourse. discourse is a concept adopted by many post-modern thinkers such as michel foucault. from these thinkers' points of view, the discourse expresses power relationships and helps to build and maintain a certain social order, which is generally considered the order in keeping with the interests of those who are dominant (foucault 1972a (foucault , 1977 . discursive power consists of three elements: first, power facts are the fundamental base of discursive power. only those powers that can maintain and overturn the social order can obtain discursive power. he who controls the discourse also controls the reality created by the discourse. second, shared rules among various social groups are at the core of discursive power. language has its own rules and symbols, which are just a means of discourse, and their purpose is to create order. the key to taking control of discourse is to draft rules of priority in distributing resources-whether these rules are fully based on linguistic rules is not important. third, social practice is the pivot of discursive power. the intermediary link between power facts and shared rules is social practice. formation of discourse cannot be divorced from social practice, since social practice makes the discourse a reality. so, discursive power is some kind of relational power which derives from the positioning of social factors by specific, usually interactive, discourse practice. and discourse is based on specific rules and logic that in turn are based on power facts. it relies on social practice to achieve the connection between shared rules and power facts and, thus, forms specific power relations. from an international political studies perspective, the discursive power of a country primarily depends on particular social facts and whether the position of power is clear or not. if the position is not clear, then the foundation of power facts is not strong and so it cannot obtain international discourse. at the same time, a country's discourse is also subject to shared rules and social practices. if a country cannot establish shared rules reflected by its position in power relations effectively, it cannot reinforce the relationship between the discourse system and power facts, damaging the discourse. only by uniting shared rules and power facts with social practice, can a country garner greater international discursive power. the fact that china has recognized the importance of international discursive power is closely related to its accumulated economic gains attributed to the reform and opening-up policy. over the past three decades, sustained economic growth has greatly enhanced china's comprehensive national strength and continuously expanded its overseas interests. meanwhile, china's emergence has aroused worldwide attention; and during the last decade of the 20th century in particular, activities 10,11,12 (bernstein and munro 1997; chang 2001; bergsten 2008; rice 2008; ikenberry 2008; christensen 2011; johnston 2013) . among these opinions, some are well meaning, some are unfair prejudices and some are conspiracies concocted by certain countries to westernize china. therefore, casting as illegitimate the ''china threat theory'' is regarded as a long-term strategic task by china's senior governmental officials (li and lu 2001) . ever-changing international opinions have shaken deng xiaoping's ''non-dispute'' principle. a progressive china needs to establish its own international discursive power, and debates on this issue have been on the upsurge in different circles. for example, the linguistic field came up with the discursive power of the chinese language, the commercial industry appeals for discursive power on the issue of price, ideological sectors call for discursive power in promotion, and diplomatic organs want discursive power in formulating international political agendas, etc. (zhang 2008) . although some proposals may have distorted the original idea of discursive power by narrowing down or generalizing the original concept, it cannot be denied that chinese consciousness of international discursive power is growing rapidly, especially after its accession to the wto in 2001, when china successively won the right to hold the 2008 olympic games and the world expo 2010. chinese leaders have become increasingly aware that china should be accustomed to being the focus of international attention and should actively introduce the world to a more genuine vision of china, creating an objective international opinion about china and building an image of a responsible power 13, 14, 15, 16, 17 (hu 2012; jin 2011; liu 2007 liu , 2012 li 2006) . in particular, since xi jinping came to power in 2012, china has begun to increasingly highlight its discursive power strategy in governance, and has attributed ever-higher strategic significance to discursive power. besides strengthening international communications, china also emphasizes its influence in high technology, international institutions and other international affairs. 18 so, china has gradually formulated a strategy for discursive power that contains setting facts straight, innovating rules, and making breakthroughs in social practice. certain objectives for discursive power strategy are generally determined by a state on the basis of judgments about discursive facts. china used to be a nation endowed with strong international discursive power. five thousand years of civilization have created a rich culture, exerting a far-reaching impact on the discursive pattern of china's neighboring areas and the world at large. after the establishment of new china in 1949 and against the backdrop of the cold war, the international discursive power of china's revolution, relying on maoism and a series of both domestic and diplomatic strategies, was stressed by the world socialist camp and other developing countries. china's international discursive power was not challenged until the implementation of economic reforms and the opening-up policy. things started to deteriorate when china chose to join the international system dominated by western values. struck by the end of the cold war and globalization, china sank into a ''structural weakness'' on the issue of discursive power (zhang 2010) . besides, as china pursued the principle of ''keeping a low profile'' (taoguang yanghui) it remained silent on several strategic issues, which has greatly constrained china's discursive power and precipitated its struggle with three contradictions involving discursive pressure from both home and abroad. first, in terms of its economic system, china is facing discursive pressure about whether to position itself as a socialist or a capitalistic state. for instance, in the disputes over ''china's market economy status'', china has been under consistent discursive pressure from the international community. the reason is that china is a ''heterogeneous'' socialist country. 19 ever since the 1990s, the ''failure'' of the socialist camp has imposed unprecedented ideological pressure on china. western discursive attacks used terms such as ''grand failure'', ''collapse of china'', ''china threat'', ''china's responsibility'', and ''china's neocolonialism'', or the current ''assertive china'' and ''china's arrogance''. socialism with chinese characteristics has remained under high pressure from western discursive power (brzezinski 1989; chang 2001) . 20,21 for most western audiences, china is still regarded as an abnormal regime because of its socialist and authoritarianism system under the political leadership of the chinese communist party. not only is their economy still growing, it has been said, but also they violate their people's rightsthe ''butchers of beijing'' (barr 2011 second, in terms of social character, china is facing a discursive positioning dilemma-whether to be a developed or developing country. entering the new century, china has gradually grown into a new economic giant gaining worldwide attention. china's international status and influence are growing dramatically and due to certain development characteristics that are different from other developing countries, the international community has become skeptical of china's identity as a developing country and many developing nations no longer treat china as an equal counterpart. although china has initially taken on the shape of a giant country in light of its aggregated economic power, the size of the population has offset the significance of its gdp growth. it is hard for china's top leaders to persuade the domestic audience to acknowledge china as a developed country or to convince the international audience to identify china as developing country (pu 2012 (pu , 2014 . so, over the long-term china will remain a developing country as determined by its social development level and a great gap in per capita development level compared with developed states. there is a discrepancy between the characteristics of a superpower and of a developing country, driving china into crises of discursive rupture when expressing itself to the outside world (zhao 2010) . third, in terms of values, china is facing a discursive positioning dilemmawhether to recognize the so-called universal values or adhere to the chinese model. in the context of the current globalized world, the mainstream discourse is dominated by western values. although china is able to accept western ideologies and values concerning freedom, democracy, human rights and rule of law, it is unwilling to regard them as ''universal values'' and even explicitly rejects western ''universal values'' such as constitutionalism and judicial independence, let alone accept the individualism contained in this model. 22 in the eyes of some chinese scholars, china's model of development is breaking through the monopoly of western universal values and even has potential to go beyond western modernization 23 (zhang 2011 (zhang , 2014 . under the discursive pressure generated from these structural contradictions, china's strategy to enhance its discursive power has transformed from grassroots opinions to actual governmental actions. china's recognition of discursive power stemmed from anti-western sentiments fermented in the mid-late 1990s. from china wakes, and the china that can say no, to unhappy china published in 2009, it can be seen that a sense of nationalism has spread from the grassroots level to the academic and cultural field (song et al. 1996; li and kang 1996; ninget al. 1999; song and wang 2009 ). entering the 21st century, more and more scholars are showing a strong negative attitude to the hegemony of western discourse. they have launched debates in the academic community on ''universal values'' and ''the chinese model'' which encourage chinese academics to compete with their western counterparts for new political discourse 24 (chen 2010; zhang 2011 cpc national congress in 2007, president hu jintao for the first time elevated the promotion of china's soft power to a national strategic height, and formulated a key strategic objective to strengthen chinese culture's competitiveness overseas for the sake of winning international discursive power. 25 from then on, china has made it a strategic goal to enhance its discursive power by insisting on influencing the overall strategic situation on the basis of soft power. more significantly, china's new generations of top leaders insist that these ideologies shall be viewed under specific historical, social and cultural conditions, for example, the issue of human rights should involve concrete rights and specific content; abstract human rights applicable to the entirety of mankind shall never be accepted 26 . for president xi and his colleges, discursive power is regarded not only as an important part of the soft power of china, but also as substantial indicator for realizing the chinese dream. china will be great nation domestically and great power internationally. successive top leaders of the cpc have always paid significant attention to theoretical innovation as an important pillar to win political legitimacy. in december 1978, china's leader deng xiaoping put forward, ''when everything has to be done by the book, when thinking turns rigid and blind faith is the fashion, it is impossible for a party or a nation to make progress. its life will cease and that party or nation will perish'' (deng 1994a) . ideological emancipation, for the cpc, is the source of all energy, as well as the inexhaustible motivating force for the innovation of discourse. in terms of discursive rules, chinese leaders are more likely to use the concept of ''chinese characteristics''. at the opening statement of the 12th conference of the cpc on september 1st 1982, deng xiaoping pointed out: ''our construction of modernization must be approached from china's actual conditions. whether it is revolution or construction, we should pay attention to studying and learning from foreign experience, however, stereotyping the mode and experience of other countries will never be successful. in this regard, we have had many lessons. the need to combine the universal truth of marxism with china's specific reality and go our own way to build socialism with chinese characteristics, this is the basic conclusion we learn from historical experience'' (deng 1994b since the beginning of the 21st century, thanks to the iraq war and the global financial crisis, the ''washington consensus'' has suffered severely compared to the ''beijing consensus'' in the eyes of latin american and eastern and southern european states. the abuses and defects of neoliberal groups in the us and britain have increasingly been exposed, accelerating the decline of the united states model and the rise of chinese social discursive power (ramo 2007 in 2008, after the international financial crisis, the chinese economy continued to develop and boom. in 2010, its gdp overtook japan's, and china became the world's second biggest economic power. the rise of china's comprehensive national strength has boosted chinese leaders' confidence in the improvement of china's discursive power. at the 17th plenary session of the central committee held in 2010, hu jintao put forward ideas about global ideological communication, interaction, and confrontation as the new characteristics of china's discursive power. he also realized that this was an important period of strategic opportunity for china, in which china should move forward to a new historical period. 28 therefore, from the long-term perspective of china's senior leaders, it is possible to face some competition from different models or actors during the process of practicing and advancing the grand reform and opening-up strategy. at this point in time, china should develop and improve its international influence and the appeal of the chinese model and constantly enrich its meaning and competitiveness. since 2012, xi jinping and other top leaders have paid much more attention to discursive power internationally and domestically. president xi proposed the highprofile concept of the chinese dream, which he markets frequently during his visits abroad. xi, to some extent, has given up the previous guideline of keeping low profile on foreign affairs, and is instead striving for achievements (yan 2014) . the new leaders have presented a succession of strategic ideas under the umbrella of the chinese dream. in his clarification on the 13th 5-year plan to the cpc central committee in 2015, xi stated clearly that the future of competition in comprehensive strength among nations will definitely be determined by the effectiveness of a country's innovation systems. so, in the coming decades, china should focus on strategic innovations and upgrade its scientific innovation capabilities, using national standards, and international discursive power. 29 all these endeavors demonstrate that discursive power has already become one of the important components of china's grand strategy. improving a country's international discursive power involves a combination of power facts and the shared rules system in practice. it includes promoting the national capacity for shaping and even solidifying the international diplomatic arena. for china, its diplomacy will meet unprecedented challenges if and when a clash occurs between the chinese model and western ideals of universal values. chinese leaders have begun to implement china's discursive power strategy on the international stage since 2003, and may face a number of international expectations and/or misunderstandings about china as a result. chinese leaders promoted debate about ''china's peaceful rise'' at the international level in 2003, in the first attempt to break through deng xiaoping's ''non-dispute'' principle since the in the 1980s. the core force behind this debate is 28 many chinese scholars and analysts question the meaning and accuracy of these new words. some international observers also note some of their shortcomings, for instance arguing that the term is ambiguous, and may contradict with the peaceful resolution of the taiwan issue (glaser and medeiros 2007) . many people doubt that china can ''rise'', believing that china's multiple economic and social problems impede its rise, and will interrupt its progress in becoming a powerful state. they insist that ''rise'' is an optimistic portrayal of china's current social and economic development. 35 others oppose the idea because of its meaning of ''power transfer''. they believe that using this terminology to relieve tensions with neighboring countries cannot help in practice (yan 2004 ''peaceful rise'' is provocative, and can be easily misinterpreted as meaning that china is keen to reach for hegemony like united states, and is trying to expand. in particular, many leaders of china's neighboring countries have expressed varying degrees of concern. among this group, the most typical viewpoint expressed is that of former singaporean prime minister lee kuan yew, who believes that asia-pacific countries welcome china's prosperity and development, but are also concerned about their own national security. 36 in ''. 41 at that point, the mantra of ''stick to the road of peaceful development, and build a harmonious world of lasting peace and common prosperity'' became the guiding principle in china's strategy to improve its discursive power, and has since been regularly expressed in the g20, apec and other united nations international forums. since 2012, president xi jinping and other top leaders have also stuck to the fundamental principle of the path of peaceful development. however, xi increasingly highlights china's core interests. particularly on taiwan, tibet, xinjiang and human rights issues, the new generation of leaders adopts a strong position towards the international community. meanwhile, china begins to be more proactive on island and maritime disputes with neighboring countries. china shows a strong attitude to japan over the diaoyu islands dispute, and has established an air chin. polit. sci. rev. (2016) 1:539-564 553 defense identification zone over the east china sea, created the sansha municipal city under the jurisdiction of hainan province and launched island constructions over the south china sea. all these behaviors were previously unimaginable, and have also been criticized by some stakeholders. besides, china has become more active in developing many international economic institutions such as the brics development bank, the asian infrastructure investment bank and the silk road fund, etc. more and more scholars and experts believe that china will challenge the existing international order, and will become another world superpower (johnston 2013; pettis 2013) . in fact, this may be the inescapable result of china's advocacy for international discursive power. in china's institutional context, there are many tools available within the political, economic, cultural, and educational sectors, as well as among social actors, to implement china's discursive power strategy. after the establishment of the prc, all of these actors were required to follow the guidelines drafted by communist party of china as the only ruling party in china. in reality, these actors did not have enough autonomy in decision-making processes. however, after the opening-up policy began in the late 1970s, the situation changed. it has become increasingly evident that more and more players are becoming involved in the game, as china increasingly integrates into a globalized world. among participants in the implementation of discursive power strategy, the politically stronger propaganda sector has played a more significant role than the diplomatic sector. traditionally, ideological work is unified under the leadership of the small leading group of publicity and ideological & political work, which is the decision-making advisory and coordinating body for publicizing the ideological work of the political bureau of the cpc central committee, and an ad hoc organization subordinate to the political bureau. in addition, its members are often indeterminate, and include principals from the main divisions of the party, government and publicity. they are usually constituted by the head of the publicity department of the cpc central committee, the director of the state council information office, the minister of education, the minister of culture, the director general of international radio, film and television, and so on. moreover, the group is attended by principals from the xinhua news agency, people's daily and other relevant departments, who perform the functions of coordination, communication, decision making, deployment and monitoring the implementation of foreign policy and the relationship between the standing committee of the political bureau and the propaganda departments of the party and government. this group is rarely exposed in the media and highly secret in its work procedures, but it regularly convenes meetings and performs unified management over propaganda, ideas, culture, ideology, spiritual civilization construction and other areas. to strengthen ideological leadership, in 2003 the cpc central committee nominated mr. li chuangchun, in charge of ideological work, for full-time membership of the standing committee of the political bureau. this nomination makes the ideological leadership team even more powerful, and the ideological leadership more vigorous in china's political system because the standing members of the political bureau hold the most powerful position in china's political decision-making process. therefore, the mechanism of ideological leadership in china has been strengthened, and many interviewed media professionals have expressed strict control of public opinion since 2003. in china, most media organizations are state owned media and controlled strictly by the party and government. so, it is impossible for mass media to violate the directions from central government, with very few exceptions such as nanfang zhoumo and other liberal media. from the beginning of the reform and opening-up era, the chinese government has strengthened its overseeing and manipulation of mass media reports to manage mainstream public opinion and consolidate domestic discursive power. the real challenge to china's discursive power strategy is from the cyber sphere. as a milestone, china gained access to the international internet in 1994 and began to be an important player in the cyber sphere. in 2014, there were more than 648 million active internet users, 331 million internet protocol addresses, near to 20 million domain names, and 3.35 million websites in china. 42 over the past 20 years, china has become the world's number two cyber power. however, there were more than 16 agencies involved in internet managerial affairs and no unified managerial system for cyber affairs before may 3rd 2011, when the state council decided to set up the state office for internet information. to strengthen the management of cyber and information security, the third plenary session of the 18th central committee of the cpc in 2013 made the decision to upgrade the internet leadership and managerial system. so, on february 27th 2014, the central internet security and informatization leading group was established, and president xi jinping was appointed as its director. as the working office, the state office for internet information provides staff and other coordinating services. with the establishment of these strong organs, china began to strengthen its management of cyber affairs. on july 6th 2015, the first draft of the cyber security law of the prc was published to invite suggestions for revision from public opinion. the draft indicates that china wants to consolidate discursive power on cyber security domestically, and that china will become more active in participating in international cyber security dialogue, and seek more international discursive power on cyber affairs. typical examples include the election of mr. lu wei, director of state office for internet information, and jack ma, president and ceo of alibaba networking technology co., as members of the global internet governance alliance, and the selection of jack ma as co-chairman of the global internet governance alliance council in 2015. another important tool for china's discursive power strategy is external publicity. in china, external publicity is an overall, strategic project as well as a vital part of its entire management of foreign affairs. since 2002, external publicity has become an important pillar of china's discursive power strategy, and china has invested increasing amounts of resources in international communication and promotion. after china's accession to the wto in 2001, china's leaders soon felt pressure from international public opinion. during the sars epidemic of 2003, china experienced pressure from overseas public opinion for the first time, 43 and the formulation of an external publicity strategy to cope with the pressure of international public opinion became an important part of china's diplomatic strategy. on september 19th 2004, the resolution of the fourth session of the 16th plenum of the central committee of the communist party of china (cccpc) explicitly identified a new phase in the international community's attention towards the country, and said that it must be responded to properly by strengthening and improving external publicity work, actively carrying out international cultural exchanges to promote good international opinion environment further, and forming an international consensus environment which is beneficial to china's development. 44 this marked the first time that the cccpc clearly proposed the idea of building an international consensus environment. from that point on, the central committee expressly treated the creation of an objective and amicable consensus environment as one of the working focuses of its new phase in foreign strategy. on january 4th 2010, mr. li changchun, one of the members of the standing committee of the political bureau of the 17th cpc central committee, emphasized at the national ministerial conference for communication that we must make new achievements on the publicity, ideological and cultural fronts by promoting our international communication capacity, holding discursive power and taking the initiative around the world. 45 that was the first time that chinese leaders combined external communication with discursive power, and showed that they clearly regarded external communication as a strategic tool for promoting discursive power. in addition, at a national conference on publicizing china overseas held in january 2010, mr. wang chen, head of the international communication office of the cpc central committee, who holds special responsibility for international communication, emphasized during his talk that, in order to perform well in communication work in 2010, we needed to plan both the domestic situation and international situation as a whole, to hold discursive power, to take a leadership role, to promote our international communication ability and 43 jakes, susan. endeavor to match the power of china's international voice with its economic and social development level and international status. 46 therefore, the promotion of china's international voice has become a function of china's international communication departments and has been included in china's international communication systems. li changchun's successor, mr. liu yunshan, a member of the standing committee of the political bureau of the 18th cpc central committee, also highlights discursive power through international communication. in china's international communication system, media plays a more significant role than diplomacy. for the media, drafting reported news and publicizing detailed facts are the first priority, and act as a means to advance their position in the chinese political system. since 2003, china has created a favorable situation of solid progress and vigorous development in external publicity, with its contents and scope continuously expanded, its method and meanings improved, and its institutions and mechanisms boldly upgraded. under the leadership of the foreign publicity leading group and the china central publicity department, china mainly relies on the mainstream media to carry out public outreach. this includes china radio international, china central television, xinhua news agency, people's daily, china daily, global times and other mainstream media. in 2002, china began the implementation of policies for the radio and television ''go out project'' and vigorously promoted the use of radio, television, cultural enterprises and products to project china's message. named the ''voice of china'', china radio international makes great efforts to strengthen its global coverage, and it falls to china radio international to broadcast all over the world. currently, there are 43 languages (38 foreign languages and chinese in four kinds of dialects) used to broadcast around the world. by the end of 2014, cctv had 14 international channels, overseas landing operations around the world, cooperation with more than 400 local media organizations, and a total of 392 channels in 141 countries and regions. and total channel users are projected to number about 170.92 million. this covers nearly 4/5 of the population around the world, and broadcasts timely news coverage from around the world, making china's voice heard through daily reports and coverage of major events and global issues. in addition to relying on domestic media, the chinese government has also been paying increasing attention to the use of foreign media, especially since the 2008 olympics greatly promoted the process of incorporating international media into china. before the beijing olympics, the chinese government relaxed control measures for foreign journalists and media so as to give more coverage by foreignowned media. during their major visits abroad, chinese leaders accept media coverage, publishing articles in foreign media, holding press conferences, interacting with the countries' local population, setting up information centers, and explaining complex theories in simple language to expound china's policy stance. this has made china appear more cooperative and responsible, resulting in a better image. before the state visit to the united states on january 17th 2011, president hu 46 2010. national working conference on external publicity has deployed external publicity work this year (quanguo duiwai yichuan gongzuo huiyi bushu jinnian waiyi gongzuo. xinhua news agency. http:// www.gov.cn/jrzg/2010-01/05/content_1503803.htm.. chin. polit. sci. rev. (2016) china has also increasingly emphasized the importance of network information management. not only have government departments set up websites, but the media has also been encouraged to set up websites. more and more focus has been placed on mobile phones, blogs, micro blogs, social media and other new media outlets, and these efforts have had a profound impact on chinese communication. generally, mass media is usually more radical than the government on public policy and tries to play the role of watchdog of public interests and works as criticizer to oversee government officials. however, under the guidelines of china's news rules, chinese media usually reports foreign policy strictly following ministry of foreign affairs (mofa) regulations and never challenge official statements. in china, media is the best friend of diplomats, and some diplomats are even former journalists. the situation has changed since the 2003 campaign for dealing with the sars virus. in that campaign, the chinese media began to play more radical role in foreign policy than ever before. it was permitted to disclose concealed details and even to criticize government officials. since then, the chinese media has gained more freedom to report on international affairs, and some media organizations have also began to conduct more ambitious strategies of internationalization, which is encouraged by the government. therefore, compared with the western media's mission of reporting facts, chinese media takes on the task of advancing china's discursive power and soft power abroad. so, what chinese media really cares about is not being recognized by others but gaining the legitimacy to lead the chinese discourse. essentially, what china wants is not only to be acknowledged as a great economic and military power, but also to be recognized as a super power in values, norms and other soft resources. public diplomacy is a vital tool to enhance chinese discursive power. as a matter of course, china's awareness of public diplomacy follows an unconscious-toconscious process. at the start, there was no idea about public diplomacy in chinese foreign diplomacy terminology-it was imported from western world by some scholars in the early 1990s, when they introduced diplomatic studies to china. however, these endeavors were not acknowledged by the party and government leaders. and they still used similar words, such as external publicity (duiwai xuanchuan) and people-to-people diplomacy (minjian waijiao), to describe formal communications between china and overseas audiences (lu et al. 2007) . the situation was changed by the september 11 incident, because the united states began to identify the emergent significance of public diplomacy. affected by the ever-increasing attention paid to public diplomacy by the usa after the 9/11 incident, the chinese foreign ministry also incorporated public diplomacy into their foreign affairs. starting from 2002, china foreign affairs university conducted a training program for junior officials, which included public diplomacy as an important component of the program and invited some professors to join the discussions. in 2003, the foreign ministry established a public diplomacy division under the information department, which took charge of china's public diplomacy. from the beginning, this division has usually dealt with communication matters such as open day events, internet management, news briefings and interviews by foreign journalists. for example, foreign ministers and top leaders usually have dialogues with the general public domestically and internationally through public speaking, interviews, online discussions and drafting articles in newspapers of other countries. in recent years, president xi jinping and primer li keqiang have become more active in publishing newspaper articles during their visits abroad. these endeavors can be regarded as chinese public diplomacy for new discourse. in 2009, president hu jintao mentioned public diplomacy, and people-to-people as well as cultural diplomacy, for the first time in a very important meeting, highlighting the significance of public diplomacy in china's foreign affairs. this statement is regarded as a milestone in china's public diplomacy efforts. since then, more and more top leaders, government agencies and even social actors have joined in the development of public diplomacy. a typical example is that mr. zhao qizheng, the director of the foreign affairs committee of the cppcc from 2008 to 2013, led a big campaign for public diplomacy studies. other important leaders like china's state councilors, foreign ministers and culture ministers are also actively involved in developing public diplomacy, in order to create new discourse within the international community. more substantially, as an institutional innovation, the ministry of foreign affairs established a new public diplomacy office as an alternative to the public diplomacy division of the information department. this change indicates that public diplomacy is the mandatory duty of all officials in the ministry of foreign affairs (mofa) and its embassies and posts abroad, rather than just as the responsibility of the information department. as a result, chinese ambassadors are required to make public lectures, accept media interviews, have dialogues with local communities, etc. mofa has also established a coordinating mechanism among various ministries and agencies involved in foreign affairs, and has set up an advisory commission on public diplomacy with responsibility for evaluating the performance of chinese public diplomacy. besides mofa, other institutions including the ministry of education, the ministry of culture, the ministry of commerce, and even local governments have also joined the public diplomacy team. confucius institutes, chinese culture centers, the beijing olympic games, the shanghai expo and other efforts can be seen as excellent examples of chinese public diplomacy programs. all these efforts, in the eyes of china's top leaders, are conferred same strategic mission of telling china's story to the world and enhancing the chinese voice within the international community (kurlantzick 2007) . particularly since the 18th congress of the communist party china, under the leadership of president xi jinping, china has launched a new wave of charm offensive campaigns worldwide, including first lady diplomacy, which are more progressive than before. all these efforts are intended to defend chinese discourse and china's political system, and enhance the chinese dream abroad. in addition, the chinese government conducts public diplomacy activities in the military, trade and academic fields, adding to china's image by means of practical actions. many overseas economic activities such as the one belt one road initiative, the new model of big power relationships, and the aiib indicate increased foreign promotion activities, and are trying to express china's intentions and interests by internationally adopting this widely used public relations tool. behind these efforts, china's top leaders just want to win discursive power on the world stage. and this mission has been clear and consistent from the beginning of china's advocacy of public diplomacy. since the end of the cold war, influenced by the termination of the war and the tiananmen events, china has been treated negatively as a red and dangerous country (bernstein and ross 1997; bork and ding 2000) . 48 however, the international department of the british broadcasting corporation (bbc) has investigated the image of various countries in global public opinion since 2005. the results show that china's national image has been consistently rising in the minds of people around the world. within the sample under investigation, there was no country in which the number of people with a negative attitude towards china exceeded 50 % among the total responses; instead, the number of people bearing the opinion that china has had an active and positive impact on the world exceeded those of the us and russia. 49 similar results have been obtained from many civil investigation institutions such as the pew center. according to the pew center's latest report, china is viewed positively and has good image in 19 of 38 nations. china wins its highest ratings in africa (70 %), asia pacific (57 %), latin america(57 %)and predominantly muslim middle eastern nations (52 %). however, china is seen less positively in much of europe and north america. in the us, less than 40 % have a favorable view. how could all of these be possible? in terms of power transition, china has seen an evident rise in economic and military power, but such a rise has not changed the power relationship between china and western countries, especially between china and the us. the rise in china's power does not bring an underlying motive for structural change, and it is impossible to generate fundamental change in international public opinion from power transition. rather, china's success depends more on china's foreign strategy. instead of the ''exporting revolution'' emphasized during the mao zedong times, what china advocates nowadays is non-interference with the domestic affairs of other countries, including the provision of assistance without any additional political conditions, which provides quite a different development model from western countries. all these factors have formed an evident contrast with foreign policies conducted by the us over many years, including humanitarian intervention, development assistance with additional conditions regarding human rights and good governance, as well as aggressive diplomacy including alliance strengthening and regime change. in addition, in the views of international society, and especially those of emerging economies and developing countries, the chinese development model has significant differences from the washington consensus model that is consistently promoted by the us, representing two alternative types of development route. however, the iraq war in 2003 and the world financial crisis in 2008 crushed the development model led by the us and shook the us' international leadership in discursive power, hence, china's discursive power obtained great benefits. meanwhile, the improvement in china's image has also resulted from the success of china's diplomacy. since 2003, the change in china's diplomacy has been mainly demonstrated in its establishment of the strategic route of peace and development. different from the western strategy of showing off their hard power, china has paid great attention to adopting strategic planning that focuses on enhancing its soft power while developing its hard power, taking a series of new measures in fields including ideology, external publicity and public diplomacy, and bringing forward a whole new set of discursive systems which are largely different from previous systems. the discursive system brought forward by china did not comply fully with the western system, and instead raised a new system in comparison with the western model. on 11 may 2004, mr joshua cooper ramo, senior consultant at goldman sachs and adjunct professor of tsinghua university, published a research report named the beijing consensus through the uk-based think tank the foreign policy centre, which triggered heated discussions about the chinese model in international society (ramo 2004) . chinese scholars have started lively debates on ''universal values'' and the ''china model'' since then. it is evident that china does not acknowledge the western concept of universal values, but instead seeks a chinese discourse based on long history and great legacy of civilization. this motivation is expressed clearly in xi jinping's proposal for the chinese dream. this slogan indicates that china will not only be great power in material capabilities but be great in discursive power as well. with china's continuous rise on the world stage, the principle will drive china to create a new political model, rather than just follow the established political order. let's cooperate with china. the washington post the rise of china's soft power work together to create a new situation in sino-russian economic and trade cooperation (xieshou kaichuang zhonge jingmao hezuo xin jumian). people's daily speech at the ministerial mialogue of the stockholm ? 40-partnership forum for sustainable development in stockholm (zai sidege'ermo ?40 kechixu fazhan huoban luntan shang de jinhua) carry forward traditional friendship and jointly open up new chapter of cooperation (hongyang chuantong youhao gongpu hezuo xinpian) jointly build partnership for bright future (gongjian huoban guanxi gongchuang meihao weilai) jointly build new future of china-latin america comprehensive cooperative partnership (gongchuang zhongla quanmian hezuo huoban guangxi xin welai) strategic analysis of chinese media seizing international discursive power (huawen meiti qiangduo guoji huayuquan celüe fenxi) who's afraid of china? the challenge of chinese soft power a partnership of equals: how washington should respond to china's economic challenge the coming conflict with china the chinese dream at the other side of the ocean-view of china from us the grand failure: the birth and death of communism in the twentieth century the coming collapse of china effectively coping with the challenge of western discourse hegemony (youxiao gai dui xifang huayu baquan). seek truth magazine 10 the advantages of an assertive china: responding to beijing's abrasive diplomacy forging china's discursive power from ideas and values (cong yisi he jiazhiguan shang dazao zhongguo yuhuaquan) emancipating the mind, seeking truth from facts, looking ahead with solidarity (jiefang yixiang, shishi qiu shi, tuanjie yizhi xiangqian kan) the opening remarks on the 12th national congress of cpc (zhongguo gongchandang di shier ci quanguo daibiaodahui kaimuci) the rise of china's public diplomacy. the hague: netherlands institute of international relations the limits of china' s soft power in europe: beijing's public diplomacy puzzle. the hague: netherlands institute of international relations. clingendael. d' hooghe, ingrid. 2014. china's public diplomacy china's road under the shadow of globalization archeology of knowledge two lectures discipline and punish: the birth of the prison cultural power (wenhuali) the change ecology of foreign policy-making in china: the ascension and demise of the theory of ''peaceful rise firmly march on the path of socialism with chinese characteristics and strive to complete the building of a moderately prosperous society in all respects (jianding bu yi yanzhe zhongguotese shehuizhuyi daolu qianjin, wei quanmian jiancheng xiaokangshehui er fendou) national soft power in the age of the internet: how to improve the discourse capability of china in the international arena the rise of china and the future of the west big power's responsibility (daguo de zeren) how new and assertive is china's new assertiveness? vatican: the power of the papacy (vatikan: die macht der paepste) charm offensive: how china's soft power is transforming the world guarding against and preventing from the western hostile forces' conspiracy to westernize and separate china promoting harmonious culture and developing socialism arts (dalituijin hexie wenhua jianshe, fanrong fazhan shehuizhuyi wenyi) behind the demonizing china (yaomohua zhongguo de beihou) on the international discourse and the chinese idea of expanding the international discourse the way to be responsible power on first-class media and china's voice era an introduction of foreign diplomacy deeply promoting publicity and explanation for party theoretical innovation and creating good opinion environment for 18th party congress (shenru tuijin dangde lilun chuangxin chengguo yichuan chanshi, wei dangde shiba dazhaokai yingzao lianghao sixiang lilun fenwei) the textbook of political economics of soviet union (excerpt) deng xiaoping's press campaign people's daily nye soft power: the means to success in world politics the great rebalancing: trade, conflict, and the perilous road ahead for the world economy limited rebranding: status signaling, multiple audiences, and the incoherence of china's grand strategy status signaling, multiple audiences, and china's blue-water naval ambition the beijing consensus. london: the foreign policy centre brand china. london: the foreign policy centre rethinking the national interest american realism for a new world the china that can say no: political and emotional choices in the post cold-war era unhappy china-the great time, grand vision and our challenges struggle for international discourse power: top-level design for china's public diplomacy (guoji huayuquan jingzheng: zhongguo gonggong waijiao de dingceng sheji). teaching and research cultural soft power strategy (wenhua ruanshi lizhan lüe yanjiu) building world-class media and actively seek international discourse (jianshe guoji yiliu meiti, jiji zhengqu guoji huayuquan) in selected works of eighty-five anniversary of the birth of comrade mao zedong (mao zedong tongzhi bashiwu danchen jinian wenxuan) political operation, ideas contribution ability and international discourse (zhengzhi caozuo, linian gongxian nengli yu guoji huayuquan) peaceful rise and maintaining peace: china's peaceful rise strategy and tactics (heping jueqi yu baozhang heping: jian lun zhongguo jueqi de zhuanlüe yu celüe) thought of world hegemony and its enlightenment (wangba tianxia sixiang ji qidi) from keeping a low profile to striving for achievement china's innovations in diplomatic theory and practice under new situation (xin xingshi xia zhongguo waijiao lilun he shijian chuangxin). seeking truth magazine 16 adhering to the socialist core values and the enhancing of the international discourse right (shehuizhuyi kexin jiazhiguan de jianshou yu guoji huayuquan de tisheng) some ideas on discursive power (guanyu huayuquan de jidian sikao). seeking truth magazine 9 china's diplomacy enters an era marked with surging discourse awareness (zhongguo waijiao jinru huayuqian yishi gaozhang shidai). window to the south 6 the china wave: the rise of a civilizational state (zhongguo zhenhan: yi ge wenmingxing guojia de jueqi) china's transcendence (zhongguo chaoyue) quality of discourse: key for enhancing international discursive power (huayu zhiliang: tisheng guoji huayuquan de guanjian) china's rise and its foreign strategic readjustment (zhongguo jueqi yu duiwai zhanlüe tiaozheng) we need to convey the concept of ''he'' to the world (xiang shijie chuanbo hezhuyi) kejin zhao is associate professor in the institute of international studies and director of center for statecraft and public diplomacy at tsinghua university, as well as a senior fellow at the chahar institute key: cord-290412-m6fesoyb authors: zhao, chang-qing; zhou, yang; ping, jian; xu, lie-ming title: traditional chinese medicine for treatment of liver diseases: progress, challenges and opportunities date: 2014-09-30 journal: journal of integrative medicine doi: 10.1016/s2095-4964(14)60039-x sha: doc_id: 290412 cord_uid: m6fesoyb abstract traditional chinese medicine (tcm) is commonly used in treating liver diseases worldwide, especially in china. the advantages of using tcm for treatment of liver diseases include: protecting hepatocytes, inhibiting hepatic inflammation and antifibrosis in the liver. in this article, we introduce tcm herbal preparations from the chinese materia medica (such as fuzheng huayu) that are typically used for the treatment of liver diseases. literature surrounding the mechanisms of tcm therapy for treatment of liver diseases is presented and discussed. we propose that side effects of herbal compounds are often under-appreciated, and that more care should be taken in the prescription of potentially hepatotoxic medicines. further, to deepen the understanding of tcm mechanisms, new techniques and methodologies must be developed. future studies will lead to the enhancement of clinical outcomes of tcm. as complementary and alternative therapies, tcms will play an expanding role in the future of liver disease treatment. in china, traditional chinese medicine (tcm), especially traditional chinese patent medicine, has been, and continues to be widely used to treat various diseases. even during the severe acute respiratory syndrome (sars) outbreak in 2003, tcm, combined with western medicines were used to control and eventually halt the spread of the disease. compared with western medicine alone, patients receiving treatment with western medicine and tcm had reduced hospital stays, pneumonia duration and mortality. early tcm treatment can also decrease glucocorticoid dosage needed in the treatment of sars [1] . before western medicine was introduced into china, the chinese health care system mainly depended on tcm. although tcm does not treat specific conditions, it treats patterns of illness such as those associated with infectious diseases [2] [3] [4] , cardiovascular and cerebrovascular diseases [5] [6] [7] [8] [9] [10] [11] , respiratory diseases [12] [13] [14] , digestive diseases [14] [15] [16] , urinary diseases [17] [18] [19] , reproductive diseases [20] and blood system diseases [21] , as well as fractures [22] , trauma [23] , ear, nose and throat diseases [24, 25] , skin diseases [26] and mental disorders [27] . tcm can improve the clinical symptoms, reverse some pathological changes and restore traditional chinese medicine for treatment of liver diseases: progress, challenges and opportunities the body's normal physiological function. since western medicine was introduced into china in the 16th century ce, most diseases listed above are treated mainly with western medicinal interventions. gradually, tcm has become an alternative medicine rather than mainstream medicine. even so, tcm therapy still has its advantages in some medical fields where western medicine has not been as effective, such as in liver diseases. this review will introduce tcm in the treatment of liver diseases. liver diseases are mainly classified into viral hepatitis, nonalcoholic fatty liver, alcoholic liver disease, autoimmune liver disease, schistosomiasis liver disease, drug-induced liver injury, hereditary liver disease, liver cirrhosis due to various causes and diverse liver tumors. tcm is widely applied in the treatment of liver diseases in china by both chinese medicine doctors and western medicine doctors because its ability to protect hepatocytes, inhibit hepatic inflammation and reduce fibrosis in the liver. in recent years, the application of tcm in liver cancer treatment has been increasingly widespread [28, 29] . it has been confirmed that tcm can not only reduce the toxic side effects of chemotherapy or radiotherapy, but also inhibit tumor growth and increase survival of patients with tumors [30] . although tcm has many uses in treating liver diseases, it cannot replace other treatment methods such as antiviral drugs, hormones, schistosomicide, surgical operation and transplantation. tcm can be applied to treat diseases in one of the two ways: treatment based on disease differentiation or syndrome differentiation [31] . for the disease differentiation approach, western medicine methods are typically employed to diagnose specific liver diseases. subsequently the appropriate tcm formula or patent drug is selected to treat the disease according to tcm's characteristics and advantages. the evaluation of the curative effect is based on the recovery of liver function or improvement in pathological changes. in the syndrome differentiation approach, tcm diagnosis of a patient's symptoms and signs is used to determine to which syndromes the patient belongs. the appropriate tcm formula or patent drug is then chosen to treat that tcm syndrome. the evaluation of the curative effect depends on the relief or elimination of the symptoms and signs. it is believed that the combination of two kinds of therapies can obtain greater curative effects for liver diseases [32] . 3 chinese materia medica is frequently used to treat liver diseases in acute stage of liver diseases, liver inflammation is prominent. materials listed in the chinese materia medica, especially those for heat-clearing and detoxifying, are often applied to protect the liver, inhibit inflammation, decrease activity of serum transaminase and reduce serum bilirubin [32] . meanwhile according to the symptoms and signs of each patient, a matching therapy, such as adjusting yin and yang, invigorating qi and blood, soothing the liver, regulating qi, clearing heat and removing dampness, is also applied. in the chronic stage of liver diseases, the symptoms of the disease are more complicated. treating the source of the disease (i.e., the virus) is one important and necessary approach. western medicine does well in inhibiting the viruses that cause hepatitis b (hbv) and hepatitis c (hcv). tcm has little effect in inhibiting the virus, but works well to protect liver function, inhibit inflammation, decrease activity of serum transaminase, reduce serum bilirubin, lower lipid levels [33] , promote diuresis [34] and relax the bowels [35] . depending on the stage of liver disease progression, or different syndrome classifications, tcm can be used to adjust yin and yang, invigorate qi and blood, sooth liver, regulate qi, clear heat and remove dampness [36] [37] [38] . zhang et al [39] summarized and provided a critical meta-analysis of randomized controlled trials (rcts) of tcm formulations for the treatment of chronic hepatitis b (chb) that were reported in china from 1998 to 2008. the results showed that (i) tcms (tcm formulations alone or in combination with interferon (ifn) or lamivudine (lam)) had a greater beneficial effect than ifn (p=0.000 3) and slightly better effect than lam (p=0.01) on normalization of serum alanine aminotransferase; (ii) tcms had a similar beneficial effect on antiviral activity when used in conjunction with inf or lam for chb, which was evidenced by the reduction of serum hbeag and hbv dna; (iii) treatment with tcms in conjunction with inf or lam resulted in improved liver function. when the liver tissue is damaged, its repair is accompanied by the formation of an extracellular matrix, also known as fibrosis. fibrosis is the common pathological process of many liver diseases, and is also reversible. antifibrotic effects are an important component in the treatment of various chronic liver diseases [40] . one famous hepatologist, professor hans popper, once said, "anyone who can stop or delay liver fibrosis would be able to cure most chronic liver diseases" [41] . the focus of western medicine scientific and medical research has been on discovering targets for antifibrotic therapy, and developing customized multi-drug regimens [42] . according to the tcm theory, diseases of liver zang will transmit to the spleen zang, thus in the course of treatment, the spleen zang should be strengthened before it is impaired. if the liver disease has been long-standing, kidney yin should be evaluated during the treatment because the liver zang and kidney zang are derived from the same source. in clinical practice, symptoms and signs of spleen-qi deficiency journal of integrative medicine www.jcimjournal.com/jim are frequently seen in patients with liver diseases. they always complain of fatigue, pain or weakness in the legs, abdominal fullness, right upper quadrant discomfort or pain, loose stool, pale tongue or swollen tongue (teeth-marked tongue) with whitish fur and weak pulse. patients with chronic liver disease additionally present symptoms and signs of kidney-yin deficiency, such as dry mouth, internal-heat, red (or red and dry) and uncoated tongue, and weak pulse. according to the theory of syndrome differentiation therapy, methods of invigorating spleen-qi and nourishing kidney-yin should be used to treat liver diseases. in tcm, the pathogenesis of liver diseases does not necessarily relate to the liver zang, it can also be related to the spleen and kidney. table 1 shows tcm functions matched with herbs and dosages commonly used in the treatment of liver diseases. herbs with different functions are selected according to syndrome differentiation. dosages within the recommended range are determined by the severity of the symptoms and signs. several patent drugs (chinese herbal formulas) for treatment clinical observations showed that fzhyc can effectively improve liver function and decrease the expression of fibrosis biomarkers such as serum hyaluronic acid, collagen type iv, procollagen type iii and laminin, in chronic liver disease patients with fibrosis or cirrhosis [43, 44] . fzhyc can also regulate immune function [45] , balance amino acid [46] and endocrine [47] metabolism and reduce portal hypertension [48] . the results of several multicenter rcts have confirmed that tcm can reverse liver fibrosis [49] [50] [51] . fzhyc was used to treat liver fibrosis in patients with chb for six months. fifty patients in the trial group were treated with fzhyc. a control group of 43 patients was treated with heluo shugan capsule, another chinese patent medicine. all patients received liver biopsies pre-and post-treatment. pathology results showed that in the treatment group, the stage of fibrosis was decreased by one or more in 52% of the patients; the remaining 48% of the patients in the trial group had no changes. however, in the control group only 23.3% patients had a decrease in fibrosis stage, 55.8% patients had no change and 20.9% of the patients had an increase in fibrosis stage [49] . in another study, fzhyc reversed the fibrosis at a rate of 57.9% early cirrhotic patients with chb [52] . to prevent esophageal variceal bleeding in cirrhotic patients, a multicenter randomized and placebo-controlled trial was carried out. the probability of survival in the fzhyc group was higher than that in the propranolol group (90.22% vs 70.92%, p=0.044 9). compared to the propranolol group the probability of esophageal variceal bleeding in the fzhyc group was significantly reduced (43.0% vs 23.9%, p=0.013 1). when the two treatments were taken together there was an even lower probability of bleeding which was also significantly lower than the propranolol alone (12.4% vs 43.0% p=0.008 6). in patients with small esophageal varices, treatment with fzhyc reduced the size of the varices. its effects may be related to the prevention of hepatic fibrosis, amelioration of liver function, and the decrease of et-1 concentration in the blood plasma [53] . a meta-analysis was conducted to evaluate the efficacy and safety of fzhyc combined with nucleoside antiviral drugs in treating fibrotic patients with chb. the analysis included seventeen rcts, with a total of 1 320 patients with chb, of which 636 were in control groups and 684 in trial groups. the meta-analysis showed that there was no significant improvement in serum hbeag level and hbv-dna copies. however, there was a statistically significant improvement in liver fibrosis and liver function after treatment for 24 or 48 weeks [54] . for the past six decades, many researchers have carried out extensive research to explore the mechanism of tcm in the treatment of liver diseases. it was found that tcm can improve hepatic microcirculation, scavenge oxygen free radicals, resist lipid peroxidation, promote bilirubin metabolism, accelerate synthesis of liver glycogen and protein, and increase the content of liver microsomal cytochrome p-450 [55] . these effects lead to a decrease in hepatocyte necrosis, inhibition of apoptosis and promotion of the hepatocyte regeneration [56] . we searched the literature for studies exploring the mechanism of fzhyc's antifibrotic activity. it has been shown that fzhyc can protect hepatocytes, resist lipid peroxidation and inhibit some cytokines [57, 58] . fzhyc can also inhibit the activation and proliferation of hepatic stellate cells (hscs), which play an important role in hepatic fibrogenesis and fibrosis [58] . fzhyc can also promote apoptosis of activated hscs, inhibit synthesis and secretion of collagen, inhibit angiogenesis and promote degradation of collagen [59] . studies showed that fzhyc achieved its antifibrotic activity through multiple signal pathways and targets [57, 58, [60] [61] [62] [63] , such as transforming growth factor β-1 (tgf-β1), smads, insulin-like growth factors-1 (igf-1), phosphatidylinositol 3-kinase (pi3k), extracellular signal-regulated kinase (erk), p38 mitogen-activated protein kinase (p38 mapk), rhoa/rho-associated coiled-coil forming protein kinase (rock) and renin-angiotensin system (ras) signaling pathways [64, 65] . the elevation of portal vein pressure is a common symptom of liver cirrhosis. the portal vein pressure is positively correlated with endothelin-1 (et-1) concentration in the liver tissue during the process of liver cirrhosis [66] . fzhyc can dramatically decrease cirrhosis-induced elevation of portal vein pressure by reducing et-1 levels in the liver tissue [67] . due to multiple ingredients in the chinese formula, the compound could not be used to incubate cells directly in vitro. only individual components or ingredients of herbal medicine are suitable for in-vitro research. to explore the underlying mechanisms of fzhyc's antifibrosis activity, we looked in the literature for research on salvianolic-acid b (sa-journal of integrative medicine www.jcimjournal.com/jim b), a component of danshen that is the main constituent herb of fzhyc. studies show that the effects of sa-b are just like fzhyc in the treatment of hepatic fibrosis and cirrhosis [64, 65, 68] . sa-b dramatically decreased the fibrosis level of rats with fibrotic liver, and also markedly decrease cirrhosis-induced elevated portal vein pressure and liver et-1 levels [16] . sa-b achieves its antihepatic fibrosis effect by inhibiting the erk and the p38 mapk pathways of tgf-b1 in hscs. it inhibits the erk pathway by inhibiting phosphorylation of mek. sa-b inhibits the p38 mapk pathway by blocking phosphorylation of mkk3/6 and inhibiting expression of myocyte enhancer factor 2 (mef2, a transcription factor), in hscs with or without tgf-b1 stimulation [69] . further, sa-b inhibits the crosstalk of the samd signaling pathway to the erk signaling pathway [63] . sa-b also significantly reduces et-1-activated hsc contractility by inhibiting rhoa/rock ii activation and the downstream mypt1 phosphorylation at thr696 [64] . although some positive effects of tcm in liver diseases are reported, we should also note the possibility of liver damage induced by some herbs during treatment. the perspective that herbs, as natural medicine, have no side effects is outdated and wrong. some chinese herbal medicines, which were used to treat liver diseases, have been reported to have hepatotoxicity in high doses or even in standard doses, such as heshouwu (polygonum multiflorum [70] . this potential toxicity should serve as a reminder that clinical practitioners should administer chinese medicine with as much caution as western pharmaceutical drugs. it is very important to take precautions against drug-induced liver injury when selecting herbs and their doses. generally speaking, applying herbs in accordance with the pharmacopeia is quite safe. for example, an aqueous solution of zhizi (gardenia jasminoides) extract, which has been reported to have hepatotoxicity, has no significant side effects on mice liver at medium dose (equivalent to 18 g dose for adults) and low dose (equivalent to 9 g dose for adults). the medium and low doses of zhizi extract did not obviously affect structure of the liver tissue or damage hepatocytes. we suggest that zhizi is not suitable for chronic use at a high dose, but short-term use at a modest dose (9 g per day) is still safe [71] . further, by appropriate preparation of herbal products, such as heshouwu, the hepatotoxicity can be reduced [72] . it is also important to note that in chinese medicine, herbs with similar names cannot be used interchangeably. for instance, using tusanqi (gynura segetum), which has severe hepatotoxicity, as a substitute for shensanqi (panax notoginseng) is dangerous, and they come from very different plants. 6 new techniques and methodologies are needed for studying tcm although tcm therapy is effective in the treatment of liver diseases, more research is required to understand the underlying mechanisms of action. at present, the pharmacological studies of chinese medicinal formulae are carried out extensively in vivo, however, the induced animal models cannot be relied on to fully mimic clinical pathogenesis of human patients. studies that examine the mechanisms behind tcm can only be conducted in vitro, are ill suited to the complex formulations of herbs used in chinese medicinal remedies and are restricted by existing research techniques and methodology [73] . current research technology is not designed to evaluate responses from multi-dimensional variables, like the herbal formulations used in tcm. this may be one of the reasons that the curative effects of tcm have been slow to receive approval among western medicinal practitioners. new research techniques and methodologies should be developed to evaluate the curative effects of tcm and to elucidate its mechanisms [74, 75] . we believe that as techniques and methodologies evolve to address the complex nature of tcm herbal formulations, a more mechanistic understanding of the use of tcm in treating liver diseases will emerge. these studies will thus lead to the improvement of clinical results and refinement of the contemporary practice of tcm. as a complementary and alternative therapy for the treatment of liver diseases, tcm is a powerful but underused tool in the present, and has great potential for future use. the authors have no conflicts of interest to declare. journal of integrative medicine (jim) is an international, peer-reviewed, pubmed-indexed journal, publishing papers on all aspects of integrative medicine, such as acupuncture and traditional chinese medicine, ayurvedic medicine, herbal medicine, homeopathy, nutrition, chiropractic, mind-body medicine, taichi, qigong, meditation, and any other modalities of complementary and alternative medicine (cam). article types include reviews, systematic reviews and meta-analyses, randomized controlled and pragmatic trials, translational and patient-centered effectiveness outcome studies, case series and reports, clinical trial protocols, preclinical and basic science studies, papers on methodology and cam history or education, editorials, global views, commentaries, short communications, book reviews, conference proceedings, and letters to the editor. • no submission and page charges • quick decision and online first publication for information on manuscript preparation and submission, please visit jim website. send your postal address by e-mail to jcim@163.com, we will send you a complimentary print issue upon receipt. effect of glucocorticoid with traditional chinese medicine in severe acute aespiratory syndrome (sars) interaction of a traditional chinese medicine (phy906) and cpt-11 on the inflammatory process in the tumor microenvironment artemisinin: discovery from the chinese herbal garden anti-infective and cytotoxic properties of bupleurum marginatum a review of the pharmacological mechanism of traditional chinese medicine in the intervention of coronary heart disease and stroke puerarin: a review of pharmacological effects potential benefits of chinese herbal medicine for elderly patients with cardiovascular diseases danqi pill protects against heart failure through the arachidonic acid metabolism pathway by attenuating different cyclooxygenases and leukotrienes b4 chinese medicine shensongyangxin is effective for patients with bradycardia: results of a randomized, double-blind, placebo-controlled multicenter trial effects of chinese herbal medicine yiqi huaju formula on hypertensive patients with metabolic syndrome: a randomized, placebo-controlled trial favorable circulatory system outcomes as adjuvant traditional chinese medicine (tcm) treatment for cerebrovascular diseases in taiwan randomized controlled multicenter clinical trial for integrated treatment of community-acquired pneumonia based on traditional chinese medicine syndrome differentiation prevention of allergic airway hyperresponsiveness and remodeling in mice by astragaliradix antiasthmatic decoction the anti-asthma herbal medicine ashmi acutely inhibits airway smooth muscle contraction via prostaglandin e2 activation of ep2/ep4 receptors clinical effects of the method for warming the middle-jiao and strengthening the spleen on gastric mucosa repair in chronic gastritis patients modified da-cheng-qi decoction reduces intra-abdominal hypertension in severe acute pancreatitis: a pilot study optimized project of traditional chinese medicine in treating chronic kidney disease stage 3: a multicenter double-blinded randomized controlled trial efficacy and safety of traditional chinese medicine (shenqi particle) for patients with idiopathic membranous nephropathy: a multicenter randomized controlled clinical trial tripterygium wilfordii hook f (a traditional chinese medicine) for primary nephrotic syndrome clinical effect of jiutengzhuyu tablets on promoting blood circulation in women with oviducal obstruction study on the efficacy and safety of xueyou mixture in treating hemophilia beneficial effects of traditional chinese medicine on the treatment of osteoporosis on ovariectomised rat models a traditional chinese medicine therapy warming meridians to nourish blood in treating chronic pain due to soft tissue injury of the neck and shoulder: a randomized controlled trial trial of chinese medicine wu-ling-san for acute low-tone hearing loss mechanism of traditional chinese medicine in the treatment of allergic rhinitis identifying core herbal treatments for urticaria using taiwan's nationwide prescription database effect of yi-gan san on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptoms of dementia traditional herbal medicine in preventing recurrence after resection of small hepatocellular carcinoma: a multicenter randomized controlled trial treatment of middle/late stage primary hepatic carcinoma by chinese medicine comprehensive therapy: a prospective randomized controlled study clinical observation on the treatment of middle-late stage liver carcinoma by combined therapy of hepato-arterial chemo-embolising and chinese drugs for strengthening pi and regulating qi studies on treatment of fatty liver with traditional chinese medicine experience of treatment for posthepatitic cirrhosis based on tcm syndrome differentiation clinical study on effect of jiangan jiangzhi pill in treating nonalcoholic fatty liver diseases effects of baogan lishui decoction on patients with ascites due to cirrhosis: a report of 84 cases. guang ming zhong yi protective effect of compound tongfu granule on intestinal barrier in patients with cirrhosis of decompensation stage effects of method of regulating qi to dissipate blood stasis and phlegm with chinese herbs on expression of srebp-1c/fas in rats liver tissue with non-alcoholic steatohepatitis a prospective cohort study on the influence of high doses of herbs for clearing heat and resolving stasis on survival rates in patients with hepatitis b-related acute-on-chronic liver failure clinical observation of clearing heat and removing dampness, cooling blood and detoxicating therapy for acute on chronic liver failure in hepatitis b. beijing zhong yi yao contemporary clinical research of traditional chinese medicines for chronic hepatitis b in china: an analytical review liver cirrhosis procollagen iii levels in serum: do they provide additional information in liver disease? reversal of hepatic fibrosis -fact or fantasy? effect of fuzheng huayu 319 recipe on serological parameters of fibrosis in treating chronic hepatitis b. zhongguo zhong xi yi jie he za zhi multicenter clinical study about the action of fuzheng huayu capsule against liver fibrosis with chronic hepatitis b effect of ganping capsule on posthepatitic cirrhosis in adjusting abnormal immune function influence of fuzheng huayu capsules on abnormal amino acids spectrum in chronic liver diseases effect of fuzhenhuayu recipe in adjusting endocrine disorders in cirrhotic patient clinical research of ganping capsule against liver fibrosis in patients with chronic hepatitis b multicenter clinical study on fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis b capsule oxymatrine in the treatment of liver fibrosis in patients with chronic virus hepatitis: a randomized, double blind clinical study on treatment of alcoholic liver disease by qinggan huoxue recipe results set of traditional chinese medicine basic theory research in 973 program a randomized controlled study of fuzheng huayu capsule for prevention of esophageal variceal bleeding in patients with liver cirrhosis meta-analysis on fuzhenghuayu capsule combined with nucleoside antiviral drug for chronic hepatitis b clinical frequently used chinese crude drugs with hepatoprotective effect research progress on mechanism of clinical hepatoprotective drugs effect of fuzheng huayu formula and its actions against liver fibrosis role of the igf-1/pi3k pathway and the molecular mechanism of fuzhenghuayu therapy in a spontaneous recovery rat model of liver fibrosis effects of fuzhenghuayu decoction on collagen synthesis of cultured hepatic stellate cells, hepatocytes and fibroblasts in rats therapeutic efficacy of traditional chinese medicine 319 recipe on hepatic fibrosis induced by carbon tetrachloride in rats curative effects of fuzheng huayu capsules on hepatic fibrosis and the functional mechanisms: a review role of jak/stat pathway in ccl 4 -induced rat liver fibrosis model and molecular action mechanism of fuzheng huayu recipe in treatment of liver fibrosis salvianolic acid b inhibits erk and p38 mapk signaling in tgf-β1-stimulated human hepatic stellate cell line (lx-2) via distinct pathways. evid based complement alternat med salvianolic acid b lowers portal pressure in cirrhotic rats and attenuates contraction of rat hepatic stellate cells by inhibiting rhoa signaling pathway salvianolic acid b attenuates rat hepatic fibrosis via downregulating angiotensin ii signaling therapeutic potential of targeting the renin angiotensin system in portal hypertension traditional chinese medicine can improve liver microcirculation and reduce portal hypertension in liver cirrhosis salvianolic acid b inhibits hepatic stellate cell activation through transforming growth factor β-1 signal transduction pathway in vivo and in vitro effect of salvianolic-acid b on inhibiting mapk signaling induced by transforming growth factor-β1 in activated rat hepatic stellate cells facing the hepatotoxicity of chinese herbal medicine observation of treatment effect and hepatic toxicity of gardenia in mouse with acute liver injury effective components, toxic effects and research advances of present situation of modernization on compound prescriptions. zhongguo shi yan fang ji xue za zhi research status, problems and thinking of multi-component of chinese medicine. zhong yi xue bao discussion on research and development models in innovative chinese material medica key: cord-287283-t1hnswsq authors: paul, norbert w.; caplan, arthur; shapiro, michael e.; els, charl; allison, kirk c.; li, huige title: human rights violations in organ procurement practice in china date: 2017-02-08 journal: bmc med ethics doi: 10.1186/s12910-017-0169-x sha: doc_id: 287283 cord_uid: t1hnswsq background: over 90% of the organs transplanted in china before 2010 were procured from prisoners. although chinese officials announced in december 2014 that the country would completely cease using organs harvested from prisoners, no regulatory adjustments or changes in china’s organ donation laws followed. as a result, the use of prisoner organs remains legal in china if consent is obtained. discussion: we have collected and analysed available evidence on human rights violations in the organ procurement practice in china. we demonstrate that the practice not only violates international ethics standards, it is also associated with a large scale neglect of fundamental human rights. this includes organ procurement without consent from prisoners or their families as well as procurement of organs from incompletely executed, still-living prisoners. the human rights critique of these practices will also address the specific situatedness of prisoners, often conditioned and traumatized by a cascade of human rights abuses in judicial structures. conclusion: to end the unethical practice and the abuse associated with it, we suggest to inextricably bind the use of human organs procured in the chinese transplant system to enacting chinese legislation prohibiting the use of organs from executed prisoners and making explicit rules for law enforcement. other than that, the international community must cease to abet the continuation of the present system by demanding an authoritative ban on the use of organs from executed chinese prisoners. electronic supplementary material: the online version of this article (doi:10.1186/s12910-017-0169-x) contains supplementary material, which is available to authorized users. before a pilot organ donation program was introduced in 2010, at least 90% of the transplanted organs in china were procured from prisoners [1] . china is the only country in the world that systematically uses organs from prisoners for transplantation [2] . after decades of denial, china finally admitted the practice in 2005 [3, 4] . however, organ procurement from executed prisoners continued. in december 2014, the chair of the china organ donation and transplant committee and former vice-minister of health, huang jiefu, announced that the country would completely cease the use of prisoner organs for transplantation in china after 2015. surprisingly, this announcement has not been followed by any changes to china's organ donation laws or regulations (see website of prc national health and family planning commission: http:// en.nhfpc.gov.cn/regulations.html). the use of prisoner organs remains legal, if so-called consent is obtained from the prisoners [5, 6] . such 'consents' , however, even those actually signed by the prisoners, are not accepted by international organisations such as the transplantation society (tts) [7] . because of the restrictions on liberty in a prison environment, it is unlikely that prisoners are truly free to make independent decisions and thus an autonomous informed consent for donation cannot be obtained [7] . organ harvesting from executed prisoners violates international principles of medical ethics [8] . the compromised autonomy of all prisoners as an ethical restriction regarding the process of informed consent had historically been derived from a thorough analysis of crimes against humanity performed by physicians during the german nazi regime mostly on prisoners in german concentration camps. in asia, crimes against humanity performed during world war ii were shamefully not prosecuted in a similar way as the nuremberg military tribunals. the vivisections and experimental atrocities performed by japanese biological warfare unit 731 against occupied chinese and prisoners of war in manchuria were not raised, addressed nor prosecuted during the tokyo trials [9, 10] . the unethical practice of organ procurement from executed prisoners in china has lasted for decades [5] . moreover, this practice is associated with large scale abuse and severe human rights violations. in part, the transgression of ethical boundaries in the case of organ harvesting is triggered by an ever growing local and global demand for transplantable organs associated with the emergence of a global (black) market [11] [12] [13] . this heavily impacts human rights, ethics and justice far beyond ideas calling for regulated markets for organs [14] . in a prior publication, we explored the historical development and status of organ procurement from death-row prisoners in china [5] . in the present article, we more closely examine transgressions of human rights (mainly focusing on legal considerations of human rights), contradictory frames offered in justification, conditions claimed for consent of this most vulnerable of populations, issues of brain death criteria in the context of china, and several specific examples. from the 1970s, organs were simply taken from executed prisoners in china without asking for the permission of the prisoners or their families. in 1984, the first "interim rules on using the body or organs of executed criminals" [15] (also translated as "provisional regulation on the use of dead bodies or organs from condemned criminals" [16]) officially allowed, for the first time, organ harvesting from executed prisoners, under the condition that either the body is not claimed; or the prisoner volunteers for organ donation; or the family consents. as prescribed by the 1984 rules, "the use of the dead bodies or organs from condemned criminals must be kept strictly confidential. […] the operation vehicles from medical institutions can be allowed entry into the execution grounds to remove organs, but vehicles with the logo of medical institutions are not to be used, and white clinic garments are not to be worn. the execution ground should be guarded against before the operation is completed. after the dead bodies are used, the crematory shall assist the [medical] units in timely cremation" [16] . in many cases, the families receive only the cremains without being informed what has happened with the body of their loved ones. recently, it has been repeatedly admitted by chinese transplant officials that organs from executed prisoners had been procured without consent [17] [18] [19] . for example, a chinese medical official admitted in 2013 that "previously, authorities used executed criminals' organs without their consent, while permission has been required in recent years" [17] . in 2014, when hong kong newspaper mingpao asked the question whether prisoners and their families are informed and consent obtained before organ procurement, huang jiefu admitted that "we have not been able to achieve this, but we will soon" [18] . in 2015, huang jiefu admitted that the problem with china's organ transplantation system was that the laws were not obeyed: "although the law provides that the use of prisoner organs must be from voluntary donation, but there are still loopholes in the law enforcement" [19] . all of these statements strongly suggest that organs were procured in china largely without consent of the prisoners or their families. although organ procurement without consent is illegal according to chinese laws, the practice appears to be tolerated by the authorities in china. at a european parliament hearing on 29 january 2013, enver tohti testified that he was ordered in 1995 to harvest organs from an incompletely executed, still-living prisoner in china [20] . more details were revealed in his interviews with abc [21] , bbc [22] and journalist ethan gutmann [23, 24] . when enver tohti got the body of the 'executed' prisoner, he noticed, however, that the prisoner was not dead. "the gunshot, gun wound was on his right chest. so, i guess that was deliberately to make this prisoner not die immediately to allow some time for us to remove that organ when he is still alive" [21] . when tohti kept making attempts to follow normal proceduresterilize, minimal exposure, sketch the cut -the chief surgeon told him to hurry up. "no anesthesia, no life support", "we are working against time". finally, tohti extracted the liver and the kidneys from the still-living prisoner [23, 24] . unfortunately, this was not the only case reported. an early case has been documented in the book "china's eyes" [25] . in 1978, zhong haiyuan, a schoolteacher from the jiangxi province, was sentenced to death for her "counterrevolutionary" thoughts. the execution was performed by three officers from the people's armed police forces on april 30, 1978 . two officers fixed zhong while the third officer put the gun against her back on the right side and fired the bullet [25] . years later, one of the officers told the books' author that the order was not to kill zhong immediately. "the kidneys must be harvested before she dies", because the army doctors wanted high quality kidneys, "kidneys from a living person" [25] . more recently, mr. wang, who currently lives in canada, revealed that he was once a member of a team extracting organs from a still-living person. the incident happened in the 1990s when wang was an intern doctor at the urology department of the shenyang military general hospital in liaoning province [26] . in march 2015, jiang yanyong told to hong kong journalists that corruption, illegal transplantation and organ trade were common in military hospitals [27, 28] . jiang elaborated on the case of li shiyong, director of the department of general surgery of the beijing military general hospital. with no prior experience in transplantation and without asking for permission of the hospital director, li founded a liver transplantation center in 2005 and appointed himself as the director. because li had found ways to obtain donor livers, he could serve as the director (see additional file 1: table s1 ). in the same tv interview, jiang also revealed that many of the prisoners used for organ harvesting were shot but not completely killed [27, 28] . the purpose was for organ harvesting while the prisoners were still alive in order to keep the warm ischemic time of the sourced organs as short as possible (see additional file 1: table s1 ). jiang as a source is, we contend, credible based on his personal story within the chinese medical system. he was a chief physician of the 301 military hospital (people's liberation army general hospital) in beijing where he witnessed the results of the trauma inflicted on the students during the tiananmen square massacre of 1989. jiang was also the person who publicized the cover-up of the severe acute respiratory syndrome (sars) epidemic by the chinese government in 2003. unfortunately, the strength of these examples is constrained by the fact that the number of executions and the detailed techniques used are state secrets in china; empirical data cannot be generated. there are no statistics available on the incidence of the practice of incomplete executions in china. a systematic international investigation into this issue is needed in the interest of (overdue) justice for the victims. in most western cultures, treating a person only as a mere means to an end of another is a challenge to core concepts of human dignity as immanuel kant and other 18th century philosophers argued [29] . even from a contemporary perspective, ethicists have always argued that transferring organs to another person either from a living donor or from post mortem procured organs must be contextualized in a way that a) human dignity, b) autonomy and c) social justifiability in the light of shared values are not endangered [30, 31] . here, human dignity is understood to be an applied concept. based on the notion of phenomenological dignity it is cognition that enables humans to identify themselves and to perceive others as human beings which are to be treated with the same respect (dignity) that one would expect for oneself. this concept is fostered by a reflexive mode of dignity in which the constant (re-)evaluation and adjustment of actions is put in place by relating both, intentions and consequences to commonly accepted values, like those which constitute our understanding of human rights. finally, the mutual appreciation of humans together with a value based evaluation and adjustment of interaction turn dignity into a relational concept which ought to be the guiding principle of human coexistence. especially the relational dimension of dignity is addressed in discourses on brain death when it comes to evaluations of those values, moral concepts and needs which need to be reflected for both, donors and recipients of organs [32] . only this clarification could lead to a situation in which the concept of brain death established the medical basis and justification to switch from life-sustaining care setting to considering a deceased person as a cadaver organ donor. ethically, brain death is the fine line on which dignity of a living and acting person changes into the dignity of a deceased person, and respecting autonomy of a living person shifts over into respecting an advanced directive or declared will to donate organs. in this context, the justifiability of organ procurement is derived from the fact that the braindead person can donate organs without suffering from vital consequences caused by organ removal (e.g. pain and death), since he or she is already dead. intensive care is provided only to protect the organs of the deceased. it is this integration of medical and ethical functions of brain death which makes organ procurement a widely accepted practice in western culture. this is especially true because of the potential for other procurement strategies, such as procurement from non-heart-beating donors (donation after circulatory death -dcd), which require careful, detailed and transparent protocols, in order to assure the avoidance of even the potential for conflict of interest regarding treatment, and verification of the death of the donor [33, 34] . circulatory death is, if not clearly defined as the irreversible cessation of cardiovascular circulation, potentially reversible. furthermore, it can be prognostically highly dependent on a number of arbitrary, concomitant circumstances (time, temperature, cause), thus requiring strict protocols, including electrocardiography and blood pressure monitoring to assure death has occurred, and is permanent. dcd donation may also lead to decreased quality of recovered organs, because of prolonged ischemia, or reduced number of organs that can be procured. it thus has to be seen as a procedure only applicable in an environment with reliable clinical standard operating procedures (sops) which have to be implemented in an evidence-based mode by well-trained medical personnel [34, 35] . however, there is yet no brain death legislation in china and circulatory death is the legal standard despite the absence of evidence-based and reliable sops [36] . china lacks any state issued official guidelines to diagnose brain death. in 2003, the ministry of health drafted "brain death determination criteria" and "brain death determination technical specifications" (comment drafts). in 2009, the ministry of health revised the two documents. in march 2012, the national health and family planning commission (nhfpc, the former ministry of health) assigned xuanwu hospital of capital medical university as the brain injury quality control evaluation center. in 2013, the center further revised and combined the two documents into "brain death determination criteria and technical specification (adult quality control version)" [37] . these criteria and technical specifications represent a suggested medical standard; it is not a standard procedure, a mandatory guideline for medical practitioners or an administrative regulation. above all, the standard is not legally binding. as stated in the editor's note accompanying its publication, "the center has revised and improved the above-mentioned documents on the basis of 10 years of clinical practice and research on brain death determination, and hopes that the new document serves as the medical standard to promote the brain death determination in our country to develop orderly and normatively" [37] . the first documented brain death diagnosis in china was performed on 25 february 2003, in wuhan, hubei province [38] . the brain death determination was carried out according to the published 2003 draft. in november 2003, the kidneys of a boy diagnosed as brain dead were used for transplantation with the consent of the parents [39] . both events were considered breakthroughs in chinese transplant medicine. both were nominated by major chinese media to be among the top 10 medical stories of 2003 [40] (fig. 1 ). since then, there have been reported increasing numbers of organ donations after brain death, although "it is illegal to take organs from the brain-dead for transplant purposes" in china, as acknowledged by china daily [41] . even though no brain death legislation has been effectuated in china, the chinese classification of deceased organ donation has been recently formulated as follows: "china category i: organ donation after brain death; china category ii: organ donation after circulatory death; china category iii: organ donation after brain death followed by circulatory death" [36] . the ambiguity of this classification together with the absence of sops, guidelines, regulations and legislation leads to a situation in which legal, medical and ethical uncertainty continues. the medical journal henan medical research published a research paper titled "the experience of homologuous orthotopic heart transplantation" (fig. 2) . the operation was allegedly performed in a hospital of the people's armed police force in 2001 and the paper published in 2003 [42] . the 32-year-old male recipient died from infection 46 days after the heart transplantation [42] . in the section 2.1 of this research paper, the "major points of donor heart removal" included: "systemic heparinization (2 mg/kg); delivery of cold cardioplegia to the heart through the aortic root until the heart stopped beating; cut of the superior vena cava at 4 cm above right atrium …" (fig. 2) . besides blood type and heart weight, no other information about the donor was provided in the paper. the fact that systemic heparinization was performed and heart beating was stopped by cold cardioplegia implies that the blood was circulating and the heart was functional before the explantation procedure. logically, one of the following two scenarios are applicable to describe the heart explantation: (i) the donor was a brain death patient and a brain death diagnosis was performed as it would have in most confirmatory brain death diagnoses based on neurological standard operating procedures (e.g. in the eurotransplant region); (ii) the donor was not a brain death patient and the cardiac death was induced by the cold cardioplegia delivered by the medical professionals. in this context, it is important to re-emphasize that there is no brain death legislation in china and circulatory death is still the legal standard in china [36] . as mentioned above, the first brain death determination in china was performed in 2003 ( fig. 1) [38] . the heart transplantation in this publication, however, was performed in 2001 and the concept of "brain death" is not mentioned. this therefore raises the question as to whether the donor was brain dead, especially given that the paper was published at a time where the diagnostic procedure alone would have captured the attention of the chinese medical community and would have contributed positively to the scientific impact of the paper. it is thus reasonable to assume that the delivery of cold cardioplegia served the purpose of execution and explantation at the same time. on 26 june 1945 in san francisco, the republic of china (roc), first in suffering axis aggression, was also first to sign the united nations charter and statute for the international court of justice, which entered into force on 24 october, establishing the united nations. the latter date followed the double tenth agreement (10/10/1945) [43] . the united nations office of high commissioner for human rights characterizes universal human rights as "interrelated, interdependent and indivisible" often expressed [40] . text in left box: 'at the beginning of 2003, the drafting group of the ministry of health completed the "brain death determination criteria (for adults)". according to these criteria, the brain death coordinating group of the tongji hospital at the tongji medical college, huazhong university of science and technology, completed the first brain death determination and treatment cessation in china on 25 february 2003'. text in right box: 'the animal model of brain death, the first brain death determination in adults, and the first brain death in children followed by unpaid organ donationthese three pioneering works were nominated by 10 major chinese media to be among the top ten medical news of 2003, ranking from 3 to 7, respectively' in treaties, customary international law (i.e. implicit norms) or general principles. documents comprise moral declarations, which implicitly presuppose a concept of human flourishing, and derivative binding treaties (covenants, conventions, protocols). the troika of the 1948 udhr and the complementary international covenants on economic, social and cultural rights (icescr) and civil and political rights (iccpr), respectively opened for signature in parallel in 1966, comprise the so-called 'bill of human rights' , with others building upon them. china is a full party to the icescr (signed 1997, ratified 2001); the convention against torture and other cruel, inhuman or degrading treatment or punishment (cat, ratified 1988); the convention on the prevention and punishment of the crime of genocide (signed 1949, ratified 1983); and the united nations convention against transnational crime (ratified 2003) whose concerns include organ trafficking (albeit patients rather than prisoner organs have comprised the transnational element in china). [42] china also signed, but has not ratified, the iccpr in october 1998. while formally not bound by iccpr provisions until ratification or accession, china is obliged not to defeat its general purpose. per the foreign ministry at the time, china's 1998 signature "demonstrates its firm determination to promote and protect human rights" as well as concretely commemorating the udhr's 50th anniversary, acknowledging a coherence bridging moral and legal rights. it also emphasized flexibility in prioritization: "the principle of the universality of human rights must be respected, but the specific conditions of each country must also be taken into consideration in observing this principle," highlighting economic development successes against poverty. the tone markedly contrasts more recent ideological tightening contra "western ideas", expressly against universal values of human rights, parallel to an anticorruption campaign short on procedural protections [44] . china domestically has circulated "alternatively phrased" translations of signed human rights conventions rather than the un's official chinese text, according to one source providing an interpretive buffer while also imprisoning those who ask for the iccpr to be ratified [45] . legally binding, however, are the official un language versions, not ccp state paraphrases. human rights violations ending in organ harvesting from prisoners are, like human rights, also interrelated and interdependent. violation cascadesone violation increasing probability of another given the substantive interrelationship of rights -increase vulnerability cumulatively whether in a specific person or in a targeted population. rights violations via detention schemes and a death penalty regime subject to manipulation with lack of sufficient representation or appeal [46] precondition the subsequent act of forced organ extraction: risk accumulates to a specific subject and identifiable population. in this sense, the implication of the title of this paper is extensive and systemic, not simply perioperative. de jure and de facto factors, frequently in violation of international human rights standards, lead to and condition the supply of prisoners being solicited before execution or simply exploited in the first instance. specifically concerning the death penalty, variability includes bringing charges across 46 potentially capital offenses; death sentences and executions waxing and waning during 'strike hard' campaigns; and executions increasing before the new year. furthermore, judges in china are not unaware that executees are the mainstay of transplantation. beyond the design of preserving public order and social control through execution is added the exogenous influence of medical demand for execution as the chief gateway to a social good (organs for transplantation), at times indirectly abetted by the international community (e.g. the transplantation society's policy supporting providing training to chinese transplant surgeons under the banner of influencing eventual reform while simultaneously expanding capacity, as in the tts ethics committee letter of 6 november 2006 to tts members [47] ). it is notable that the initial 1984 rules officially allowing organ harvesting from executed prisoners cited the initiative of medical personnel, not the state, as seeking to exploit this context for organ sourcing [16] . the practice of organ procurement in china that we have described violates freedom from torture and other cruel, inhuman or degrading treatment or punishment (udhr, cat, iccpr art. 7). nowhere is an individual as subject to state power than in prison, and nowhere in prison than when awaiting execution. however, it is the contiguous context, not merely local 'choice' , that is proper object of the human rights critique, exposing the step-wise cumulative vulnerability of prisoners at risk of being exploited in and through execution. this is aided and abetted by medical demand by an occupation that first pushed for exploiting execution for organ harvesting, and by a citizen population willing to rely upon, benefit from, and exploit the bound population -evident from ongoing reticence to participate in voluntary donor registration, yet seeking transplantation surgeries. in general, an alibi of system reform has been countenanced too long. after over a decade of reform claims and the redefinition of the status of prisoners, the ethical outcome respecting human rights in china, here conforming with international medical ethical standards, is categorical cessation of organ sourcing from prisoners. practically, this would remove the perverse incentives shared and relied upon by medical and judicial establishments, and by the general population. given the nature of the violations and delay, justification of gradually realizing an ethical practice fails. this recognition should hold for actors and institutions of influence outside of china now in possession of over a decade of knowledge. while human rights violations in china span systemic structural preconditions, augmented by political whim, the most proximate point of intervention still lies with the medical community and professional societies. admitting the failure of gradualism, and increasing, rather than decreasing, professional sanctions, may more quickly realize the intent: cessation of prisoner organ sourcing generally; reducing perverse incentives in death penalty demand (moral hazard); and confronting the general population with two ethical alternatives: supporting or declining voluntary organ transplantation as a system, while bearing the cost of either choice. the unethical practice of organ procurement from executed prisoners in china is associated with a large scale of abuse and a cascade of severe human rights violations, including, we contend, organ explantation from stillalive human beings, and, upstream, conditioning the supply of prisoners exploited per se or then solicited to 'freely' offer organs as atonement for real or supposed crimes. those involved in organ harvesting from stillalive prisoners must be prosecuted. the unethical practice of lethally procuring vital organs from the living must be prevented by a law prohibiting use of prisoner organs generally, supporting change in the practical legal, medical and popular culture surrounding transplantation in china. finally, greater influence may be exerted by international institutions through change of strategy. additional file 1: table s1 . government policy and organ transplantation in china open letter to xi jinping, president of the people's republic of china: china's fight against corruption in organ transplantation china to 'tidy up' trade in executed prisoners' organs. the times organ procurement from executed prisoners in china historical development and current status of organ procurement from death-row prisoners in china transplant medicine in china: need for transparency and international scrutiny remains the use of prisoners as sources of organs-an ethically dubious practice victims of japan's notorious unit 731 sue unit 731 and moral repair organ trafficking: global solutions for a global problem human organ markets and inherent human dignity transplant tourism and unregulated black-market trafficking of organs regulating the sale of human organs: a discussion in context with the global market provisional regulations on the use of dead bodies or organs from condemned criminals (1984). in: organs for sale: china's growing trade and ultimate violation of prisoners' rights: hearing before the subcommittee on international operations and human rights of the committee on international relations, house of representatives, one hundred seventh congress, first session chinese medical official admits that organs were extracted without consent. epoch times high official admitting that prisoner organs are still being used -without consent of the prisoners or their families (in chinese) former vice-minister of health: foreigners have demonized chinese doctors because of use of prisoner organs (in chinese) a horror story. unpo. 2013 china promises prisoner organ donation phasing out. abc.net.au. 20 may 13 the xinjiang procedure. weekly standard the slaughter : mass killings, organ harvesting, and china's secret solution to its dissident problem chinas eyes (chinese edition isbn: 9787539168944). nanchang city: 21th century publishing house former chinese hospital intern recounts a live organ harvest. epoch times retired military doctor jiang yanyong: trading of organs from executed prisoners common in militaryhospitals military doctor of conscience jiang yanyong denounced serious corruption in the army (in chinese) groundwork of the metaphysics of morals : a german-english edition. cambridge replacement parts : the ethics of procuring and replacing organs in humans the ethics of organ donation by living donors transplantation ethics presumed consent for organ preservation in uncontrolled donation after cardiac death in the united states: a public policy with serious consequences non-heart-beating organ transplantation: medical and ethical issues in procurement donation after cardiac death: respecting patient autonomy and guaranteeing donation with guidance from oregon's death with dignity act voluntary organ donation system adapted to chinese cultural values and social reality brain death determination criteria and technical specification (for adults; quality control version) (in chinese) china's first brain death determination in children and free organ donation and transplantation brain death and organ donation: the ultimate combination of modern science and humanism health authorities to define legal brain death. china daily the experience of homologuous orthotopic heart transplantation (in chinese with english abstract) ministry of foreign affairs of the peoples republic of china. the signing of the international convention on civil and political rights by the chinese government china takes aim at western ideas suppressed in translation: how chinese versions of un covenants gloss over human rights false promises of fair trails we thank the bmc medical ethics reviewers and editors for their comments and suggestions that helped us substantially to revise this article. this work was partly supported by the grant graduiertenkolleg (grk) 2015/1 "life writing -life sciences" from the deutsche forschungsgemeinschaft (dfg), bonn, germany. the datasets supporting the conclusions of this article are included within the article and its additional file. some reports (e.g. references [19] and [41] ) are additionally archived on a publicly accessible server (https://archive.is). the web addresses of the archived reports are provided at the end of the references.authors' contributions nwp drafted the manuscript and critically revised the manuscript. ac helped to draft the manuscript and critically revised the manuscript. mes helped to draft the manuscript and critically revised the manuscript. ce helped to draft the manuscript and critically revised the manuscript. kca drafted the manuscript and critically revised the manuscript. hl drafted the manuscript and critically revised the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests. ethics approval and consent to participate not applicable. submit your next manuscript to biomed central and we will help you at every step: key: cord-304490-q9ab1pji authors: iqbal, najaf; fareed, zeeshan; shahzad, farrukh; he, xin; shahzad, umer; lina, ma title: nexus between covid-19, temperature and exchange rate in wuhan city: new findings from partial and multiple wavelet coherence date: 2020-04-22 journal: sci total environ doi: 10.1016/j.scitotenv.2020.138916 sha: doc_id: 304490 cord_uid: q9ab1pji abstract this study attempts to document the nexus between weather, covid-19 outbreak in wuhan and the chinese economy. we employ 24-h daily average temperature, daily new confirmed cases of a covid-19 in wuhan, and rmb exchange rate to represent the weather, covid-19 outbreak, and chinese economy, respectively. the methodology of wavelet transform coherence (wtc), partial wavelet coherence (pwc), and multiple wavelet coherence (mwc) is used to analyze the daily data collected from 21st january 2020 to 31st march 2020. results reveal significant coherence between series at different time-frequency combinations. overall results show the insignificance of an increase in temperature to contain new covid-19 infections. the renminbi exchange rate showed a negative coherence at specific time-frequency spots suggesting a negative but limited impact of the covid-19 outbreak in wuhan on the chinese export economy. our results are contrary to many earlier studies, which show a significant impact of increased temperature in slowing down covid-19 spread. these results can have important implications for economic and containment policy making regarding the covid-19 outbreak. the world is passing through an unprecedented situation as novel corona-virus (covid-19) is sweeping across -massive population of the world recently. the first case was reported in china's wuhan during december 2019, and a statement from who confirmed the novel nature of the virus on 9 th january 2020 (zhu et al., 2020) . within the same month, who declared public health emergency of international concern (pheic) on 29 th january 2020, citing concerns for the response capacity of countries with weaker health systems (sohrabi et al., 2020) . due to the highly contagious nature of covid-19 (r 0 =2-5) and an ever-increasing number of cases in other parts of the world, soon it became a pandemic (liu, gayle, wilder-smith, & rocklöv, 2020) . the total number of confirmed cases and deaths worldwide amount to 2,127,873 and 141,454 respectively at 04:33 hours beijing time on 17 th april 2020, according to data from johns hopkins university. a recent study in madrid suggests that covid-19 may become more contagious along time, implying that r 0 may increase (garcia-iglesias & de cos juez, 2020) . the health impact is severe enough to put more than half of the world's total population under some form of restric tion, while the economic impact is being called worse than the 2008-09 global financial crisis and compared with the great depression of 1930. stock markets around the world have seen a worse decline for decades (baker et al., 2020) . researchers across the globe are struggling to document the nascent knowledge acquired through primary j o u r n a l p r e -p r o o f observation and experience of the situation. efforts on a global scale are being made to know more about this virus and to slow down and ultimately stop the spread of this menace. figure 1 shows the daily time trend of new confirmed cases in wuhan city. [ insert figure 1 here] a sudden huge increase in new cases on 13 th february 2020 is due to the inclusion of new criterion (clinical symptoms) in detecting confirmed covid-19 cases. figure 2 showing the map where the coronavirus originated. novel corona-virus belongs to the family of severe-acute-respiratory-syndrome (sars) and bears flu like symptoms. since the weather is a key variable in predicting flu, hence it is likely to be an important factor for covid-19 too (sajadi et al., 2020) . since severe cold, wind speed and rain (weather variables) are expected to contribute to flu, cold, fever, cough and pneumonia etc. all of which are possible symptoms of covid-19, it is imperative to know how weather is associated with daily new confirmed infections of covid-19 in wuhan during this outbreak. figure 3 displays the 24-hourly daily average temperature of wuhan city. covid-19 has severely restricted peoples' mobility and disturbed routine-life-activities of almost more than half of the world population. in this scenario, the negative economic impact of this disease is imminent, especially in the country where it was reported first (china) and which is also amongst the worst affected (82,341infected and 3,352 dead till 17 th april 2020). as china is a production house of the world and a major portion of its gross domestic product (gdp) depends on exports, the renminbi (rmb, chinese currency) exchange rate is expected to be also affected (feng, li, & swenson, 2016) . due to lockdown in hubei (central chinese province of which wuhan is the capital), the movement of people and goods to and from this place was completely halted. due to the novel nature of covid-19, it became difficult to ascertain if the virus could be spread through goods transport or not. in this uncertainty, other countries felt reluctant to allow chinese made products to enter their borders. production had already suffered due to complete lockdown in a whole province and then reduced demand overseas added further to declining exports in china. all these factors can affect the exchange rate of rmb, which is primarily linked to foreign trade flows (li, ma, & xu, 2015) . in such a scenario, it is interesting to know how the chinese rmb exchange rate moved with the emerging situation of the covid-19 outbreak, explicitly speaking the number of new daily confirmed cases in wuhan during this period. figure 4 shows the daily time trend of the rmb exchange rate against usd. this study attempts to document the relationship between local weather (temperature), economy (exchange rate of rmb), and covid-19 outbreak (daily number of new confirmed covid-19 cases) in the chinese city of wuhan where it was first reported, using wavelet analysis. as it is an emerging situation, the research on different aspects of this global outbreak is still naive at the moment. soon after reporting of early cases of covid-19, it is established that human-to-human transmission is taking place lai, shih, ko, tang, & hsueh, 2020) . temperature is an important factor in infectivity reduction of the human coronavirus (lamarre & talbot, 1989) . experience with sars had demonstrated that the disease disappeared in warm weather during late july (wallis & nerlich, 2005) . similar behavior has been expected by some in the case of covid-19, also due to its relationship with the same family i.e., corona-virus (wilder-smith, chiew, & lee, 2020). temperature and humidity is an important factor in the survival of coronavirus on metal and other surfaces (casanova, jeon, rutala, weber, & sobsey, 2010) . higher humidity, lower temperature and tropical areas were found to be more feasible for the coronavirus spread during sars outbreak (chan et al., 2011) . a recent study finds an association between meteorological factors, air pollutants and number of deaths in wuhan during covid-19 outbreak using the generalized additive model (ma et al., 2020) . weather is found to be associated with the daily number of covid-19 cases in the indonesian capital city of jakarta also (tosepu et al., 2020) . research studies on the sars outbreak found that daily infections could increase as higher as 18.18 times at low temperatures as compared to high temperatures (merlo et al., 2006) . a study involving 429 cities around the world suggests that temperature may be an important factor in covid-19 infection and transmission and regions with similar weather conditions as of wuhan should be extra cautious in preventing an outbreak . the same study suggests that there may be the best temperature for covid-19 transmission and low temperature is more feasible for this infection and transmission. another research, including data from all cities of china suggests that increase in temperature leads to increase in doubling time of covid-19. this implies that high temperatures may reduce the speed of transmission of covid-19. although the model from this study explains only 18% of the variation in doubling time of covid-19 cases, it still provides an important insight into how temperature can play a role in the containment of this outbreak (oliveiros, caramelo, ferreira, & caramelo, 2020 ). while the above mentioned studies suggest a decisive role of increased temperature in reducing covid-19 spread, the current spread around southern hemisphere suggests there may be only little if any role of temperature in this regard. according to research on global scale, high temperature does not seem to slow down the covid-19 spread (jamil, alam, gojobori, & duarte, 2020) . another study on community outbreaks j o u r n a l p r e -p r o o f throughout the world suggests that covid-19 is a seasonal respiratory virus, spreading along similar latitude (sajadi et al., 2020) . in this uncertain situation where literature is inconclusive about the role of temperature in the covid-19 spread, we attempt to analyze the number of daily new covid-19 cases and average daily temperature in this regard. a better-modeled association helps to understand the behavior of this disease in varying weather conditions which can ultimately help to save precious human lives by taking preventive measures. what has happened in wuhan is important for the rest of the world to know to enable them to making informed and better decisions related to covid-19 containment. a recent study cited measures taken in wuhan as a model to contain the covid-19 elsewhere in the world (m. . a few recent studies confirmed the negative impact of the covid-19 outbreak on the chinese economy during its early stages (al-awadhi, al-saifi, al-awadhi, & alhamadi, 2020; mckibbin & fernando, 2020) . the chinese economy is export-oriented, and significant changes in exports due to covid-19 can affect its exchange rate. a lot of research is available on the relationship between the exchange rate and exports of a country, especially in the case of china (burdekin & willett, 2019; taylor, 2016) . a lot of studies conclude a positive relationship between the depreciation of rmb and chinese exports (park, yang, shi, & jiang, 2010) while others are inconclusive (cheung, chinn, & qian, 2012) . however, the current situation may be different as compared with the classical exchange-rate-exports relationship due to its novel nature. in the ongoing scenario, the rmb exchange rate is expected to show some coherence with the covid-19 outbreak, both directly and indirectly. weather is represented by "average daily temperature" in wuhan and calculated by taking 24-hourly local observations and then averaging throughout every day. covid-19 outbreak is represented by the "number of daily new confirmed infections" of covid-19 and the numbers are taken from national health commission of china's official website. data on chinese exchange rate v/s us dollar is taken from imf website. all data values are collected on daily basis from 21 st january 2020 (lockdown start date of wuhan city) to 31 st march, 2020. we have employed continuous wavelet transform (cwt), wavelet transform coherence (wtc), partial wavelet coherence (pwc) and multiple wavelet coherence (mwc) to analyze the association between the average daily temperature of wuhan, number of daily new confirmed covid-19 cases in wuhan city and rmb exchange rate. wavelet methodology is used mostly in geophysics and recently j o u r n a l p r e -p r o o f getting footprints in weather, environment, economics, and finance studies also (afshan, sharif, loganathan, & jammazi, 2018; ng & chan, 2012 ; wu, tan, guo, li, & chen, 2019) . it can capture non-linear association between multiple series of data (benhmad, 2012) . such methodology has not been employed in any studies related to covid-19 up to the best of our knowledge till now. there are several advantages of using wavelet methodology in multiple time series analysis; 1) assumption of stationarity can be relaxed. 2) a series with non-normal distribution can be used. 3) events localized in time can be captured efficiently. 4) analysis is done from a time-frequency perspective. 5) its very efficient in capturing non-linear relationships (which is the case most frequently in real world scenarios). 6) it can determine strength and direction of association and distinguish between short, medium and long term relationships at the same time. 7) different types of wavelet functions can be used depending upon the nature of data which allows more efficient and accurate tracking of the association. 8) it can capture bi-directional (lead-lag) relationship at the same time at different time-frequency domains between two time series (grinsted, moore, & jevrejeva, 2004; ng & chan, 2012; vacha & barunik, 2012) . the mathematical equation for wavelet transforms coherence is presented below; (1) the wavelet coherence ranges from 2 0 ( , ) 1 r m n  . zero means no coherence at all and one means perfect coherence. the method of monte carlo simulation is employed. in this methodology, the coherence is studied between two variables while controlling for the common effects of third variable. the mathematical representation of this method is given as under; the simplest way of understanding multiple wavelet coherence to compare it with multiple correlation. in this method, coherence is studied between one dependent variable y and the combination of two other x1 and x2 variables. the mathematical representations of mwc is shown below; ; descriptive statistics show that average number of daily cases of covid-19 is 704.31, ranging from minimum "0" to maximum 12,523 during our observation period. average daily temperature is 10.7 degree celsius, ranging from a minimum of 3 degree to a maximum of 21 degree centigrade. exchange rate average is rmb 6.99 per usd fluctuating between 6.90 and 7.115 which shows limited variation (maximum 3%) during this period. correlation between all three variables is positive and significant at the 1% level. coefficient for correlation is 0.61 between covid-19 and temperature, 0.56 between covid-19 and exchange rate and 0.53 between temperature and exchange rate respectively. inside from the light ones outside is called "cone of influence" and represents essential "edge effects" along its borders. figure 5(b) shows the significant variations in temperature that can be seen in frequency bands of 0-4, 4-8 and 8-16 during 3 rd , 3 rd -4 th and 8 th , and 3 rd -6 th weeks of observation respectively represented by an "l" and a long oval shaped dark red contours. can be interpreted as a correlation that is loca lized in time-frequency domain in simple terms but possesses many advantages as compared to simple correlation (grinsted et al., 2004) . the direction of clusters of small arrows observed in the figure 6(b), represents the direction of association between covid-19 and temperature while the colored bar on the right side tells us the strength of this association. arrows pointing towards right side mean a positive association (in phase) between these variables while negative (out phase) towards the left. arrows inside the circle (contour) mean a significant association. rightward direction of arrows inside the contour represents positive association between temperature and covid-19 in frequency band of 8-16 periods during third week of observation. red color inside the circle matches with a correlation of almost 0.80 which is shown on the colored bar on the right side representing a strong association. black cone shape lining from top to bottom on both sides is called "cone of influence" and represents significance level. temperature and exchange rate are in phase as shown by the arrows point ing towards right in the circle shown on the base of the figure 6(c) inside the cone of influence. red color inside is matching with almost 0.80 shown on the colored bar on the right which means a strong association in the frequency range of 16 and onwards during 4 th and 5 th week of observation. there are notable edge effects also in the same frequency band before and after 4 th and 5 th week. there is another very small cluster of arrows j o u r n a l p r e -p r o o f pointing left and downwards in the frequency range of 0-4 periods during 2 nd week which implies an out-phase association running from exchange rate to temperature. figure 7a-1 shows result of partial wavelet coherence (pwc) involving covid-19, temperature and exchange rate. it shows wavelet coherence between covid-19 and temperature while controlling for exchange rate. one small and the other large red colored contour can be observed in frequency domain of 0-4 and 8-16 periods respectively showing short and long term coherence within the given time period. short term coherence is observed during 1st week while long term between 2nd and 3rd week of the observation. red color inside contour matches with almost 0.80 on the colored bar on the right side of the figure showing a strong association. if we compare this result with wtc result of covid-19 and temperature from figure 6a, both are almost same. this implies that exchange rate has no significant impact on the relationship between covid-19 and temperature and results of wtc show true coherence between covid-19 and temperature. mwc shows how good the linear combination of independent variables co-moves with a dependent variable. figure 7a -2 presents result of mwc involving covid-19 as dependent while temperature and exchange rate as independents. linear combination of both independent variables explains variation (small and large red circles with black outlining) in covid-19 in almost all frequency bands including 0-4, 4-8, 8-16 and 16 to onwards during 1 st , 3 rd -4 th , 2 nd -3 rd and 4 th -5 th weeks of observation respectively. figure 7b-2 shows mwc results of temperature as dependent while exchange rate and covid-19 as independent variables. here also red colored islands with black outline can be observed in all frequency bands including 0-4, 4-8, 8-16 and onwards during 1 st -2 nd and 9 th , 3 rd , 3 rd -4 th and 5 th week of observation respectively. these small and large red colored contours show the strength of combination of exchange rate and j o u r n a l p r e -p r o o f covid-19 in predicting temperature. the more red the color, the more the variation can be explained in temperature by the combination of exchange rate and covid-19. figure 7c-2 shows mwc results involving exchange rate as dependent while temperature and covid-19 as independent variables. two small circles can be observed in the frequency band of 0-4 during 2 nd and last week of observation respectively while a large red circle in frequency band of 16 and above during 4 th and 5 th week of observation. these red areas show the association between exchange rate and a linear combination of temperature and covid-19 in that particular time-frequency space. average daily temperature of wuhan shows a positive (in phase) coherence with daily new number of covid-19 cases in medium term considering the given observation time period. this suggests that increase in temperature did not play any significant role in reducing the covid-19 spread in wuhan. this result is contrary to a lot of other studies suggesting that increase in temperature may help to contain covid-19 spread. our results are applicable for a temperature range between 3 degree and 21 degree centigrade which is the minimum and maximum temperature observed during the observation period. although exchange rate and covid-19 show a significant negative (out phase) coherence for a short period of time during 4 th and 5 th weeks of observation, the impact of covid-19 on rmb exchange rate is not very large. the mwc results downplay any huge combined impact of covid-19 and temperature on rmb exchange rate suggesting little impact on chinese exports during the observation period. overall results show a significant co movement and coherence between covid-19, exchange rate and weather in wuhan. although wavelet analysis is relatively new and better than correlation and many other time series techniques from many aspects as stated above in methodology section, results from this approach still need a caution in interpretation while talking about causality. in absence of any sound economic/scientific/social theory, there may not be any causation and data may show correlation and co-movements merely. modeling nonlinear granger causality between the oil price and us dollar: a wavelet based approach china's global interdependence: international reserves, capital inflows, financial market transmission, and exchange rate determination effects of air temperature and relative humidity on coronavirus survival on surfaces the effects of temperature and relative humidity on the viability of the sars coronavirus clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records are chinese trade flows different 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in multilevel logistic regression to investigate contextual phenomena geophysical applications of partial wavelet coherence and multiple wavelet coherence role of temperature and humidity in the modulation of the doubling time of covid-19 cases exporting and firm performance: chinese exporters and the asian financial crisis temperature and latitude analysis to predict potential spread and seasonality for covid-19 world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19) the role of the chinese economy in the world economy: a us perspective correlation between weather and covid-19 pandemic in jakarta co-movement of energy commodities revisited: evidence from wavelet coherence analysis disease metaphors in new epidemics: the uk media framing of the 2003 sars epidemic temperature significant change covid-19 transmission in 429 cities can we contain the covid-19 outbreak with the same measures as for sars? multi-scale relationship between land surface temperature and landscape pattern based on wavelet coherence: the case of metropolitan beijing a novel coronavirus from patients with pneumonia in china j o u r n a l p r e -p r o o f key: cord-306448-pxdqvk1p authors: zhang, li; sun, yang; chen, ting; xu, qiang title: selective depletion of glycyrrhizin from si-ni-san, a traditional chinese prescription, blocks its effect on contact sensitivity in mice and recovers adhesion and metalloproteinases production of t lymphocytes date: 2005-03-21 journal: int immunopharmacol doi: 10.1016/j.intimp.2005.02.015 sha: doc_id: 306448 cord_uid: pxdqvk1p in the present study, we performed to selectively deplete glycyrrhizin from si-ni-san, a traditional chinese prescription that consists of 4 chinese herbs including radix glycyrrhizae uralensis, and examined its influence on the suppressing activity of si-ni-san against contact sensitivity in mice. an immunoaffinity column was made by covalently coupling the polyclonal antibody, obtained by the immunization with glycyrrhizin–bsa conjugate, to cnbr-activated sepharose 4b. by using this column, glycyrrhizin in si-ni-san was selectively and almost completely depleted from the whole extract, which was confirmed by high-performance liquid chromatography (hplc). both 200 mg/kg of si-ni-san and 10 mg/kg of glycyrrhizin, the dose corresponding to its proportion contained in si-ni-san, significantly reduced the ear swelling of picryl chloride (pcl)-induced ear contact sensitivity in mice and the inhibition by si-ni-san was stronger than that by glycyrrhizin. the adhesion activity to type iv collagen of the isolated spleen cells from pcl-sensitized mice was significantly decreased by both si-ni-san and glycyrrhizin. however, the glycyrrhizin-depleted sample of si-ni-san (si-ni-san(gl−)) only showed a slight inhibition on the cell adhesion. furthermore, the spleen cells from pcl-sensitized mice produced more matrix metalloproteinase (mmp)-2 and -9 than naive spleen cells did, and both si-ni-san and glycyrrhizin remarkably reduced mmp-2 and mmp-9 production. in contrast, si-ni-san(gl−) only showed a slight inhibition. these results suggest that glycyrrhizin may act as one of the active constituents of si-ni-san in inhibiting delayed-type hypersensitivity reaction via down-regulating the mmp production and the cell adhesion to extracellular matrix. the present study also provides a new approach to recognize and validate an active constituent in traditional prescription through a selective depletion. contact sensitivity has served as the classical model for delayed-type hypersensitivity (dth) reactions in skin [1] . the cellular and molecular mechanisms of dth reactions have been intensively studied. during the lymphocyte localization and infiltration to inflammatory locus, lymphocytes should interact with endothelial cells and the underlying basement membrane and extracellular matrix [2, 3] . in the process of these immune responses, matrix metalloproteinases (mmps) are known to degrade basement membrane and extracellular matrix and to enhance the inflammatory infiltration of t lymphocytes into target tissues [4] . furthermore, there are increasing evidences that some kinds of monoclonal antibodies and synthetic peptides could ameliorate inflammation via inhibiting lymphocyte adhesion to extracellular matrix [3, 5, 6] . these findings demonstrated that inhibition on t cell adhesion and interference with the activities of the proteinases including mmps may represent a useful approach to the treatment of t cell-mediated immune diseases. to find such an approach, in addition to the immunosuppressants and anti-inflammatory agents, research has also been focused on the effect of various traditional chinese medicines. many extracts from chinese herbs and their principles have been evidenced to improve t cell-mediated diseases, such as hepatitis and arthritis, via inhibiting the t cell function [7] [8] [9] [10] . our group has also found the strong effect of a traditional chinese prescription, si-ni-san, in treating immunological liver injury and contact sensitivity [11, 12] . these effects of the prescription have also been recognized to be related to the inhibition on the t cell functions. si-ni-san written in the treatise on febrile diseases, a medical classic by zhongjing zhang in east han dynasty, comprises an equal ratio of four chinese medicines: chaihu (radix bupleuri chinensis), shaoyao (radix paeoniae alba), zhishi (fructus citri aurantii) and gancao (radix glycyrrhizae uralensis). this ancient prescription has been believed to be effective in curing some inflammatory diseases and widely used as a mediation recipe to treat hepatitis, gastritis, neuralgia, appendagitis during the long history of china [13] [14] [15] . among the herbal drugs composed in the prescription, glycyrrhiza uralensis fisch (licorice) is a common medicinal herb in traditional chinese medicine. in clinics, it is used to treat hepatitis, diabetes, and peptic ulcer [16] . as a major component of licorice root, glycyrrhizin, consists of glycyrrhetic acid and two molecules of glucuronic acid (fig. 1) . so far, glycyrrhizin exhibits a number of pharmacological effects, including antiinflammation, anti-ulcer, anti-allergy, anti-carcinogenesis, and immunomodulation [17] [18] [19] [20] . the compound is also used as a potential therapeutic agent for several virus diseases, including chronic hepatitis, acquired immunodeficiency syndrome, and herpes infection [21] [22] [23] [24] . recently glycyrrhizin was also proved to be effective against severe acute respiratory syndrome (sars)-associated coronavirus [25] . taking these reports into consideration, we presumed that glycyrrhizin might make an important contribution to the pharmacological efficacy of si-ni-san. although si-ni-san has been widely used in clinics and its action mechanisms have been partially elucidated [11, 12] , the active constituents and the pharmacological properties of their potency are not sufficiently clarified yet. for exploring the active principles of a chinese herb and its blended prescription, a common method is to isolate the compounds contained by a chemical purification or the activity-guided purification [26] . such assay is usually based on the activity of purified compounds but difficult to reflect the actual contribution of the compound in total prescription. on the other hand, immunoaffinity chromatography is one of the most powerful techniques to selectively isolate or concentrate minor components of interest from a complex mixture [27] . its selectivity is derived from the use of an immobilized specific biomolecule, such as antibodies, receptors and specific proteins. in the aspect of traditional chinese medicines, antibodies to the chemical principles contained in the crude materials have been made and applied to the quantitative determination of some active compounds in various traditional chinese prescriptions or herbs by using elisa [28] . in order to obtain antibodies against the components, the compounds are usually bound with a protein, such as bovine serum albumin (bsa), and the complex is then used as an antigen. according to these findings, in the present study, we designed to make the antibody vs glycyrrhizin, and then we tried to selectively deplete glycyrrhizin from si-ni-san to define the role of the compound in the whole si-ni-san in inhibiting ear contact sensitivity, a typical delayed-type hypersensitivity reaction, with regard to lymphocyte adhesion and mmp production. female icr strains of mice (conventional), 6-8week-old and 20 f 2 g were obtained from the experimental animal house of china pharmaceutical university (nanjing, china). they were maintained with free access to pellet food (jiangsu cooperation medical and pharmaceutical company, nanjing, china) and water in plastic cages at 21 f 2 8c and kept on a 12-h light / dark cycle. male new zealand white strain rabbit, 8-month-old, weighing 2-3 kg were purchased from jiangsu academy of agricultural sciences (nanjing, china) and maintained on the premises under standard animal house conditions. animal welfare and experimental procedures were carried out strictly in accordance with the guide for the care and use of laboratory animals (national research council of usa, 1996) and the related ethical regulations of our university. all efforts were made to minimize animal's suffering and to reduce the number of animals used. the crude drugs used in this study were purchased from nanjing medicinal material co. (nangjing, china) and identified as bupleurum chinese dc. . they were mixed in an equal ratio (25 g of each drug; in total 100 g) to make up si-ni-san, a mixed powder of material crude drugs. these materials were used for making 70% ethanol extracts as reported with small modification. briefly, the materials (100 g) were extracted twice with 5-fold volumes of 70% ethanol (500 ml) at 70 8c for 1 h each time. then the supernatant, after centrifuging at 2000 âg, was pooled and lyophilized to make a powder with 23.2% yields for si-ni-san. the dosages of these extracts were indicated as the powders. the contents of main components in the 70% ethanol extracts of si-ni-san were determined by high-performance liquid chromatography (hplc) as 0.25% of saikosaponin a, 1.0% of paeoniflorin, 2.7% of naringin and 4.6% of glycyrrhizin. the powders were dissolved in water for in vivo assay by gavage oral administration to mice and in rpmi 1640 medium for in vitro assay. other drugs and reagents used in this study were as follows: glycyrrhizin (wako, japan), bovine serum albumin (bsa, sigma), ovalbumin (ova, sigma), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (edc), n,ndimethylformamide (dmf), freund's complete and incomplete adjuvants (pierce), peroxidase-labeled goat anti-rabbit igg (wuhan boster biotechnology co., ltd, china), o-phenylenediamine (opd), sephadex g-25 (beijing baidier biotechnology co., ltd, china), cellulose de-32 (beijing dingguo biotechnology co., ltd, china), cnbr-activated sepharose 4b (pharmacia biotech), injection dexamethasone sodium phosphate (dex, nanjing 3rd pharmaceutical factory, nanjing, china), picryl chloride (pcl, nacalai tesque inc, kyoto, japan), rat tail type iv collagen (sigma), phorbol myristate acetate (pma, sigma), acrylamide and bis-acrylamide (shanghai sangon biotechnical co., ltd, shanghai, china), gelatin and coomassie brilliant blue r-250 (sigma), crystal violet (shanghai yuanhang reagent factory, shanghai, china), 96-well culture plates (nunclon). all other chemicals were standard commercial products of analytical grade. analytical hplc was performed on a pump (waters 600) equipped with a uv detector (254 nm, waters 2487). ods-c 18 column, 150 â 4.6 mm, i.d., 5 am (ymc, japan) was used. methanol : water : acetic acid (70 : 25 : 5, (v / v)) was used as mobile phase (flow rate 1.0 ml/min). to 10 ml pbs (ph 7.6) solution containing 25 mg bsa and 20 mg edc, 21 mg glycyrrhizin in 1.0 ml dmf solution were added dropwise. five mg edc were added to the above reaction mixture again 30 min later and then stirred at room temperature for 12 h. the reaction mixture was dialyzed against h 2 o for 3 days, and then lyophilized to give glycyrrhizin-bsa conjugate (30 mg). meoh solution 4.0 ml containing 60 mg glycyrrhizin was added to the h 2 o solution (4.0 ml) of naio 4 dropwise, and stirred for 60 min. to the above reaction mixture, a carbonate buffer solution (ph 9.6, 14 ml) containing ova (50 mg) was added. the reaction mixture was adjusted to ph 10.0 with 1 m na 2 co 3 solution and stirred at room temperature for 6 h, and so dialyzed for 3 days against h 2 o, and then lyophilized to give glycyrrhizin-ova conjugate (80 mg). rabbits were bled through the marginal ear vein before immunization and the blood was collected from individual rabbits into separate tubes. after clotting for 60 min at 37 8c and overnight at 4 8c, the separated pre-immune serum was taken from the clot and centrifuged at 10,000 âg to remove any remaining insoluble material for 10 min at 4 8c. these sera were stored in aliquots at à 20 8c and used as blanks for enzyme-linked immunosorbent assay (elisa). to make polyclonal antiserum against glycyrrhizin, two rabbits were immunized with the glycyrrhizin-bsa conjugates. namely, 2 mg of glycyrrhizin-bsa was dissolved in 500 al sterile pbs (ph 7.2) and mixed with freund's complete adjuvant in a ratio of 1 : 1. then, these emulsions were injected subcutaneously into 10-20 sites on the back of the respective rabbits. the rabbit was boosted intramuscularly at multiple sites on day 14 and day 21 with 3 and 5 mg of the glycyrrhizin-bsa in 500 al of sterile pbs (ph 7.2) mixed with 500 al of freund's incomplete adjuvant, respectively. on day 28, each rabbit was boosted again with 4 mg glycyrrhizin-bsa in 500 al of sterile pbs (ph 7.2) by ear vein injection. blood was sampled via the ear vein and antibody titres were checked by direct elisa. once the desired antibody titre had been confirmed, the rabbits were sacrificed and bled out. the immune sera against glycyrrhizin were stored at à 20 8c. a 100 al portion of glycyrrhizin-ova (500 ag/ ml in 50 mm carbonate buffer) was allowed to adsorb onto the wells of a 96-well immunoplate (nunclon) at 4 8c overnight. the plate was treated with 200 al of pbs containing 5% newborn calf serum at 37 8c for 1 h to reduce nonspecific adsorption, washed three times with pbs containing 0.05% tween-20 (pbst), and reacted with 100 al different dilutions of antiserum at 37 8c for 1 h. appropriately diluted non-immune serum was used as the control. the plate was washed three times with pbst, and then the antibody was combined with 100 al of 1 : 1000 dilution of peroxidase-labeled goat anti-rabbit igg for 1 h at 37 8c. after washing the plate three times with pbst, 100 al of substrate solution, 0.1 m citrate buffer (ph 4.0) containing 0.15% h 2 o 2 and 0.4 mg/ ml of opd diammonium salt, were added and incubated for 20 min in darkness. then, 50 al of 2 m h 2 so 4 were added to stop the reaction. the absorbance was measured using an elisa reader (sunrise remote/touch screen, tecan, austria) at 492 nm. antibodies in the sera were precipitated by threestep procedure. the first step consisted in the addition of ammonium sulfate up to 50% saturation and the suspension was stored overnight at 4 8c followed by centrifugation at 10,000 rpm for 20 min. the supernatant was discarded. the precipitate protein was dissolved in ammonium sulfate to the final concentration of 33% saturation and the suspension was kept at 4 8c for 2 h under gentle stirring. the precipitate was collected by centrifugation at 10,000 rpm for 20 min. the protein was precipitated again with ammonium sulfate to the final concentration of 33% saturation. a glass column (2.5 â 45.0 cm) was packed with sephadex g-25 and equilibrated with 400 ml of 0.0175 m phosphate buffer at ph 6.4. a flow rate of 60 ml/h was maintained. the precipitate resulting from ammonium sulfate fractionation 33% saturation was dissolved in 3 ml of 0.0175 m phosphate buffer and applied to the sephadex g-25 gel bed and protein was eluted with 0.0175 m phosphate buffer at ph 6.4. absorbance at 280 nm was monitored for each protein fraction with a uv spectrophotometer (21c-a, shanghai kanghua bio-instrument factory, china). fractions that showed highest protein content were collected. a glass column (2.5 â 45.0 cm) was packed with slurry of cellulose de-32 and equilibrated with 200 ml of 0.0175 m phosphate buffer at ph 6.4. the fractions of highest absorbance at 280 nm from gel filtration on sephadex g-25 column pooled and applied to the cellulose de-32 column. elution was performed with 0.0175 m phosphate buffer at ph 6.4, at a flow rate of 60 ml/h. fractions (5 ml) were collected, protein content for each fraction were monitored. the fractions possessing highest protein content were collected and lyophilized. igg purity characterization was carried out on a bio-rad electrophoresis system. sodium dodecyl sulfatepolyacrylamide gel eletrophoresis (sds-page) was performed according to the method of laemmli, uk [31] . electrophoresis was performed in 7% polyacrylamide gels with a current of 25 ma for approximately 2 h. standard molecular weight marker containing 10 proteins ranging in size from 10 to 200 kda (bio-rad, usa) was used as reference in the lane. the gels were stained with coomassie brilliant blue r-250 for 2 h with constant shaking on a rocker table. purified igg (10 mg) in 0.01mol/l pbs was added to a slurry of cnbr-activated sepharose 4b (500 mg) in coupling buffer (0.1 m nahco 3 containing 0.5 m nacl, ph 8.0). the slurry was rotated end-over-end for 2 h at room temperature. after washing away the excess ligand with 5 bed volumes of coupling buffer, the slurry was treated with 0.1 m tris-hcl, ph 8.0, for a further 2 h at room temperature to block remaining activate groups. then the slurry was washed three times with alternate cycles of 0.1 m acetate buffer, ph 4.0 containing 0.5 m nacl, and 0.1 m tris-hcl, ph 8.0 containing 0.5 m nacl. finally, the affinity gel was centrifuged and the supernatant removed. the washing solution and the supernatant were combined, and unbound protein measured at 280 nm for determining coupling efficiency, which was found to be 87% of the igg added. the immunoaffinity gel was washed with pbs and packed in glass mini-columns in volumes of 2.5 ml. before breakthrough column, the immunoaffinity column was conditioned with 0.01 mol/l pbs at 4 8c. then 1 ml of the solution of filtered si-ni-san in 0.01 mol/l pbs was applied to the column and the effluent was collected and measured by hplc until glycyrrhizin appeared in the effluent. thereafter, the fraction without glycyrrhizin was collected and evaporated to dryness on a 50 8c water bath. mice were sensitized by painting 0.1 ml of 1% pcl in ethanol on the shaved skin of their abdomens. five days later, they were challenged by painting 30 al of 1% pcl in olive oil on right ear lobe [12] . eighteen hours later, the mice were sacrificed under anesthesia and then the ear thickness of right against left was measured with a digimatic micrometer (0.001 mm, mitutoyo co., tokyo, japan). the control animals were run parallel with other groups except for gavage p.o. the same volume of water. adhesion assay was performed according to the report [32] with some modifications. briefly, a flatbottom 96-well microplate was coated with 50 al solution containing type iv collagen (50 ag/ml) and left at 4 8c overnight. nonspecific binding sites were blocked with 0.2% bsa for 2 h at room temperature followed by washing three times with phosphate buffer solution. the cells were suspended in rpmi 1640 and spleen cells (5 â 10 5 ) were added to each well. the cells were incubated at 37 8c for 1 h with or without pma (100 nm) and the non-adherent cells were removed by washing three times with rpmi 1640. then cells were fixed with methanol / acetone (1 : 1), and stained with 0.5% crystal violet in 20% methanol. unbound dye was removed in tap water and the plate was dried in air. bound dye was extracted with 1% sds. the absorbance of the samples was measured at 592 nm. the wells, which were fixed and stained without previous washing, were regarded as the absorbance of total cells. the results were expressed as the mean percentage of total cells from triplicate wells and the experiments were repeated three times. spleen cells from control animals were subjected to the same assay procedures in parallel. specificity of cell adhesion assays was corroborated using bsa as substratum. analysis by zymography on gelatin gel allows detection of enzymatic activity of the secreted collagenases mmp-2 and mmp-9 [33] . briefly, spleen cells isolated from various treated mice were suspended in serum-free rpmi 1640 medium at a density of 5 â 10 5 / well and incubated at 37 8c in 5% co 2 for 24 h. spleen cells from control animals were subjected to the same assay procedures in parallel. twenty microliters of the supernatants were mixed with 10 al sample buffer (62.5 mm tris-hcl containing 10% glycerol, 0.00125% bromophenol blue and 12% sodium dodecyl sulfate (sds)) without reducing agent, and they were subjected to sds-page in 5% polyacrylamide gels that were copolymerized with 2 mg/ml of gelatin at 4 8c for 1 h. after electrophoresis, the gels were washed twice in the rinsing buffer (50 mm tris-hcl containing 2.5% triton x-100, 5 mm cacl 2 , 1 am zncl 2 , 0.05% nan 3 ) for 1 h at room temperature to remove sds. then, they were incubated for 36 h at 37 8c in the incubation buffer (50 mm tris-hcl containing 5 mm cacl 2 , 1 am zncl 2 , 0.05% nan 3 ). the gels were stained with 0.1% coomassie brilliant blue r250 for 30 min, and destained for 8 h in a solution of 10% acetic acid and 10% isopropanol. the proteolytic activity was evidenced as clear bands (zones of gelatin degradation) against the blue background of stained gelatin. results were expressed as mean f sd of three independent experiments and each experiment includes triplicate sets in vitro and of eight animals of each group in vivo. statistically evaluated by student's t test when only two value sets were compared, and one-way anova followed by dunnett's test when the data involved three or more groups. p b 0.05 was considered to be significant. as shown in table 1 , when orally administered for 6 days from the sensitization, si-ni-san at 200 mg/kg significantly inhibited the ear swelling. glycyrrhizin at the dose of 10 mg/kg, which was corresponding to its proportion contained in si-ni-san, also showed a significant reduction in the ear swelling. such result was confirmed in the repeated experiment where si-ni-san and glycyrrhizin at the dose of 100 and 5 mg/ kg, respectively showed a tendency of inhibition and those at 200 and 10 mg/kg significantly inhibited the contact sensitivity. dexamethasone as a positive drug also showed a strong inhibition. as described in fig. 1 , two conjugate products of glycyrrhizin were obtained with carrier protein. glycyrrhizin was coupled to bsa to prepare the complete antigen, which was used to immunize rabbits. glycyrrhizin was also coupled to ova as coating antigens. the reactivity of obtained antiserum was tested by varying antibody concentration and by performing a dilution curve with direct elisa method as indicated in fig. 2 . the crude antiserum was partially purified by fractional precipitation with ammonium sulfate and it was pooled and further purified by sephadex g-25 and cellulose de-32 columns. the purity of igg was confirmed by sds-page. as shown in fig. 3 , the purified igg separated into two subunits with molecular masses of 25 and 50 kda. the purified polyclonal antibody was coupled to cnbr-sepharose 4b to generate the immunoaffinity column. si-ni-san was loaded on the immunoaffinity column and the effluent was collected and measured by hplc. as shown in fig. 4b , the content of glycyrrhizin in si-ni-san was 4.6% according to the ear contact sensitivity was induced to picryl chloride in mice. eighteen hours after the challenge, the thickness of right and left ears were measured and the swelling was evaluated by the increase in ear thickness. si-ni-san and glycyrrhizin were given orally and dexamethasone was given intramuscularly for 6 days after the sensitization. each figure indicates the mean f sd of 8 mice. t p b 0.05. tt p b 0.01 vs control; (dunnett's test). standard (fig. 4a) . after passed through the column, the compound was almost undetectable and its content decreased about 95.5% (fig. 4c ). si-ni-san, glycyrrhizin and si-ni-san glà on the adhesion ability to type iv collagen of splenocytes from pcl-sensitized mice mice were sensitized by pcl as described in materials and methods. five days after the sensitization, the spleen cells were isolated for adhesion assay. as shown in fig. 5 , in the presence of pma, the splenocytes from pcl-sensitized mice showed a significantly increased adhesion to collagen as compared with the cells from naive mice. against this, si-ni-san and glycyrrhizin significantly inhibited the adhesion. in comparison with the original si-ni-san, the glycyrrhizin-depleted sample of si-ni-san (si-nito examine the reactivity of the antiserum, gradiently diluted antiserum were added to each well of a 96-well immunoplate coated with 500 ag/ml glycyrrhizin-ova. san glà ) only showed a slight inhibition on the cell adhesion. 3.5. effect of si-ni-san, glycyrrhizin and si-ni-san glà on the production of mmp-2 and mmp-9 in splenocytes isolated from pcl-sensitized mice as shown in fig. 6a and b, the splenocytes isolated from pcl-sensitized mice secreted a higher level of mmp-2 than those from naive mice. against the increased secretion, both si-ni-san and glycyrrhizin, which had treated the cells for 24 h, significantly decreased the cell adhesion. however, si-ni-san glà only showed slight redution. in the case of mmp-9, there were the similar results ( fig. 6c and d) . in the present study, we first confirmed the anti-dth activity of si-ni-san, a traditional chinese prescription, by using a mouse model of pcl-induced ear contact sensitivity, a typical dth reaction. since si-ni-san contains high content of glycyrrhizin, which possesses a wide range of pharmacological properties including strong anti-inflammatory activity, the activity of si-ni-san at 200 mg/kg was compared with this major component according to its amount (10 mg/kg) contained in 200 mg/kg si-ni-san. as the result, both si-ni-san and glycyrrhizin showed a significant inhibition on the ear swelling though the inhibition intensity by glycyrrhizin was less than that by si-ni-san at the used doses (table 1 ). this finding suggests that glycyrrhizin, at least, is one of the main components contained in si-ni-san to interfere with the activation of t lymphocytes involved in the ear inflammation. next, we attempted to prepare an immunoaffinity column against glycyrrhizin to selectively deplete this compound from si-ni-san. for this purpose, we first made an antibody to the compound. as shown in fig. 1 , we conjugated glycyrrhizin with bsa to prepare the complete antigen and used it to immunize rabbits. at the same time, glycyrrhizin-ova conjugate was also synthesized as coating antigens with different method to avoid cross-reaction. serum from immunized rabbits was seen to give strong titres when test by elisa against glycyrrhizin-ova (fig. 2) . then the polyconal antibody against glycyrrhizin was purified from the antiserum by ammonium sulfate fractionation, and consecutive column chromatography using sephadex g-25 and deae-cellulose. after these purification steps, two subunits with molecular mass of 25 and 50 kda were detected in the purified polyconal antibody, which in good agreement with that of the light and heavy chains of igg being determined under denatured conditions on sds-page (fig. 3) . these results indicated that we have successfully obtained the purified polyconal antibody against glycyrrhizin. today separations based upon imunoaffinity techniques are more and more common in a large field of applications. due to the specificity of the antigen-antibody interactions, methods based on immunorecognition are very selective. immunorecognition methods carried out in chromatographic columns can be used for both isolation and analysis [34] . it has been reported that some monoclonal or polyconal antibodies against various bioactive natural products have been made to develop new elisa fig. 5 . effect of si-ni-san, glycyrrhizin and the glycyrrhizindepleted sample of si-ni-san (si-ni-san glà ) on the adhesion of splenocytes from pcl-sensitized mice to type iv collagen. mice were sensitized by pcl as described in materials and methods. five days after the sensitization, the spleen cells were isolated and incubated with si-ni-san, glycyrrhizin and si-ni-san glà all at 10 à 4 g/ml at 37 8c in 5% co 2 for 2 h. then the cells were washed and used for adhesion assay. each column represents the mean f sd of three independent experiments and each experiment includes triplicate sets. spon: cell alone; cont: cells + pma; *p b 0.05, **p b 0.01 vs cont (dunnett's test); ## p b 0.01 vs si-ni-san (student's two-tailed t test). methods for the quantification of principles in crude drugs or prescription samples [28] . however, using these antibodies to deplete specific component in traditional chinese prescription has not been reported yet. in the present study, the antibody raised against glycyrrhizin was covalently bound to the chromatographic packing. the coupling efficiency defined as the percentage of immobilized antibody accounted for the original amount, was observed to be 87%. then si-ni-san extract was passed through this imunoaffinity column, where glycyrrhizin was captured and concentrated by the glycyrrhizin antibody while the rest of components of the samples were eluted. in fig. 4 , we observed the content of glycyrrhizin in si-ni-san decreased greatly after passed through the column, accounting for about 95.5% of the original amount. this result indicated that glycyrrhizin has been selectively depleted from si-ni-san by this approach. considering the crucial role of the adhesion ability to type iv collagen of lymphocytes to extracellular matrix in the progress of dth reaction [3] , we next examined the influence of si-ni-san, which had been depleted of glycyrrhizin on the adhesion of spleen cells from pcl-sensitized mice to type iv collagen in vitro. the adhesion activity of the spleen cells was significantly enhanced when the cells were stimulated by protein kinase c (pkc) activator, pma in vitro. against the increase, the pretreatment with si-ni-san and glycyrrhizin significantly inhibited the adhesion almost to the normal level. however, the glycyrrhizindepleted sample of si-ni-san only showed a slight inhibition. in other words, the depletion of glycyrrhizin significantly blocked the inhibition of si-ni-san on the lymphocyte adhesion (fig. 5) . these findings indicated that glycyrrhizin might make an actual contribution to the inhibition of si-ni-san on the cell adhesion. lymphocyte localization to the inflammatory sites requires cooperation between adhesion molecules and mmps. as many reports indicated, mmps that can degrade extracellular matrix is indispensable for the adhesion of lymphocytes to extracellular matrix. excretion of mmp-2 and mmp-9 conspicuously increases when the integrins on t cell surface bind to their ligands in extracellular matrix [35] . in fig. 6, fig. 6 . effects of si-ni-san, glycyrrhizin, and the glycyrrhizin-depleted sample of si-ni-san (si-ni-san glà ) on the productions of mmp-2 and mmp-9 in splenocytes isolated from pcl-sensitized mice. a and b: mmp-2. c and d: mmp-9. five days after pcl sensitization, the isolated spleen cells were incubated with si-ni-san, glycyrrhizin and si-ni-san glà all at 10 à 4 g/ml at 37 8c for 24 h. after the incubation, the supernatants were aspirated and used for zymography assay. the figure shown here is the representative of three different experiments. we observed the activities of mmp-2 and mmp-9 produced by spleen lymphocytes from antigen-sensitized mice. such production of mmp-2 and mmp-9 was remarkably inhibited by si-ni-san and glycyrrhizin. however, once glycyrrhizin was depleted from si-ni-san, the extract only showed a slight inhibition. these results suggested that glycyrrhizin also plays an important role in the inhibition efficacy of si-ni-san on mmps production. in addition to glycyrrhizin, there are many other active components contained in si-ni-san. for instance, saikosaponins from radix bupleuri were well known to have excellent anti-inflammatory activity [36] ; paeoniflorin from radix paeoniae showed a potent analgesic action [37] ; and naringin from fructus citri aurantii had antioxidant effects in cholesterol-fed rabbits [38] . all these findings as well as those on the biological activities of glycyrrhizin so far, were obtained by pharmacological assays using the purified compounds. however, in these investigations, it is usually difficult to know whether the compounds actually act in the total prescription. on the other hand, our previous study focused on the effect of si-ni-san and its effective constituents on t cell-mediated disease models. our data demonstrated that the activities of si-ni-san were better than its single herbs on the animal inflammation. by analyzing the composition of si-ni-san, we found that the effect of this prescription was mainly contributed by the combination of chaihu and shaoyao, as well as shaoyao and gancao [12] . we also found that saikosaponin mainly inhibited t lymphocyte activation and proliferation (unpublished data), while glycyrrhizin showed strong inhibition on t lymphocyte adhesion to extracellular matrix and mmps secretion (figs. 5 and 6) . these data indicated a fact that si-ni-san showed an integrated effect from many components contained and there still remain a lot of questions. from this view, the attempt to specifically deplete one or more components from a traditional chinese prescription as used in the present study may be helpful for the elucidation of the activity of traditional chinese medicines. overall, glycyrrhizin may act as an active constituent of si-ni-san in inhibiting dth reaction involving down-regulation of mmps production and the cell adhesion to extracellular matrix. a further study of the detailed mechanisms is now in progress. effects of cilomilast on dendritic cell function in contact sensitivity and dendritic cell migration through skin tissue specificity of lymphocyte migration into sheep gingival tissue regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis matrix metalloproteinases in immunity anti-inflammatory activity of c(ildv-nh(ch2)5co), a novel, selective, cyclic peptide inhibitor of vla-4-mediated cell adhesion inhibition of contact hypersensitivity reaction to picryl chloride: effect of small molecular weight peptidomimetic compounds possessing inhibitory activity against metalloproteinases anti-inflammatory and antiviral effects of glossogyne tenuifolia suppressive effects of tripterygium wilfordii hook f., a traditional chinese medicine, on collagen arthritis in mice astilbin prevents concanavalin ainduced liver injury by reducing tnf-alpha production and t lymphocytes adhesion astilbin suppresses collagen-induced arthritis via the dysfunction of lymphocytes alleviating effects of si-ni-san, a traditional chinese prescription, on experimental liver injury and its mechanisms si-ni-san, a traditional chinese prescription, and its drug-pairs suppress contact sensitivity in mice via inhibiting the activity of metalloproteinases and adhesion of t lymphocytes clinical pathological study of si-ni-san on treating chronic hepatitis and hepatic fibrosis treatment of chronic gastritis by si-ni-san, one hundred and eighty-six cases treatment of chronic atrophic gastritis by si-ni-san, fifty-eight cases the long-term efficacy of glycyrrhizin in chronic hepatitis c patients glycyrrhizin and related compounds downregulate production of inflammatory chemokines il-8 and eotaxin 1 in a human lung fibroblast cell line the influence of commonly prescribed synthetic drugs for peptic ulcer on the pharmacokinetic fate of glycyrrhizin from shaoyao-gancao-tang anti-allergic activity of 18beta-glycyrrhetinic acid-3-o-beta-d-glucuronide management of chronic hepatitis c and prevention of hepatocellular carcinoma glycyrrhizin-induced reduction of alt in european patients with chronic hepatitis c mechanisms underlying the activation of cytotoxic function mediated by hepatic lymphocytes following the administration of glycyrrhizin effect of glycyrrhizin, an active component of licorice roots, on hiv replication in cultures of peripheral blood mononuclear cells from hiv-seropositive patients glycyrrhizin increases survival of mice with herpes simplex encephalitis glycyrrhizin, an active component of liquorice roots, and replication of sars-associated coronavirus relationship between the antidiarrhoeal effects of hange-shashin-to and its active components automated real-time immunoassay of biomolecules a quantitative elisa using monoclonal antibody to survey paeoniflorin and albiflorin in crude drugs and traditional chinese herbal medicines antibodies to bradykinin and angiotensin: a use of carbodiimides in immunology formation of a monoclonal antibody against glycyrrhizin and development of an elisa cleavage of structural protein during the assembly of the head of bacteriophage t4 tnf-alpha associated with extracellular matrix fibronectin provides a stop signal for chemotactically migrating t cells laminin deposition to type iv collagen enhances heptotaxis, chemokinesis, and adhesion of hepatoma cells through h1-integrins development and characterization of an immunoaffinity column for the selective extraction of bisphenol a from serum samples differential induction of gelatinase b (mmp-9) and gelatinase a (mmp-2) in t lymphocytes upon alpha4beta1-mediated adhesion to vcam-1 and the cs-1 peptide of fibronectin in vivo and in vitro anti-inflammatory activity of saikosaponins anticholinergic action of paeony root and its active constituents comparison of antioxidant effects of naringin and probucol in cholesterol-fed rabbits this study was supported by the national natural science foundation of china (no.90209040) and natural science foundation of jiangsu province (no. bk2003206). we should thank mr. dongfeng liu for his technical assistance on the antibody preparation. key: cord-319016-ymypvg6k authors: li, yu-xi; li, juan; zhang, yue; tian, yan-ping; zhang, yong-gang; jin, rong-jiang; guo, yan; clarke, mike title: clinical practice guidelines and experts’ consensuses for treatment of coronavirus disease 2019 (covid-19) patients with chinese herbal medicine: a systematic review date: 2020-10-08 journal: chin j integr med doi: 10.1007/s11655-020-3431-x sha: doc_id: 319016 cord_uid: ymypvg6k nan diarrhea, which also relates to dampness. therefore, in cm, the combination of the outbreak location and clinical manifestations of covid-19 patients, shows that the onset of covid-19 is mostly caused by pathogen of dampness. (6) this leads to the suggestion that herbs with functions of promoting fei (lung) and expelling dampness can be applied, and the use of cm has been associated with benefi ts against covid-19. (7, 8) this study provides a summary and appraisal of these guidelines, using systematic review methods. we this systematic review is reported in accordance with the preferred reporting items for systematic reviews and meta-analysis (prisma) guidance. (11) the study protocol was registered in the international p r o s p e c t i v e r e g i s t e r o f s y s t e m a t i c r e v i e w s (no. crd42020179205) and has been published. (12) the full prisma checklist and fl ow diagram are in appendix 1. clinical practice guidelines, expert consensus statements and guidance documents which provided information on using chm for covid-19 patients were included. to be eligible, the guidelines should be two reviewers (lyx and zdl) independently identified potentially eligible guidelines according to predetermined criteria. disagreements were discussed and arbitrated by a third reviewer (zyg). in order to achieve consistency in extracted items, the data extraction process was piloted using a sample of eligible the methodological quality and reporting quality of the included guidelines were evaluated using the appraisal of guidelines for research and evaluation (agree) ⅱ tool (14) and reporting items for practice guidelines in healthcare (right) statement, (15) respectively (see below). to ensure at least 80% consistency in quality assessments, we pre-assessed a sample of eligible guidelines and discussed the results among reviewers. the kappa coeffi cient was also evaluated. subsequently, 2 reviewers (lyx and lj) independently appraised the quality of each included guideline. discrepancies were discussed and resolved among the reviewers. the agree ⅱ instrument is a tool that can be used to assess the methodological rigour and transparency in the development of a guideline. (13, 16) it consists of 23 items in 6 domains: (1) scope and purpose (items 1-3), microsoft excel 2019 was used to summarize and analyze the recommendations for treating covid-19 patients with cm formulae and cpm, as well as the results of quality assessment. a total of 275 records in electronic databases and 26 records on websites of governments and organizations were identifi ed. after careful assessment, 45 of these met the inclusion criteria and were included for analysis (appendix 2). (10, as noted above, in cm theory, the main pathogens the kappa values for our independent assessments of the included guidelines using the agree ⅱ checklist and right checklist ranged from 0.73 to 0.82, indicating good consistency for quality assessments. using agree ⅱ, we rated only one of the 45 included guidelines as moderate quality (achieving 63%). the others were all of low quality, with scores from 18% to 44%. the score of each domain of agree ⅱ and the overall quality of each included guideline are summarized in appendix 5. domain 4 (clarity of presentation) achieved the highest mean score at 72% (range 28% to 83%), however, it is still clear that some guidelines, such as those published by expert groups or associations, need to improve their methodological and reporting quality to allow them to meet the standards of agree ⅱ and right. to achieve a solid evidence, future research should follow the agree ⅱ and right checklist during the guideline development. (70) recently, ang, et al (71, 72) published two rapid reviews of guidelines of herbal medicine for covid-19. we have improved on those by systematically searching and retrieving more guidelines relating to the recommendation of chm for covid-19 patients based on cm theory. we also conducted this systematic review with prior study design and registration, and independently evaluated each included guideline against recognized standards for practice guidelines: agree ⅱ for methodological quality and right for reporting quality. these fi ndings provide useful insights for future guideline developers and people studying guidelines and guideline development. this study has some limitations: (1) we only searched chinese and english databases, so our findings may not apply to guidelines in other languages; (2) we summarized formulae and cpms if they were originated from chinese classic medical books with prescription names and if they were recommended in more than 2 guidelines, which means that there may be some missing information, such as prescriptions based on local doctors' experiences or recommendations in a single guideline; (3) the methodological and reporting quality of most of included guidelines was low, which may infl uence the certainty of our results. in conclusion, this study has summarized current recommendations for the use of chm to prevent covid-19 and to treat it during the medical observation period and clinical treatment period; including in the early, development, critical and recovery stages. however, the general quality of present guidelines is low and the development of future guidelines should include increased awareness of the features of good quality guidelines. a novel coronavirus emerging in china-key questions for impact assessment preliminary prediction of the basic reproduction number of the wuhan novel coronavirus 2019-ncov characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention clinical features of patients infected with 2019 novel coronavirus in wuhan, china effi cacy and safety of lianhuaqingwen capsules, a repurposed chinese herb diagnosis and treatment of novel coronavirus pneumonia based on the theory of traditional chinese medicine traditional chinese medicine for covid-19 treatment treatment efficacy analysis of traditional chinese medicine for novel coronavirus pneumonia (covid-19): an empirical study from wuhan novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china diagnosis and treatment guideline of novel coronavirus pneumonia preferred reporting items for systematic reviews and meta-analyses: the prisma statement clinical practice guidelines and experts' consensuses of traditional chinese herbal medicine for novel coronavirus (covid-19): protocol of a systematic review practical statistic for medical research agree ii: advancing guideline development, reporting, and evaluation in health care a reporting tool for practice guidelines in health care: the right statement quality of clinical practice guidelines about red blood cell transfusion a rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-ncov) infected pneumonia (standard version) health commission of the inner mongolia autonomous region. diagnosis and treatment of pneumonia caused by novel coronavirus by traditional chinese medicine in the inner mongolia autonomous region traditional chinese medicine differentiation and treatment protocol for novel coronavirus pneumonia in jiangsu province (trial version 3) military medical expert group on the front-line. diagnosis and treatment protocol for covid-19 from military medical team supporting wuhan (trial version 2) anhui province expert consensus of new coronavirus pneumonia chinese medicine treatment 2020 suggested prescription of traditional chinese medicine intervention for pneumonia caused by new coronavirus infection in sichuan province health commission of shandong province health commission of hebei and hebei administration of tcm. tcm diagnosis and treatment plan of new coronavirus pneumonia in hebei province tcm diagnosis and treatment for novel coronavirus pneumonia of tianjin province treatment of pneumonia caused by novel coronavirus in liaoning province (trial 2nd version) expert group of key diseases in pediatric base of national clinical research base of traditional chinese medicine. experts interpretation of traditional chinese medicine treatment in diagnosis, treatment and prevention of corona virus disease 2019 in children: experts' consensus statement (version 1) expert consensus on the diagnosis of novel coronavirus infections in children hunan administration of tcm. tcm diagnosis and treatment scheme of pneumonia caused by new coronavirus infection in hunan province (trial version 3) expert consensus on prevention and rehabilitation of integrated traditional chinese and western medicine during the outbreak of new coronavirus pneumonia in cancer patients in hubei province expert consensus on diagnosis and treatment of novel coronavirus pneumonia in the elderly expert guidance on the comprehensive intervention plan of tcm for the recovery of new coronavirus pneumonia (draft) chinese association of chest physicians. guide for the prevention and treatment of coronavirus disease guidelines for the prevention of pneumonia caused by novel coronavirus in taiyuan city health commission of henan province. novel coronavirus infection pneumonia prevention plan of chinese medicine in henan province chinese medicine prevention program for pneumonia of infl uenza and new coronavirus infections in winter and spring in shandong health commission of yunnan province. tcm program for prevention and treatment of pneumonia infected by novel coronavirus in yunnan province health commission of xinjiang uygur autonomous region. prevention and treatment of pneumonia caused by novel coronavirus in xinjiang uygur autonomous region by tcm tibetan medicine program for prevention and treatment of pneumonia caused by novel coronavirus infection in tibet autonomous region (trial 1st ed). 2020 health commission of qinghai province. tcm prevention and treatment for pneumonia infected by novel coronavirus in qinghai province (trial 2nd ed). 2020. available at health commission of nanjing city. tcm prevention and treatment for pneumonia infected by novel coronavirus in nanjing city (trial implementation) expert consensus on prevention and treatment of novel coronavirus pneumonia in guangdong with integrated traditional chinese and western medicine (trial version 1) guizhou novel coronavirus pneumonia reference scheme for chinese medicine prevention and control health commission of hainan province. prevention and treatment of novel coronavirus infection in hainan province with tcm hubei provincial traditional chinese medical hospital novel coronavirus pneumonia prevention and treatment plan of chinese medicine (third edition) tcm diagnosis and treatment plan and prevention plan of novel coronavirus pneumonia in tongji hospital affiliated to tongji medical college of huazhong university of science and technology professional commission of geriatric medicine of hubei society of tcm. expert consensus on prevention and treatment of novel coronavirus pneumonia in the elderly (first edition) health commission of heilongjiang province. prevention and treatment of pneumonia caused by novel coronavirus in heilongjiang province tcm prevention and treatment program of new coronavirus pneumonia in jiangxi province administration of tcm of ningxia hui autonomous region. prevention and treatment of pneumonia caused by new coronavirus infection in ningxia hui autonomous region (trial) prevention and treatment program of tcm for novel coronavirus pneumonia in tianjin (trial third edition) traditional chinese medicine prevention and treatment program for novel coronavirus pneumonia in beijing (trial version 4) health commission of gansu province. prevention and treatment of pneumonia caused by new coronavirus infection in gansu province (trial 2nd ed). 2020. available at summary of experience in the treatment of severe covid-19 with tcm and suggestions on treatment plan health commission of shaanxi province. tcm treatment for pneumonia infected by novel coronavirus in shaanxi province tcm treatment plan for novel coronavirus pneumonia in guangdong province (trial version 2) health commission of guangxi zhuang autonomous region. treatment of novel coronavirus pneumonia in the guangxi zhuang autonomous region with chinese medicine (trial) health commission of jilin province. treatment of novel coronavirus pneumonia in jilin province by tcm how does qingfei paidu decoction work quickly and effectively clinical observation of therapeutic effect of lianhua qingwen granule combined with abidor on mild coronavirus pneumonia clinical observation on 63 suspected cases of coronavirus pneumonia treated by lianhua qingwen granule combined with western medicine conventional therapy efficacy analysis of 51 covid-19 patients treated with chinese medicine lianhua qingwen: a multicenter retrospective study efficacy and safety of integrated traditional chinese and western medicine for corona virus disease 2019 (covid-19): a systematic review and meta-analysis clinical observation of qingfeipaidu decoction in the treatment of covid-19 treatment efficacy analysis of traditional chinese medicine for novel coronavirus pneumonia (covid-19): an empirical study from wuhan guideline-based chinese herbal medicine treatment plus standard care for severe coronavirus disease 2019 (g-champs): evidence from china chm for treating novel coronavirus (covid-19) pneumonia: protocol for a systematic review and metaanalysis quality assessment of clinical practice guidelines for infectious diseases in china herbal medicine and pattern identification for treating covid-19: a rapid review of guidelines herbal medicine for treatment of children diagnosed with covid-19: a review of guidelines key: cord-253182-s60vzf3q authors: fang, evandro f.; xie, chenglong; schenkel, joseph a.; wu, chenkai; long, qian; cui, honghua; aman, yahyah; frank, johannes; liao, jing; zou, huachun; wang, ninie y.; wu, jing; liu, xiaoting; li, tao; fang, yuan; niu, zhangming; yang, guang; hong, jiangshui; wang, qian; chen, guobing; li, jun; chen, hou-zao; kang, lin; su, huanxing; gilmour, brian c.; zhu, xinqiang; jiang, hong; he, na; tao, jun; leng, sean xiao; tong, tanjun; woo, jean title: a research agenda for ageing in china in the 21st century (2nd edition): focusing on basic and translational research, long-term care, policy and social networks date: 2020-09-21 journal: ageing res rev doi: 10.1016/j.arr.2020.101174 sha: doc_id: 253182 cord_uid: s60vzf3q one of the key issues facing public healthcare is the global trend of an increasingly ageing society which continues to present policy makers and caregivers with formidable healthcare and socio-economic challenges. ageing is the primary contributor to a broad spectrum of chronic disorders all associated with a lower quality of life in the elderly. in 2019, the chinese population constituted 18 % of the world population, with 164.5 million chinese citizens aged 65 and above (65+), and 26 million aged 80 or above (80+). china has become an ageing society, and as it continues to age it will continue to exacerbate the burden borne by current family and public healthcare systems. major healthcare challenges involved with caring for the elderly in china include the management of chronic non-communicable diseases (cncds), physical frailty, neurodegenerative diseases, cardiovascular diseases, with emerging challenges such as providing sufficient dental care, combating the rising prevalence of sexually transmitted diseases among nursing home communities, providing support for increased incidences of immune diseases, and the growing necessity to provide palliative care for the elderly. at the governmental level, it is necessary to make long-term strategic plans to respond to the pressures of an ageing society, especially to establish a nationwide, affordable, annual health check system to facilitate early diagnosis and provide access to affordable treatments. china has begun work on several activities to address these issues including the recent completion of the of the ten-year health-care reform project, the implementation of the healthy china 2030 action plan, and the opening of the national clinical research center for geriatric disorders. there are also societal challenges, namely the shift from an extended family system in which the younger provide home care for their elderly family members, to the current trend in which young people are increasingly migrating towards major cities for work, increasing reliance on nursing homes to compensate, especially following the outcomes of the ‘one child policy’ and the ‘empty-nest elderly’ phenomenon. at the individual level, it is important to provide avenues for people to seek and improve their own knowledge of health and disease, to encourage them to seek medical check-ups to prevent/manage illness, and to find ways to promote modifiable health-related behaviors (social activity, exercise, healthy diets, reasonable diet supplements) to enable healthier, happier, longer, and more productive lives in the elderly. finally, at the technological or treatment level, there is a focus on modern technologies to counteract the negative effects of ageing. researchers are striving to produce drugs that can mimic the effects of ‘exercising more, eating less’, while other anti-ageing molecules from molecular gerontologists could help to improve ‘healthspan’ in the elderly. machine learning, ‘big data’, and other novel technologies can also be used to monitor disease patterns at the population level and may be used to inform policy design in the future. collectively, synergies across disciplines on policies, geriatric care, drug development, personal awareness, the use of big data, machine learning and personalized medicine will transform china into a country that enables the most for its elderly, maximizing and celebrating their longevity in the coming decades. this is the 2nd edition of the review paper (fang ef et al., ageing re. rev. 2015). the research agenda in response to rapid population ageing in china has been broad, covering areas including the study of the ageing process itself in laboratory and animal studies, to clinical-level studies of drugs or other treatments for common chronic diseases, and finally policy-level research for the care of the elderly in hospital, community and residential care settings, and its influence on health and social care policies . chinese population statistics taken between 1950-2050 show a reduction in crude death rate (cdr) and total fertility rate (tfr), accompanied by an increase in life expectancy at birth and an expansion of the population aged 65 and above (65+, termed the elderly) (fig. 1a) . as of 2019, the population of mainland china constitutes 18% of global total, with 164.5 million chinese citizens aged 65+, 26 million of whom are 80+. by 2050, it is expected that there will be 1.4 billion chinese, with 365 million aged 65+, a number representing 26.1% of the country's total population (fig. 1b) . furthermore, among this ageing population, 115 million are expected to reach an age of at least 80 and 0.6 million are expected to become centenarians (fig. 1b) . when compared with their counterparts born a decade earlier, the current 80+ generation has reduced annual mortality and disability rates, but has increased cognitive impairment and reduced objective physical performance capacity (zeng et al., 2017b) . to achieve what may be considered a 'healthy ageing society', it is first important to address and prepare for the challenges and issues that are associated with rapidly ageing populations. ageing is the primary driver of most, if not all, chronic diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases, particularly alzheimer's disease (ad) and parkinson's disease (pd) (kerr et al., 2017; lautrup et al., 2019; lopez-otin et al., 2013) . the most predominant diseases affecting the elderly in china (65+, data from 2017) include sensory diseases, other non-communicable diseases, digestive diseases, respiratory infections and tuberculosis, skin and subcutaneous diseases, neurological diseases, and musculoskeletal disorders, among others (fig. 1c) . from 1990 to 2017, there were dramatic increases in prevalence of all 21 diseases, excluding a very minor reduction in 'neglected tropical diseases and malaria' (fig. 1c) . the major diseases responsible for death of the elderly in china are cardiovascular diseases, neoplasms, chronic respiratory diseases, and neurological diseases, among others (figs. 1d and 2). compared to their younger counterparts, the elderly population are more fragile, and susceptible to conditions such as cardiovascular diseases, chronic respiratory diseases, diabetes, kidney diseases, unintentional injuries, hiv/aids and sexually transmitted diseases (stds), among others (fig. 2b ). in comparison with data from 1990, new patterns of disease mortality characterize the modern elderly, such as a dramatic reduction in the percentage of death contributed by 'neurological disorders' with an increase in deaths due to hiv/aids and stds (fig. 2b, d) . recognition of the current disease demographics in the elderly in china, and accurate prediction of future trends will enable us to be best prepared for different healthcare needs at different times. in wake of the expanding ageing society in china, and the formidable socio-economic and healthcare challenges, we offer the 2 nd edition of our previously published review . here, we aim to provide an update regarding the situation of the elderly in china using a range of expertise and suggestions from multiple fields which may further propel the exciting and ongoing reforms to china's healthcare system. we hope to explore different ageing care models that can be used to best produce a healthy ageing society (chen, 2009; yip et al., 2019; zhan et al., 2019) . the following sections highlight recent developments in the above areas as well as areas for future research. based on ageing phenotypes and the major disease demographics in the elderly in china (figs. 1 and 2), we chose to focus on frailty (including sarcopenia as an independent subsection), cncds (including cardiovascular disease as an independent subsection), mental health disorders, dental health challenges, elderly infections and immune diseases, as well as hiv, syphilis, and other stds. in view of recent reviews on other grand challenges, including cancer tsoi et al., 2017) , chronic respiratory diseases (zhu et al., 2018) , diabetes and kidney diseases (hu and jia, 2018; wei et al., 2019) , these areas will not explored here. frailty is a biologic syndrome characterized by deteriorating function across a broad spectrum of physiological symptoms (fried et al., 2001) . it can be thought of as a state of vulnerability. some have proposed an index approach to categorize different degrees of frailty; however, these attempts are complicated by the multidimensionality of the underlying causes of frailty, thus creating a dynamic, ever-changing value that is difficult to index (rockwood et al., 2006) . the term physical frailty has been applied to age-related loss of muscle mass and function, that is sarcopenia (detailed in the next section). in recent years, frailty research has increased rapidly in china as a strategy to prevent disability in response to an ageing population (chhetri et al., 2019) . research projects were showcased in the following scientific conferences: the 1 st and 2 nd international china conference on frailty in china, jointly organized by the who collaborating centre on frailty, clinical research and geriatric training at the gerontopole, toulouse, france, the chinese embassy in paris, and the national clinical centre for geriatric diseases, china, and the 4 th asian conference for frailty and sarcopenia in dalian in october 2018, organized by the chinese geriatrics society, beijing institute of geriatrics and gerontology and the chinese health promotion foundation. wide-ranging topics included basic science, epidemiology, definitions and measurements, management, as well as service models. such conferences greatly accelerate basic and clinical research on as well as clinical treatment for frailty. frailty may be used as a population indicator of ageing, and be a useful indicator of a need for treatment. research into prevalence, risk factors, prevention, and incorporation into service delivery models in community, hospital and residential care settings are an important part of the ageing research agenda for china. the importance of recognizing frailty in communitydwelling older people in china has been highlighted in a systematic review and meta-analysis by he et al. (he et al., 2019a) . risk factors for a worsening in frailty among community-living older adults include hospitalizations, older age, previous stroke, lower cognitive function, diabetes and osteoarthritis, while higher socioeconomic status and neighborhood green space were protective factors (lee et al., 2014; yu et al., 2018c) . a comparison of prevalence and incidence of frailty between populations may stimulate further research into prevention strategies and inform government policies. using data from a nationally representative study, wu et al. found that 7% of community-dwelling adults aged 60 years or above were frail in mainland china and the prevalence increased dramatically with age, reaching 32.5% for those aged 85 years or above ). substantial regional disparities exist in the prevalence as well as incidence of frailty in mainland china. for example, the incidence rate of frailty in the northeast was more than double than that in the southeast . furthermore, a comparison of frailty and its contributory factors across three chinese populations (hong kong, urban and rural populations of taiwan) using the ratio of frailty index (fi) to life expectancy (le) as an indicator of compression of morbidity showed higher fi/le in taiwan compared with hong kong. risk factors include low physical activity and living alone . the importance of protein intake to slow the decline in muscle mass and physical function over four years supports the importance of nutrition as an underlying factor for physical frailty .the role of inflammatory cytokines in the pathophysiology of sarcopenia is supported by the finding of slower decline in grip strength for those in the highest quartile of telomere length (woo et al., 2014b) . simple tools for frailty and sarcopenia may be used in a community setting as case finding, without the need for professionally trained personnel (woo et al., 2014a; woo et al., 2015b) . this may represent the first step in the approach to community-based intervention such as group exercises with or without nutritional supplementation for frailty and sarcopenia (yu et al., in press; . how community services may be developed to make frailty as a cornerstone of health and social care systems (woo, 2018) depends on the development of existing community infrastructures. two examples have been described previously: the tai po cadenza hub, and the jockey club e health project, where screening data based on the who integrated care for older people toolkit (who) were collected via ipad, followed by action algorithms for items where action is indicated: e.g., frailty, sarcopenia. this model emphasizes the empowerment of older people and their care-givers, societal-level behavioral changes, and the use of technology in the absence of a low cost primary care system orientated to meeting the needs of older people (woo, 2019) . in the hospital setting, detection of frailty may inform choice of therapies and prognosis, such as mortality and hospitalization in chronic heart failure . closely related to the concept of frailty, sarcopenia is an age-related gradual loss of mass and strength of skeletal muscles resulting in reduced physical performance. major pathological features include a loss of satellite cells and motor neurons, as well as less active neuromuscular junctions (cruz-jentoft et al., 2010) . following the publication of the european consensus group on sarcopenia (cruz-jentoft et al., 2019; cruz-jentoft et al., 2014) , an asian group including chinese researchers formed a panel to arrive at a consensus on the definition of sarcopenia, published in 2014 , and recently updated in 2019. the asian criteria differed from the european consensus definitions. an individual international statistical classification of diseases and related health problems code (m62.84) was assigned to 'sarcopenia' which has stimulated both diagnostic and therapeutic trials worldwide. in china, sarcopenia diagnosis requires some special considerations, including anthropometric and cultural differences. the 2019 guideline of asia working group of sarcopenia (awgs) provides updated guidelines on epidemiology, case-finding, the diagnostic algorithm, measurements of muscle mass, muscle strength and physical performance, and intervention and treatment. the prevalence of sarcopenia is estimated to be between 7.3-12.0% among the general older population and was over 25% in the oldest populations (85+) wang et al., 2018a; woo et al., 2015a; xu et al., 2020, in press; yu et al., 2014) . while old age is the primary risk factor for sarcopenia, other risk factors in the chinese population include household status, lifestyle, physical inactivity, poor nutritional and dental status, and some diseases (osteoporosis, metabolic diseases, etc.). in terms of longer-term clinical outcomes, awgs-defined sarcopenia was significantly associated with increased risks of physical limitations at 4 years, slowness at 7 years, and 10-year mortality, but not of hospitalization wang et al., 2018a; woo et al., 2015a; yu et al., 2014) . interventional strategies for the elderly of china have been the subject of recent research. for instance, an intervention for community-dwelling older adults yielded significant improvements in muscle function based on which when protein was offered as an oral nutritional supplement in combination with resistance exercises (kang et al., 2019) . similar findings were reported in j o u r n a l p r e -p r o o f major behavioral risk factors that are responsible for cncds are prevalent among the elderly in china. nearly 80% of deaths are attributable to unhealthy diet, high blood pressure, smoking, high glucose, air pollution (indoor and outdoor), and physical inactivity (who, 2014) . in china, 56.6% of adults aged 60+ have insufficient dietary balance (daily intake of <400g fruit and vegetables), 22.4% are current smokers, 45% use unclean fuel for cooking, 84% are physically inactive, and 11.4% have harmful alcohol use (who, 2012) . risk factors for major cncds, particularly smoking and alcohol use, are unevenly distributed among older men and women. the prevalence of cigarette smoking is substantially higher among men (41.5%) than women (4.3%). the prevalence of harmful alcohol use among men is more than three times as much as that among women (13.3% vs. 4%). substantial rural-urban disparities in the distribution of risk factors exist among older chinese adults. rural residents have a higher prevalence of smoking (23.7% vs. 19.9%), harmful alcohol use (13.3% vs. 7.5%), insufficient dietary intake (60% vs. 49.5%), and unclean fuel use (89% vs. 7.1%) than those in urban areas, while residents of urban areas have a substantially higher prevalence of physical inactivity than their rural counterparts. 2016, cvd was ranked first in mortality rates, higher than the mortality rates attributed to tumors and other prevalent diseases. studies have shown that in 2013, age-standardized cvd mortality in china was 21% lower than in 1990 (gbd, 2015; zhou et al., 2019) . although the age-standardized cvd mortality rate has declined, the absolute number of cvd deaths is still rising rapidly, and increased by 46% between 1990 and 2013. cvd is a large burden for the chinese healthcare system. with the development of medical technology, and the government's focus on chronic disease management, the problem of cvd in china has improved. however, due to the problems arising from population ageing, cvd still has a great impact on national health. major factors for cvd include hypertension, dyslipidemia, diabetes, air pollution, and excess weight (overweight and obesity). some risk factors are specific to china compared to other countries, however, this is changing as china's economy develops and the population ages. hypertension is an important public health problem in china. the prevalence of hypertension in china among those over the age of 18 is 23.2%, and the number of patients with hypertension in china is estimated to be 245 million . in 2013, 2.5 million deaths were attributed to hypertension in china, accounting for 27.5% of all causes of death (trammell et al., 2016) . with the rapid development of the economy and the ageing population, problems with blood lipid levels in china have gradually increased, and the prevalence of dyslipidemia has increased significantly. the main symptoms of dyslipidemia seen in china are low levels of low-density lipoprotein cholesterol (ldl-c) and hypertriglyceridemia (pan et al., 2016) , while dyslipidemia in the west is characterized by hypercholesterolemia and high levels of ldl-c (toth et al., 2012) . with the change of lifestyle following china's economic development, the number of chinese diabetic patients is growing. overall, 47% of adults in china have diabetes or pre-diabetes, which is slightly lower than the 49-52% in the united states . in recent years, there has been a significant increase in the prevalence of excess weight (bmi: 24.0-27.9kg/m 2 ) and obesity (bmi≥28.0 kg/m 2 ) in chinese residents, as noted over a five-year study period (he et al., 2017b) . the prevalence of combined overweight and obesity among men was 33.8%. air pollution is another important factor leading to cvd. among different particles, pm2.5 (an aerodynamic diameter of 2.5 μm or less ) is most closely related to cvd (brook et al., 2010) . a follow-up study of cohorts of elderly people 65+ in hong kong showed that for every 10 μg /m 3 increase in pm2.5 concentration, the risk of total cvd death increased by 22% (wong et al., 2015) . air pollution is also associated with increased blood pressure. for each 10 μg/m 3 increase in pm2.5 concentration, the per capita systolic blood pressure level increased by 1.30 mmhg, the per capita diastolic blood pressure level increased by 1.04 mmhg, and the risk of hypertension increases by 14% . coronary heart disease, atrial fibrillation (af), heart failure, and atherosclerosis are common forms of cvd. technological developments have allowed for an increase in treatment options and testing methods, including percutaneous coronary intervention (pci), radiofrequency ablation, implantable cardiac defibrillator (icd) and pacemaker implantation. since elderly patients are often associated with more complications, treatment decisions for cvd in elderly patients need to be adjusted individually based on an overall scoring of health. coronary heart disease is a common fatal cvd. for the treatment of coronary heart disease, the number of pci cases has steadily increased in china (zhao et al., 2018b) . the creative study explored antiplatelet treatment options for patients after pci in china, and studies have shown that for patients with low response to antiplatelet drugs after pci, a triple antiplatelet intensive therapy combined with cilostazol is safe and effective (tang et al., 2018) . bleeding events should be paid special attention when administrating dual antiplatelet treatment to acs patients aged 75 and older receiving pci (zhao et al., 2018a) . the risk of all-cause, cardiovascular, and stroke deaths in patients with af is significantly higher than in patients with sinus rhythm . the proportion of chinese patients receiving anticoagulation treatments is low. only 12.7% of patients with af and a chads2 score of 2 or more received anticoagulation treatment . patients with af aged 75+ tend to higher chads2 scores but receive less anticoagulation therapy. the risk of one-year follow-up deaths and adverse events in the elderly is more than doubled compared to other populations yang et al., 2014) . cases of af ablation procedures and icd implantation have steadily increased in china. however, european danish studies suggest that primary prevention through icd implantation has limited benefits in elderly patients with non-ischemic cardiac diseases (kober et al., 2016) . therefore, it is necessary to pay attention to the indications when expanding the population eligible for icd implantation in china. in recent years, the etiology of heart failure in china has changed significantly. the proportion of valvular disease (especially rheumatic valvular disease) has decreased. as china is becoming an ageing society, the number of elderly patients with heart failure has increased. at present, most studies suggest that coronary heart disease is a common cause of heart failure in the elderly, and the proportion of hypertension and pulmonary heart disease in elderly patients with heart failure increases with age. in recent years, the use of diuretics in hospitalized heart failure patients in china has not changed significantly, while the usage rate of digoxin has shown a downward trend. the use of acei, arb, aldosterone receptor antagonists and beta-blockers have shown a significant upward trend . lower extremity atherosclerotic disease (lead) is a common disease in the elderly and an important starting point for systemic atherosclerosis. early detection of lead is of great value in the diagnosis and treatment of systemic atherosclerosis (hiramoto et al., 2018) . to reduce the burden of cvd in china, we recommend interventions directed at altering lifestyles and programs dedicated to the detection and management of risk factors, especially for elderly people. research modeling has shown that if dyslipidemia and hypertension are effectively managed, medical expenses to the tone of $932 billion us from 2016-2030 (stevens et al., 2016) . controlling blood lipids and blood pressure of elderly people over 65 years of age represents the most cost-effective strategy (stevens et al., 2016) . mental health disorders, particularly dementia and depression, are major diseases in the elderly of china. alzheimer's disease international (adi) estimates that over 50 million people worldwide were living with dementia in 2019, and that this figure will rise to 152 million by 2050; the current annual cost of dementia is estimated at 1 trillion us dollars which will be doubled by 2030 (adi, 2019). it is estimated that the number of patients with dementia in china constitutes 25% of the dementia population worldwide, with the prevalence of dementia ranging from 5.14% (95% ci 4.71-5.57, in 2014) to 5.60% (95% ci 3.50-7.60, in 2019) for individuals aged 65+ jia et al., 2014; jia et al., 2020) . the patterns and spread of dementia in china vary geographically and between genders. women are 1.65 times more susceptible than men. western china has a higher prevalence at 7.2%, while central and northern china are lower at 5.2 and 5.5%, respectively, southern china has the lowest prevalence at 4.8%, this variation is possibly due to a variety of reasons including diet, exercise, social networks, healthcare, etc. (chan et al., 2013; jia et al., 2020; wu et al., 2018b) . the incidence of dementia in individuals aged 65+ ranged from 17.7 to 24.0 per 1000 person-years using 10/66 dementia research group criteria, while it was 12.14 per 1000 person-years using dsm-iv criteria (jia et al., 2020; prince et al., 2012; yuan et al., 2016) . while health conditions such as depression, diabetes mellitus, and insomnia correlate with dementia in a global fashion, epidemiological evidence from different regions in china also suggests smoking and heavy alcohol consumption as high risk factors (fan et al., 2019; pei et al., 2014; xue et al., 2019) . depression, a risk factor for dementia, is a common but often neglected disease in the elderly in china . data from a cross-sectional study suggest a prevalence of depression of 39% in the elderly which increases to 45% in the most elderly (yu et al., 2012) . in view of the stigma of mental illness in some areas of china coupled with inadequate health services in rural areas, depression is likely underdiagnosed suggesting the real prevalence may be higher. in addition to its contribution to dementia, depression aggravates the quality of life of the elderly and of their family members, brings the risk of death caused by different reasons, and accordingly is a heavy burden on the society and the healthcare system (zhang and li, 2011) . much effort should be made to address mental health disorders in china, including increasing government investment, the training of more geriatric care professionals with specialties in mental disorders, and raising public awareness, especially in conjunction with more active social activities and exercises. although there have been increased care facilities for citizens 65+ and improved access to health services, the diagnosis and management of dementia and depression are still inadequate, especially in rural areas (jia et al., 2020) . the inclusion of steps to manage dementia in the 13 th five-year plan of the central chinese government marked a major step forwards, and such efforts need to be continued. in view of the insufficiency of medical professionals in regards to mental disorders, especially in rural areas, we recommend increased training to such professionals, and the development of policies to encourage health professionals to work (at least for a short period) in rural areas . in recent years, the public awareness of mental disorders, especially ad, has greatly improved thanks to efforts from social media (e.g., drama shows on ad) and dementia organizations. professional interventions, comprising medicine and combined cognitivepsychological-physical intervention (e.g., family and community support plus playing mahjong and practicing taichi) can mitigate subclinical depression and improve overall mental health (kong et al., 2019; wang et al., 2019c; wong et al., 2014) . although no drug at present is available to cure ad, recent progress on the understanding of ad etiology, such as the involvement of impaired mitophagy and reduced grid-cell-like representations in the human ad brain, along with the development of novel stem cell models, and the use of artificial intelligence (ai), will undoubtedly propel the development of novel drugs (fang, 2019; fang et al., 2019; gilmour et al., 2020; kunz et al., 2015; lin et al., 2018) . the china brain project, covering studies on basic neuroscience, brain diseases, and brain-inspired computing, will greatly benefit the development of novel drugs for different neurological diseases (poo et al., 2016) . while oral health is an important part of the whole body, the prevalence of oral disease is high in the elderly in china, but is largely ignored, while here we focus on dental health. dental caries (tooth decay), periodontal disease and tooth loss in the elderly are issues of global health concern. the burden on healthcare cost and the quality of life of these dental diseases in the elderly remain high . maintaining good dental health is an integral part of healthy ageing. as such, developing effective preventive and therapeutic interventions are needed to protect and enhance dental health and well-being tonetti et al., 2017) . dental caries and periodontal diseases are common oral diseases in the elderly and often lead to tooth loss, edentulism (toothlessness), impaired masticatory function and poor nutrition. according to the 4 th national oral health epidemiological survey (fnohes, 2015 (fnohes, -2016 covering the whole of mainland china, caries and periodontal diseases are highly prevalent in the elderly in china; while the prevalence of caries was above 50% in all age groups (3-5, 12-15, 35-44, 55-64, and 65-74 years) , the rate was 98% in the 65-74 years groups (lu et al., 2018; si et al., 2019) . in adults aged 65-74 years, 90.7% had periodontal diseases, including gingival bleeding (82.6%), dental calculus (90.3%) and a deep periodontal pocket (14.7%) (lu et al., 2018; si et al., 2019) . human oral tissues naturally and gradually degrade with age; a fact also exacerbated by modern lifestyle choices, including the prevalence of sugary diets and a lack of oral hygiene (belibasakis, 2018; lamster et al., 2016) . more specifically, age-dependent changes include a reduction in periodontal support, loss of elastic fibers, and thickening and disorganization of collagen bundles in the connective tissue of the oral mucosa (belibasakis, 2018; lamster et al., 2016; wu et al., 2016b) . severe dental health challenges can cause loss of self-esteem, social difficulties, while also being drivers of common diseases, such as ad, pd, diabetes, and hypertension (belibasakis, 2018; bollero et al., 2017; dominy et al., 2019; lamster et al., 2016) . major risk factors of the high prevalence of dental diseases in the elderly in china include the scarcity of dental health knowledge in the general population, low frequency of daily oral hygiene practices, insufficiency of dental care services, and unhealthy diet habits. daily oral hygiene practices are effective for removing plaque and preventing gingivitis. the average awareness rate of dental health in the chinese elderly was 47.6%, only 30.1% of the elderly brush their teeth twice daily, and a mere 0.8% used dental floss (lu et al., 2018; si et al., 2019; . increased attention to the dental health needs of an ageing population urgently requires combined efforts by relevant stakeholders (lu et al., 2018; si et al., 2019; tonetti et al., 2017; . specifically in the case of older adults, knowledge and competence in oral care, awareness of medical comorbidities and of medications relevant to oral care should all be strengthened. epidemiological surveillance and monitoring of oral diseases and oral healthrelated quality of life in the elderly is needed. oral self-care, access to treatments and preventive services and assuring the affordability of dental care are critical for oral health. looking after teeth and gums by brushing twice a day with fluoride toothpaste and cleaning with dental floss are effective in achieving a good oral health status. likewise, the control of risk factors, such as refraining from the frequent consumption of foods and drink high in sugar, and refraining from smoking, are also important. provisions to expand services to older adults, to meet increasing oral healthcare needs in the ageing population, and to ensure the affordability of dental care should all be emphasized by policymakers. we suggest programmes that promote general oral health education as well as public outreach programmes directed towards the elderly via understandable brochures, and the use of television and other social medias. additionally, it is important to improve the country's dental care infrastructure by training more dentists and oral specialists and ensuring the provision of affordable dental healthcare. it has been well documented that altered immune system components and function are characteristic of ageing and form part of the causes of age-related diseases (nikolich-zugich, 2018) . in ageing, a significant decline in the homeostatic, defensive, and surveillance functions of the immune system is noted. prominent features of the ageing immune system include thymus involution, a decrease in naïve lymphocytes, and an accumulation of memory and senescent lymphocytes; more recently, the concept of 'inflammageing' has been developed (ferrucci and fabbri, 2018) . functionally, impaired immune defense, especially against new antigens for which no memory exists, makes older adults increasingly vulnerable to incident and more severe infections. in addition, a decline in immune surveillance hampers the elimination of premalignant cells, leading to cancer development. older adults also manifest a chronic low-grade inflammatory phenotype (clip), a manifestation of the inflammageing concept, that likely results from uncompensated inhibitory immune regulation and/or an inability to eliminate senescent cells (chen and yung, 2019; chen et al., 2019b) . as such, immune dysregulation is a general feature of ageing. here we provide an update on infectious diseases in the elderly in china. we carried out a comprehensive review on infections in china based on the following public databases: the chinese center for disease control and prevention (ccdc), the data-center of china public health science (ccdc, 2019), and the national bureau of statistics of china (nbsc, 2019). the three most common infectious diseases in 2017 were viral hepatitis, pulmonary tuberculosis (tb) and syphilis (detailed in section 2.8) while the three with the highest mortality rate were aids, tb, and viral hepatitis ( fig. 3a-d) . of note, pulmonary tb was more prevalent than the other two in older adults over 65 years of age (fig. 3c ). generally speaking, infectious diseases are more frequent and deadly in older adults, as seen with the recent 2019-ncov epidemic worldwide huang et al., 2020) ; thus, infectious diseases deserve more attention. viral hepatitis is caused by the hepatitis viruses a, b, c, d, and e (hav, hbv, hcv, hdv, hev) and is prevalent throughout the world, posing a significant threat to human health. china is a highly epidemic area of viral hepatitis with 86.6 million people infected with hbv and 7.6 million infected with hcvas of (who, 2018 . in 2018, there were 1.28 million new cases and 531 deaths among the chinese population (nbsc, 2018) . according to the chinese statutory infectious disease report, viral hepatitis mainly occurred in adults between 20 to 65 years old (83.68%, fig. 3e ). its morbidity in older adults was estimated to be 13.52% in 2016 ( fig. 3e ). however, compared with the morbidity, the mortality of viral hepatitis was higher (28.31%) in the aged population ( fig. 3e ). from the survey, the morbidity and mortality rate of viral hepatitis have ranked in the top five for many years. the morbidity of viral hepatitis was stable in last decade, which is likely due to the wide usage of the hepatitis vaccine ( fig. 3g , h). however, the morbidity of hepatitis in the elderly continues to increase yearly. since most cases of viral hepatitis developed into chronic hepatitis, the lifespan extension seen in china has contributed to a higher number of elderly hepatitis cases. luckily, the mortality of hepatitis has declined in both the aged population and the population at large (fig. 3h ). among the five hepatitis viruses, hdv is rarely detected and is not discussed here. hcv (20.13%) and hev (22.6%) demonstrated high morbidity in the aged population (fig. 3f) . however, the highest mortality is caused by two acute types, hav (60%) and hev (66.7%) (fig. 3f) , indicating a weakened immune responses against acute infection in the elderly. significantly, both the morbidity and mortality of hbv in the aged population were lowest among the four types ( fig. 3f ), further indicating the benefit of the hbv vaccine. however, prophylactic vaccines for hcv and other types of viral hepatitis are still lacking. for patients who have been infected, current treatments are still limited, especially for the elderly patients. one of the reasons for this is the lack of a long-term infection model for use in laboratory conditions (winer et al., 2017) . developing an elderly-representative model would be a useful tool for screening treatment options for those affected by hepatitis diseases. mycobacterium tuberculosis and is typically transmitted through coughs and sneezes. the lack of global tb control is the result of several factors, including hiv coinfection, limited vaccine efficacy, a lack of highly specific and sensitive diagnostic tests, and the rise of multidrug-resistant (mdr) and extensively drug-resistant (xdr) tb strains (venketaraman et al., 2015) . according to the who's 2019 global tuberculosis report, china is ranked third in terms of tb burden when compared with other countries (who, 2019a). pulmonary tuberculosis (p-tb) is the second highest ranked cause of morbidity and mortality among the 28 infectious diseases ranked in 2017 (fig. 3a, b) . however, it is the most frequent infectious disease in the elderly (fig. 3c ). the elderly occupied more than half (54.9%) of all deaths from p-tb (fig. 3e ). in the last decade, the incidence of p-tb has decreased year to year, however, the incidence and mortality rates of p-tb in the elderly remains high in china (fig. 3g , f). there are several reasons for the high incidence and mortality rates of p-tb in the elderly: i) an increasingly ageing population; ii) immune decline; iii) delay of diagnosis and treatment. with the increase of the number of elderly patients, p-tb is rapidly becoming a new public health challenge. several risk factors, such as immune decline, smoking, malnutrition, hiv infection and other chronic diseases, make the elderly susceptible to tb . compared with p-tb in the young, p-tb in the elderly has its own characteristics. elderly patients with p-tb are more contagious than the young, and elderly men are more likely to suffer from tuberculosis than elderly women (lee et al., 2017) . in the elderly, early symptoms of tb are atypical and insidious, and can result in misdiagnosis (rajagopalan, 2001) . furthermore, chronic fibrous cavitation and hematogenous disseminated tb are more common in the elderly population. most elderly patients with p-tb get tb in their youth at which time it is better controlled but, as they age, p-tb can result as immune function declines. moreover, elderly tb patients usually present with several complications, which further complicates diagnosis and treatment (nagu et al., 2017) . all these characteristics have brought special focus on the treatment and diagnosis of tb in the elderly. at present, there are several tb guidelines for high-risk groups (who, 2016b), but few for the elderly. previous studies in the elderly have also focused less on the evaluation of targeted strategies for control and prevention. thus it is necessary to pay more attention in the future to the production of control programs and evaluation of targeted interventions for tb in the elderly. aids is a chronic, potentially life-threatening infectious disease caused by hiv, which was first detected in the united states in 1983 ( barré-sinoussi et al., 1983) . in the last decade, the morbidity and mortality of hiv/aids has increased yearly ( fig. 3g, h) , and it has become the top cause of death by infectious disease in china, including in the elderly (fig. 3b, d) . the morbidity and mortality of hiv/aids in the elderly population is also rising significantly, and notably the mortality in the elderly is much higher than that seen in the young (ccdc, 2016). furthermore, because elderly people have many basic diseases and low awareness of selftesting after hiv infection, the elderly are more likely to already be aids patient at the time of diagnosis of their hiv infection (xing et al., 2014) . a study has shown that 35.5% of newly diagnosed elderly hiv infectors had already developed into the aids stage (liu et al., 2012) . with increasing use and efficacy of antiretroviral therapy for hiv infection, the lifespan of hiv/aids patients has been greatly extended, and more and more hiv/aids patients will enter old age (nizami et al., 2019) . the problem of hiv/aids in the elderly will become increasingly serious in the future. firstly, hiv infection is not commonly checked in the elderly in china upon visit to the hospital, which may lead to uncontrolled disease progression and infection to others. second, the treatment of aged hiv/aids patients may cause more adverse effects, such as cardiovascular disease (hanna et al., 2016; kramer et al., 2009) , ad (brousseau et al., 2009) , and diabetes (guaraldi et al., 2018) . furthermore, cognitive disorders, loneliness, shame and depression may increase the likelihood that they fail to follow their drug regimen, or refuse treatment altogether (greene et al., 2018; vincent et al., 2017) . interestingly, hiv infection is also likely a driver of early ageing, as aids patients age more rapidly than the general healthy population (he et al., 2019b; lin et al., 2019) . to address these problems, the diagnostic process in the aged population should be addressed more cautiously; therapeutic drugs and technologies suitable for the elderly patients should be developed. special attention should also be paid to psychological problems of elderly patients. the hiv epidemic as a sexually transmitted disease will be discussed further below. influenza is an acute viral infection caused by the influenza virus. at present, a total of four types of influenza viruses have been identified, including influenza a, b, c, and d (iav, ibv, icv and idv) (petrova and russell, 2018) . among them, only iav and ibv are able to cause seasonal epidemics and clinical disease. yearly, the extent of the influenza pandemic varies around the world, which causes high morbidity and mortality. because elderly individuals above 65 years of age are immunocompromised and may have preexisting conditions, they are more susceptible to influenza infection and its complications. data accumulated in the last decade showed that the morbidity of influenza has increased in both the general and aged populations (fig. 3g ). like other acute infections, the mortality of influenza in aged patients was higher than in younger population (fig. 3h ). during january 1, 2018 to september 28, 2019, a total of 1626 severe influenza cases were reported in hong kong, among which 1058 patients (65.07%) were over 65 years old (chp, 2019b). in 2018, a total of 5984 influenza cases were reported in macau, among which there were 188 cases were over 65 years (hbgm, 2019a) . however, only a small number of influenza cases acquires laboratory confirmation, as patients usually die of other related illnesses brought on by influenza. thus, the influenza-related mortality rate is greatly underestimated. in 2012, the ccdc estimated that the death rate caused by influenza was 18/100000 in northern china and 11.3/100000 in southern china, and most of the deaths occurred among people aged over 65 years (77.8% in southern cities and 69.6% in the northern) (feng et al., 2012) . the excess mortality of respiratory and circulatory diseases caused by influenza was 12.4/100000 and 8.8/100000, respectively, among which 86% occurred in people aged over 65 years (feng et al., 2012) . pneumonia is an acute respiratory infection that affects the lungs, which is especially deadly in children under 5 years and in the elderly (65+). pneumonia has become one of the major causes of death for the elderly over 65 years. the harm and mortality of pneumonia increases with age. the "2018 china health statistics yearbook" reported that the mortality rate (/100000) of urban residents aged 65-69, 70-74, 75-79, 80-84, and over 85 with pneumonia was 19.63, 34.48, 68.38, 219.07 and 865.53, respectively; and that of rural residents was 11.62, 23. 67, 48.61, 127.90 and 445.93, respectively (nbsc, 2018) . since 2003, pneumonia has been one of the top three causes of death in hong kong (chp, 2019a) . according to statists by the hong kong centre for health protection, the mortality rate of pneumonia was 39/100000 in 2017, with a total of 8032 pneumonia-related deaths. of these cases, 94.68% occurred in people aged over 65 years (chp, 2019c) . in macau, pneumonia also has been cited as one of the top three causes of death for many years (hbgm, 2019b). in summary, old age is known to affect the immune system negatively. immunocompromised elderly adults are more susceptible to common diseases such as influenza and pneumonia, both of which were responsible for many deaths in this age group. in some cases, these infections may lead to complications that then lead to death, and this likely contributes to underreporting, hiding the true effects of influenza and pneumonia. there are multiple methods for improving and maintaining healthy immune function in the elderly: physical activity and exercise are known to enhance the immune system, however effective ranges still need to be established and disseminated (venjatraman and fernandes, 1997) . additionally, the development of vaccines must be prioritized, although challenges exist such as finding suitable mass production methods. perhaps surprisingly, sexually transmitted diseases (stds) are becoming an increasing problem among older age groups. many people aged 50 years or older in china remain sexually active, and the shift towards nursing homes has led to an increase in exposure to possible sexual partners (yang and yan, 2016) . unfortunately, many older adults do not take precautions in their sex life, due to reasons such as a decreased worry about pregnancy (tht_uk, 2018) . high-risk sexual behaviors render them vulnerable to the transmission of hiv and other sexually transmitted diseases (stds), likewise low awareness of the potential risks and low use of sexual health services can result in late diagnosis and treatment of stds among older adults. we here describe the current situation of hiv/aids and other stds in older adults in china, and propose potential preventative measures. as mentioned before the incidence and proportion of older adults in the total number of reported hiv/aids cases is on the rise in china (fig. 3a-d) . the rise in both the number of absolute cases and the proportion of std infections was observed in both genders. the vast majority of cases in older adults resulted from heterosexual copulation, and has brought about an alarming increase in the rate of new infections. for example, in chongqing, the proportion of hiv infections reported in those aged 50 years and older increased dramatically from 27 to 58.4% between 2011 and 2019 (chinanews, 2019)at the same time, the overall number of male cases quadrupled, and the female cases tripled between 2012-2018 (wu, 2019) . among women newly diagnosed with hiv in china between 2010-2016, the proportion of those aged 50 years and older increased from 17.8% in 2010 (2 959/16 603) to 38.1% in 2016 (9 981/26 196) . this proportion is even higher in regions with larger rural populations. in guangxi, 46% of newly reported hiv cases in 2014 were men aged 50+ (hu et al., 2019a) . in addition to the increase in newly reported infection among older adults, people infected with hiv can now survive to an older age, increasing the proportion of advanced-age hiv cases. in addition to hiv other stds are increasing in prevalence among the elderly in china. from 2000 to 2013, the incidence of syphilis in people over 60 years of age increased by over 30%. the proportion of people aged 60 years and older among all syphilis cases was also on the rise, from 8.5% in 2004 to 22.0% in 2013 . between 2008-2016, the incidence of condyloma acuminate in china showed a downward trend, with an average annual decline of 2.2%. however, the incidence rate among people aged 50 and over increased by 4.8% annually (yue et al., 2017) . gonorrhea is not common in the elderly, and china saw an average annual decline of 7.9% in the incidence of gonorrhea. this trend was also seen in older adults (4.5%-10.9%) (gong et al., 2015) . this phenomenon may be related to the short incubation period of gonorrhea, the high self-medication rate of patients, the sensitivity of gonococcal bacteria to antibiotics, and the insignificant clinical symptoms of female patients (wang and ni, 2008) . there are several contributing factors behind hiv/stds transmission in older adults. ageing is associated with various physiological changes in the human body collectively known as frailty. however, physiological changes in sexual function often fail to attract societal attention. male sexual dysfunction and disorders often manifest in the slowing of penile erection, prolonged ejaculation, the dampening of sexual desire, impotence, etc. as women age, their vaginal tissue becomes thinner, drier, and less likely to become fertile. for the above reasons, the use of condoms in the elderly seems to be less important. older women may have less interest in or need for sexual intercourse; however, their male counterparts may continue to be sexually active for a long period of time. cravings for sex combined with loneliness may push men to resort to commercial sex to quench their desire for sex. in rural areas, the hiv prevalence is high among street-based female sex workers and female sex workers working at sex-on-premise venues with low quality of hygiene, such as hairdressing shops. use of condoms and other precautions in these scenarios is likely to be lacking . sexual education in older adults is nearly absent, and it is generally assumed that "age is a condom". embarrassment may discourage older adults from obtaining condoms and other precautions. in a survey in guangxi, although 87.9% of respondents were willing to accept condoms issued free of charge by healthcare services, 64.1% of the respondents were unwilling to take them of their own due to embarrassment (qi and pang, 2012) . despite the growing importance of sexual health among older adults, many of them do not seek health services for sexual problems. in china, data on sexual health in older adults are scarce. existing research focuses mostly on males (jiang, 2016) . few actions have been taken to accommodate older adults' sexual health needs in china. engaging older adults in health program development and policy changes is particularly challenging due to concurrent incidences of disability, frailty, and other comorbidities. conventional top-down strategies are often unappealing and less trusted by the target audience. innovative solutions are needed to develop contextualized sexual health services and ensure that they are inclusive, trusted, and reliable. collectively, hiv/stds are becoming an increasing problem in the elderly in china due to diminished precautions in their sex life, a lack of condom usage, and insufficient sexual education, among other issues. future research focuses should include a) routine sexual healthcare and screening for hiv/stds among older adults, especially those who have highrisk sexual behaviors; b) sexual health education and hiv/stds prevention among older adults; c) late diagnosis of hiv/stds among older adults; and d) healthcare providers' attitude on the sexual health of older adults. modifiable health-related behaviors (hrbs) are key contributors to chronic diseases and early mortality, such that by maintaining a vigorous lifestyle, the processes of frailty, disability, and dementia can be postponed or even prevented (lafortune et al., 2016; rizzuto and fratiglioni, 2014; who, 2019c) . similar public health recommendations for hrbs have been promoted worldwide, namely, refraining from smoking and excessive alcohol consumption, consuming a balanced diet, partaking in regular physical exercise, and maintaining frequent social engagements (who, 2015d ). an international comparison study revealed a large degree of consistency in hrb clustering across six nationally-representative ageing cohorts in the east and west, alongside considerable gender-and country-specific variations (liao et al., 2019b) . particularly, older chinese males were characterized by a much higher probability of being smokers (57%) than their counterparts in japan (28%), korea (38%), usa (17%), uk (15%), and in other european countries (21%~33%) (liao et al., 2019b) . comparable findings have been reported in the who's 2019 report on the global tobacco epidemic, which further indicates that the progress of smoking reduction tends to be noticeably slower in china than the global average (who, 2019d). nevertheless, positive developments of china's concerted tobacco control efforts, such as smoke-free public places, a strengthened ban on tobacco advertising, etc., should be acknowledged (li and galea, 2019) . these smoke-free movements have challenged and hope to gradually change social norms regarding smoking, though they may be less effective among older generations with poor health literacy (hu et al., 2016) . the implementation of the healthy china 2030 action plan provides an opportunity to increase tobacco control (li and galea, 2019) , as well as to address a range of risk factors via a population-based multi-sectoral approach (nhcprc, 2019a) . aiming to enhance the overall health of the chinese population, the plan prioritizes 15 major actions, including the promotion of health literacy, the improvement of nutrition, a new national exercise campaign, more tobacco control measures, the promotion of mental health and environmental health; and specific actions dedicated to four target populations (i.e. women and children, teenagers, older adults, and those undertaking special occupations) and five categories of diseases, i.e. cardiovascular and cerebrovascular diseases, cancer, respiratory diseases (e.g. copd), diabetes, and infectious diseases. besides health-related targets for the health promotion actions for older adults, the importance of building an elderly-friendly and engaging environment is highlighted, which embodies "ageing in place" with humane, equitable and sustainable health and social care resources. social engagement is a key determinant of active ageing (world health organization, 2002) , especially within china's collective cultural background (liao et al., 2019b; liao et al., 2020) . in tandem with physical exercise, social activities may generate health benefits not only for the body but also for the soul. chinese square dancing is a social group-based exercise performed to music in public squares or parks. this low-cost and easy-participation activity is highly popular among middle-aged and retired chinese women, estimated at 100 million participants in 2015 (fang, 2015) . square dancers can meet as often as every day, usually in the early morning or evening after dinner, and sometimes both, upon meeting they organize themselves into rank and file, and exercise for nearly two hours, led by the most proficient dancer (liao et al., 2019a) . as an aerobic exercise accompanied by a dance rhythm, square dancing mobilizes the participants' whole body, improving their balance and cardiopulmonary function (liu and guo, 2013) . it is also cognitively challenging, requiring participants to listen to and process the music, focus on movement and balance, and dance to the rhythm with coordinated body movements (kattenstroth et al., 2010) . moreover, square dancing creates a socially enriched environment for participants to interact with peers, keeping them socially engaged and dispelling loneliness (liao et al., 2019a; liao et al., 2020) . square dancing is a typical example of a grassroots group activity that may serve as inspiration for the design of culturally appropriate health promotion programs for older adults. one possibility is developing similar programs that can be implemented throughout the country, and possibly tailoring them to the local needs and/or cultures. in the past five years, central and local governments in china have made enormous efforts in establishing a multi-dimensional geriatric care system to support healthy ageing in chinese society. more than 30 national policies have been issued to drive the development of this care system, including cross-ministerial policy measures for promoting the growth of elderly services and the integrated development of medical, health and elderly care, through the guiding opinions on advancing the development of age-friendly livable environment (ndrc, 2016) , and the state council opinions on promoting the development of elderly care services (nhcprc, 2019b, c) . following the strategies of the national 5-year plan, provincial and municipal governments have all issued local implementation plans. in places such as shanghai, shandong, jiangsu, zhejiang and guangdong, political will has been accompanied by strong financial support (cnca, 2020). as compared to q3 2014, in q3 2019 there was an additional 2.4 million beds added in public and private nursing homes across china, resulting in a total national supply of 7.55 million beds (mcaprc, 2019a, b) . in 2018, the ministry of civil affairs allocated rmb 2.9 billion (usd 400 million) to support the local expansion of care beds in nursing homes as well as the development of community and home care services. in terms of service utilization, the occupancy rate of nursing home beds is at around 50%, i.e. at any time, there are less than 3.8 million residents in these facilities. 748,000 elderly benefited from nursing care subsidies while 5.22 million benefited from social care subsidies (mcaprc, 2019a, b) . in july 2016, the first national pilot of a long-term care insurance (ltci) program was announced in 15 cities across different regions of china (mhrssprc, 2016) . identification of elderly people with severe care dependency was carried out, and local models of financing care for them in nursing homes, community centers as well as at home were implemented. by june 2019 this pilot program covered a total of 88.54 million people, funding services for 426,000 beneficiaries at rmb 9,200 per year per person (nhsaprc, 2019). while geriatric care system development has attracted strong attention from stakeholders and become a major theme for policy, research and investment, the following challenges need to be understood and addressed before meaningful progress can be made to prepare the country for its rapid entrance into an ageing society. the first challenge is that care needs must be assessed comprehensively and should be subject to regular reassessment in order to develop personalized care plans and identify goals that are aligned among care recipients, providers and payers (who, 2017) . generally, there are currently two types of assessments in use in china: one conducted before admission into nursing homes, the other for entry into the ltci programs. the first type can be quite comprehensive but is often used to decide the charge levels associated with the care service. the second type uses a simple 6-item adl questionnaire and links its results to the funding schemes, e.g. maximum hours of care per month. as the assessment of care needs tends to be one-off and disconnected to care plans or goals (hua, 2019; ma, 2017) , it is difficult to allocate resources dynamically and to analyze care performance or economics. the second challenge involves problems with service capacity. on the one hand, 45% of nursing home beds are left unoccupied and, contrary to international best practice, for the beds that are occupied, only less than 20% are actually utilized by people with severe dependency; on the other hand, according to the national health commission, nearly 188 million seniors have chronic diseases, and 40 million have various levels of disabilities (nhcprc, 2019b, c) . among the over 40 million people with different degrees of care dependency and care needs, under 10% have been served by community and home, and the majority have yet to be cared for (mcaprc, 2019a, b) . some policies have been put in place to attempt to fill the huge gap in caregivers, stating that 10 million more caregivers are needed just to care for the existing group of dependent seniors. however, if the current mainstream model of "replacive care" is not changed, growing care service capacity will only lead to an accelerated rate of care dependency among the high-risk population. additionally, such a model of care is highly unattractive to potential workforce candidates. as a corrective move, the central government has now set a goal to train 2 million more caregivers by 2022 (mcaprc, 2019a, b) . the third challenge is distorted allocation of resources. up until the end of 2018, despite plans to establish a home care-dominant, community-backed and nursing home-supplemented system, investment has remained predominantly in heavy assets, i.e. the development of nursing homes as well as senior-living property projects, resulting in the above-mentioned "oversupply" of care beds (qiao, 2019) . since the 13 th five-year plan, the central government has committed to an annual funding of rmb 1 billion to support innovative pilots of home-or community-based care models (mcaprc, 2017 (mcaprc, -2019 . however, for many local governments, the first and foremost priority when developing local care capacity is to specify land for elderly care use and invest in care facilities construction before or while looking for operators of such facilities. in addition to resistance and reluctance from nursing homes and preexisting policymakers, difficulty in understanding senior population's care needs and evaluating care competency among community and home care providers have prevented financial support schemes from materializing in most parts of china. typical examples of the insufficient support for community and home care service development can be seen in the number of government purchase tenders that fell through without enough qualified bidders. while there is no lack of political will and resources to be invested in further developing the care system, there is an urgent need to pay for access and quality. a value-based resource allocation model focusing on improving population health rather than the current fee-for-service care model would provide china a rare opportunity to benefit from a healthily ageing society (gyurmey and kwiatkowski, 2019; mandal et al., 2017) . to address the above-mentioned challenges and seize the opportunity associated with them, pilots should be designed based on local evidence and should be established in four dimensions. firstly, development of care plans should be focused on individually centered goal based on comprehensive assessments. as highlighted in the latest who icope (integrated care for older persons) package, it is essential for countries and health systems to align the efforts of different stakeholders with a shared care plan that is customized to serve the individuals' priorities and goals. secondly, health and social care resources should be integrated to support the realization of personalized goals of care and, at the population level, to delay and reduce care dependency. rather than further developing passive care capacity to compensate for the increasing need for other fragmented services, devoting resources to the reaching of a consensus among care providers and receivers will serve to empower the population itself, and maximize the pooling of financial and human resources, decreasing the need for an expansion of passive services (who, 2019b). thirdly, the education and training of "integrated care managers" should be developed, whose job would be to work actively in primary care settings to identify care needs and coordinate care resources crucial to achieving societal and individual care goals. mobilizing talents with various backgrounds to understand and operate under the comprehensiveness of geriatric health needs, developing their capability to better communicate and coordinate care efforts across public and private sectors would not only facility the integration of various care services, but make the care work more attractive for those seeking long-term career opportunities (wang and song, 2019) . fourthly, a reform of the payment model used in elderly care services should be carried out, focusing on value rather than volume of care for populations at risk of care dependency. healthcare payments have long been moving from an inefficient, fragmented, fee-for-service model to a value-based capitation or bundled payment model. for geriatric care financing, this reform is likely to develop faster than the reform of payments for healthcare services. setting sustainable goals for care and allocating resources accordingly will be a viable realistic solution to caring for the millions of chinese citizens in need . we recognize the complexity of establishing such a health-oriented care system. for the four dimensions of an integrated care system to be aligned around common goals as discussed above, a pre-requisite should be the interconnectivity of data: linking results across personal health records, assessments of geriatric care needs, and total costs of care, including: social and commercial health insurance payment, out-of-pocket private payment, social welfare payment, as well as other sources of funding for elderly care (threapleton et al., 2017) . palliative care is emerging as a new alternative for hospitalized elderly with life-threatening illness. the who defines palliative care as the prevention and relief of suffering of adult and pediatric patients and their families facing the problems associated with life-threatening illness (including malignant and non-malignant diseases). these problems include physical, psychological, social and spiritual suffering of both patients and their family members the aim of palliative care is to enhance the quality of life, promote dignity and comfort, and may also positively influence the course of illness (who, 2016a). palliative care is the basic skill of medical staff in departments where medical care is provided to end-stage patients (e.g. icus, emergency rooms, geriatric and oncology departments) (ning, 2018) . the 2015 quality of death index survey showed that the death quality of mainland china ranked 71 st out of 80 countries, while taiwan and hong kong ranked 6 th and 22 nd , respectively (eiu, 2015) . while palliative care is widely available in western countries, it is limited in mainland china. according to a report in 2016, only 0.7% (146/22,000) of hospitals offered palliative care services. in china, the proportion of course in palliative medicine at medical schools is relatively low and, often only available as electives for undergraduates or postgraduates (liu and yuan, 2009) . questionnaire data of 5 th year medical students in 2017 and of geriatric nurses in 2016, showed that 58.7% of medical students and 55.7% of nurses had no training or education regarding death or terminal care, and 93% of medical students and 94.3% of nurses had not received any education about hospice and palliative care. thus the need for course education in hospice and palliative care at chinese medical schools is extremely urgent. palliative care is recommended to be introduced early in curative treatments when patients are diagnosed with a life-limiting disease or when the palliative care needs of patients are identified. current palliative care in mainland china is still mainly focused on patients with cancer, with only a few palliative care resources available for other chronic conditions such as copd, hiv and renal failure . therefore, in the future, palliative care should be extended to both patients with cancer, with other life-limiting diseases, and their families. many palliative care guidelines have emphasized that the discussion of advanced decisionmaking among patients and their families should be initiated when patients still possess decision-making capacity (cheng, 2018) . patients in mainland china sometimes fail to grasp or accept the truth of a diagnosis and limited survival time (cheng, 2018) . moreover, according to questionnaire reports from 1,084 patients in 2016, awareness of the concept of advance care planning or advance directives in china is still low (kang et al., 2017) . in mainland china, family members are often held responsible for making decisions for the elderly in their care, despite a lack of knowledge or training, and thus may resort to homeopathic remedies. healthcare professionals generally have to ''respect'' any decision made by the families and try their best to ''save'' patients' lives using many life-sustaining treatments, although they generally hold negative attitudes to useless treatments. such an approach is regarded as an appropriate measure in terms of protecting themselves from medical conflicts. misunderstanding of palliative care as 'giving up on treatment and waiting for the death of the patients' by family members of the patients as well as even by some doctors, should be corrected (hu et al., 2019b; ning, 2018; xiao et al., 2019) . there is an urgent need for the development of hospice and palliative care in china. in recent years, hospice and palliative care have witnessed rapid development. more and more patients, families, and health-care professionals come into contact with the concept and realize the benefit of hospice and palliative care, while more and more educators, organizations, government and other intermediary leaders have paid more attention to the promotion and development of hospice and palliative care. the current trend towards an ageing society poses difficulties due to the additional challenges seen in diseases in the elderly, including longer disease durations, more complications, underwhelming responses to treatment, and poor prognosis, thus in response to this trend, china has established the national clinical research center for geriatric disorders (ncrcgd) (o'meara, 2020; yu et al., 2018a) . funded by the central government, the ncrcgd aims to provide innovative models for the diagnosis, management and further research into geriatric diseases at a national level. the ncrcgd focuses mainly on comprehensive and systematic research into pathogenesis, prevention, diagnosis and treatment of age-related diseases such as ad, pd, and cerebrovascular disease (xwhosp, 2017b, 2019). at the same time, it is committed to building a national elderly medical service network and scientific innovation system by integrating resources of clinical and basic research. for instance, a health data management platform for the elderly could provide a scientific basis for management and decision making. furthermore, through the education and promotion of new theories and technologies of geriatrics to grassroots hospitals, the ncrcgd can build a better medical service system, improving the health of elderly people. the ncrcgd strives to promote the combination of academic and clinical research (xwhosp, 2017b, 2019). research on agerelated diseases has been carried on such various aspects as diagnosis, treatment, and prevention in fields such as immunology and molecular biology (o'meara, 2020). the characterization of the gene pool, a series of research findings and new technologies have been applied at the clinic, which promotes the development of gerontology in the direction of precision medicine for early diagnosis, early prevention, and early treatment. the ncrcgd also serves as an educational harbor to foster the training of geriatricians and promote academic exchange (frailty-china, 2019; xwhosp, 2017b, 2019). the organization also undertakes other social responsibilities, including partnerships with hundreds of institutions across the country, relying on their collaborative research network to successfully carry out a comprehensive assessment of multiple systems for the elderly (xwhosp, 2017a). through a comprehensive assessment of the multiple aspects of the elderly's diseases, fitness, cognition, psychology and society, it may be possible to develop a system for early identification of health imbalances in the elderly that characterize certain diseases, aiding in their early prevention, and helping to reduce the burden of the ageing chinese society, as well as improving the elderly health service system. prospectively, the ncrcgd will also play its essential role in guiding the research and clinical guidelines for elderly people care as well as making more contributions to improve elderly people's quality of life in china. in order to deal with the ongoing boom in the elderly population, the chinese government has put more effort into funding research on ageing and its related diseases in recent decades. during the recent (2019) outbreak of coronavirus in china, older patients with preexisting ageing-related diseases were found to have a much higher casualty rates than younger patients (chen n et al, 2019) , again highlighting the importance of preventing ageing-related diseases. in response to this, along with the growing need for improving the quality of life of the elderly in china, more attention has been placed on the development of pharmacological strategies against ageing, organ degeneration and major ageing-related diseases. in this section, we will discuss recent world-wide progress in pharmacological attempts to improve healthspan, and the significant contributions that chinese researchers have made. calorie restriction (cr) was first demonstrated as an effective way to extend lifespan in rodents (de cabo and mattson, 2019), however the physiological mechanisms behind its anti-ageing effectiveness were not fully understood at the time, and remain uncertain. later studies have suggested that cr might extend lifespan by regulating insulin-like growth factor (igf) and mammalian target of rapamycin (mtor) pathways. metformin is primarily known for treating type 2 diabetes, with its underlying molecular mechanisms leading to the to down-regulation of igf-1 signaling, and the inhibition of cellular proliferation, mitochondrial biogenesis, ros production, dna damage, activity of the mtor pathway, etc. . the anti-ageing effect of metformin is under investigation by the tame (targeting ageing with metformin) trial in the usa. acarbose, an antidiabetic drug, could also disrupt the igf pathway. acarbose has been shown to partially mimic the effects of cr and extend lifespan in mice by controlling blood sugar and slowing carbohydrate digestion (harrison et al., 2019) . a clinical trial on acarbose (clinicaltrials.gov identifier: nct02953093), named study of acarbose in longevity (sail), is in phase 2, and will hopefully shed some light on its pro-longevity effect in humans. mtor is a pivotal nutrition sensor that links cellular metabolism with proliferation, growth and survival by regulating amino acid metabolism, proteostasis, mitochondria dynamics, cellular senescence, etc. (liu and sabatini, 2020) . rapamycin, a well-known inhibitor of mtor, has shown life-extending effects in all model organisms and postpones the onset of age-associated diseases harrison et al., 2009; liu and sabatini, 2020) . despite the promising pro-longevity outcome of using rapamycin in animals, its clinical application in human has been obstructed by growing concern of potential side effects from immunosuppression and hyperglycemia (pallet and legendre, 2013) . whether the dosage can be fine-tuned to avoid these side effects will be the determining factor in whether or not rapamycin becomes a future pro-longevity drug. the application of induced pluripotent stem cells (ipscs) from healthy and pathological ageing individuals (liu et al., 2011) is also propelling further mechanistic studies and translational applications for cr. nicotinamide adenine dinucleotide (nad + ) is a fundamental molecule in human life and health; while there is an age-dependent reduction of nad + , nad + augmentation extends lifespan and improves healthspan in different animal models as well as shows potential to treat different neurodegenerative diseases based on phase i clinical trials (gilmour et al., 2020; lautrup et al., 2019; yoshino et al., 2018) . nad + precursors such as nicotinamide riboside (nr) and nicotinamide mononucleotide (nmn) have emerged as promising approaches for intervention against ageing phenotypes and age-related diseases. supplementation via these precursors can elevate nad + level in vivo and improve glucose metabolism, mitochondria biogenesis, dna repair, neovascularization and neuroprotection . additionally, more than five phase i clinical trials indicate that orally taking nr is well tolerated and able to elevate nad + in the blood (gilmour et al., 2020; lautrup et al., 2019) . several clinical trials are currently operating in parallel, investigating nr's effects on metabolic function in bones (nct03818802), in immunity (nct02812238), and nmn's effect in cardiometabolic function (nct03151239), with others also ongoing. in china, although nad + precursors have become widely available commercially as supplements, clinical trials exploring their disease-treating ability in humans are still lacking. senescent cells accumulate in aged tissues and this accumulation is considered one of the driving forces of ageing. senolytics are a class of molecules specifically designed to induce apoptosis of these senescent cells. clearing senescent cells in mice has been shown to substantially alleviate ageing phenotypes, producing potent therapeutic effects in ageingrelated diseases such as ad (bussian et al., 2018; zhang et al., 2019b) , atherosclerosis (childs et al., 2016) and osteoarthritis (jeon et al., 2017) . in 2016, a joint research team of chinese and american researchers found that the molecule abt263 reduced irradiationinduced senescent bone marrow hematopoietic stem cells (hscs) and muscle stem cells (muscs) in mice . abt263 (a bcl-2 family inhibitor), together with dasatinib (an anticancer drug) and quercetin (an apoptosis inducer) are the most commonly used senolytic drugs. the senolytic cocktail of dasatinib plus quercetin (dq) decreased naturally occurring senescent cells, improved mobility and reduced the risk of mortality . however, a small pilot clinical study using the same dq cocktail in patients with idiopathic pulmonary fibrosis (ipf) reported no change in pulmonary function, frailty index, clinical chemistries and reported health, though the beneficial effects on mobility were still noted (justice et al., 2019) . while clinical trials on senolytic drugs are mainly conducted in the usa, the concept of reducing senescent cells to delay the ageing progress has attracted interest from all over the world. since 2016, the national natural science foundation of china (nsfc) has set up special programs, providing millions of rmb to support research on cellular senescence and organ degeneration. as such, it is recommended that china further expand its investment in senolytics research. targeting the microbiota may also improve age-related diseases, including ad. in 2019, china approved the first domestically invented ad drug, oligomannate (gv-971) (wang et al., 2019d) . considering there has been no new approved anti-ad drugs in the past 17 years, this has been exciting news. despite the potential of these advances, more work is necessary to understand how gv-971 works. additionally, due to the relatively short clinical trial period, further investigation with longer lasting trials is highly recommended. most human trials for potential anti-ageing drug candidates are conducted in patients with certain age-related diseases. despite partial overlap of the pathologies of these diseases, the knowledge from these trials cannot be interpreted as treating ageing itself. therefore, to reach the goal of identifying anti-ageing compounds, a more comprehensive study on disease-free, healthily ageing groups with no obvious health issues is in immediate need. china has the advantage of a large and diverse population, providing an ideal subject pool for this type of study. the knowledge gained from such studies would likely open new avenues to better understand the fundamental aspects of ageing mechanisms, facilitating their treatment. from a public health and policy perspective, it can be seen that continuing research into prevention and management strategies will be important for both non-communicable diseases as well as geriatric syndromes, to ensure that it is not only life expectancy that is increased, but also the quality of life, by promoting independence and reducing reliance on elderly care services. regular monitoring of trends in incidence and case fatalities of common chronic diseases would enable estimates of future disease burdens and guide preventive health policies (chau et al., 2013a; chau et al., 2013b) . in addition, solutions to trends in the occurrence of disability and frailty are also needed (yu et al., 2018b) . such data would inform the design of elder-friendly service delivery models across the whole spectrum, from prevention to primary care, hospital and residential care settings (woo et al., 2013; yu et al., 2019) . currently, hong kong, a special administrative region (sar) of china, has the longest life expectancies in the world for both men and women, such that the need to redesign service models is particularly pressing. by 2064, it is predicted that 33% of the population in hong kong will be aged 65 years and over; 70% will have at least one chronic condition, with an increasing prevalence of disability also predicted (yeoh and lai, 2016) . while the health and social care systems are well developed, there is a mismatch of needs as those with chronic conditions are predominantly managed in the public hospital systems, whereas primary care is predominantly in the private sector. a recent review concluded that better integration of health and social care systems with a primary emphasis on the community could be the best way forward for the ageing population in hong kong (threapleton et al., 2017) , exemplified by the formation of nurse-led district health centers in 2019 (fhb, 2019). other community models with an emphasis on promoting group activities to prevent frailty and aid selfmanagement of chronic diseases have also been developed (cadenza). such developments have the potential to enhance the role of primary healthcare professionals in preventing functional decline (morley et al., 2017) , so that many can retain independence even as life expectancy increases. the who's integrated care for older people (icope), formally launched in october 2019, will form a useful blueprint for policymakers to build on their existing health and social care infrastructure (who, 2015c). experiences of elderly healthcare in the european union (eu) may provide useful tips for the situation in china (table 1 ). in the eu, elderly care is provided in each country based on its own social security system and cultural norms. in most european countries, the family and the state are the main providers of support to older people both in activities of daily living (adl) and in instrumental activities of daily living (iadl) (schmid et al., 2012) . europe is characterized by three types of care provision: 1) 'crowding out', whereby the state largely replaces family care; 2) 'crowding in', whereby the state promotes family care; 3) 'mixed responsibility', whereby both the state and the family take a joint responsibility for care, yet have separate functions (brandt et al., 2009) . in china, family is still the traditional provider for elderly care (wu et al., 2016a) . under current national and social developmental conditions of china, the chinese government encourages a '90/7/3' pattern of eldercare system, namely: 90% of all older people are cared for at home, 7% are cared for in communities, and 3% are cared for in institutions (mayston et al., 2017) . a 'crowd out' system dominates in the nordic countries (denmark, finland, norway, sweden, iceland) , where the government strives to create a comprehensive system of care services in order to reduce the care obligation of the family. in continental european countries such as austria, belgium, france, germany and the netherlands, systems are more mixed in their provision of elderly care, though tend towards a 'crowd out' approach (kasearu and kutsar, 2013) . in the island countries, i.e. the uk and ireland, the system is more mixed, and the private market is the dominant welfare provider, with the government providing two main social care services to older people, one being old age pensions and the other being healthcare . southern european countries (e.g. greece, italy, portugal, spain) have a 'crowd in' system whereby families have more responsibilities for care services to older people (kasearu and kutsar, 2013; wu et al., 2014) . eastern european countries have undergone dramatic political, social and economic changes after the soviet era and experienced a rapid change from 'crowd out' to a 'crowd in' system where family is the main care provider and the government provides basic formal care services (kasearu and kutsar, 2013; wu et al., 2014) . in china, owing to confucian culture and its emphasis on the family, it is taken for granted that the family, most notably adult children, has the responsibility to care for older parents, especially in the rural areas of china, thus older people rely mainly on their children or family for support (chen and silverstein, 2000; wu et al., 2016a) . rapid demographic ageing increases the demand for care in all ageing societies. currently, european countries face the enormous challenge of implementing major reforms to elderly care in order to ensure that the needs of older people can be continuously met in the future (brandt et al., 2009; broese van groenou and de boer, 2016) . to this end, european governments have increasingly relied on informal care in addition to regular and traditional formal care providers from professional home care services, day care units and nursing homes (broese van groenou and de boer, 2016; verbakel et al., 2017) . informal care for older people is generally provided by caregivers from both kin and non-kin groups, including spouses, children, relatives, neighbors, friends, etc. (swinkels et al., 2016) . in europe, around a third of people aged 50 years or older provide informal care to older people. however, shrinking family sizes, the increasing participation of females in the workplace, and rising retirement ages, may pose a drastic challenge to informal care in the future (verbakel et al., 2017) . china is currently facing challenges in its family-based elderly care model due to new family formation, the spread of individualistic values, and frequent internal migration from rural to urban areas encouraged by rapid economic development (wu et al., 2018a) . moreover, china's one-child policy has sped up the process of population ageing by accelerating the change of the fertility rate and, in turn, has weakened the family-based elderly care model in china . in europe, new elderly care arrangements have been gradually developing based on a new combination of family obligations, market provision and public support. in nordic countries, the state, family and market have been changing with regards to their roles in the provision of elderly care, specifically by increasing the provision of publicly funded care services in a forprofit capacity (marketization of elderly care) and increasing the importance of family care (szebehely and meagher, 2018) . in estonia, the idea of community-based support for older people has been increasingly set forth in order to postpone the need for institutional eldercare (tulva et al., 2016) (tulva et al., 2017) . when it comes to the current trend of eldercare in china, marketization has also been discussed to a large extent both at academic and policy levels. the 'public-private-partnership' (ppp) model may improve the efficiency of familybased eldercare. in the 13 th five-year plan for national economic and social development (2016-2020) , the opening-up of the market for elderly care services (e.g. purchase of services by the government) was clearly stated (du and wang, 2016) . elderly care reforms might create new challenges for both europe and china, an important challenge being an increase in inequality in eldercare service utilization among different social groups of older people. older people with higher socioeconomic status will be able purchase private care services whereas those with less social capital will have to rely on more family-based care. in addition, for the chinese government, there is a need to take into account larger inequalities derived from immense resource variations across regions during the development and reform of elderly care services. while mainland china can learn many successful experiences from hong kong, the eu, etc., there remains many unique features that demand the creation of an elderly care system tailored to mainland china. in addition to responding to changes and preparing to adapt to an ageing society at the societal and individual levels, understanding of the mystery of ageing at a molecular level will aid the development of novel strategies to slow ageing and to promote healthy longevity. in the below sub-sections, we will focus on how to use centenarians, the china national genebank database (cngbdb), and ai to further propel ageing research. in china, the numbers of the oldest-old individuals (those aged 80+), near-centenarians (95+), and centenarians are increasing at roughly 10% yearly (fig. 4a-b) , providing unique resources for both basic research and clinical studies. there were 3,384 centenarians in 1953, with the number rising to 35,934 by 2010 (abida and gu, 2008) . based on the un's medium variant projection, by 2050 over a quarter of the global oldest-old population will live in china. as the numbers of the most elderly have expanded, the gender structure of centenarians, the proportion from urban and rural areas, and differences in geographical distribution have formed "three-high" trends in china (data from china's 2010 population census, excluding hong kong, macau and taiwan) . first, there is a gender difference, with 75% of centenarians being female (peng, 2011) (fig. 4a) . data from the 6 th population census of china (2010) reported 27,082 (75.37%) female and 8,852 (24.63%) male centenarians. this could be due to both physiological (e.g., female hormone estrogen) and cultural differences (women often do more housework, pay more attention to healthcare) (austad and fischer, 2016; peng, 2011) . second, urban and rural disparities were clear, wherein more centenarians (56%) live in rural areas, possibly due to a healthier living environment, diet and lifestyle in these regions (cai, 2013; peng, 2011; zeng et al., 2017a) (fig. 4c ). and third, there was geographical difference in the distribution of centenarians. the distribution of longevity areas in china presents several significant characteristics, including province-specific: being majorly in hainan, guangxi, sichuan, yunnan, guangdong and xinjiang, and mostly distributed along river basins, with more centenarians along the pearl and yangtze rivers and the lancang river basins. these characteristics of the area distribution of centenarian suggest that areas beneficial to longevity can be divided into two types: 'natural' and 'economically developed' longevity areas (he et al., 2017; zeng et al., 2017a) (fig. 4d) . studies of centenarians can provide valuable information for early prevention of major diseases, premature ageing, and early death, thus providing the scientific support necessary to cope with the quickly approaching arrival of an ageing society in china. centenarians may represent a prototype of successful ageing. a longitudinal study of a danish 1905 cohort suggests exceptional longevity does not result in excessive levels of disability (christensen et al., 2008) . in fact, some centenarians experience a delayed onset of age-related illnesses (delayers), whereas others did not succumb to any age-related illnesses (escapers) (christensen et al., 2008; hitt et al., 1999) . in addition, one case-control study showed that older individuals had a delayed age of onset of cancer, cardiovascular disease, diabetes mellitus, hypertension and osteoporosis than their respective younger reference groups (ismail et al., 2016) . the china hainan centenarian cohort study (chccs) on 1,002 centenarians is now in progress, focusing primarily on examining biological indicators and medical aspects, and extensively examining psychological and sociological factors (he et al., 2017) . all in all, the study of centenarians is a topic of immense importance for population and health policymakers, as well as for the larger aim to achieve long, healthy lives. state-of-the-art technologies enable the 'big data'-based investigation of the molecular mechanisms of human ageing and its associated diseases, providing unique information for therapies and interventions. the cngbdb is a centralized 'big data' hub of biological data, providing data sharing, knowledge search, computational analysis, management authorization, and visualization services to the global research community. built and maintained by the china national genebank (cngb), cngbdb draws from 3 "banks": the living biobank, the biorepository, and the bioinformatics center, and from 2 "platforms": the digitization platform and the synthesis and editing platform. the research data system of cngbdb integrates molecular data from internal and external sources into nine sub-databases including literature, gene, variation, protein, sequence, project, sample, experiment, and assembly (https://db.cngb.org/news/2/). comparative analyses of species and tissues can identify the molecular causes of ageing phenotypes, corroborate or disprove theories on ageing, and help to understand differences in j o u r n a l p r e -p r o o f the mechanisms of ageing across species. genotype comparisons within a species at the level of individuals and populations can help identify genetic reason for differences in lifespan. this approach may be used to compare populations from different regions of china, or chinese and foreign populations, such as ashkenazi jews and okinawan centenarians in japan, two populations well-known for their longevity, facilitating the discovery of chinese-specific agemodifying genes. the identification of potential life-extending genes eases the design of therapeutics that can mimic the effect of these genes in people without those genes. likewise, treatments can be designed for age-related diseases that result from mutated or nonfunctional genes in specific populations. it is also possible to comparatively analyze gene expression at the tissue level, as tissues age at different speeds. since many age-related diseases, such as ad, occur within a specific tissue, understanding the speed at which tissues age can help chinese gerontologists assess the risk of and help to prevent tissue-specific age-related diseases (wieser et al., 2011) . the advent of 'big data' and machine learning have eased the collection and identification of biomarkers associated with biological age and may allow for the development of personalized clinical diagnostic tools for physicians in the near future (aman et al., 2019) . in the field of medicine, biomarkers refer to measurable indices capable of identifying a condition, state of being, disease, or environmental marker whose presence may reflect a pathophysiological state (naylor, 2003) . the use of biomarkers has been applied to the field of anti-ageing technologies, including the prevention and treatment of age-related disease, and has been used to explore methods to delay or offset the ageing process altogether, and will likely serve as key components to advances in the field (campisi et al., 2019) . in some cases biomarkers may more accurately represent a patient's 'biological age', as opposed to a patient's simple 'chronological age', the former of which is thought to be more clinically relevant (lopez-otin et al., 2013) . the following sections will review three applications of biomarkers at the molecular, individual and societal levels, including current findings as well as potential research directions. as stated above, there are multiple tests that can be used to obtain molecular biomarkers, and several have been validated to some degree by current research. molecular biomarker studies can be roughly separated into 2 classes: smaller scale studies attempting to determine the utility of a given biomarker, and machine learning studies involving thousands of samples with the intention of developing clinical assessment tools. as an example of this, a recent study involving elderly hypertensive patients was used to investigate a wide library of potentially useful biomarkers . here, 416 elderly chinese participants were matched with subjects from a pool of 9,000 normal volunteers. after adjusting for confounding covariate factors, the researchers found that only elevated triglyceride levels were strongly linked to high blood pressure (hong et al., 2017) . while these cross-sectional studies are certainly important for determining which biomarkers should be considered for clinical evaluation, one of the limitations, at least in comparison to machine learning studies, is that they have a low number of samples. in the above examples, most participant groups contained less than 500 people. while this is a surplus number in other medical contexts, one of the advantages of machine learning is its ability to process thousands of samples granting increased accuracy. fittingly, one of its primary uses is to draw meaningful conclusions from mass, simple, cheap, and non-invasive tests. another key limitation is that biomarker assessment studies using these 'smaller' cohorts tend to lack any external validation. perhaps one of the most easily accessible tests that comes to mind is a standard blood test, here the usefulness of machine learning has been demonstrated by putin and colleagues, who designed a modular ensemble of 21 deep neural networks (dnns) of varying depth, structure and optimization for the prediction of human chronological age using a basic blood test (putin et al., 2016) . the team trained the dnns using a collection of over 60,0000 samples from routine blood biochemistry and cell counting assays. the researchers reported that the accuracy of their results provided evidence to suggest that machine learning algorithms could be used to design minimally invasive biomarker tracking methods for ageing that would only improve with greater access to training samples (putin et al., 2016) . another study examined 19 serum biomarkers, and its results were externally validated using a separate data set from the framingham heart study (sebastiani et al., 2017) . such studies highlight the ability of machine learning techniques to infer conclusions from basic samples, and to externally validate such conclusions. still, this was one of the very few studies with this type of external validation and more are needed for clinical application. big data can also be used to assist geriatricians for personalized medicine, defined as a medical approach in which treatment is customized on an individual basis based upon disease subtype, genetics, risk, prognosis, or treatment response using specialized diagnostic tests (frohlich et al., 2018) . for instance, predictive biomarkers for the early detection of certain diseases, may help both patients and doctors to decide on appropriate treatment pathways. in addition, the 'internet of things' refers to the ability of technology to send and receive data via the internet. as wearable/compact technologies become more prevalent (i.e., phone pedometers, pacemakers, insulin trackers) and their data becomes easier to store and share, so too does it become easier to use life-logging data to track individual's wellbeing. unfortunately, while there is great potential for this type of technical approach, there are currently very few cases of applications within clinical practice (frohlich et al., 2018) , with many studies still in an exploratory phase, requiring further research. for example, one study shows that machine learning techniques have significant potential in developing personalized decision support for chronic disease tele-monitoring systems; however, it was noted that the system would be improved with a larger library of comprehensive predictive markers (finkelstein and jeong, 2017) . the use of radiomics, the high-throughput mining of quantitative image features from standard-of-care medical imaging that enables data to be extracted and applied within clinical-decision support systems, has also been proposed, especially within the realm of dementia prevention and detection . these studies have benefited from large sample sizes (>1,000 images) using machine learning. this brings us to the issue of noise reduction, which is crucial for effective use of big data and will enable a more robust extraction of features. given the immense amount of data expected to be handled in future projects, finding ways to store, process, and analyze this data also presents a challenge for future research. at the societal level biomarkers have numerous applications. monitoring population-level biomarkers will likely provide an accurate, real-time view of the health state of a given area. this will allow for targeted interventions catered to suit the specific needs of a population. as stated earlier in this piece, modern medicine has provided for major increases in both quality of life at old age, and life expectancy, however, this can also be considered a potential societal burden. earlier the use of federated systems with respect to online medical records and data sharing was discussed as a potential hurdle to some countries and medical systems in the world. china has recently embraced a centralized health informatics scheme, with over 80% of medical organizations above the county/district level, 27% of town level hospitals and all cdc above the county/district level capable of transmitting real-time reporting on the status of epidemics via the public health information system (zhang et al., 2007) . in the future, the data provided by a centralized medical record system has the capacity to train numerous machine learning algorithms for use with biomarkers. another challenge for population-level biomarker implementation is to select low-cost, minimally invasive testing that can be used at a large scale. with respect to china, great advances have been made in the use of medical informatics within the past 30 years. however one of the hurdles going forward for the country is that much of this investment has been driven by industry and the private sector, and a major priority for the country's future should be to divert resources to academic research (liang et al., 2017) . this is especially true for the poorer members of society, or those without ready access to healthcare, as biomarker are an asset in devising appropriate healthcare plans for populations in need . addressing rural areas may be a challenge both in terms of healthcare delivery and biomarker testing, as these regions may lack sufficient infrastructure for both, posing a challenge for the future . we recommend the use of mobile-equipped information technology services to reach more remote regions. in summary, biomarkers have a great deal of potential for how doctors can prevent, diagnose, and treat illness associated with ageing. while there are many hurdles going forward, the application of machine learning and big data to biomarker research will provide new opportunities to understand ageing at the molecular level, deliver personalized treatment at the individual level, and design influential and effective policy at the societal and population level. since the beginning of the 21 st century, china started to enter a period where it may be classified as an ageing society. at the same time, the compulsory healthcare insurance systems in china has undergone a comprehensive and rapid development, while still emphasizing the ideologies of health equity and social justice . three major health insurance schemes have been launched, achieving near-universal coverage in a short time, which gained early appraisal by emulating the goal of the provision of affordable and equitable basic healthcare for all by 2020 (yip et al., 2012) . after the establishment of the urban employee basic medical insurance (uebmi) in 1998, the chinese government implemented the new rural cooperative medical scheme (ncms) for rural residents in 2003, and the urban residents basic medical insurance (urbmi) for urban residents without employment in 2007. as a result, social health insurance coverage increased from 29.7 to 87.9% between 2003 and 2008, and further to 95.7% by 2011, and has been stable since (meng et al., 2012) . in order to further reform the fragmented health insurance system, the latter two of these schemes were combined into the basic medical insurance for rural and urban residents in early 2016, with a target of making the system less complicated, but more equitable for various social groups. in the past 10 years of the new round of healthcare reform beginning in 2009, the chinese government dramatically increased financial investment, with half of all investment in the form of funded premium subsidies for residents to be covered by the social health insurance system (yip et al., 2019) . universal coverage has since led to improved access to and utilization of healthcare (meng et al., 2019) , decreased the prevalence of catastrophic health expenditure (yip et al., 2019) , and reduced out-of-pocket expenditure as a proportion of total health expenditure, especially for vulnerable groups, including older adults (xu and mills, 2019) . however, the social health insurance system in china still faces the dual challenge of population ageing (demand) and inefficient delivery on the side of the healthcare system (supply), raising both health expenditures and individual disease burden. out-of-pocket expenditure as a proportion of disposable personal income increased from 4.98% in urban regions and 5.17% in rural areas in 2008 to 5.59% in 2017 (xu and mills, 2019) . concretely speaking, population ageing addressed the increasing health and social care needs of older people. according to the report on the fifth national health services survey, the prevalence of non-communicable disease had increased more than 20% between 2003-2012, from 50.1 to 71.8%, while the inpatient rate rose from 7.6 to 17.9% in between 2003-2013. the outpatient rate also increased to 49.7% in 2013 (nhfpc, 2015) . the reimbursement of social health insurance improved rapidly and accounted for 42% of total health expenditure in 2017, though while out-of-pocket payments dropped from 60% in 2000 to 28% to 2017, financial protection and services packages were insufficient for the elderly (meng et al., 2019) , especially for those in rural regions. reported a three times-higher risk of catastrophic health expenditure among the old population in rural regions . in 2013, expenditures on hospitalization for older people in urban areas were reimbursed 64% by social health insurance and 53% were covered for their rural counterparts (who, 2015b). regional disparity in health benefits for the elderly with insurance aside, a problem of inequity among different health insurance schemes on health outcomes for older adults is still a great challenge. uebmi recipients were found to have better physical and psychological health outcomes compared to those with urbmi or ncms insurance. this demonstrates a transformation in health insurance reform from an emphasis on the opportunity-oriented health equity measured by coverage and healthcare accessibility to stressing outcome-based equity composed of health outcomes for the elderly, namely "outcome-based health equity", giving priority to disadvantaged groups . in terms of supply-side deficiency and unsatisfied progress in the past 10 years, gaps in the public hospital and pharmaceutical reform have tremendously limited the effectiveness of social health insurance reform, even though the public hospital has removed mark-ups for drug sales, adjusted pricing mechanism, reformed provider payment systems and changed governance structures at the county level (yip et al., 2019) . the hospital-centered health delivery system has induced the growth of both health expenditure and health insurance expenses, which worsened the control of non-communicable diseases and health outcome improvement in ageing society. unexpectedly, the usage of outpatient and inpatient services in primary health facilities declined from 62% and 29% in 2009 to 54% and 18% in 2017 . due to the lack of qualified long-term care facilities, the length of hospitalization was longer for the old population aged 60 and over (who, 2015b), demanding higher expenditure input to cope while wasting health resources. we advocate the immediate application of an integrated health and social care-oriented, particularly in community settings, with the objective of increasing affordability and improving the quality of care for older people. population ageing, family structure shift, and migration, were three major challenges limiting the efficacy of traditional informal care provided by families and their networks. a large proportion of older people with functional disability or dementia will continue to create enormous challenges for an immature long-term care system in china . it was estimated about 40 million (19.5% of the elderly) older people had some sort of functional disability by 2015, among which 12.4 million (6.05% of old population) had a serious status of disability (nhfpc, 2015) . at the same time, china has become the largest country in the world to have over 9.5 million people with dementia (jia et al., 2020) . in response to the increasing need for social care of older people with disability, the central government of china has implemented a pilot practice of ltci policies in 15 cities, while some local governments were also encouraged by the central government to initiate county-level pilot experiments on ltci since 2016, in hopes of stimulating the growth of long-term care providers (luo and zhan, 2018) . most ltci schemes were based on the social health insurance system, though these pilots had distinct and diverse eligibility conditions, premium contributions, need assessment instruments, and benefit packages. the reason for carrying out a pilot practice rather than fully implementing a uniform nation-wide scheme reflected the complexity of ltci, and a worry about cost escalation noted ltci introduction in the more mature ageing societies of japan and germany. after two years of practice, a few evaluations were conducted to estimate the outcome of these pilot practices, identifying a host of problems. there are several characteristics and unique features present in the chinese ltci scheme. at first, coverage was narrow and limited only to older people with the most serious degrees of disability, and excluded older adults with dementia due to security issues and lower quality of care skills. by the end of 2017, less than 2% of the older population in the pilot cities were covered by ltci plans in qingdao (zhu and osterle, 2019) , which was the first city to launch the ltci scheme in china, a higher proportion of those 65 years and older was achieved in the ltci practice of the mature ageing populations in germany (11.7%) and japan (12.8%) (oecd, 2013) . secondly, the need assessment tools used by each pilot city were fragmented and biased. some pilot cities or counties only employed the barthel index to measure physically functional disability, but did not measure cognitive function with any scales, thus leading to the exclusion of older people with dementia from ltci coverage. more seriously, the results of need assessment were not applied to long-term care service provision, but only used as a "gate keeper" for receiving the fixed benefit package. assessment tools should be transformed from simple to comprehensive, from a physically oriented test to a multi-dimension health status one, even from health assessment to service assessment. thirdly, in most pilot plans, long-term care was provided by designated institutions through a contract, and a homeand-community-based caregiver was paid by the insurance scheme, however reimbursements were limited such that a large proportion of costs was still paid out-of-pocket by service users themselves, and unmet needs were still high among the disabled elderly . in addition, the inequality in access to long-term care services between advantaged and vulnerable elderly was enlarged. in most pilot schemes, higher numbers of benefit packages were allocated to insured groups living in nursing homes or receiving formal care than to those living at home receiving informal care. retired people with uebmi had higher affordability and preferred to live in the institutions and received higher reimbursements from insurance. rural residents could not access good quality long-term care facilities, and received fewer benefits. the inequality that remains in ltci practices highlights how policy reform ought to reevaluate and reconstruct the currently fragmented schemes and direct more attention to the disabled elderly with lower socio-economic status and without financial or family support. although china attempted the ltci scheme, its most urgent priority was to establish a unified meanstest public budget system to cover the most vulnerable social groups regardless of their living locations. through lu et al. (2017) 's projection, an investment as small as 0.25% of gdp (equivalent to about 1.25% of fiscal revenue) would greatly benefit the frail elderly and those with serious problems of functional disability and/or poor financial status . in 2016, the central committee of the communist party of china and the state council issued the healthy china 2030 plan. corresponding with the health-related sustainable development goal (sdg), this is a national mid-term and long-term strategic plan for moving towards universal health coverage and improving health equity, with emphases on health coverage for the whole life circle, including healthy ageing (prc, 2019). in 2018, china made a major restructuring of national healthcare governance. the national health commission (originally called the ministry of health) administers and regulates the healthcare delivery system and include two new areas of responsibility: elderly care and tobacco control (yip et al., 2019) . in addition, the national healthcare security administration was established. it is in charge of administering essential health insurances (urban employee basic health insurance, urban-rural resident basic health insurance, which integrated the original urban resident basic health insurance and new cooperative medical scheme) and medical assistance for the poor and vulnerable groups as well as deciding on pricing and drug procurement. rapid ageing and an alarming increase in non-communicable diseases (ncds) have arisen as major health concerns in china marten et al., 2014) . in 2009, the national basic public health service program was established, which included health management for elderly people, patients with major ncds (hypertension and diabetes), among others (nhfpc, 2017) . the program is financed by government funds, and the government's per capita allocation increased from 15 to 55 rmb between 2009 (nhfpc, 2017 . china's ongoing healthcare system reform prioritizes transforming hospital-centered treatment care to integrated and continued care through a tiered healthcare delivery system (meng et al., 2019) . a tiered healthcare delivery model defines the functions at each health facility level, and coordinates care across levels. a common model is that hospitals lead medical alliances to deliver integrated care, and provide support and training to strengthen primary health services wang et al., 2018b; wbwho, 2019) . in addition, residents are able to register with a family doctor team who provide preventive and basic healthcare as well as referral services. the government target is universal registration by 2020 (nhc, 2016) . china has made good progress in improving equal access to healthcare and financial risk protection for socially vulnerable people over the past decade (fu et al., 2018; meng et al., 2019; yip et al., 2019) , but challenges remain. there is a lack of qualified primary healthcare providers who are able to serve as gatekeepers, and the quality of primary healthcare is poorly characterized meng et al., 2019) . previous studies reported very low proportions of blood pressure and blood glucose control among patients with hypertension and diabetes seeking care from primary health facilities, and common over-prescription of antibiotics su et al., 2017; wang et al., 2014) . patients persistently bypass primary health facilities and seek perceived good quality of care in high level hospitals, despite many patients complaining of high medical costs and long wait times . on the other hand, most hospitals still largely rely on fee-for-service payment and tie doctors' salary to the hospital revenue generation, which gives hospitals an incentive to attract and retain patients rather than shifting them primary healthcare. overuse and overprovision of health services are common in china (meng et al., 2019; yip et al., 2019) . consequently, health expenditure has continued to escalate, a trend which threatens the long-term financial sustainability of basic health insurance schemes. the efficiency in using health resources is low (meng et al., 2019; yip et al., 2019) . as china continues to progress as an ageing society, strengthening primary healthcare system to provide integrated care will be fundamental to meet growing health needs and obtain the best value from existent health resources. it is difficult to shift from treatment-based intensive care to population-based preventive care and health management while perverse financial incentive for hospitals are not controlled or eliminated. this requires effective collaboration across related sectors led by a strong coordinating authority and needs to bridge policy dialogue to ensure health in all policies workable and achievable. china's prolonged demographic shift has led to decreased fertility, elevated sex ratios, rapid ageing, fast urbanization and major geographic redistributions (peng, 2011) , an interdisciplinary collaborative approach is necessary to prepare and face the challenges as society continues to age. we present a summary on ways to achieve a healthy ageing society in china at societal, individual, and molecular levels (fig. 5) . breaking knowledge gaps and eliminating boundaries among different sectors to further integrate and synergize different healthcarerelated parties at societal, individual, and molecular levels will optimize the outputs of the chinese healthcare system. the chinese government has adopted a positive stance to investment across the whole spectrum of ageing policies, medical education and training, basic ageing and geriatric research, prevention, primary care, and hospital and residential care. it is necessary to establish updated ageing policies on retirement age, to incentivize employment of the elderly, to encourage lifelong learning, and to invest in senior volunteer programmes (yeoh and lai, 2016) . the education and practice of geriatric medicine has been and will continue to be enhanced, including to further increase the teaching of geriatrics-related subjects in medical school, to design high-quality residency and fellowship programs, and to further integrate geriatric principles into general clinical practice (yu et al., 2018a) . the establishment of the national alliance of ncrcgd has been highly appreciated and welcomed and it will continue to serve as a national platform to educate and train geriatricians. while the achievement of healthy ageing and longevity is emerging as an important task for china as in many other countries, this may also be accompanied by socio-economic challenges. one of the major concern is that creating a society where healthy and active ageing and longevity are taken for granted may lead to a swelling of the elderly in the workforce, leading to limitations in job availability for the young, and proving to be a potent economic issue. countries like china and south korea are entering a society of population ageing, showing low birth rates and increased life expectancy, which changes the whole economy korea, 2017) . population ageing will likely have several macro-economic effects, touching various domains such as overall industrial structure, current account and inflation, output growth, household finance, labor markets, consumption, and even fiscal and monetary policy (korea, 2017) . it is therefore imperative to give a comprehensive assessment of population ageing in view of its effects on society and the economy in the long-term, to provide evidence to inform future policies. while a challenging task, some suggested responses to the early-emerging changes that could be taken to offset the effects of the ageing society include promoting the production of larger families in the young, finding ways to ensure jobs remain for the young should the elderly be able to continue longer in their positions, along with more general preparations on transform to an elderly-friendly society. it is delightful to witness the progress of basic and translational ageing research in china, as supported by increases in the number of grants and funding opportunities, as well as by rising numbers of high profile publications and discoveries (he et al., 2019c) . joint efforts from the government and stakeholders of each and every sector should be encouraged to nurture an elderly-friendly society, of most import are reforming the social support system to support china's ageing society, and the introduction of health service/investment interventions aimed at reducing inequalities in health among older people in china. we suggest current research focus on basic and translational gerontology to improve healthy longevity in the elderly, and on developing an integrated and affordable health and social care delivery system to meet the complex needs of a growing elderly population, and to finally transform china into an ageenabling country where well-being and healthy longevity can be celebrated for decades to come. in response to the ageing 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(per 10000 people) of viral hepatitis, pulmonary tuberculosis (p.tb), influenza, hiv infection and aids from 2004 to 2016 were extracted and presented as general (open) or aged (65 years or older, closed) population ), the 6 th population census of china (2010) and projection (2020-2050) of china's national bureau of statistics. c. women account for 75% of the total number of centenarians in china and the proportion of rural centenarians is far higher than that of urban area. data source: china's 2010 population census, excluding hong kong, macau and taiwan area. the map was made by r. d. geographical distribution of the relative number of centenarians. the proportion of centenarians in china's total population (centenarian ratio) has a significant regional imbalance the authors acknowledge the valuable work of the many investigators whose published articles they were unable to cite owing to space limitations. the authors thank dr. vilhelm bohr at the nia and university of copenhagen for reading of the manuscript. e.f. key: cord-297599-y4lu8m4k authors: luo, hua; zhao, mingming; tan, dechao; liu, chang; yang, lin; qiu, ling; gao, yan; yu, hua title: anti-covid-19 drug screening: frontier concepts and core technologies date: 2020-10-28 journal: chin med doi: 10.1186/s13020-020-00393-z sha: doc_id: 297599 cord_uid: y4lu8m4k the outbreak of covid-19 has recently evolved into a global pandemic. up to july 2020, almost every country has confirmed covid-19 cases reported worldwide. many leading experts have predicted that the epidemic will persist for relatively a long period of time. thus far, there have been no remedies proven effective against the disease. as the nation where covid-19 broke out first, china has adopted a combination of traditional chinese medicine and western medicine to fight against the disease, and has achieved significant clinical result. up to now, the covid-19 pandemic has been effectively controlled in china. however, the rest of the world (except for a limited number of countries and regions) is still in deep water. this paper thoroughly summarizes interdisciplinary notions and techniques, including disease model, biochip, network pharmacology, and molecular docking technology, etc., providing a reference for researchers in the screening of drugs for covid-19 prevention and treatment. these methodologies may facilitate researchers to screen out more potential drugs for treating covid-19 pneumonia and to tackle this global crisis. covid-19 is an acute respiratory infection caused by a novel coronavirus (sars-cov-2). the main symptoms of this disease include fever, dry cough, and fatigue, often accompanied by diarrhea, sore throat, runny nose, muscle pain, and so on. severe cases can rapidly develop into respiratory distress syndrome, septic shock, metabolic acidosis and coagulopathy, and multiple organ failure [1] . sars-cov-2 is a coronavirus with a membranous envelope, in a spherical or oval shape, often polymorphic, with a diameter of 60-140 nm [1] . the viral infection involves entry of sars-cov-2 virus into host cells [2] [3] [4] [5] mainly via a cell receptor angiotensin-converting enzyme ii (ace2). covid-19 can be transmitted through human saliva and physical contact, with an incubation period of 1-14 days. it is also highly contagious during the asymptomatic period, with 44 percent of transmission occurring before the onset of symptoms. the viral load in the patient's saliva peaked during the first week of the onset of new covid-19 symptoms such as fever and cough [3, [6] [7] [8] [9] . no precise vaccine or drug has been approved to prevent covid-19 effectively, leading to the rapid global spike of confirmed cases. until 3rd august in 2020, more than 17 million cases of covid-19 infections and with more than 680,000 deaths have been confirmed in 209 countries and regions worldwide. in china, anti-viral drugs such as interferon-α, ribavirin, lopinavir/ritonavir, chloroquine phosphate and arbidol, as well as a combination with traditional chinese medicine (tcm) are recommended to treat covid-19 [1] . however, lopinavir or ritonavir did not outperform the benefits to those of the standard treatment in hospitalized adults with severe covid-19 [10] . on the other hand, tcm has been observed to play an important role in preventing and controlling the epidemic. according luo et al. chin med (2020) 15:115 to data released by chinese center for disease control and prevention on 23rd march 2020, 74,187 of the newly diagnosed patients of covid-19 in china were treated with chinese medicine, accounting for 91.5 percent of total patient population at that time. in hubei province, 61,449 patients were treated with tcm, accounting for 90.6 percent [11] . clinical observation showed that the total effective rate of chinese medicine reached more than 90% [11] . tcm efficiently relieved the symptoms of the patients and promoted a fast recovery of their bodies, thus effectively reducing the number of patients whom changed from mild to severe conditions, as well as the overall mortality rate of the patients [11] . at present, a large amount of research work has been invested in searching for the treatments of coivd-19 worldwide. in china, promising therapies for coivd19 have been recommended according to the accumulated experiences of tcm in fighting with various epidemics during the long history. in this paper, we mainly focus on summarizing the advantages of tcm in treating covid-19 and several advanced techniques and concepts for drug screening of anti-covid-19 drug candidates. varieties of in vitro and in vivo models for drug screening are also introduced. we expect that this review to provide researchers valuable ideas and approaches in fast finding out the precise therapies and/or effective drugs against covid-19. as a single-stranded rna virus belonging to the c family of coronavirus, sars-cov-2 features four structural proteins, s protein, n protein, m protein, and e protein [12] . the current results suggest that the virus enters cells by binding to the host surface receptor, ace2, via the s protein, and then fuse with the host cell [13] . compared with sars-cov and mers-cov, the pathogenicity of sars-cov-2 is lower but is easier to spread [14] . whether fecaloral route transmission of sars-cov-2 plays an important role in spreading the virus, reminiscent of sars-cov, needs to be further studied for confirmation. of particular concern is whether sars-cov-2 will become as seasonal as community-acquired hcov. the heredity, pathogenicity, and continuous transmission of sars-cov-2 in the human body will influence the developing trend of covid-19 which is currently outbreaking globally [14] . to the origin of sars-cov-2 virus, researchers have thus far put forward two hypotheses: (1) it is a natural selection in animal hosts before zoonosis transfer; (2) it is natural selection after the zoonosis shift [15] . both hypotheses are helpful for further investigate and elucidate how the virus initially transmitted from animals to humans. at this stage, some researchers believed that the virus was originally from a natural host of bat, a report show that the 2019-ncov is 96% identical at the whole-genome level to a bat coronavirus [3] . the rtg13 sequence helped reveal key rbd (receptor-binding domain) mutations and multiple base-cutting sites. the virus may recombine to evolve in wild animals such as pangolins, and then cross the species barrier to humans through other intermediate hosts [16] . as of april 5, sars-cov-2 has been observed and reported to be effectively replicated in ferrets and cats, and transmitted through respiratory droplets in cats [17] . at present, there are two main detection methods for sars-cov-2 virus: nucleic acid detection and immunological detection. nucleic acid detection methods include gene sequencing, fluorescent quantitative pcr, digital micro-drop pcr, gene chip, and loop-mediated isothermal amplification. immunoassays include immunochromatographic strips, elisa, and chemiluminescence immunoassay [12] . since the outbreak of covid-19 pneumonia, there has been no precise drugs for treatment of this disease with regulatory approval. next, we will review and make a comprehensive analysis of drug targets, as well as possible therapeutic paradigms such as vaccine and therapeutic antibody, general antiviral drugs, protease inhibitor, and convalescent plasma therapy. the s protein is the receptor via which the virus binds to the host cell, and participates in cell fusion. it is a key target for the development of antibodies, vaccines (especially polypeptide and mrna vaccines), small molecular compounds against this virus. the receptor for sars-cov-2 infected cells is ace2, which is similar to sars-cov and also relies on transmembrane serine protease, is also a target for drug development [18] . according to the previous research of sars-cov, a rbd region on the correct conformation of s protein may be an ideal immunogen for vaccine design and development [16] . besides, an inhibitor of lipoprotein nucleotide fusion based on hr2 sequence was designed, called ipb02, which is highly active in sars-cov-2 s protein-mediated cell-to-cell fusion and pseudovirus infection [19] . sars-cov-2 major protease (mpro) is a key cov enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target. shanghai institute of materia medica, in collaboration with several institutions, has designed and synthesized two lead compounds against sars-cov-2 mpro, both of which have shown effective anti-infectious activity [19] . besides, activation of nlrp3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3) inflammatory bodies is lacking in bats, so the use of nlrp3 inhibitor mcc950 may be helpful in the treatment of covid-19 [14] . viral 3-chymotrypsinlike cysteine protease (3clpro), which controls the replication of coronavirus, is a drug target of sars-cov and mers-cov. nine potential anti-sars-cov-2 active compounds have been identified via this molecular pathway [20] . as the most effective medical means of epidemic prevention and control, vaccine can effectively block the spread of the virus [21] . at present, china is focusing on the simultaneous implementation of three technical routes: influenza vector vaccine, recombinant protein vaccine, and nucleic acid vaccine. led by academician wei chen from the medical research institute of the academy of military medical sciences, the team has successfully developed a recombinant new crown vaccine, which is now in phase i clinical trial (registration number of recombinant sars-cov-2 vaccine (adenovirus vector) registration no. chictr200030906). at the same time, some international pharmaceutical companies include gene one life science inc. and inovio pharmaceuticals inc. have conducted relevant animal experiments to develop the covid-19 vaccine. moderna and the vaccine research center of the national institute of allergy and infectious diseases conducted the first phase i clinical trial of a novel lipid nanoparticle (lnp)encapsulated mrna-based vaccine, mrna-1273, which encodes the spike protein (s protein) of sars-cov-2, began in the united states [22, 23] . scholars proposed two very far-sighted global solutions in the event of a new virus that triggers a pandemic in the future. one solution is to establish a global distribution of production capacity, where surveillance in animal reservoirs combined with characterization of the virus can identify members of the virus family that are likely to cause a pandemic, candidate vaccines using these isolates can then be produced, and this capability can be activated if new viruses emerge. this strategy is currently applied to h5 and h7 avian influenza vaccines. another solution is the development of a broad-based protective vaccine covering the entire family or genus of the virus, which is currently underway for influenza viruses and may be applied to coronaviruses in the future [24] . therapeutic antibodies are also specific therapeutic drugs. sars-cov-2 and rbd of sars-cov have high homology. the strong neutralizing antibody cr3022, which targets sars-cov rbd, can be effectively combined with sars-cov-2 rbd. thus it is a potential anti-sars-cov-2 antibody [18] . mode rna therapeutics, wuxi biologics and vir biotechnology are developing monoclonal antibody for sars-cov-2 and several pre-clinical studies have been completed and clinical trials have also begun. vaccines, in the form of monoclonal antibody, oligopeptides, and peptide molecules, take months to years to develop. considering approved antiviral drugs against a variety of viruses such as hiv, hbv, hcv, sars, and mers, guangdi li et al. recommended some of these current antiviral drugs for treating covid-19, such as nucleoside inhibitors favipiravir, ribavirin or ridgisivir [25] ; common antiviral drugs chloroquine phosphate, favipiravir, and arbidol; protease inhibitors disulfiram or lopinavir/ritonavir and immunosuppressants may also work against covid-19 [25] . in the absence of specific therapeutic drugs, convalescent plasma therapy (cpt), a passive immunotherapy, has been one of the potential treatment options for covid-19 [26] . the strategy has been used to treat flu, viral infections, sars, and other infectious diseases. since the plasma who meets the medical requirement is rather limited, and the quality of blood products is demanding, the use of cpt has failed to popularize, in spite of demonstrated efficacy [26] . therefore, researches on exploring and developing effective drugs for preventing and treating covid-19 are necessary and urgent. as very limited modern medicine has shown clinically approven efficacy for covid-19, lessons can be drawn from the effective treatment experience from the use of the combination of tcm and western medicines. during the screening of effective drugs and potential formulations or medicinal combinations, a variety of in vitro and in vivo screening models has been employed. therefore, disease models and some core technologies would be introduced in the following paragraphs for facilitating researchers to screen drugs for treating covid-19. using in vitro models (e.g. certain cell lines), the antiviral effect of a drug candidate could be quickly predicted preliminarily. at present, the most commonly used cell line in antiviral test of chinese medicine is mdck (madin-darby canine kidney) cells. in addition, hep-2, a549, mbck, and mouse macrophage raw264.7 are also frequently applied for screening of antiviral drugs. mdck cells are susceptible to multiple influenza virus strains, supporting numerous passages of virus replication (capable of 35 consecutive rounds), and are widely used in antiviral activity assessment, mechanism research, and influenza vaccine development. mdck cells are the most widely used cell lines for antiviral research in tcm [27] [28] [29] . single herb such as scutellariae radix (黄芩) [30] , isatidis radix (板蓝根) [31] , lonicerae japonicae flos (金银花) [32] , houttuyniae herba (鱼腥草) [32] , etc. and tcm formulations such as fufangyizhihao granule (复方一枝蒿颗粒) [33] and lianhua qingwen capsule (连花清瘟胶囊) [33] have shown potentials on attenuating the proliferation of a/ pr/8/34(h1n1), a/aichi/2/1968(h3n2) and other influenza viruses in mdck cells. a549 human lung adenocarcinoma epithelial cell line is a commonly used tool to investigate the interactions between virus and host, the biochemistry of viral proteins, and to analysis genes that are overexpressed to suppress viral infections, to perform large-scale drug screening, for example, screening for crispr activation, [34] . it was previously demonstrated that tcm reseda odorata (木犀草) decreased the caspase-9, caspase-8 and caspase-3 expression in a549 cells infected with h1n1 virus [35] and chuanxiong rhizoma (川芎) [36] . in addition, the inhibitory effects of scutellariae radix on a 1/fm/166/85(h1n1) virus and influenza a and b viruses have been demonstrated in a549 cell line [37, 38] . researchers have used vero e6 cells to understand covid-19. for instance, vero e6 cells were used to test the antiviral activity of lianhua qingwen capsule against sars-cov-2 [39] . more interestingly, recent studies on vero e6 cells demonstrated that tmprss2 could enhance sars-cov-2 infection, which was in common with middle east respiratory syndrome and sars-cov. given the various variants containing point mutations or 15-30-bp deletions (del-mut) found accordingly at the s1/s2 junction via plaque purification of vero-e6 cells cultured with sars-cov-2 and the fact that adaptive function could disappear due to replication of permissive vero-e6 cells, it was suggested that strong selective pressure might be responsible for sars-cov-2 infection in humans promoted by the unique cleavage motif [40] . additionally, a tmprss2-expressing veroe6 cell line was considered helpful for propagating and isolating sars-cov-2, because it was easily accessible to infection of sars-cov-2 [41] . yi zhi hao granule has been reported to present obvious anti-h1n1 activity on human laryngeal carcinoma epithelial cell hep-2, and can alleviate lung injury and reduce the mortality of infected mice [42] . xiaoqinglong decoction (小青龙汤) can effectively inhibit the infection of hep-2 cells by the human respiratory syncytial virus [43] . in addition, mouse macrophages, raw264.7 are increasingly favored for screening antiviral drugs. for instance, yinhua ping gan granule (银花平感颗粒) was observed to efficiently inhibit the proliferation of a/pr/8/34(h1n1) virus in raw264.7 cells, which might be related to the following elements: regulates type i interferon and pattern recognition receptor signaling pathway; up-regulates the expression of ifn-γ and anti-myxvirus protein 1; downregulates the expression of il-6, tnf-α and phosphorylated tank binding kinase 1, and signal transduction and transcription activator 1 [33] . as in vitro screening can only offer potential drugs against covid-19, proper animal models have to be established to further understand covid-19 disease evolvement and to screen drugs for effective treatment, before possible clinical trials. researchers are testing mice, rats, ferrets, and even monkeys to answer key questions about the diseases and to fast-track potential drugs and vaccines for clinical trials. after outbreak of covid-19, china institute of laboratory animal sciences (cnilas) has taken the lead in establishing the disease models in transgenic mice and rhesus monkeys with covid-19, enriching the understanding of the etiology and pathology of covid-19. with the model, 5 patent medicines have been thoroughly evaluated in vivo for potential treatment of covid-19, and 6 vaccines and 4 more patent medicines are currently evaluated [44] . it was reported that academician dr. zhong nanshan's team has created the world's first non-genetically modified mouse model infected with sars-cov-2. compared with the traditional receptor transgenic mouse model, this model has a shorter construction time and does not need to reproduce; therefore, it is suitable for large-scale popularization in a short time. this model is useful for in vivo validation of antiviral drug and protective neutralizing antibodies, and vaccines. besides, the model can be used to study the immune response and pathogenesis of sars-cov-2 in vivo. in addition to mice and rhesus monkeys, other animals similar to human viral infections have been used in previous studies to screen for an antiviral drug. mouse plays an important role in researches on the pathogenesis of respiratory diseases associated with human virus infection [45] [46] [47] [48] [49] . some researchers are currently using mice as an animal model to test drugs and vaccines and to investigate the nature of the infection of sars-cov-2 [49] [50] [51] . however, mice often shrug off infection with sars-cov-2 and only exhibited a relatively mild clinical disease [24, 52] , because mouse ace2 receptor features several differences from that of humans [53] . for instance, out of 29 key amino acids in this important domain,11 in mouse were different from that in human [54] . luckily, engineering mice that could express both the human and mouse version of the receptor's gene, ace2, has been suggested as an effective way to remove the roadblock. in fact, in a study led by qin chuan on sars, engineered mice that could express human ace2 protein was successfully established, leading this chinese team pioneered the establishment of a sars-cov-2 infected hace2 transgenic mouse model [54] . during investigation of the pathogenicity of the virus in this mouse model, weight loss and virus replication in the lung was observed. therefore, this model still needs to be optimized since the weight loss and signs of pneumonia were mild and very different from that of humans [54] . currently, researchers are accelerating animal model research for sars-cov-2, and the transgenic mice developed for sars-cov are in short supply. for example, an effective and convenient novel mouse model in evaluating in vivo protective capacity of the sars-cov-2 vaccines was developed through stitching the human gene for ace2 into an adenovirus by perlman et al. in his unpublished work, in which mice was infected with it then receptor was created by some of their lung cells [55] . surprisingly, 20% of weight loss, which was greater than twice in qin's study, ruffled fur, other illness sign with no death were occurred in those mice infected with sars-cov-2. in addition, pacific inflammatory responses and pneumonia were found in the most recent study, in which both young and aged wild-type balb/c mice were effectively infected with mouse-adapted sars-cov-2 at passage 6 (macsp6) [55] . furtherly, a receptor-binding domain (rbd)-based sars-cov-2 subunit vaccine was found to conferred full protection against sars-cov-2 macsp6 challenge and elicited highly potent neutralizing antibodies, and the protective activity of it was determined in vivo. of the 29 amino acids in the key region of the human ace2 receptor that binds to the virus, 13 amino acids differ from that of the rat [54] . therefore, rats might not be a suitable model for studying sars-cov-2 infection. in terms of susceptibility to sars-cov-2, rats also had no advantage. however, the large size of rats has some advantages in many experiments that require repeated blood collection. syrian hamsters are gaining increasing attention in the fight against covid-19. in hamster, only 4 of 29 amino acids of ace2 receptor are different from those of human [56] . despite of the subtle symptoms, coronavirus was found to easily infect hamsters and cause serious acute respiratory syndrome (sars) as early as fifteen years ago, nevertheless, hamster did not catch much attention as an effective animal model for the disease at that time [57] . now, however, the tables have turned in the case of covid-19 since this model comes under spotlight again caused by a related virus, sars-cov-2. the first new hamster model was published in january by a physicianscientist of the university of hong kong (hku) jasper fuk-woo chan, whose work become one of the earliest studies in which asymptomatic infection and humanto-human transmission of sars-cov-2 were reported. eight hamsters were infected with sars-cov-2 by chan and his co-workers in their study, afterwards, a body weight loss, ruffled fur, lethargy, a hunched posture and rapid breath occurred with high levels of sars-cov-2 found in the lungs and intestines, tissues studded with the virus' target, ace2 of the animals [58] . interestingly, another team also at hku. led by hui-ling yen suggested comparable results closely behind of this study [58] . what's more inspiring, those hamster studies may contribute to understand the spreading way of the virus. in both above studies, transmission of sars-cov-2 happened whenever an uninfected hamster was put together with an infected one in a cage, apart from the possible transmission through respiratory droplets, chan and his colleagues also noticed the fact that hamsters ate feces, and therefore, a fecal-oral spread way could not be ruled out [58] . ferret shares remarkably similar lung physiology with humans, unsurprisingly, it is widely used in researches of respiratory viruses that infected humans and as one of the best animal models for another respiratory disease and influenza [59] . they are susceptible to human influenza viruses and various of the clinical symptoms of influenza infection in humans can be found on them [59] . a team of researchers in china recently found that sars-cov-2 could replicate in the upper respiratory tract of ferrets for up to eight days, without causing severe disease or death. the authors believed that the ferret could be a potential candidate animal model for assessing vaccine candidates and antiviral drugs against covid-19 [60] . by contrast, in the same study, livestock including chickens, pigs and ducks were demonstrated to not susceptible to sars-cov-2, while dogs had low susceptibility and cats were highly susceptible to the virus. besides, kim et al. [61] reported similar results. they found that ferrets were highly susceptible to sars-cov-2 infection, and exhibited the elevated body temperature and virus replication. although fatalities were not observed, ferrets effectively transmitted the virus by direct or indirect contact, recapitulating human infection and transmission. more importantly, kim also suggested that older ferrets might serve as a better animal model than younger ones. regardless of the unclear reasons, it is widely accepted that sars-cov-2 strikes the elderly much harder than the younger in humans, and similar phenomenon happened in the ferrets. kim had observed more severe symptoms causing loss of white blood cells and platelets in older ferrets infected with the virus, besides, 93% of older ferrets died of viral infection while no symptoms showed in younger ones infected with the same virus [62] , which indicated again that ferrets might be an ideal animal model for understanding and defeating against covid-19 since it presents similar features. non-human primates, especially rhesus monkeys, have similar immune responses to human viral infections due to their genetic and physiological similarities [63] . nonhuman primates are the closest species to human being who is subject to the infection of viruses [64] . different species of monkey have been infected with sars-cov-2 by intense efforts that closely followed by the isolation of the virus from human. a team from wuhan institute of virology, chinese academy of sciences, published the first study of sars-cov-2 infected rhesus monkey model [65] . they found that sars-cov-2 caused acute localized-to-wide to spread pneumonia as proved by pathological studies in rhesus macaques, although without obvious clinical symptoms of respiratory disease. another research team observed more serious interstitial pneumonia in old monkeys infected by sars-cov-2 than that in young monkeys, which provided insights into the pathogenic mechanism and may facilitate the development of vaccines and therapeutics against sars-cov-2 infection. in their study, two 15 years old and three 3-5 years old rhesus macaques were infected with sars-cov-2, then viral replication of anal swabs, nasopharyngeal swabs and the lung in old monkeys was found to be more active than that in young monkeys 14 days after the virus infection [44] . typical interstitial pneumonia characterized by thickened alveolar septum along with edema and inflammation was developed in monkeys, and diffuse severe interstitial pneumonia was observed in old monkeys. the research team led by qin chuan has obtained similar conclusions. they further found that sars-cov-2 had a conjunctival infection transmission route in the rhesus monkey model, which suggested conjunctival infection could cause mild covid-19 symptoms [66] . another critical finding was that the reinfection by sars-cov-2 of rhesus macaques might be decreased by a remarkably enhanced neutralizing antibody response, suggesting that primary sars-cov-2 infection might contribute to protection of monkeys from subsequent reinfection [67] . besides, some scientists inoculated cynomolgus macaques with sars-cov-2 or mers-cov and compared with historical sars-cov infections and found that the severity of sars-cov-2 infection was intermediate between that of sars-cov and mers-cov [68] . lu et.al recommended that macaca mulatta could be used to investigate viral pathogenesis and evaluate vaccines and drugs of covid-19. two different families of non-human primates, including new world monkeys (6 callithrix jacchus) and old world monkeys (6 macaca fascicularis, 12 macaca mulatta) were involved in their study, and they reported that macaca mulatta was most susceptible to sars-cov2 infection, followed by macaca fascicularis and callithrix jacchus [69] . a mers-cov primate model was successfully established in a latest study, which firstly reported the dosedependent effects of highly pathogenic coronavirus infection of primates and used a route of infection (small particle aerosol) with potential relevance to mers-cov transmission in humans with twelve african green monkeys [70] . african green monkeys may serve as primate model for covid-19, with considerably potential value in viral pathogenesis and therapeutic development researches [70] . taken together, monkeys might be used as suitable animal models to evaluate vaccines and drugs for covid-19. through data mining to screen the clinical use of the tcm formula for covid-19, high frequency/core drugs in tcm formula could be selected. also, the induction and analysis of four properties and five tastes (四气五 味) and meridian tropism (归经) of many chinese medicines from tcm formula could be made. effective guidance for the prevention as well as clinical treatment of covid-19 could be provided through investigations of the characteristics of commonly used medicine. through data mining, the key chinese medicine to prevent new coronary pneumonia is saposhnikoviae radix [72] . from the meridian tropism point of view, the lung meridian, stomach meridian are dominant. according to the classification of efficacy, the top four herbs used most frequently were heat-clearing herbs, antipyretic herbs, qi-invigorating herbs, and yin-tonifying herbs. it was found that in the prescriptions of tcm for the prevention and treatment of covid-19 in various regions, the main methods were to clear away heat and reinforce deficiency, and to strengthen the spleen and stomach. in the later period, most of tcm used were tonifying qi and yin. molecular docking is a model based on applied mathematics, biology, and computers to predict the binding affinity of small molecules to specific receptors, which can be used to predict drug affinity at target binding sites and drug-specific metabolic enzyme interactions to better understand the complexity of living systems. studies have shown that sars-cov virus infections are through the expression of s-protein and human ace-2 binding, which leads the virus to enter the cells [65, 73] . through molecular docking technology, 46 active components from tcm formula with high binding capacity could act on the binding region of sars-cov-2 s-protein of human ace2 protein. the screened components mainly belong to lonicerae japonicae flos, mori folium and other seven herbs [74] . papain-like protease (plp) plays an important role in the replication of coronavirus. in the process of virus replication, the small rna virus first encodes a large polymer precursor protein, and then the polymer protein is hydrolyzed to produce a functional protein, the hydrolysis process is mainly completed by 3clpro. therefore, it is important to search for inhibitors of 3cl hydrolase of sars-cov-2 coronavirus for the prevention and treatment of covid-19. through molecular docking technology, trichosanthis fructus (瓜蒌) and fritillariae cirrhosae bulbus (川 贝母), obtained by plp inhibitors screening and ace2 inhibitors screening respectively, were parts of the sangbei zhisou powder (桑贝止嗽散) and xiaoxianxiong decoction (小陷胸汤), which had the effect of clearing away heat and phlegm [75] . they can be applied to the syndrome of cough with slight dyspnea caused by external pathogenic factors in the early stage of viral action. radix et rhizoma rhei (大黄) and trichosanthis fructus, screened by mpro and plp respectively, are in maxing shigan decoction (麻杏石甘汤) and xuanbai chengqi decoction (宣白承气汤). they can be applied to syndrome types of the lung obstructed by pathogenic heat or blocked by toxin, and viscera-solid knot in the severe stage of the disease. mori folium, lonicerae japonicae flos and forsythiae fructus obtained by ace2 inhibitors screening have been included in the sangju beverage (桑 菊饮) and yinqiao powder (银翘散), which can be used in the early stage of the disease, such as the syndromes of warming evil invading the lung and slight cough and asthma. network pharmacology, which constructs network models centering on medicinal materials and disease targets, can provide a reasonable experimental basis and a brandnew research idea for discovery of new drugs and excavation of potential drugs. combining the study of the entire network with the holistic characteristics of tcm, network pharmacology can be used to study the basic theory of tcm from the perspectives of multi-approach, multi-component, and multi-target. screening the active substances, predicting the target protein, finding the signal pathway, constructing the network and analyzing it by network pharmacology, so the potential mechanism between the active components, target proteins and the network of pathways related to the occurrence and development of diseases may get understood, consistent with the overall concept of tcm. subsequently, the function of the key active components and covid-19 related proteins can be studied by molecular docking technique, and the potential material basis of treating covid-19 with prescription can be therefore explored, which could provide theoretical reference for preventing and treating covid-19 with prescriptions. using jean-baptiste de lamarck genetic algorithm and virtual docking technology, small molecular components of chinese herbal medicine were screened from the component library of chinese herbal medicine based on s-protein and ace2. using s-protein as the target, 12 [76] . through the analysis of weixuening mixture by network pharmacology, 326 components and 555 related targets were obtained, of which 35 targets corresponding to 101 components were closely related to covid-19. more specifically, herbs-active compounds-targets network and gene ontology function enrichment analysis as well as kyoto encyclopedia of genes and genomes pathway enrichment analysis were performed by cytoscape software and database for annotation, visualization and integrated discovery. the enrichment analysis of the target pathway showed that weixuening mixture mainly acted on infectious disease, inflammatory reaction, and immune regulation. it is suggested that weixuening mixture may play a potential role in the prevention and treatment of covid-19 by regulating the immune and inflammatory responses [77] . besides, with network pharmacology, it was found that the core active compounds in yupingfeng powder (玉屏风散) regulates multiple signal pathways by binding with ace2 to esr1, ar, ptgs2, and other targets to prevent and treat covid-19 [78] . jinhua qing gan granule (金花 清感颗粒) can regulate the signal pathway of ptgs2, hsp90ab1, hsp90aa1, ptgs1, and ncoa2 by combining 2019-ncov3cl hydrolase and ace2 to prevent and treat covid-19 [79] . taking advantage of the nascent computer technology and professional software, researchers could quickly screen out the regular pattern of anti-covid-19 drugs according to the existing pharmacological knowledge. in combination with clinical experience, it can further provide effective suggestions to clinical medication. this method can also screen out the active substances, target proteins, and possible signal pathways of related drugs. the application of computer virtual screening technology can greatly reduce the blindness in the screening of prescriptions and medicines, and save manpower, material, and financial resources. however, this method is limited by the information of drug structures and targets. biochip technology can detect numerous information simultaneously, which is helpful to explore the molecular mechanism of compounds from chinese medicine, optimize the dosage and prescription. gene chip can connect the characteristics of multicomponent, multi-target, multi-pathway action, and gene expression together; compare their difference in expression profiles; and determine the corresponding gene expression targets. according to the expression of organ specificity and the level of expression and the compound theory of monarch, minister, assistant and guide, and correlates with medication dose. at the same time, according to the interaction of the corresponding gene targets of different compatibility, the close relationship between each compound medicine can be analyzed, and the material basis of drug action and internal compatibility law would be elucidated. through gene chip technology observing the changes of gene transcription in an apoptotic signal pathway, a study found that luteolin could down-regulate the differentially expressed genes of casp3, casp8, and myd88, and interfere with cell apoptosis in a549 cell infected by h1n1 [80] . therefore, biochip technology presents great potential being used for screening tcm formulas in treating covid-19. the response of clinical studies of tcm in the prevention and treatment of covid-19 have been very rapid, and the current registration scheme covers the whole process of disease prevention, treatment, and rehabilitation. tcm formula has the characteristics of multi-component, multitarget, and multi-way synergy, which are the advantages of clinical treatment of tcm. however, perspective from the modern medicine, clarification of the relationship between chemical basis and biological mechanisms for tcm is still a challenge to be concerned. the substance basis, curative effect, and mechanism of tcm formula need to be further investigated and demonstrated. besides, many means of tcm diagnosis and treatment rely on personal experience. to guide the clinical medication, it is important to establish an objective and standardized diagnosis and treatment standards. traditional methods for screening antiviral chinese medicines are limited by the experimental cycle; since the high infectivity of sars-cov-2, the high requirements of laboratory conditions greatly lag the progress of drug screening. the common techniques of computer-aided drug design (cadd) include molecular docking, reverse docking, qsar, pharmacophore, and prediction of drug absorption, distribution, and metabolic transport. discovery and optimization of drug targets and the application of lead compound in the absorption, distribution, metabolism, excretion, and toxicity prediction of compounds have greatly accelerated the process of drug screening. cadd is also a tool for studying tcm, expounding the mechanism of action of tcm, and optimizing the development of new tcm prescriptions. among them, the technologies of molecular docking (dock), inverse molecular docking (invdock), similarity search, substructure search, pharmacophore search, pharmacophore screening, and chemical component toxicity prediction are of great significance to the study of tcm and its prescription. it is an important tool to explain the mechanism of tcm scientifically and reasonably [80] . in order to find out the potential chinese medicines or active ingredients against covid-19, scholars used data mining and network to mine the highfrequency chinese medicines and formulas from ancient prescriptions, then explored binding rates between the main ingredients in high frequency chinese medicines and the key targets of sars-cov-2 via using molecular docking approach. finally, a network pharmacology was used to uncover the potential molecular mechanism [81] . researchers can quickly screen out potential medicines by cadd, but further animal experiments and clinical studies should be performed to confirm the safety and effectiveness of these medicines. the tcm prescription is composed of different compounds, and its function is to target multiple target genes. it can directly inhibit viruses by target protein, and indirectly inhibit virus by human target protein. therefore, predicting the gene-target interactions of active components could help to decipher the mechanism of multitarget action for tcm. in the search for new antiviral drugs, studies have been conducted on molecular docking and molecular dynamics simulations to identify components or derivatives of chinese medicines or tcm formulations that can block channel activity or drugs at sialic acid binding sites. a study examined six viral proteins that could be targeted by antiviral drugs, including neuraminidase, hemagglutinin, matrix protein 1, m2 proton channel, nucleoprotein, and nonstructural protein 1 [82] . molecular docking techniques were used to identify potential inhibitors of 13,144 tcm compounds. the results showed that 56 compounds could inhibit more than two drug targets simultaneously. the interactions of these compounds with host targets were studied by molecular reverse docking. finally, it was found that 22 compounds inhibitors could stably bind to host targets with high binding free energy [82] . significant research works have provided indispensable insights into the technology and methodologies in screening drugs treated coivd-19 that likely contribute to the development and progression of interdisciplinary strategies in the understanding to prevent and treat coivd-19. as stated prior, in vivo and in vitro models have been developed to verify 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potential treatments of covid-19 from traditional chinese medicine (tcm) by using a data-driven approach study on the mechanisms of active compounds in traditional chinese medicine for the treatment of influenza virus by virtual screening publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to acknowledge and thank prof. yitao wang for his wonderful help with organizing and designing this study; we would like to thank prof. xiuping chen for participating in the revision. authors' contributions hy organized, conceived, and supervised the study. hl, mz, dt, cl, ly, and ql drafted the manuscript. yg and hl revised the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests.received: 25 may 2020 accepted: 15 october 2020 key: cord-033146-2v1kuq50 authors: boylan, brandon m.; mcbeath, jerry; wang, bo title: us–china relations: nationalism, the trade war, and covid-19 date: 2020-10-04 journal: fudan j doi: 10.1007/s40647-020-00302-6 sha: doc_id: 33146 cord_uid: 2v1kuq50 the trade war between the usa and china has shocked many across the world. a disruption to the interdependence of the two largest economies seemed unfathomable. however, in an effort to thwart china’s economic practices and boost the us economy, president trump’s administration levied tariffs on chinese imports shortly after taking office, moving us foreign economic policy from liberalism, practiced for decades, to protectionism. china has retaliated, and the trade war continues today. with conceptual insights from the nationalism literature, we explore the nationalist roots of the trade war from both the us and chinese perspectives. in the usa, the trump administration’s plan to achieve energy autonomy, decrease reliance on foreign resources, and reinvigorate the manufacturing sector has led to protectionist policies, the othering of china, and hence the trade war. although reluctant to enter the conflict, china has rebuffed the usa, resisting and counterattacking us actions, owing to a long-felt sense of persecution in the global space and an eagerness to participate fully, and lead in some issue areas, in international affairs. the conflict continues into the covid-19 era, marked by us scapegoating of china and hits to economic performance. until both sides are convinced they have achieved their goals, or the usa undergoes an administration change, the conflict will likely continue. linking the two largest economies, the us-china trade relationship is the world's most important. however, in recent years, nationalism in each country, the trade war, and covid-19 have strained this relationship. guided by the literature on nationalism, we explore how rising nationalist frustrations in both the usa and china have contributed to the trade war, a conflict exacerbated in the covid-19 era. while they have common elements, the sources of nationalism in the two countries are different. in the usa, a growing segment of the domestic public, believing it lacked political representation and protection of its values, responded to an "america first" agenda, culminating in the election of donald trump. in return, president trump has continued to oppose china for domestic political support, particularly from the manufacturing and agricultural sectors and from an ethnically and religiously homogeneous base. in china, political leaders resented the lack of global political status commensurate with rapid economic growth and rising military might. they demanded more respect for their sphere of influence, and they mobilized against us threats to chinese sovereignty. indeed, china has aspirations to global leadership status on par with the usa and russia. in this article, we first provide the main features of the us-china trade war. we then highlight insights from the nationalism literature to frame the ways in which nationalist grievances in the usa and china have contributed to the ongoing trade dispute. from the us side, we examine the push for energy independence, the revival of manufacturing, and internal and external xenophobia-factors that have led to the scapegoating of china and motivated the conflict. from the china side, we assess historical victimization, economic reforms and internationalism, and leadership in the international community. feeling a sense of historical repression, and with a goal of being a full participant in global affairs, china has asserted economic and political power in the trade conflict. throughout, we discuss how the covid-19 pandemic has influenced the trade war. during his presidential election campaign, donald trump routinely condemned china for what he and others believed were unfair trade practices and decried its trade surplus with the usa (bbc news 2016). promoting an "america first" foreign policy agenda marked by us nationalism, protectionism, and unilateralism, and appealing simultaneously to large corporations (through tax cuts) and the us manufacturing and agricultural sectors (through shoring up jobs), he vowed to take a hard line on china in response to its reported currency devaluation, export subsidies, and theft of us intellectual property (long 2016; daniels 2016) . as president, trump oversaw the establishment of economic policies that launched a trade war, placing tariffs and nontariff restrictions on chinese imports. in early 2018, his administration imposed tariffs on imported solar panels and washing machines (lynch 2018) and later on steel and aluminum (donnan 2018). although the tariffs applied to imports from many countries, chinese goods were seemingly the primary target. in retaliation, china imposed tariffs on an array of products from the usa. from july to december 2018, the tariff war escalated in a tit-for-tat fashion. after fragile progress of negotiations in early 2019, the trump administration raised tariffs from 10 to 25% on $200 billion worth of chinese goods in summer 2019 (bryan 2019) . china retaliated with its own tariffs. in august 2019, china suspended the purchase of new us agricultural products, and the u.s. treasury department declared china a "currency manipulator" (u. s. department of the treasury 2019). the two countries made progress in repairing trade relations in fall 2019 and agreed to a trade deal in january 2020. however, despite the deal, in which china promised to import more us agricultural goods, it has not met its purchasing targets, especially in the wake of covid-19 (bermingham 2020) . china's decreased importation of agricultural products from the usa has harmed us farmers. these products include soybeans, grain sorghum, pork, cotton, and cattle hides. although china purposefully targeted the us agricultural base in the hope that farmers would pressure the trump administration (li et al. 2018 ), farmers continued to support the president. based on surveys of corn and soybean farmers in 2018, zhang, rodriguez, and qu argue that three factors account for their support (zhang et al. 2019) : first, the trump administration has given billions in assistance to offset profit losses. second, farmers believe that decline in profits in the short term will lead to better gains in the long term. third, china has been inconsistent over time in its purchases of agricultural goods, according to farmers. thus, despite chinese efforts and some economic setbacks, farmers could continue to support the president. the trump administration has also attempted to thwart chinese theft of intellectual property and espionage. in may 2019, it banned us companies from working with huawei, a large chinese multinational telecommunications and electronics company, over concerns it was stealing intellectual property and spying on companies and the government (paletta et al. 2019). a month later, it targeted five supercomputing companies-chengdu haiguang integrated circuit, chengdu haiguang microelectronics technology, higon, sugon, and the wuxi jiangnan institute of computing technology-over fears they were using their technology for military purposes (leonard and donnan 2019) . in june 2020, president trump proposed visa restrictions on chinese students and scholars associated with china's "militarycivil fusion strategy" in the belief that the chinese government used them to acquire intellectual property illegally from the usa (redden 2020). in late july 2020, the federal bureau of investigation (fbi) arrested chinese students who had not disclosed they had connections with the people's liberation army (pla) when applying for admissions and student employment positions at various us universities. chen, chen, and dondeti contend that "the trade war is not, in fact, about trade but about technological dominance, and that both sides might fall into a 'thucydides's trap,' the pattern of large-scale conflict when a rising power challenges a dominant one" (chen et al. 2020) . amid the covid-19 outbreak, president trump referred to the disaster as the "chinese virus" (rogers et al. 2020) and later, at a rally in tulsa, oklahoma, as "kung flu." he said that the us government is determining if the virus originated from the wuhan institute of virology. he has also accused the world health organization (who) of acting like the "public relations agency for china" and has withdrawn us funding from the institution (al jazeera 2020). trump's former national security advisor john bolton accused him of asking president xi jinping for domestic support in his bid for reelection (bolton 2020) . in one example, bolton argued that trump pressured china to purchase large amounts of soybeans to boost farmers' support as the presidential election neared. indeed, the president has had a difficult balance to achieve: remaining politically and rhetorically tough on china for failing to keep many of its trade promises and for cracking down on hong kong, while encouraging a market rebound before the election, itself partly contingent on the progress of us-china trade relations. meanwhile, his credibility and trustworthiness seem to fluctuate in accordance with this inconsistent behavior. from the chinese perspective, the trade war has come as a surprise. in earlier administrations, and especially since china's entry into the wto in 2000, trade relations had been amicable and permissive. chinese were thus shocked at president trump's unconventional approach to negotiations by threatening to increase tariffs on chinese goods and to do so swiftly. chinese leaders interpreted this as bullying or baling in mandarin ("ba" meaning a "tyrant," and "ling" meaning "insulting"). "face" or mianzi is an essential virtue in traditional chinese culture, and trump's coercive and bullying approach awakened memories of the "100 years of humiliation," when foreign powers transgressed chinese sovereignty. for many, the chief culprit became the usa. however, the chinese state media employed a moderate approach in covering the trade conflict, criticizing the trump administration for its protectionist policies instead of blaming the usa as a whole for economic aggression (zeng and sparks 2020) . chinese commentators on the growing trade hostilities took different stances. hu xijin and jin canrong, both with large bases of support, voiced incendiary economic nationalist memes. moderate opinion leaders, such as yao yang (a professor at beijing university), called for a rational and cooperative approach in the management of us-china trade disputes (yao 2019). spokespersons for the chinese ministry of foreign affairs occasionally used tit-for-tat discourse as the conflict unfolded, which foreign audiences probably thought was undiplomatic. ironically, economic nationalists welcomed this type of rhetoric that targeted a domestic audience. however, it was subject to misperception by foreign actors (wang and mcneil 2019) . the chinese ministry of commerce is less visible to the chinese public than the ministry of foreign affairs is, and it is largely free from the pressure of chinese nationalism. during the trade negotiations, it played a constructive role as the economic and commercial expertise while its officers built confidence across the negotiating table. the outbreak of the covid-19 pandemic, first in china and then in europe, the usa, and elsewhere, made bilateral trade negotiations more complicated. controversies outside the trade conflict-for example tensions in the south china sea, the chinese national government's promulgation of national security articles in hong kong, us-china disputes concerning the who, and the like-added fuel to the flames of nationalism. upon the rapid deterioration of political and security relations between the two countries, first foreign minister and chinese community party (ccp) political bureau member wang yi, and then yang jiechi (also a ccp political bureau member), delivered speeches dismissing talk of us-china disengagement. yang also visited the usa and met with secretary of state mike pompeo to ease tensions. speeches of chinese leaders expressed a willingness to cooperate and compromise with their us counterparts, and they also served to bridle disorderly domestic nationalist impulses. in this section, we review concepts and literature related to nationalism to develop a foundation to analyze the drivers of the us-china trade war. these concepts include nationalism, state nationalism, economic nationalism, and american exceptionalism. elites have long employed nationalist ideas to differentiate from others, and at times scapegoated and blamed these differentiated others, to achieve their strategic objectives. nationalism is a devotion to the nation and its people, identity, and culture. it stems from a national consciousness and prioritization that is in opposition to or comes at the expense of other nations. often, social movements spring from nationalist convictions and aim to protect and promote the nation. gellner (1983) argues that the principal goal of nationalism is to achieve the congruence of the national and political units. infrequently do the boundaries of nations and states completely align, however, and movements to build nation-states often fail. civic nationalism is a movement to advance the political community, while ethnic nationalism aims to advance the political, economic, and cultural interests of the ethnic group. smith argues that nationalism is "an ideological movement to attain and maintain autonomy, unity, and identity on behalf of a population, some of whose members believe it to constitute an actual or potential 'nation'" (smith 2009, 61) . state nationalism is a form of civic nationalism that attempts to transform the sovereign state to a nation, what can be called the "state-nation." state nationalists contribute to this agenda by othering and marginalizing both internal and external actors. to build the state-nation, leaders and their followers scapegoat ethnic and racial minorities, immigrants, and political and cultural challengers within the state, while at times paradoxically embracing some of these ethnic and political "others" if they support the nation building project. state nationalists blame global forces, international institutions, and other countries and peoples for their challenges, revisioning them as threats to the state's advancement of their interests and to state expansionism. leaders and followers in the state-nation project have a complex and mutually reinforcing alliance. leaders reward their constituents with rhetorical and material benefits in exchange for their support to exact a domestic and foreign policy agenda to move the state to a state-nation. this alliance is often tenuous: leaders' failure to deliver these rewards could weaken constituent support. state nationalism ranges from benign patriotism on the one end of the spectrum to violent fascism on the other. one form of state nationalism is state economic nationalism (or mercantilism). economic nationalism is an ideology that prioritizes the state's economy over all others. economies elevate state security and military power according to the ideology. economic wealth is seen in realist and zero-sum ways. a leading international relations realist, and scholar of economic nationalism, gilpin (1987, 31) writes, "its central idea is that economic activities are and should be subordinate to the goal of state-building and the interests of the state." he further argues, it "recognizes the anarchic nature of international affairs, the primacy of the state and its interests in international affairs, and the importance of power in interstate relations" (gilpin 2001, 14) . contrasting economic liberalism, it opposes globalization and free trade and what is deemed as their destructive forces. instead, economic nationalists aim to safeguard and control their own economies through protectionist measures like tariffs, quotas, and excessive regulations. economic nationalism aims for economy diversification, while economic liberalism aims for specialization. often, industrialization processes and the manufacturing and agricultural sectors are prioritized in the economic nationalist perspective. economic nationalists routinely scapegoat others for economic losses. such others include economic liberals and other countries. (a racialized version also blames immigrants and ethnic minorities.) china's version of economic nationalism has been state corporatism, in which the government intervenes heavily in the market and owns or partially owns many corporations. although nationalist movements are pervasive around the world, nationalism in the usa holds a distinctive place in world history. a young state but old democracy, the usa is often characterized by its "exceptional" status-a label first applied by de tocqueville (1838) . as old as the country itself, american exceptionalism is rooted in the american revolution and u.s. constitution. according to lipset (1996) , americans are committed to a common set of values: individualism, antistatism, populism, and egalitarianism. as the "first new nation" (lipset 1963) , other states are not born out of the same suite of ideals. based on a conviction that the usa is not only exceptional but superior, the usa believes it has a special mission to transform the world, which has justified international interventionism and democracy promotion since world war i. inherent in american exceptionalism is a recognition of how the usa differs from other countries-both enemies and allies. as we show in the next sections, the trump administration has both galvanized and capitalized on domestic economic frustrations to perpetuate a state nationalist project to secure support for its domestic and foreign policy goals. in the international sphere, this project has targeted primarily china. meanwhile, china's recent economic and political rise is also driven by nationalism and an antagonism toward the usa. although nationalism in each country contributes to the trade war, the roots and character of these nationalisms differ. nationalism in the usa has contributed to the othering of china and the ongoing trade war. in this section, we consider three expressions of us nationalism: energy independence, revival of manufacturing, and internal and external xenophobia and then assess how each contributes to the trade conflict. the trump administration's push to become more energy independent, decrease the country's reliance on foreign resources, and protect manufacturing jobs has led to the resurgence of economic protectionism. veiled in xenophobic rhetoric, china has been made a target in this context in an attempt to increase domestic support. the trump administration has striven for energy independence. it has aggressively pursued fossil fuels and minerals development in the country, with critical financial and political support early in the administration (2017-2018) and rollback of environmental laws and rules considered obstacles to energy independence and economic development before and during the covid-19 pandemic. shortly after his election to the presidency in 2016, trump promised a new era of "energy dominance," a term he coined, perhaps to imply that there would be no obstacles to increasing production of conventional and tight oil and gas, making coal "king" again for electricity generation, and expanding nuclear energy and hydropower (council on foreign relations 2017). this was a much more aggressive agenda than that of previous republican presidents, and it responded to the interests of large oil companies, allied interests (e.g., oil field service firms), and constituent groups such as older caucasian voters, the lower middle class, and less educated workers. having promised during his presidential campaign that he would end the "war on american energy," trump, three years into his presidency, claimed that the usa had attained energy dominance. as the economic recession and covid-19 pandemic spread in the usa, the trump administration went to great lengths to further the objectives of the fossil fuel industry. in forming a task force called the "great american economic revival" of industry groups to "reopen" the economy, he appointed nine executives from oil and gas corporations, two from the utility sector, one from oil mining, but no one from renewable industries. then, in early 2020 when oil and gas prices decreased, trump played a broker role seeking a reduction in global oil production from saudi arabia and russia. the president tweeted, "we will never let the great oil & gas industry down … i have instructed the secretary of energy and secretary of the treasury to formulate a plan … so that these very important companies and jobs will be secured long into the future" (dillon 2020). he sought to reduce the global oil glut and ease pressure on us oil and gas, reserve prices for which were briefly negative. when administration plans to purchase millions of barrels of oil for the strategic petroleum reserve (spr) conflicted with congress, the u.s. department of energy leased space providing aid to the industry (lee and clark 2020). the u.s. federal reserve board of governors increased liquidity in the economy, and then the president and congress offered the largest stimulus program since the great depression (by mid-2020, amounting to nearly $5 trillion). hundreds of billions in loans-much of which did not need to be repaid-went to businesses harmed by the pandemic, including energy companies (cahlink and koss 2020) . republicans, and industries such as tobacco, oil and gas, coal, and chemicals, have long advocated for revision of federal agency, especially epa, rulemaking. the trump administration placed regulatory reform high on its agenda and planned an unprecedented rollback of environmental regulations, but the reform process was interrupted by the transition in power as democrats gained control of the house after the 2018 midterm elections and then the 2019 impeachment proceedings. regulatory reform gained urgency for the upper echelons of the administration in 2019, especially as energy prices fell and the stock market failed. the trump administration's targets of regulatory reform have long been icons of the us environmental movement: the clean air act, the national environmental policy act (nepa), the clean water act, as well as waters of the us (wotus) regulations. critics viewed these regulations as impeding energy and other apparently hazardous proposed developments. too, regulatory reforms limited the application of the endangered species act (esa) protections of migratory routes and curbed the length of public comment periods for responding to proposed environmental impact statements (eis) reviews. altogether these rollbacks challenged the environmental law and regulatory system established in a generation, although environmental groups challenged all reforms in court (see, for example, farah and hijazi 2020). the trump administration also sought to expand access to federal lands for oil and gas drilling, coal mining, and mining of strategic minerals such as rare earth elements (see hao and liu 2011) . most remaining us public lands are in the west, and since the sagebrush rebellion of 1982, elected federal and state officials in western states have resisted "federal overreach." thus, the administration's efforts garnered praise, while environmentalists and a few other interests (e.g., cattle ranchers, fisheries) were in opposition. moreover, lands once reserved from development of rare, precious, and threatened species, such as the western sage grouse, were opened as well. by mid-2020, the usa produced 95 percent of the fossil fuels it consumed. energy independence is a subset of economic nationalism. the trump administration aims to decrease its reliance on other states for fossil fuels (e.g., oil, gas, and coal) and use us resources to provide power to factories, businesses, and residences. energy independence increases national power in competition with global rivals (e.g., russia) that are self-sufficient in fossil fuels. it increases national economic development and wealth, as few expensive resources need to be imported. and it increases diplomatic flexibility, as preferred outcomes (e.g., support for israel) are not constrained by resource dependence. fossil fuel dominance also protects and rewards large oil and gas corporations that have bankrolled republican leaders including president trump, and it ensures continued employment for hundreds of thousands of oil/gas/coal field workers and sustenance of communities in which they live. this expression of nationalism is linked directly to trade protectionism and thus the us-china trade war. the decline of us manufacturing was an issue in the 1980s, and the circumstances regarding manufacturing enterprises have worsened since then (pierce and schott 2016) . in the 2016 election, candidate donald trump called for a renaissance of manufacturing. as the economic downturn set in, and then the covid-19 pandemic erupted, the focus became primarily the automobile industry and the global supply chain that undergirded it. the us automobile business was once dominated by the "big 3"-general motors (gm), chrysler, and ford. however, the detroit auto industry's continued production of high fuel consumption vehicles, when oil shocks pushed gas prices skyward, created openings for inexpensive, fuel-efficient foreign automobiles. to cultivate political support, increasingly foreign manufacturers opened plants in the usa. notwithstanding attempts by some manufacturers to limit foreign sourcing of auto parts, the supply chain for vehicles became more global than national. the detroit auto industry lost considerable political support when gm and chrysler, having declared bankruptcy, gained bailouts of $64 billion from the federal government in 2009, as corporate executives flew by lear jets to washington, dc for hearings (lassa 2011) . given their global linkages, us multinationals were at odds with president trump's rhetoric. for example, in a cost-cutting action gm announced it would close five factories and lay off 14,000 workers in north america. in response, the president tweeted that he was considering ending electric vehicle (ev) subsidies: "general motors made a big china bet… when they built plants there … don't think this bet is going to pay off. i am here to protect america's workers!" (joselow 2018) . as president trump began his reelection campaign in 2019, he claimed, "many, many plants are now under construction in michigan and ohio, pennsylvania, north carolina, south carolina, florida. they hadn't built one in decades and now they're all over the place." although little new plant construction occurred under the trump administration (robertson 2019), the industry had become compliant with the president. as auto sales fell, and the covid-19 crisis erupted in early 2020, trump administration agencies allowed exemptions to warehouse and factory safety restrictions so that workers would not lose their jobs. when in march 2020 us car sales seemed likely to drop more than 40%, and us factories closed, the industry received loan guarantees, tax deductions for employees' paid leave, and deferred corporate tax payments. the president also used the emergency provisions of the defense production act to configure factories of gm, ford, and tesla to produce ventilators and other medical supplies (joselow 2020) . through action on new fuel efficiency standards, the trump administration made its strongest efforts to revive the auto industry. the trend since 1974 had been to reduce the amount of gasoline or diesel fuel consumed by cars and light trucks through raising standards of miles-per-gallon. shortly after taking office, the trump administration proposed a rollback of obama administration targets which would have the effect of increasing us greenhouse gas emissions, while reducing the prices of cars and trucks. the auto industry was divided about the proposal. the catalyst was the koch brothers and their conservative network, but most environmental nongovernmental organizations (ngos) were opposed. a new york times investigation contended that the motivation behind the campaign to lower fuel efficiency standards was the surplus of fossil fuels in the usa and the need to increase demand for their products (and fossil fuel dominance) (tabuchi 2018) . this change, along with historically low gas prices, gave us automakers strong incentives to produce more big "dirty" cars (ferris 2020) . manufacturing nationalism is another form of economic nationalism. although it increases consumer costs, as us labor and most material costs are higher than those in mexico and other developing nations, reversing the hollowing out of us corporations avoids the flight of us jobs to mexico (through the north american free trade act) and emerging economies (through the world trade organization). it increases national wealth and power by spurring innovation and technology, which lead to productivity growth. increasing exports and reducing imports improves economic health by reducing reliance on other states. too, reduction in balance of payments deficits makes the usa more competitive vis-à-vis its global rivals, especially china. new manufacturing enterprises add hundreds of thousands of jobs to the economies of depressed regions and states and electoral success to national leaders. this form of economic nationalism inspires protectionism and has contributed to the us-china trade war. xenophobia in the usa can be internal or external. the internal, or inward, dimension refers to actions and events within the country and involves the scapegoating of persons or groups along racial, ethnic, religious, or gender lines. the external, or outward, dimension refers to the racialized and hostile treatment of other countries. for example, in the george w. bush administration, an "axis of evil" (north korea, iran, and iraq) preoccupied us policymakers. in the trump administration, the fixation has been on mexico and china. political elites use both forms of xenophobia in an attempt to garner domestic support. during the 2016 presidential campaign, trump lambasted previous administrations for failing to enforce border security and stop drug smugglers and other criminal elements from entry into the usa. the most potent message of his campaign was to "build a wall," and this appealed strongly to caucasians (and even some latinos) in his base. during the first two years of his administration, construction of new sections to the already existing wall was a regular story on the public agenda. most dramatic was conflict between the executive and the house of representatives when the latter body, under democratic control after the 2018 midterm election, refused to appropriate funds to pay for wall construction. the ensuing government shutdown was the longest in us history. the administration did stop the flow of immigrants and began the return of some asylum seekers, but us law made instant resolution impossible. republican leaders focused on the "flood" of illegal immigrants, most from central america transiting through mexico to cross the us border. the numbers had escalated since the previous immigration reform legislation, totaling at least 11 million. in addition to their lack of legal status, illegal immigrants, according to the critics, used us public services (schools, hospitals, and reduced transportation and housing fares) at taxpayers' considerable expense and took jobs from us citizens. supporters of legalizing immigrants' status offered evidence that immigrants on balance contributed toward the services they received and in most cases worked in jobs (e.g., farm labor, domestic cleaning, and health care) that most americans did not desire. economic and political conflicts with china changed the dynamics of xenophobia in the usa. as mentioned, conflicts over trade rules and policies grew during the second and third year of the trump presidency, and relations worsened greatly when the covid-19 pandemic reached the us homeland. president trump and several conservative pundits accused china of genetic manipulations in wuhan laboratories, causing outbreak of the virus and then failing to disclose it, a pattern repeating the chinese regime's actions in the 2002-2003 sars epidemic. then, us leaders accused china of infiltrating us laboratories, research institutes, and universities; stealing intellectual property; and hacking us computer systems. several chinese students who were apprehended had worked for the china's people's liberation army (pla). by mid-year 2020, us-china relations had become the worst since 1972. in addition to trade sanctions, risky military encounters (e.g., chinese ships in the us continental shelf), the cessation of nearly all flights into the usa from china (and most of those from the usa to china), and the closure of the houston consulate exacerbated relations. the us labeled huawei technologies co. and its telecom companion zte as a national security threat. secretary of state mike pompeo said that the relationship between the two nations should be based on the principle of "distrust and verify" and went on to say that the diplomatic opening of china by president nixon in 1972 had undermined us interests (wang and myers 2020) . both political and economic dimensions of nationalism stimulated xenophobic responses within the usa and in its international behavior. the political malaise was the expression of endless wars fought by the usa without clear victory or just compensation for its contributions. economic discontent was the result of several decades of globalization that left large numbers of citizens behind (e.g., less educated, laid-off manufacturing workers). political leaders and particularly donald trump exploited this dissatisfaction and its victims and found targets to blame: foreigners (e.g., central americans, mexicans, chinese, africans) and democrats (who supported "illegal" immigrants and were the elites of the "deep state" who grew rich from globalization). scapegoating of these groups relieved emotional stress of those who believed they had been forgotten. once mobilized, leaders then directed the anger of the "forgotten" to others, and the states appearing to represent them, such as china. this strategy has become a dominant feature of president trump's reelection campaign. although china's history as a civilization extends many thousands of years into the past, its modern identity as a nation dates to the nineteenth century, and it is expressed in four forms: economic, ethnic, cultural and political. nationalist sentiments in china, as in the usa, have contributed to the trade war. from a longfelt perspective of being persecuted, and with a desire to participate fully in global affairs and exert leadership over some issue-areas, china has rebuffed us demands and contributed to the trade war. an ancient source of chinese nationalism is its long history as a civilization. china prides itself on the longevity of the chinese language and culture and the ancient belief that china was the central power of the world. chinese leaders are keen to create state nationalism and unity in light of the multiethnic composition of the population. chinese nationality formally includes all of the state's official 56 ethnic groups. although more than 90% of the people are han chinese, leaders state that cultural inclusiveness is an important value (gao and zhu 2010) , despite the reality. china celebrates an elaborate tribute system, brought up to the present in the belt and road initiative. it also has a global diaspora, which connects mainland china to hundreds of thousands of chinese communities throughout the world. most western researchers, including ethnic chinese researchers in the west, emphasize china's memory of humiliation from foreign invasion, particularly the "100 years of humiliation" from the opium war to the end of world war ii and past grievances at the hands of foreign enemies. from this follows the memory of identity as a victimized people, who should "never forget national humiliation" (wang 2012; zhao 2014) . western scholars' research in other contexts has suggested that nationalism is one of several factors driving public support for aggressive external policies. some see a rise in aggressive nationalist rhetoric from both official and popular sources (see, among others, whiting 1995) . in the 1990s, the media provided greater opportunity and incentives for grassroots nationalist expressions (he 2007) . they featured angry and sometimes violent protests following international incidents involving the usa and japan (gries 2001) . this has led several western observers to characterize chinese nationalism as irredentist, insecure, and virulently anti-foreign (whiting 1995) , and this played a role in the increase of regional and bilateral tensions (cotillon 2017; yahuda 2013) . on the other hand, some chinese opinion leaders believe china has been subject to provocation analogous to that of germany and japan before world war ii. nationalist commentators, such as hu xijin (chief editor of global times), jin canrong (professor at renmin universitiy), hu an'gang (professor at tsinghua university), and kong lingdong (professor at beijing university), appear to subscribe to radical nationalist beliefs and have large internet followings. in either case, a nationalism centered on a long-felt sense of persecution has contributed to the ongoing trade war. china's history of being othered has created a "we" and "they" mentality and an insecurity that four decades of economic growth cannot easily remedy. modern chinese economic reform emerged at the fall of the qing dynasty in 1911-1912 and the rise of the republic of china, notwithstanding political turmoil until the establishment of the people's republic of china (prc) in 1949. private entrepreneurship, which had long been suppressed under imperial rules, thrived, as evidenced in the slogan, "entrepreneurship saves china" (shiye jiuguo). after three decades of marxist and maoist rule, china's reforms and open door policies were adopted upon deng xiaoping's return to power in 1978. more recently, china has strategized to invest ambitiously in locations all around the world, from africa to the arctic, and trade with a host of partners, all supported by the belt and road initiative, a strategy to develop roads, railways, and ports in several countries around the globe. economic reforms established state capitalism as a system to create wealth and power in china. state-owned enterprises remained pillars of the economy, in sectors of national security importance such as transportation, energy, natural resource extraction and production, electricity, and several types of manufacturing. china's doors were opened to multinational corporations and importation of their technology and capital. china's integration into the global economy brought great pride in the chinese nation as it became the world's premier production center. chinese competitiveness was essential for reduction of poverty and the rise of a middle class, but this came at the cost of national independence-as noted in xenophobic responses associated with both cultural and ethnic nationalism and directed at groups like the uyghers, tibetans, and taiwanese. china has been able to provide elementary school education to nearly all youth. middle school education is not yet universal, and access to high school and college is limited to those passing entrance examinations. still, young people today are much more likely to be knowledgeable about the global community than they were fifty years ago. the increase in educational opportunity facilitates independent and critical thought about the linkage of china's national interest and economic interdependence (qin and zhu 2005) . further, scholars generally agree that economic reforms increasing competitiveness and promoting global integration have been beneficial to china's national interest (chen 2000; brien and he 2002) . therefore, as the trump administration sought to sever economic and cultural ties with china, the majority of chinese, including elites, objected. they wanted to prevent a trend leading to disengagement from global affairs. when chinese considered the degree to which china had advanced as a consequence of ties with the outside world and particularly the usa, they harnessed nationalist instincts in the developing trade war. the chinese communist party was founded on marxism, and during the first three decades of the prc the regime followed the soviet model of a state-owned and managed economy. during that period, ideological disputes within the fabric of marxism and maoism prompted the great leap forward to surpass the usa and uk, followed by the cultural revolution which attempted to purge capitalist elements from society. less than two decades later, leaders staged a "patriotic education campaign," designed to shore up support for the ccp in the wake of the student movement of 1989 and the setback to marxism as represented in the fall of the berlin wall and ultimate dissolution of the soviet union in 1991. western scholars' research on chinese nationalism focuses on public attitudes and foreign policy making (weiss 2014; sinkkonen 2013) . for chinese leaders, the politics of nationalism are more complicated and have both domestic and foreign targets. president xi jinping envisions china and the global community as sharing a common destiny and expects china to play a positive and active leadership role in global governance. in xi's vision of the chinese dream, china will exercise responsibility in producing more public goods, including harmonious interactions between humans and nature (bhattacharya 2019) . thus, xi is under pressure to end the trade war and reassert china's growing leadership role in international relations. this vision of china's role in global governance, along with china's visible benefits from participation in the global economic system, most notably with the usa, are key factors balancing against the bitter feelings chinese harbor toward the trump administration for disrespectful treatment during the course of trade negotiations. china and the usa have different political and ideological belief systems. china is an outsider to the global security network, which features a us-led alliance network. these differences will be difficult to eliminate in the short term, and for this reason trade relations increasingly appear risky. when these factors become dormant, trade issues will be easier to resolve. of course, increasing global economic benefits would ease trade hostilities, but the slowdown in global growth due to the covid-19 pandemic limits the ability of both china and the usa to soften in their trade positions. a number of uncertainties remain for both countries regarding the role nationalism plays in trade relationships. in the usa, domestic politics are polarized, and there are problems in economic recovery. in china, there are concerns in the process of domestic political development as to whether the open door and economic reform policies should continue. too, there is the question of china's identity as a responsible global actor. thus, china counteracts us aggression in the trade war, not only to protect its economic interests but also to assert power to international audiences. although the trump administration initiated the trade war, china has retaliated with tit-for-tat measures and exerted a great deal of power to protect its economic and political interests and its burgeoning leadership role in global affairs. both sides' participation in the conflict rests on several nationalist factors. in the usa, president trump has pushed to wean the country off foreign sources of oil and other natural resources and has promised to bring manufacturing jobs back to the rust belt and other areas. both of these agenda items have led to economic nationalist and protectionist steps and to the weakening of the us-china trade relationship. in this context, trump and other high-level administrators have used xenophobic rhetoric in an attempt to blame china for us economic ills. the rhetoric ramped up at the onset of the covid-19 pandemic (and in the year of a presidential election campaign). for the trump administration, the pandemic was an opportunity to further blame china for domestic economic problems long in the making. initially surprised at the high tariffs imposed on its goods, china has stood up to us pressure, in part owing to its identity of being historically marginalized and its desire to continue to grow economically and politically on the world stage. what have been the effects of the us-china trade conflict? it has led to higher consumer prices, lower corporate profits, unstable markets, and slower economic growth (norland 2020; ungarino 2019; lawder 2020) . one analysis shows how president trump's tweets related to the trade conflict have adversely affected the stock market (burggraf et al. 2019) . account deficits and manufacturing decline in the usa are the result of low savings, high labor costs, and rising service sectors rather than imports from china (sheng et al. 2019) . of greater alarm, the trade war has exacerbated account deficits and eroded the usa's comparative advantage in the technological sector and human capital by pressuring china to invest in high technology industries (sheng et al. 2019) . moreover, deficit reductions have not promoted economic growth (moosa 2020) , and the trade deficit reduction with china will likely lead to deficits with other countries (lai 2019 ). it appears that the usa will not reduce its trade deficit with china, and even if it could do so, the usa will not achieve strong economic progress but instead develop deficits with other countries. the trump administration, as long as it is in power, will likely not let up in its pressure toward china. its othering of china continues to be relevant as long as the usa continues to maintain unsatisfactory wages and societal interruptions owing to the pandemic. although the usa has legitimate reasons for pressuring china, the country is also a convenient target for domestic grievances. although china would prefer to return to the status quo, it will resist and counterattack us actions to both prevent economic decline and showcase power to domestic and foreign audiences. funding we did not receive funding for this research. we do not use a software program for this paper and do not have separate coded data. bbc news. trump accuses china of 'raping' us with unfair trade policy china falling further behind us trade deal energy targets, even as crude oil imports soar to record volumes chinese nationalism under xi jinping revisited the scandal of trump's china policy. the new york times trump just ramped up tariffs on $200 billion worth of chinese goods. here are all the products that will get hit political news and stock prices house sends $2.2 t stimulus bill to trump wto and economic nationalism: china's car industry in the 21st century the us-china trade war: dominance of trade or technology? territorial disputes and nationalism: a comparative case study of china and vietnam council on foreign relations (cfr) us files trade complaint over china's 'excessive' ag subsidies, cnbc clean cars rollback adds to evs from national identity to national identity in a multi-national country nations and nationalism the political economy of international relations global political economy: understanding the international economic order tears of rage: chinese nationalist reactions to the belgrade embassy bombing rare earth minerals and commodity resource nationalism history, chinese nationalism, and the emerging sino-japanese conflict the us-china trade war, the american public opinions, and its effects on china lawder, david. drag from trump's trade wars continues to ripple through trump says demand is back trump blacklists more china tech companies days before xi summit lessons from previous the first new nation: the united states in historical and comparative perspective american exceptionalism: a double-edged sword trump imposes tariffs on solar panels and washing machines in first major trade action the thucydides trap as an alternative explanation for the us-china trade war trump administration cracks down on giant chinese tech firm, escalating clash with beijing: the president also signed an executive order to protect u.s. networks from foreign espionage, a move that appears to target china the surprisingly swift decline of us manufacturing employment neo-internationalism and china's diplomacy trump proclamation bars entry of certain chinese students. inside higher ed trump's repeated falsehood on auto plants trump defends using 'chinese virus' label, ignoring growing criticism. the new york times why will trump lose the trade war? nationalism, patriotism, and foreign policy attitudes among chinese university students ethno-symbolism and nationalism the oil industry's covert campaign to rewrite american car emissions rules. the new york times as trump's trade war escalates to department of the treasury. treasury designates china as a currency manipulator never forget national humiliation: historical memory in chinese politics and foreign relations officials push u.s.-china relations toward point of no return. the new york times china voices strength, pushes nationalism around trade war powerful patriots: nationalist protest in china's foreign relations chinese nationalism and foreign policy after deng china's new assertiveness in the south china sea it is dangerous to advocate china-us disengagement popular nationalism: global times and the us-china trade war 3 reasons midwest farmers hurt by the u.s.-china trade war still support trump. the conversation a nation-state by construction: dynamics of modern chinese nationalism conflict management and peace science, nations and nationalism, and studies in conflict and terrorism, among others. his collaborative projects have been funded by the national science foundation, us department of commerce, and norwegian centre for international cooperation in education. he teaches a range of undergraduate and graduate courses in international relations, comparative politics, and research methods. he is faculty advisor for model united nations and model arctic council at uaf mcbeath is professor emeritus of political science at the university of alaska fairbanks (uaf) his publications include approximately sixty journal articles and book chapters and sixteen books, the most recent of which are big oil in the united states (mcbeath, 2016) and environmental education in china (mcbeath and mcbeath, with tian qing and huang yu he has published dozens of peer reviewed journal articles in both chinese and english. he has also led several research programs granted by apec, china's national social sciences foundation, and other state and provincial foundations we have no conflicts of interest or competing interests in this project. our data are open source and cited. key: cord-293265-qqxlwpju authors: zeng, yong; zhang, bo; zhang, xufeng; yi, cunjian title: clinical characteristics of 9 cancer patients with sars-cov-2 infection date: 2020-05-14 journal: chin med doi: 10.1186/s13020-020-00328-8 sha: doc_id: 293265 cord_uid: qqxlwpju in december 2019, a cluster of pneumonia cases was caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) in wuhan, china. cancer patients are a special group, the immunity of them will be suppressed because of various anti-tumor treatments, and the risk of infection will be greatly increased, so we will report clinical features of 9 cancer patients with sars-cov-2 infection. 5 (56%) patients were ordinary type, 3 (33%) were severe type, and 1 (11%) was critical type. a total of 8 patients received combined therapy of traditional chinese medicines and western medicines. from the clinical outcomes of these 8 patients, western combined therapy of traditional chinese medicine was indeed an effective treatment method. d-dimmer rise, infection index rise, and chest ct(computed tomography) progression may be clinical warning indicators for severe patients, in our study, more 50% of patients had elevated levels of these indicators, but only 44% (including the dead) of patients had received treatment in the intensive care unit. 5 (56%) ordinary type patients had been discharged, while the 1 (11%) critical type patient died 3 days after admission. cancer comorbidity seems to have no direct relationship with severe events, and the combination of traditional chinese medicine and western medicine may be effective in the prevention and treatment of novel coronavirus-infected pneumonia (nicp). in december 2019, a cluster of pneumonia cases caused by the sars-cov-2 occurred in wuhan, hubei province [1, 2] . now it has developed into an international public health emergency. however, in this new outbreak of novel ncip there is a special population that cannot be ignored-cancer patients. after receiving various antitumor treatments, the immunity of cancer patients will be suppressed, and the risk of infection will be greatly increased [3] [4] [5] [6] .liang found that cancer patients in sars-cov-2 infection had poorer outcomes [7] . however, neither yang xia [8] nor hanping wang [9] through there was a strong link between cancer and sars-cov-2 infection. here, so we will report the clinical features of cancer patients with sars-cov-2 infection to provide further knowledge of this disease. this study was approved by the institutional ethics board of yangtze university. a retrospective, single-institutional review of cancer patients with sars-cov-2 infections was conducted between january 23 and february 29 2020, at the first people's hospital affiliated with yangtze university in jingzhou, china. basic information, clinical manifestations, laboratory, medical imaging and outcome dates were collected from patients' medical records and were exhibited in additional file 1: appendix 1, additional file 2: appendix 2, additional file 3: appendix 3 and additional file 4: appendix 4 respectively. the median time was exhibited in fig. 1 , included from onset of symptoms to sars-cov-2 positivity, from onset of symptoms to intensive care unit admission, from sars-cov-2 positive to negative. as of march 3, 2020, chinese medicine this disease belongs to the category of traditional chinese medicine epidemic diseases, and caused by the plague poison. studies [10] found that the combination of traditional chinese medicine and western medicine was effective in the prevention and treatment of nicp in all stages, and the response rate of symptoms such as fever, cough and fatigue were significantly increased in ordinary patients after taking lianhua qingwen granules. in the critical stage, modern medicine approaches can play a powerful role in patients' life support and the control of complications, xuebijing injection combination with modern medicine approaches can improve the cure rate. in addition, compared with the western medicine group, the chinese-western combined treatment group had shorter test negative conversion time, higher symptom improvement rate and shorter hospital stay. therefore, the combination of chinese medicine and western medicine was effective in the treatment of nicp. in our study, a total of 8 patients received combined therapy of traditional chinese medicines and western medicines. 8 (89%) patients received oral antiviral treatment using lianhua qingwen granules and arbidol. 3 severe patients were given additional intravenous xuebijing injection. in addition, through the different stages of covid-19 infection of the body dialectical, based on lung cleaning and detoxifying decoction, flexible use of chinese medicine prescription. all patients were given antibiotics. 8 (89%) patients were given a combination of antibiotic treatments. 5 (56%) patients were given intravenous methylprednisolone. immunoglobulin was provided to 3 (33%) patients (10-14 days). 7 (78%) patients were treated with oxygen inhalation (nasal catheter or mask), 4 (44%) were treated with high-flow oxygen inhalation, and one patient used non-invasive mechanical ventilation. from the clinical outcomes of these 8 patients, western combined therapy of traditional chinese medicine was indeed an effective treatment method, but due to the limited case data, more clinical practice data were needed to evaluate. of the 9 patients, 5 (56%) patients were ordinary type, 3 (33%) were severe type, and 1 (11%) was critical type. 1 patient (critical type, 82 years old) died from multiple organ failure, and the interval time from onset of symptom to death was 3 days. 5 patients (ordinary type) had been discharged, and their median time of hospitalization was 26 (7-29) days. all other patients were still in hospital. according to the pneumonia diagnosis and treatment protocol for novel coronavirus infection released by the national health commission (version 6), d-dimmer rise, infection index rise, and chest ct progression may be clinical warning indicators for severe patients. in our study, a majority of patients had differing degrees of increased infection index, which may represent more prominent inflammation. 78% of patients had increased d-dimmer, and previous studies had found that d-dimmer increase was related to severity of illness [11, 12] . 56% of patients showed signs of multiple mottling and ground-glass opacity, in other studies, earlystage chest ct examination mostly showed multiple, small patch-like shadows and interstitial changes [13] , which may indicate that in cancer patients with sars-cov-2 infections lung lesions progressed faster. but only 44% (including the dead) of patients had received treatment in the intensive care unit. additionally, of the 5 cancer patients with sars-cov-2 infections receiving anti-tumor treatment in the last year, only 2 (40%) also had been diagnosed as severe type, with the other (60%) diagnosed as ordinary type. this seems to indicate that cancer comorbidity may have no direct relationship with severe events. by analyzing 9 cancer patients with sars-cov-2 infection, cancer comorbidity seems to have no direct relationship with severe events, and the combination of traditional chinese medicine and western medicine may geneva: world health organization outbreak of pneumonia of unknown etiology in wuhan china: the mystery and the miracle nosocomial infections in patients with cancer selective depletion of regulatory t cell subsets by docetaxel treatment in patients with nonsmall cell lung cancer features of postoperative immune suppression are reversible with interferon gamma and independent of interleukin-6 pathways myeloid suppressor cells in cancer and autoimmunity cancer patients in sars-cov-2 infection: a nationwide analysis in china risk of covid-19 for cancer patients risk of covid-19 for cancer patients state administration of traditional chinese medicine. press conference on the prevention and control of the epidemic in hubei province clinical characteristics of 140 patients infected with sars-cov-2 in wuhan china clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all the patients who participated in this study, their families, and the investigators. we thank all the medical worker who participated in the outbreak of ncip. • fast, convenient online submission the datasets used and analysed during the current study are available from corresponding author on reasonable request. this study was approved by the institutional ethics board of yangtze university. informed consent of the study was waived because of the retrospective nature and the analysis used anonymous clinical data. the analysis used anonymous clinical data. none. key: cord-280691-nzc8ir0n authors: guo, sun-wei title: china’s “gene war of the century” and its aftermath: the contest goes on date: 2013-08-30 journal: minerva doi: 10.1007/s11024-013-9237-7 sha: doc_id: 280691 cord_uid: nzc8ir0n following the successful cloning of genes for mostly rare genetic diseases in the early 1990s, there was a nearly universal enthusiasm that similar approaches could be employed to hunt down genes predisposing people to complex diseases. around 1996, several well-funded international gene-hunting teams, enticed by the low cost of collecting biological samples and china’s enormous population, and ushered in by some well-connected chinese intermediaries, came to china to hunt down disease susceptibility genes. this alarmed and, in some cases, enraged many poorly funded chinese scientists, who perceived them as formidable competitors. some depicted foreign gene-hunters as greedy pilferers of the vast chinese genetic gold mine, comparing it to the plundering of national treasures from china by invaders in the past, and called upon the government and their fellow countrymen to rise up and protect china’s genetic gold mine. media uproar ensued, proclaiming the imminent “gene war of the century.” this article chronicles the key events surrounding this “war” and its aftermath, exposes some inherent complexities in identifying susceptibility genes for complex diseases, highlights some issues obscured or completely overlooked in the passionate and patriotic rhetoric, and debunks some misconceptions embedded in this conflict. in addition, it argues that during the entire course of this “war,” the public’s interest went conspicuously unmentioned. finally, it articulates several lessons that can be learned from this conflict, and outlines challenges facing human genetics researchers. around 1997, and amid the talks of hong kong's upcoming return to china and later the asian financial crisis, a recurring topic in the chinese media was the so-called ''gene war of the century'': the lopsided condemnation of foreign scientists coming purportedly to pilfer china's vast genetic resources for a profit. some scientists wrote articles and gave lectures, calling for heightened vigilance for the pilfering act, and proposed that the country protect its precious genetic resources by conducting genetic research on its own. while the public might have been completely flummoxed by some esoteric and arcane jargons, the message was nonetheless loud and clear: the western capitalists were trying to profit from china's unique genetic heritage. in a country with a past history of repeated foreign invasion, defeat, and humiliation, this message struck a tender emotional chord and caused an eruption of national furor. the person who likely triggered, perhaps unintentionally, the first spark of this ''war'' is xiping xu, a chinese expatriate at harvard at the time. despite his repeated proclamation as a staunch and unwavering patriot loyal to his beloved motherland and dedicated to the advancement of china's science and technology, he nonetheless later became embroiled in an avalanche of controversies surrounding the ''gene war.'' he effectively became a lightning rod for all the controversy on genetic resources, intellectual rights, informed consent, and the protection of human research subjects. well over a decade has since passed. what was at stake? did these precious genetic resources actually exist? who was the most likely beneficiary of the gene-hunting endeavor? how did this ''war'' end? who were the winners and losers, if there were any in the first place? what happened after the conflict? as war is invariably a continuation of politics by other means, what was the politics behind it? what happened to the people who were embroiled in the ''war''? the answers to all these questions can be addressed, at least in part, now with the benefit of a 20/20 hindsight. war breaks out simply because of irreconcilable conflicts in interest. the ''gene war,'' whether it was real or fictitious, was no exception. this article chronicles the key events surrounding the ''war'' and its aftermath, exposes some inherent complexities in identifying susceptibility genes for complex diseases, highlights some issues obscured or completely overlooked in the passionate and patriotic rhetoric, and debunks some misconceptions embedded in the lopsided condemnations. in addition, it describes how, during the entire course of the ''war'' of intense and often politically charged uproars, the patients' interest was conspicuously unmentioned and likely overlooked. examining the larger issues regarding science and politics, it also argues that the ''war'' and its surrounding events can be best understood through the lens of credibility contest vying for resources. finally, it lists several lessons that can be learned from this conflict, and outlines challenges facing current researchers in human genetics. ''gene war of the century'': the genesis in 1990, the human genome project (hgp) was launched. with a price tag of 3 billion us dollars and a 15-year timeline, this ambitious megaproject aimed to sequence the entire human genome, with the ultimate goal of ''understand[ing] the human genome'' and ''knowledge of the human as necessary to the continuing progress of medicine and other health sciences as knowledge of human anatomy has been for the present state of medicine.'' supported by the us department of energy (doe) and the us national institute of health (nih), the hgp was the culmination of several years of research building on a series of breathtaking breakthroughs in molecular genetics. considered the ''genetic blueprint for human beings'' and hailed as the ''book of life'' or simply the holy grail, the human genome, when completely sequenced, would purportedly unlock the secrets underlying a plethora of human traits as mundane as facial resemblance between parents and offspring and as complex as human behavior. against this foreground, human genetics research entered a golden age. in 1989, scientists identified (called ''cloned'') the genetic mutation responsible for a rare genetic disease called cystic fibrosis, that is, the gene responsible for the disease was identified with known location and size. in the inaugural year of the hgp, a gene responsible for breast cancer was localized, or ''mapped,'' to chromosome 17. in the following few years, the genes responsible for huntington's disease, breast cancer (5-10% of the cases), alzheimer's disease and other rare genetic diseases often with a tongue-twisting name would be cloned (see table 1 for the timeline of research milestones and events surrounding the ''gene war''). following on the heels of successful cloning of genes for these mostly rare mendelian diseases in the early 1990s, there emerged a nearly universal enthusiasm, hope or even conviction that similar gene-mapping approach could be employed to hunt down susceptibility genes predisposing people to various complex diseases -primarily common chronic diseases such as asthma, diabetes, and cancer that invariably have an elusive pathogenesis and collectively contribute to the major health burdens (lander and schork 1994; risch and merikangas 1996) . it was hoped that once genes were identified, the characterization of their functions would not only help better understand genotype-phenotype relationships, but also facilitate the development of specific therapies and preventative measures and the identification of people at increased risk of developing the disease (collins and mckusick 2001) . it was also hoped that once the risk of particular combinations of genotype and environmental exposure is known, medical interventions, such as lifestyle changes, could then be institutionalized to target high-risk groups or individuals (collins and mckusick 2001) . some biotech companies quickly saw the potential of enormous business opportunities and joined the fray. human genome sciences, founded in 1992 by william a. haseltine, a noted harvard professor and aids researcher, partnered with some genomics companies and soon filed patents on 100,000 genes 1 and, in 1999, quadrupled its stock price (zimmer 2009 ). other genomics companies followed suit. yet this practice had one problem: most, if not all, patented ''genes,'' in fact, rna transcripts, were merely pieces of cdna without any known functions at the time of filing. to understand what a gene does and how it does, and to establish the causal relationship between a gene and a human disease, let alone treatment, is by no means an easy task, even with modern technology. very often, it is a slow, arduous, painstaking, and imprecise process full of dead-ends and false leads. many other biotech companies and academic scientists took a different approach called ''positional cloning.'' this approach eliminates the need to understand the molecular genetic mechanisms underlying the disease of interest. instead, through the collection of pedigrees enriched with patients having the disease, the existing genetic sign posts (called dna markers, which are scattered around the human genome with known locations and content) would be used to localize the responsible gene in a particular region. 2 this would allow researchers to zero in the gene, identify it, and ultimately figure out its function and its relationship with the disease through extensive lab work. thus, by ''positioning'' the gene, the gene could be cloned and its functions and roles in disease pathogenesis elucidated without any prior knowledge of the possible pathogenesis of the disease. 3 this conceptual simplicity and beauty, coupled with increasingly fast and affordable methods of making genetic signposts (called ''genotyping'') attracted many biomedical scientists and even converted many of them this discovery was later found to hold universally true in all organisms, including humans, and became a corner stone and a principle in genetics. basically, if a trait is determined by a gene, then the gene will tend to go hand in hand with its neighboring signposts when transmitted from parents to offspring-thus the term ''linkage.'' if many relatives in a pedigree having the same trait all carry the same signposts, then there is a chance that the gene responsible for the trait is near to the signposts. although different cross-breeding cannot be made in humans for obvious reasons, this difficulty can be offset by statistical computations. the advent of personal computers in the 1980s coincided with the booming of human genetics and proved to be indispensable in this endeavor. the discovery of various classes of dna markers also facilitated the gene hunting. 3 the approach based on pedigree data is called ''linkage analysis.'' since 1997, scientists found that for common diseases, another approach, called ''association studies,'' can be more powerful in gene hunting. association studies identify disease genes by finding the significant gene frequency differentials between a group of unrelated healthy individuals and another group of unrelated people with the disease of interest. ''gene war of the century'' and its aftermath 489 to human genetics, who were frustrated by the slow, arduous and often fruitless process of finding the cause(s) for disease. thus, in the 1990s hardly a week went by without a news report or announcement of the discovery of genes for some disease, at least in the us. one high-profile study, published in 1993 in a prestigious journal, science, reported the localization of a gene in chromosome x 28q that is responsible for male sexual orientation. 4 this approach has one catch, however. one critical prerequisite for position cloning is the availability of a sufficient number of pedigrees saturated with people having the same disease, along with correct diagnoses or precise measurements of the disease (called ''phenotyping''). once such pedigrees are collected, phenotyping and genotyping can proceed and the positional cloning endeavor can start. since genotyping and phenotyping a large number of people can be costly, there are strong incentives to cut the cost of either process. everything else equal, locations with low costs of acquiring blood samples (for genotyping purposes) and labor (for phenotyping purposes) would be extremely attractive. in 1995, sequana therapeutics, a start-up biotech company located in la jolla, california, announced that it had achieved two significant research milestones related to its asthma gene discovery program. it analyzed dna collected from about 300 people on tristan da cunha, an island in the south atlantic, about 1,500 miles from south africa. approximately 30% of the island residents had asthma, presumably passed on from an original settler generations ago. the announcement prompted cash payments of $2 million from boehringer ingelheim, ingelheim, germany, based on a prior agreement. boehringer later paid sequana an additional $13 million for its exclusive right to market the drug derived from the putative asthma gene, while sequana retained the exclusive right for developing gene-based diagnostics. sequana announced in late may 1997 that it had identified a mutated gene that predisposes people to asthma, a feat hailed by one clinical investigator as ''perhaps this century's most important finding in the etiology of asthma'' (asthma gene discovered. 1997). early in the same year, sequana announced that it had signed a letter of intent with pe applied biosystems to form a broad-based dna sequencing joint venture in shanghai, china. circa 1996, several well-funded international gene-hunting teams, lured apparently by the low cost of collecting biological samples and the sheer population size and also ushered in by some well-connected chinese scientists working in north america, arrived in china to hunt down susceptibility genes for various complex diseases (shou 1997) . one biotech company from california announced that it had discovered a large pedigree of hundreds of people enriched with asthma patients in a small village in zhejiang province, china. 5 perhaps the most notable team was one led by dr. xiping xu, who was at that time working at harvard and was well-connected in anhui, china. an anhui native, xu spent the mid-1970s after high-school as a ''barefoot doctor'' in anhui, providing basic medical care for peasants after a small amount of training at a time when access to medical care in rural china was a luxury. he received his medical degree from anhui medical college (now anhui medical university) in the early 1980s, and was admitted to beijing medical college (now peking university school of medicine) for a student exchange program, a prep program for oversea studies. he went on to get his ph.d. degree in epidemiology in japan, went to harvard to receive his post-doctoral training in epidemiology in respiratory diseases, and received his master's degree in biostatistics from harvard university school of public health (hsph). he stayed on at hsph as a faculty member. even at harvard, xu apparently kept close ties with the anhui medical college, and was involved in several epidemiological studies in the anhui province. when his post-doc supervisor, dr. scott weiss, a harvard university respiratory epidemiologist, told geoffrey duyk, a geneticist who had left harvard to join a biotechnology start-up called millennium pharmaceuticals, that one of his postdoctoral fellows came from the anhui province and had access to a large number of dna samples, they instantly saw the potential and quickly formed a collaborative relationship to discover susceptible genes in complex diseases in anhui (keim 2003) . a formal partnership between harvard and millennium was established, where xu would direct the collection of a large number of dna samples in anhui, for which millennium would pay the university $3 million (keim 2003) . with tens of thousands of blood samples provided by anhui's villagers, the partnership hoped to identify the susceptibility genes predisposing people to asthma, obesity, miscarriages, schizophrenia and other illnesses. contingent upon its access to the anhui population's dna, millennium also secured sizable capital shortly afterwards from the swedish pharmaceutical company astra ab and from another pharmaceutical giant, hoffmann-la roche. the company's access to dna from the ''large, homogeneous population'' of anhui province was also featured prominently when millennium went public in 1996, raising $54 million in its initial public offering (keim 2003) . leveraging the existing and some preliminary data collected from anhui, xu went on to apply for more funding support from the nih. a search of crisp, a searchable database of nih-funded biomedical research projects (crisp 2010) using ''xiping xu'' as the principal investigator (pi)'s name reveals that xu received 1 grant on genetics of airway responsiveness and lung function in 1997 besides two other nih non-genetics grants, and in 2000 he received 5 nih grants on genetics of osteoporosis, airway responsiveness and lung function, nicotine addiction vulnerability, hypertension, and asthma on top of 4 other nih grants (table 2) . being a pi almost concurrently on 9 nih grants is remarkable, especially for a junior faculty without much track record, but having nih grant support in diverse research areas ranging from osteoporosis, hypertension, nicotine addiction, and asthma to human reproductive effects due to endocrine disruption or rotating shift work is extraordinary and certainly breathtaking. in all, he received well over 10 million usd in grant support from the nih, the pharmaceuticals industry, the march of dimes, and other funding agencies to investigate genetics of various complex diseases (yang 2003; keim 2003) . recognizing his scholarly potential and the growth area he was in, hsph promoted xu to associate professor in 1996 and made him the director of the newly established program in population genetics (now disbanded) in hsph. the solid financial backing and extensive connections allowed xu to enlist the enthusiastic support of the local government officials and his alma mater, who helped xu collect thousands of blood samples from rural villagers. a nearly palpable aura of harvard university which xu embodied and was (and still is) revered by many in china as the premium research institution and the most prestigious institution of higher learning also helped. many villagers were illiterate, had no idea what would be done with their samples, and were given merely empty promises of free medical care in exchange for their blood samples. these lapses of oversight, deliberate or otherwise, would return later to haunt xu and his team. the increasing number of scientists like xu with huge financial backing arriving in china to conduct genetic research alarmed many poorly funded chinese scientists, who perceived the situation as a major threat to their profession and a danger of eclipsing their own work. in november 1996, about 30 leading chinese biomedical and genetic researchers gathered in xiang shan, beijing, and held a conference on ''the human genome project and the development strategy for the 21 st -century medicine'' to evaluate and discuss the situation. 6 one incident further fueled the concern shared by all participants. a translated version of a science article was presented at the conference, which stated that xu sought to gain ''access to 200 million chinese through collaboration with six chinese medical centers.'' but in the chinese version, the program became one that would ''take blood samples from 200 million chinese'' (hui and jue 1997) . this seemingly astronomical figure incensed all conference participants, who were at that time cash-strapped and still playing catch-up with the west. they quickly reached a consensus and soon made it public: (1) china's genetic resources should not be pilfered by foreigners; (2) chinese scientists should immediately grasp the opportunity to find disease genes and patent them; (3) we should educate the people, and raise the awareness and importance of protection of our genetic resources; (4) we welcome all international collaborations based on fairness and mutual benefits; (5) through various avenues, the chinese scientists should be vocal about certain views deemed to be harmful to china's genetic research (xiao et al. 1997) . soon after the xiang shan conference, some scientists published articles depicting foreign gene-hunters as greedy pilferers of the vast chinese genetic gold mine and comparing them to past foreign invaders plundering china's national treasures. they called upon the government and their fellow countrymen to rise up and protect the putative genetic gold mine of the chinese gene pool (fang 1997a, b; lv 1999) . shortly after, financial details about the millennium-harvard deal based on anhui samples were leaked to the chinese press and caused a media blitz of condemnations. the media called it an imminent ''gene war of the century'' (shou 1997) . in fact, the notion of foreign capitalists profiting from china's precious genetic resources sparked such a fury that several other genetic research projects unrelated to xu were stalled for a year (hui and jue 1997) . around the same time, it was rumored that one prominent geneticist, who received his ph.d. from cal-tech in the 1930s for his work on ladybug genetics, yet had no training in either medical genetics or genetic epidemiology, had written a letter to president jiang zemin urging the government to take the matter seriously and to protect china's precious genetic resources. this, along with the media furor, duly alarmed the central government. in 1998, the office for management of china's human genetic resources was quickly established under the auspice of the ministry of science and technology, and charged with overseeing the handling and export of all biological specimens potentially containing genetic materials. soon a de facto law, the interim measures for the administration of human genetic resources, promulgated by the general office of the state council (ministry of science and technology & the ministry of public health, 1998), was enacted in june 1998. it mandated that genetic resources were not allowed to be taken abroad without explicit permission and observance of due procedures as defined in the interim measures. funding for domestic human genetic research subsequently poured in (swinbanks 1998), which spurred human genetics research in china (du et al. 2001) . two genome research centers, one located in beijing and the other in shanghai, were established. while the phrase, ''china's genetic resources,'' has been used widely and extensively, surprisingly no definition has ever been officially provided. some scientists likened china's genetic resources to natural resources, claiming that, as the most populous nation in the world, china has the largest number of ethnic groups and also has the widest and the most complex disease spectrum (xiao et al. 1997 ). in addition, with a long documented history and many isolated populations, there were many genetic isolates and thus china has the purest genetic heritage in the world. therefore, china is a ''gene giant'' and ''the new world of genes,'' making many technologically advanced nations envy and salivate (xiao et al. 1997) . however, the analogy between ''genetic resources'' and natural resources has several problems. granted, the vast population facilitates the recruitment of patients with rare diseases for medical research and the low cost of collecting specimens is conducive to large-scale biomedical research. however, china did not and still does not necessarily have more types of diseases, and even if it did, few people outside china would be interested in finding the genetic causes for diseases that are unique to the chinese population. in fact, for many rare genetic diseases (called ''orphan diseases'') for which susceptibility genes have been cloned, many pharmaceutical companies are often reluctant to invest in drug research and development (r&d) for these diseases due to concerns of profitability. the values of natural resources are determined by their amount, their extractability, and market demand. there are two forms, renewable (such as wind power) and non-renewable (such as fossil fuels). a commodity is considered a natural resource when the primary human activities associated with it are extraction and purification, as opposed to creation. thus, mining, petroleum extraction, fishing etc. are natural resource industry, but agriculture is not. since gene identification requires much more than collecting blood samples and are both labor and knowledge intensive, genetic resources are, by definition, not natural resources. in addition, unlike fossil fuels, genetic resources are not entirely non-renewable, if the disease spectrum remains the same. with dramatic economic and social changes, the living standard in china has risen remarkably in the last 30 years. following these changes, diet and lifestyles also have changed quite dramatically. as a result, the disease spectrum in the chinese has shifted, especially in coastal regions. the incidences of breast cancer, colon cancer, prostate cancer, hypertension, and type 2 diabetes all have risen sharply in the last decade (xiang et al. 2004) . in large cities such as beijing, childhood obesity is used to be very rare but now it is reported to be in the range of 10% (and another 10% of children are overweight). in contrast, incidence of stomach cancer has decreased, especially in those highincidence areas where living standards have been improved. ''gene war of the century'' and its aftermath 495 the rapidly changing disease spectrum means that, firstly, the genetic resources would be forever lost if not used in a timely fashion for gene-hunting purposes. secondly, hunting disease susceptibility genes for a disease that obviously has a strong environmental component was an uncharted territory -no one at the time was absolutely certain how it would turn out. over ten years would elapse before people realized that heritability would vanish even for human traits that are known to be mostly hereditary (maher 2008) . lastly, the notion of china's genetic resources touched upon some thorny issues. unlike other natural resources, genetic materials, as in blood samples, exist only in the human body, which is technically owned by their hosts, not by the state. if a person strikes a deal with a drug company, or acts simply out of genuine altruism, and is willing to give away his blood sample, does the state have the right to intervene? if so, would such intervention infringe on the donor's human rights? giving away or even selling one's blood sample is certainly different from prostitution or selling one's own body parts. if the state does have the right to intervene, where can we draw the line? unfortunately, such questions were never raised and discussed. for biomedical research, there surely is such thing as a genetic resource. but what is it? what constitutes a genetic resource? contrary to the popular belief, population size and diversity of diseases, in and by themselves, actually do not make china ''an ideal place for gene hunters'' (guo et al. 1997) . few among the common diseases in china are known to have a hereditary component or to be amenable for positional cloning. in fact, while a small portion of breast cancer cases, for example, may be attributed to gene mutations, the large proportion of common and complex diseases is unlikely due to a few gene mutations or polymorphisms (see below). as demonstrated by an interventional study conducted in finland, by reducing body weight, eating healthy and regularly engaging in physical exercise, the risk for developing type 2 diabetes can be reduced by nearly 60% (tuomilehto et al. 2001 ). the dramatic changes in incidence of various diseases in china clearly show that many complex diseases have a very strong environmental component. indeed, a 20-year interventional study conducted in da qing, china, shows that, after merely 6 years of lifestyle intervention after recruitment, those in the intervention groups had a 43% lower incidence over the 20 year period as compared with control participants (li et al. 2008) , very similar to the finnish results. what constitutes a genetic resource, then? an ideal population for positional cloning 7 and association studies should have a well-enumerated genetic disease 7 positional cloning is a method of gene identification in which a gene for a specific disease is identified. a scientist can know nothing about the disease etiology. but just by collecting family data, dna, and some sleuthing, s/he could roughly localize the putative gene in a chromosomal region (i.e. positioning). then, with other molecular genetic tools, the scientist can then identify the gene from the region-thus the phrase, positional cloning. heritage, such as that of the finns (norio et al. 1973) , and a relatively welldelineated population genetic structure, such as in finland, where extensive church records often exist that document pedigree information for many populations. 8 the catalogue of the genetic disease heritage would allow for correct specification of genetic models and facilitate gene identification. a well-delineated genetic structure of the population should facilitate fine-mapping (i.e. zero-in) and genetic association studies. in contrast, when the ''gene war'' broke out, the documentation of chinese disease heritage was scant at best, and its research in population genetics and genetic epidemiology lagged far behind that of other developing countries. since genetic epidemiology is itself a new branch of epidemiology, and since the design, execution and analysis of genetic epidemiologic studies require not only the expert knowledge of disease epidemiology but also a good command of statistical genetics, genetic epidemiology in china was in its infancy at the time. consequently, there was little, if any, genetic epidemiologic research in china. as a result, little was known of the mode of inheritance, penetrance, 9 and gene frequency for major complex diseases. even credible estimates of disease incidence/prevalence were hard to find. therefore, the notion that china is ''an ideal place for gene hunters'' is questionable and somewhat dubious. the fact that after well over a decade no genes for any common, chronic disease have been identified in china is a testament to this. while calling for protection of china's genetic resources and equating large number of dna samples to huge commercial profits, virtually no one at the time was even remotely aware that there are actually numerous obstacles to this gene prospecting. first, there were huge financial barriers. hunting susceptibility genes for complex diseases usually requires a large number of blood samples, along with accurate phenotypic data in the first place. while genotyping costs have been reduced substantially, they were still expensive in the late 1990s, especially when the whole genome would be scanned. these procedures alone would require a significant upfront capital investment. and like any other scientific endeavor, the gene hunting expedition would carry inherent risk of failure, lacking any guarantee that the investment would bear any financial rewards. the demand for huge resources, coupled with the uncertainty of yield from the investment, raises the question as to whether these endeavors were actually good investments, especially in a developing nation like china where there were and still are problems in providing affordable and equitable medical care for all its citizens (hsiao 2009 ). indeed, lifting living standard for all, improving child and maternal health, and better health education on healthy lifestyles (smoke-cessation, healthy 8 a well-enumerated genetic disease heritage can provide the scientists with basic information about the disease of interest, such as mode of transmission and disease frequency. a well-delineated population genetic structure would come in handy when trying to narrow down the gene in a chromosomal region. 9 penetrance refers to the probability that a person with a certain genotype (a genetic makeup) will develop the disease. ''gene war of the century'' and its aftermath 497 diet, physical exercises etc.) can have a proven improvement of health of the general population. secondly, there were numerous scientific hurdles, some seemingly insurmountable. hunting for complex disease genes was an uncharted territory in 1997, and no one could be reasonably sure as to whether there were susceptibility genes, and, if so, whether they could be identified, especially with reasonable time and resource constraints. even if they could be identified, whether they could fulfill the promises of better diagnosis and treatment is also completely uncertain. the genetic mechanism for sickle cell anemia has been known for well over half a century, for example, but so far no gene-derived therapeutics is available. 10 lastly, there were technical hurdles. to genotype large number of samples with high accuracy and reasonable cost was still a challenge around 1997. methodologically, how to analyze the data for diseases which apparently are also influenced by environmental factors and aging process was, and still is, a serious challenge. in addition, how to handle gene-gene interaction, gene-environment interaction, and variable age of onset posed formidable analytical challenges (di and guo 2007) . these hurdles were further compounded by the lack of a systematic catalogue and documentation of hereditary diseases in china in terms of disease frequency, mode of transmission and penetrance, the lack of documentation of population genetic structures in china, and the scarcity of well-trained genetic epidemiologists. even though the per-sample cost of sample collection was relatively low, this only advantage rarely offset the other, more fundamental deficiencies, and boded ill for many gene-hunting endeavors. viewing the xiping xu case as the nexus of international, transnational, national, and local interests, sleeboom eloquently provides ten different perspectives representing the views and ideals of different interest groups on xu's genetics research program in china (sleeboom 2005) . indeed, it is often stated that there are several stakeholders in the putative ''gene war'': chinese scientists, foreign gene hunters, and the chinese government. all of them apparently had a vested interest, mostly financial, in china's genetic resources. however, one critically important stakeholder and a potential beneficiary of this gene prospecting, obscured by the media blitz, were actually the patients of various complex diseases in china and the rest of the world. somehow, their voices were muffled and not heard. indeed, from a patient's perspective, it really does not matter which country finds the genes first and comes up with an efficacious therapeutics as long as s/he can access it at a reasonable cost and within a reasonable timeframe. in the 1990s, china's drug r&d lagged significantly behind the west. most, if not all, drugs and diagnostic kits with proven efficacy used in china today have 10 sickle cell anemia is a life-long blood disorder, characterized by abnormal, sickle-shaped red blood cells that do not have usual elasticity as normal red blood cells do. the disorder is caused by a single mutation in a gene called hemoglobin and manifests excruciating pain and shortened lifespan. it has been known to be an abnormality in the hemoglobin molecule since 1949. been first discovered and developed outside china. in fact, all major pharmaceutical companies have now set up manufacturing facilities in china, and almost all drug companies market their products in china once approved by the state food and drug administration of china, a counterpart of the fda of the us. in fact, anecdotal evidence suggests that, when money is not an issue, many patients in china, especially those with potentially fatal diseases, usually prefer imported drugs or drugs made by foreign companies even though cheaper, domestically made drugs of purportedly equal efficacy are available. thus, one simple fact was overlooked in the entire media blitz: an intellectual right on genes can be profitable only when it has a market. china's market is too big to ignore for any rational pharmaceutical company. and when a drug company sells its gene-derived products to china using materials collected from chinese, some patients may still reap the fruits of gene prospecting. this seemingly obvious fact was completely overlooked at the height of the ''gene war.'' the attention that xu's projects drew was certainly unexpected and was likely distracting to xu's projects. xu vehemently denied that he was exploiting poor villagers in anhui for personal gains. he lamented that ''i came from china, and i love the country. but i have been treated like a traitor'' (hui and jue 1997) . fearing that the media furor and the lopsided condemnation from scientists in china would torpedo his projects in anhui, xu quickly moved to act. when a letter to the editor appeared in science questioning the validity of the ''gene war'' (guo et al. 1997) , xu quickly translated it into chinese and circulated it among chinese officials. xu also enlisted the support of several established chinese scholars in the us. he appealed to peng peiyun, who was then the director of the state family planning commission, soliciting support for his projects. he adamantly maintained that he was patriotic, and his projects in anhui and elsewhere in china had already trained chinese scientists and elevated their research capabilities. xu apparently had mastered the finesse of keeping a good relationship with the government officials and adroitly played the card of a patriotic oversea chinese scholar. the official people's daily reported in 2001 that ''in the last few years, the chinese biomedical researchers collaborated with the world-famous harvard university on various projects, and achieved exciting results in the pathogenesis of complex chronic diseases…. in particular, the research in genetic epidemiology of asthma and hypertension is now at the forefront in the world'' ([benefiting thousands and thousands of families.] 2002). in another report, it said that ''harvard's project has so far produced 8 postdocs, 4 doctoral students, 20 visiting scholars, and 4 senior investigators'' ([east and west collaborate for the health of humankind.] 2001). in xu's hometown, the provincial newspaper reported, after enumerating various human genetics research projects with harvard, that ''these collaborative projects not only injected new vitality to anhui's science and technology but also helped attract investment in the amount of about 50 million ''gene war of the century'' and its aftermath 499 rbm yuan'' ([anhui-native scientist climb peak of human genetics.] 2002). it remarked that ''these projects helped establish tens of laboratories with advanced instruments, …, and laid the foundation for our nation to catch up and surpass the west in human complex diseases research in the 21 st century'' ([anhui-native scientist climb peak of human genetics.] 2002). xu's preference for dealing with the high-rank officials, however, went overboard and nearly caused his undoing (see below). as xu's various gene-hunting projects in anhui took off, some disturbing incidents involved in these projects gradually surfaced and leaked to the press. participants were initially promised by the research team that they would get free or reduced-cost medical care, but these promises were never honored. informed consent supposed to be obtained from potential participants actually was not-a flagrant violation of nih regulations. rumors circulated regarding coercion by local officials to participate in the projects, sample mishandling and mix-ups in the lab. prompted by these allegations, a fact-finding team of six people from harvard, including xu and his mentor, scott weiss, arrived in anhui in march 1999 to investigate the ethical and scientific integrity of xu's projects, but found no irregularities. five months later, the department of health and human services (dhhs) launched its own investigation of harvard's genetic research in china, based on the complaint of a whistle-blower from hsph alleging violations of us human subject protection regulations (pomfret and nelson 2000) . in late 2000, the washington post ran a lengthy report detailing the allegations that chinese villagers had not been given low-cost medical care as they were promised in exchange for providing blood samples for xu's us-funded genetic research. the report also included allegations of xu's lapses in informed consent (pomfret and nelson 2000) . partly because of the controversy surrounding this case and others like it in china, the us embassy in beijing issued an advisory recommending that american scientists stop conducting medical research in extremely poor areas of china like anhui. in march 2001, an investigative report by two xinhua news agency reporters was published in outlook, a major chinese magazine. the report reiterated some of the allegations made in an earlier report published in the washington post and supplemented them with interviews with chinese farmers in an isolated region of the anhui province and their various predicaments. the controversies surrounding xu's anhui projects reached a new crescendo at the symposium on bioethics, biotechnology and biosecurity held in early april 2001, which was sponsored by the united nations educational, scientific, and cultural organization (unesco) and organized by the hangzhou municipal government. xiong lei, the lead reporter of the outlook report, presented her investigation and findings with their interview with chinese rural villagers in anhui. her presentation elaborated various irregularities in xu's projects, including the lack of informed consent, broken promises of providing medical care for those who participated in xu's projects, and xu's taking more blood samples than officially approved. an intense debate ensued, starting with xu's anhui collaborators, who maintained that the rate of getting informed consent was close to 100%, and that the chinese side did reap benefits from the collaboration with the harvard team. but their presentation was confronted by incensed chinese scientists, who questioned their numbers and practice. xu's legal counsel also made some comments, but the comments were challenged and ridiculed. some scientists expressed grave concerns about the loss of chinese genetic materials to the west, in fear of jeopardizing china's own genetic research. prompted by the outlook report, china's office for management of human genetic resources also launched its own investigation. it soon concluded, in june 2001, that xu's projects did not violate any chinese regulations, and told the us embassy so (pomfret 2001a) . but the controversy took another turn in late june 2001. in a letter to xu dated june 26, 2001, the dean of the hsph reprimanded him, strongly criticizing him for writing two letters to senior chinese government officials, in which xu urged the government to silence the voice from his detractors and to take actions against a major figure who had criticized his work. defending himself as a patriot, xu's letter suggested that the outlook report had released state secrets to ''foreigners'' (pomfret 2001b) . the dean condemned xu's actions, and warned him that he would ''not receive the continued support of the school for you or your research if you persist in exercising independent action.'' if he continued his campaign against journalists and others who questioned his research, the letter said, xu would face ''appropriate sanction'' (pomfret 2001b ). yet xu's woes, unfortunately, showed no sign of abating. on march 28, 2002, the federal office for human research protections (ohrp) of the dhhs issued a scathing indictment of the hsph research. the ohrp found that 15 projects in china that hsph was involved, including 12 projects on which xu served as the pi, failed to be approved by institutional review boards (irb); where approval had been granted, significant and unannounced changes were often made. it found that many of the informed consent documents approved by the hsph irb included complex language that would not be comprehensible to all subjects, particularly for rural chinese subjects. hsph was charged with failing to minimize risks to their vulnerable subjects, such as economically or educationally disadvantaged persons. in the end, subjects never even received the free medical care as promised. as a result of the indictment, xu was ordered to suspend all human subject interventions in his active studies pending the outcome of an internal audit. this new development was soon reported dutifully in china's press (xiong and wang 2002) . on may 14, 2002, lawrence summers, then the president of harvard university, gave a speech at peking university. when responding to a question from a student in the audience regarding harvard's projects in anhui, summers admitted that some irregularities in the projects were ''wrong.'' xu eventually breathed a sigh of relief when ohrp sent a letter to hsph in early may 2003, stating that all issues raised in the hsph-involved china studies have been either resolved or dissolved because of unsubstantiated allegations (as in alleged forged informed consent documents). consequently, ''there should be no need for further involvement of ohrp'' in these matters. notably, the letter acknowledged that xu had decided not to continue the hypertension study due to ohrp's concern that some of the interventions in the protocol exceeded the level of minimal risk. shortly afterwards, hsph held a press release announcing the ''[c]onclusion of u.s. government's inquiry into hsph genetic research in china. '' 11 soon after the hsph news release, one internet article, by xiong lei, alleged complacency and a likely cover-up on the part of the chinese government. it raised several issues (xiong 2003) . first, among the 15 harvard projects in china that the ohrp found to have problems, 12 projects were headed by xu. yet officially, only 3 of xu's projects had ever been approved by the government. hence there was a glaring discrepancy. second, the official from the office for management of human genetic resources, who was in charge of the investigation of the allegation of irregularities in xu's projects, told xiong privately that it was not an official investigation. however, the same official then turned around and told the american embassy that no violation was found. it was rather strange that the results of this unofficial investigation, which was shielded from the media and the public, would then be used by the americans to prove that there are no irregularities in these projects. lastly, one peasant in anhui whose ordeal led to the exposure of apparent lapses in informed consent later recanted his story after talking with officials from anhui and the central government. presumably, he changed his story because of pressure he experienced. this changed story explained why the ohrp eventually found no wrong-doings in xu's projects (xiong 2003) . since xiong's article appeared in a website that is officially blocked in china, it did not cause any stir. in china's news media, the criticism of xu's anhui projects also subsided consequently. xu's woes finally ended. more than a decade has passed since the purported ''gene war.'' despite well over a decade of hard work and well over 10 million us dollars in grant support of various forms, xu's team has so far not cloned a single gene for any complex disease or disorder. in fact, they are not even close. other teams were no luckier. in fact, besides numerous reports of association of diabetes, asthma, and other complex diseases with certain genetic polymorphisms, so far not a single gene has been proven to be chiefly responsible for any of these diseases. most genetic loci identified to be associated with the disease risk confer only miniscule relative risks, ranging from 1.02 to 1.5 (kraft and hunter 2009) . even when genetic polymorphisms that are associated with a modest increase in risk are combined, they generally have a low discriminatory and predictive ability (janssens and van duijn 2008) . a more recent study reports that after examination of 101 genetic variants reportedly linked to heart disease, the variants turned out to have no value in predicting disease among 19,300 women who had been followed for over 12 years and that family history had better predictive value (paynter et al. 2010 ). for human height, a trait that is known to be mostly hereditary, it is calculated that approximately 93,000 single nucleotide polymorphisms that are required to explain 80% of the population variation (goldstein 2009 ). this nearly astronomical number certainly inspires no enthusiasm for conducting large-scale gene hunting projects, and questions their value in genetic screening, genetic testing, and the possibility of developing gene-derived therapy (wade 2009 ). the idea that disease genes can be quickly identified, patented, and then quick profits can be made now seems to be too naïve. indeed, 10 years after the first draft of the human genome was completed, medicine has yet to see any large part of the promised benefits (wade 2010) . even gene patenting, the very topic that made the ''gene war'' so contentious, has begun to encounter resistance (kintisch 2009 ). there is indication that, at least in the united states, the status of gene patenting is changing (kintisch 2009 ). in fact, the us government recently decided that human and other genes should not be eligible for patents because they are part of nature (pollack 2010) . this move, viewed as ''a bit of a landmark, kind of a line in the sand,'' followed a surprising ruling made in march 2010, by judge robert w. sweet of the united states district court in manhattan, which ruled the patents held by myriad pharmaceuticals and the university of utah on two genes that predispose women to breast and ovarian cancer invalid (pollack 2010 ). on june 13, 2013, the u.s. supreme court ruled in association for molecular pathology vs. myriad genetics that ''naturally occurring'' dna sequences, but not lab-created synthetic cdnas, are off-limits for patent protection. millennium pharmaceuticals, the initial financial backer of xu's projects, pulled out of anhui early in 1999, with no significant medical or business discoveries to show for its $3.5 million investment (pomfret and nelson 2000) . it since has moved into a field of drug r&d that seeks to customize medical treatments for individual patients. it has grown into a successful, billion-dollar enterprise. yet no doubt xu's anhui projects played a crucial role early in its success by securing a much needed infusion of funds (pomfret and nelson 2000) . for sequana therapeutics, despite its public announcement of the discovery of the asthma gene in 1997, so far there have been no publications from the company regarding the gene. the claim has never been independently verified. the prospect of making diagnostics or therapeutics derived from the putative gene never materialized. it was acquired by arris pharmaceuticals, forming axys pharmaceuticals which later on formed axys advanced technologies, later bought by chemrx. the remains of axys were bought by celera. what used to be sequana therapeutics no longer exists. human genome sciences' stock price reached its peak at $109 on january 31, 2000 and went through two splits in 2000. its president and founder haseltine said that his work ''speeds up biological discovery a hundredfold, easily.'' he talked of finding ''the fountain of youth'' in genes in the form of ''cellular replacement'' therapies. 12 the company raised more than $2 billion in investments by 2000. in september 2000, the company reported that it had found a way to treat large, painful sores that often plague elderly patients, using a protein spray called repifermin, made by a human gene called keratinocyte growth factor-2. in february 2004, however, the company said that it was ending the development of repifermin because it showed no more benefit than a placebo in clinical trials. another initial drug also failed in clinical trials. in late 2004, the company announced haseltine's retirement and named h. thomas watkins the new president and ceo. in 2000, the first draft version of the human genome was published, thanks to collaborative work among geneticists from china, france, germany, japan, united kingdom and united states. in 2003, the completed version of the human genome was published, marking the completion of the hgp. from the first draft of the human genome, it was quickly learned that there are about 20,000 genes, less than one quarter of 100,000 ''genes'' patented by the human genome sciences. along with this shrinkage in the number of genes, the company stock price also shrank dramatically: the closing price on july 14, 2009, was $2.50, a reduction of 97.7% from its historical high. other genomics companies have not fared much better. iceland-based decode genetics, for example, was founded in 1996 to identify human genes associated with common diseases using population studies. its stock price reached $28.75 on september 11, 2000, but plummeted to $0.53 on july 14, 2009, a reduction of 98.2% in value. its stock was removed from the nasdaq biotechnology index in november 2008. the company's 2006 annual report reveals that its net losses were in excess of 530 million us dollars, and that they have never turned a profit. 13 its 2009 annual report says that ''decode has recorded substantial operating and net losses over the past 3 years'' and the company filed for chapter 11 bankruptcy in the same year (http://www.decode. com/investors/dcgn-sec-filings.php). it was acquired by amgen at the end of 2012 for 415 million usd. on the chinese side, human genetics research moved on with the infusion of research funding from the government. most scientists who participated in the 1996 xiang shan symposium established themselves in genetics research. several of them were later elected to the chinese academy of sciences, the most prestigious honor that can be bestowed on to a scientist in china. besides all the trappings and perks, being an academy member also carries far more influence and political clout than its us counterpart. huangmin yang, the most vocal in criticizing xu's projects, went on to establish china's premier genome research center, and his career culminated recently in the completion of the diploid genome of the first asian individual (wang 2008) , rumored to be the dna extracted from yang himself. the purported ''gene war'' has a profound resonance. even today, over a decade after, the reverberations of the media blitz and the fallout are still palpable: a google search of ''gene war'' or ''genetic resource'' turns up numerous websites still talking about the ''gene war'' or even the purported attempt by the us to wage war against china using ''gene weapons'' (tong 2003) . the ''war'' also spurred a flurry of research papers in chinese scholarly journals, universally calling for the protection of china's genetic resources and profit-sharing arising from gene research (jia and wang 2006; jiang and wei 2006) . xu left harvard in 2005 and joined the school of public health, university of illinois in chicago, as a non-tenure track research professor of epidemiology (http:// www.cade.uic.edu/sphapps/faculty_profile/facultyprofile.asp?i=xipingxu), apparently failing to secure a tenured position at harvard. the negative publicity surrounding xu likely made him seem more a liability than an asset to hsph, especially when he and his group had made no important discoveries. in 2008, the epidemiologist-turned genetic epidemiologist went through another metamorphosis and became an entrepreneur. he was the chief technology officer and, as of writing, is now the president of ausa pharmed company in shenzhen, china. in a glowing profile of xu and his company by people's daily, xu is quoted as saying, ''i used to write prescriptions for people in a small village, and now i am writing a big prescription for people all over the world'' (wang 2008) , 14 apparently referring to the company's blockbuster-to-be drug for stroke prevention, yiye (''yi'' is the pronunciation of the first syllable of enalapril in chinese and ''ye'' is that of folic acid). according to the company's website, 15 the drug, a polypill consisting of a combination of enalapril (an angiotension converting enzyme inhibitor, or acei, used as an anti-hypertensive drug, on which merck had a patent, now expired) and folic acid (a member of the vitamin b family, used to prevent neural tube defects for pregnant women, and, as an auxiliary, to treat hyperhomocysteine and other conditions), is the fruit of extensive research by ausa scientists, ''the only class i cardiovascular drug approved by the state food and drug administration (the us fda counterpart in china) in the last three years with all china-owned intellectual rights, and is the first novel drug in the world that can simultaneously control two risk factors for stroke, hypertension and hyperhomocysteine.'' in 2009, xu was among the first that were granted the ''thousand scholars'' support, a program designed to attract full-professor-level senior professionals from overseas to work in china. 16 this is a title with enormous privileges and perks given to a select group of best scholars recruited from overseas by beijing. on december 14, 2008, xu was featured in the oriental satellite tv's special program, 30 people in 30 years, a program that profiled 30 prominent people and their achievements in the 30 years of economical reform in china. in the program, xu talked about his early life as a ''barefoot doctor,'' his admission to peking university and then to harvard, and his dream, as a youth, of ''writing big prescriptions for people all over the world.'' he talked about his work in epidemiologic studies of air pollution and health and his new venture in developing drugs for chinese people. he made no mention, however, about his genetics studies and their associated controversies, and showed no trace of bitterness. 17 curiously, the ausa-sponsored clinical trial on the evaluation of yiye in prevention of stroke was registered at the clinical trial registry, www. clinicaltrials.gov, on november 19, 2008 , which coincided with the official approval from the sfda of yiye. 18 the registered trial, china stroke primary prevention trial (csppt), is a phase iv trial (nct00794885), which compares the efficacy of enalapril and folic acid combination vs. enalapril alone in preventing strokes. as of writing, its status is listed as ''on-going, but is not recruiting participants.'' its estimated completion date is august, 2014. in modern society, science has become a firmly institutionalized social activity, attracting people through offering generally prized opportunities of engaging in socially approved patterns of association with one's fellow and the consequent creation of cultural products esteemed by the group, in addition to economic benefits that science may offer (merton [1938 ). as merton eloquently put it, ''such group-sanctioned conduct tends to continue unchallenged, with little questioning of its reason for being. institutionalized values are conceived as selfevident and require no vindication'' (merton [1938 ). in modern science, especially in biomedical research, scientific enquiries often require large amount of resources-expensive instruments and reagents, lab space, and talented and hardworking students. hence the pressure for getting resources is enormous. anything that promises to help ease the pressure is welcome. scholars of sociology of science often view science as agonistic, made up of rival individuals or groups vying to have their scientific ideas or views recognized and/or accepted as valid (greenhalgh 2008) . science, as a space of maps of culture, is drawn by scientists hoping to have their research accepted as valid and recognized, their practices esteemed and patronized, and their culture sustained as home of objectivity, reason, truth or utility. the maps are then used by all who are unsure about the reality (gieryn 1999 ). yet maps of science change over time, as competing cartographers are constantly drawing, erasing, and redrawing the boundaries of science. by doing this, the scientist cartographers claim authority over a particular issue by taking it within their science or turf. thus, vying for acceptance or the valid ''truth'' among scientists is essentially a credibility contest, with winners viewed as the epistemic authority (gieryn 1999) . the one with the epistemic authority obviously would be the most influential, and their views and voices would be the most visible and vocal when it comes to policy issues (greenhalgh 2008 ). gieryn's credibility contest metaphor aptly depicts the quest for epistemic authority in science, it also is applicable, rather fittingly, to the situation when scientists vie for resources from funding agencies. in fact, when the process of deciding who would get resources lacks procedural justice, and when there is a lack of tradition for open and rational debate and of a checks-and-balances system, the credibility contest becomes literally a ''beauty'' contest-the most glamorous, in terms of rank, status, or simply seniority in the administrative ladder, but not necessarily the vision, merit, or talent, would get the resources. in a country where political loyalty and connections are valued far more than scientific merit and talent, the credibility contest further becomes a contest of political correctness or patriotism. coupled with the lack of a clean and efficient government and of transparency and also with the pervasiveness of guanxi or personal connections, this contest might create winners who are not necessarily the scientifically most visionary. as human beings, scientists are also susceptible to all human frailties. aside from questing for epistemic authority, they also compete for resources and influence, and often vie for political clout, credit, fame, and even glamour, especially when such activities help their quest for epistemic authority or increase their professional and personal gains. if there are no set rules of the game with certain procedural justice or a checks-and-balances system in place that can curtail the tendency and channel it into the maximization of the common good, the human frailties, coupled with the lack of proper avenues for open debate, the contest would be an invitation for inefficiency, waste, corruption, and even disaster. winners might take all, but in the long run the bad money drives out the good. the spectacular fiasco in containing the sars epidemic and in sequencing the coronavirus that causes sars are a prime example (enserink 2003; cao 2004) . lured mostly by the low cost of collecting large dna samples and the perceived genetic homogeneity, many gene hunters from the west came to china in the hope to identify genes responsible for complex diseases, and some of them may have hoped to get rich in the process. this was mostly accomplished through some wellconnected chinese intermediaries ''as experienced guide,'' as washington post reporter john pomfret put it (pomfret and nelson 2000) . letting the intermediary do the leg work did spare them from doing the dirty field work but also insulated them from the sentiment from villagers and the scientific establishment in china and prevented from establishing a rapport with these people. from a scientific standpoint, many gene-hunting projects were launched without much understanding of the population genetic structure of the chinese population or foundational genetic epidemiologic data, let alone the appreciation of the inherent risk in this scientific endeavor. there was no plan b that one could have something to fall back on in case what was planned did not pan out. the execution also was fraught with various deficiencies. with little or no oversight, the daily work was left to the hands of not-so-well trained people. and when rumors of irregularities surfaced, inspection was largely perfunctory, nothing more than sugar-coating or bandaging. it would have been a miracle if such projects were ever productive. faced with numerous well-endowed gene hunting teams coming to china, the cash-strapped chinese genetics scientists had every reason to be worried. the taking of large number of dna samples and, worse yet, the tracking down of some large pedigrees with rare genetic diseases would effectively deprive their chance of finding disease genes, outshining them in the genetic research of chinese populations and threatening their careers. providing dna materials without any reasonable share of possible future financial payoff for the people who donated their blood could also be a concern, but it is not clear which was the primary concern. by calling the attention of the central government through evoking nationalism via calling the protection of china's genetic resources, they got the resources and also claimed a territory that would be off-limit to ''foreign devils.'' yet by doing so, no one apparently was aware then of numerous and enormous hurdles to gene prospecting and vastly underestimated its complexity and challenge. by evoking the urgency to protect china's genetic resources, some scientists played the card of nationalism, wining the contest in getting resources through nudging the unsuspecting government to cough up some much needed funds to thwart ''foreign devils''' pilfering act. through the drafting and implementation of the interim measures for the administration of human genetic resources, the domestic scientists effectively enacted an embargo of the transfer of all dna-containing materials from china to the outside by drawing a clearly demarcated boundary. this may explain why dr. xiping xu repeatedly proclaimed, in many public occasions during the entire course of the ''war,'' that he is a patriot. well-connected and clearly a master of nuances of guanxi, he certainly knew the psyche of many chinese and government officials. lapses and missteps aside, he was no match to domestic scientists united in the name of patriotism. yet his biggest deficiency in the credibility contest was attributable to his betting on a wrong horse: many, if not all, of his well-funded projects did not pan out in the end, producing no headline scientific discovery and failing to establish an epistemic authority. while credibility contest to quest for epistemic authority depicts science and its working, the contest for credibility, glamour or patriotism in getting resources as we see in the ''gene war'' may be ultimately detrimental to china's science and technology. today, china's r&d investment, in terms of dollar amount, has increased dramatically as compared with the era of ''gene war.'' it reached a historical high of 868.7 billion yuan, or about 133.6 billion us dollars, in 2011, amounting to 1.84% of china's gdp. 19 as a result, china's scientific output, measured by the number of papers published in international journals, also has increased remarkably and is reportedly ranked as the second in the world, just behind the us. 20 yet in terms of average number of citations-a rough measure of impact or research quality, china was ranked a distant 14 th . a more disconcerting observation is that the fruit of biomedical research seldom translates into better patient care, better therapeutics, better prognostics, or better prevention. in other words, the vast majority of tax-payers have not received any tangible benefit from the supposedly noble and grandiose scientific endeavor. this situation, if left unchanged, is not going to justify for heavy investment in biomedical research and to win the continued support from tax-payers in the long-run. ultimately, it would raise the issue of sustainability of biomedical research in china. this problem will become all the more acute as china enters into an aging society in which health care cost will surely skyrocket. it should be noted that, at the height of the ''gene war,'' similar concerns were also raised in finland and india. however, few seemed to have framed their concerns at the level of nationalism, and even fewer have gone overboard and demonized, often in passionate and patriotic rhetoric, all foreign-supported gene hunting projects. the near paranoid that instigated towards all foreign-backed gene-hunting project did help to cough up some much needed research funding from the government, but also fermented xenophobia and some utterly unfounded yet sensational non-sense such as ''gene weapons'' 21 (tong 2003) and tarnished genetic research in china. remarkably, when a book was published in 2003, sensationally claiming that the sars virus was deliberately manufactured by the west based on dna materials smuggled out of china (tong 2003) , no one stood out and debunked such scientific rubbish. the chinese also carry a burden of humiliation and painful memories of the past as a result of repeated ravages by foreign aggression and exploitation in the last two centuries. consequently, issues that may be remotely related to national sovereignty or foreign exploitation are hot-button ones. minor incidents can be easily escalated into a major event, as evidenced by the calls for boycotts of french carrefour and other foreign retailers in china in response to the disruptions of the olympic torch relay in paris in 2008, and, more recently, by the vandalization of japanese-made cars in many chinese cities at the height of anti-japanese sentiment rekindled by the territorial dispute between china and japan. china's current funding system and the science policy-making also are vulnerable to subterfuge of various kinds, behind which personal gains are often masquerading as patriotism or national interest. as ambrose bierce once defined, patriotism is a ''combustible rubbish ready to the torch of any one ambitious to illuminate his name.'' it is a challenge to weed out charlatans impersonating as patriots, but the best bet would be a transparent system that values merit, talent and vision above cheap patriotic or nationalistic rhetoric. as china is aspiring to be a leader in science and technology, this ''gene war of the century'' and its aftermath, as narrated here, serve as a cautionary tale. it reminds us, first and foremost, how important it is to be clear-headed and not to follow blindly whatever in vogue. very often, what we see is the conspicuous ''me-too'' science, following whatever fashionable. yet the most important ball that all eyes should lay on, i.e. better health for all, is seemingly lost. in the absence of procedural justice in the process of deciding who would get resources, and when there is a lack of tradition for open and rational debate and of a checks-and-balances system, the credibility contest for resources would easily become a ''beauty'' contest. in a country where political loyalty and nationalism are valued more than scientific merit and talent, the credibility contest would further become a contest of political loyalty, political correctness, or patriotism. the news of pilfering of china's genetic resources by foreign companies could easily strike a chord of painful memories of foreign aggression and exploitation in the last two centuries. the isolation from the world community for nearly three decades since 21 one key finding of the hgp is that all human races are 99.99% identical-dna sequence-wise. therefore, racial differences are genetically insignificant. for many genes, it has been established that genetic variations within the same racial group are larger than those among racial groups. thus, scientifically, it is impossible to devise a ''gene weapon'' to target a specific racial or ethnic group. ''gene war of the century'' and its aftermath 509 the founding of the people's republic purportedly due to the prejudice, discrimination, and containment of the western imperialists and capitalists-or so it was told by the state media-also helped foster or reinforce a nearly xenophobia attitude towards anything perceived to be dangerous if coming from outside of china, especially it touches on ideology. thus, a spark of minor incident could easily kindle the fire of tumultuous nationalistic uproar. hence, the ''gene war'' holds a lesson that being seemingly the most patriotic is not an assurance for good science. the mere possession of resources does not guarantee scientific productivity, either. vision and brain are more important when it comes to scientific innovation and discovery. the over-politicizing science will ultimately prove to be detrimental to china's science and technology. we have seen it during china's great cultural revolution, in which nearly everything in science and technology was politicized. but science and technology then were essentially decimated, and the characteristic hallmark was jia, da, kong or falsehood, grandeur, and emptiness. in addition, when political loyalty prevails over talent and vision, some unscrupulous scientists can hijack the value system to their own advantage. and when there is also a lack of avenue for open debate, then one project purported of to be of national importance could be usurped by another with purportedly greater importance. the conflict also reminds us that scientists are no more than human beings and have all the human frailties. personal gains or some ulterior motives can be camouflaged as patriotism or public interest, as shown in the politics of paleoanthropological nationalism in china (sautman 2001) . as merton succinctly put it, ''any extrinsic reward-fame, money, position-is morally ambiguous and potentially subversive of culturally esteemed values. for as rewards are meted out, they can displace the original motive: concern with recognition can displace concern with advancing knowledge. an excess of incentives can produce distracting conflict'' (merton [1968 ). without any measures or system to guard against this, the interest of the nation and of the public will suffer. in human genetics, china's premier challenge now remains to be, as was a decade ago, ''to build up a critical mass of highly competent and visionary scientists who will be able to bring chinese genetics into the world community'' (guo et al. 1997) . the ultimate goal of biomedical research in general and human genetics in particular is to bring tangible benefits and better health to the general public, not merely some ranking of scientific output, for it is the source of gaining sustainable support from the general public and of economic prosperity. science thrives on openness, reason, and the competition of ideas, and it suffers when subjected to political agenda, faux patriotism or nationalism. anhui-native 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research projects in china a ''violation advances in science and progress of humanity: a global perspective on dna the gene puzzle acknowledgments the author would like to thank drs. cong cao, partha majumder, margaret sleeboom-faulkner for their constructive comments on an earlier version of this manuscript. he also thanks dr. yang huanmin for the reading of an earlier draft, two anonymous reviewers and the editors for their helpful comments. thanks also goes to charles guo for his critical reading of and helpful comments on the manuscript. key: cord-313418-v5rtsqtx authors: zhu, annah; zhu, george title: understanding china’s wildlife markets: trade and tradition in an age of pandemic date: 2020-08-04 journal: world dev doi: 10.1016/j.worlddev.2020.105108 sha: doc_id: 313418 cord_uid: v5rtsqtx environmentalists have long been concerned about the rate at which china is consuming and trading in threatened and endangered wildlife. the recent covid-19 global pandemic has made wildlife consumption an issue that concerns everyone around the world. formerly obscure practices like wet markets and commodities like pangolin scales or bear bile have gained international notoriety. along with that attention has come increasing politicization and ideological polarization. beyond the global fight against the pandemic, there has been another global struggle over the meaning and origin of the disease, as evidenced by the spread of terms like “wuhan flu” and “bat soup.” what has become obscured by the news cycle struggling to keep up with the rapid spread of the virus and the political sound and fury surrounding it is any meaningful understanding of china’s wildlife consumption and trade. deeply ingrained in chinese culture and history, the wildlife trade is not going away anytime soon. despite a national ban, already wet markets are returning across china. addressing the wildlife trade in china, we argue, requires first understanding it. environmentalists have long been concerned about the rate at which china is consuming and trading in threatened and endangered wildlife. the recent covid-19 global pandemic has made wildlife consumption an issue that concerns everyone around the world. formerly obscure practices like wet markets and commodities like pangolin scales or bear bile have gained international notoriety. along with that attention has come increasing politicization and ideological polarization. beyond the global fight against the pandemic, there has been another global struggle over the meaning and origin of the disease, as evidenced by the spread of terms like ''wuhan flu" and ''bat soup." what has become obscured by the news cycle struggling to keep up with the rapid spread of the virus and the political sound and fury surrounding it is any meaningful understanding of china's wildlife consumption and trade. deeply ingrained in chinese culture and history, the wildlife trade is not going away anytime soon. despite a national ban, already wet markets are returning across china. addressing the wildlife trade in china, we argue, requires first understanding it. ó 2020 elsevier ltd. all rights reserved. the link between wildlife and pandemics is simultaneously obvious and contested. ebola, zika, sars, and many other infectious diseases all spread through human-environment interactions. initially, pristine wilderness teeming with diverse species was considered to be the breeding ground of these diseases (vidal, 2020) . 1 the recent covid-19 pandemic, however, seems to demonstrate the opposite: that infectious disease can proliferate in spaces of intense human-wildlife interaction, such as the now infamous wuhan wet market thought to be the origin of the outbreak. it confirms a growing suspicion that human exploitation of wilderness and deforestation -not pristine forests -contribute to viral outbreaks (rulli, santini, hayman, & d'odorico, 2017 , olivero et al., 2020 . the take-away, then, is to keep forests intact and humans and wilderness separate (scientific american, 2020 , trent, 2020 . shifting the culprit of global pandemic from intact wilderness at one extreme, to deforestation and human-wildlife interaction at the other, obscures a more significant cause and a more relevant dynamic to viral spread -namely, globalization. transmission of infectious disease to humans is one thing, global spread is another. wet markets in china, for example, date back millennia, but only in the past two decades have they become connected to ski resorts in the italian alps, cruise ships in the south pacific, and megachurches in south korea via international trade and travel. globalization -or rather, ''hyper-globalization" (rodrik, 2017) -is the force driving the spread of pandemic to every country on earth. in the case of covid-19, the ''cause" then -if one could be pinpointed at allis not an inauspicious ''bat soup" somewhere in wuhan, but rather our hyper-globalized world. to identify globalization as a ''cause" of global pandemic is, in a way, stating the obvious. but recognizing covid-19 as a global phenomenon -and a product of a hyper-globalized world -also reinforces the need to address it globally. global problems, after all, call for global solutions. yet, the responses seen thus far are more likely to proffer isolationism, politicization, and ideological polarization -all of which conjure anti-globalization sentiment without any productive consideration of what contemporary forms of globalization should indeed look like. governments around the world are now asking, some louder than others: what should be done with china? how to extract concessions? in terms of the environment, many are demanding that chinese https://doi.org/10.1016/j.worlddev.2020.105108 0305-750x/ó 2020 elsevier ltd. all rights reserved. ⇑ corresponding author. e-mail address: annah.zhu@wur.nl (a. zhu). 1 this was one of the take-always from the ebola outbreak in 1996, which was thought to have originated from chimpanzees hunted in the forest. many believed that ebola outbreaks occurred in intact forests, where bushmeat hunting was still a possibility because, well, there was still bushmeat (herman, 2014) . ''i don't think it has anything to do with deforestation," a lead virologist at the development research institute commented in response to the outbreak (vidal, 2004) . world development 136 (2020) 105108 world development j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / w o r l d d e v authorities stop the trade and consumption of wildlife altogether (mukpo, 2020) . demanding reparations from china, or the cessation of the wildlife trade, is a highly antagonistic rather than collaborative global response. curtailing the wildlife trade in china and securing wet markets against future pandemics requires first understanding why the trade persists despite trenchant international opposition. this, in turn, requires grappling with cultural, historical, and philosophical dimensions that are only superficially acknowledged within environmental debates. working toward this deeper understanding, we highlight three facets of china's wildlife trade often overlooked in western media and scholarship, but that are vital to understanding its dynamics and persistence: (1) the fundamental importance of traditional chinese medicine in everyday life in china, (2) the speculative aspect of demand for rare wildlife, and (3) the reliance on captive breeding as a conservation tool for preventing species extinction. together, these three factors illustrate china's wildlife trade not from the perspective of environmentalists with the mission to stop it, but from the perspective of hundreds of millions of people following millennia-old traditions in our contemporary, hyperglobalized society. they show why wildlife trade and consumption will likely persist despite the threat of pandemic, but also they provide hints for how it might be more collaboratively restricted moving forward. there can be no real understanding of china's wildlife trade without addressing traditional chinese medicine, and in particular the radical difference it reveals between how food and medicine is delineated in china versus the west. compared to western consumers, chinese consumers typically do not categorize medicine and food separately; rather everything ingested has potential effects on one's health. the consumption of exotic and endangered species, therefore, is often related to health and healthful practices more than ''conspicuous consumption." wet markets are ''wet" precisely because live or freshly slaughtered animals are understood to be more vital to health than those frozen or already killed. far from an eccentric practice that might simply fade away in the face of western medicine, traditional chinese medicine forms the foundation of a chinese approach to health and vitality. the recent inclusion of traditional chinese medicine in world health organization guidelines, its status as a growing cultural export (cyranoski, 2018) , and its hope for treating the virus (ren, zhang, & wang, 2020) all suggest that wildlife consumption will likely become more prevalent in and outside of china, not less. this is not to say that wildlife consumption cannot be more safe and sustainable, but critiques of wet markets must be measured and specific; they cannot be conflated with critiques of traditional chinese medicine as a whole or they will surely backfire. while wildlife is a vital component of traditional chinese medicine and has been for centuries, more recently, it has also become a speculative investment. the most endangered resources in china -ivory, rhino horn, tiger parts, and rosewood -are not bought to be used and consumed, but rather for their potential to appreciate in value (zhu, 2020a) . stocks of ivory, rhino horn, and rosewood are traded like speculative commodities and their values rise and fall based on financial events ('t sas-rolfes et al., 2014 , gao & clark, 2014 . this may seem to have little to do with the wet markets of wuhan, but the diversity and rarity of species found in chinese wet markets are in fact related to this speculative dynamic. pan-golin -an endangered mammal suggested to be linked to the transmission of covid-19 to humans -provides a prime example. pangolin scales can sell for nearly $800 per kilogram, higher than the price of silver (challender, harrop, & macmillan, 2015) . to be sure, the rarity and exoticism of the pangolin contributes to the value they command on the market, but the greater factor is their perceived value as a prized ingredient in traditional chinese medicine. the speculative dimensions of markets for endangered species are poorly documented if not entirely ignored in western media, but need to be understood if wildlife consumption is to be curtailed. this is especially urgent given the fact that trade restrictions can have the unintended consequence of artificially driving demand higher given conditions of market speculation (biggs, courchamp, martin, & possingham, 2013 , zhu 2017 , 2020a . total bans can only be effective if they come from within china and are perceived as well-enforced and permanent, rather than internationally imposed (harvey, alden, & wu, 2017) . this was the case with china's ivory ban in 2017, a success by most standards (wwf 2019). while a comprehensive ivory ban was more feasible because ivory is not an ingredient in traditional chinese medicine, successful bans on traditionally consumed wildlife are possible as a long as they are not perceived as part of a broader attack on chinese culture. one of the most interesting ways china has tried to address domestic demand for endangered species is through the promotion of captive breeding programs. china has had considerable success in captive breeding of endangered species, from its panda breeding programs to more recent attempts at breeding tigers and bears (hong et al., 2019 , wang et al., 2019 . 2 within china, these programs are often perceived to have both environmental and economic benefits: meeting demand and reducing speculative potential, while providing rural livelihoods and saving species. captive breeding thus appears as a logical supply-side response. many environmentalists, however, trenchantly oppose china's breeding programs, claiming the trade in captive bred individuals will only legitimate and intensify consumption practices that should be criminalized and stigmatized. 3 the global impact of covid-19 has further entrenched this opposition, with more fervent calls for china to end captive wildlife breeding. china has responded swiftly, issuing a temporary order to suspend all wet markets and captive breeding programs until further notice and to amend the national wildlife protection law regulating the industry (npc, 2020). the pandemic will certainly alter china's policies towards wildlife trade and captive breeding programs; however, it is unlikely to end these practices entirely. indeed, there currently remain provisions for the trade in wild animals for medicine, pets, and research to continue. while conservation groups fight to stop categorizing wildlife as a resource to be utilized altogether (jiang, 2016) , many in china note that there is no conservation without utilization and, in certain cases, captive breeding offers ''the only feasible approach to china's wildlife conservation-utilization dilemma" (wang et al., 2019) . 2 in fact, china has its own ''tiger king," famed long before the netflix special. unlike joe exotic and his reality show infamy, china's tiger king, zhou weisen, is a respected businessman who is often lauded in chinese media for his rags to riches success story. 3 scientific arguments against captive breeding question the genetic integrity of captive versus wild animals, noting genetic drift and inbreeding in the former. similarly, more symbolic arguments oppose the grim reality of apex predators like tigers and bears -sublime symbols of animal wildness -being reduced to the status of domestic animals, like chickens or pigs. the covid-19 pandemic has opened an unprecedented window of opportunity to pursue reforms, as indicated by china's temporary ban on wet markets and ongoing revisions to the wildlife protection law. this window of opportunity, however, must be approached strategically. there is a clear willingness on the part of chinese leadership to continue wildlife reforms, but also an extreme sensitivity to demands that are considered an attack on chinese culture and tradition. 4 some features of china's approach to wildlife trade and consumption are on the table for negotiation, and some simply are not. rather than the blunt instrument of comprehensive bans that can be dismissed as cultural imperialism and ignorance, policymakers and advocacy groups need a tempered, strategic approach -a scalpel, not a hammer. they need to focus on realistic goals, collaboratively achieved. below, we outline two recommendations for moving forward. first, start with the low hanging fruit: pangolins and other small mammals prone to spread infectious disease. china's recent ivory regulations have demonstrated that a comprehensive ban can reduce the speculative potential of endangered resources if it is well-backed by authorities within china. advocating a permanent and well-enforced ban on pangolin and other high-risk mammal sales and captive breeding -while making abundantly clear that it is not an attack on traditional chinese medicine, nor its foundations based on wildlife utilization -can go a long way to reducing the threat of pandemic and saving species. such a targeted ban would not rule out captive breeding approaches entirely, but would recognize that captive breeding is limited in an age of global pandemic. similarly, such a ban would not challenge the fundamental approach to wildlife as a utilizable resource, but would acknowledge that wildlife utilization is simply not feasible for certain high-risk species. second, advocate for the regulation and international oversight of wet markets, rather than a total ban. in certain parts of the world, banning wet markets is tantamount to banning supermarkets or other ''essential services." rather than overturning wholesale this practice that dates back millennia, it needs to be adapted for a globalized world. as with domesticated animal production, large-scale wet markets require regulation and oversight. china is now taking steps to do this. the international community should be a part of this process, but this requires recognizing the value live animals represent to healthful practices in chinese culture. again, policymakers and advocacy groups cannot demand the wholesale reconceptualization of wildlife as something to be protected and not used. indeed, for many chinese people, there is no protection without use. in conclusion, covid-19 has exposed the hidden fault lines in contemporary global life: while the world is materially and economically more interconnected than ever before (''classic" globalization), the ability of international bodies to collectively and legitimately mediate global connections (a second-wave, sociocultural globalization) lags far behind. as the virus crosses geopolitical and geographical boundaries with equal alacrity, the global response has been provincial in nature, hamstrung by competing political ideologies and cultural inertia. this lamentable dynamic is echoed in the contemporary wildlife trade, where international approaches remain highly polemical or culturally blindered rather than cooperative. although international fora for realizing global cooperation do indeed exist -the world health organization, the convention on international trade in endangered species -too often these platforms are instead leveraged to serve nationalistic agendas and rally domestic constituencies. more than any specific institutional architecture, global collaboration requires a good faith effort to engage in dialogue: to understand the culture and motivations of different global actors. this is not about cliched ideals of embracing cultural difference, but rather about realizing the practicalities of global compromise. this second-wave of globalizing mindsets -alongside globalizing connectivities -is long overdue. yet it is precisely what is needed for collective action to address collective crises. our portrayal of wildlife trade in china offers a small step toward that end. legal trade of africa's rhino horns understanding markets to conserve trade-threatened species in cites why chinese medicine is heading for clinics around the world elephant ivory trade in china: trends and drivers speculating a fire sale: options for chinese authorities in implementing a domestic ivory trade ban did deforestation cause ebola? takepart creative conservation in china: releasing captive giant pandas into the wild draft animal protection law worries activists. global times as calls to shutter wildlife markets grow decision of the standing committee of the npc on comprehensively prohibiting illegal wildlife trade, eliminating the abuse of wild animal eating and safeguarding public health human activities link fruit bat presence to ebola virus disease outbreaks traditional chinese medicine for covid-19 treatment straight talk on trade: ideas for a sane world economy the nexus between forest fragmentation in africa and ebola virus disease outbreaks how covid-19 took hold and why we must end the wildlife trade. the revelator mostly they died. the guardian destroyed habitat creates the perfect conditions for coronavirus to emerge captive breeding of wildlife resources-china's revised supply-side approach to conservation beware of the west attacking traditional chinese medicine under the name of wildlife protection. xinhua two years after china bans elephant ivory trade, demand for elephant ivory is down rosewood occidentalism and orientalism in madagascar hot money, cold beer: navigating the rosewood and vanilla export economies of northeastern madagascar we are the nation that created traditional chinese medicine which has a tradition of millennia of use," the article observes, ''we should not ignore our cultural background and blindly adopt western values china's rosewood boom: a cultural fix to capital overaccumulation restricting trade in endangered species can backfire, triggering market booms. the conversation the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. key: cord-006092-v25ji4zt authors: zhenzhen, li; jiuchun, zhang; ke, wen; thorsteinsdóttir, halla; quach, uyen; singer, peter a; daar, abdallah s title: health biotechnology in china—reawakening of a giant date: 2004 journal: nat biotechnol doi: 10.1038/nbt1204supp-dc13 sha: doc_id: 6092 cord_uid: v25ji4zt nan the communist regime of the 1950s, chinese achievements in science suggested that the country would soon join the elite group of countries spearheading innovative scientific research. after the 'cultural revolution' that began in 1966, however, and its devastating impact on chinese science for the next 10 years, china's scientific capacities quickly fell behind those of developed nations and vital scientific personnel were lost. by the late 1970s and early 1980s, extensive government reformsincluding policies that began to shift the nation from a centralized, planned economy toward a market-based one-identified the science system as central for the country's modernization and economic development. although these reforms have set china's health biotechnology innovation system on a solid footing, the reorganization of r&d organizations and activities, the promotion of linkages between various actors and even the political and legal environment remain in flux. nevertheless, spurred by the goal of 'catching up' with the advanced, industrialized nations, the past two decades have seen china work hard to move products from the laboratory to the market. china's participation as the only developing country in the human genome project showcased its capability in genomics and its intent to become one of the world's leading contributors to the field of biotechnology. the country quickly set up major institutions in genomics, the beijing genomics institute and the chinese national human genome center (with branches in beijing and shanghai), equipped with state of the art sequencing facilities and computers. even though they entered the project relatively late, chinese researchers successfully sequenced 1% of the human genome with an accuracy rate of 99%. they have continued to demonstrate their strength in the field, and in 2002 sequenced the rice genome of the most widely cultivated subspecies in china 1 . the country's participation in the human genome project is indicative of how rapidly china has reached world standards in sequencing, and this in turn reflects its general advanced state of development in health biotechnology. since china initiated research in the field in the late 1980s, it has approved several vaccines and diagnostics and therapeutics for the market (see table 1 ). many of these are based on technologies developed abroad, but chinese innovation in this field is increasing and resulting in new products. china is focusing on several subfields of health biotechnology, including therapeutic antibodies, severe acquired respiratory syndrome (sars) research, gene therapy, funcgenomics and stem cells. the world's first commercial gene therapy was announced in china (see box 1). in addition, several research institutions in china are pioneering research on adult stem cells (e.g., from blood and umbilical cord) and on embryonic stem (es) cells; a chinese research group recently reported the capacity of nonhuman oocytes to reprogram human adult somatic cells into bona fide es cell lines 2 . there are stem cell banks and related services in several centers, including beijing, shanghai, sichuan, guangdong and zheiiang. with a comparatively liberal environment and access to important materials for this type of research, china has the potential to become a leader in human embryo biotechnologies 3 . in addition, china is continuing to work in the field of genome sequencing. it is using its large population and the availability of several homogeneous subpopulations to move more into functional genomics and the identification of disease genes. it now has more than 150 health biotechnology products in clinical trials 4 and is increasing the number of health biotechnology patents by around 30% per year 5 . a comparison of china's health biotechnology publications in international peerreviewed journals with its patents granted in the united status patent and trademark office (uspto, washington, dc, usa) between 1991 and 2002 provides another indicator of the country's innovation level in terms of scientific output and commercial potential (fig. 1) . data derived from science-metrix show that china's scientific publications have been increasing, particularly in the late 1990s in the area of health biotechnology 6 . the country's patent activity is still modest but is increasing (based on a search of inventors' addresses in uspto granted patents in health biotechnology carried out in july 2004, http://www.uspto.gov/). bureaucracy at the central and local level in china has hampered implementation to promote biotechnology; nevertheless, initiatives to foster an innovation system that promotes private sector development have provided a solid basis for encouraging biotech venture creation. china's strong public education and research programs are driving innovation in both state-owned enterprises and the burgeoning number of private enterprises. although public discussion of health biotechnology issues has been limited, several initiatives are in place to inform the population more effectively about these technologies and their societal impact. government. the chinese government has played a central role in promoting capacity building and innovation in the health biotechnology sector. however, with the 'nationalization' of science and technology in the 1950s, china's science and technology system experienced heavy top-down government intervention. this led to inflexible management structures, rigid hierarchies and inefficient allocation of resources that hindered both innovation and the industrialization of scientific achievements. the origins of modern biotechnology research in the country can be traced to the late 1950s. in 1958, the policy of the 'great leap forward' was launched in an effort to catch up with, and try to surpass, the technological development of industrially advanced countries. one part of the policy was an initiative to develop synthetic bovine insulin, which succeeded in 1965 when chinese scientists successfully developed the first synthetic protein in the world. after 10 years of hiatus following the cultural revolution, the 1978 state reform was passed to once again encourage chinese science. in 1986, the government launched 'the national high technology research and development program of china,' also known as the '863' program to promote development in six priority fields, including health (medical) biotechnology. under the 'ninth five year plan' in 1997, the health biotechnology research system received increased financing and support to build up institutions and research capacity. as part of its program to establish a national system of innovation, the government now is promoting innovation and industrialization of the health biotechnology sector. this includes the special project on biotechnology of 1999, which has promoted venture creation in this area 7 . the government has also been active on the regulatory and legal front. in 1978, china began implementing a patent system, and a patent office was established in 1980. however, even with the 1985 patent law of the people's republic of china, ip protection covered process, rather than product, innovations 8 have played a major role in health biotechnology. from 1991 to 2002, they published about 20% of all the chinese-authored papers in this field that appeared in the international peer-reviewed literature 6 . in the 1950s, china adopted policies similar to those in the soviet union to encourage higher education development, creating both comprehensive and more focused universities. however, the role of universities has changed extensively since the 1980s. although they traditionally have concentrated on teaching and training human resources, universities are now moving into the research realm. according to data compiled by science-metrix, universities have been very successful in making this transition in health biotechnology, and they have become strong producers of new knowledge in this field 6 . in addition, they are expanding their teaching programs and setting up new educational options in biotechnology. an initiative that began in 2002 is aimed at training scientists and technologists for the life sciences industries. thirty-six universities and colleges are participants in this special initiative. these programs combine teaching, research and industrialization 10 . industry. health biotechnology industrialization was not initiated until after the mid-1980s but expanded rapidly when some of the public research institutes were transformed into enterprises for manufacturing medicines. during these first 10 years, industry was mainly involved in copying products developed abroad, and government almost exclusively funded r&d activities. with the collaboration of canada's international development research centre (ottawa) from 1996 onward, the chinese government has increased its commitment to foster a national innovation system. policy is focused on placing firms at the center of innovation in the country. as a result of these initiatives, china's health biotechnology industry is rapidly expanding. today, there are about 500 biotechnology firms in china, employing more than 50,000 people. around 300 of those firms work in health biotechnology, and about half of them were established in the past 5 years 5 . in a recent ernst & young report, china/ hong kong had the second largest biotech sector (behind australia) in the asian region 11 . with biotechnology identified as a strategic target by the government, this new approach is expected to develop and commercialize indigenous health biotechnology products that are internationally competitive. there are two main types of health biotechnology firms in china. the first type consists of state-owned enterprises developed from the former public research institutions. they typically receive generous government support, are well equipped, operate in a policy environment that is favorable to them and have an advanced technological capacity. many of them, however, suffer from inflexible management structures and have relatively limited innovation potential. the second type of firm is the small private enterprise, often set up by former employees of public research institutes or by chinese professionals who have returned from abroad. the latter group brings into the country technological and management knowledge from overseas and promises to become a new force in the sector. the therapy cost the company more than $9.6 million to develop, in addition to research grants from the government and over five years of clinical trials. in china, hundreds of thousands of patients die each year of cancer without having access to any kind of therapy. gene therapy may be an attractive option although it has until now not lived up to its early promise. there are some recent promising signs, though, and currently, five gene therapies are being tested in china. number of patents 2 0 0 2 2 0 0 1 2 0 0 0 1 9 9 9 1 9 9 8 1 9 9 7 1 9 9 6 1 9 9 5 1 9 9 4 1 9 9 3 1 9 9 2 1 9 9 1 society. yet, the chinese government has made some efforts to encourage public engagement in science and technology. these include suggestions through the internet on how the country should rebuild its science and technology by 2020 (ref. 12 ). china has also introduced tax measures to promote science communication. a new law will exempt any science museums, planetariums and laboratories in colleges and research institutions from import duties and valueadded tax if they regularly engage in science communications aimed at the public 13 . although there has been rapid growth in the chinese health care biotechnology sector in recent years, the scientific excellence and expertise available in universities and public research institutions has not been exploited to its full potential. in addition, although an increasing number of expatriate scientists are returning to china to form startups, the proportion of chinese scientists that work and study abroad may be limiting growth of the national health care biotechnology sector. the creation of new ventures in technology and health care is also limited by insufficient venture capital and a lack of exit options for investors. health care biotechnology enterprises find it particularly difficult to attract investment because of the short-term expectations of the chinese investor community. limited domestic collaboration. experts in china have singled out the limited collaboration among different actors within the health biotechnology sector as the foremost challenge to its development (see box 3). in particular, universities and public research institutions carry out world-class research, but their activities are not connected to the budding industrial sector. patent statistics reveal that public research institutes and universities own 80% of all biotechnology patents 14 . only 6% of new biotechnology therapeutics and vaccines in china are the result of joint developments by universities and enterprises 5 . in an effort to encourage domestic collaboration, the government has established programs and initiatives such as the national engineering and technique research centre (beijing), the research center of engineering & technology for medical bioengineering (guanzhong city, china) and several incubator institutions. there are signs of increasing collaboration. in 1991, only 13.6% of all the articles published by chinese scientists in the international peer-reviewed literature included authors from more than one institution, but by 2002 the number had risen to 30% (ref. 6) . limited funding. the shortage of financing options creates another major bottleneck for the health biotechnology sector in china. the government remains the main source of funding for r&d and commercialization. in terms of r&d, insufficient and shortterm funding has been criticized as a major cause of china's low scientific impact 15 . moreover, with direct government control over research, major funding is generally awarded to projects clearly defined by the government and scientific administrators wield enormous power over the allocation of resources 16 . the government is slowly reducing its dominant presence and encouraging private sector investment in high-technology enterprises in the country. for example, in the early 1990s, the state science and technology commission (beijing), the ministry of finance (beijing) and the industrial and commercial bank of china (beijing) set up the national science and technology venture capital development centre (beijing) to promote industrialization of high tech in the country. in its early days, most funding originated from the government, but over time it also came from other channels, including national the chinese academy of sciences (cas) 27 was established in 1949 in an effort to manage the nation's science and technology. since the 1970s, cas has been a significant actor in promoting and developing a research base for china's economic and social needs through its numerous research bodies throughout the country. the academy's research, education and training activities are diverse and cover a broad spectrum of scientific fields. it has also been involved in policy innovation, including the restructuring of research institutions, restoring the graduate student system and reforming the 'closed' system of innovation. it provides support to other research institutes, including the beijing genomics institute, which was founded by overseas chinese scientists in 1999, and was involved in the human genome project. cas is also involved in promoting scientific collaboration with developed and developing countries. the shanghai institutes for biological sciences (sibs) is a key actor in health biotechnology within cas. this r&d organization consists of several research institutes, including the institute of biochemistry and cell biology, the institute of neuroscience, the institute of medica materia, the health science centre and the institute for nutritional science. these institutes focus on eight key research fields, including functional genomics, proteomics, and bioinformatics; brain development and functions; and biotechnology development. enterprises, foreign-funded organizations and financial organizations 17 . nevertheless, chinese firms still have very limited access to venture capital. investors in china are focused on returns on investment that can be had more rapidly than typical for health biotechnology ventures, which are renowned for their risky nature and protracted development times 18 . foreign investors have also been reluctant to enter the chinese venture capital market. the lack of exit strategies that would allow investors to pull out with their capital gains discourages foreign venture capitalist funding. in addition, interactions between foreign investors and chinese entrepreneurs are complicated by cultural differences in how business is conducted and remaining uncertainties in ip laws 19 . as a consequence of these conditions, chinese companies have steered away from high-risk, capital-intensive r&d activity in health biotechnology and toward industrialization of more mature (less risky) technology (e.g., generic manufacture). brain drain. china has stressed higher education and has actively promoted foreign education for its citizens. in the early days following the communist revolution, chinese students went mainly to the soviet union and eastern european countries, but since the 1980s, students have been departing for the united states, japan and western european countries. during the 1980s and 1990s, there was a massive increase in the number of chinese students studying abroad, and many of these have not returned home. china's ministry of personnel estimates that about 580,000 chinese students have gone overseas to study since the late 1970s, with only about 160,000 returning 20 . of the nearly 300,000 chinese students overseas at present, onethird of them are involved in the biotechnology field 21 . china is a populous country, with a population of more than 1.3 billion, highly developed public education and research institutions, and rapid economic growth (gross domestic product grew more than 7% from 1998 to 2002). the size and power of the chinese economy may mean that many aspects important in encouraging growth of the health care biotechnology sector in china may be difficult to implement in less populous countries. provide long-term government support. the chinese government has supported health biotechnology innovation in the public and private sectors from the mid-1980s, and this has provided the necessary knowledge capacity to make a growth of enterprises in the health biotechnology sector possible. china has been willing to take risks and support uncertain research fields, and it has been willing to prioritize its support. by channeling resources, it has built up strong capacities in promising fields of health biotechnology (for example, stem cells or genomics). many of these fields are still under development and have not yet produced an impressive list of health biotechnology products, but by continuing to support them, china is making bold efforts to invest in the future. in particular, china has kept a focus on stimulating the formation and innovation of high-tech enterprises. more recently, an increased emphasis in policies to foster venture creation and to transform research institutions into enterprises is helping a strong manufacturing base evolve into an engine of innovation. past problems in knowledge sharing between the private and public sectors are being addressed by encouraging collaborations among universities, public research institutes and companies. there has been a substantial increase in such linkages since the country started to focus on more systemic innovation. attract expatriate professionals. from the late 1990s, the chinese government has taken active steps to encourage expatriates to return home. this includes such incentives as government financing for scientists who wish to set up laboratories in china and support programs to facilitate entrepreneurs interested in setting up startup companies. there is evidence that expatriates are increasingly returning. 24 . it has been only a few years since this policy of actively encouraging expatriates to return to china has been in operation, and the expatriates are already making their mark. in years to come, these individuals are likely to be a strong driver for promoting innovation in the chinese health biotechnology sector. biotechnology development must go handin-hand with regulation. safety concerns play a central role in promoting successul new technologies like health biotechnology. it is always risky to be at the forefront of a new field and it is therefore important that as health biotechnology progresses appropriate policies and facilities are set up to ensure the safety of the new products. with new developments such as the introduction of gene therapy products, a strict and competent regulation regime is an essential prerequisite. china has been active in modifying its safety regulations and has set up a number of new regulations and laws to direct the development of the technologies. they include, for example, 'guidelines on the technological requirements of the clinical research on new preventative biological products,' 'essentials of the quality control on the recombinant dna products in human therapy' and a new drug administrative law. in 2003, china also reorganized its state drug administration into a new entity called the state food and drug administration (beijing), which makes it possible to coordinate the regulations of new food and drug products. leverage china's population base. having the world's largest population has been an asset to china in developing its health biotechnology sector. local companies have a large domestic market for their products; in fact, most chinese companies in health biotechnology focus entirely on the local market. many of the new health biotechnology products in china have such a large market potential that several domestic firms produce them. for example, 16 firms are involved in producing recombinant human granulocyte colony-stimulating factors that stimulate the generation of white blood cells. the large population in china has also attracted many foreign firms, including large pharmaceutical firms that have established joint ventures with chinese companies. this has given china access to new technology and management expertise. expatriates are likely to be a strong driver for promoting innovation in the chinese health biotechnology sector. not only is the large population an asset in marketing products, but also it is an asset in developing and testing them. the country has more than 50 different ethnic groups and a number of homogeneous populations that can make it easier to identify disease genes. this is a great resource to develop therapeutics and diagnostics based on genomics. the large population also makes it easier to arrange clinical trials, and in the age of genomics, targeted clinical trials based on the genomics characteristics of the population will play a key role in health biotechnology. attracting international linkages in terms of researchers and firms based on this advantage is also promising in that, as the chinese population shows an increasing incidence of diseases of relevance to western companies and their markets (e.g., there is a growing rate of cardiovascular disorders in china 25 ), foreign researchers and companies are also to be more likely to form linkages with chinese companies and institutions. the population advantage of china in health biotechnology is therefore likely to increase in the years to come. china rapidly developing biotechnology and bioindustry. beijing. 4 data derived from information (subset of science citation index expanded database) prepared by the institute for scientific information (isi, philadelphia, dc18 volume 22 supplement december 2004 nature biotechnology pa, usa). © institute for scientific information report of the development of bio-tech industry in china the breeding and emergence of patent law of china on the threshhold. the asia-pacific perspective global biotechnology report the research and quality control of medical bio-technology report on the development of venture investment of china's leap forward in biotechnology key: cord-262201-4pab383g authors: wang, lei; zhang, rui-ming; liu, gui-ying; wei, bao-lin; wang, yang; cai, hong-yan; li, feng-sen; xu, yan-ling; zheng, si-ping; wang, gang title: chinese herbs in treatment of influenza: a randomized, double-blind, placebo-controlled trial date: 2010-06-22 journal: respir med doi: 10.1016/j.rmed.2010.05.015 sha: doc_id: 262201 cord_uid: 4pab383g objective: to investigate the efficacy and safety of antiwei, a traditional chinese prescription, in the treatment of influenza. methods: in a multi-center, randomized, double-blind, placebo-controlled trial, we recruited 480 adults aged 18 to 65 years within 36 h of onset of influenza-like symptoms. there were 225 patients with confirmed influenza. eligible patients were randomly assigned 6 g of antiwei (n = 360) or placebo (n = 120) twice daily for three days. all patients recorded their temperature and symptoms on diary cards during treatment. analyses were performed in both the influenza-like population and the influenza-confirmed population. results: antiwei increased patients’ recovery by 17% (p < 0.001), and reduced the severity of illness measured by the median symptom score by 50% (p < 0.001) in both the influenza-like and the influenza-confirmed populations, compared to placebo. the influenza-confirmed patients reported reductions in the severity of fever (p = 0.002), cough (p = 0.023) and expectoration (p = 0.004) after one-day of treatment with antiwei, compared to placebo. the adverse event profiles were similar for antiwei and placebo. conclusion: antiwei was effective and well tolerated in treatment of natural influenza infection in adults. antiwei represents a clinically valuable intervention in the management of influenza. traditional chinese herb; influenza; randomized controlled trial summary objective: to investigate the efficacy and safety of antiwei, a traditional chinese prescription, in the treatment of influenza. methods: in a multi-center, randomized, double-blind, placebo-controlled trial, we recruited 480 adults aged 18 to 65 years within 36 h of onset of influenza-like symptoms. there were 225 patients with confirmed influenza. eligible patients were randomly assigned 6 g of antiwei (n z 360) or placebo (n z 120) twice daily for three days. all patients recorded their temperature and symptoms on diary cards during treatment. analyses were performed in both the influenza-like population and the influenza-confirmed population. influenza caused by infection with either influenza a or b viruses, is one of the most common and important respiratory illnesses affecting all ages. uncomplicated influenza is generally resolved over a 2-to 5-day period, although cough and malaise can persist for weeks. influenza epidemics such as the influenza a (h1n1) pandemic in 2009, which is the first pandemic since 1968, are associated with increased morbidity and hospitalization rates, and excess mortality 1,2 within the most vulnerable populations, including the elderly, infants and those with underlying medical conditions. 3 although drugs such as the adamantanes (i.e., amantadine and rimantadine) and the neuraminidase inhibitors (i.e., oseltamivir and zanamivir) are available to treat or prevent influenza, recent emergence of adamantane resistant strains has rendered these agents less effective. 4, 5 in addition, sporadic cases of oseltamivir-resistant influenza a (h1n1) virus infection have been reported worldwide following the h1n1 pandemic of 2009. 6 even though vaccination strategies against influenza a (h1n1) virus are now present in china, some patients may look beyond conventional treatments and consider complementary and alternative medicines, including traditional chinese medicine (tcm), in this situation. tcm represents one aspect of chinese medical philosophy that is characterized by an emphasis on maintaining and restoring balance. chinese medicinal herbs, the most important component of tcm, are derived from plants and usually incorporate one or more herbs as the basic drugs to treat the disease. 7 supplemental use of chinese medicinal herbs were found to be beneficial in the management of severe acute respiratory syndrome (sars) in 2003 8e10 and, based on that supplementary treatment, chinese medicinal herbs might also show promise for treating or preventing influenza and influenza-like illness. some randomized controlled trials (rcts) have been published, but the evidence for treating or preventing influenza by tcm has not yet been convincingly established, due to poor reporting quality and small sample size. 11, 12 antiwei granule is a traditional chinese prescription, consisting of mahuang (herba ephedra), baimaogeng (rhizoma imperatae), gegen(radix puerariae), guizhi (ramulus cinnamoumum), kuxingren (semen armeniacae amarum.), ganjiang (rhizoma zingiberis) and gancao (radix glycyrrhizae). one gram of antiwei granule equals 3.83 g of crude drug. the resource, pharmacological actions and components in this formula are listed in table 1 . 13 according to tcm, mahuang and baimaogen in this formula, which are regarded as "the principal" herbs, could relieve exterior disorder and defervesce. gegen and guizhi, which serve as "the minister", cooperate with "the principal" to relieve exterior syndrome and defervesce. kuxingren and ganjiang are "the adjuvant drug", which can open the inhibited lung-energy, regulate the flow of qi, eliminate phlegm and relieve cough. gancao serves as "the guiding drug", which can moisten lung to arrest cough and coordinate all of the drug actions of this formula. antiwei has been used widely based on clinical experience rather than the evidence of rcts in the treatment of influenza-like illness (such as fever, headache, pain and cough) in china. 14 therefore, a prospective, multi-center, randomized, double-blind, placebo-controlled clinical trial was undertaken to investigate the efficacy and safety of antiwei granule for the treatment of naturally acquired influenza in humans. patients and ethics eligible patients, who presented with fever over 37.4 c and at least one respiratory symptom (cough, sore throat, or nasal symptom) and at least one constitutional symptom (headache, fatigue, myalgia, thirst or chills), were recruited from emergency departments from january to june, 2007. the inclusion criteria were as follows: (1) clinical diagnosis of influenza; (2) age 18 to 65 years; (3) within 36 h of onset of influenza-like illness; (4) written informed consent. the exclusion criteria were as follows: (1) any treatments after onset of influenza-like illness; (2) other confirmed upper respiratory viral infections; (3) suspected bacterial infection (based on symptoms, leukocyte count > 10.0 â 10 9 /l or neutrophil granulocyte ! 80%); (4) pregnancy or breast-feeding; (5) allergies to food additives, drugs, and any components in antiwei granule; (6) current alcoholism or drug abuse; (7) severe diseases of cardiac, respiratory, hepatic, renal, central nervous system, haematopoietic system cancer; (8) the inability to understand and complete this study; (9) current psychiatric illness or dementia; (10) clinically important chronic illnesses or known hiv infection, receiving steroids or other immunosuppressants, or having been vaccinated against influenza in the previous 12 months. we also required that patients of childbearing age use contraception. to reduce heat in cases of exterior syndrome with fever and painful stiffness of the back and nape; to relieve thirst in febrile diseases and diabetes mellitus; to arrest diarrhea in spleen insufficiency; to promote eruption for measles 16 .48 guizhi the died young stem of cinnamomum cassia presl. (family lauraceae) to induce sweating for releasing the muscles in cases of wind-cold affliction; to warm and unblock the meridians to relieve various pains due to cold and congealing blood; to stimulate menstrual discharge for treating amenorrhea to replenish qi and tonify the heat for treating arrhythmia in cases of heart qi deficiency; to tonify the spleen for treating lassitude, anorexia and loose bowels in cases of spleen insufficiency; to relieve epigastric colic and spastic pain of the limbs; to dispel phlegm and arrest cough; to clear heat and counteract toxin for treating sore throat, boils, sores and drug overdose; most frequently for modulating the ingredients in a prescription data from classified dictionary of traditional chinese medicine by zhu-fan xie. 13 the medical ethics committee of west china hospital at sichuan university approved this study (no. irb-2007-13) , and it is in accordance with the recent principles of the declaration of helsinki. 15 all patients gave informed consent and were free to withdraw from the study at any time. this was a prospective, multiple-center, randomized, double-blind, placebo-controlled trial, which was undertaken at eight chinese centers: three in north china, three in northeast china, one in northwest china, and one in west china. patients were randomized in a double-blind fashion to receive either antiwei granule or placebo. the randomization code was generated by the prco plan of the analysis system of sas (version 6.12 for windows). allocation details were sealed in an envelope, and were unknown both to investigators and participants in this study. antiwei and placebo were supplied by tasly group (tianjin, china), the herbal composition of antiwei is presented in table 1 . the placebo granule was composed of starch and bitter agents, but was visually indistinguishable from the antiwei in appearance, color, size and packaging. the subjects in the antiwei group received 6 g of antiwei granule twice a day for three days, whereas the patients in the placebo group received 6 g of placebo twice a day for three days. all patients were treated in an equivalent fashion. we assessed compliance by daily diary cards and review of the returned medication at the end of treatment. we took present, past and personal medical histories, measured vital signs such as temperature, respiration rate, heart rate and blood pressure, did physical examinations of pharynx, larynx and lung in respiratory system, and collected baseline virological samples before treatment. after accepting treatment, patients recorded their axillary's temperature every 2 h for up to 12 h on day one. on days 2 and 3, they recorded their axillary's temperature at 8am, 10am, 12am, 4pm and 8pm in a diary card. to exclude other respiratory illnesses, subjects received chest x-ray screening before beginning treatment. the presence and severity of influenza symptoms, including cough, sore throat, nasal obstruction and rhinorrhoea, headache, fatigue, myalgia, thirst and chills, were recorded once daily using a four-point scale (0 absent, 1 mild, 2 moderate, and 3 severe). the first record was performed when the patient was admitted, and the next two records (on days 1 and 3 after treatment) were done in the morning. influenza was confirmed by a direct immunofluorescent antibody assay (dfa) of nasopharyngeal swabs, which showed sensitivities of 89.7% for influenza a virus and 87.9% for influenza b virus and specificities of 99.3% for influenza a virus and 100% for influenza b virus. 16 treatment assignment was blinded during virological testing, which was done at west china hospital, sichuan university, chengdu. the primary endpoints were severity of illness (measured by the mean symptom scores for the whole treatment period) and the number of recovered patients in the intention-to treat and influenza-confirmed populations. recovery was defined as absence of fever (temperature < 37.4 c) and all nine symptoms (chills, headache and myalgia, nasal obstruction, sore throat, fatigue, cough, rhinorrhoea, expectoration, and thirst). secondary outcomes included the length of time to alleviate fever within the first 24 h after treatment, the severity of each symptom, and the rate of influenza-viruspositive conversion to negative for the influenza-confirmed population at entry. participants were required to record any unexpected signs, symptoms, or feelings during the treatment period, and routine tests of blood, urine, stool, as well as hepatic and renal functions and electrocardiogram (ecg) were performed at admission and again after treatment to assess safety in both groups. a sample size of 135 for the antiwei group and 45 for the placebo group, at a ratio of 3:1, were calculated according to published data 17 to have a power of 80% or greater to detect a difference of 10 percent in recovery rate, assuming a significance level of 0.05. sample size calculations were performed using a normal approximation to the wilcoxon rank-sum test. influenza-like and influenza-confirmed populations were both analyzed, with the influenza-like population consisting of randomized patients who received at least one dose of medication in this study. safety analyses were performed on those populations, which included all patients who received at least one dose of medication and who had at least one follow-up for safety, whether or not they were withdrawn prematurely. all analyses were performed using stata 11.0. measurement data showing a normalized distribution were described as mean ae standard deviation and analyzed with analysis of variance to determine the difference between the antiwei and placebo group. measurement data showing a non-normalized distribution were described as median and analyzed by the wilcoxon rank-sum test. frequency data were analyzed using the chi-squared (c 2 ) or fisher's tests. the primary endpoints were analyzed using the survival method. kaplanemeier curves were constructed and significance-tested using the log-rank method. for the mean symptom scores we used analysis of variance. the rate of influenza-virus-positive conversion to negative was compared between different groups with c 2 test. p 0.05 for two-tailed tests was considered to be significant. a total of 480 eligible patients were enrolled and randomly assigned to receive antiwei granule (n z 360) or placebo (n z 120). of these, 34 patients withdrew from the study early for several reasons including lost to follow-up (antiwei: n z 6; placebo: n z 7), protocol violation (antiwei: n z 15; placebo: n z 3), and refusal to continue (antiwei: n z 1; placebo: n z 2). overall, 225 (48.2%) patients had laboratory-confirmed influenza (fig. 1 ). of these, 125 (55.6%) had influenza a, 74 (32.9%) had influenza b and 26 (11.5%) had both influenza a and b ( table 2 ). all available data from these patients were included in the efficacy and safety analyses. no differences were observed between two groups in the demographics and clinical characteristics. safety of the study drug was assessed for all 480 patients. for influenza-confirmed patients, antiwei resulted in significantly more patients recovering or showing a reduction in the severity of illness. the number of patients recovering after three days of treatment was 42 of 177 (23.2%) in the antiwei group (p z 0.009) (fig. 2) compared to 3 of 48 (6.25%) in the placebo group, and this benefit was also seen in the patients with influenza-like disease (86/353 vs. 10/114, p < 0.001). similarly, antiwei resulted in significant reductions in the total symptom score after three days of treatment in the influenza-confirmed population (à15.20 ae 6.25 vs. à10.26 ae 7.72, p < 0.001) and in the influenza-like population (à15.07 ae 6.32 vs. à8.81 ae 6.99, p < 0.001) compared to placebo. after one-day treatment, the improved percentage of symptom score (difference between the symptom scores at baseline and after one-day treatment is divided by the symptom score at baseline) in fever (57.9% vs. 34.4%, p z 0.002), cough (32.9% vs. 16.3%, p z 0.023) and expectoration (32.9% vs. 16.3%, p z 0.004) was significantly reduced in the antiwei group compared to placebo in influenza-confirmed patients. there was no statistically significant reduction seen in the severity of chills (34.9% vs. 28 (fig. 3) . at the same time, the median temperature fell by 0.8 c from baseline in the antiwei group but by only 0.4 c in the placebo group (p z 0.0001). treatment benefit for fever was apparent as early as 10 h after the start of treatment (fig. 4) . antiwei treatment resulted in 20% more patients becoming afebrile within 24 h, as compared to placebo (p z 0.011). in the influenza-confirmed population, influenza virus decreased to 27.2% in the antiwei group and 58.7% in the placebo group after three days of treatment (p z 0.001) (fig. 5 ). compliance with medication was high in both treatment groups. the majority patients (n z 446) recorded taking more than 90% of medication. antiwei was generally well tolerated compared with placebo, with no increase in withdrawal rates because of adverse events. one patient given antiwei reported mild paroxysmal palpitation but this resolved within two days and did not result in withdrawal from the study. laboratory results, ecg and vital signs did not differ significantly from baseline between the two groups. most of the patients included in this study came from an epidemic region during the influenza season. 18e23 after dfa screening with nasopharyngeal swabs, the positive rate in our study was 48.2%, which is slightly lower than 61.0% in zambon's study. 24 the oral administration of 6 g of antiwei twice daily was associated with significant clinical and antiviral effects in healthy adults with naturally occurring influenza when given within 36 h of onset and was generally well tolerated. for patients with influenza-like illness, the number of recovered patients after three days of treatment in the antiwei group increased 17% and the severity of symptoms was significantly reduced 50% compared to placebo. after one-day treatment, antiwei's benefit for reducing fever was apparent and the other two key symptoms (cough and expectoration) were significantly improved by the end of treatment. at the same time, antiwei was well tolerated, with safety similar to placebo. since the introduction of tcm to the world, there have been debates regarding a role for herbal medicines in the therapy of illness such as influenza infections. according to treatise on cold-induced diseases (shang han lun), a variety of herbal formulas have been used to treat patients with infectious diseases for over 1800 years. chinese medicine is widely accepted amongst chinese populations. the use of chinese medicine in treating pandemic and endemic diseases has long been described in traditional medical books such as shang han lun, and huangdi's canon of medicine (huangdi nei jing). the prescriptions for infectious diseases were made based on the clinical presentations, rather than laboratoryconfirmed pathogens, which were beyond their knowledge at that time. only a small fraction of the thousands of medicinal plants used worldwide has been tested rigorously in randomized, placebo-controlled trials. yet randomized, controlled trials are the best way to demonstrate the efficacy of any medical, herbal or conventional therapy. 25 although herbs or herbal products, as part of complementary and alternative therapies, have been proposed, their effectiveness in treating or preventing influenza has not been established beyond reasonable doubt. 11 the extract of elderberry was used to treat the influenza in the past, 26 and two studies have demonstrated a significant benefit of herbal products in prophylaxis against viral infection. 27, 28 herbal supplement users have also reported significant improvement in influenza-like symptoms such as chills, cough, fatigue, and headache and quality-of-life measures such as mental health score, 27 as they have in our study. figure 3 improved percentage in symptom scores after oneday treatment in influenza-comfirmed patients. *p < 0.05, placebo vs. antiwei. improved percentage in symptom scores defines that difference between the symptom score at baseline and after one-day treatment is divided by the symptom score at baseline. a variety of chinese herbs have been widely used as antipyretic drugs for clearing accumulated heat in the lungs, according to the theory of tcm. one recent study by kubo t. et al. showed that there is a more antipyretic effect of mao-to, a japanese herbal medicine, for treatment of type a influenza infection in children, in comparison to oseltamivir. 29 the japanese traditional herbal medicine includes mahuang, guizhi, kuxingren and gancao, which as components were included in antiwei. in our study, the antipyretic effect was apparent within 24 h of antiwei administration, when influenza symptoms are generally most troublesome. although we did not assess economic effects, the indirect costs of influenza such as workplace absenteeism and performance at work could be improved according to the clinical benefits observed in the influenza-confirmed population and in the population with influenza-like illness. 30 studies in animal experiments and in vitro, have confirmed that antiwei can inhibit growth of a variety of virus, including influenza a and b, respiratory syncytial virus (rsv), adenovirus etc (data not shown). we now show that antiwei can significantly reduced the positive rate of influenza virus after treatment. these findings are consistent with results from studies of other antiviral drugs for influenza and other self-limiting viral diseases, for which increased therapeutic benefit is obtained when treatment is started as early as possible after symptom onset. 31 the duration of cough and expectoration was shorter and the severity of the two symptoms was generally lower in the antiwei groups (data not shown). influenza is transmitted by virus-laden secretions. cough and expectoration could be the most distressing symptoms of influenza and also contributes to the spread of infection. patients who received antiwei had significantly lower positive rate of virus on laryngopharynx swabs than those in the placebo group. such differences, together with improvement of symptoms, including cough and expectoration, may help to reduce transmission of the virus. antiwei was generally well tolerated, with almost no adverse events reported. only one patient given antiwei reported mild paroxysmal palpitation, which was resolved within two days without additional treatment. this symptom was not associated with discontinuation rates in the antiwei group compared to placebo. no other adverse effects or abnormalities in laboratory test were associated with antiwei treatment. it must be noted that the antiwei contains mahuang, which has been reported to have some side effects (such as chest pain, hypertension, arrhythmia, myocardial infarction, stroke, or death 32 ) when served as a dietary supplement for weight reduction and performance enhancement, but the use of mahuang in this study was not associated with any significant adverse events. in our prescription, 6 g of antiwei equals to 23 g of crude herbs, in which there is 2.5 g of mahuang, so the daily dose of mahuang was only 5.0 g, which is a small dosage compared with the conventional dose in other tcm treatments. we recognize that this study does have some potential limitations. we did not include follow-up after treatment, and the symptoms of influenza were observed for only 4 days, thus by the end of study many patients had not fully recovered. therefore, the duration of illness and the time of alleviation could not be exactly evaluated. in addition, the protocol specifically excluded individuals with medical conditions which would place them in high-risk populations that are often associated with more severe influenza. in conclusion, our study clearly indicated that antiwei was an effective treatment of influenza-confirmed and influenza-like illness in otherwise healthy adults, and antiwei can provide an alternative to conventional treatment for influenza or influenza-like symptoms. antiwei might also be a potent medication for use in influenza pandemics and in situations where a shortage of antiviral agents and vaccines exists. our findings provide a rationale for continuing studies of this agent in the treatment of influenza, and these should now include studies in children and in high-risk populations. further large-scale studies to investigate the other antiviral effect of antiwei, and studies of its mechanism(s) are also now required. intensive care adult patients with severe respiratory failure caused by influenza a (h1n1)v in spain the transmissibility and control of pandemic influenza a (h1n1) virus epidemiology of influenza high levels of adamantane 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medicine traditional chinese medicine in cold-pestilential pathogen and severe acute respiratory syndrome the declaration of helsinki direct detection of influenza virus antigen in nasopharyngeal specimens by direct enzyme immunoassay in comparison with quantitating virus shedding a multiple center, randomized, controlled, double-blinded and double-dummy trial of yiqing shuangjie capsule and tablet in treating acute upper respiratory tract infection with the syndrome of heat attacking the lung and weifen (chin) analysis of the antigenic and genetic characteristics of influenza virus subtype a3 circulated in sichuan province during analysis of surveillance of influenza in xinjiang from analysis of influenza surveillance in sichuan province analysis of influenza surveillance in changchun during analysis of surveillance of influenza in tianjing from analysis of influenza surveillance in changchun during diagnosis of influenza in the community: relationship of clinical diagnosis to comfirmed virological, serologic, or molecular detection of influenza herbal remedies inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (sambucus nigra l.) during an outbreak of influenza b pannama the use of an herbal formula by hospital care workers during the severe acute respiratory syndrome epidemic in hong kong to prevent severe acute respiratory syndrome transmission, relieve influenza-related symptoms, and improve quality of life: a prospective cohort study efficacy and safety of the standardised ginseng extract g115 for potentiating vaccination against the influenza syndrome and protection against the common cold antipyretic effect of mao-to, a japanese herbal medicine, for treatment of type a influenza infection in children the impact of influenza and influenza-like illness on productivity and healthcare resource utilization in a working population efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections ephedra-containing dietary supplements in the us versus ephedra as a chinese medicine the authors would like to thank ms. feng m. and mr. she b. for their work in documenting the data, he clara, phd. and none declared. key: cord-315997-x7gf49qz authors: li, li-juan; chen, xuan; yang, wen-na; xu, xiang-mei; lu, li-ying; wang, jie; kong, yi-xuan; zheng, jing-hui title: traditional chinese medicine for the treatment of pulmonary fibrosis: a protocol for systematic review and meta-analysis of overview date: 2020-07-31 journal: medicine (baltimore) doi: 10.1097/md.0000000000021310 sha: doc_id: 315997 cord_uid: x7gf49qz background: since december 2019, there have been many cases of viral pneumonia of unknown causes in wuhan city, hubei province. during the period of novel coronavirus, according to the observation of limited autopsy and biopsy pathological results, pulmonary interstitial fibrosis appeared in some pathological changes of lung. idiopathic pulmonary fibrosis (ipf) is a chronic progressive interstitial pneumonia with unknown etiology and pathological changes limited to the lung. at present, there is still a lack of reevaluation of systematic evaluation of traditional chinese medicine treatment ipf. therefore, a systematic re-evaluation of the systematic evaluation of traditional chinese medicine in the treatment of pulmonary fibrosis may help to understand the effective treatment scheme of traditional chinese medicine in the treatment of pulmonary fibrosis and provide more reliable evidence for the first-line clinicians to treat novel coronavirus. methods: we will search 3 foreign electronic databases (cochrane library, embase, pubmed) and 4 chinese electronic databases (china national knowledge infrastructure [cnki], wangfang database, chinese biomedical literature database [cbm], and chinese scientific journal database [vip]) to collect potential systematic reviews from their inceptions to february 2020. the language of publication is limited to chinese or english. we will consider srs and meta-analysis of traditional chinese medicine for the treatment of pulmonary fibrosis. two reviewers will identify relevant studies, and then assess the methodological quality by assessment of multiple systematic reviews-2 tool. using the preferred reporting items for systematic reviews and meta-analyses (prisma) report checklist to assess the quality of reports included in the study. in order to better evaluate the systematic evaluation included in this research, risk of bias in systematic review tool is included in this research to evaluate the methodological quality. the quality of evidence of the included systematic reviews was assessed by the grading of recommendations assessment, development and evaluation (grade) approach. the primary outcomes include: clinical total effective rate, curative effect of tcm symptoms, pulmonary function and blood gas analysis. results: the results of this study will be published in a peer-reviewed journal. conclusions: we expect to obtain reliable evidence from systematic analysis of traditional chinese medicine treatment of pulmonary fibrosis in an available and useful document. registration number: inplasy202060029 since december 2019, there have been many cases of viral pneumonia of unknown causes in wuhan city, hubei province. [1] on february 11, the world health organization (who) officially named the disease caused by novel coronavirus infection as "covid-19". the new coronavirus and sarsr-cov and mersr-cov belong to the coronavirus. fever, dry cough and fatigue are the main manifestations of the cases. severe patients may develop dyspnea, acute respiratory distress syndrome, etc. [2] during the period of novel coronavirus, according to the observation of limited autopsy and biopsy pathological results, pulmonary interstitial fibrosis appeared in some pathological changes of lung. [3] idiopathic pulmonary fibrosis (ipf) is a chronic progressive interstitial pneumonia with unknown etiology and pathological changes limited to the lung. its histopathology or high-resolution ct manifestations are common interstitial pneumonia, with dry cough without sputum or only a small amount of foam sputum, chronic progressive dyspnea and systemic fatigue as the main clinical symptoms. [4] ipf mainly occurs in adults, males outnumber females, and most of them have a history of smoking. [5] moreover, ipf is related to family gene abnormality and is a malignant progressive interstitial pneumonia. [6] the typical manifestation is occult dyspnea in patients aged 60 to 70 years old. [7] pulmonary fibrosis is the replacement of healthy tissues by altered extracellular matrix, destruction of alveolar structure, resulting in decreased lung compliance, interruption of gas exchange, and eventually respiratory failure and death. [8] the average survival rate of clinical manifestations is 2 to 5 years. [9] there is no name for pulmonary fibrosis in ancient chinese medical literature. according to chinese medical literature and clinical manifestations of the disease, doctors attribute it to diseases such as "lung flaccidity", "lung arthralgia", "asthma", "cough" and "lung distension", while most doctors attribute the disease to "lung flaccidity." [10] severe acute respiratory syndrome (sars), which broke out as early as 2002, can lead to pulmonary fibrosis due to the further aggravation of pulmonary exudation. [11] studies have shown that sars may cause the proliferation of fibrous cells in alveolar septa to form septa fibrosis, which continuously fuse with each other, further compress alveolus to shrink them, eventually turning large areas of lung tissue into solid fibrosis areas, completely losing ventilation/ventilation function, and causing extremely difficult breathing. [12, 13] the results of zhang and zhang [14] clinical trials show that the traditional chinese medicine compound 861 granule is effective in treating pulmonary fibrosis or pulmonary fibrosis caused by sars. the results of he et al [15] clinical trial show that the combination of traditional chinese and western medicine can improve the patient's condition and shorten the course of disease. chest imaging shows that the degree of pulmonary fibrosis is reduced. the treatment of sars by integrated traditional chinese and western medicine is generally superior to the treatment of western medicine alone in terms of fever, improvement of dyspnea and other symptoms, acceleration of lung lesion absorption, reduction of complications and so on. [16] after first-line clinicians took drugs, it was found that traditional chinese medicine had obvious effect on novel coronavirus. therefore, the experts on traditional chinese medicine medical treatment and rehabilitation in state administration of traditional chinese medicine recommended compre-hensive intervention strategies based on traditional chinese medicine, traditional non-drug therapy, psychology, diet and exercise techniques after systematic demonstration. [17] in recent years, with the development of traditional chinese medicine research, a large number of traditional chinese medicine preparations have been applied to the clinical practice of ipf, and their effectiveness and safety are also widely concerned. traditional chinese medicine has obvious clinical effect and less adverse effect on ipf, and has significant effect on helping patients to improve clinical symptoms and quality of life. in recent years, a number of rct have been completed to verify the total effective rate, lung function and curative effect of traditional chinese medicine in treating ipf, and a number of systematic reviews (srs) based on traditional chinese medicine in treating ipf have been published. however, the relevant sr was published in different years, with various kinds of traditional chinese medicines included, different outcome indicators and no unified conclusion. at present, there is still a lack of reevaluation of systematic evaluation of traditional chinese medicine treatment ipf. therefore, a systematic re-evaluation of the systematic evaluation of traditional chinese medicine in the treatment of pulmonary fibrosis may help to understand the effective treatment scheme of traditional chinese medicine in the treatment of pulmonary fibrosis and provide more reliable evidence for the first-line clinicians to treat novel coronavirus. based on the fact that novel coronavirus has pulmonary interstitial fibrosis in part of the pathological changes of lung, and the effect of traditional chinese medicine on novel coronavirus is obvious at present, this study mainly discusses the systematic evaluation of traditional chinese medicine on pulmonary fibrosis for re-evaluation, and finally analyzes the clinical total effective rate, lung function, curative effect of traditional chinese medicine symptoms, blood gas analysis and other outcome indicators. this protocol was recorded in the international platform of registered systematic review and meta-analysis protocols (inplasy), registration number inplasy202060029. and if there are any changes, we will describe it in our full review. ) to collect potential srs) from their inceptions to february 2020. the language of publication is limited to chinese or english. the following search terms will be used: chines medicine, traditional chinese medicine, pulmonary fibrosis, meta-analysis, meta-analysis, meta analyses, systematic review, srs, etc. a draft search strategy using pubmed, one of the planned electronic databases to be searched, is presented in table 1 . the bibliographies yielded by the literature search will be imported into endnote for management. two reviewers (llj and ch) will independently read the literature titles, abstracts, and full texts, in sequence, to identify eligible srs. any differences will be resolved through discussion to reach a consensus or by using a third author (zjh) to adjudicate. the planned selection process is shown in a flow chart (fig. 1) population, intervention, comparison, outcome and study (picos) strategy was employed. systematic review/meta-analysis based on randomized controlled trials (rct). according to the diagnostic criteria of pulmonary fibrosis, the patient's sex, age, race, onset time and source of cases are not limited. traditional chinese medicine preparation (such as traditional chinese medicine decoction, chinese patent medicine, traditional chinese medicine monomer, etc.) or traditional chinese medicine combined with western medicine is used for routine treatment. use conventional western medicine, placebo or blank control therapy. 3.9. types of outcome measurements 3.9.1. primary outcomes. clinical total effective rate, curative effect of tcm symptoms, pulmonary function and blood gas analysis. 3.9.2. secondary outcomes. 6-minute walking test, quality of life, adverse reactions. repeated publication of documents; conference papers and comments, etc.; documents whose data cannot be extracted; intervention measures are other tcm therapies, such as acupuncture, massage, etc. systematic evaluation of other basic diseases with pulmonary fibrosis; non-chinese and english literature. two reviewers (ywn and xxm) will independently extract the following data: authors' name, publication year, country, language, sample size, participants, intervention(s), comparison (s), outcome(s), and some relevant characteristics from the fulltext. if the data reported is insufficient or missing, wj will attempt to contact the author for further information to supplement the missing data. in case of any divergence, we will resolve it through discussion and decision by both parties or by consensus with the third reviewer (kyx). 3.11. evaluation of the methodological quality of the included studies 3.11.1. assessment of multiple systematic reviews-2 measurement tool. this study used amstar2 measurement tool to evaluate the methodological quality of the incorporated system evaluation. [18] multiple system evaluation (amstar) is a reliable methodological quality evaluation tool. [19] during the use of amstar measurement tool, researchers pointed out that the items are difficult to understand and the evaluation options are inappropriate, thus affecting the accuracy of the evaluation results. [20, 21] amstar-2 is an update of amstar, which can be used to appraise srs of both randomized and non-randomized controlled trials. [22] at present, there are 40 quality evaluation tools, [23] among which amstar tool is widely used and is considered to have good reliability, structural validity and practicability. [24] amstar-2 includes 16 items, with each of the 16 criteria given a rating of "yes" (definitely done), "no" (definitely not done), "can't report" (unclear if completed), or "not applicable" based on information provided by the srs on which reviewers put an evaluation when the criterion is met. 3.11.2. preferred reporting items for systematic reviews and meta-analyses (prisma) item. in order to reflect the integrity and transparency of this study, two authors (llj and lly) of the overview will independently evaluate the reporting quality in each review included to assess whether they met the criteria specified in the prisma. [25] in case of any difference, it will be settled through discussion between them and arbitrated by a third general author (cx) if necessary. 3.11.3. risk of bias in systematic review tool. in order to better evaluate the systematic evaluation included in this research, robis is included in this research to evaluate the methodological quality. the development of robis tools is divided into four stages, [26] and the whole process is scientific, rigorous and transparent. robis tool is mainly used to evaluate the bias risk of systematic evaluation. it is not only used to evaluate the bias risk in the production process and result interpretation process of various systematic evaluations including intervention, diagnosis, etiology and prognosis, but also used to evaluate the correlation between systematic evaluation problems and practical problems to be solved by users. [27] 3.11.4. evaluation of the evidence quality of the included studies. the quality of evidence of the included srs was assessed by the grading of recommendations assessment, development and evaluation (grade) approach. [28] the overall quality of evidence was judged as "high," "moderate," "low," or "very low." factors leading to rct degradation include limitations of research, inconsistency of research results, uncertainty as to whether it is direct evidence (indirect or indirect), insufficient accuracy or wide confidence interval (imprecise), and publication bias. limitations of this study: due to language limitations, this study only included systematic evaluation in both chinese and english, and did not search for relevant gray literatures, which may lead to the risk of missed detection; the number of documents included is limited, and there may be low quality of documents, which may affect the accuracy of results. it is possible that the appraisers are subjective in the evaluation of the most moderate quality, which leads to bias and thus affects the final evaluation results. the purpose of this study is to reevaluate the existing systematic evaluation of traditional chinese medicine in the treatment of pulmonary fibrosis. in recent years, a number of rct have been completed to verify the total effective rate of traditional chinese medicine in the treatment of ipf, lung function, curative effect of traditional chinese medicine symptoms, etc., and a number of sr based on traditional chinese medicine in the treatment of ipf have been published. however, the relevant sr was published in different years, with various kinds of traditional chinese medicines included, different outcome indicators and no unified conclusion. at present, there is still a lack of reevaluation of systematic evaluation of traditional chinese medicine treatment ipf. at present, during the period of novel coronavirus, novel coronavirus may lead to the formation of pulmonary interstitial fibrosis, and clinical medication shows that chinese medicine has obvious effect in treating novel coronavirus. therefore, this article evaluates the methodological quality and evidence quality of the published sr of chinese medicine in treating ipf, and provides reference for the prospect and future research of chinese medicine in treating ipf during the period of novel coronavirus treatment. author contributions epidemiological and clinical features of the2019 novel coronavirus outbreak in china general office of national health committee general office of national health committee the rising incidence of idiopathic pulmonary fibrosis in the u.k management of patients with idiopathic pulmonary fibrosis in clinical practice:the insights-ipfregistry drug therapy for idiopathic pulmonary fibrosis idiopathic pulmonary fibrosis in us medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival idiopathic pulmonary fibrosis idiopathic pulmonary fibrosis on "lung flaccidity" in traditional chinese medicine and "pulmonary fibrosis general office of the ministry of health of the people's republic of china. clinical diagnostic criteria for infectious atypical pneumonia. ministry of health of the people's republic of china the clinical pathology of severe acute respiratory syndrome (sars): a report from china lung pulmonary pathology of severe respiratory syndrome study on diagnosis and treatment of pulmonary fibrosis in recovery period of sars by integrated traditional chinese and western medicine discussion on sars treatment by combination of traditional chinese and western medicine stage treatment of sars by integrated traditional chinese and western medicine interpretation of "suggestions on rehabilitation of traditional chinese medicine in recovery period in novel coronavirus (trial) interpretation of amstar 2, a qualitative evaluation tool for systematic evaluation of random or non-random preventive research development of amstar: a measuring tool for evaluating the quality of system review methods critical appraisal of amstar: challenges, limitations, and potential solutions from the perspective of an assessor from systematic reviews to clinical recommendations for evidence-based health care: validation of revised assessment of multiple systematic reviews (r-amstar) for grading of clinical relevance interpretation of system evaluation methodology quality evaluation tool amstar 2 robis:anew tool to assess risk of bias in systematic reviews was developed amstar is a reliable and valid measurement tool to assess the methodological quality of systematic reviews entries for priority reports of systematic reviews and meta-analyses: prisma statement guidance for developers of health research reporting guidelines robis: a new tool for systematic evaluation of bias risk methods for formulating clinical practice guidelines -grade method theory medicine (2020) 99:31 www.md-journal key: cord-269958-nj0ub9in authors: woods, eric taylor; schertzer, robert; greenfeld, liah; hughes, chris; miller‐idriss, cynthia title: covid‐19, nationalism, and the politics of crisis: a scholarly exchange date: 2020-07-19 journal: nations natl doi: 10.1111/nana.12644 sha: doc_id: 269958 cord_uid: nj0ub9in in this article, several scholars of nationalism discuss the potential for the covid‐19 pandemic to impact the development of nationalism and world politics. to structure the discussion, the contributors respond to three questions: (1) how should we understand the relationship between nationalism and covid‐19; (2) will covid‐19 fuel ethnic and nationalist conflict; and (3) will covid‐19 reinforce or erode the nation‐state in the long run? the contributors formulated their responses to these questions near to the outset of the pandemic, amid intense uncertainty. this made it acutely difficult, if not impossible, to make predictions. nevertheless, it was felt that a historically and theoretically informed discussion would shed light on the types of political processes that could be triggered by the covid‐19 pandemic. in doing so, the aim is to help orient researchers and policy‐makers as they grapple with what has rapidly become the most urgent issue of our times. covid-19 reinforce or erode the nation-state in the long run? together, these questions allow the contributors to reflect on how covid-19 may affect nationalism and the nation-state and how these core aspects of politics will in turn shape the response to covid-19. the first question asks contributors to explain how they understand nationalism, how it may shape the response to covid-19 and whether covid-19 will in turn impact on nationalism. in their replies, greenfeld, hughes and miller-idriss discuss the ways in which nationalism is shaping the response to the pandemic. greenfeld argues that ethnic nationalism is a key variable shaping the responses of many states to covid-19 when compared with previous pandemics such as h1n1. miller-idriss strongly agrees and points out that states led by populist nationalists are faring much worse than others. hughes picks up on these themes by arguing that the medical and health care response is being 'weaponized' to support nationalist aims. on the other hand, the contributors argue that covid-19 will also shape nationalism. on this point, woods and schertzer put forward a typology for analysing how the pandemic could affect the development of nationalism, arguing that it could be constitutive, amplifying or transformative. ultimately, among these three possible trajectories, they argue that the most likely impact of the pandemic will be to amplify existing ethnic and national cleavages. miller-idriss joins woods and schertzer in highlighting this amplifying effect by pointing to rising anti-immigrant, xenophobic and conspiratorial anti-state sentiments in many states in the wake of covid-19. hughes takes a slightly different view here by drawing attention to the potential for covid-19 to act as a transformative moment in chinese nationalism that revolves around pride for containing the virus. the second question asks contributors to reflect upon one of the most pressing issues on people's minds today-the potential for covid-19 to trigger and enflame ethnic and national conflict. several commentators have already raised the possibility of large-scale global warfare, given parallels to the decades following the spanish flu in 1918 and the economic ruin of the interwar period. however, there are many different types and levels of conflict: ethnic and national conflict has external (interstate) and internal (intrastate) dimensions, and it runs the gamut from largely peaceful political conflict to outright violence and warfare (schertzer & woods, 2011) . in their responses, the contributors consider these differing dimensions of conflict. focusing on the potential for covid-19 to exacerbate conflict between china, hong kong and taiwan, hughes notes how the pandemic has already provided the chinese government with a pretext for accomplishing its nationalist aims of integrating the territories with the mainland. on the other hand, hughes observes that taiwan has also used covid-19 to secure greater visibility in the international arena. this, in turn, risks drawing in more state actors, to become a larger interstate conflict between china and the west, particularly with the united states. on this score, greenfeld agrees that covid-19 risks amplifying conflict between china and the united states. greenfeld also comments on the possibility of the pandemic amplifying ethnic nationalism leading to the persecution of ethnic minorities. miller-idriss similarly focuses on the potential for covid-19 to increase persecution of minorities, noting the rise in anti-asian racism in the united states. however, for miller-idriss, it is in the fragile states of the global south where the risks of nationalist and ethnic conflict are greatest. for their part, woods and schertzer discuss many of these same themes, highlighting the specific risks that occur when a "politics of blame" is combined with nationalism. they argue that this combination can increase the risks of conflict with individuals and communities who are perceived as 'others.' finally, the third question asks contributors to project forward and reflect on whether the pandemic will have a lasting impact on the building block of our international order-the nation-state. as noted above, covid-19 arrived in a world where nationalism, trade protectionism and migration controls were on the ascent. it is possible that the pandemic will amplify these forces, leading nation-states to turn further inward. at the same time, the global nature of the virus may force international collaboration to mount an effective response. among these possible futures, no matter how much upheaval that may be caused by covid-19, greenfeld doubts that it will shake the ideal of the nation-state as a vehicle for securing the identity and dignity of its citizens. quite the opposite, greenfeld suggests that the pandemic will work to erode global institutions. here, hughes broadly agrees with greenfeld, while also highlighting the ways in which the response to the pandemic could be used as a cover to strengthen the nation-state. hughes also warns that even the scientific community may not be immune to a process of nationalization. miller-idriss parts ways from greenfeld and hughes by suggesting that while the powerful nation-states may be strengthened by covid-19, it is likely that the pandemic will erode the more fragile states of the global south. woods and schertzer pick up on this theme, while also pointing to a range of potential threats that covid-19 may throw at the nation-state, whether "from above" by neo-imperialisms or "from below" by new nationalist movements. however, while these threats may undermine some individual nation-states, they argue, like greenfeld, that this will not necessarily erode the potency of the nation-state as an idea. to answer these questions, as any question regarding the relationship between nationalism and other phenomena, it is necessary, first, to have a clear understanding of how cultures and societies function and evolve, in general, and of the nature of the cultural and social phenomenon of nationalism, specifically. to address these issues in 2,000 or so words fully is impossible, so i shall only state the empirical conclusions of my investigations and proceed on this basis. even these introductory remarks, however, must be introduced with a methodological consideration. when i am talking about a clear understanding, i do not mean to say "my understanding"; this would be tantamount to a chemist, for instance, saying "my understanding of gas is such and such," presuming that someone else's understanding is expected to be different. rather, assuming that cultures, societies and nationalism, just like gases, are empirical phenomena, i am approaching social and historical facts, following classical methodological recommendations, as things, without any prejudgement (bloch, 1964; durkheim, 2014) . the cultural (social, political, economic, etc.) process occurs simultaneously on the level of the individual mind and the collective level of the surrounding culture and consists of the constant give and take between these two levels. every collective trend begins with a new individual experience, to which the mind will react using existing cultural resources, but the reaction may be creative, that is, unpredictable. if the experience is sufficiently provocative and common, a new interest may transform this creative individual reaction into a shared ideal, eventually resulting in a new way of thinking and acting, that is, give rise to a new social institution, adding to the cultural resources and changing the institutional structure-the nature-of a society (greenfeld, 2013 (greenfeld, , 2016 (greenfeld, , 2019 . this, in most basic terms, is how societies change and evolve, in general, and how nationalism evolved, in particular. in regard to nationalism, specifically, one must keep in mind the following. (a) it is a historical, modern phenomenon: before the 16th century, there were no nations. (b) it is essentially a way of thinking, the basis of any institutional structure-thinking that the social world is naturally divided into sovereign communities of fundamentally equal members (communities called nations) and that a just society, consistent with the human nature, therefore, is an egalitarian society based on the principles of popular sovereignty. (c) as a result, nationalism implies democracy, every nation being a democratic society by definition. (d) the democratic/national principles of fundamental equality of membership and popular sovereignty can be interpreted and implemented differently, producing several types of nationalism: not every nationalism is ethnic. in the monotheistic civilization alone, in which ethnic nationalism is indeed the most common type, there exist two other types of nationalism: individualistic nationalism (such as the original english one) and collectivistic-civic nationalism (such as the french). (e) the broad appeal of nationalism is due to the fact that fundamental equality of membership in the nation and the consciousness of popular sovereignty dignify personal identities of members of the nation (greenfeld, 1992) . in this framework, we can examine the relationship between nationalism and covid-19. let us begin with the possible effects of nationalism on the course of the pandemic. the course of the pandemic was certainly affected by the ways it was handled in different countries, and the way it was handled, i would argue, was a direct function of nationalism, specifically, of the national conflict between china and the united states. what leads me to say this? the comparison between coronavirus and previous pandemics: be it h1n1, sars, mers, ebola, hiv-aids of the recent decades, or such historically remote lethal attacks of infectious disease as the spanish flu of the last century or the plague (black death) in the middle ages. none of the previous pandemics involved worldwide lockdowns, cessation of normal activities and massive statesponsored and state-controlled mitigation. both the black death, which, incidentally, also came from china, and the spanish flu were incomparably more lethal than coronavirus: the plague would kill one in two people, 50%, in settlements it reached; if one contacted it, the fatality rate was between 85% and 100%. yet, only a few governments, such as that of the city of milan, ruled by a most brutal dictator, attempted to mitigate (benedictow, 2004) . of course, one can argue, no government at the time but a brutal dictatorship in a small city-state had the means to control its population (and the spread of the disease) to the extent that nationstates of today have. but this cannot be said of the influenza of 1918 and even less of recent pandemics (sars, h1n1, etc.), when the means of disease control at the disposal of governments were identical to what they are now. sars and h1n1, for instance, were at least as frightening as coronavirus (snowden, 2019) . but no worldwide panic ensued. neither the world economy nor that of any separate nation came to a standstill. one may argue that all of the recent pandemics proved far less devastating than was originally expected. but mitigation of coronavirus on a massive, coordinated scale began before it was known how devastating it might be (which is still not really known): reports that china was investigating a respiratory illness in wuhan appeared only on december 31, 2019. the chinese government imposed a lockdown on the 10-million-large city of wuhan on january 23, 2020. on january 29, when only one case of infection on the american soil was identified, the coronavirus task force was created in the united states, and on january 31, a ban on travel from china was imposed. closure of inessential businesses and schools, stay-at-home orders and construction of new medical coronavirus-ready facilities in record-breaking times followed. although the response of some other countries (japan, south korea and taiwan in the immediate vicinity of china, but also italy) was independent, most of the world was directly influenced by the reaction of china and the united states. within the first two months of the pandemic, economies contracted around the world, registering negative growth, unemployment skyrocketed, lives were universally disrupted, leaders interpreting this as they would results of a war on domestic soil and publics taking this in stride as they would indeed a war effort. what was different in the cases of h1n1, for instance, and coronavirus in the first two months of the declared pandemic? nothing. the difference in the reaction was not a function of the known difference in the nature or threat of the virus; it was a function of a difference in the political configuration of the world at the two points in time when the virus appeared. in april 2009, when h1n1 was first reported, the united states was still the one uncontested (though resented and attacked) superpower in the world. no nation yet took the place of the soviet union vis-à-vis it, challenging its position as the world's leader and arbiter. the superiority, the dignity and authority of the united states were beyond competition, if not beyond idle question. in 2020, this was definitely not so. china, which only announced its nationalism in 2008 at its coming out party during the beijing olympics, has been steadily and at an increasing speed gaining on the united states in this competition in the past 11 years, and the chief american national interest-the interest in superiority, dignity and authority-was now at stake. chinese leadership used coronavirus (whether intentionally or not) to challenge the united states to a single combat, so to speak. could you match us, president xi essentially offered, in containing a pandemic? the united states could no more disregard this challenge than it could disregard the sputnik in 1957. and so, the public health race started: who could build a larger hospital in a shorter period of time, produce more ppe, administer more tests, stop outbreaks sooner and ensure more cooperation from the population? what could the rest of the world do, but follow the example of the two giants, disputing who would preside over it past 2020? now let us address the question of the possible effects of the pandemic on nationalism. would it, for instance, strengthen nationalist and especially ethnic-nationalist conflicts? given the news reaching us from washington and beijing, it seems clear that it has strengthened the nationalist conflict between the united states and china, which is as momentous as a nationalist conflict for the world today, as the nationalist conflict between the united states and russia (ruling over the soviet union) was at the time of the cold war. it is also quite clear that the pandemic had brought to the surface the nationalist conflicts within the eu, undermining the confidence in globalization in the one region which has been seen by experts as its empirical proof-the proof that human society was becoming transnational, transcending its national stage and moving towards a global community-and even among its staunchest erstwhile supporters. the universal reversion to nationalist policies and defence of particularistic national interests at the expense of transnational solidarity during the pandemic, however, only proved that rumours of nationalism's demise in the core western european nations have been grossly exaggerated. widespread manifestations of euroscepticism, such as strong national feeling in france, italy, the netherlands and so on, or even brexit, have not been regarded by theorists of globalization as an empirical contradiction of their theoretical position, but as proof of reactionary, right-wing or even extreme right political agenda of populist leaders and benighted, false consciousness among their uneducated followers. now it is obvious to all that the theorists were wrong (though how long this would remain obvious is another question): thanks to the pandemic, globalization today no longer seems the obvious current stage of human development, and nationalism no longer appears as the stage obviously transcended. nationalism in western europe (in distinction to central and eastern europe, for instance) has traditionally not been ethnic however, but rather individualistic, as in britain, or collectivistic-civic, as in france, italy and spain. would the pandemic fuel ethnic nationalist conflicts? the psychological foundation of ethnic nationalism is ressentiment, that is, existential envy, which is most efficiently assuaged by the humiliation to the point of elimination of the envied other; therefore, ethnic nationalism is inherently aggressive (greenfeld, 1992; greenfeld & chirot, 1994) . where it exists, anything can serve as fuel for ethnic aggression. the pandemic has already added to anti-semitic conspiracy theories (very much in line with medieval poisoning of the wells narrative born during the black death) in palestine and among certain publics in europe (adl, 2020). anti-semitism, of course, is the most deeply embedded institution (established way of thinking and acting) in the monotheistic world, predating nationalism by many centuries-and for this reason offering a particularly virulent and reliable channel of expression to ethnic nationalism-but one can imagine temporary flare-ups of less widespread ethnonational hostilities, in which a group identifies the object of ethnic national antagonism as the carrier of the virus. and, finally, will covid-19 reinforce or erode nation-state-that is, nationalism, nationalist institutions-in the long run? leaving aside the question of what can be said about the long run, in general, we should consider this in the wider framework of processes involved in social change, briefly sketched above. to use the most striking example of the social disruption caused by a sudden assault of infectious disease, the black death, the plague might have disrupted the medieval society of orders and shaken this social structure. land became cheap and labour dear, which allowed people from the lower classes to behave as if they belonged to the upper ones and encouraged intermarriage between poor noblemen and daughters of rich commoners. however, as with a dilapidating building, the unravelling of society did not in itself provide any orientation for reconstruction. the thinking remained the same, and for several centuries after the plague years of 1348-1350, the reconstruction took the form of piecemeal patch-ups: sumptuary laws characterized the period, reflecting both that the old order was unravelling and that the only way society was imagined was exactly as it had been before the pandemic (cantor, 2001; cohn, 2010; herlihy, 1997) . only when reality was reimagined and new (national, as it happened) consciousness appeared did the direction of reconstruction became clear and set. institutions, which, as already durkheim emphasized, are just established ways of thinking and acting, are never stable-they are always in the process of waxing and waning, strengthening, weakening and modifying. conceptualization-ways of thinking, that is, to use weber's terminology, ideals, especially if encoded in laws, sacred texts, whether religious or secular, such as the american declaration of independence, popular and high culture, and so on-is always their strongest feature, but can rapidly be abandoned, if the interests supporting these ideals disappear. the interest behind nationalism and its institutions (e.g., nation-state)-dignity of personal identityis alive and well. covid-19 also ranged behind it the essential material interests (health, life and livelihood), pointing at the same time to the inability of transnational institutions-globalization-to serve these interests. it is transnational institutions, rather than nation-state, that are likely to fall victim to the pandemic. i would like to interpret the three questions as addressing national identity, policy-making and state-building, respectively. greenfeld is right to highlight how covid-19 has been politicized by growing tensions between the united states and china over a range of issues. this can be explored further by looking at the way in which covid-19 is being used in a process of mutual identity construction, which makes it impossible for medicine and science to be politically neutral. a good starting point is the naming of the virus. who has been aware that identifying the geographical origin of a virus can provoke a backlash against members of a particular religious or ethnic community since 2015, at least, when it produced guidelines that call on governments to avoid this (who, 2015) . the convention was breached when the trump administration saw political mileage in using labels such as "wuhan virus" and "china virus" instead of the neutral name "covid-19," leading the chinese government to castigate it as suffering from an "ideological virus" (people's daily, 2020; wang, 2020) . this is despite the fact that the chinese government had already used the name "wuhan virus" to imply that the epidemic was a localized outbreak. it may be true, as greenfeld points out, that there has been an unprecedented scale of international coordination to contain covid-19, but the history of pandemics shows that measures to control movement can be used to form national identity. this actually goes back to the age of empire, when thousands of muslim pilgrims were detained under sanitary controls imposed on the red sea area. in contrast, few people called for the quarantine of lawrence of arabia or other allied soldiers returning from the middle east in world war i (chase-levenson, 2020). a similar dynamic can be seen when various countries responded to covid-19 by imposing bans on travel from china in february 2020, motivating the chinese government and commentators to make accusations of racial prejudice. beijing's ambassador to israel even went so far as to liken the closure of borders to the turning away of jewish refugees during the holocaust, which the embassy had to quickly retract (the guardian, 2020). this is typical of the process by which governing elites use the spectre of the external enemy, or the "other," to build national identity, that woods and schertzer draw attention to. at present, china and the united states are clearly using covid-19 in this way. this is illustrated by the controversy that blew up when the wall street journal published an article titled "china is the real sick man of asia" in february 2020 (mead, 2020) . china reacted by expelling three of the newspaper's reporters, while its foreign ministry warned that it "must be held responsible for what it has said and done," to which us secretary of state mike pompeo responded that "mature, responsible countries understand that a free press reports facts and expresses opinions." it is also important acknowledge that the pandemic is being used for a more positive construction of identity. this is quite clear in the way that the chinese government is using its apparently successful containment of the pandemic to propagate the superiority of the "china model" of politics, after the legitimacy of the chinese communist party (ccp) was badly dented by the early mismanagement of the crisis. by describing the campaign in terms of a "people's war," it can also be linked with the narrative of the ccp's "salvation of the nation" from japanese aggression and misrule by the nationalists in the 1930s and 1940s. one of the most disturbing aspects of the covid-19 crisis is the way in which it is used to weaponize medicine in ethnic and nationalist conflicts. this is most evident in the ccp's attempts to exert control over territories that are central to its nationalist mission. it could already be seen in the summer of 2019. during that time, medics were subjected to police intimidation, arrest and surveillance as they came to the aid of citizens who were injured in demonstrations against the introduction of a law to extradite residents to mainland china, according to dr darren mann's eyewitness testimony before the house of lords on december 18, 2019. such behaviour is in breach of the principle that access to treatment is a universal right without distinction of race, religion, political belief and economic or social condition, as enshrined in the who charter. this was already a strong deterrent to demonstrators when beijing took advantage of a ban on mass gatherings in the territory to impose a national security law in may 2020, which will criminalize criticism of the ccp as unpatriotic and secessionist. when demonstrators defied the ban, they were condemned as a "political virus" (scmp, 2020). the use of covid-19 to fuel a nationalist conflict can also be observed in china's insistence that taiwan should be excluded from who, on the grounds that it is a part of china, despite its excellent record in containing the pandemic. it is too early to know how covid-19 will shape taiwan's identity politics, but the same situation during the sars epidemic of 2002-2003 allowed its incumbent president to use the "chinese plague" to galvanize flagging support in the polls by holding a referendum on demanding representation in international organizations, which helped him to win re-election in 2004. given that an opinion poll conducted before the virus hit taiwan shows that the proportion of the population who self-identify as taiwanese has already risen to a new high of 66%, while 28% identify as both taiwanese and chinese (pew, 2020), taiwan's current president can gain substantial political capital by ramping up the campaign for who representation. the potential for covid-19 to fuel a nationalist conflict is further heightened when such issues become part of global and regional geopolitics. this is deepening as taiwan gains substantial support from other democratic states, while china appears to be taking advantage of the health crisis to step up its naval and air force intrusions into the waters around the island and into the south china sea. this growing linkage of the pandemic with the national security of the united states and china creates a context within which individuals in both countries are likely to be harassed as carriers of covid-19, especially in the context of the rising populism that is highlighted by miller-idriss. this can be seen in the united states, where anybody deemed to be "chinese" due to their east asian features has become more liable to be harassed and assaulted. in china, where popular nationalism has long been used by the ccp as a source of legitimacy, xenophobia been fed by the narrative that the party is fighting and winning a "war" against a virus that was sent by the united states and is being spread by foreigners. there have been particularly serious cases of racism towards africans, due to the erroneous belief that they are unhygienic carriers. while miller-idriss is right to point to the ways in which covid-19 has been used to fuel anti-government extremism and conspiratorial sedition, it is also possible to find examples where civil society actors have criticized its use for nationalistic purposes: some 53 reporters and editors at the wall street journal signed a letter calling for the "sick man" headline to be changed and for an apology to be made; chinese commentators have pointed out that it was their own intellectuals who began to refer to their country as a "sick man," going as far back as the defeat of the qing empire by japan in 1895. such voices will remain marginal compared with the advocates of nationalism, however, unless covid-19 gives medical science sufficient authority to force the kind of cooperation between states that will weaken national sovereignty. history provides little evidence to support this prospect, however. from the coordination of quarantine procedures between the italian city-states down to today's who, contagious diseases have allowed governments to steadily accrue power over their citizens. china's use of information and communications technology to surveil its citizens as it manages covid-19 marks a new stage in this process. the dangers posed to civil liberties in democratic systems are also shown by cases such as the use of mobile telephones to identify and trace a disproportionate number of south korea's lgbt community, who face serious discrimination as a result. the state will become even more powerful if covid-19 justifies the introduction of new barriers to migration and the targeting of border health checks according to the national origins of travellers. the current crisis also shows how disease can be used not only to undermine the authority of scientists and medics, as miller-idriss points out, but also to turn them into political actors and national symbols. most controversial is the casting of dr li wenliang, as a "martyr" after he died from the virus, despite having been detained and disciplined by the authorities for trying to warn his colleagues at the early stage of the outbreak in wuhan. he the harnessing of scientists and medics to the nation-state can even be traced back to the china's first international conference, a meeting of epidemiologists in 1911 to discuss a pneumonic plague that had killed some 60,000 people in manchuria. to be sure that a "chinese" scientist should play a leading role, the qing empire appointed dr wu lien-teh (1879 -1960 as its representative, despite the fact that he was born in malaysia and was thus a subject of the british empire. having been on the receiving end of the racism of european scientists and diplomats, wu was happy to lead a project that was partly seen as a way to prevent japan and russia from using the plague to assert their growing control over manchuria (wu, 2004) . he would go on to become an authority in the emerging international health system, challenge british interests in malaya by establishing an anti-opium society, campaign to remove racial discrimination in the provision of public services, and co-author a history of chinese medicine (wu & wong, 1977) . members of the scientific community can thus be agents of nationalism as much as they can be a force for cooperation. the latter becomes less likely as the decoupling of the united states and china requires them to prove their loyalty or face accusations of subterfuge or even espionage. the need for states to ensure self-sufficiency and reliable partnerships for the supply of essential medicines and protective equipment is also leading to the securitization of health, which will accelerate the deglobalization of trade and the movement of people. the recent decision of the united states to withdraw from who due to its handling of the pandemic thus looks more like a throwback to the years when sovereignty trumped international cooperation and brought down the league of nations than a world in which the nation-state is in decline. i thus agree with greenfeld that transnational institutions are more likely than the nation-state to be damaged by the pandemic. there are several dimensions to the relationship between nationalism and covid-19 that ought to be disentangled, but first, let me be clear about how i understand the concept of nationalism itself and the version of it i analyse here. nationalism is an exclusionary political project to make the state congruent with the nation (fox and miller-idriss 2008) . this can take many forms, from fully secessionist and independence movements to xenophobic and antiimmigrant expressions within an existing state. the current form of nationalist governance that we have seen emerge in several global states is what i call populist nationalism. populism is both a schema (way of thinking) and a rhetorical strategy that pits the ordinary, pure people against the corrupt elites (bonikowski, 2017; canovan, 1999; brubaker, 2017; miller-idriss 2019; mudde, 2004; müller, 2016) . populist nationalism, in turn, extends this pure people-nefarious elite dichotomy to a framing in which all "others" pose an essential threat to the pure nation and its ordinary people. only a stronger state, so the argument goes, can protect the nation from the growing danger posed by immigrants, ethnic others, non-christian religions and more. this is what jan kubik (2018) calls a "thick" form of populism, in contrast to mudde's (2004) description of populism as having a thin ideology. others have described "thick" populism using slightly different terms, such as rogers brubaker's classification of vertical and horizontal dimensions of populism, where the vertical dimension positions the people against the elite and the horizontal dimension creates intense polarization and fixed boundaries between groups of people (brubaker, 2017; berezin, 2019; kubik, 2018; miller-idriss, 2019) . populist nationalism is the form and expression of nationalism that i refer to in this essay, although i will also use the shorthand "nationalism" to refer to it. with this understanding of nationalism, i return to the relationship between nationalism and covid-19. i suggest that there are at least three major impacts to explore. first, early indicators suggest that there is a direct impact of populist nationalism on the public health, infection rates and mortality rates of covid-19. as i write this, several of the countries in the world with the highest covid-19 infection rates are led by populist nationalist leaders-including the united states, brazil and the united kingdom. the united states alone is responsible for over a quarter each of covid-19 infections and deaths globally, although the us population represents only 4.25% of the global population (see world health organization, 2020, online; united states census bureau, 2020, online). why would populist nationalism itself be detrimental to a public health crisis? one reason is that populist nationalists' attacks on the "corrupt elite" have gone well beyond critiques of political leaders and opponents to include other "elite" experts, academics and scientists, as evidenced by a rejection of climate science and global environmental agreements, for example. undermining and delegitimizing scientific expertise and global cooperation and information sharing makes it significantly more difficult to convince the public of the benefits of shelter in place orders or practices to reduce the spread of the disease. in the case of covid-19, populist nationalist leaders are thus more likely than other national leaders to reject scientists' advice, attack global organizations like who, promote scientifically unproven and potentially harmful treatments for covid-19 and reject scientifically proven practices like wearing masks in public. populist nationalist anti-elite and antiscience sentiments have undoubtedly led to higher covid-19 infection and mortality rates as a result. populist nationalists do not only attack and undermine scientific expertise, of course. the purity of the people, within populist nationalist frames, rests both in contrast to corrupt elites and to racial, ethnic, religious and immigrant "others." this is where the second impact of nationalism on covid-19 outcomes becomes clear. across europe and north america, there has already been a documented rise in xenophobic, anti-immigrant, anti-asian and anti-semitic hate during the global pandemic. the us administration's insistence on using the term "wuhan virus" or "chinese virus" is one of "many strategies of apportioning the blame for the (spread of the) virus to a specific place/country and to construct the disease as a foreign-grown threat to the nation" (nossem 2020: 5). in the united states alone, over 1,700 anti-asian hate incidents were reported within the first 6 weeks of a new website established by asian american and pacific islander civil rights groups (lee & yadav, 2020) , to name just one example (see stop aapi hate reporting center, n.d. online) . such xenophobic expressions of nationalism are part of a clearly documented, pre-covid-19 rise in far right and extremist hate and the legitimation of white supremacist extremism (ebner, 2020; miller-idriss, 2018 mudde 2019) . white identity and the need for its protection and defence is a common thread across white supremacist and white nationalist beliefs and practices (belew, 2016) . during the covid-19 pandemic, these expressions have found a home in the circulation of memes and social media commentary that scapegoat entire populations as being responsible for the virus and its spread (see anti-defamation league, 2020) . dehumanizing language about "dirty" immigrants carrying disease has accompanied immigration bans along with border closures, asylum application denials, deportations and more, even while the practices of local "native" populations that rapidly spread the virus in local churches, parties, funerals, ski lodges and more have continued in more or less unchecked ways. at the extreme fringe, moreover, there are clear risks that the covid-19 era will help reinforce white supremacist extremists' sense of white victimhood and concomitant emotional appeals to protect, defend and take heroic action to restore sacred national space, territory and homelands (miller-idriss, 2020) . the third impact that has emerged as a result of the relationship between nationalism and covid-19 is the rise in anti-government extremism and conspirational sedition (finkelstein et al., 2020) . anti-government and apocalyptic far right extremists have rapidly grown in online and offline presence across the united states and europe, in part through organized protests against state and national shelter in place orders. calls for violent uprising against the state, political opponents and law enforcement-resulting in part from widely circulating misinformation and disinformation about governments' responses to covid-19-have already inspired several violent attacks on law enforcement and at least two planned or enacted plots against hospitals. the growing popularity of conspiracies about a "deep state" and an apparent new convergence among anti-government groups across the political spectrumincluding anti-vaxxers and flat earthers, qanon conspiracy theorists, guns' rights advocates, patriot militias and white supremacist extremists-have created a combustive mix that brings a high risk of serious violence, particularly as we head into a likely second wave of spiking infections and shut downs in the fall of 2020. conspiracy theories about governments' and corporations' plans to use a vaccine to microchip, neuter or control citizens are also circulating widely in extremist circles, which suggests that nation-states have a significant implementation challenge ahead of them even after a vaccine is successfully produced. covid-19 is likely to fuel ethnic and nationalist conflict in several ways. in the global north, as discussed above, rising xenophobia, conspiracy-fueled anti-asian and anti-semitic violence and anti-immigrant hate are already prevalent during the covid-19 pandemic. the potential short-and long-term impacts of school and university closures on youth radicalization are also significant. in the united states alone, over 70 million youth in the primary, secondary and postsecondary systems are currently affected by school and college closures. this has led to massive increases in online engagement in ways that create incalculable risks of engagement with extremist material and recruiters. shortly after the pandemic began, us federal law enforcement issued warnings about the increased risk of child exploitation as a result of highly online youth presence, combined with reduced parental/caregiver supervision and lessoned interactions with other trusted adult networks, including teachers, coaches, youth group leaders and adult relatives outside the home (federal bureau of investigation, 2020, online). similar risks exist for online radicalization (e.g., see state of new jersey office of homeland security and preparedness, 2020). the impact of extraordinary amounts of time spent online during the covid-19 pandemic-along with a risk in the drivers and grievances that create susceptibility to radicalization, such as anxiety, uncertainty, isolation and lack of purpose-will be clearer as time passes, but should be understood for now as a high-risk situation related to potential future violent extremism and terror. in the global south, covid-19 will potentially exacerbate ethnic tensions or fuel new ones in already-fragile states. a heightened lack of trust between local communities and governments or international organizations is part of the problem-in some cases, caused by very real abuses and instances of violence perpetrated by some frontline police and military responders during covid-19 curfew enforcement. in places where trust in governments is already low, or where there are existing grievances about inequitable distribution of resources, uneven responses in health care provision or distribution of resources can fuel ethnic conflict. these vertical tensions (between communities and authorities) are matched by deeper horizontal tensions between ethnic groups as shelter-in-place orders have reversed gains that had been made through promising communal engagement programmes that brought people together across dividing lines. as families retreat into ethnic communities, the fragile bonds from emerging crossethnic forms of engagement and cooperation are at risk. finally, both kinds of tensions-vertical and horizontal-are further heightened through the actions of bad actors who have circulated unreliable sources of information, disinformation, misinformation and conspiracy theories about the virus. some campaigns have targeted ethnic minorities through labels like the "rohinga virus," the "muslim virus" or the "refugee virus," aiming to produce fear and uncertainty and incite conflict (see search for common ground, n.d.). i would expect to see splintering on this question, for several reasons. one has to do with the issues of trust in government discussed above. in countries where the national response has strengthened public trust in the government-such as germany and new zealand-the nation-state will likely be strengthened. but in places where trust is weakened as a result of the government's response to covid-19, including in the united states but also in more fragile states in the global south, the nation-state will likely be further eroded. the widespread circulation of misinformation, disinformation and conspiracy theories related to the virus and a covid-19 vaccine will also exacerbate declines in the nation-state's power, particularly in states where elected officials have failed to counter or have actively supported some conspiracy theories, even prior to covid-19 (see rosenblum & muirhead, 2019) . the same is likely true for the ways that covid-19 has illuminated existing disparities in health care provision across ethnic and racial groups. the drastically different infection and mortality rates for minorities compared with whites in the united states, for example, make it clearer than ever that the nation-state does not serve all its people equally. the uneven loss of life for black americans and communities of colour should be a wake-up call to nationstates and their citizens about the need for systematic change in social services and health care provision, as well as the need to address ongoing legacies of structural racism and discrimination. i would argue that the extent to which nation-states respond to these grievances will play a big part in whether the pandemic ultimately is a strengthening or a weakening force for the nation-state more generally. finally, increases in ethnic group conflict and political or ethnic group polarization and hate in the wake of covid-19 continue will also likely have differential impacts, depending on how states react. countries whose local, regional and national leadership firmly and unequivocally condemns hate and scapegoating related to the virus may be able to come out of the pandemic with stronger and more resilient communities and nation-states. but in places where political leaders ignore or exacerbate these tensions and contribute to further polarization, it is hard to see how covid-19 will not contribute to the further decline of the nation-state and the people's identification with it. we approach all three questions through a lens that conceives of the covid-19 pandemic as a crisis. this enables us to construct a typology of the differing ways that crises can impact the development of nationalism. we then use this typology to frame our discussion of how the pandemic could shape nationalism and how nationalism in turn could shape the response to the pandemic. covid-19 constitutes a severe global threat. it has significant potential to trigger multiple, cascading crises in nearly every aspect of our lives. in addition to the presence of a threat, crises typically involve systemic disruption, uncertainty and stress (brecher, 2019; quarantelli & dynes, 1977; rosenthal et al., 1989) . as a result of this widespread upheaval, crises have a high potential for triggering change (falleti & lynch, 2009 : 1155 . the concept of crisis has not been a specific focus in the field of nationalism studies. that being said, events that could readily be defined as crises, such as warfare, revolution or economic catastrophe, have been central to research on nationalism. this literature suggests that crises can impact the development of nationalism in three distinct ways: they can be (1) constitutive, (2) amplifying, or (3) transformative crises as constitutive events. crises, particularly those that are associated with revolution, can be constitutive events in the formation of new nationalisms. indeed, the french revolution of 1789 is often depicted as the formative event for the worldwide spread of nationalism. during a revolution, the struggle against perceived illegitimate rule can provide a catalyst for the emergence of nationalist sentiment-the idea that "we" constitute our own nation and therefore ought to have political autonomy (see hobsbawm, 2010; bell, 2001) . similarly, warfare can be a powerful catalyst for the emergence of nationalist sentiment through conflict with a common threat (hutchinson, 2017, pp. 36-42) . crises as amplifying events. crises can also have an amplifying effect on existing nationalisms. as such, they can reinforce both solidarity and division within and between national communities. solidarity is often expressed through a "rally around the flag effect," in which people unite under national leaders during the crisis (brody & shapiro, 1989; mueller, 1970; oneal, lian, & joyner, 1996) . nationalism can also provide a collective cipher for succour and inspiration during a crisis, whereby myths, symbols and practices associated with past crises are "rediscovered" and applied to the new crisis (hutchinson, 2006) . the crisis might also give rise to new cultural content and practices, which can further reinforce solidarity (hutchinson, 2006) . however, the inevitable search for responsibility that accompanies a crisis can also amplify divisions with perceived malevolent "others," both within and outside the national community. thus, during a crisis, it has been widely observed that attacks against internal minorities tend to surge, while the potential for conflict with external adversaries is heightened. crises as transformative events. as much as crises can amplify existing nationalisms, they can also be transformative. for example, crises can lead to new configurations of cultural boundaries between who is perceived to belong and who does not. previously excluded minorities might be incorporated into the national "we" as they make common cause against the threat. for example, the war against a genocidal germany was an important catalyst for the increased social inclusion of jews in america (alexander, 2006: chapter 19) . however, by the same token, minorities that were once included, or at least tolerated, might now be excluded if they become associated with the new threat. thus, after the terrorist attacks of september 2001, muslims in the west became the new significant "others" (byng, 2008; poynting & mason, 2006) . in the international sphere, perceptions of who is the "friend" and "foe" can also undergo reconfiguration during a crisis. this occurred, for example, in the dramatic reversal of how the west perceived the soviet union following the world war ii. so, which of these potential pathways might nationalism take in the wake of covid-19? it is too early to tell whether this pandemic will be a constitutive event for the rise of new nationalisms. the same goes for whether it will have a transformative impact. there are signs of a potential "hamiltonian" moment in europe with the agreement between germany and france to pursue a €500bn aid package for the eu, but there are no guarantees that all 27 member states will agree to the proposal, nor whether this will persuade the citizens of those states to relinquish their national identities in favour of a pan-european identity. nevertheless, in some instances, there are early signals that covid-19 could move the boundary of who belongs and who does not. in the united kingdom, the importance of ethnic minorities to the nation has been made salient through their increased visibility in the professions on the frontlines of the struggle against the pandemic (hirsch, 2020) . this is also happening in canada, where leaders are considering making asylum seekers permanent residents to recognize their work in long-term care facilities (seidle, 2020) . but these are only two examples and it is still early days; in many other cases, we are seeing the opposite happen where migrants are being targeted. we therefore think that among the three pathways we described, the most likely impact of covid-19 will be to amplify existing nationalisms. there are already indications that covid-19 is amplifying nationalism across numerous contexts. most national leaders are enjoying a surge of support. myths and symbols related to how nations endured past crises, such as warfare, have been rediscovered and repurposed by national leaders in order to inspire their constituents as they confront the pandemic. new collective rituals have also emerged, such as weekly national "clapping" for key workers in the united kingdom, or the newly founded national days of mourning in spain. but this amplifying effect has not been entirely solidary. for example, in the united states, there has been a surge in racist attacks against asian americans (tavernise & oppel, 2020) . meanwhile, as we discuss in our response to question 2, it is fuelling division in the international sphere. the divisive othering and attribution of responsibility that stem from a crisis can increase the likelihood of intrastate political conflict, but not necessarily lead towards interstate violence. the splitting of populations into categories of "us" and "them" is central to nationalism. as fredrik barth (1969) points out in relation to ethnic identity, it is through contact with "others" that we construct a sense of "our" group. this othering tends to also entail a moralizing process that glorifies "us" and vilifies "them" (schertzer & woods, 2020a) . and therein lies the rub: at times of crisis, this tendency can propel ethnic and national conflict because it creates logics that rationalize violent or discriminatory practices against perceived malign or corrupted "others." this is because nationalism provides a cultural roadmap for attributing responsibility for a crisis, in the sense that it is typically the vilified "others" that shoulder the blame. with covid-19, attributing responsibility to an "other" is somewhat indirect, because ultimately, the responsibility lies with a virus rather than human actors. covid-19 is an "invisible enemy," as donald trump likes to quip. in this regard, the pandemic is akin to a natural disaster. but even natural disasters typically provoke efforts to attribute responsibility to human actors-to lay blame at the feet of an individual, group or institution for failing to act appropriately (bucher, 1957; yates, 1998) . this process of attributing blame can be highly conflictual. as the conflict takes shape, it tends to align with and amplify existing cleavages (tilley & hobolt, 2011) . for example, after hurricane katrina, an emotive struggle over responsibility ensued that ultimately enflamed a longer running conflict over the place of african americans in america (eyerman, 2015) . similar processes are emerging in relation to covid-19. the pandemic is amplifying nationalist sentiment (see legrain, 2020) , which is precipitating a "politics of blame." this is particularly visible in relations between the united states and china. as hughes discusses in this exchange, a relationship that was already strained is now rapidly worsening, as the two countries blame one another for the pandemic. there is a fear that these political disputes may lead towards violent conflict. the vastly simplified argument here is that covid-19 creates a series of economic, social and political crises that increases incentives and opportunities for interstate conflict. and when rising nationalism is added to the mix, it increases the probability that leaders will opt for war (see hutchinson, 2017) . in our view, this account gives too much power to nationalism as the key driver of conflict. we know many of the conditions and logics that drive interstate warfare, and covid-19 does not necessarily lead us down these pathways. as others have argued, the pandemic has created significant logistical issues for mass troop mobilization, it has shaken the confidence of states and leaders and there is no necessary link between economic downturns and warfare-recessions are a bad predictor of interstate conflict (posen, 2020; walt, 2020) . while nationalism can shape decisions and introduce irrationality, it does not necessarily have the structuring power to overcome the current barriers to interstate warfare. the view that increasing nationalist sentiment will inevitably lead to violent conflict also oversimplifies nationalism. this logic assumes that nationalism is always dangerous and illiberal, which in our view is an outmoded that builds on a normative distinction between bad (ethnic) and good (civic) forms of identity. what is more likely is that covid-19 will amplify internal ethnic divisions within states. the process of othering, the search for blame and the calls to protect our "own" are driving a dynamic whereby foreigners and migrants are being targeted in many states. as miller-idriss details in her contribution, asians in western countries are suffering racist and violent attacks as perceived stand-ins, carriers and collaborators of the "silent enemy." migrants are facing hostility as potentially dangerous vectors of the virus and threats to the host society. asylum seekers are being denied entry into many countries or held in dangerous camps where they are at greater risk of contracting covid-19. in short, some ethnic divisions within states are becoming increasingly salient. this type of internal ethnic conflict is not directly attributable to the pandemic. rather, it reflects how the internal dynamics of a national community are shaping the response of leaders and the public at a time of crisis. political culture matters in how covid-19 is shaping nationalism: it is the nation's cultural and political characteristics that are driving the emergent dynamics of conflict. these dynamics are not necessarily marching us down a path towards interstate violence, but they are making existing ethnic divisions within and between nations more salient. the nation-state has a privileged position in our political order. the international system is based upon the idea that political communities, called nation-states, deserve autonomy. the logic of nationalism provides legitimacy to this order: it is because states protect and represent a nation that they have sovereignty (mayall, 1990) . at first blush, we might expect that a global pandemic would erode the status and autonomy of nation-states: international collaboration and a pooling of resources are necessary to combat the virus. and yet, nation-states are leading the response to covid-19, while the legitimacy of international organizations like the who is being questioned. given these early trends, and what we know about the endurance of nation-states, in our view, covid-19 will likely reinforce the nation-state. the early signals point towards a trend of nation-states greatly increasing their power in the face of covid-19. they are reinforcing borders, curtailing migration, limiting internal population movements, spending vast amounts of money on economic stimulus and increasing surveillance of citizens. many of these moves have come at the cost of individual liberty and privacy (economist, 2020) . some of these measures will be relatively short lived, and others will likely be difficult to roll back. regardless, these patterns recentre the state in our lives. they bring the state back into view as a powerful actor (skocpol, 1985) . but these developments are about more than simply expanding the administrative capacity of states-they also reinforce the nationalist idea that they represent "nations." leaders and publics alike have embraced the rationale that increased state authority and power is necessary to protect the safety and way of life of the nation. this rationale is evident in the competition over medical supplies, which is increasingly nationalist in tone (goodman, thomas, wee, & gettleman, 2020) . european union states have worked against one another by limiting the export of protective equipment to other members in need. the united states has taken actions to limit the export of protective equipment to canada. conflicts over the production and distribution of an eventual vaccine are already taking shape. rather than concerted international collaboration and coordination, we are seeing increasingly protectionist approaches driven by the logic of the nation-state. at the same time, the nation-state is facing threats-from below and from above. there is an argument that substate national movements may use covid-19 to push for greater autonomy. this could trigger renewed instability, particularly in multinational states. but the evidence so far suggests the contrary. many multinational states are seeing a remarkable degree of pan-national solidarity. both dynamics are playing out now in the united kingdom: an early surge in solidarity across the union is increasingly diverging along national lines, with scotland, wales and northern ireland adopting different approaches to the pandemic. however, even if covid-19 does destabilize multinational states through national minority mobilization, this does not completely threaten the idea of the nation-state. national minorities seeking independence are not working to undermine the international society of nation-states; they are working to join it (williams & schertzer, 2019, p. 680 ). covid-19 may also threaten the nation-state from above. the economic and political crises that it will inevitably trigger can create opportunities for powerful nation-states to extend their influence over less powerful ones. in this regard, the pandemic may enable new forms of imperialism, undermining the status and sovereignty of nationstates. there are clear parallels supporting this argument: "foreign aid" provided by powerful states and institutions during past crises often belied thinly veiled forms of neo-colonialism (see charbonneau, 2008; fieldhouse, 1999; langan, 2018) . but even a resurgent imperialism may not undermine the idea of the nation-state system. history can serve as a guide. during the "cold war," the idea of the sovereign nation-state was strengthened. despite the widespread influence of the united states and soviet union, the idea that the world was fundamentally composed of sovereign nation-states did not diminish. therefore, we tend to agree with greenfeld that the covid-19 pandemic will not diminish the nation-state system in the long run. if we are right-if covid-19 reinforces the nation-state-then there are some potential perils. the amplification of power and autonomy of nation-states, paired with limited checks and accountability, may have long-lasting effects for privacy, security and democracy. people are rightly fearful that newly emboldened nation-states may hinder the necessary international collaboration to manage the pandemic. but this fear rests on a false dichotomy: a strengthened nation-state is not irreconcilable with strong international collaboration-quite the opposite (schertzer & woods, 2020b) . the security and autonomy afforded by the nation-state can allow actors to engage in meaningful international collaboration. the establishment and growth of our key international institutions and related norms principally stem from actions taken by states, often following major crises. if this collaboration can be undertaken while being mindful of existing power imbalances-listening to the better angels of our nature-it could both assist in the immediate response to the pandemic and improve international institutions and norms over the longer-term. the civil sphere how the world will look after the coronavirus pandemic international scapegoating of israel and jews for spreading covid-19 ethnic groups 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'u.s. and world population clock will a global depression trigger another world war? foreign policy speech of 24 is indigeneity like ethnicity? theorizing and assessing models of indigenous political representation who issues best practices for naming new human infectious diseases online. who coronavirus disease (covid-19) dashboard plague fighter: the autobiography of a modern chinese physician history of chinese medicine: being a chronicle of medical happenings in china from ancient times to the present period attributions about the causes and consequences of cataclysmic events covid-19, nationalism, and the politics of crisis: a scholarly exchange key: cord-282298-8tcw3cll authors: wang, jie; xiong, xingjiang title: current situation and perspectives of clinical study in integrative medicine in china date: 2012-02-21 journal: evid based complement alternat med doi: 10.1155/2012/268542 sha: doc_id: 282298 cord_uid: 8tcw3cll integrative medicine is not only an innovative china model in clinical practice, but also the bridge for tcm toward the world. in the past thirty years, great achievements have been made in integrative medicine researches, especially in clinical practice. the clinical achievements mainly include the following three: innovating methodology of disease-syndrome combination, excavating the classical theory in traditional chinese medicine (tcm), preventing and curing refractory diseases. the development ideas and strategies of integrative medicine for future mainly include (a) standing on frontier field of international medicine and improving the capability of preventing and curing refractory diseases; (b) moving prevention and control strategy forward and improving the curative effect of common and frequent disease; (c) excavating the classical theory of tcm and broadening the treatment system of modern medicine; (d) improving the innovation level of new high effective drugs on the basis of classical prescriptions and herbs in tcm; (e) rerecognizing the theory of formula corresponding to syndrome in tcm and enhancing the level of clinical research evidence based on evidence-based medicine. integrative medicine will do obtain greater achievements in creating new medicine and pharmacology and make more tremendous contributions for the great rejuvenation of the chinese nation and human health care. the coexistence of western medicine (wm) and traditional chinese medicine (tcm) began to appear when wm was introduced to china from the middle of 16th century. the tendency of "confluence of chinese and western medicine" appeared as the two medical systems contacting and influencing with each other since then. with the development of modern medical technology, intercourse, and cooperation between tcm and wm, integrative medicine was established in the 1980s. under the guidance of "system learning, comprehensively mastering, sorting, and improving," predecessors of integrative medicine have been exploiting the complementary advantages of macro and micro, global and local, structure and function, traditional and modern, disease differentiation, and syndrome differentiation in wm and tcm, in order to create new medicine and pharmacology theory. through unremitting efforts of integrative medicine staffs at home and abroad, remarkable achievements have been made in health care, teaching, researching, academic development, discipline construction, talent training, and so forth. so we can say that integrative medicine is not only an innovative china model in clinical practice, but also the bridge for tcm toward the world [1] [2] [3] . now the clinical achievements of the past 30 years and developing strategies of integrative medicine are described as follows. research. the relationship between disease and syndrome is thought to be one of the most significant problems in tcm clinical and basic practice. as a new mode for syndrome research, disease-syndrome combination mainly refers to absorbing the idea and theory of disease differentiation in western medicine (wm) as 2 evidence-based complementary and alternative medicine well as syndrome differentiation in tcm. the mode, which originates from the medical practice since more than half a century ago, has realized mutual compensation of advantages of tcm and wm [1, 2] . combining whole thinking, imagery thinking, and dialectical thinking in tcm with materialism of modern medical sciences, the mode can be regarded as a good cut-in point and successful control pattern for integrative medicine [3] . it has complementary advantages of wm and tcm and marks a new era created by integrative medicine in clinical researches. seminar on the academician chen keji's academic thinking about "the new mode of disease-syndrome combination and its application in clinical practice" was held in beijing on may 23, 2011. professor chen and his students discussed the scientific connotation of this new mode and its application in diagnosis, treatment, and scientific research together. china news of traditional chinese medicine, a famous domestic media, made followup report on the symposium, which had evoked large repercussions. academician chen keji pointed out that modern view of disease-syndrome combination includes six aspects: (a) mode of disease differentiation by wm combined with syndrome differentiation by tcm; (b) mode of syndrome differentiation and treatment combined with specific prescription for certain illness; (c) mode of treating according to disease staging; (d) mode of differentiation of the basic pathogenesis combined with syndrome differentiation and treatment in tcm; (e) mode of treating according to syndrome differentiation rather than disease differentiation when there's no disease can be diagnosed in wm; (f) mode of treating according to disease differentiation rather than syndrome differentiation when there's no syndrome can be diagnosed in tcm [4] . the emphasis of the mode could be played on either syndrome or disease. as the connotation of syndrome in tcm is significantly different from disease in wm, laying special emphasis on syndrome means that syndrome is just the basis of therapeutic scheme. on the contrary, effective therapeutic plans should be formulated according to disease differentiation when special emphasis is laid on disease. this new mode is beneficial to the original innovation in diagnosis and treatment. the advantages of the mode include four aspects as follows. (a) definitely diagnosing. as the disease diagnosis in tcm is vague and extensive, it is entirely necessary and possible to absorb some relevant achievements of disease diagnosis in wm for definitely diagnosing. (b) targeted treating. as the new mode pays more attention to the therapeutic evaluation of disease, it could achieve more definite therapeutic targets and stable curative effect compared with syndrome differentiation mode alone. (c) accurately prognosing. summarization of clinical phenomena is the principal judgment basis for prognosis in tcm, therefore, the prognosis judgment is always not very accurate. however, the new mode has vital guidance value for treatment and prognosis judgment. (d) deepening classics. due to the succinctness and conciseness of tcm classics, the essential features of the disease and syndrome could be rerecognized and deepened through combining with the modern cognition of pathology, diagnostics and pharmacology study in wm. syndrome is not only the core of tcm basic theory and syndrome differentiation, but also the bridge to associate disease and formula. different from diagnosis based on pathological mechanism, syndrome is a classification according to subjective symptom and objective sign collected by physical examination [5] [6] [7] . premise studies on diseasesyndrome combination lies in syndrome diagnostic criteria and therapeutic evaluation system. researches on syndrome diagnostic criteria aim at establishing the scientific and normative diagnosis system, while researches on therapeutic evaluation aim at constructing an objective evaluation system. under the leadership of academician chen keji, we are the first to study and report on blood stasis syndrome in coronary heart disease based on the new mode. contributed to the diagnosis of blood stasis syndrome in coronary heart disease, 19 items such as precordial pain, dark purple tongue color, and erythrocyte deformability were selected based on the calculation analysis of 48 kinds of examination items in 92 cases patients with coronary heart disease. and the clinical diagnosis accordance rate was 89%. 6 items giving the greatest contribution to diagnosis such as blood viscosity and total cholesterol (tc) were confirmed by a stepwise regression analysis for 21 items such as hemorheology and blood lipid [8] . correlation analysis of blood stasis syndrome and pathological changes shown in coronary angiography with coronary heart disease showed that the blood stasis syndrome score was significantly correlated to the maximal stenosis degree and coronary lesion score demonstrated by coronary angiography before percutaneous coronary intervention (pci), and the correlation was increased along with the increasing of the patients' age and the course of the disease. conclusions were also verified in our related researches [9] [10] [11] . through mathematical statistics method and computational intelligence approach, it was found out that the major syndrome factors of coronary heart disease are blood stasis, qi deficiency, turbid phlegm, qi stagnation, heat deposition, yang deficiency, yin deficiency, and cold coagulation based on calculation analysis of 5099 cases patients reported on literatures and 1069 cases patients with coronary heart disease validated by coronary angiographic. we also constructed the diagnosis scales of blood stasis syndrome and its accompanied syndromes in coronary heart disease, such as qi deficiency and blood stasis syndrome and qi stagnation and blood stasis syndrome [12] [13] [14] . in the study of therapeutic evaluation system, taking coronary heart disease as example, important indexes such as syndrome evaluation scale, clinical critical events, and quality of life were selected on the basis of completely evaluating the present indexes through application of clinical epidemiology-/evidencebased medicine method. meanwhile, high validity and reliability of therapeutic evaluation system of coronary heart disease was constructed through comprehensive analysis of various index by the hall for workshop of metasynthetic engineering. clinical efficacy scale of tcm syndrome and the primitive entry pool of scale for patient-reported outcomes of coronary heart disease were established by our team [15] . evidence-based complementary and alternative medicine 3 it is meaningful to promote the original innovation in integrative medicine researches through further understanding the connotation of syndrome diagnosis, therapeutic principle, and classical prescription by modern science and technology. among these studies, three researches below are honored. the first one is blood stasis syndrome theory and the clinical application of the method of promoting blood circulation and removing blood stasis. blood stasis syndrome theory is first recorded in the songs of chu, a classical literature written in ancient china. shuo wen jie zi (text notes and word explanations) written by xu shen in the eastern han dynasty explained that blood stasis is hematocele. and it was frequently mentioned in tcm classics such as the canon of internal medicine, treatise on febrile diseases, and synopsis of golden chamber. inspired by the prominent tcm doctor guo shikui's experience in treating angina pectoris by decoction for removing blood stasis, a classic formula developed by wang qingren in qing dynasty, academician chen keji advocated treating coronary heart disease by activating blood circulation to dissipate blood stasis principally. his team was the first to study the diagnostic criteria of blood stasis syndrome and report the quantitative scoring method, which had been extensively used in domestic and was the first study in using objective quantitative method in tcm syndrome study. objectified study of abdomen diagnosis on blood stasis syndrome was also superior to the research methods of japan in the same period. standards of syndrome differentiation and therapeutic evaluation of coronary heart disease were formulated according to above-mentioned researches, which had already become national standards. the essence of blood stasis syndrome and mechanism of treating coronary heart disease by activating blood circulation to dissipate blood stasis had been elucidated at various levels of intact animal, tissue, cell, molecule, and gene protein expression. as coronary restenosis after coronary artery balloon injury and stent placement have been considered an international difficult problem, academician chen firstly treated it by decoction for removing blood stasis and optimized the prescription to a more simplified and effective recipe, xiong shao capsule (xsc). a randomized controlled trial (rct) about xsc showed that the restenosis rate in xsc group treated by xsc on the basis of routine western therapy was decreased by 45% compared with routine western therapy group, and the experimental studies showed that xsc could suppress the gene expression of proliferation of vascular smooth muscle cells [16] [17] [18] [19] . with important academic value and clinical significance, the study has promoted the academic development of tcm greatly, which had been awarded the first award of national science and technology progress in 2003. the second study is the theory of dispelling interior pathogenic factors and purgation and its application in the treatment of acute abdomen. according to the theoretical basis of "the six fu-viscera function well when unobstructed," academician wu xianzhong began to explore integrative medicine therapy on acute abdomen in early years. through unifying standard for syndrome differentiation and defining operative indication, his team accumulated a large number of valid acute abdomen cases with the therapeutic method of expelling pathogens by purgation. under the leadership of professor wu, the multidisciplinary and prospective researches included the effects of dispelling interior pathogenic factors and purgation on the splanchnic blood flow and caecal single smooth muscle cell, the clinical characteristics of multiple organ dysfunction syndrome (mods) caused by several different kinds of elements, the changes of nerve-endocrine-immunological network in mods and the effects of purgative herbs on information transmission mechanism of immune cells through four times of different scale joint research in the seventh to tenth five-year plan period. after years of efforts, significant progress had been made and the operation rate had been reduced in the treatment of acute abdomen, such as severe acute cholangitis, acute severe pancreatitis, and complicated biliary stones, which was awarded the second award of national science and technology progress in 2003 [20] [21] [22] . the third one is the theory of "treating the toxifying disease with poisonous agents" and researches for arsenic trioxide (as 2 o 3 ) treating acute promyelocytic leukemia (apl). the theory is a traditional simple understanding of hypertoxic drug treating difficult and complicated diseases. it was recorded in compendium of materia medica that the herbal nature of arsenolite is very hot and poisonous, while white arsenic sublimed from arsenolite is more poisonous. white arsenic is a traditional external drug for removing the necrotic tissue and promoting granulation plaster, the effective component of which is as 2 o 3 . the research was enlightened by the prominent tcm doctor's experienced external prescription for treating skin cancer. on the basis of verification of curative effects and optimizing prescription, researchers developed the arsenous acid injection from the experienced external prescription, which had definitive curative effect for the patients with apl and reached the top level in the world [23] [24] [25] [26] . the mechanism of arsenous acid treating apl was illustrated from the perspective of molecular oncology, including degradation of pml/rara fusion proteins, downregulating gene expression of bcl2 and inducing apoptosis in leukemia cells. arsenous acid became the first antileukemia drug of inducing apoptosis in the world arousing the medical research fever of arsenic trioxide [27] [28] [29] . it was honored as "ancient remedy performs new tricks" in 1996 by science [30] . sloan-kettering and his coworkers reported that 12 patients with recurrence of apl after conventional chemotherapies were treated with as 2 o 3 , and 11 cases of them relieved completely in 1996. this paper, published in new england journal of medicine, directly led to the widely acceptance of as 2 o 3 in the treatment of apl in the international medical field [31] . as the frontier field and hot issue of cardiovascular diseases, restenosis after percutaneous coronary intervention and myocardial ischemia reperfusion injury (miri) during open heart surgery of cardiopulmonary bypass has become the best innovative points of clinical studies in integrative medicine. researches showed that restenosis after percutaneous coronary intervention was closely related to blood stasis syndrome. predominantly evaluated by restenosis (rs) rate estimated by coronary angiography (cag), a prospective randomized controlled study was carried out on rs after pci to observe the intervention effect of xiong shao capsule (xsc). compared with the control group, the incidence of rs rate in the xsc group was significantly lower (24.1% versus 48.5%, p < 0.05) and the extent of angiostenosis and diameter of the culprit arteries, determined by cag, also significantly reduced after patients had been treated for 6 months with [(2.21 â± 0.85) mm versus (1.72 â± 0.99) mm, p < 0.05], and [(26.58 â± 20.72) % versus (41.19 â± 30.92) %, p < 0.05], respectively. the incidence of clinical end-point event was significantly lower in the xsc group than that in the control group (11.7% versus 27.6%) and the p value was close to statistical significance (p = 0.051). comparing with the control group, the blood-stasis syndrome score in the xsc group was also significantly lower (p < 0.01). the results showed that xsc had a wide range of therapeutic effects including effectively preventing rs after pci in combination with conventional western medical treatment, decreasing the attack of angina pectoris and improving the blood stasis syndrome. experimental researches on blood activating herbs showed that it can significantly inhibit pathological vascular remodeling after balloon injury, thus reduce late lumen loss and prevent restenosis [32] [33] [34] [35] [36] . as the establishing the cardiopulmonary bypass of open heart surgery is key point of successful operation, myocardial ischemia reperfusion injury (miri), which is very obvious during the recovery of circulation, has become the hot issue needed to be resolved. some scholars found that the pathogenesis of miri during open heart surgery of cardiopulmonary bypass is deficiency of heart qi in the origin and excess of heart blood stasis and internal turbid toxin in the superficiality and the therapeutic principles are boosting qi and nourishing heart, activating blood circulation and resolving toxin simultaneously. it was proposed that of astragalus injection and tetramethylpyrazine injection for boosting qi and activating blood circulation should be given by vein injection during operation and hu xin bao (compatibility of extracts of ginseng and panax notoginseng with taurine) for boosting qi, activating blood circulation, and resolving toxin should be given by oral administration before operation. the research showed that astragalus injection combined with tetramethylpyrazine injection could reduce the content of mda and myocardial enzymes' release and improve the activity of sod, no, and nos. serial studies demonstrated that boosting qi combined with activating blood circulation have significantly synergetic effects, and boosting qi, activating blood circulation, combined with resolving toxin were superior to those simple boosting qi, activating blood circulation, resolving toxin, and boosting qi combined with activating blood circulation [37, 38] . multiple organ dysfunction syndrome (mods) is one of the difficult problems in the field of the critical care medicine, which is characterized by acute onset, rapid progress, and extremely high mortality. since the 1970s of 20th century, some scholars began to take vigorous action to explore a new way of preventing and treating mods by integrative medicine and a new theory of "bacteria and bacterial toxin treated simultaneously" was presented ultimately. they also perfected schemes for the diagnosis procedure and treatment standard of mods by both tcm and integrative medicine. and four therapeutic principles for the main types of syndromes were put forward, such as activating blood circulation to dissipate blood stasis therapy on blood stasis syndrome, clearing heat and toxin therapy on heat toxin syndrome, reinforcing the vital energy and consolidating the constitution therapy on acute deficient syndrome, and dispelling interior pathogenic factors and purgation therapy on yangming fu-organ syndrome. integrative medicine therapy can effectively improve the clinical efficacy and shorten the course of the disease thus reducing mortality. a famous injection of chinese medicine, "shen nong 33," with the effect of activating blood circulation to dissipate blood stasis and antiendotoxin, was developed, which has reduced the mortality of international recognized infectious four or more organs failure from 100% to 50% and reached the international advanced level. furthermore, a new strategy of "bacteria, bacterial toxin, and inflammatory mediator treated simultaneously" was put forward on the basis of the theory of "bacteria and bacterial toxin treated simultaneously." xue bi jing injection, the first chinese medicine preparation in emergency medicine, was developed, which have made great contributions to the advancement of critical care medicine [39] [40] [41] [42] [43] . chronic hepatitis b is the common disease in china, as well as in the world, causing great affliction to patients. it has become the major issue in the treatment of chronic liver disease. the progression of chronic hepatitis b may lead to liver cirrhosis and hepatocellular carcinoma. hepatic fibrosis is the common pathological end stage of various chronic liver diseases regardless of the etiology, and blocking the occurrence and development of fibrosis of liver is very important in chronic hepatic diseases' treatment and prognosis. tcm has become the important therapy in treating chronic hepatitis, liver fibrosis, and liver cirrhosis. some scholars put forward the hypothesis that liver fibrosis and early liver cirrhosis can be reversed. they found out that the basic pathogenesis of liver fibrosis is weakened body resistance and blood stasis, so therapeutic method of strengthening body resistance and dispelling stasis was established, and "fu zheng hua yu capsules," a new drug for treating liver fibrosis, was developed. predominantly evaluated by liver tissue fibrosis, clinical researches were carried out to observe the curative effect of the therapeutic method of strengthening body resistance and dispelling stasis. the total inversion rate of liver tissue fibrosis was 52% to 58.3% compared before and after treatment, which also confirmed that liver fibrosis can be reversed and treated. the mechanism includes significantly inhibiting lipid peroxidation, the proliferation of hepatic stellate cell and activation of collagen expression, reducing inflammation of hepatocytic injury model, increasing the activity of matrix metalloproteinases, promoting the degradation of pathological liver collagen, and so on [44] [45] [46] . combining the macroscopic view with microscopic view, syndrome differentiation with disease differentiation, regional with global, taking stopgap measures with taking radical measures, supporting healthy aspects with eliminating pathogens, tumor treatment model by integrative medicine emphasizes contriving individual treatment plan and evaluation standard on the basis of biological characteristics and the course of disease. malignant tumors could be treated by tcm therapies such as reinforcing the vital energy and consolidating the constitution, supplementing qi and nourishing yin, and clearing away heat and toxic materials, combined with conventional therapies such as radiotherapy, chemotherapy, and surgery. tcm treatment has significances in decreasing toxicity and increasing efficacy on radiotherapy and chemotherapy. integrative medicine theory has a remarkable effect in alleviating symptoms such as dry mouth in hyperpyrexic consumption of yin syndrome and deficiency of both qi and yin syndrome caused by head and neck cancer after radiotherapy, relieving symptoms such as cough caused by acute radiation pneumonitis, improving immune function, and survival quality of postoperative patients, preventing the tumor from recurrence or metastasis and prolonging survival time. the new model of combining tcm and modern cancer treatment has attracted widespread attention in the world, which is known as "china model for cancer treatment" [47] . in addition, screening of tumor inhibition from more than 3,000 species of chinese herbs and nearly 300 chinese herbal compound, effective components having directly killing effect on cancer cell such as indirubin, camptothecin, vinblastine, matrine, and aclitaxel were extracted. some chinese herbs, having the effect of immunological enhancement and biological response modifier-like action such as polyporus, poria cocos, and mushroom, were also found out. apl is a special type of acute leukemic (al). tcm suggests that the pathogenesis of apl is weakened body resistance and excessiveness of pathogen, so therapeutic method of eliminating pathogenic factors and strengthening body resistance was established. some scholars developed the compound realgar natural indigo tablets (realgar, indigo naturals, salvia and radix pseudostell) on the basis of clearing away heat and toxic materials and supplementing qi with activating blood circulation and promoting hemogenesis method. 155 cases of apl patients were treated by the compound realgar natural indigo tablets and the remission rate was 97.42% after treating for 6 months. no side effect, serious infection, bleeding, and dic were found during the treatment course. it was also characterized by higher negative conversion rate of pml-rarî± fusion gene and simple application. the results demonstrated that the complete remission rate of treatment of the compound realgar natural indigo tablets were 10-15% higher than that of all-trans retinoic acid (atra). on this basis, the effect of post-remission therapy mainly with compound realgar natural indigo tablets on long-term survival of 74 cases patients with apl showed that the median remission time was 48 months with recurrence rate only 14.86% and 10-year survival probability was 75.38% [48] [49] [50] . since the 1970s of 20th century, the basic syndrome of type 2 diabetes included yin deficiency with internal excessive heat, deficiency of both qi and yin, and deficiency of both yin and yang, therefore, iii-type differentiation of type 2 diabetes was established and developed. it had already been adopted by national guidelines for new drug in the late 1980s. as deficiency of both qi and yin was the important basic syndrome of the disease, "jiang tang jia tablets," a new chinese herb of supplementing qi and nourishing yin, could improve insulin resistance, islet î²cell function, and the level of glucose and lipid metabolism, the total effective rate of which was 76.54%. in addition, researches of tang wei kang capsule treating early diabetic nephropathy and tang xin ping treating diabetic cardiopathy have gotten progress [51, 52] . some scholars also found out that blood stasis was another significant pathogenesis of type 2 diabetes due to the changes of hemorheology with different degree were found. so they advocated treating the disease by promoting blood circulation and removing blood stasis principally. based on this idea, promoting blood circulation by removing blood stasis recipes, such as nourishing yin and activating blood recipes and xian zhen tablet of reinforcing kidney and activating blood, were developed. those recipes have multilevel and multitarget effects, including improving symptoms, reducing blood glucose, improving blood rheology and blood flow, lowering triglycerides (tgs), and malondialdehyde (mda), enhancing activity of erythrocyte sod, na + -k + -atp enzyme and ca 2+ -mg 2+ -atp enzyme, and so forth. the experimental studies showed that the effect of xian zhen tablet includes lowering blood glucose and glycosylated hemoglobin, decreasing urine protein excretion, improving renal function, reducing the pathological changes of glomerular mesangial expansion and basement membrane thickening, decreasing ages amounts of renal cortex, and downregulating rage-mrna expression in renal cortex and endothelia of heart vessel. it provided a new idea for preventing and treating diabetic and chronic vascular complications [53, 54] . severe pancreatitis, namely, acute hemorrhagic necrotizing pancreatitis, is characterized by acute onset, rapid progress, high mortality, and poor prognosis. 65% of the death cases are due to complicating with acute respiratory distress syndrome (ards). according to the theoretical basis that "the six fu-viscera function well when unobstructed" and "the lung and the large intestine are interior-exteriorly related," acute pancreatitis is treated by expelling pathogens by purgation, and the average cure rate reached to 97%, while the average cure rate of severe pancreatitis was 80%. compared with our country and abroad, the mortality has reached the lowest level. qing yi decoction, a famous antipyretic and purgative prescription, protected the lung from injury in many aspects, by preserving the damage of gut barrier function, reducing or eliminating endotoxemia derived from the gut, inhibiting the production, and release of tnf, il-6, and the translocation of bacteria. the results may fully show the superiority of integrative medicine in treating serious diseases [55, 56] . a certain progress was also made on dermatosis and burn medicine by integrative medicine therapy. vitiligo was effectly treated by taking modified tao hong si wu decoction, external application of compound tar traditional chinese rubbing-drugs and melagenine extracted from placenta. evidence-based complementary and alternative medicine 243 patients with vitiligo were treated by modified tao hong si wu decoction and the total effective rate was 68.2%, the mechanism of which was related to upregulation of tyrosinase activity, increasing the melagenine content, and promoting melanocyte proliferation [57] . moist exposed burn therapy (mebt), a new therapeutic system of burn medicine in integrative medicine, has become the leading enabler throughout the world. it is found out that the burn wound should be kept in a moist but not macerated environment in order to promote in nature recovery and generation of the skin rather than in traditional dry environment. and the exact curative effect was obtained by mebt and moist exposed burn ointment (mebo) [58] . severe acute respiratory syndrome (sars) has aroused international attention for strong infectiousness, rapid progression, poor prognosis, and high mortality, which has no special effective therapy yet. 524 patients of sars in china were divided into integrative medicine treatment group (n = 318) and western medicine treatment group (n = 206). the existence rates for the symptoms of weakness, short breath, dyspnea in the first group were significantly lower than that in the second group after treatment. the duration of weakness was averagely shortened by 1.5 days in the first group. and short breath, dyspnea, and muscle aching pain were averagely shortened by 2 days, 1 day, and 2 days, respectively. researches showed that the effect of integrated therapy of tcm and wm for treating sars was superior to wm treatment alone, and the integrative medicine could improve clinical symptoms such as weakness, short breath, and dyspnea [59] [60] [61] . the exact clinical curative effect was also recognized by world health organization (who). diseases. previous achievements in clinical researches of integrative medicine showed that it is absolutely necessary to keep a foothold at frontier field of international medicine and life science and derive the wisdom and new theories from these subjects in order to find the innovation and breakthrough from subject cross and osmosis. aiming at the hot issues and knotty problems confronted in clinical medicine, we could put forward scientific hypotheses in exploring the etiology and pathogenesis of the disease and seek for the effective therapeutic principles and classical prescriptions. basing on the research mentioned above, the clinical efficacy should be objectively evaluated by randomized controlled trials (rct), and the potential mechanism should be illustrated ultimately. by summarizing the clinical regularity in time, it will contribute to the innovation of the medical theory and guide clinical practice. taking coronary heart disease as example, despite great advancements in the fields of basic and clinical researches made by modern medicine, there are still some issues to be resolved, such as acute coronary syndrome complicated by microvascular thrombosis, myocardial ischemia-reperfusion injury, no-reflow phenomenon, stent thrombosis, obvious subjective symptoms such as hypodynamia and shortness of breath remained after percutaneous coronary intervention (pci), and ventricular remodeling following myocardial infarction [62] [63] [64] . previous study showed that the prospects of integrative medicine is brightening in treatment for coronary stent thrombosis and protecting the myocardial ischemia-reperfusion injury. in addition, as viral infectious disease belonged to the category of epidemic febrile disease in tcm thousands years ago, chinese ancients had accumulated rich experience and formed a systematic and complete theory in treatment. currently, better therapeutic efficacy of viral infectious diseases could be achieved by combining two medical systems, especially in sars, n1h1, and bird flu. also, more similar breakthrough points of integrative medicine can be found, for instance, improving the low success rate of assisted reproductive technology (art) by combining art with tcm therapeutic method of reinforcing kidney and activating blood, and so forth. disease. "moving prevention and control strategy forward" is a national macrohealth policy, which well adapted to the new medical model, "physiological-psychological-socialenvironmental" model. it means that the focal point of medicine will be transferred from treating disease to health care, and disease prevention will be paid more attention to. therefore, the policy of "prevention first" will be carried out instead of traditional ideological concept "treatment is more major than prevention." it is similar to the tcm theory of "preventive treatment of disease," including principles of "preventing measure taken before the occurrence of disease" and "preventing measure taken after the occurrence of disease" in canon of internal medicine. concrete measures of "moving prevention and control strategy forward" include concept forward, funding forward, emphasis of the researches forward, and measures to be carried out forward. it could reduce the incidence of the major diseases from the origin and effectively control the medical expense and save resources in medicine and health. integrative medicine researches should also observe the principles above and pay more and more attention to improve the curative effect of common and frequent diseases. taking cardiovascular disease, for example, there are about 30% of the population in the world died from cardiovascular and cerebrovascular events, among which 62% of stroke and 49% of cardiovascular events were directly caused by hypertension [65] . according to the china cardiovascular reports (2008-2009), the occurrence and mortality of cardiovascular disease is still increasing in our country, and it is estimated that the number of patients with cardiovascular disease is at least 230 million. it also demonstrated that there were about 200 million hypertensive patients in china with more than 10 million patients increased annually. as the primary cardiovascular risk factor, the risk level of hypertension is equivalent to three other cardiovascular risk factors together. that is why more evidence-based complementary and alternative medicine 7 emphasis should be taken on prevention and intervention of earlier-stage hypertension in clinical researches of integrative medicine. additionally, hyperlipidemia, hyperglycemia, obesity, and other risk factors also should be paid more attention to. it is reported by world health organization (who) that if risk factors were controlled as early as possible, 80% of the disease can be prevented effectively, such as coronary heart disease, stroke, and diabetes. furthermore, paying 1 yuan in prevention will save 7-8 yuan in treatment. broadening the treatment system of modern medicine. jama, an international authoritative journal, have commented that traditional medicine should joint tracks with modern medicine. it suggested that not only should we inherit traditional academic thoughts but also keep an eye on modernization of tcm and study it in a scientific and systematic way [66] . the target is to fully digest the traditional chinese medicine, and apply it to modern medical system. how to do it? the first is further understanding of the essence in tcm, while giving up the dross. the second is illustrating the mechanism of the traditional therapy by using advanced scientific technology in order to improve the safety of the treatment and alleviate the toxicity adverse effect. viscera, meridians, prescriptions, and syndromes, the precious wealth in tcm left by our ancients, are worth deeply researching into. however, as the theory is profound, classical, and concise, combining with clinical practice is the unique way to understand the connotation. for example, the lung and the large intestine are interior-exteriorly related, that is to say, the lung was associated with the large intestine by meridians. in the clinical practice, dysfunction of the large intestine conduction could cause no descending of the lung qi, conversely, no descending of the lung qi also can result in obstruction of fu-qi. it is reported that introducing fuunblocking and purgation therapy into adults' acute pneumonia is a rapid and effective treatment. in the 70th of the last century, professor wang had applied liang ge san (cool diaphragm powder) to treat sirs and mods, which mainly manifested as yangming visceral substantive syndrome. the result demonstrated that the respiratory function of 80% patients with respiratory failure was rapidly improved, and the recovery was greatly promoted. among the patients with acute pancreatitis accompanied with mods, the therapy also received superior efficacy. all of these theories mentioned above, including blood stasis syndrome theory, theory of dispelling interior pathogenic factors and purgation, and theory of "treating the toxifying disease with poisonous agents," were all worth deeply excavated, which have being greatly broadened the treatment system of modern medicine. compared with tcm theory, chinese herbs are much easier to be modernized and recognized. therefore, it is of great significance in promoting modernization, industrialization, and industrialization of the chinese herbs, by ways of combining modern technology with fully understanding of classical prescriptions and herbs. china is a great power with rich herb resources. according to the records in formula dictionary of traditional chinese medicine, there are approximately 100 thousand prescriptions, including special prescriptions and herbs for certain diseases. the classical prescriptions and herbs provided with definite clinical indications are of more meaning to be developed. that will provide an effective shortcut to improve the capability of developing new drugs, which is characterized by definite chemical structure, explicit action mechanism, obviously curative effect, advanced formulations, convenience for taking, and low price. at present, the effective fractions and monomers extracted from chinese herbs had obtained reliable clinical benefits. for instance, artemisinin extracted from sweet wormwood (artemisia annua l.) have a definite effect in the treatment of falciparum malaria, which had been confirmed by multinational joint researches. the new therapy developed by professor tu youyou has saved millions of lives across the globe, especially in the developing world, which had also been listed in the catalog of "essential medicines" by the world health organization (who) [67] [68] [69] [70] [71] . therefore, professor tu was awarded the 2011 laskerâ�¼debakey clinical medical research award for the discovering artemisinin and its utility for treating malaria. the research will raise a new global round of climaxes of modernization and internationalization of tcm. in addition, indirubin extracted from indigo naturals in danggui long hui wan (pill of angelica sinensis, gentian and aloe) could treat leukemia. diterpenonid versicolaction extracted from tripterygium wilfordii hook can be used as immunosuppressive agents for treating rheumatoid arthritis (ra). biphenyl dimethyl dicarboxylate (ddb) extracted from schisandra chinensis could decrease the alt and ast activity. tetramethylpyrazine extracted from ligusticum chuanxiong hort has showed a good effect for ischemic cerebrovascular disease. cantharidin extracted from mylabris could treat liver cancer. moreover, other active components such as ginsenoside, total puerarin flavonoids, polyporus umbellate polysaccharides, ganoderma lucidum polysaccharide, anisodamine, tanshinone, trichosanthin, tetrahydropalmatine, tetrandrine, rubidate, ilexonin a, and ferulic acid sodium. evidence-based medicine (ebm) is a new subject quickly developed in the clinical medicine field in the 1990s. the core thinking is to combine evidence, personal experiences, and patients' actual situation to formulate scientific measures for preventing diseases, promoting the recovery and improving life quality. among them, clinical evidence originates mainly from randomized controlled trial (rct), systematic review, and meta-analysis. with medical science transforming from traditional experience medicine into evidence-based medicine, fundamental changes have taken place in clinical medicine. therefore, following the principle of respecting science and evidence, it is of the utmost importance to enhance the level of clinical research evidence in tcm and integrative medicine [72] [73] [74] . it is noteworthy that the treatment concept, formula corresponding to syndrome, lied in classical works of tcm, is similar to the ideas of ebm. however, it had been ignored for a long time. the theory of syndrome differentiation and formula corresponding to syndrome are two characteristic inheritance veins in tcm. generally speaking, the former is always the mainstream ideology in tcm, while the latter has been paid little attention. clinical medication based on pathogenesis is the core idea of syndrome differentiation, while clinical medication based on formula syndrome is not exactly the same as it. the most significant difference between them is whether giving attention to the objective evidences of formula utilization. the theory of formula corresponding to syndrome attaches great importance to the objective indications of herbs, which mainly comes from long-term, large-scale and repeated clinical trials by chinese ancients. as the indications of herbs are objective and concrete, clinical effect could be repeated at anytime, anywhere, and for anybody. so it is suggested that, facing with one patient, 10 tcm physicians may prescribe the identical prescription and get rapid treatment effect simultaneously according to the indications of formulae and herbs. this is just the reason why the significant curative effect can be by classical prescriptions get in treating severe and lingering illness. the extractive process of indications is similar to the evidencebased research, and indications of herbs have probably exceeded the category of expert experience in ebm. therefore, carrying out clinical studies under guidance of ebm and formula corresponding to syndrome is helpful to summarize the indications of formulae and herbs, and enhance the level of clinical research evidence in tcm [75] [76] [77] [78] [79] . the history of man's science development showed that the crossing and blending of two kinds of knowledge systems will be able to set up a new knowledge system. integrative medicine, an unprecedented task in present world, is a new pattern of medicine, which is formed by the integration of tcm and wm. the current situation of integrative medicine career was highly evaluated by academician han qide. he pointed out that integrative medicine is an inevitable choice for the development of chinese medicine and the breakthrough point of development for modern medicine, which have unique advantages and will play an important role in china. with changing of the disease chart, increasing of metabolic disease, malignant tumor, iatrogenic disease and drug-induced disease, and the coming of senile society as well as the change of people's views on health and medical mode, both opportunities and challenges have been brought to the development of integrative medicine. thus we believed that under the guidance of "pay equal attention to both wm and tcm" and "implementing the integrative medicine and developing tcm," integrative medicine will obtain great achievements in creating new medicine and pharmacology, which builds on the combination of both wm and tcm, and make tremendous contributions for the great rejuvenation of the chinese nation and human health care [80] . mao zd and integrative medicine chinese medicine pattern diagnosis could lead to innovation in medical sciences integrative medicine: the experience from china past and present of combination of disease differentiation and syndrome differentiation a systematic analysis of the theory and practice of syndrome differentiation pondering on syndrome differentiation of diseases chinese medicine pattern differentiation and its implications for clinical practice computerized stepwise regression for blood stasis symptom-complex in coronary heart diseases study on correlation of blood-stasis syndrome and its accompanied syndromes with pathological changes showed in coronary angiography and restenosis after percutaneous coronary intervention relationship between coronary angiography and syndrome differentiation type of tcm research on relationship between coronary lesion and blood stasis syndrome based on coronary angiography study on syndrome element characteristics and its correlation with coronary angiography evidence-based complementary and alternative medicine 9 prospective research on the deficiency-syndrome of the viscera of 1069 patients of coronary heart disease with multiple rotating center study on syndrome elements and their association law of angina pectoris with 5099 cases reported on literatures establishment and primary screening of primitive entry pool of rating scale for patient-reported outcomes of coronary heart disease angina xs0601 reduces the incidence of restenosis: a prospective study of 335 patients undergoing percutaneous coronary intervention in china inhibition of vascular remodelling in a porcine coronary injury model by herbal extract xs0601 a multi-center randomized double-blind placebocontrolled trial of xiongshao capsule in preventing restenosis after percutaneous coronary intervention: a subgroup analysis of senile patients analysis on outcome of 5284 patients with coronary artery disease: the role of integrative medicine modern research on purgation method of traditional chinese medicine-application of the method in acute abdominal diseases and experimental studies clinical and experimental study of effect on acute phase protein of multiple organ dysfunction syndrome treated with dachengqi decoction effect of dachengqi granules on level of endotoxin in ente rogenous endotoxemia in rats clinical observations on 6 cases of leukemia treated by ailing injection study on chinese herbs containing arsenic treating leukemia studies on treatment of leukemia with traditional chinese drugs containing arsenic arsenic trioxide, a therapeutic agent for apl use of arsenic trioxide (as 2 o 3 ) in the treatment of acute promyelocytic leukemia (apl): i. as 2 o 3 exerts dose-dependent dual effects on apl cells use of arsenic trioxide (as 2 o 3 ) in the treatment of acute promyelocytic leukemia (afl): ii. clinical efficacy and pharmacokinetics in relapsed patients in vitro studies on cellular and molecular mechanisms of arsenic trioxide (as 2 o 3 ) in the treatment of acute promyelocytic leukemia: as 2 o 3 induces nb4 cell apoptosis with downregulation of bcl-2 expression and modulation of pml-rarî±/pml proteins ancient remedy performs new tricks complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide clinical study on effect of xiongshao capsule on restenosis after percutaneous coronary intervention clinical effect of xiongshao capsule on preventing restenosis post-ptca or/and stenting effect of xiongshao capsule on vascular remodeling in rabbit with experimental atherosclerosis prevention and treatment of restenosis after pta in rabbit with xuefu zhuyu concentrated pills effect of xiongshao capsule on vascular remodeling in porcine coronary balloon injury model clinical study on myocardium protection of huxinbao during open heart surgery of cardiopulmonary bypass clinical study on effection of replenishing qi, activating blood circulation and the compatibility of replenishing qi and activating blood circulation in myocardial ischemia reperfusion injury during open heart surgery of cardiopulmonary bypass bacteria and bacterial toxin treated simultaneously' in 50 patients with infections multiple system organ failure (msof): a new theory and verification of its clinical value bacteria, bacterial toxin and inflammatory mediator treated simultaneously is a new strategy for the treatment of severe sepsis from 'bacteria and bacterial toxin treated simultaneously' to 'four therapeutic principles and methods treating four main types of syndromes': developing and perfection of syndrome differentiation of multiple organ dysfunction syndrome by integrative medicine research of the new strategy for the treatment of systemic inflammatory response syndrome and mutiple organ evidence-based complementary and alternative medicine dysfunction syndrome: an experimental study of the effect of traditional chinese herb-'xuebijing protective effects of xuebijing on tissue and endothelial cells in rats with septic multiple organ dysfunction serum pharmacological effects of fuzheng huayu decoction on ito cell proliferation and collagen synthesis in rats clinic and mechanism study of health-supporting and stasis-resolving decoction on chronic hepatitis b effect of fuzheng huayu recipe in treating posthepatitic cirrhosis integrative medicine: a characteristic china model for cancer treatment clinical study on the treatment of acute promyelocytic leukemia mainly with composite indigo naturalis tablets effect of postremission therapy mainly with compound huangdai tablet on long-term survival of patients with acute promyelocytic leukemia the influence on long-term survey of the patients with acute promyelocytic leukemia treated alternatively with compound huangdai tablets and chemotherapy study on prof. lin lan's theory of iii-type differentiation of type 2 diabetes clinical observation on treatment of diabetic nephropathy by tangweikang capsule effect of xianzhen tablet on content of advanced glycosylation end products (ages) and mrna expression of age-specific cellular receptor in renal cortex of diabetic rats regulative effects of xianzhen tablets on the expression of rage-mrna in the aorta in diabetic rats effect of qingyi decoction on rats with acute lung injury caused by severe acute pancreatitls effect of qingyitang on acute lung injury induced by severe acute pancreatitis in rats curative efficacy and mechanisms of modified tao-hong-si-wu-tang, a traditional chinese medicine, in the treatment of vitiligo chinese medical concept of moist exposed burn therapy effect of integrated therapy of tcm and wm on clinical symptoms in 318 cases of sars preliminary study on clinical efficacy of integrative chinese and western medicine in treating severe acute respiratory syndrome (sars) efficacy evaluation of tcm in treatment of patients with severe acute respiratory syndrome (sars) in recovery stage coronary microembolization: from bedside to bench and back to bedside reperfusion injury, microvascular dysfunction, and cardioprotection: the "dark side" of reperfusion prevention of no-reflow phenomenon in acute coronary syndrome hypertension, society, and public policy promoting the integration of tcm and wm by fully utilizing modern science and technology a new sesquiterpene lactone-qinghaosu clinical studies on the treatment of malaria with qinghaosu and its derivatives china cooperative research group on qinghaosu and its derivatives as antimalarials the discovery of artemisinin (qinghaosu) and gift from chinese medicine artemisinin (qinghaosu) and artemisinin derivatives evaluation of clinical therapeutic effect for traditional chinese medicine evidence-based medicine and integration of traditional chinese, and western medicine an innovative method to accommodate chinese medicine pattern diagnosis within the framework of evidence-based medical research connotation and principle of formulae corresponding to syndromes clinical application of the tcm classic formulae for treating chronic bronchitis connotation of syndrome in the theory of prescriptions corresponding to syndromes formula syndrome differentiation is different from syndrome differentiation discussion of related problems in herbal prescription science based on objective indications of herbs integrating traditional medicine with biomedicine towards a patient-centered healthcare system the current work was partially supported by the national basic research program of china (973 program no. 2003cb517103) and the national natural science foundation project of china (no. 90209011). the first author and the corresponding author contributed equally in this paper. all authors manifest that there is no conflict of interests. key: cord-314538-l4ek54cu authors: lin, peng; ye, xiujuan; ng, tb title: purification of melibiose‐binding lectins from two cultivars of chinese black soybeans date: 2008-12-16 journal: acta biochim biophys sin (shanghai) doi: 10.1111/j.1745-7270.2008.00488.x sha: doc_id: 314538 cord_uid: l4ek54cu a dimeric 50 kda melibiose‐binding lectin was isolated from the seeds of the cultivar of soybean (glycine max), called the small glossy black soybean. the isolation procedure comprised ion exchange chromatography on q sepharose, sp sepharose and mono q followed by gel filtration on superdex 75. the lectin was adsorbed on all three ion exchangers, and it exhibited an n‐terminal sequence identical to that of soybean lectin. of all the sugars tested, melibiose most potently inhibited the hemagglutinating activity of the lectin, which was stable between ph 3‐12 and 0‐70 °c. the lectin evoked maximal mitogenic response at about the same molar concentration as con a. however, the response was much weaker. the soybean lectin inhibited the activity of hiv‐1 reverse transcriptase as well as the proliferation of breast cancer mcf7 cells and hepatoma hepg2 cells with an ic(50) of 2.82 μm, 2.6 μm and 4.1 μm, respectively. there was no antifungal activity. another lectin was isolated from a different cultivar of soybean called little black soybean. the lectin was essentially similar to small glossy black soybean lectin except for a larger subunit molecular mass (31 kda), a more potent mitogenic activity and lower thermostability. the results indicate that different cultivars of soybean produce lectins that are not identical in every aspect. a dimeric 50 kda melibiose-binding lectin was isolated from the seeds of the cultivar of soybean (glycine max), called the small glossy black soybean. the isolation procedure comprised ion exchange chromatography on q sepharose, sp sepharose and mono q followed by gel filtration on superdex 75. the lectin was adsorbed on all three ion exchangers, and it exhibited an n-terminal sequence identical to that of soybean lectin. of all the sugars tested, melibiose most potently inhibited the hemagglutinating activity of the lectin, which was stable between ph 3−12 and 0−70 ºc. the lectin evoked maximal mitogenic response at about the same molar concentration as con a. however, the response was much weaker. the soybean lectin inhibited the activity of hiv-1 reverse transcriptase as well as the proliferation of breast cancer mcf7 cells and hepatoma hepg2 cells with an ic 50 of 2.82 µm, 2.6 µm and 4.1 µm, respectively. there was no antifungal activity. another lectin was isolated from a different cultivar of soybean called little black soybean. the lectin was essentially similar to small glossy black soybean lectin except for a larger subunit molecular mass (31 kda), a more potent mitogenic activity and lower thermostability. the results indicate that different cultivars of soybean produce lectins that are not identical in every aspect. keywords purification; melibiose-binding lectin; chinese black soybean lectins are proteins that exhibit carbohydrate-binding specificity. they can be divided into groups, such as mannose-binding, glucose/mannose-binding, nacetylglucosamine-binding, galactose-binding, nacetylgalactosamine-binding, fucose-binding, and sialic acid-binding, according to their carbohydrate-binding specificity. lectins have been isolated from a diversity of organisms including flowering plants [1] , animals [2, 3] , fungi [4] , and bacteria [5] . many biological activities, including anti-proliferative, anti-tumor, immunopotentiating, anti-insect, antifungal, antiviral and antibacterial activities, have been found in lectins [6−11] . as a result, lectins have captured the attention of many investigators. soybean is an agricultural crop of great importance. from it, many important proteins and non-proteinaceous compounds have been isolated. they comprise trypsin inhibitors [12] , lectins [13] , antifungal proteins [14] , and phytoestrogens [15] . phytoestrogens are reported to be protective against osteoporosis and cardiovascular disease [15, 16] . soybean trypsin inhibitor has an anti-tumor action [17] . soybeans have been made into a variety of food products including drinks and bean curds. as stated in ben cao gang mu by li shizhen published in 1590, the black soybean is used in traditional chinese medicine for treating backaches, combating debility and preventing aging. according to current popular literature, the black soybean has more protein, potassium and vitamins than the yellow soybean [18] . the former has chlorophyll and black pigment while the latter has carotenoids. different cultivars of the same species may produce different proteins; for example, the miraculin-like antifungal protein sativin and the ribosome-inactivating protein pisavin, which has similar sequence to miraculin, are produced by different cultivars of pisum sativum, the sugar snap and the garden pea, respectively [19, 20] . different cultivars of soybean exist, including the yellow soybean, chinese black soybean and japanese black soybean. the yellow soybean produces trypsin inhibitors of the bowman-birk type and also the kunitz type [12] . the chinese dull black soybean produces only the kunitztype trypsin inhibitor [21] , whereas the japanese black soybean produces only the bowman-birk type [22] . thus different cultivars may have dissimilar protein products. lectin from yellow soybeans has been isolated and characterized. however, it is not known if the chinese black soybean produces the same lectin. the chinese black soybean is a special cultivar of soybean that differs from the common yellow soybean in pharmacological activities in traditional chinese medicine. thus, it was deemed worthwhile to isolate a lectin from each of the two cultivars of chinese black soybean, namely the chinese small glossy black soybean and the chinese little black soybean, to compare them with the lectin from common yellow soybean, and to explore other potentially exploitable activities of the lectins. small glossy black soybeans and little black soybeans (glycine max) from china were purchased from a local vendor. they were authenticated by prof. shiuying hu, honorary professor of chinese medicine, the chinese university of hong kong (hong kong, china). the same isolation procedure and assay were employed for both cultivars. the beans were homogenized in distilled water. tris-hcl buffer (ph 7.4) was added to the dialyzed supernatant until the concentration of tris attained 10 mm. the supernatant was then loaded on a 5 cm×20 cm column of q sepharose (ge healthcare, hong kong, china) in 10 mm tris-hcl buffer (ph 7.4). after removing the unadsorbed fraction, adsorbed fractions (q1, q2 and q3) were eluted with starting buffer containing 0. 2, 0.5 and 1 m nacl, respectively. after examining the hemagglutinating effect of fractions q1−3, the lectin-enriched fraction q1 was dialyzed against 10 mm nh 4 oac buffer (ph 4.5) at 4 ºc, and then chromatographed on a 2.5 cm×20 cm column of sp sepharose (ge healthcare), which had previously been equilibrated with and was then eluted with 10 mm nh 4 oac buffer (ph 4.5). unadsorbed proteins were eluted with the buffer, and then adsorbed proteins were eluted stepwise with the same buffer containing 0.2 m nacl and 1 m nacl, respectively. the fraction eluted with 0.2 m nacl was then applied on a 1 ml mono q (ge healthcare) column in 10 mm nh 4 hco 3 buffer (ph 9). following elution of unadsorbed materials, adsorbed proteins (fraction s1, s2 and s3), were desorbed with two nacl concentration gradients (0−0.3 m and adsorbed proteins 0.3−1 m) in 10 mm nh 4 hco 3 buffer (ph 9). the adsorbed fraction (s2), which was eluted by approximately 0.2 m nacl, was the lectin-en-riched fraction. it was dialyzed, lyophilized and subjected to gel filtration on a superdex 75 hr 10/30 column (ge healthcare) using an akta purifier (ge healthcare) in 10 mm nh 4 hco 3 buffer (ph 9.4). the first eluted absorbance peak constituted purified lectin. molecular mass determination by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (sds-page) and by fast protein liquid chromatography (fplc)gel filtration sds-page was carried out in accordance with the procedure used by nielsen and reynolds [23] , using a 12% resolving gel and a 5% stacking gel. the gel was cast on the miniprotein set ii (bio-rad, shanghai, china). samples were diluted with sample loading buffer (10% glycerol, 0.4% sds, 0.005% bromophenol blue and 20 mm edta in 0.5 m tris-hcl, ph 7.5) followed by addition of 5% βmercaptoethanol. the samples were boiled in a water bath for 10 min. electrophoresis was performed at a constant current of 10 ma at room temperature. at the end of electrophoresis, the gel was stained with coomassie brilliant blue. fplc-gel filtration was carried out using a superdex 200 hr 10/30 column (ge healthcare) that had been calibrated with molecular-mass standards (ge healthcare). amino acid sequence analysis was carried out using an hp g1000a edman degradation unit and an hp 1000 hplc system from hewlett/packard (palo alto, usa) [20] assay of hemagglutinating activity in the assay for lectin (hemagglutinating) activity, a serial two-fold dilutions of the lectin solution in microtiter uplates (50 µl) were mixed with 50 µl of 2% suspension of rabbit red blood cells in phosphate-buffered saline (ph 7. 2) at 20 ºc. the results were recorded after about 1 h, when the blank containing only red cells had fully sedimented and appeared as a dot at the bottom of the well. the hemagglutination titer, defined as the reciprocal of the highest dilution exhibiting hemagglutination, is defined as one hemagglutination unit. specific activity is the number of hemagglutination units per mg protein [11] . the hemagglutinating inhibition tests to investigate inhibition of lectin-induced hemagglutination by various carbohydrates for 30 min at room temperature were performed in a manner analogous to the hemagglutination test [11] . serial two-fold dilutions of sugar samples were prepared in phosphate buffered saline. all of the dilutions were mixed with an equal volume (25 µl) of a solution of the lectin with 32 hemagglutination units. the mixture was allowed to stand for 30 min at room temperature, and then mixed with 50 µl of 2% rabbit erythrocyte suspension. the minimum concentration of the sugar in the final reaction mixture, which completely inhibited 32 hemagglutination units of the lectin preparation, was calculated. the effects of temperature and ph on hemagglutinating activity of the lectin were examined [11] . a solution of lectin was incubated at various temperatures (0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 °c) for 30 min. the tubes were then put on ice and assay of hemagglutinating activity was then carried out. a solution of lectin was incubated at various ph values (ph 1−14) for 30 min. the reaction mixtures in the tubes were neutralized and assay of hemagglutinating activity was then carried out. incubation of splenocytes from balb/c mice (20−25 g) was carried out at 37 ºc in a humidified atmosphere of 5% co 2 in the presence or absence of the lectin for 24 h in a 96-well culture plate. we added 10 µl (methyl-3 h) thymidine (0.25 µci; ge healthcare) before the splenocytes were incubated for another 6 h under the same conditions. the splenocytes were then harvested onto a glass fiber filter, and the radioactivity was measured [24−26] . tumor cells, mcf7 and hepg2, in their exponential growth phase were seeded into a culture plate and incubated for 3 h before addition of the lectin. incubation was carried out for another 48 h. radioactive precursor, 1 µci of (methyl-3 h)thymidine, was then added to each well and incubated for 6 h. the cultures were then harvested, and the incorporated radioactivity was determined [25] . the assay was carried out by using an enzyme-linked immunosorbent assay kit as described by collins et al [16] . the assay for hiv reverse transcriptase inhibitory activity was carried out in accordance with instructions supplied with the assay kit from boehringer mannheim (berlin, germany) since some antifungal proteins possess this activity. the assay takes advantage of the ability of reverse transcriptase to synthesize dna, starting from the template/primer hybrid poly(a) oligo(dt)15. the digoxigenin-and biotin-labeled nucleotides in an optimized ratio are incorporated into one of the same dna molecule, which is freshly synthesized by the reverse transcriptase (rt). the detection and quantification of synthesized dna as a parameter for rt activity follows a sandwich elisa protocol. biotin-labeled dna binds to the surface of microtiter plate modules that have been pre-coated with streptavidin. in the next step, an antibody to digoxigenin, conjugated to peroxidase, binds to the digoxigenin-labeled dna. in the final step, the peroxidase substrate is added. the peroxidase enzyme catalyzes the cleavage of the substrate, producing a colored reaction product. the absorbance of the sample at 405 nm can be determined using a microtiter plate reader and is directly correlated to the level of rt activity. a fixed amount (4− 6 ng) of recombinant hiv-1 reverse transcriptase was used. the inhibitory activity of the lectin was calculated as percent inhibition as compared to a control without the lectin [27] . the assay of hiv-i integrase and severe acute respiratory syndrome (sars) proteinase activities was conducted as previously reported [28] . hiv-1 integrase assay a non-radioactive elisa-based hiv-1 integrase assay was performed according to the dna-coated plate method. in this study, 1 µg of smailinearized pbluescript sk was coated onto each well in the presence of 2 m nacl as target dna. the donor dna was prepared by annealing vu5br (5'-biotin-gtgtggaaaatctctagcagt-3') and vu5 (5'-actgctagagattttccacac-3' ) in solution containing 10 mm tris-hc1, ph 8.0, 1 mm edta and 0.1 m nacl at 80 ºc followed by 30 min at room temperature. integrase reaction was performed in 20 mm hepes (ph 7.5) containing 10 mm mncl 2 , 30 mm nacl, 10 mm dithiothreitol and 0.05% nonidet-p40 (sigma, st. louis, usa). after the integrase reaction, the biotinylated dna immobilized on the wells was detected by incubation with streptavidin-conjugated alkaline phosphatase (boehringer mannheim), followed by colorimetric detection with 1 mg/ml p-nitrophenyl phosphate in 10% diethanolamine buffer (ph 9.8) containing 0.5 mm mgcl 2 . the absorbance of each well due to the alkaline phosphatase reaction was measured at 415 nm. screening for inhibitory effect on sars coronavirus (cov) protease the activity of sars cov protease was indicated by a cleavage of designed substrate which was composed of two proteins linked by a cleavage site for sars cov protease. the reaction was performed in a mixture containing 5 µm sars cov protease, 5 µm sample, 20 µm substrate and buffer (20 mm tris-hcl, ph 7.5, 20 mm nacl and 10 mm beta-mercaptoethanol) for 40 min at 37 ºc. after 40 min, the reaction was stopped by heating at 100 ºc for 2 min. then the reaction mixture was analyzed by sds-page. if sars cov protease is inhibited by the test sample, there is only one band, which is the intact substrate, shown in sds-page. the crude extract of small glossy black soybeans was fractionated on a q sepharose column into an unadsorbed fraction and three adsorbed fractions (q1, q2 and q3) were obtained by stepwise elution with 0.2, 0.5 and 1 m nacl in tris-hcl buffer [ fig. 1(a) ]. hemagglutinating activity was confined to fraction q1. this fraction was resolved on an sp sepharose column into an unadsorbed fraction and two adsorbed fractions (sp1 and sp2) respectively when eluted with 0.2 m nacl and 1 m nacl in the nh 4 oac buffer [ fig. 1(b) ]. hemagglutinating activity resided in the smaller fraction sp1. fraction sp1 was further resolved by ion exchange chromatography on an fplc-mono q column into a tiny unadsorbed fraction and several adsorbed fractions [ fig. 1(c) ]. hemagglutinating activity was recovered only in fraction s2, which was subsequently separated on a superdex 75 column into a sharp larger fraction and a smaller fraction. activity was detected only in the larger fraction [ fig. 1 (d) ]. from chinese little black soybeans, a lectin was isolated using the same procedure except for the omission of ion exchange chromatography on mono q (fig. 2) . the small glossy black soybean lectin product appeared as a single band with a molecular mass of 25 kda in sds-page (fig. 3) , and exhibited a single peak with a molecular mass of 50.2 kda in gel filtration on superdex 75 [ fig. 1(d) ]. the little black soybean lectin appeared as a single band with a molecular mass of 31 kda in sds-page (fig. 3) , and exhibited a single peak with a molecular mass of 62 kda in gel filtration on superdex 75 [ fig. 2(c) ]. the small glossy black soybean lectin was obtained with a specific activity of 7168 u/mg and a purification fold of 29 ( table 1 ). the n-terminal sequence of the lectin was 1 aetvsfswnkfvpkq 15 , which was identical to lectin from yellow soybean and similar to partial sequences near the n-terminals of medicago sativa ( 27 aettsfs-itkfvpdq 41 ) and robinia pseudoacacia lectins ( 35 esvsfsftkfvp 46 ). there was only one peak in every sequencing cycle, indicating that the lectin preparation was homogeneous. it appears that soybean lectins are similar in n-terminal sequence to only some members of the pea family fabaceae. the n-terminal sequence of little black soybean lectin was identical to that of small glossy black soybean lectin ( table 2) . determination of sugar specificity, ph stability and thermostability of hemagglutinating activity melibiose, arabinose, raffinose and galactose at 40 mm concentration inhibited the hemagglutinating activity of the small glossy black soybean lectin. however, glucose, fucose, rhamnose, mannose, lactose, xylose, glucuronic acid, polygalacturonic acid, and mannosamine had no effect ( table 2 ). the hemagglutinating activity was stable after exposure for 30 min to the ph range 3−12 and the temperature range 0−70 ºc. the carbohydrate specificity of little black soybean lectin was identical to that of small glossy black soybean lectin. the hemagglutinating activity of little black soybean lectin was stable only up to 40 ºc for 20 min, but the small glossy black soybean lectin was stable up to 70 ºc for 30 min. the small glossy black soybean lectin inhibited proliferation of hepg2 cells and mcf7 cells with an ic 50 of 4.1 µm and 2.6 µm, respectively (fig. 4) and the activity of hiv-1 reverse transcriptase with an ic 50 of 2.82 µm (fig. 5) . chromatographic glucose, fucose, rhamnose, mannose, lactose, xylose, glucuronic acid, polygalacturonic acid, and mannosamine were all inactive when tested in 500 mm. +, inhibition of hemagglutinating activity of lectin; −, no inhibition of hemagglutinating activity of lectin. the mitogenic activity of the lectin on mouse splenocytes is shown in fig. 6 . both the lectin and con a stimulated maximal mitogenic response at similar concentrations. however, the maximal response achieved by small glossy black soybean lectin was weaker than that evoked by con a (fig. 6) . small glossy black soybean lectin did not inhibit hiv integrase or sars proteinase when tested up to 20 μm (data not shown). the little black soybean lectin inhibited hiv-1 reverse transcriptase with an ic 50 of 3.54 μm (fig. 5) . the maximal mitogenic response that both the small glossy black soybean lectin and the little black soybean lectin elicited was about 20% of the maximal response to con a. the maximal mitogenic response was achieved by similar concentrations of small glossy black soybean lectin, little black soybean lectin and con a (fig 6) . a comparison of the characteristics of the two black soybean lectins isolated in this study with those of soybean lectins is presented in table 3 . the two chinese small glossy black soybean lectins differ somewhat from common yellow soybean lectin (hereinafter referred to as soybean lectin) in carbohydrate specificity. soybean lectin is galactose-specific [13] , whereas chinese black soybean lectins are melibiose-specific although the latter two are also galactose-specific. the two chinese black soybean lectins potently inhibit hiv-1 reverse transcriptase (ic 50 about 2.8 µm). it is known that some lectins exhibit hiv-1 reverse transcriptase inhibitory activity and inhibit hiv replication [27, 29, 30] . however, just like the french bean defensin [28] , the two black soybean lectins are devoid of hiv-1 integrase inhibitory and sars proteinase inhibitory activity. the antiproliferative and anti-tumor activities of lectins are well documented [25,27,31−33] . chinese small glossy black soybean lectin exerts potent antiproliferative activity toward hepg2 and mcf7 cells, with an ic 50 of 4.1 µm and 2.6 µm, respectively. both black soybean lectins manifest weaker mitogenic activity than con a toward splenocytes. this is in line with findings on other lectins [24, 25] . the mitogenic activity of soybean lectin toward human and murine lymphocytes is enhanced after polymerization by physical or chemical means [34] . soybean lectin has immunomodulatory and anti-tumor actions [34] . natural suppressor cells from the spleen and cyclophosphamide-generated suppressor cells react specifically with soybean lectin and can thus be isolated by agglutination from the bone marrow [35, 36] . soybean lectin is employed for purging the marrow of t cells during treatment of acute lymphoblastic leukemia in order to decrease the risk of graft-versus-host disease [37] ; soybean lectin reacts with and eliminates cancer cells from the marrow [38] . this investigation's findings on the two black soybean lectins' mitogenic activity towards splenocytes and their antiproliferative activity toward tumor cells are consistent with previous observations [34, 38] . an anti-tumor action mechanism of soybean lectins has been proposed involving the action of the lectins on tumor cell membranes, the reduction of tumor cell proliferation, the induction of tumor-specific cytotoxicity of macrophages, and apoptosis. thus, tumor cells are more susceptible to attack by macrophages after treatment with lectins. furthermore, lectins exert an immunomodulatory effect on altering interleukins production [39] . soybean lectin reportedly reacts preferentially with some rumen fungi [40] , but an antifungal action has not been demonstrated. likewise, the two black soybean lectins are devoid of antifungal activity (data not shown). the lectins started to evoke a mitogenic response at a lower concentration than con a although the maximal response was much smaller in magnitude. in fact, to date, only a handful of lectins have been reported with antifungal activity [41, 42] . small glossy black soybean lectin has fair ph stability and thermostability. its hemagglutinating activity is preserved in the ph range 3−12 and in the temperature range 0−70 ºc. little black soybean lectin is stable in the ph range 3−12 and in the temperature range 0−40 ºc. yellow soybean lectin is active in the ph range 3−12 and in the temperature range 0−50 ºc. french bean lectin is stable in ph range 4−10 and in the temperature range 0−90 ºc [30] . hence the french bean lectin and small glossy black soybean lectin appear to be similar in stability. the protocol employed in the present investigation for purifying the two black soybean lectins entailed successive ion exchange chromatography on q sepharose, sp sepharose and mono q (with the exception of little black soybean lectin), and gel filtration on superdex 75. french bean lectin was isolated using a similar procedure involving chromatography on sp sepharose, affi-gel blue gel, q sepharose and superdex 200 [28] . the two black soybean lectins were adsorbed on sp sepharose and q sepharose. thus, the three leguminous lectins appear to have similar chromatographic behavior. a 29-fold purification was obtained in the present study for small glossy black soybean lectin compared to 10-fold purification in the case of french bean lectin [28] . thus lectins from the two cultivars of chinese black soybean appear to differ in subunit molecular mass, thermostability and mitogenic activity, although they share the same n-terminal amino acid sequence and carbohydrate specificity and have similar hiv-reverse transcriptase inhibitory activity. this finding is reminiscent of the observation that lectins from different cultivars of the bean phaseolus vulgaris, such as the pinto bean [24] , haricot bean [25] , red kidney bean [30] , and dark red kidney bean [26] , have similar but not identical n-terminal sequences. their other characteristics, including carbohydrate specificity and antiproliferative activity toward tumor cells, may not be all alike [24] [25] [26] 30] . the results of the present investigation indicate that different soybean cultivars produce lectins that are not identical. the lectins isolated in the present study are characterized by potent antiproliferative activity toward cancer cells and inhibitory activity against hiv-1 reverse transcriptase, as well as moderate ph stability and thermostability. its antiproliferative activity against cancer cells of mammalian origin and hiv-1 reverse transcriptase inhibitory activities indicate that it is a defense protein. this is in line with the defense function of lectins in plants [43] . as such, the biological activities of black soybean lectins are potentially exploitable in medicine. isolation and characterization of two korean mistletoe lectins isolation and characterization of l-rhamnose-binding lectin, which binds to microsporidian glugea plecoglossi, from ayu (plecoglossus altivelis) eggs identification and characterization of an intracellular lectin, calnexin, from aspergillus oryzae using n-glycan-conjugated beads structural basis for mannose recognition by a lectin from opportunistic bacteria burkholderia cenocepacia a tuber lectin from arisaema jacquemontii blume with anti-insect and anti-proliferative properties purification of a lectin from eugenia uniflora l. seeds and its potential antibacterial activity antitumor effect of plant lectins the role of galectins in the initiation, amplification and resolution of the inflammatory response the role of dectin-1 in antifungal 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inhibitor on spontaneous, experimental and peritoneal disseminated metastasis in mouse model the great dictionary of chinese medicine sativin: a novel antifungal miraculinlike protein isolated from legumes of the sugar snap pisum sativum var. macrocarpon purification and characterization of novel ribosome inactivating proteins, alpha-and beta-pisavins, from seeds of the garden pea pisum sativum a stable trypsin inhibitor from chinese dull black soybean with potentially exploitable activities a b owma n-b i r k t r ypsi n i nhi bi tor wi t h antiproliferative activity from hokkaido large black soybeans measurements of molecular weights by gel electrophoresis purification and characterization of a galactose-specific lectin with mitogenic activity from pinto beans a h om o te tr a me r i c a gg lu ti n in w it h antiproliferative and mitogenic activities from haricot beans a hemagglutinin with mitogenic activity from dark red kidney beans purification of a trypsin-stable lectin with antiproliferative and hiv-1 reverse transcriptase inhibitory activity isolation of a homodimeric lectin with antifungal and antiviral activities from red kidney bean (phaseolus vulgaris) seeds primary structure and carbohydrate binding specificity of a potent anti-hiv lectin isolated from the filamentous cyanobacterium oscillatoria agardhii concurrent purification of two defense proteins from french bean seeds: a defensin-like antifungal peptide and a hemagglutinin a soybean kunitz trypsin inhibitor suppresses ovarian cancer cell invasion by blocking urokinase up-regulation mistletoe lectin induces apoptosis and telomerase inhibition in human a253 cancer cells through dephosphorylation of akt plant lectins as inhibitors of tumor growth and modulators of host immune response enhancement of the biological activities of soybean agglutinin by cross-linking with glutaraldehyde soybean agglutininpositive natural suppressor cells in mouse bone marrow inhibit interleukin 2 produ ction and utilization in mixed lymphocyte reactions heterogeneity of splenic natural suppressor cells induced in mice by treatment with cyclophosphamide transplantation for acute leukaemia with hla-a and b nonidentical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells differential agglutination by soybean agglutinin of human leukemia and neuroblastoma cell lines: potential application to autologous bone marrow transplantation the anticarcinogenic potential of soybean lectin and lunasin fate of the antinutritive proteins of soyabean in the ovine gut antifungal properties of lectin and new chitinases from potato tubers h nmr study of the interaction of n, n',n''-triacetyl chitotriose with ac-amp2, sugar binding antimicrobial protein isolated from amaranthus caudatus lectins as plant defense proteins key: cord-315665-pe56le2s authors: smyth, russell; mishra, vinod; qian, xiaolei title: the environment and well-being in urban china date: 2008-12-01 journal: ecol econ doi: 10.1016/j.ecolecon.2008.05.017 sha: doc_id: 315665 cord_uid: pe56le2s we examine the relationship between atmospheric pollution, measured as sulphur dioxide emissions, environmental disasters, traffic congestion, access to parkland and well-being in urban china, using a large survey administered across 30 cities in 2003. we find that in cities with high levels of atmospheric pollution, environmental disasters and traffic congestion chinese citizens report significantly lower levels of well-being ceteris paribus while in cities with greater access to parkland chinese citizens report significantly higher levels of well-being ceteris paribus. china's pollution problems are well-known. according to the world bank, china has 16 of the world's 20 most polluted cities, with four of the worst in the main coal producing province of shanxi. in 2005, only 31% of chinese cities met national air quality standards and more than 75% of water in rivers in china's urban areas cannot be used for drinking or fishing (economy, 2007) . the world bank (2007) estimates that only 1% of china's urban population of 560 million breathe air considered safe in the european union. the world bank (2007) estimates that the health costs of air and water pollution amount to 4.3% of gross domestic product (gdp) and the nonhealth impacts to 1.5% of gdp, making the total cost of air and water pollution in china, 5.8% of gdp. recently there has been a surge of interest in economics in studying subjective well-being (see frey and stutzer 2002; dolan et al., 2008 for reviews) . this interest has emerged in the wake of several decades of research by psychologists on the topic (see diener et al., 1999) . while economists were initially sceptical about the value of using subjective well-being as a measure of utility, as kahneman et al. (1997) note the use of direct scientific measurement of utility represents a return to the origins of classical economics. most economic models assume that utility equates with consumption, such that income is the best measure of well-being. the use of selfreported measures of utility has the advantage that it can assist to clarify the relationship between income and a host of indicators including personal traits, socially developed characteristics, beliefs, how we spend our time and overall life satisfaction. economists have primarily been concerned with examining the correlation between (absolute and relative) income or unemployment and subjective well-being. a consensus exists that the unemployed report lower well-being than those in employment ceteris paribus (clark and oswald, 1994) . how-e c o l o g i c a l e c o n o m i c s 6 8 ( 2 0 0 8 ) 5 4 7 -5 5 5 ever, there continues to be much debate about the relationship between income and subjective well-being with several recent studies examining the relationship between relative income and subjective well-being with a range of alternative comparators (see clark et al., 2008 for a review of the literature on the relationship between income and subjective well-being). compared with the large literature examining the relationship between income and well-being, little research has examined the relationship between the environment and subjective well-being. this study adds to this paucity of literature through examining the correlation between environmental variables and subjective well-being using a survey of 8890 individuals in 30 chinese cities, collected in september, 2003. this research is important for two reasons. first, the speed at which china can effectively address its environment problems requires knowledge about people's preferences. this, in turn, depends on the relationship between environmental surroundings and subjective well-being. in china, there are two competing aspects of this issue that the central government is attempting to balance. on the one hand, china has a nascent environmental movement at the citizen level. since the mid-1990s about 3000 environment oriented non-government organizations (ngos) have been established in china. these organizations, such as the well-known 'friends of nature' and 'global village of beijing', primarily focus on education, raising awareness and hands-on environmental activism (martens, 2006) . the chinese central government provides tacit support for this movement as a means of scrutinizing environmental protection at the local level, although criticism of the central government is not permitted (larson, 2007; martens, 2006; mol and carter, 2006) . as economy (2007) notes, while the chinese central government has enunciated a much greater commitment to environmental protection in recent times, such commitments mean little in practice if lower levels of government refuse to enforce central directives or regulations as has been the case. in this respect, the central government sees environmental ngos as a means to put pressure on lower levels of government. however, at the same time, the chinese central government is worried about the potential for environmental concerns to manifest themselves in the form of widespread political and social unrest. for this reason environmental protection, along with reducing corruption and rural-urban income inequalities, is a cornerstone of hu jintao's commitment to more balanced growth. the deterioration in the environment resulted in 51,000 pollution disputes in 2005, amounting to 140 per day (zhang, 2007) . citizen complaints about the environment, expressed on official hotlines and in letters to local officials are increasing at 30% per annum and were expected to top 450,000 in 2007 (economy, 2007) . there are also an increasing number of political demonstrations complaining about the environment. economy (2007) mentioned one such demonstration in 2005 when 30,000 to 40,000 people in zhejiang province vandalised 13 chemical plants as part of a protest about air pollution. knowledge of the relationship between pollution and other environmental variables and subjective well-being is useful for the central government in balancing support for environmental ngos with a need to avoid social and political unrest. the second reason research on the correlation between environmental surroundings and subjective well-being is important is that the results help to strengthen the foundations of the ecological economics literature on the detrimental effects of economic growth (ferrer-i-carbonell and gowdy, 2007) . this is particularly apposite for a country such as china which has been described as 'choking on its own success' (kahn and yardley, 2007) . the literature on sustainability suggests that social welfare rather than per capita income should be the focus of government policy (gowdy, 2004 (gowdy, , 2005 . in 2004, for the first and only time, the chinese government reported figures for green gdp, which adjusted gdp to reflect the cost of pollution. the figures, however, were sobering, with the pollutionadjusted growth rates in several provinces being close to zero. the idea of reporting green gdp in china has since been shelved because of strong opposition from local government officials (kahn and yardley, 2007) . local officials were opposed to green gdp as a concept from the start because lower adjusted growth rates reduce their prospects for promotion (economy, 2006) . a better knowledge of the relationship between environmental surroundings and well-being in urban china has the potential to put broader notions of social welfare, such as green gdp, back on the policy-making agenda. since economic reforms commenced in the late 1970s china has had one of the highest rates of growth in the world, but this has also generated massive environmental problems. for two decades through the 1980s and 1990s china's collective township and village enterprises (ctves) were the driving force behind china's high growth rate. however, most ctves had no wastewater or hazardous waste treatment facilities. through the 1980s and 1990s ctves were responsible for 50% of industrial wastewater and air pollutants (who, 2001) . china is the largest coal producer in the world. coal contributes 90% of china's sulphur dioxide emissions and about 70% of china's total dust, nitrogen oxide and carbon dioxide emissions (zhang, 2007) . china has twice the sulphur dioxide emissions of the united states with some estimates suggesting that in the future china's sulphur dioxide emissions will be up to five times their current level. motor vehicle emissions are also becoming an important source of ambient air pollution. by 2020 china is expected to have 130 million cars and by 2040-2050 china will have more cars than the united states (economy, 2007) . walsh (2000) estimates that motor vehicles contribute between 45 and 60% of the no x emissions and 85% of the carbon monoxide emissions in chinese cities. as a result, some have argued that urban air pollution in chinese cities is shifting from a predominantly coal-burning type to a coal-vehicle mixed type (see deng, 2006 and references cited there in). according to world bank estimates from the 1990s, the number of annual pollution-related premature deaths in china from a mixture of outdoor air pollution in large cities, indoor air pollution from inhaling fumes from coal-burning stoves and cooking oil as well as cancers and diarrhoea from drinking polluted water, were about 400,000 (toy, 2007) . in a preliminary version of the world bank's (2007) most recent study on pollution in china, it estimated that the annual number of premature pollution-related deaths in china are as high as 750,000. while this figure was censored from the final version of the world bank (2007) report, it was openly discussed at the conference launching the world bank study and has been reported in the media (see e.g. kahn and yardley, 2007; toy, 2007) . china's air pollution is also held responsible for an increase in the prevalence of asthma in chinese cities. according to official figures, throughout the 1990s the prevalence of asthma among urban children increased 64%. more recent data is not available, nor is data available for adults, although chinese doctors have estimated that the number of asthma cases they treated increased 40% over the period 2000 to 2005 (watts, 2006 ). as discussed above there is a vast literature in economics and psychology on subjective well-being. as a subset of this literature there are a growing number of studies for transitional economies. there are studies of which variables are correlated with well-being in russia (see e.g. eggers et al., 2006; frijters and van praag, 1998; frijters et al., 2006; graham et al., 2004 among others) ; the former soviet republics (namazie and sanfey, 2001) and central and eastern europe (see e.g. andren and martinsson, 2006; hayo and seifert, 2003; hayo, 2007; lelkes, 2006; sanfey and teksoz, 2007) . other studies have examined the subjective well-being of former east germans and west germans following reunification (see e.g. frijters et al., 2004) . correlation between well-being and other variables is a significant issue on the research agendas of economists and psychologists studying china's rapid modernisation, though to date, studies in the english language literature have been confined either to clinical samples (e.g. yan and sellick, 2004) ; age-specific samples, such as adolescents (e.g. edwards set al., 2005) ; specific occupations (e.g. law et al., 2008) ; the elderly (e.g. chen, 2003) , rural residents or off farm migrants . cheung and leung (2004) who examined subjective well-being of residents in beijing is the only study to consider this issue for urban residents. there are no studies of subjective well-being among urban residents for cities other than beijing. moreover, one feature of all of these studies for transitional economies, including china, is that few consider the relationship between the environment and subjective well-being. of those studies which do consider environmental factors, frijters and van praag (1998) find that climate is correlated with people's standard of living in russia and that people dislike cold winters and hot summers. , in their study of rural china, find that people living in hilly and mountainous terrains report lower levels of well-being ceteris paribus. there are few studies by economists of the relationship between the environment and subjective well-being. some studies have found a positive correlation between climatic variables and subjective well-being (in addition to frijters and van praag, 1998 see rehdanz and maddison, 2005; brereton et al., 2008) . studies have found a negative correlation between air and noise pollution and subjective well-being (di tella and macculloch, 2008; van praag and baarsma, 2005; welsch, 2002 welsch, , 2006 rehdanz and maddison, 2008) . in addition to climatic conditions, brereton et al. (2008) examine the relationship between environmental surroundings proxied by indicators such as proximity to a major road, airport, a landfill or hazardous waste facility, and subjective well-being. ferrer-i-carbonell and gowdy (2007) examine how environmental attitudes are correlated with subjective well-being. in short, existing studies that have considered the relationship between environmental surroundings and subjective well-being have been primarily restricted to developed countries. there are no studies that have focused on the relationship between environmental variables and well-being in a developing country such as china. empirical approach 4.1. we employ a specification where we express subjective wellbeing (swb) as a function of: (i) variables capturing the environmental surroundings of the individual (es), (ii) attitudes to the environment (ea); (iii) personal characteristics (p) and (iv) attitudes to other political and socio-economic issues (oa). this relationship can be expressed as follows where ɛ is the error term, reflecting unobserved random factors. to measure subjective well-being we use respondents' answers to the question: 'how satisfied do you feel with your life these days?' respondents can answer on a scale of 1 to 5 where 1 denotes 'very unsatisfied' and 5 denotes 'very satisfied'. overall, 2.6% were 'very unsatisfied', 13.4% were 'unsatisfied', 41.9% were 'neither satisfied nor unsatisfied', 39.3% were 'satisfied' and 2.8% were 'very satisfied'. the mean satisfaction rating for respondents to the survey was 3.26 (sd = 0.82). to measure environmental surroundings we employ variables for atmospheric pollution, measured in terms of sulphur dioxide emissions, the number of environmental disasters, traffic congestion and the area of parkland per capita in the city in which the respondent lives. to measure environmental attitudes we used two variables denoting whether environmental protection is a social problem of major interest to the respondent (environment awareness) and the respondent's perception of changes in the environmental consciousness in the neighbourhood in which he or she lives in the two years prior to the survey (neighbourhood environment). for personal characteristics of the respondents we use commonly employed controls; namely, age, age squared, education, employment status, gender, occupation and marital status. we control for the individual's attitudes on a range of other socio-economic and political issues other than the environment. specifically, we control for whether the individual is promarket and whether the individual considers each of income inequality, social protection, reunification of mainland china and taiwan and the severe acute respiratory syndrome (sars) epidemic is a social problem of major interest. sars is a relevant issue because the survey we use was administered in late 2003 soon after the height of the outbreak of the epidemic in china. table 1 contains a complete list of explanatory variables and descriptive statistics for each variable. to estimate eq. (1) we use an ordered probit model. this means that subjective well-being is assumed to be a categorical the cmmrc survey asks respondents a number of questions relating to attitudes on a range of social and economic issues as well as background characteristics of the respondent such as age, education, gender, income, marital status and occupation. cmmrc employs multi-stage stratified random sampling to ensure a representative sample in terms of age, gender and income. the respondents were interviewed in person in shopping districts of each city by a trained cmmrc interviewer. in each city there were four individuals conducting the survey in four different shopping districts. all responses were checked for accuracy three times prior to being entered into the database; initially by a supervisor on location, then by a supervisor for the city and finally at the cmmrc offices in beijing. all respondents who participated in the survey were aged 18 years or above and had an urban household registration. from table 1 , the mean age of respondents in the sample was 39.1 years, 51.2% were female, 69.4% were married and the median household income of respondents was 2001 rmb to 2250 rmb per month. of the respondents, 16.3% had a four year higher degree or better, 11.4% had completed a polytechnic level education and 28.4% had completed senior middle school. in terms of occupation, 35.6% of respondents were in professional occupations, 31.3% were manual, semi-skilled or technical workers, 15.9% were retired, 8.8% were unemployed and 8.4% were not in the labour force. overall, with the exception of the education profile, the characteristics of the sample are fairly representative of the urban population as a whole. in 2003, average household income of urban employees in the 35 provincial capitals and separate planning cities was 1800 rmb, the mean age of urban residents was 37 years and 75% were married (nbs, 2004a) . in 2003, 49.62% of the urban population was female (nbs, 2004c) . in 2003 the official urban unemployment rate was 4% (nbs, 2004a); however, giles et al. (2005) suggested that the real unemployment rate for those with an urban household registration, once laid-off (xiagang) workers were taken into account, was about 11% in 2002. knight and xue (2006) estimated a similar figure for the end of the 1990s. the retirement age for blue collar workers in urban areas is 55 for women and 60 for men. in 2002 9.8% of the urban population were aged 60 years or older and 14.4% were aged 55 years or older (nbs, 2003) . in order to reduce the surplus labour problem in soes, some enterprises have introduced semiretirement (neitui) at ages younger than the official retirement age, with semi-retired workers receiving 50-70% of their position wage with no bonuses (smyth et al., 2004) . it is conceivable that some of the respondents in the sample who are designated as retired are semi-retired. according to the statistics from the communiqué of the first national economic census in 2004, of the urban workforce, 42.0% had completed junior secondary school or less, 33.6% had completed senior secondary school and 24.4% had a three year college education or higher (nbs, 2005a,b) . this means that in our sample, those with a junior middle school education or less are under-represented and those with a tertiary degree are over-represented relative to the urban population as a whole. one explanation for the education profile of our sample is that the survey was conducted in large cities where the educational level is much higher than in other urban areas. previous studies which have interviewed respondents in large chinese cities have also found better educated individuals to be disproportionately represented relative to the urban population as a whole. for example, in a survey of employees in manufacturing enterprises in nanjing, shanghai and tianjin in 1994 -1995 , zhu (1997 found that 73.3% of respondents had tertiary qualifications. this peculiarity with respect to educational level also seems to reflect respondents in street surveys more generally. holbrook et al. (2003) found that the educational levels of respondents are skewedrespondents with a lower education level are generally reluctant to respond to street surveys as they believe they may have more to lose. studies comparing the education levels of respondents in various surveys have also found fewer low-education respondents in telephone samples than in face-to-face samples (see e.g. greenfield et al., 2000; groves, 1977) . the data on each of the environmental variablesatmospheric pollution measured in terms of sulphur dioxide emissions, environmental disasters, access to parkland and traffic congestion taiyuan, huhehaote, shenyang, changchun, harbin, shanghai, nanjing, hangzhou, hefei, nanchang, jinan, zhenzhou, wuhan, changsha, guangzhou, nanning, haikou, chongqing, chengdu, guizhou, kunming, lhasa, xian, lanzhou, xining, yinchuan, wulumuqi. in addition to these 30 cities, fuzhou and xiamen, both in fujian, were also sampled in the survey. however, in the data provided by cmmrc both were given the same code, which was a provincial code for fujian, so were not able to distinguish between these cities. as a result, the data for these two cities had to be dropped from the analysis. sudden accidents, due to economic or social activities that are contrary to environment protection laws or due to unforeseen factors or natural disasters, that lead to environment pollution, destruction of protected wild animals, plants or nature reserves, damage to human health, economic and property losses, and other negative impacts on the society". table 2 reports the results for eq. (1) with and without city dummy variables. specification i reports the results without city dummy variables. specification ii reports the results with city dummy variables. the dummy variables for each city x were defined such that dum_x = 1 if city =x, 0 otherwise with shanxi the reference category. including the city dummy variables addresses the fact that city differences exist; for example, cities differ with respect to factors such as public services, housing, climate and the labour market to name a few. dummy variables for the cities help to capture those differences, meaning that the results with the city dummy variables are more robust. for this reason in the discussion we concentrate on the results from specification ii for those variables where the specifications give different results. there are two such cases. congestion and parks are statistically insignificant in specification i, but statistically significant in specification ii. the results from specification ii suggest that in cities with higher levels of atmospheric pollution, more environmental disasters and greater traffic congestion respondents report lower levels of well-being ceteris paribus, while in cities with greater access to parkland respondents report higher levels of well-being ceteris paribus. because the dependent variable is categorical in nature, the explanatory variables represent the probability of moving from one category to another in the dependent variable. the dependent variable takes the value of 1 for 'very unsatisfied' and 5 for 'very satisfied' and in-between we have categories 2, 3 and 4 representing increasing levels of satisfaction. in specification ii, the coefficient for atmospheric pollution is − 15.58. this indicates that a 1% increase in the level of atmospheric pollution in the province increases the probability of a respondent classifying himself or herself in a lower well-being category compared to the one which he or has reported (say from 5 to 4, 4 to 3, 3 to 2 or 2 to 1) by 15.58% ceteris paribus. similar interpretations hold for the other variables. a 1% increase in traffic congestion will increase the probability of moving to a lower well-being category by 0.05%; a 1% increase in environmental disasters will increase the probability of moving to a lower well-being category by 0.02%, whereas a 1% increase in parkland will increase the probability of moving to a higher well-being category by 0.5%. thus, from a policy perspective, lowering atmospheric pollution, measured as sulphur dioxide emissions, has a much more pronounced effect than changing any of the other environmental variables on the probability that chinese urban resident will report a higher category of well-being. of the environmental attitude variables, there is no statistically significant relationship between environmental awareness and well-being. the variable measuring perceptions of environmental consciousness in the neighbourhood, however, is statistically significant with a positive coefficient. the results for the neighbourhood environmental consciousness variable reflect the public goods aspect of environmental activism (hardin, 1982) . improving the environment requires collective action and an improvement in environmental consciousness in the respondent's neighbourhood will result in a better environment for the individual. for example, if local factories reduce pollution emissions because of an improvement in environmental consciousness in the neighbourhood, this will improve the quality of the air the respondent breathes, having a positive effect on subjective well-being. the results for the other control variables in table 2 are generally consistent with expectations and findings from previous studies. of the personal characteristics of the respondent we find that household income has a positive effect on subjective well-being, while being unemployed has a negative effect on subjective well-being. we find a non-linear u-shaped relationship between age and subjective well-being however, education, gender and marital status are statistically insignificant. of the social attitude variables, people who considered social protection and income inequality important as well as those who were pro-market report lower levels of well-being ceteris paribus, while those who considered national reunification and sars important reported higher levels of subjective well-being ceteris paribus. the results for attitudes to income inequality and social protection could reflect concern about widening income disparities and large numbers of low income individuals, including sizeable numbers of laid-off workers, who have been the losers of the market reforms. however, it is likely that such attitudes will differ between different segments of the urban population and more detailed study is needed before firm conclusions can be drawn about these attitudes and subjective well-being. the results for pro-market attitudes differ from a study by graham and pettinato (2001) which found that having pro-market attitudes are associated with higher subjective well-being in latin america and russia. comparing china and russia the different results could lie in the speed of the reform. china's 'gradual approach' to market reforms has been much slower than russia's 'big bang' reforms. thus, individuals who support further marketization in china might have lower subjective well-being because they are frustrated with the relatively slow pace of the reforms. in this paper we have examined the relationship between environmental variables and subjective well-being in urban china. the approach is in the tradition of a growing literature on the economics of happiness that use self-reported measures of utility to obtain insights into how people think and feel about their lives. the approach is consistent with the view that economists should move beyond the traditional assumption that interpersonal comparisons of utility should be avoided and that well-being can be measured in terms of consumption and income alone. there are parallels with the ecological economics literature on the limits of growth, although with few exceptions there has been little research on the relationship between atmospheric pollution or other environmental variables and self-reported measures of utility. the main finding is that in cities with high atmospheric pollution, environmental disasters and traffic congestion urban residents report lower levels of well-being while in cities with greater access to parkland, respondents report higher levels of well-being controlling for the respondent's attitudes towards the environment and other social and political issues and the personal traits of the respondent. from a policy perspective, for a 1% change in atmospheric pollution there is a much higher probability that an individual will move up or down one category of well-being on the five point scale than for a 1% change in other environmental variable. hence, our results suggest that reducing atmospheric pollution will generate the biggest gains in terms of improving well-being in urban china. this finding adds to the results from previous studies that have examined the relationship between the environment on subjective wellbeingprimarily employing data for developed countriesfor a large developing country with a sizeable population base and serious pollution problems. in light of the findings the question then becomes what is the best method to stem atmospheric pollution? as environmental scholars such as economy (2007) have noted, it is difficult for the central government to impose 'top down' directives to reduce atmospheric pollution problems or other environmental problems. in this respect, an important implication of the results is people report higher life satisfaction if they believe there is an increase in the will in the local community to improve environmental protection, ceteris paribus. this finding lends support to the view that the chinese central government should further relax restrictions on environmental ngos. while environmental issues are sanctioned as a topic for public debate in china, there are limits, particularly where there are links with related issues such as ethnic tensions and human rights, which remain under strict control. the dividing line, however, between those environmental topics which can and cannot be discussed is constantly shifting (martens, 2006) . relaxing the strict control over environmental ngos would not only act as a pressure group at the local level for environmental change, but would have a positive effect on well-being, given that our findings suggest the latter is positively correlated with environmental consciousness. what contributes to life satisfaction in transitional romania? happiness, geography and the environment revisiting the disengagement theory with differentials in the determinants of life satisfaction forming life satisfaction among different 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sydney morning herald using happiness surveys to value intangibles: the case of airport noise transportation and the environment in china doctors blame air pollution for china's asthma increase preferences over prosperity and pollution: environmental valuation based on happiness surveys environment and happiness: valuation of air pollution using life satisfaction data environment and people's health in china. who, geneva. world bank quality of life of chinese patients newly diagnosed with gastrointestinal cancer: a longitudinal study china is moving away from the pattern of 'develop first and then treat the pollution human resource development in china during the transition to a new economic system key: cord-327253-gge6wzly authors: villa, simone; jaramillo, ernesto; mangioni, davide; bandera, alessandra; gori, andrea; raviglione, mario carlo title: stigma at the time of the covid-19 pandemic date: 2020-08-07 journal: clin microbiol infect doi: 10.1016/j.cmi.2020.08.001 sha: doc_id: 327253 cord_uid: gge6wzly nan respiratory infectious disease outbreaks marked by significant morbidity and mortality tend to produce serious distress in the general population. physical distancing is necessary to reduce the chances of transmission of the pathogen. but this practice may engender stigma and discrimination, which can have the counterproductive effect of hindering disease control. people start to hide their symptoms, avoid seeking medical attention and testing until they are seriously ill, and do not collaborate in contact investigation efforts. epidemic outbreaks have historically been accompanied by stigma, discrimination, and xenophobia. tuberculosis, hiv, and leprosy are well known stigmatised infectious diseases. more recently, survivors of the 2013-16 west africa ebola outbreak have faced exclusion and unemployment once they returned to their communities. 1 beginning in late january 2020, when the covid-19 epidemic was still largely limited to china, verbal and physical attacks against chinese or people of asian descent have been documented in many countries. 2 in italy, for example, numerous racial and violent actions have taken place, including physical violence. in the vicenza province a young asian man was beaten and verbally assaulted and a young asian woman was insulted and accused of spreading covid-19; 3 in rome some private stores began to exclude clients of asian origin barring "all people coming from china" from entering. 2 similar incidents were reported in countries like france, where there were cases of people refusing to be served by asian persons in shops and restaurants, and the united states of america, where a single week in march saw around 650 racist acts against asian americans. 4 uses of language by some media, newspapers and political leaders sometimes contribute to fuel stigma. for instance, in january 2020 numerous italian newspapers used the terms "chinese virus" and "chinese syndrome" as if a nationality could be attributed to a virus or a disease. 5 likewise, in france, provocative and imprudent headlines such as "the alert jaune", namely the "yellow alert", appeared in le courrier picard. the president of the united states of america has frequently described covid-19 as the "chinese virus". in italy, some politicians accused chinese people of poor hygiene and unhealthy cultural practices, including that of eating "live mice". 6 in rome, a school principal asked all chinese students to exhibit a formal medical certificate declaring that they were disease-free, if they were to be allowed to attend classes. 2 some regional governors proposed to exclude children of chinese descent from class. counteracting this j o u r n a l p r e -p r o o f language with gestures such as the condemnation of race-based discriminatory behavior by the italian prime minister or the visit of the italian president to a primary school in rome where half of the children are of chinese origin might be insufficient to mitigate the stigma and fear already created. in france, initiatives such as the hashtag #jenesuispasunvirus (i am not a virus), spread on twitter after provocative headlines in french newspapers. once the pandemic reached italian territory, stigma was rapidly redirected towards ethnic italians. 7 the blame went immediately towards people from the north of italy, the area initially affected by the covid-19 epidemic, with (fortunately isolated) threats from people from southern italy of not renting houses to those from the north. stigmatizing a population can also serve political needs. some italian political parties, for example, managed to shift the blame to germany, stating that the italian outbreak originated in that country. 8 when covid-19 became a pandemic affecting more than one hundred countries, stigma and discrimination changed their pattern once again. it is well documented how healthcare workers and ambulance crews in the most affected areas in some latin-american, african, and european countries became the target of stigma and discrimination. 9 the general public started to see them as the "anointers" -those individual perceived to voluntarily favour the spread of plague in the community during the middle ages -and, as a result, deplorable actions have been documented. for instance, in the city of pisa, italy, a medical doctor going back home found a notice in which the neighbours asked her to be careful not to touch anything in the common area of the building where she lives. covid-19 survivors also have had to cope with stigma, especially from neighbours. given the shortage in testing kits and the overwhelming of laboratories, people who survive could not always be retested as proof of final cure. this led to avoidance and social isolation due to the fear of becoming infected. 10 in contrary, uninfected covid-19 people may be facing discrimination when applying for jobs in some countries that may implement covid-19 passport strategies, despite recommendations of the world health organization against such a practice. 11 most countries are struggling to implement an appropriate risk communication strategy to prevent and mitigate covid-19-related stigma. the role played by stigma and discrimination in favouring the spread of infection has been repeatedly highlighted. 12, 13 stigma, for instance, can lead ill people to hide their symptoms in the attempt to avoid marginalization. this reactive behaviour facilitates spreading of infectious pathogens especially among those with mild symptoms who avoid seeking medical attention and act j o u r n a l p r e -p r o o f as usual not to raise suspicion on their condition. besides easing transmission, this behaviour can be conducive to deterioration of clinical conditions and may have psychological consequences. on the other hand, patients with covid-19 diagnosis frequently suffer from anxiety and depression, mainly as a consequence of hospitalization or home quarantine, or due to the sense of guilt towards family members or acquaintances. the world cannot bear a parallel pandemic of stigma, which only serves to boost the spread of infectious diseases and worsen people's health conditions and social behaviours. noteworthy, individuals with covid-19 may develop poor health-seeking behaviours (e.g. avoiding testing) because, by anticipating and fearing stigma, they may perceive the risk of losing their job and being marginalised in the society. this stress, together with the one caused by hiding symptoms, may further exacerbate conditions linked to biological stress response (i.e., elevated cortisol) leading to immune depression and delay in timely and adequate treatment. 12 governments, backed by civil societies, have the responsibility to act urgently and make a definite commitment to fight any form of stigmatization, discrimination and xenophobia fuelled by infectious outbreaks. 13 we need to identify and isolate those who exploit the human tragedies of infectious epidemics for their political aims. interventions to mitigate social stigma should embrace risk communication strategies to fill the knowledge gap in the general population with additional attention to specific, vulnerable segments such as migrants and ethnic minorities, and to prevent the "fake news" from spreading. for instance, medical and scientific societies should encourage health care and public health professionals to develop ad hoc materials to educate patients and the general public. in doing so, public health authorities should seek advice from communication and social media experts especially when developing key messages (e.g., on mask use) and technical guidelines as these can be potentially misunderstood by media and the general public. technical information should also be paired with comprehensible and clear messages for non-technical recipients. ebola virus disease-related stigma among survivors declined in liberia over an 18-month, post-outbreak period: an observational cohort study outbreaks of xenophobia in west as coronavirus spread. the guardian as if we were the disease': coronavirus brings prejudice for italy's chinese workers. the guardian asian americans report over 650 racist acts over last week, new data says politician apologizes for saying coronavirus caused by chinese people eating 'live mice' italiani untori you could lick the benches': life for the first wave of u immunity passports" in the context of covid-19. geneva: world health organization 2020 infectious disease stigmas: maladaptive in modern society social stigma associated with covid-19 world health organization. effective media communication during public health emergencies -a who handbook. geneva: world health organization key: cord-334401-i5dz7ufc authors: adja, k.y.c.; golinelli, d.; lenzi, j.; fantini, m.p.; wu, e. title: pandemics and social stigma: who's next? italy's experience with covid-19 date: 2020-06-04 journal: public health doi: 10.1016/j.puhe.2020.05.054 sha: doc_id: 334401 cord_uid: i5dz7ufc nan on december 31, 2019, chinese authorities reported to the world health organization the first case of what is now known as covid-19, a respiratory syndrome caused by sars-cov q2 -2. four months later, the virus caused a pandemic that has changed the lives of billions of people. in the weeks after the announcement of the first covid-19 case, while some asian countries (i.e. south korea, singapore, taiwan) 1,2 promptly equipped themselves to face a probable national outbreak, most western nations minimized the risks posed by the virus and limited their actions to travel bans, whose effectiveness is still debated. 3 italy, one of the first and most severely hit countries in the western world, was among them. however, discussions on whether to admit people coming from the outbreak epicenter in china raged immediately not only at the political level but also on the media and social media, paired with xenophobic comments on chinese wet markets and culinary habits. nowadays, it is a short step from digital discussions to real life, and at first, it was not the virus to hit italy but another dangerous enemy: prejudice. weeks before the national lockdown of march 11, 2020, when the bel paese had declared the state of emergency but everyday life was going on as always, the sentiment toward the chinese community changed: their restaurants were left empty, more and more parents did not want their children to go to school if they had a chinese classmate, and a high-profile politician offended the chinese by saying on tv that 'we have all seen them eat live mice'. this behavior is not new to the humankind: covid-19, similar to other epidemics before, has gone hand in hand with xenophobia. foreign populations were stigmatized and scapegoated when facing novel pathogens across history and, sadly, this time is no exception. we can find some parallel to today's pandemic-related xenophobia already in the 5th century bc when tucidide, narrating the plague of athens, writes that athenians were accusing spartans of poisoning the water, or in the 14th century, when during the black death, an outbreak of the bubonic plague, jews were accused of the same thing. more recently, in 1918, when the spanish flu was not already being referred to as such, brazilians called it the german flu and the senegalese called it the brazilian flu, underlying the tendency for some kind of need to find someone to blame. italians too were accused in the us of the spreading of the flu, as reported in two newspaper clips. 4 'catastrophes reveal the weakness of human memory', 5 this time it was the chinese who got targeted. however, despite facing episodes of xenophobia, their behavior has been nothing but commendable. notably, one of the most important and populated chinese communities in europe is in prato, 6 a city in tuscany, italy, that is famous for its textile manufacturers, where they represent the 9.9% of the resident population (the national figure is 0.4%). this created fear among italian authorities, especially when it was reported that in late january 2500 people were returning from china, after the chinese new year celebrations. what was remarkable at the time and is worthy of praise now is that the chinese took the threat raised by the virus very seriously from the beginning, after closely what was happening in china. this led to a change in habits that is now common to everybody but that nobody had ever experienced before. the chinese living in prato started to take measures to contain the spread of the virus voluntarily, before the government began acting. social networks allowed them to keep in contact with relatives and friends in china to try to understand firsthand what was happening and consequently how to behave. moreover, the members of the community have close relationships, and everyone was involved, trying to be proactive. whenever meeting the chinese around the city, they were always using masks, both on the streets and at the workplace, asking everybody to do the same when exchanging contacts with them. italians were taking no precautions at that time and this worried the chinese community who knew how serious the situation was and that it was fundamental to adopt non-pharmaceutical public health measures to mitigate the risk of covid-19. some of them also stopped sending kids to school, while still open, and started a voluntary quarantine; in the meantime, italians took advantage of the eventual closure of the schools to go skiing. the italian national institute of statistics has released on may 4 the all-cause mortality data of the first quarter of the year 7 to evaluate the impact of covid-19 across the country. the comparison with q3 2015e19 data has shown us that not only was prato not among the worst-hit areas but, quite surprisingly, was one of the least affected provinces of the country (the only province under 0% of excess mortality in north-central italy, fig. 1 ). public health 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 the behavior of the chinese community may have played an important role in avoiding the spread of the virus, and had their conduct been taken as an example from the start, nobody knows what the history of the pandemic could have been. however, instead of trying to understand, the human nature propelled xenophobic actions while preparedness efforts culpably lagged behind, favoring the spread of the virus. there will always be new and unknown threats to cope with in the future for humankind, but it is time that we start learning some lessons from our past. unfortunately, old habits die hard, and once more it has been proven that diseases do not discriminatedpeople do. nevertheless, with our actions as humans and scientists, we can actively help dissipate the harm that prejudice and stigma cause by providing accurate information. while all our efforts are addressed toward the battle against this virus that we will hopefully beat in the foreseeable future, it is clear that there is another long standing fight that we must win: the time to eradicate the stigma pandemic is now, and only united we will be victorious. none sought. none declared. letter to the editor / public health xxx (xxxx) xxx 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 puhe3893_proof ■ 3 june 2020 ■ 3/3 covid-19 in singaporedcurrent experience: critical global issues that require attention and action response to covid-19 in taiwan: big data analytics, new technology, and proactive testing spanish flu": when infectious disease names blur origins and stigmatize those infected twentieth-century lessons for a modern coronavirus pandemic coronavirus is the greatest global science policy failure in a generation. the guardian none declared. data are publicly available. key: cord-300517-41pr3dwa authors: zhang, dan; zhang, bing; lv, jin-tao; sa, ri-na; zhang, xiao-meng; lin, zhi-jian title: the clinical benefits of chinese patent medicines against covid-19 based on current evidence date: 2020-05-05 journal: pharmacol res doi: 10.1016/j.phrs.2020.104882 sha: doc_id: 300517 cord_uid: 41pr3dwa the outbreak of emerging infectious pneumonia caused by 2019 novel coronavirus (2019-ncov) has posed an enormous threat to public health, and traditional chinese medicine (tcm) have made vast contribution to the prevention, treatment and rehabilitation of coronavirus disease 19 (covid-19) among chinese population. as an indispensable part of tcm, chinese patent medicines (cpms) are highly valued and critically acclaimed in their campaign to contain and tackle the epidemic, they can achieve considerable effects for both suspected cases under medical observation period, and confirmed individuals with serious underlying diseases or critical conditions. given this, based on the guideline on diagnosis and treatment of coronavirus disease 2019 in china, the present review summarized the basic information, clinical evidence and published literatures of recommended cpms against covid-19. the details were thoroughly introduced involving compositions, therapeutic effects, clinical indications, medication history of cpms and the profiles of corresponding research. with regard to infected patients with different stages and syndrome, the preferable potentials and therapeutic mechanism of cpms were addressed through the comprehensive collection of relevant literatures and on-going clinical trials. this study could provide an insight into clinical application and underlying mechanism of recommended cpms against covid-19, with the aim to share the chinese experience in clinical practice and facilitate scientific development of tcm, especially cpms in the fierce battle of covid-19. in the theory of traditional chinese medicine (tcm), 2019-ncov infected pneumonia was deemed to the category of "pestilence", and the characteristics of its pathogenesis was "dampness, toxin, stasis and closure" [19] [20] . over the past few months, tcm exhibited remarkable benefits against covid-19 in china, and it was convinced that tcm achieved satisfactory therapeutic superiority for patients infected by 2019-ncov with regard to preventive treatment of diseases, comprehensive therapies and rehabilitation by the accumulation of clinical experience and scientific evidence [21] [22] . as recommended in the guideline on diagnosis and treatment of coronavirus disease 2019 (revised 7th version) which was officially released by national health commission of the people's republic of china, tcm could exert favorable effects for patients with different syndromes and distinct stages of covid-19, contributing to infections in the periods of both medical observation and clinical treatment [23] . recently, the latest official data showed that 91.5% of confirmed subjects with covid-19 (74,187 cases) received tcm in china, and increasing results of clinical observation indicated that the total effective rate of tcm reached more than 90% [24] . these promising advantages were associated with its unique therapeutic principles including syndrome differentiation and treatment, boosting the individual's endogenous healing ability, balancing yin and yang, various therapies and personalized treatment in first-line clinic [25] [26] . with the development of technology in tcm domain, chinese herbal products were transformed into varied dosage forms, chinese patent medicines (cpms) were consumer-near and popular "folk medicine" that contributed to widely application in clinical practice among chinese citizens [27] [28] . compared to herbal decoction, cpms had the advantages of stable quality, curative efficacy, considerable safety, rapid absorption, high bioavailability, convenience of taking, carrying and storing [29] [30] . similarly, as an indispensable part of tcm, cpms were substantial utilized in combination with western medicine for the management of covid-19, and proposed as adjunctive and therapeutic options to fight the public health emergency of 2019-ncov by national and provincial guidelines in china [31] [32] [33] . given the paucity of published english research concerning cpms against covid-19 currently, the present review performed a descriptive analysis of recommended cpms from both clinical trials and published literatures, based on the following aspects: information retrieved from their instructions (compositions, therapeutic effects, and clinical indications), medical evidence, pharmacodynamic mechanism, dominant components, applicable patients, clinical cautions and so on. as regarding to some types of cpms without accessible published evidence for treating 2019-ncov, we introduced the relevant results of infectious or health-threatening diseases. the aim of present review was to provide the scientific basis and share clinical experiences for promising choices of cpms against covid-19. j o u r n a l p r e -p r o o f first, the comprehensive retrieval of electronic databases in both chinese and english (the china national knowledge infrastructure database, wangfang database, sinomed database, pubmed and embase) was performed for collecting the published research from inception to apr 10, 2020. on the one hand, the following terms of covid-19 were adopted: "covid-19 [supplementary concept]," "2019 novel coronavirus", "covid19", "sars-cov-2", "2019-ncov", "coronavirus disease 2019", "coronavirus disease-19". on the other hand, the searching terms of cpms mainly included their mandarin chinese and trade name. the results of literature search were displayed in figure 1a , a total of 28 citations were yielded initially for eight cpms. only one eligible study was in english, focused on the anti-viral and anti-inflammatory activities of lianhuaqingwen capsule for treating covid-19, which published by the team of distinguished academician nanshan zhong. in addition, the on-going clinical trials concerning on cpms anagist covid-19 were supplemented to identify the potential evidence by utilizing the platform of chinese clinical trial figure 1b ). according to aforementioned guidelines of covid-2019 in china, totally 14 types of cpms were officially issued to prevent and treatment covid-19, 57.14% (8 types) of them were chinese herbal injection, and others were oral dosage forms of tcm. as illustrated in figure 2 figure 3 . further, the details involving compositions, therapeutic effects, clinical indications for recommended cpms were summarized in table 1 , to provide the relative references for clinician j o u r n a l p r e -p r o o f and specialists to control the spread of this fatal disease. based on the findings of related review, the cpms including huoxiang zhengqi capsule, jinhua qinggan granules, lianhua qingwen capsule, shufeng jiedu capsule could be presumably as preventive measure for the patients in the medical observation period [34] . it was noteworthy that early treatment was essential for suspected or mild cases, accumulated evidence of bioinformatics, pharmacodynamics and clinical findings suggested that these multiple component chinese herbal products also exerted effects on immune regulation, symptom improvement, anti-inflammation and so on during the treatment of covid-19. the results of previously pharmacological research indicated that huoxiang zhengqi capsule or other dosage forms could improve gastrointestinal dysfunction, modulate immune responses, and anti-inflammation [35] . with regard to the national and provincial guidelines against covid-19 in china, huoxiang zhengqi capsule was recommended for patients with fatigue and gastrointestinal discomfort [36] . through the techniques of network pharmacology and molecular docking, huoxiang zhengqi oral liquid could regulate multiple signaling pathways involving hepatitis b, small cell lung cancer, non-small cell lung cancer and inhibit the replication of 2019-ncov to exhibit the preventive or therapeutic effects on covid-19, and its active compounds had definite affinity with angiotensin converting enzyme ii (ace2) and 3-chymotrypsin-like protease (3clpro) [37] [38] . compared with other recommended cpms, jinhua qinggan granules posed the shorter period of medication history, nevertheless, it was proved that the application of jinhua qinggan granules could significantly alleviate clinical symptoms such as fever, cough, fatigue, expectoration, and relieve psychological anxiety of mild cases suffered from covid-19 [39] . the results of systems biology and bioinformatics revealed that the mechanism of jinhua qinggan granules in the treatment of covid-19 involving multiple targets, namely mapk1, casp3, tp53, alb, tnf, il6, and multiple pathways, which might be related to antiviral, immune regulation, inflammation inhibition and apoptosis regulation via pi3k-akt, hif-1, tnf, mapk, nf-κb pathways, and dominant principles including kaempferol, baicalein and oroxylin a could take participate in multiple signal pathways (such as ptgs2, hsp90ab1, ptgs2, bcl2 and casp3) by binding with ace2 [40] [41] [42] . relieving typical symptoms and representative complications, diminishing inflammation and infection, the chinese herbal products of lianhua qingwen capsule was recognized as an excellent antidote in this anti-epidemic by adequate clinical and fundamental research [34, 43] . according to preliminary clinical evidence of retrospective, multicenter study and cases reports, for general type patients and suspected cases with covid-19, the scheme of lianhua qingwen capsule combined among them, only xiyanping injection was applied for treating severe patients, whereas others were also recognized as the complementary choices for critical cases with covid-19. compared with oral administration of tcm, the chinese herbal injections possessed the benefits of rapid onset, high bioavailability, and content accuracy [57], therefore, they were more suitable for the severe or critical patients with covid-19. some scholars concluded that xiyanping injection was reputed as effective alternative to antibiotics in clinical practice [58] . modern pharmacological studies showed that its active ingredient, sulfonated andrographolide had notable effects of antipyretic, anti-inflammation to treat various infectious diseases [59] . in addition, prevenient chinese research pointed out its clinical j o u r n a l p r e -p r o o f advantages that were related to improve respiratory symptoms, inhibit concurrent bacterial infection, and regulate immune function, superior clinical safety, especially certain hepatoprotective effects, suggesting it might have potentials to relieve some drug-induced liver injury during the treatment of covid-19 for serious cases [60] . remarkably, it was reported that andrographolide sulfonate could ameliorate sepsis in mice through suppressing mapk, stat3 and nf-κb pathways, these pathways also played the important role in pulmonary diseases [61] [62] [63] . the prescription of xuebijing injection originated from therapeutic principles of tcm, that was proposed by famous integrative medicine emergency experts, professor jin-da wang, it was approved as second grade national new medicine for treating sepsis in china over 15 years [64] [65] . in this clinical fight against covid-19, considerable effects of xuebijing injection had been displayed by retrospective study and relevant review, the results revealed that xuebijing injection could promote the absorption of lung infection, and improve clinical efficacy and negative rate of nucleic acid [66] [67] . besides, some research demonstrated its characteristics of multi-target and multi-pathway in treating covid-19 based on the approaches of network pharmacology and molecular docking. among a series of involved signaling pathways, such as hif-1 and pi3k-akt were represented pathways against covid-19 in terms of lung inflammation, virus infection and lung injury. besides, core targets including tnf, mapk1, jun, il6, stat3, egfr, etc. were closely correlation with the inhibition of cytokine storm in severe cases, and fatal risk of cytokine storms in the immune system of serious patients might result in organ failure and even death [68] [69] [70] . reduning injection was widely utilized to treat upper respiratory tract infection with multiple functions such as clearing heat, dispelling wind, and detoxification, and previous pharmacological research proposed that it could ameliorate paraquat-induced acute lung injury involved in regulating ampk/mapk/nf-κb signaling pathways [71] . in this regard to treating covid-19, reduning injection might be related to anti-inflammatory, immunoregulation of active compounds through multi-target and multi-pathway. on the one hand, the critical targets were namely ptgs2, ptsg1, ccl2, rela, nos2, hmox1, casp3, il6 and mapk1, some of them belonged to chemokines, which posed the immune activation profiles of 2019-ncov. on the other hand, kegg pathway enrichment analysis revealed 45 related pathways, mainly il-17, c-type lectin receptor, hif-1 and nf-κb signaling pathways [72] [73] . a large number of clinical data had accumulated to confirm superior efficacy of tanreqing injection in the treatment of acute bronchitis disease, tuberculosis and so on [74] [75] . in particular, the severe patients with covid-19 suffered similar clinical manifestations of its dominant diseases. meanwhile, the underlying mechanism and binding activity of tanreqing injection were elucidated, the results in molecular level showed that it might be potential as antiviral agent due to critical interesting, the core targets involved il6, il1b, mapk1, il10, il4, cxcl8, ip10, etc. [76] . this finding was consistent with former clinical report regarding severe patients with higher level of il2, il7, il10, gscf, ip10 in the plasma [77] . the commercialized injectable product of xingnaojing injection was extracted and refined scientifically from classic chinese emergency prescription "angong niuhuang pill", it had the functions of clearing heat and detoxication, cooling blood and activating blood circulation, inducing resuscitation and widely used in the treatment of intracerebral haemorrhage, cerebral ischemia, and nervous system disorders in china [78] [79] [80] . in view of critical cases with covid-19 might suffer from consciousness disturbance, xingnaojing injection had major biological effects to relax the cerebral vascular and protect the mature neuron, in vivo and in vitro research, it was confirmed that the mechanism of cerebrovascular protection might be relevant to the activation of pi3k/akt/enos signaling pathways and the suppression of nlrp3 inflammasomes [81] [82] . in aforementioned guidelines, five cpms were recommended as adjuvant rescue just for critical infections with covid-19, namely suhexiang pill, angong niuhuang pill, shenfu injection, shengmai injection, shenmai injection. currently, there were paucity of accessibly published evidence concerning on these cpms and 2019-ncov simultaneously, it was urgent and essential that subsequently clinical trials or pharmacological research to provide sufficient references for clinical recommendation. herein, we brief summarized the findings in the field of infectious or health-threatening diseases to supplement the correlative knowledge. although both of them were famous chinese emergency prescription and contained same resuscitation-inducing aromatic herbs as bingpian (borneolum syntheticum), suhexiang pill and angong niuhuang pill were used for patients with opposite syndromes. the former was adopted to seizures, infantile convulsions and stroke with cold syndromes [83] , therefore, suhexiang pill might achieve therapeutic effectiveness for covid-19 cases with critical conditions such as delirium, phlegm syncope, central nervous depression, and coma or worsen. its neuroprotective, anticonvulsant and antioxidative effects had been proven by fundamental research both in vitro and in vivo, suggesting its pharmacological mechanism involved the suppression of jnk hyperactivation and apoptosis, inhibition of egfr/erk pathways and glial cell proliferation, decreasing ros formation and restoring mitochondrial function [84] [85] [86] [87] . as a recipe of "liangkai sanbao" in tcm theory, the latter was recognized to treat heat diseases only, including acute ischemic stroke, viral encephalitis, acute hemorrhagic stroke, and trauma brain injury, angong j o u r n a l p r e -p r o o f niuhuang pill could play desirable role for treating critical infections with 2019-ncov in attenuating the negative symptoms including hyperthermia, stupor, coma, etc. [88] . meanwhile, based on the research was conducted on a high-fat and vitamin d3-induced rodent model of atherosclerosis, the results presented that angong niuhuang pill had antiplatelet aggregation, lipid regulatory, antioxidant, anti-inflammatory and anti-apoptotic properties contributing to robust antatherosclerosis and cardio-protective effects [89] , which might be beneficial for critical cases with cardiovascular and cerebrovascular diseases. the mechanisms of angong niuhuang pill exhibited the neuroprotection was related to depressed bax/bcl-2 ratio and caspase-3 level, resulting the inhibition of apoptotic cell [90] . injection had similar therapeutic effects of tonifying qi and preventing exhaustion, they could be adjuvant rescue and alternative treatment of covid-19 patients with septic shock, viral myocarditis, and cardiogenic shock in clinical practice [91] [92] [93] . for example, in rabbits with lps-induced septic shock, shenfu injection could increase mean arterial pressure, decrease the serum lactate dehydrogenase (ldh), aspartate aminotransferase (ast), and glutamate transaminase (alt) levels, improve the tissue morphology of heart, liver and kidney, and increase the contents of atp and taurine in the heart tissue during septic shock [94] . besides, previous studies demonstrated that shenfu injection, shengmai injection and shenmai injection were associated with protective effects on lung ischemia-reperfusion injury, reducing chemotherapy-induced adverse effects, and promoting cellular immunity and cognitive dysfunction and so on, presumably, these clinical functions might improve symptoms of critical patients with covid-19 in terms of lung inflammation, virus infection, drug-induced disease lung injury [95] [96] [97] [98] . since the globally health-care-associated outbreaks of 2019-ncov, in china, the implementing "attach equal importance to tcm and western medicine" policy in clinical practice exerted essential effects for treating covid-19 [99] [100] . based on unique guiding principles of syndrome differentiation and treatment in tcm, its clinical superiority had considerable recognition and public acclaim in the furious battle for 2019-ncov, the cumulative number of research revealed that its curative advantages involved in whole treatment process, namely prevent disease progression, alleviate clinical symptoms, improve the hospital stay and negative results of nucleic acid detection, and promote the physical recovery [21] [22] 101] . [104] [105] . moreover, our study highlighted that its clinical beneficial effects in severe cases was closely associated with the inhibition of cytokine storm, improve virus infection and lung injury, superior binding activities with 3clpro and ace2. in addition, three types of recommended herbal injectable dosage forms contained hongshen (ginseng radix et rhizoma rubra), ginseng was generally known for its tonic properties, and previous findings also suggested it might be a promising supplemental remedy against infectious diseases, this administration of ginseng could fast and accurate adjust excess or deficiency between yin or yang and restore their balance among critical patients [106] [107] [108] . when great attention was paid to the application of tcm in real-world, there were growing concerns related to the potential toxicity or inevitable adrs of herbal medicines. the results of pharmacovigilance pointed out the risk factors of adrs triggered by tcm including responsible chinese materia medica, susceptible patients and clinical administration [109] . in this regard, our research should emphasize the following aspects, including poisonous composition, the safety status of chinese herbal injection, special population, and irrational drug use. first, angong niuhuang pill contained cinnabar (hgs) and realgar (as 2 s 2 ) which were correlated to hepatorenal toxicity [110] . fuzi (aconiti lateralis radix praeparaia) in shenfu injection was associated with narrow therapeutic window, its cardiac adrs has been frequently observed that mainly manifested as palpitations, hypotension, arrhythmia, ventricular fibrillation, and even shock [111] [112] . second, compared with other dosage forms of tcm medications, chinese herbal injections were associated j o u r n a l p r e -p r o o f with the higher risk of adrs, especially serious side effects [113] [114] . therefore, during the treatment of covid-19, corresponding measures including drug safety monitoring and risk management for cpms should be strengthened to achieve optimal benefits and minimal hazards. third, the available evidence highlighted that special population including children, gravida and elderly people were particularly vulnerable to unfavorable drug responses, because their pharmacokinetic and pharmacodynamic profiles differed from the general population [115] . indeed, clinical medication was complicated, the irrational uses reflected in misuse or abuse application of in the treatment of covid-19 was more effective than patients receiving western medicine alone, which can significantly shorten the hospitalization, improve clinical symptom and imaging results [117] . in conclusion, the present study was devoted to summarize the comprehensive information and the authors of the manuscript that titled "the clinical benefits of chinese patent medicines against covid-19 based on current evidence" declared that there are no conflicts of no financial/personal interest. emerging 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outcome in patients with sepsis or septic shock shenmai injection enhances the cytotoxicity of chemotherapeutic drugs against colorectal cancers via improving their subcellular distribution administrations of preoperative shenmai injection and postoperative shenfu injection, two ginseng containing tcm formulas, improve cognitive dysfunction in aged rats effects of shengmai injection add-on therapy to chemotherapy in patients with non-small cell lung cancer: a meta-analysis interpretation of the expert guidance on a comprehensive intervention program of traditional chinese medicine for the recovery of novel coronavirus pneumonia(draft) in silico screening of chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus clinical features and treatment of covid-19 patients in northeast chongqing protective effect of phillyrin on lethal lps-induced neutrophil inflammation in zebrafish phillyrin is an effective inhibitor of quorum sensing with potential as an 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traditional chinese medicine injections used in chinese children respiratory syncytial virus prophylaxis and the "special population do ethanol and metronidazole interact to produce a disulfiram-like reaction? observation on clinical effect of modified qingfeipaidu decoction in treatment of covid-19 this work is supported by the programs foundation for leading talents in state administration of traditional chinese medicine of china-"qihuang scholars" project (10400633210004), the national natural science foundation of china (grant no. 81874349), and national special support plan for high-level talents (plan of ten thousand people)-famous teacher program to professor bing zhang. heat diseases including invasion of pericardium by evil, febrile convulsion, coma and delirium. apoplectic coma, encephalitis, cephalomeningitis, toxic encephalopathy, hematencephalon, septicemia belongs to the above syndromes. key: cord-303217-xdi9b6a7 authors: feng, yibin; siu, kayu; wang, ning; ng, kwan-ming; tsao, sai-wah; nagamatsu, tadashi; tong, yao title: bear bile: dilemma of traditional medicinal use and animal protection date: 2009-01-12 journal: j ethnobiol ethnomed doi: 10.1186/1746-4269-5-2 sha: doc_id: 303217 cord_uid: xdi9b6a7 bear bile has been used in traditional chinese medicine (tcm) for thousands of years. modern investigations showed that it has a wide range of pharmacological actions with little toxicological side effect and the pure compounds have been used for curing hepatic and biliary disorders for decades. however, extensive consumption of bear bile made bears endangered species. in the 1980's, bear farming was established in china to extract bear bile from living bears with "free-dripping fistula technique". bear farming is extremely inhumane and many bears died of illness such as chronic infections and liver cancer. efforts are now given by non-governmental organizations, mass media and chinese government to end bear farming ultimately. at the same time, systematic research has to be done to find an alternative for bear bile. in this review, we focused on the literature, laboratory and clinical results related to bear bile and its substitutes or alternative in english and chinese databases. we examined the substitutes or alternative of bear bile from three aspects: pure compounds derived from bear bile, biles from other animals and herbs from tcm. we then discussed the strategy for stopping the trading of bear bile and issues of bear bile related to potential alternative candidates, existing problems in alternative research and work to be done in the future. bears live in all the continents except africa, antarctica, and australia, and they are classified into eight species including giant panda (ailuropoda melanoleuca). the largest among all is polar bear (thalarctos maritimus), followed by brown bear (ursus arctos), american black bear (ursus americanus), asiatic black bear (selenarctos thibeta-nus), spectacled bear (tremarctos ornatus), sloth bear (melursus ursinus), and sun bear (helarctos malayanus). all of these species are endangered -five are listed in convention on international trade in endangered species of wild fauna and flora (cites) appendix i, whilst the remaining three are listed in appendix ii [1] . china was the first country utilizing bear bile and its gall bladder in traditional medicinal products and this usage was adopted by korea and japan [2,3] centuries ago. today the use of traditional chinese medicine (tcm) was widespread not only in asia but also throughout asian communities in other areas of the world, including europe and america. many of these consumers bought bear bile products, either because they believed it was a traditional medicine, or because the products were marketed well by local tcm pharmacies. bear bile and bile extraction in tcm were under the category of animal drugs. its medicinal functions were well documented in ancient chinese medicinal and modern chinese medicine publications [4, 5] . some recent textbooks and books of tcm still recommend formulae containing various animal tissues such as tiger bones, antelope, buffalo or rhino horns, deer antlers, testicles and penis of the dog, bear or snake bile. some of them have drawn attention from international [6, 7] . usually, animal tissues were combined with medical herbs to form chinese medicine preparations and in most of the cases, the medical use of these preparations was justified in terms of the rules of tcm. however, only a few researches have been done to prove the claimed clinical efficacy of tcm animal products. still, j. (2003) [8] has published a review paper in discussing some related ecological, ethicolegal and health concerns about hunting, breeding and trading with endangered species, risks of transmission of zoonoses, quality of the products, and alternatives to the preparations from endangered species. bear bile (xiongdan in chinese) is the dried gallbladder with bile of selenarctos thibetanus curvier or ursus arctos l. the dried gallbladder with bile from other species of ursidae can be also used as bear bile. bear bile was first recorded in <tang ban cao> (newly revised materia medica, tang dynasty, 659 a.d.), the first official book compiled and issued by the government and considered to be the first pharmacopoeia in china. from the point of view of tcm, bear bile was considered as a cold medicine, bitter in flavor, cool in nature and attributive to liver, gallbladder and heart, so it could clear heat to relieve toxin, stop endogenous wind to arrest convulsion and clear away liver fire to improve eyesight [5, 9, 10] . in traditional clinical practice, bear bile was used in fever fighting, detoxification, inflammation, swelling and pain reduction. it was also used in the cure of carbuncle of heat type, pyocutaneous diseases, hemorrhoid, overabundance of liver-fire, convulsion caused by the overabundance of heat, epilepsy, tic, and redness of eyes due to liver heat etc [5] . for seasonal febrile disease with high fever in children and infantile convulsion, bear bile can be dissolved in milk or succus from bambusae (zhulishui in chinese). for heat-toxin syndrome manifested by skin carbuncle, sore throat and hemorrhoids, bear bile can be used as oral administration or external use. in treating conjunctivitis and nebula, it is prepared to be a water solution as eyewash or used together with borneolum (bingpian in chinese) [5] . besides traditional use, the modern application of bear bile was extensive spread to many modern diseases based on traditional indications and pharmacological studies (also see pharmacological study of bear bile and scientific research). usage and dosage 0.25-2.5 g is taken as a dose in pill or powder. it is mainly single use and rarely used together with other herbs. due to its fishy and bitter taste that may induce vomiting, it should be given as capsules. for external use, the fine powder can be applied to the local area or used with water [5] . being extremely bitter and cold, it is easy to injure yang-qi of the spleen and stomach and so, it is contraindicated for deficiency and cold of the spleen and stomach [5] . over the years, extensive research has been done in establishing methods to analyze and quantify the total and individual bile acids and their glycine and taurine conjugates in serum [11, 12] , pharmaceuticals [13, 14] , and bile [15] [16] [17] , including bear gall drainage [18] . these methods mainly consisted of thin layer chromatography [13, 18, 19] and high-performance liquid chromatography [11, 12, [14] [15] [16] [17] 20, 21] . modern chemical research indicated that bear bile was mainly composed of bile acids, amino acids, bile pigments, fat and a few phospholipids and trace metals [22, 23] . bile acids were regarded as the principle components of bear bile in medical applications. it contained ursodeoxycholic acid (udca), chenodeoxycholic acid (cdca), and cholic acid (ca). they usually occurred in form of conjugates solely with taurine in n-acyl linkage [22, 24, 25] . udca (3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid) was found to be the primary bile acid produced in the liver of bears [26, 27] and the relative high content of udca (1-39%) in bear (ursidae) bile made it different from the ones originated from pandas, related carnivores (< 0.5%) [28] and other vertebrates [29] . it is important to note that variation of bile acid composition in bear bile was present. espinoza eo et al. (1993) [24] reported that the bile originated from farmed bears (bears with chronic biliary fistulae, see also section 4.2 extracted bear bile powder) was characterized by a decrease in the percent composition of tauro-cholic acid (tca) and a dramatic increase in that of tauro-ursodeoxycholic acid (tudca) and tauro-chenodeoxycholic acid (tcdca). however, results of later investigation [30] indicated that the low content of tca was common among wild and farmed asian bears, while the samples from polar and north american black bears showed a relative high content of tca. modern pharmacological research showed that bear bile has the following pharmacological actions: (1) antimicrobial and anti-inflammatory effect, (2) anti-hepatotoxic effect, (3) choleretic lithagogic effect, (4) anti-liver fibrosis, anti-tumor, anti-pyretic and sedative effect, (5) anticonvulsant and analgesic effect, (6) lowering lipid and hypotensive effect, (7) anti-tussive and anti-asthmatic effect, (8) improving eyesight, (9) anti-stress and relaxing effect [22, 31] . as an anti-inflammatory drug in its clinical utilization, the suppressive effect of bear bile on inflammation was also investigated in extensive non-clinical studies. using the model of rat granulation and feet swelling, it was reported that bear bile can significantly suppress inflammation in animal models. moreover, it was also observed that bear bile can reduce the permeability of capillary vessel [32, 33] . recently, an investigation has been conducted to investigate the inhibitory effect of bear bile powder on rat liver fibrosis induced by dimethylnitrosamine (dmn). the results suggested that the bear bile powder could prevent the formation of liver fibrosis induced by dmn. the mechanism might relate to its inhibitory effect on the activation of kupffer cell (kc) and hepatic stellate cell (hsc) [34] . another study investigated the effect of tauroursodeoxyecholic acid (tudca), the characteristic compound of bear bile, on activity of glutamic pyruvic transaminase (gpt), and observed that tudca could significantly reduce gpt activities in mice serum and the inhibitory effect is independent to the concentration of substrate. no toxicity of tudca could be observed in this study [35] . these research demonstrated bear bile's clinical function as a hepatoprotective agent. since bear bile has a wide range of pharmacological actions with little toxicological side effect, it is now being used clinically for curing hepatic and biliary disorders, cardiovascular and cerebrovascular disorders, pulmonary disorders, and ophthalmological disorders, while the pure compound derived from bear bile, udca, is widely used for hepatic and biliary disorders (also see 5.3 scientific research). bear bile as well as its chinese medicine formulae could also be applied to diabetes, nephritis, chincough, hemorrhoids, chronic hepatitis b induced jaundice, and falling sickness, etc. [22, 31, 36] . natural bear bile traditionally, bear bile (xiong dan in chinese) was the dried gall bladders of tibetan brown bears (ursus arctos pruinosus) or asiatic black bears (from north-eastern and northern part of china) under the family of ursidae. later on, gall bladders from american black bears, sun bears and himalayan brown bear (ursus arctos isabelinus) were also used in tcm [33] . the bear bile could be further divided into two types, namely, "yun dan" and "dong dan" in commercial market of tcm. the quality of the former was considered to be better. gall bladders might be sold in whole pieces, in shavings, or in powder form which was put into capsules. long time ago, people got bear bile via hunting activities but nowadays, people are used to getting bile from living bears. in the 1980's, the people's republic of china has developed bear farms where over 7,000 brown bears and asiatic black bears were kept in small cages. an un-sterile latex or stainless steel catheter was inserted through the external fistula directly into the gall bladders of each bear to drain the fluid daily either by gravity into a tray or by suction with an un-sterile syringe. this extraction method was called the "free-dripping fistula technique". the fluid was then dried and manufactured as "bear bile powder" (bear bile extraction) [37] . the bears were suffering extreme pain due to daily bile extractions. many of them often die from illnesses (such as cholecystitis, cholelithiasis, polyp formation, obstruction of the cystic duct, strictures and partial herniation of the gall bladder wall, liver cancer) and chronic infections caused by the presence of foreign bodies and their open wounds [38, 39] . products made from farmed bear bile included powder, capsules, ointments, tablets, tinctures, wines, suppositories, eye drops and bile tea. bear bile powder was the most common type of product. it was usually produced and packaged by the bear farms themselves. comparative studies in chemical components of natural bear bile and bile extraction have been done in the past years and the results showed that both of the natural bear bile and the bile extraction contained similar chemical components and the quality of natural bear bile was much better [40] [41] [42] [43] [44] . trading of gall bladders from wild bears has been extensive over the past few decades. tens of thousands of bears have been killed in the wilds to obtain their gall bladders and body parts, such as the paws (a delicacy in some eastern countries), hide, claws, meat, fat and bones. moreover, gall bladder has been the prize as it has the greatest commercial value. it was because prices of bear parts in china have dramatically risen. in 1970 one kilo of bear gall bladder cost around us $200, but by 1990 the price had risen to between us $3,000 and us $5,000 per kilo [45] . recent market price with legal certification has risen to between us $30,000 and us $50,000 per kilo (our experience in legal market of hong kong). this has led to an increased threat to bears in the past few decades as price for bear gall bladder has increased making it a lucrative trade for hunters and middlemen alike. illegal products containing bear bile were on sale in traditional medicine shops in usa, canada, japan, taiwan, korea, singapore, australia and new zealand according to the new findings from investigations led by the world society for the protection of animals (wspa) [46] . the report showed bear products offered by these shops were originated from china's bear farms. with the great demand for bear bile products, fraudulent products were found in the markets. two surveys reported that most of the bear bile products were indeed gall bladders or bile originated from domestic pigs, goats, and water buffalo or mixture with the true bear bile. only minority of the specimens was found purely from bears [24, 30] . from killing bears to get bear bile to adopting bears to extract bear bile, it failed to protect bears; on the contrary, cruelly put them in more pity position. non-governmental organizations (ngos) and the public could also play important roles on this issue, such as arousing public awareness, sharing of survey information that might assist governments, and raising the profile of this issue during communications with national authorities and international bodies. wspa and its global network of member societies were working hard in requesting the chinese government to close down the bear farms. in july 2000, an official signing ceremony among animals asia foundation (aaf), the china wildlife conversation association in beijing and the sichuan forestry department of china present, took place in public in hong kong where the "china bear rescue" agreement was announced to the worldwide press. the agreement summary was as follows [47] : (1) the short-term goal was to close down the worst farms in sichuan, china and to rescue 500 bears; this goal had been reached by end of march, 2008. (2) the medium-term goal was to expand this program across china and continually reduce the number of bears on farms; and (3) finally, the long-term goal was to end bear farming and provide care and refuge for the remaining number of bears. in this agreement, effort was given in supporting the research about the manufacture and the use of herbal and synthetic substitutes to bear bile and, in encouraging all consumers to refuse the use of any products containing bear bile. the chinese officials would continue to maintain her policy of prohibiting the export of bile internationally. they would also launch public education programmes on the protection of wildlife and to preserve and protect the natural habitat of bears. the aaf had agreed to pay a certain level of compensation to the farmers in an effort to ensure that none of these bears were slaughtered anymore for their parts. at the same time, it helped those affected bear farmers moved into alternative areas of employment. the sichuan government passed the original copies of all confiscated licenses to aaf and a countrywide policy was set up in china to ensure that no new bear farm license would be issued. however, bear farming still existed and wspa believed there was no humane method of bile extraction. the farming bears for bile should be stopped as soon as possible due to the extreme animal cruelty involved and the negative effects on wild bear conservation. to stop the illegal bear products trade and to protect wild bear populations, collaborations between cites (convention on international trade in endangered species of wild flora and fauna), national and local governments were needed to ensure that effective regulations and legislation were founded and executed. in addition, direct communication with chinese government was necessary to determine her long-term strategy for the bear farms, and to explain the reasons why bear farming should be ended. if the demand for the bear bile products diminished, then illegal trade would stop automatically. thus, public and consumer awareness programs should be carried out in key countries. educational materials for the traditional medicine communities, including practitioners, traders and consumers need to create awareness of the wildlife conservation and animal welfare issues associated with the bear products. as the major production country of bear bile products, the chinese government implemented some measures to protect the bear. in 2001, ministry of health announced that health products made of bear bile powder would not be approved any more in order to protect the sources of wild animals and guarantee the safety of health products. since then, no such product was approved by ministry of health. in 2005, regulations on the usage of bear bile in chinese medicine products were stipulated by the chinese government. food and drug administration of all provinces, and municipality directly under the central government should strictly adhere to the regulations by limiting the usage of bear bile powder in chinese medicine products. manufacturers of these products should submit their applications to their local food and drug administration by listing out their categories, number of production and materials used, especially if there was bear bile powder. as a matter of fact, it became a dilemma of whether bear bile should be used or not. the usage of bear bile was a problem of history, culture and economy and it might also become a political issue. on the one hand, there was pressure from wild animal protection groups on the mainland and overseas. on the other hand, bear bile was an important raw material of tcm. no alternative materials could replace its integrative effects of pain-killing and anti-inflammatory for the time being. by far, there were 123 chinese medicine products made of bear bile and 183 enterprises supported by bear bile powder [48] . facing these two challenges, if bear farming industry had to be eliminated within china, an alternative for bear bile should be found out and widely promoted for producing chinese medicine products. to look for an alternative of bear bile, a systematic research has to be done. the definition of "alternative" was a kind of material, which originated from animals or plants that were not classified as endangered species. it should also have medicinal effects similar to that of bear bile and could totally replace it in terms of clinical use. in fact, some research has been done on alternative for bear bile from three aspects including: (1) animal drug substitutes, (2) pure chemical substitutes, and (3) plant drug substitutes. however, it would not be able to stop using bear bile immediately even an alternative was avail-able. it was because it needs a long time to promote this alternative and gain acceptance from people by changing their culture, economic system and medical practice. the bile acid compositions of several fowls and domestic animals, including toad, rabbit, chicken, pig and cattle, were preliminarily studied [29] . the results indicated that toad bile mainly composed of ca. in chicken bile, there were both cdca and ca. deoxycholic acid (dca) was found in rabbit bile, while hyodeoxycholic acid (hdca), lithocholic acid (lca) and cdca were present in pig bile. the composition of cattle bile was characterized by ca, dca and minor cdca. the studies on bile of rabbits and pigs have been extensively carried out in comparison with those from other animals. it was reported that both bear and pig bile solutions were shown to have anti-inflammatory, anti-convulsion and analgesic effects. they could also prolong the survival time of mice under hypoxic conditions. it was possible that pig gall bladders could be developed as an alternative for bear gall bladders in certain prescriptions of chinese medicine [49] . comparison between pharmacologic actions of rabbit bile and bear bile was also carried out. it was reported that many pharmacologic actions of the rabbit bile were similar to those of bear bile. it was also demonstrated that the effects of the rabbit bile were more obvious than those of bear bile in positive inotropic action, sedation, anti-tussive action, and anti-histaminic action, etc. [50] . these two kinds of gall bladders were generally considered to be able to substitute bear bile based on their chemical and pharmacological effects. among the chemical components in bear bile, bile acids were the main effective components, which consisted of udca and cdca. these two bile acids were a pair of isomer and the former made bear bile different from other animal biles. in other words, bears were the only mammals to produce significant amounts of udca (apart from giant pandas, which do not produce udca). it was also the udca which gave bear bile beneficial medicinal effects. although udca was also found in other animal species and could be extracted from pig bile and cow bile, the quantity was too little for large scale production. japanese scientists succeeded in chemically synthesizing udca in 1955 [51] . today, large quantities of udca were made synthetically and widely used in western medicine to dis-solve gallstones. it was estimated that 100,000 kg of this synthetic udca was being consumed each year in china, japan and south korea, and that the world consumption may double this figure. oral administration of either udca or cdca could desaturate bile and contribute to the dissolution of cholesterol gallstones. however, the former was found to be better tolerated with fewer adverse side effects in comparison with the latter. in addition, recent evidence suggested that udca might be an effective drug in various chronic liver diseases, especially cholestatic disorders such as primary biliary cirrhosis [52] . a review paper was found to explain the rationale supporting the use of udca for the treatment of patients with cholesterol gallstones and chronic liver diseases and to describe the results obtained in clinical trials. the conclusion was that udca was a safe and effective drug for the treatment of patients with cholesterol gallstones [53] . in tcm, bear bile was classified under the category of clearing heat and detoxification drugs. in respect to the same medicinal functions, some chinese herbs were also found to have the efficacies of clearing heat and detoxification, purifying liver and improving eyesight. it was suggested that one or more of these herbal medicines could be used as an alternative for bear bile [10, 54, 55] . a recent study on herbal alternatives to bear bile reported scutellaria baicalensis georgi, huangqin in chinese, and its active components, chrysin and wogonin, exhibited inhibitory effect on il-6 promoter activity, indicating its potential as an anti-inflammation agents and an alternative to bear bile, traditional anti-inflammatory agent [56] , but it is hard to say that huangqin is a good candidate for substitute of bear bile because bear bile has multiple pharmacological action. although bear bile had the efficacy of clearing heat and detoxification, purifying liver, improving eyesight, and could be used to treat eclampsia, epilepsy, tic, hot liver, red eyes and swollen problem, it did not have the functions of protecting liver and could not be used to treat visual disturbance caused by weak liver and kidney according to tcm theory. as a result, scientists in pharmacology of chinese medicine and chinese materia medica were required to work together with tcm practitioners closely in order to find an alternative for bear bile. in other words, experts were required to carry out detailed research work and to propose scientific research methodology. afterwards, stringent implementation should be ensured for proving the similar efficacies and mutual substitutability of the alternative. among the possible alternatives for bear bile, coptis ("huanglian" in chinese) was a possible choice since both of these materials were under the category of clearing heat. apart from that, both bear bile and coptis could detoxify, purify liver, improve eyesight, as well as treating eclampsia, epilepsy, tic caused by fire, carbuncle of heat type, pyocutaneous diseases. at present, prescriptions with coptis (such as huang lian jie du tang, qing ying tang, and an gong niu huang wan) were widely used to treat symptoms such as coma, eclampsia, epilepsy, tic and we have also used it to treat liver diseases (major active compound, udca derived from bear bile is mainly used for liver diseases) and cancer in tcm clinical practice [57] . now, we are doing comparative research between bear bile and coptis in chemical analysis, pharmacological study and clinical efficacy to clarify what we concern. [58] . brief history of the traditional use of coptis coptis (huanglian) was firstly recorded in, <shen nong ben cao jing>, a medical classic written in han dynasty, and was selected as a herbal drug for clearing heat and scavenging toxics. moreover, in the ancient pharmacopeia <ben cao gang mu> in ming dynasty, coptis and its formulations were used as therapeutic agents for eye diseases and diarrhea. a recent study summarized that coptis in single dose form was most commonly used for the treatment of eye diseases in some ancient medical books (comprising 14.58% of the total records) [59] . considering that optical system has close relationship with liver according to chinese medicine theories, these records indicates that coptis may function to benefit liver organ, which is also regarded as parts of the pharmacological effect of bear bile in its traditional utilization. these links provide some evidences even inspirations for the use of coptis as an alternative to bear bile. in terms of clinical applications, it was surprising to find the unexpected similarities between coptis and bear bile, such as detoxify, purify liver, improve eyesight, as well as treating eclampsia, epilepsy, tic caused by fire, carbuncle of heat type, pyocutaneous diseases, sore throat and hemorrhoids. the chemical composition of coptis is complicated and dependent on species of samples. however, some common components amongst different species have been isolated and identified, including berberine, coptisine, palmatine, jatrorrhizine and magnoflorine [60] . in china pharmacopeia (edition 2005), berberine is used as a criterion for quality control of the coptis. thin layer chromatography and high performance chromatography analysis on berberine provide qualitative and quantitative evaluation to the herbs. nonetheless, single criterion has its limitation in quality control system. studies in our group have established, using hplc-ms/ms, the chemical profile of coptis and have made comparison on the chemical composition amongst species (data not shown). differences can be easily observed from chromatograms so this provides a direct but comprehensive approach for the quality control of coptis. extensive studies exhibited that coptis has many pharmacological actions with strong clinical implications, including antibacterial, antiviral, antiinflammatory, antineoplastic, antihypertensive, antioxidative, antihyperglycemic and cholesterol-lowering effects [61] [62] [63] [64] [65] [66] [67] [68] . bioavailability of pure compound berberine derived from coptis is variety, traditionally it has been thought that berberine is poorly absorbed, but it has been reported that absorption in the mouse and human is good [69] [70] [71] . previous studies in our group displayed that coptis and its major component berberine showed promising potential as drug candidates for the treatment of liver injury [ [72] and unpublished data]. it was also found from our in vitro study that coptis and berberine can suppress cancer cell lines [ [73] and unpublished data]. these positive data add new pharmacological activities for coptis and berberine and indicate the potential of coptis and berberine as an alternative to bear bile. now comparative study on coptis and bear bile is our ongoing phd program training project. to summarize, it was believed that the usage of bear bile is a problem of history, culture and economy and it may also become a political issue. before stopping use of bear bile, it needs combined efforts from various routes of the society. as we reviewed in this paper, research on alternative for bear bile has been conducted in the past decade including comparative studies of various animal biles, the major effective components of bear bile, and substitutes of bear bile by artificial materials and herbal medicines. in this review, it showed that animal biles, such as those from pigs and rabbits, the synthetic compound of udca, and herbs, such as coptis, were possible substitutes for bear bile. however, plant substitutes were only suggested in literature without solid evidence to support, while some animal substitutes were superficially studied. thus, it is necessary for us to design systematic, serious and comparative research to get convincing data. it is important to note that animal substitutes will be found contradictory to the tenets of world animal protection sooner or later. the final choice will be using plant materials to substitute bear bile. our previous study showed coptis was a promising drug due to its similarity to bioactivity characteristics of bear bile, therefore comparative study for both coptis and bear bile will be carried out. more persuasive research has to be done to explore their integrative functions and prove their similarities to bear bile in terms of medicinal use. on international trade in endangered species of wild fauna and flora (cites) bear bile and ursodeoxycholic acid bear bile resources -past and 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literature of chinese medicine recent advance in huanglian research. lishizhen medicine and materia medica research pharmacology and applications of chinese materia medica optimization of antibacterial activity by gold-thread (coptidis rhizoma franch) against streptococcus mutans using evolutionary operation-factorial design technique in vitro inhibition of coronavirus replications by the traditionally used medicinal herbal extracts, cimicifuga rhizoma, meliae cortex, coptidis rhizoma, and phellodendron cortex inhibitory effect of coptidis rhizoma and scutellariae radix on azoxymethane-induced aberrant crypt foci formation in rat colon huanglian, a chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin b1 and inhibiting cdc2 kinase activity in human cancer cells coptidis rhizoma: protective effects against peroxynitriteinduced oxidative damage and elucidation of its active components the effects of coptidis rhizoma extract on a hypercholesterolemic animal model effects of san'o-shashin-to and the constituent herbal medicines on theophylline-induced increase in arterial blood pressure of rats measure berberine in bio-samples by hplc study on absorption, distribution and elimination of berberine research on efficacy of oral medication of "huã¡ng liã¡n sã¹"(berberine) the anti-cancer effect and the possible mechanism of berberine 7th meeting of consortium for globalization of chinese medicine (cgcm) program & abstracts antioxidative and hepatoprotective effects of coptis extract on liver damage in rats the study was financially supported by grants from the research council of the the authors declare that they have no competing interests. fy and sy retrieve data of bear bile, other animal biles and chinese herbs from databases of medline, pubmed, other databases and data analyses and drafted the manuscript. wn retrieves data in chinese from database of china journals full-text database and translated them into english. nkm analyzed and summarized chemical data from above database. fy, tsw, nt and ty conceived of the study, supervision of the work and revision of the manuscript. all authors read and approved the final manuscript. key: cord-321041-51b7oh8s authors: chiappelli, francesco title: 2019-ncov towards a 4th generation vaccine date: 2020-02-12 journal: bioinformation doi: 10.6026/97320630016139 sha: doc_id: 321041 cord_uid: 51b7oh8s the first report of the unusual manifestation of pneumonia-like symptoms in wuhan city, china was made on 31 december 2019. within one week, the chinese authorities reported that they had identified the causative agent as a new member of the coronavirus family, the same family of that was responsible for mers and sars not so many years ago. the new virus was called novel coronavirus 2019 (2019-ncov). three weeks later, the world health organization declared that 2019-ncov was capable of direct human-to-human transmission, the virus had spread across several countries in three continents, and had infected close to two thousand people, of whom at least 1 in 5 quite severely. the number of fatalities was fast rising. yet, the world health organization officially announced that there is still at present no recommended anti-ncov vaccine for subject at-risk, nor treatment for patients with suspected or confirmed ncov, let alone 2019-ncov. it is therefore timely and critical to propose new possible and practical approaches for preventive interventions for subjects at-risk, and for treatment of patients afflicted with 2019-ncov-induced disease (corona virus disease 2019; covid-19) before the present situation explodes into a worldwide pandemic. one such potential clinical protocol is proposed as a hypothesis. on 31 december 2019, the world health organization was alerted to several cases of pneumonia in wuhan city, hubei province of china. the causative pathogen was suspected to be a virus, but it did not match any other known virus. the following day, wuhan city officials closed the huanan seafood market, suspected to be the source of the mystery pathogen, because it was reported that certain patients presenting with the symptoms were vendors at that public market. by january 4 2020, the chinese health organization reported 44 active cases. on 7 january 2020, chinese authorities confirmed that they had identified the causative agent as a novel coronavirus (cov). that family includes viruses of the common cold as well as viruses known to cause middle-east respiratory syndrome (mers); severe acute respiratory syndrome (sars). the new cov was named novel coronavirus (emerged late) 2019 (2019-ncov). two days later, chinese authorities reported the first fatality linked to 2019-ncov: a 61-year-old male who had been admitted in the first cohort of patients. he had several other underlying medical conditions, which may have contributed to weakening his immune system. apart from respiratory failure and severe pneumonia caused by 2019-ncov, the patient suffered from abdominal tumors and chronic liver disease. on 12 january, chinese scientists released the genetic sequence of 2019-ncov, in part because nonofficial report of international spread of 2019-ncov had commenced. the next day, thailand officially reported its first imported case of 2019-ncov: a 61-year-old woman from wuhan -she, however, denied having visited the huanan seafood market. on january 15 2020, chinese authorities reported the 140 ©biomedical informatics (2020) second death attributed to 2019-ncov: a 69-year-old male who also suffered of other unrelated severe pathologies, including myocarditis. infection with 2019-ncov, nonetheless, were thought to be responsible for his abnormal renal function, and severely damaged to multiple organ functions. the following day, japan reported its first case of 2019-ncov: a chinese man in his 30s, who also denied having visited the huanan market. on january 17, thailand confirmed the second imported case of 2019-ncov. chinese authorities noted a spike in 2019-ncov infections between january 18 and 19, 2020. that observation arose the suspicion that 2019-ncov was capable of direct human-to-human transmission. the following day, 20 january 2020, south korea confirmed its first case of 2019-ncov infection: a male patient who denied having visited any public markets in wuhan. on january 21 2020, the world health organization confirmed human-to-human transmission of 2019-ncov. as of that date, the total official number of cases has risen to 222, although it was suspected to be in reality much higher. infection had spread to health-care workers, and it was suspected that one mode of transmission may be via the eye mucosa. chinese authorities have also reported a fourth death. the situation was fast becoming alarming: suspected cases appeared in france, italy and other countries of europe. australia seems to be affected as well. other countries in asia also reported suspected cases, including the philippines and singapore. suspected cases of 2019-ncov were reported in north america. the following day, 22 january 2020, world health organization director-general tedros adhanom ghebreyesus convened an emergency meeting to decide whether 2019-ncov should be declared to constitute a worldwide public health emergency of international concern. despite a significant rise in confirmed cases of individuals infected with 2019-ncov -in china alone, at 580 infected individuals, with a death toll now at 17 in the hubei province alone -the emergency committee deferred its decision on whether to advise director-general ghebreyesus to declare the 2019-ncov outbreak a public health emergency pandemic of international concern. on january 23, chinese authorities shut down the city of wuhan: no public transportation, closed airport and railway station for 11 million people. later that same day, the city of ezhou is also in complete lockdown. festivities for the upcoming chinese new year were cancelled throughout china to minimize human contact in crowds. the following day, the city of huanggang was declared under lockdown. singapore confirmed its first imported case, and vietnam confirmed two cases. director-general ghebreyesus declared that, indeed, the 2019-ncov outbreaks is a public health emergency of international concern. on january 24 2020, the official number of confirmed cases of patients infected with 2019-ncov had risen to 830 in china alone, with 177 (21%) among them in severe and critical condition. the number of fatalities caused by 2019-ncov in china was now 25. japan confirmed its second 2019-ncov case. nepal confirmed its first case. the following day, australia confirmed its first case of 2019-ncov, as did france. two suspected cases in italy were being closely monitored. in china, the official number of new infections -that is, over the previous 24 h -was 444, and the number of new deaths was 16 above and beyond the number reported the previous day. the official number of individuals confirmed to be infected with 2019-ncov in china became 1,287, including 237 (20.7%) in severe and critical condition. there is no first-, second-or third-generation vaccine available for any members of the cov family, nor is there practically the time to develop, raise, test and evaluate the effectiveness of a vaccine for 2019-ncov. moreover, the world health organization stated in its 12 january 2020 recommendations entitled 'clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected -interim guidance; who/ncov/clinical/2020.1' that "…there is no current evidence from rcts to recommend any specific anti-ncov treatment for patients with suspected or confirmed ncov…". in brief, the international medical community is totally devoid of tools to combat the unfolding 2019-ncov thereat to global public healthnot in terms of preventive medicine to protect subjects at-risk, and not in terms of clinical interventions for infected patients. what is known, however, is that 2019-ncov, like all corona viruses belong to the coronaviruses (coronaviridae) family of rna viruses that cause diseases in mammals and birds that include diarrhea in cows and pigs, and upper respiratory disease in chickens. in humans, the virus causes respiratory infections, which are generally often mild, rarely lethal. the trends we begin to observe with 2019-ncov suggest that it can be directly transmitted humanto-human, and that it causes serious infections in roughly one in five patients that can lead to death: staggering preliminary statistics. previous research with other cov members indicates that proteins of coronaviruses that could be used in the generation of vaccines include the spike, the envelope, the membrane and the ©biomedical informatics (2020) nucleocapsid proteins. the spike protein is of particular interest because it is responsible for the penetration of the virus into the cell, which leads to the initiation of viral replication and proliferation. the spike protein binds to the angiotensin-converting enzyme 2 (ace2) transmembrane -receptor on the eukaryotic host cell. case in point, sars-cov binds to ace2, as does mers-cov [2] . indeed, ace2 is the obligate cellular receptor for cov entry process via the spike protein [3] . while the development of a vaccine of the 1 st , 2 nd or 3 rd generation against the spike protein is possible but time consuming, it is therefore timely ad critical to propose new possible and practical approaches for preventing infection of subjects at-risk and for treatment intervention of patients infected with 2019-ncov, or any other cov for that matter. one such alternative protocol is proposed below. short of 1 st , 2 nd or 3 rd generation vaccine measures for preventive cov, and short of clinical treatment interventions for patients infected with cov, and specifically, 2019-ncov, it is timely and critical to evaluate new alternatives. here, we propose that one putative 4 th generation vaccine to control 2019-ncov explosion might simply involve the genetic engineering a soluble binary molecule (i.e., ace2r-ace2r; [ace2r] 2) or its quaternary form (i.e. two intertwined ace2r-ace2r; [ace2r] 4). this process is fast, reliable and precise by today's standard, and doable in any modern biochemistry laboratory. the obtained sterile molecule could be injected in individuals at high risk as a preventive 4 th vaccination measure, or as a treatment intervention in confirmed cases of 2019-ncov infection. the soluble molecule is expected to bind the spike protein of circulating cov with higher affinity than the transmembrane ace2r, and to render the cov particles, therefore, incapable of binding to the cell receptor, of penetration into the cells, and of replicating inside the cell. the proposed 4 th generation vaccine would, besides protecting the cells from cov infection, also preserve ace2 intracellular functional activity, and guard against the rise of serum angiotensin ii levels, which can be pathogenic to lung cell integrity. in brief, the 4 th generation vaccine proposed here would prevent at-risk individuals from becoming sick from any incipient infection: that is, in the true meaning of the term, it would 'vaccinate' them against cov in general, and in the present case of high emergency provide substantial protection against2019-ncov. moreover, should the molecule be genetically engineered to incorporate a neutral protein, such as human serum albumin, the soluble albumin-[ace2r] 2 or albumin-[ace2r] 4 complex injected in 2019-ncov-infected patients would bind the circulating cov. patients could then undergo a treatment intervention of 'cleaning' their blood from albumin-[ace2r] n-cov complexes by a clinical protocol akin to dialysis. the patient's blood would be passed through a sterile column constructed with high affinity anti-human albumin antibodies. the anti-albumin antibody-albumin-[ace2r] n-cov moieties would be retained on the column, and the 'cov-cleaned' blood returned to the patient to dampen the infection. it is possible that the binding of cov spike protein to ace2 is a down regulation of its expression, resulting in increased serum angiotensin ii levels, and lung injury. indeed, administration of recombinant human ace2 in experimental models of cov infection ameliorates lung injury in animal models [4] . therefore, we propose that the 'cov-cleaned' blood returned to the patient would also be enriched with recombinant human ace2 to ameliorate lung injury. vaccines that are raised from whole pathogens -attenuated or inactivated -are called 1 st generation vaccines. protocols that involve utilizing specific protein components extracted from the pathogens to reduce risks and side -effects in the host produce 2 nd generation vaccines. by contrast 3 rd generation vaccines are vaccines derived from administration of genetically engineered dna or mrna to induce the host cells to produce an antigen in vivo, which in turn is expected to be recognized as non-self, and generate protective antibodies [5] . here, we propose a new avenue in vaccinology: the generation of a molecule with the purpose of preventing infectious disease -that is, a vaccine -, but not based on the traditional norms of antigen-idiotype binding. the 4 th generation vaccine we theorize here depends upon the specificity of receptor-ligand binding, but is a biochemical molecule constructed trn-rewired cov are neither, properly speaking, 1 st or 2 nd generation vaccine, and neither are they 3 rd generation vaccines: they are efficacious hybrid measures that prevent or slow down sars-cov, and possibly mers-cov epidemic. however, the urgency of the present moment precludes the somewhat lengthy experimentation time that would be required for the development and testing of a 3 rd generation vaccine of the sort. since scientists have had several issues up to this point in the process of producing a 3 rd generation vaccine for sars or mers, whose epidemics were several years ago, it implausible that they could now develop such a 3 rd generation vaccine for 2019-ncov in the emergency the world is experiencing today. taken together, the important points brought forth above emphasize the fact that the field of vaccinology cannot and must not be limited strictly to 1 st , 2 nd or 3 rd generation vaccines. a 4 th generation of vaccines is now emerging that may seem unconventional, but converge toward the same goal of preventing the spread of infectious disease. these 4 th generation vaccines may be particularly relevant in the case of flaming epidemics, when the time to generate, test, evaluate and distribute 1 st , 2 nd or 3 rd generation vaccines is prohibitive, such as is precisely the case now with 2019-ncov. in certain circumstances, public health urgency demands immediate intervention, and precludes the time required to generate and test new vaccine species. case in point, the threat now posed by the new member of the coronavirus family (2019-nconv), whose discovery was announced by the chinese health authorities on chinese authorities reported having isolated a new type of coronavirus on 7 january 2020. whereas 2019-ncov is reported to a beta coronavirus closely related to sars and other coronaviruses that originate from bats, it is unclear -and at this point almost irrelevant -to date if 2019-nconv originated from bats or from snake or other animals and subsequently transferred to bats. what is clear is that 2019-nconv is capable of direct humanto-human transmission, and its infection patterns grows alarmingly fast across all continents. to be clear, three weeks into its original reporting, 2019-ncov has infected children, men, women and elderly in all continents. in china alone, the number of confirmed cases are over thirty-seven thousand infected individuals (n=37,593 as of day 21), and the number of fatalities from the disease has risen over eight hundred (n=813). whereas both the percent confirmed cases and the percent death rate seem to have steadily decreased in parallel over the past 21 days, the case-fatality percent rate has remained steady above 2% (mean ± sd: 2.34% ± 0.39) (figure 1) . as a reference point, the case-fatality percent rate of the spanish influenza following world war i worldwide was at, or slightly above 2.5%; that same statistic for measles with no preventive vaccination measures is close 15%. in brief, 2019-ncov seems to be less lethal than the spanish flu, and may be abating somewhat at its original epicenter; it has generated heightened fear for a global pandemic as other epicenters have emerged, including singapore and thailand. in this hypothesis report, we have proposed here a new avenue into 4 th generation vaccines. thus, vaccine protocols that do not involve the generation of antibodies against whole pathogens uses protein extracts obtained from pathogens, or nucleic acids related to pathogens. rather, the preventive and protecting ability of the intervention we propose, which still relies on the specific binding of the pathogen to a substrate generated specifically against it, is a biochemical construct, which could actually best be generated by artificial intelligence of immune surveillance [8] algorithms in the not so distant future. the construct we propose here, specific to cov, and applicable to 2019-ncov in the context of the immediate urgency that is upon us, can be generated and expanded quickly, simply and reliably in any biochemistry laboratory. we also describe how it can be effectively utilized in treatment protocols of patients already infected with 2019-ncov, in a slight modification of the common clinical protocol for renal dialysis. ©biomedical informatics license statement: this is an open access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited articles published in bioinformation are open for relevant post publication comments and criticisms, which will be published immediately linking to the original article for free of cost without open access charges. comments should be concise, coherent and critical in less than 1000 words. key: cord-303039-rteysj8j authors: liu, ming; gao, ya; yuan, yuan; yang, kelu; shi, shuzhen; zhang, junhua; tian, jinhui title: efficacy and safety of integrated traditional chinese and western medicine for corona virus disease 2019 (covid-19): a systematic review and meta-analysis date: 2020-05-11 journal: pharmacol res doi: 10.1016/j.phrs.2020.104896 sha: doc_id: 303039 cord_uid: rteysj8j covid-19 has now spread to all parts of the world and almost all countries are battling against it. this study aimed to assess the efficacy and safety of integrated traditional chinese and western medicine (hereinafter referred to as “integrated medicine”) to corona virus disease 2019 (covid-19). we searched six major chinese and english databases to identify randomized controlled trials (rcts) and case-control studies (ccss) of integrated medicine on covid-19. two reviewers independently screened, identified studies, and extracted data. cochrane risk of bias tool and the newcastle-ottawa scale were used to assess the quality of included rcts and ccss, respectively. stata (version 13.0; statacorp) was used to perform meta-analyses using the random-effects model. risk ratio (rr) was used for dichotomous data while the weighted mean difference (wmd) was adopted for continuous variables as effect size, respectively, both of which were demonstrated in effect size and 95% confidence intervals. a total of 11 studies were included. four were rcts and seven were ccss. the samples of including studies ranged from 18 to 100 (total 982). the traditional chinese medicine included chinese medicine compound drugs (qingfei touxie fuzhengfang) and chinese patent medicine (such as shufeng jiedu capsule, lianhua qingwen granules). compared with the control group, the overall response rate [rr = 1.230, 95%ci (1.113, 1.359), p = 0.000], cure rate [rr = 1.604, 95%ci (1.181, 2.177), p = 0.002], severity illness rate [rr = 0.350, 95%ci (0.154, 0.792), p = 0.012], and hospital stay [wmd = -1.991, 95%ci (-3.278, -0.703), p = 0.002] of the intervention group were better. in addition, integrated medicine can improve the disappearance rate of fever, cough, expectoration, fatigue, chest tightness and anorexia and reduce patients’ fever, and fatigue time (p < 0.05). this review found that integrated medicine had better effects and fewer adverse drug reactions for covid-19. more high-quality rcts will be needed in the future. against it. this study aimed to assess the efficacy and safety of integrated traditional chinese and western medicine (hereinafter referred to as "integrated medicine") to corona virus disease 2019 . we searched six major chinese and english databases to identify randomized controlled trials (rcts) and case-control studies (ccss) of integrated medicine on covid-19. two reviewers independently screened, identified studies, and extracted data. cochrane risk of bias tool and the newcastle-ottawa scale were used to assess the quality of included rcts and ccss, respectively. stata (version 13.0; statacorp) was used to perform meta-analyses using the random-effects model. risk ratio (rr) was used for dichotomous data while the weighted mean difference (wmd) was adopted for continuous variables as effect size, respectively, both of which were demonstrated in effect size and 95% confidence intervals. a total of 11 studies were included. four were rcts and seven were ccss. the samples of including studies ranged from 18 to 100 (total 982). the traditional chinese medicine included chinese medicine compound drugs (qingfei touxie fuzhengfang) and chinese patent medicine (such as shufeng jiedu capsule, lianhua qingwen granules). medicine can improve the disappearance rate of fever, cough, expectoration, fatigue, chest tightness and anorexia and reduce patients' fever, and fatigue time (p<0.05). this review found that integrated medicine had better effects and fewer adverse drug reactions for covid-19. more high-quality rcts will be needed in the future. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 j o u r n a l p r e -p r o o f as a member of coronavirus subfamily coronaviridae, the coronavirus can infect human beings, many kinds of mammals and birds. some coronavirus can spread between humans, livestock, and poultry. in december 2019, many cases of novel coronavirus pneumonia china has been gradually controlled, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 traditional chinese medicine (tcm) has a history of thousands of years and has saved the chinese from major infectious diseases on many occasions. now, tcm has been practiced worldwide. during the sars epidemic in 2003, tcm played a huge role [6] [7] [8] . belongs to the category of "pestilence" in tcm. its main clinical manifestations are fever , 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 fatigue, dry cough, and the disease is situated in the lung and related to the spleen, stomach, and heart. like during the sars period, tcm played a major role in the "fight against the pestilence in china", saving many people's lives [5, 9, 10] . there is now evidence that compared with the simple treatment of western medicine; integrated traditional chinese and western medicine (hereinafter referred to as "integrated medicine") for covid-19 may have better effects [11] [12] [13] [14] [15] . however, these studies have small sample sizes, and no convincing evidence is available to demonstrate the benefits and risks of integrated medicine for covid-19. this study summarized controlled trials and methods of integrated medicine treatment of covid-19, including the changes of clinical symptoms. the secondary outcome is the changes of laboratory indicators and the safety of integrated medicine of covid-19. this meta-analysis was based on the preferred reporting items for systematic reviews and meta-analyses (prisma) [16] . in addition, because this study is linked to tcm, we also performed according to some other reporting guidelines [17] [18] [19] . the protocol for this study has been registered in the international prospective register of systematic reviews (prospero, crd42020177097). a pre-developed search strategy was used to identify all relevant clinical trials, regardless of languages or types of publication (excluded unpublished). we searched the following six chinese medicine", "western medicine", "integrated traditional chinese and western medicine", "novel coronavirus pneumonia", "2019-ncov", "covid-19", "sars-cov-2" and "ncp". the search strategy of the pubmed database is presented in appendix table 1 . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 j o u r n a l p r e -p r o o f further assessment. finally, resolve any differences through discussion between two reviewers or consultation with a third reviewer. a pre-formed data form was used to extract the relevant information, such as the author, journal, study type, study location, study time, interventions, the dose of drugs, outcomes. primary outcomes including the changes of clinical symptoms, such as cure rate, total effective rate, nausea disappearance rate, fever disappearance rate and fatigue disappearance rate. second outcomes including the changes of laboratory indicators and the safety of integrated medicine of covid-19, such as crp, tnf-α, wbc count, liver damage and diarrhea. the risk of bias (rob) assessment tool from the cochrane handbook was used to assess the methodological quality of rcts [20] , and the newcastle-ottawa scale (nos) was used to assess the quality of ccss [21] . each rct was assessed at low risk, high risk, or unclear risk relating to the following items: sequence generation, allocation concealment, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. the nos assesses the quality of ccss with eight questions in three broad categories: (1) patient selection; (2) comparability of study groups; (3) assessment of the outcome. the total score is 9, the higher the score, the better the quality of the study. two reviewers independently completed the data extraction and quality assessment. any disagreement between reviewers was resolved by discussion or consultation with a third reviewer . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 stata (version 13.0; statacorp) was used to perform the statistical analysis. risk ratio (rr) was used for dichotomous data while weighted mean difference (wmd) was adopted for continuous variables as effect size, respectively, both of which were demonstrated with effect size and 95% confidence intervals (ci). considering heterogeneity of drugs used in different trials, we calculated all results based on the random effect model. we assessed statistical heterogeneity in each pairwise comparison with i 2 statistic, and value of <25%, 25-50%, and >50% considered as low, moderate, and high level of heterogeneity, respectively [22] . we would perform subgroup analyses and sensitivity analyses to explore sources of heterogeneity if enough data were available. the egger's test and funnel plots were used to detect the potential publication bias if the number of included trials was larger than ten for an outcome. statistical significance was set at p<0.05. figure 1 showed the study selection process. a total of 11 studies were included in our study. all the articles were published by chinese, among them, four studies were rcts [12, [23] [24] [25] and seven were ccss [11, 12, [26] [27] [28] [29] [30] . the detail of these studies is shown in table 1 . except for two studies that did not provide the range of study time [23, 24] , the study time was from january 01, 2020 to march 02, 2020. the samples of the included studies ranged from 18 to 100 (total 982). the duration of treatment ranges from 5 to 30 days, with an average of 13.55 days. two studies did not 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 j o u r n a l p r e -p r o o f provide specific chinese medicine compound drugs and chinese patent medicine [11, 13] . one studies intervention groups were chinese medicine compound drugs (qingfei touxie fuzhengfang) [24] . and the other studies were chinese patent medicine (such as shufeng jiedu capsule, lianhua qingwen granules). the drugs used in the control group were lopinavir, ribavirin, arbidol and et al. the rob of the included rcts is shown in table 2 [12, [23] [24] [25] . fours rcts described the adequate random sequence generation process, but only one rct [25] described the methods used for allocation concealment. only one rct [25] described the blinding of participants and personnel and blinding of outcome assessment (high risk), and none described how the incomplete outcome data were processed and reported selective outcome reporting. overall, the quality of the included rcts was low. seven ccss were assessed for quality by the nos [11, 13, [26] [27] [28] [29] [30] . the maximum quality score is 9 and the range of scores was 3 to 7 (table 3) , with a median of 6 (5.4±1.4). only one study did not report the case definition [13] , and all study report the definition of controls and comparability of cases and controls [11, 13, [26] [27] [28] [29] [30] . none of the studies were reported representativeness of the cases and selection of controls [11, 13, [26] [27] [28] [29] [30] . the reporting for exposure was better, but only one study reported non-response rate [30] . these studies showed a moderate quality sufficient to conduct a meta-analysis. we the common adverse drug reactions of integrated medicine were nausea and vomit, diarrhea, liver damage, and reduced blood cell count. as showed in table 6 , there was no significant difference in the adverse drug reactions caused by the two different interventions (p>0.05). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 results of the subgroup analysis of the chinese medicine compound drugs and chinese patent medicine for the primary outcome were shown in appendix since the number of studies in any comparative analysis did not exceed ten, we did not conduct a risk assessment of publication bias . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 to critical [11, 24] . however, the use of these traditional herbs has been controversial due to unclear composition and lack of scientific evidence [32] . in our study, we found that the quality of these studies was low. in the treatment of many diseases, tcm is only used as 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 adjuvant therapy [33, 34] . so, standard treatment and outcome index need to be developed. in this way, the best evidence can be systematically reviewed, summarized and disseminated to better provide evidence-based tcm decision-making. tcm is superior to western medicine in improving the symptoms and quality of life of patients. this study found that integrated medicine can improve the disappearance rate of fever, cough, expectoration, fatigue, chest tightness and anorexia and reduce patients' fever, and fatigue time. this is related to tcms can affect immune cells and cytokine production associated with immune responses [35] . immune regulation maintains the homeostasis of the immune system, protects the body from sources of infection or other harmful substances, thereby alleviating the clinical symptoms. it is essential for normal health. however, we found that the outcome indicators were not uniform in the included studies. this situation is dangerous and increases the waste of research resources, may cause some ineffective or adverse interventions to be applied clinically [36] . the diversity of outcome indicators also exists in the laboratory indicators and the adverse reaction indicators. although we found that the integrated medicine may change the inflammation index and have fewer adverse drug reactions than western medicine. but these are not enough, we found that many important indicators cannot be analyzed due to outcome indicators were not uniform. such as erythrocyte sedimentation rate, each interleukin type, macrophage ratio [13, 24] . as a new kind of respiratory disease, covid-19 has many unknown factors to be solved. we found that included studies had a short duration, the ranges from 5 to 30 days. covid-19 is likely to require a longer period of follow-up. in this way, the efficacy and possible adverse drug reaction of covid-19 can be better observed. besides, adverse events should be 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 monitored through standardized and effective reporting systems, and some serious adverse events should be observed through epidemiological studies [37, 38] . however, this study also has the following limitations. the tcm and western medicine used in the intervention group and the control group is different. but we did not perform subgroup analysis or sensitivity analysis. and many merger statistical analysis studies have more heterogeneity. in addition, most of the included trials had flaws in the methodological design, including randomization, concealment of allocation, and inadequate reports on blinding, withdrawal, and sample size estimates. we also tried to contact the authors who participated in the trial for detailed information; however, we did not get a response at the end. above all, covid-19 is a sudden outbreak disease. there are difficulties for clinicians to conduct rcts, especially in the acute or critical period. so we included both rcts and ccts in this study. therefore, some high-quality rcts are needed to evaluate the effect of integrated medicine for covid-19. the study results showed that compared with western medicine, the integrated medicine for covid-19 has better effects and fewer adverse drug reactions. however, due to the low number of included studies, low quality, and inadequate methodologies, high-quality rcts are needed to evaluate the effect of integrated medicine for covid-19. acknowledge: none . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 clinical experience of treating sars in guangdong hospital of tcm some research clues on chinese herbal medicine for sars prevention and treatment on the rational exertion for the prescriptions and drugs of tcm in prevention and treating sars to explore the value of chinese medicine in the treatment of covid-19 from the perspective of treatment of covid-19 by pneumonia no.1 prescription and pneumonia no.2 prescription clinical study on 34 cases of covid-19 treated by integrated chinese and western medicine clinical study on 37 cases of covid-19 treated by integrated chinese and western medicine clinical observation of 49 cases of non-critical covid -19 treated by integrated traditional chinese and western medicine in shanghai lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (sars-cov-2) traditional chinese medicine for covid-19 treatment preferred reporting items for systematic reviews and meta-analyses: the prisma statement the methodological and reporting quality of systematic reviews from china and the usa are similar network meta-analyses could be improved by searching more sources and by involving a librarian the reporting characteristics and methodological quality of cochrane reviews about health policy research the cochrane collaboration's tool for assessing risk of bias in randomised trials the newcastle-ottawa scale (nos) for assessing the quality of non-randomised studies in metaanalysis measuring inconsistency in meta-analyses clinical value of glycyrrhizinate in the treatment of patients with common new coronavirus pneumonia clinical effect and mechanism of qingfei touxie fuzheng recipe in the treatment of novel coronavirus pneumonia clinical observation of jinhua qinggan granule in treating pneumonia infected by new coronavirus observation on the clinical effect of shufeng jiedu capsule combined with arbidol hydrochloride capsules in the treatment of covid-19 retrospective clinical analysis on treatment of novel coronavirus-infected pneumonia with traditional chinese medicine lianhua qingwen analysis of the value of shufeng jiedu capsules combined with abidol in the treatment of mild new type of coronary toxin pneumonia analysis of 51 cases of new coronavirus pneumonia treated with traditional chinese medicine lianhua qingwen: a multicenter retrospective study multi-center clinical observation of reyanning mixture in treatment of novel coronavirus pneumonia effect of integrated traditional chinese and western medicine on sars: a review of clinical evidence atheroprotective effects and molecular targets of bioactive compounds from traditional chinese medicine recent advances in traditional chinese medicine for kidney disease anti-ageing active ingredients from herbs and nutraceuticals used in traditional chinese medicine: pharmacological mechanisms and implications for drug discovery the immunopharmaceutical effects and mechanisms of herb medicine standardising outcomes for clinical trials and systematic reviews adverse event: cochrane the revised consort statement for reporting randomized trials: explanation and elaboration appendix table 1 search strategy appendix table 2 results of subgroup meta-analysis for covid-19 about the primary outcome (dichotomous data) appendix table 3 results of subgroup meta-analysis for covid-19 about the primary outcome (continuous variables) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 key: cord-281333-fj2u5uif authors: rittichainuwat, bongkosh title: ghosts a travel barrier to tourism recovery date: 2011-04-30 journal: annals of tourism research doi: 10.1016/j.annals.2010.10.001 sha: doc_id: 281333 cord_uid: fj2u5uif abstract this study aims to assess whether or not beliefs in ghosts really deter tourists from traveling to disaster-hit destinations. to many it may appear that cultural differences do play a role in travel decision making between asian and western tourists. however, it is vital to provide empirical evidence of the impact of cultural differences in beliefs through a case study of the tsunami-hit destinations. thus, this study aims to examine tourist barriers associated with tsunami-hit destinations, and also to assess cultural differences regarding such beliefs between asians tourists from china and thailand and western tourists from britain, germany, and the united states and also across demographic profile. previous studies have found that perceived risks cause more damage to destinations than actual risks (beirman, 2006; hall, 1989; mitchell & vasso, 1997; roehl & fesenmaier, 1992; tarlow, 2006) , as can be seen in the reactions to severe acute respiratory syndrome (chien & law, 2003; henderson, 2004; mckercher & chon, 2004; rittichainuwat & chakarborty, 2009; tse, so, & sin, 2006) , foot and mouth disease (page, yeoman, munro, connell, & walker, 2006) , terrorism (floyd, gibson, pennington-gray, & thapa, 2003; reichel, fuchs, & uriely, 2007; sönmez, 1998; sönmez & graefe, 1998) , and tsunami (rittichainuwat, 2006) . this is because a crisis creates a ripple effect to non-affected destinations causing them to also be perceived as risky (cavlek, 2002) . hence, it is suggested that tourism bureaus must dissociate an unaffected destination from a problematic destination (mansfeld, 2006) by promoting safer alternative destinations (pizam, 2002) . it is of interest to note that, in some cases, a destination can be physically safe, but still perceived as unsafe psychologically, as in the case of the tsunami-hit beaches of phuket, khao lak, and phi phi island in the south of thailand. many chinese tourists cancelled their new year's trips to those places not only due to these sites being under reconstruction but partly because of the association of ghosts and bad luck with them (thai press reports., 2005) . according to rittichainuwat (2006) , many inbound chinese and thai tourists substituted their original travel itineraries to tsunami-affected areas with trips to other beach resorts due to perceived risks affiliated with ghosts and uncomfortable feelings about enjoying themselves at a resort where a lot of people had been killed, because the place was thought to be too sorrowful and inappropriate to celebrate the chinese new year. in contrast, it is almost a given that westerners would not consider the issue of ghosts important in deciding whether to visit such places. in fact, the natural beauty and relaxing atmosphere of the tsunami-hit beaches, which some asian tourists avoid for fear of ghosts, have motivated scandinavian tourists (rittichainuwat, 2008) . in light of these independent findings and report, it is important to assess whether or not beliefs in ghosts really deter tourists from traveling to disaster-hit destinations and more especially, whether or not there are differences between asian and western tourists. to many it may appear that cultural differences do play a role in travel decision making between asian and western tourists. however, it is vital to provide empirical evidence of the impact of cultural differences in beliefs. thus, this study aims to examine travel barriers associated with tsunami-hit destinations, and also to assess cultural differences regarding such beliefs between asians tourists from china and thailand and western tourists from britain, germany, and the united states and also across different demographic variables. previous studies have shed some light on destination recovery after a disaster (ahmed, 1991; barton, 1994; faulkner, 2001; pizam, 2002) . durocher (1994) notes that destination recovery depends on the efficiency of tourism partners in bringing their facilities back to a predisaster level, and an effective marketing message that clearly communicates that the destination is once again open and ready for business. however, misinformation is one of the biggest obstacles to destination recovery (beirman, 2006; henderson, 1999; tarlow, 2006) . specifically, an image of a destination still in the process of recovery and under reconstruction persists when some hotels continue to remain closed, either due to physical damage, insurance claims, change of ownership, or the renegotiation of land leases (durocher, 1994) . hence, it is important to restore confidence in the destination and to control the extent of the damage caused by misperception (beirman, 2006; henderson, 2003) . though giving incentives such as discounts and value-added extras are frequently used to stimulate demand for travel to recovering destinations (henderson, 1999; huan, beaman, & shelby, 2004; huang & min, 2002; pizam, 2002) , such incentives are unable to motivate tourists unless destinations are perceived as safe, as most tourists would not trade off their safety for discounts (henderson, 1999 (henderson, , 2007 rittichainuwat & chakarborty, 2009; sönmez, 1998; sönmez & graefe, 1998) . additionally, news reports sometimes exaggerate the situation and negatively affect the travel intentions of tourists by creating an image that the entire destination has been damaged (henderson, 1999; huang & min, 2002; milo & yoder, 1991) . since media coverage of catastrophes increases ratings and circulation, news organizations may use the crisis to respond to the demands of their audience (milo & yoder, 1991) . due to geographic distance, non-tourists and potential inbound tourists rely on media coverage as their information source to keep them aware of occurrences in distance places and to evaluate perceived risks associated with destinations (castelltort & mäder., in press ). the larger the viewer audience of local television stations and the larger the media circulation of newspapers, the greater possibility of negative news affecting potential consumers (castelltort, in press ). such news frightens away potential tourists who do not thoroughly evaluate the validity of the message and this can delay the speed of destination recovery (henderson, 2005; huang & min, 2002; mansfeld, 2006; milo & yoder, 1991) . therefore, during destination recovery, marketers must minimize any inaccurate images of the entire destination as having been devastated (henderson, 2005; huang & min, 2002; rittichainuwat, 2006; sönmez, 1998) . positive media coverage of special events can counter balance the negative news and enhance a positive image of the destination and its recovery (ahmed, 1991; castelltort, in press ). to eliminate the image of ''under-construction'', it is also necessary to make certain that the information given by operators matches the actual recovery reality (durocher, 1994) . the best way to eliminate the image of a destination still under construction is by bringing travel agencies, meeting planners, and news reporters to a destination to witness for themselves the extent of the recovery and thus help overcome reluctance to book business (durocher, 1994; henderson, 2007) . moreover, opinion leaders play a key role in minimizing perceived risks at a destination (milo & yoder, 1991) . lacking information from a more credible source, the mass media, for one, may fulfill the role of opinion leader (milo & yoder, 1991) . thus, the speed of the destination recovery does not only depend on the effectiveness and efficiency of authorities and local operators to bring infrastructure and business back to normal as soon as possible but also on marketing communication plans that have been integrated into disaster management strategies (beirman, 2006; durocher, 1994; faulkner, 2001; henderson, 2005; mansfeld, 2006; tarlow, 2006) . unfortunately, even when a positive image of destination recovery has been promoted and the destination is physically safe, it may still be perceived by some tourists as unsafe due to culturally-held beliefs regarding ghost. in different cultures, such as those found in africa, north america, latin america, europe, and asia, people describe and perceive the presence of ghosts in a variety of shapes and kinds (jacobi, 2003) . in christianity, both ghost and spirit not only refer to the third in the holy trinity but also refer to the soul of a dead person (oxford dictionary, 1988) . ghost and spirit are used interchangeably to refer to the soul of a deceased person (comaroff, 2007; formoso, 2001; freed & freed, 1990; yang, huang, janes, lin & lu, 2008) . while spirit is also defined as a disembodied soul thought of as separate from the body; ghost refers to the spirit of a dead person appearing to somebody still living (oxford dictionary, 1988) . in the thai context, spirit is more often used than ghost to refer to the soul of a deceased person (cohen, 1990 (cohen, , 1991 komin, 1991; tambiah, 1970 tambiah, , 1984 terwiel, 1994) . however, ghost is a generic term used in many cultures, of which spirit is one of its categories used in describing the soul of a dead person. thus, this study uses ghost instead of spirit because it is a generic term widely recognized by most people. ghosts can be divided into two categories; one includes incorporeal ghosts, which are either transparent or are lifelike apparitions of their former selves, whereas the second is corporeal ghosts, which are horribly gaunt, such as those with empty faces, devoid of eyes and lips (jacobi, 2003) . in thai culture, a ghost is pictured as an after-death, human phenomena with differing dominant characteristics, ranging from benevolence, with prestige given by the living and with responsible power, such as ancestors and guardian ghosts, to malevolence, of notoriety and caprice, which are either free-floating, localized ghosts in the world of human beings or those condemned to hell (crowder, 2003; tambiah, 1970) . this study defines ghosts as disembodied and restless spirits of deceased individuals that cannot be touched, nor can they physically touch the living because they are incorporeal and do not have a material form (jacobi, 2003) . cultural differences between asians and westerns may be explained by distinct religious philosophies (reisinger, 2003) . specifically, christianity promises transformation of the body in preparation for life in heaven or hell, whereas buddhism, hinduism, and taoism believe in the transmigration of a soul, which leaves the body at death in order to enter a new form via the cycle of rebirth, though in certain circumstances some souls continue to roam on earth in the form of ghosts (davies, 2010; harvey, 2009 ). such beliefs have taken root based on animism, buddhism, hinduism and taoism, which teaches that souls of the dead are capable of existing after the death and dissolution of the body (cano & mysyk, 2004; freed & freed, 1990; kaneko, 1990) . additionally, such beliefs are embedded early in life in the form of social rituals such as ancestor worship and ghost stories (crowder, 2003; terwiel, 1994) . for example, thai children are taught about and are made well aware of the existence of ghosts and their potential dangers, and are taught to chant protective spells and to wear small buddha amulets around their necks to ward off ghosts (komin, 1991; terwiel, 1994) . likewise, chinese children are taught to avoid proximity to dead bodies as they are believed to bring bad luck (chan & lai cecilla., 2009) . the fear of ghosts is instilled in children very early and continues into adult life. though such beliefs among young people today and the educated may be weakening, on the whole they remain strong and influential (chan & lai, 2009 ), as education does not necessarily eradicate culturally-held beliefs in ghosts (burnard, naiyapatana, & lloyd 2006; lindeman & aarnio 2007) . for example, komin (1991) finds that even thai scientists admit that they believe in the existence of certain kinds of ghosts. more importantly, beliefs in ghosts are not individual but are socially shared beliefs. according to the chinese, the main components of the universe are gods, saints, guardian ghosts, ghosts, ancestors, and the living (formoso, 2001) . while ancestors and guardian ghosts protect the descendants and inhabitants who worship them, other ghosts can harass the living. likewise, singaporean chinese believe that to end one's life and be buried without proper rituals is highly undignified and causes the victim to suffer as a restless ghost, to wander without peace and to harass the living (comaroff, 2007) . similarly, taiwanese believe that wandering ghosts of those who have drowned bring with them a higher risk of accidents for the living, especially during the ''ghost month'', when it is believed wandering ghosts are temporarily released from hell (yang et al., 2008) . according to thai beliefs, death also brings about a dramatic change when a soul transforms into a ghost (tambiah, 1970) . more especially, those who die ''abnormally,'' without having completed their natural life cycle and the orderly succession of status, their unfulfilled and clinging interests in and attachment to life in this world causes them to be malevolent, and to seek a substitute soul of a living person to exchange places with them because they are removed from the channels of rebirth (tambiah, 1970) . however, only a small number of thai buddhists understand the buddha's teachings that deny the existence of an eternal soul (cohen, 1991) and, most thais integrate a belief in ghosts and buddhism into thai culture and form social value and norms (cohen, 1991; mulder, 2000) . beliefs in ghosts affect people in daily life and in their decision making. for example, taiwanese who adhere to beliefs regarding ghost month might either decrease their exposure to water-related activities or involve themselves in less risky behaviors, as a kind of risk compensation, consequently resulting in a reduction in the number of potential drowning deaths (yang et al., 2008) . although some people might not consciously believe in the existence of ghosts, they may continue to adhere to collective norms by postponing some outdoor recreational activities, especially water-related activities such as playing on the beach, swimming, boating, fishing, and barbecuing on the bank of a river, to reduce exposure to water and the possibility of death by drowning (summala, 1996; yang et al., 2008) . belief in ghosts has been a travel barrier for tourists from china, taiwan, hong kong, and singapore who did not go to the tsunamiaffected beach resorts immediately after the 2004 tsunami for fear of bringing bad luck, such as 'ghost illness,' home with them, since a place where a lot of people have been killed is considered a 'bad luck location' (huang, chuang, & lin, 2008; rittichainuwat, 2006) . thus, it is not surprising that the tsunami-hit destinations are perceived as ghost-haunted destinations, and thus suffer from a decrease in the number of tourists. according to thai and chinese beliefs, restless ghosts can cause misfortune to the living, such as illness (fever, choking or difficulty breathing) and possession (mental disorder) (burnard et al., 2006; cohen, 1990 cohen, , 1991 freed & freed, 1990) . also, possession in the form of sickness diagnosed as ghost malaise is often found in those who have visited haunted places (comaroff, 2007) . hence, an uninhabited place is carefully avoided, especially if there is a suspected high concentration of restless ghosts constituting a threat to the living (formoso, 2001) . beliefs in ghosts also persist in western cultures, though it is considered more strongly held in asian cultures than in western cultures. for instance, a gallop poll shows that 37% of americans believe in haunted houses (musella, 2005) , and a poll of british adults shows that 40% believe in ghosts, and of these, 37% claim to have personally experienced the presence of a ghost (mori, 1998) . also, a study by wiseman, watt, greening, stevens, and o'keeffe (2002) conducted at hampton court palace in britain finds that ghost-believers interpret unusual experiences as being caused by ghosts (such as an unusual change in temperature, a sense of another's presence, a strange noise, a sense of dizziness, headaches, sickness, shortness of breath, or intense emotional feelings). similar to the chinese and thai cultures, historically in the west, there have also been malevolent ghosts, which have also been associated with water-related death. english and american sailors in the 15th and 16th century believed that people who had died violently and/or in an accident and had not received proper burial, were not able to rest peacefully and so became restless ghosts who returned to trouble the living at sea, which is perceived as a threshold from which the dead can sometimes return (stewart, 2005) . since the sea allows the horizontal movement of ghosts across its surface, the permeable nature of water makes the sea conducive to vertical connections between the upper-world on the surface and the underworld in the depths; thus, the sea is perceived as a threshold rather than a barrier that links the living and the dead (stewart, 2005) . moreover, a ''watery grave'' does not allow for the comforting solidity offered by the earth (stewart, 2005) . beliefs in ghosts in western cultures finds support in christian theology, which recognizes the existence of ghosts in the new testament (cohen, 1990 (cohen, , 1991 , though, the rationalism of the enlightenment and the demythologizing theologies of contemporary protestantism seem to have done much to weaken such beliefs (long, 1987 : 286 cited in cohen, 1990) . because of these influences, a belief in ghosts is considered irrational (jones, 2005) , deviant and dangerous, as superstitious people rely on unsubstantiated external forces rather than on their own actions (national science foundation., 2000) . this weakening of beliefs is also the result of the process of secularization in the modern western world, where a smaller percentage of the population has maintained its traditional christian beliefs (sjödin, 1995) . a modern scientific outlook on the world, especially from the perspective of materialistic naturalism in the sciences with its emphasis on proven validity, gives a better understanding of the cause-effect relationships that explain our world, which in turn make superstition (such as belief in ghosts) an obstacle to understanding reality and gaining knowledge of ourselves and the world (sjödin, 1995) . consequently, superstition no longer has a strong foothold on the norms of a western culture that values rational science (reisinger, 2003) . based on the literature, it can be concluded that beliefs in ghosts are more strongly held in asian (chinese and thai) cultures than western (american and british) cultures because of cultural differences. whereas the chinese and thais believe in the existence of ghosts in the human world and consider the challenge to such supernatural power as unintelligent action, such beliefs have been substantially weakened in western culture because of scientific rationalism, secularization and demythologizing theologies of contemporary protestantism (cohen, 1990 (cohen, , 1991 inglis & holmes, 2003; long, 1987 , p. 286 cited in cohen, 1990 sjödin, 1995) . hence, this study hypothesizes that while belief in the existence ghosts is a travel barrier for asian (thai and chinese) tourists, it would not deter western (american, british, and german) tourists from visiting the tsunami-affected areas. regarding demographic profile, the national science foundation (2000) reports that beliefs in ghosts are higher among women than men. however, freed and freed (1990) found that beliefs in ghosts can be found in children and adults of both genders as well as in all age ranges. moreover, education does not eradicate culturally-held beliefs in ghosts (burnard et al., 2006; lindeman & aarnio, 2007) . thus, this study hypothesized that there is no significant difference regarding beliefs in ghosts across respondents of different gender, age, and education. the research settings of this paper were phuket, khao lak (a beach resort in phang nga province), and phi phi island (a beach resort in krabi province) in the south of thailand, where more than 5000 local residents and foreign tourists were killed by the tsunami on december 26, 2004 (see figure 1 for location). this study used a triangulation of data collection (interviews, content analysis and survey). in the first stage, items in the questionnaire were derived from in-depth interviews with a purposive sample of one german news reporter, one thai travel writer and one general manager of a chinese inbound tour company at a press conference, as well as eight tourists (one german, one belgian, two mainland chinese, and four thais) who survived the 2004 tsunami. the interviewees were asked, with an open-end question, to identify travel barriers which would deter them and the people they knew from visiting the tsunami-affected beach resorts. the researcher recorded the responses from the interviews and selected the most frequent key words and used them to develop the questionnaire items. the items in the questionnaire were also the results of the content analysis of news reports about the 2004 tsunami on thai tourism. the interviews and content analysis resulted in 14 travel barrier attributes which are listed in table 2 . the instrument of this study was a self-administered survey questionnaire used to determine travel barriers associated with the tsunami-hit destinations. the questionnaire was written in three languages: english, simplified chinese, and thai. the questionnaire contained three sections: tourist behavior, travel barriers, and demographic profile. regarding the travel barriers, the respondents were asked: what would deter/discourage you from traveling to the disaster (tsunami) affected areas? the respondents were asked to indicate the level of agreement with each of the 14 travel barrier attributes on a 5-point likert scale, which ranged from one (strongly disagree) to five (strongly agree). a pilot test was given to 40 local residents and tourists in august 2005 to check understanding of the wording in the questionnaire. a panel of experts in the field of tourism checked the content validity of the instrument. the target populations were domestic and international tourists who were checking in for departure flights to destinations other than the three tsunami-hit provinces of phuket, krabi, and phang nga, at bangkok international airport in september 2005. in order to exclude residents and tourists to the tsunami-hit destinations from the study, two screening questions were included in the survey (are you a resident of phuket, krabi, and phang nga? and did you visit those places during this trip?). a single stage cluster sampling was used to randomly select domestic flights for which 500 passengers were waiting at departure gates, who were approached by five thai and chinese research assistants to participate in the survey. a field editing was conducted to check for the completeness of the questionnaires. the first step in the data analysis was to run descriptive statistics to determine frequency distribution. secondly, an exploratory factor analysis was used to identify the underlying dimensions of the travel barriers associated with the tsunami-hit destinations. it was also used to construct summated scale scores for subsequent analysis. finally, multivariate analysis of variance was employed to determine how travel barriers vary between asian and western tourists and different demographic variables. in addition, follow-up interviews with six thai, chinese, belgian, and german tourists were undertaken at cha-am and hua hin beach resorts, (which were the substituted destinations for the tsunami-hit destinations) from december 30, 2009 to january 4, 2010, to offer a better insight into travel barriers associated with disaster-hit destinations. respondents were asked about their perception towards the travel barriers with the following questions: what would deter you from traveling to the tsunami-hit areas? does fear of ghosts deter you from traveling to a disaster-hit destination? do you believe that places where people have been killed under tragic circumstances such as a natural disaster are haunted by ghosts? how long does it take for a place to be free from ghosts? out of the 500 tourists approached, 413 tourists participated in the survey, yielding a response rate of 82%. there was an equal distribution between male and female. regarding age distribution, the majority of tourists (80%) were between 20 and 39 years old, followed by 11% who were between 40 and 49 years old. as for marital status, slightly more than half of the respondents (58%) were single, followed by 35% of married couples. in education, most tourists were highly educated, with 85% having college or graduate degrees, followed by 11% with secondary or high school diplomas. regarding occupation, more than a quarter were sales and office workers (37%), followed by students (19%), entrepreneurs and managers (16%), government officers (8%), housewives and retirees (6%), and teachers (5%). more than half were thai residents (68%), whereas major inbound tourists came from the united kingdom (11%), china (10%), the united states (6%), and germany (5%). when asked whether the respondents had plans to visit tsunami-affected beach resorts after the disaster, about 38% were undecided, 37% said they had plans to do so, and 25% had no plans to visit such resorts. as can be seen in table 1 , the survey reveals that thais and chinese held stronger images of infrastructure and hotels under reconstruction than american, british, and german tourists. table 1 also shows that the means on ghosts, bad luck, undiscovered corpses, and uncomfortable feelings about being in disaster-hit destinations of the thais and chinese are higher than those of the american, british, and german tourists. then, the exploratory factor analysis (via principal component analysis) with oblique rotation, scree-plot, and the latent root criterion reduced the 14 travel barrier attributes to four underlying factors. the bartlett test of sphericity in this study was significant at the level of 0.000, indicating that a non-zero correlation exists among variables. the measure of sampling adequacy of 0.85 exceeds the necessary threshold of sampling adequacy, which requires a minimum of 0.50 (hair, anderson, tatham, & black, 1998 ) (see table 2 ). the results of the multivariate analysis of variance show no significant difference on main effects nor interaction effects on travel barriers across age, gender, marital status, education, or occupation. thus, the hypothesis that there is no significant difference on beliefs in ghosts across respondents with different age, gender, and education seems valid. unlike the report by the national science foundation (2000), this study supports the study by freed and freed (1990) , which found that beliefs in ghosts can be found in both genders and in a range of ages. this result also supports previous studies indicating that education does not necessarily cause belief in ghosts to disappear (burnard et al., 2006; lindeman & aarnio, 2007) . particularly, education has not necessarily affected cultural beliefs in ghosts among the thais, who have acquired such beliefs from childhood (burnard et al., 2006; komin, 1991; terwiel, 1994 ). yet, there is a significant difference on such beliefs across country of residence at the multivariate level on all dimensions of travel barriers considered together (wilk's lambda = 0.75, f = 7.6, p-value < 0.01). please see table 3 . the post-hoc bonferroni test indicated that these four travel barrier factors were significantly different (at the 5% level of significance) between asian (chinese and thai) and western (american, british and german) tourists. chinese and thai tourists perceived higher risks due to beliefs in ghosts, unsafe destinations, images of site under reconstruction and uncomfortable feelings than did american, british and german tourists. the bonferroni test only found a significant difference on the uncomfortable feeling factor between thai tourists and german tourists, the british and the american, and between chinese and british. thai tourists perceived higher risks due to uncomfortable feelings than did their western counterparts, whereas chinese tourists had stronger uncomfortable feelings than the british. images of site under reconstruction and destination safety. it was found that chinese and thai non-tourists had stronger pre-conceived images of a site under reconstruction than western tourists. conversations with some respondents revealed that most of them knew of the 2004 tsunami occurrence but were unaware of the destination recovery reported by international headlines news or their local televisions and newspapers. due to geographic distance, people rely on media as their information source to keep them aware of occurrences in distance places (castelltort, in press ). however, international headline news rarely reports updates on destination recovery. hence, non-tourists are unaware of the recovery. in addition, most international news, from sources like cnn and bbc, are in english and a language barrier for people who do not understand english, and thus have little or no access to reports on the progress of the recovery. in contrast, americans and british have more access to news from such agencies and to reports on the internet as they are in english. consequently, reports on destination recovery reach more western than asian markets, which is of significance to this study. this calls for destination marketers to increase frequency of news reports about the physical and psychological safety of the destinations to correct negative images, especially among chinese and thai markets. uncomfortable feelings. as the findings suggest, thai respondents tend to have a more significant traumatic response to having lost someone in the tsunami, due to the fact that the tsunami occurred in thailand, making thai tourists more 'emotionally attached' to the tragedy than inbound tourists. most thai respondents in this study said they knew at least one person who had been killed by the tsunami. one thai participant responded: ''my family and i will never go to phuket because it reminds us of the loss of our family's friend in the tsunami even through five years have passed.'' beliefs in ghosts. both the survey and interview reveal that belief in ghosts is a travel barrier primarily among chinese and thai tourists, but is not dominant with american, british, and german tourists. similar to previous studies by deridder, hendriks, and zani (1995) and pepitone and saffiotti (1997) , this finding supports the hypothesis that beliefs in ghosts are more strongly held in asian (chinese and thai) cultures than in western (american, british, and german) cultures. likewise, informal conversations with thai and chinese tourists who participated in the survey revealed that people who hold such beliefs tend to avoid traveling, especially during the new year's holidays, to places where someone has been killed, due to the belief that ghosts and bad luck would haunt them throughout the new year. interviews with one thai respondent also revealed that: ''i fear another tsunami, which could occur because several corpses have not been discovered.'' another said that: ''the souls of undiscovered corpses could cause another tsunami or earthquake because they had been deprived of rebirth and thus are malevolent ghosts.'' similar to the studies by comaroff (2007 ), formoso (2001 , freed and freed (1990) , huang et al. (2008) , rittichainuwat (2006) , tambiah (1970) , tambiah (1984) , terwiel (1994) and yang et al. (2008) thai and chinese respondents in this study believe malevolent ghosts prey on the living and affect tourist decision making. such belief adheres to the collective thai and chinese norm to avoid traveling to places where death occurs. in contrast, informal conversations with some american tourists revealed that they would visit the place once the destination has physically recovered. also, one commented: ''i am not concerned about the occurrence of another tsunami on the assumption that the disaster would probably not repeat itself at the same place.'' according to one german news reporter: some germans have returned to phuket six months after the disaster. these tourists are repeat tourists and have friends or relatives living at the tsunami-hit destinations. hence, they have a better understanding of the extent of the damage. most of them also have searched for more information about tourist destinations by chatting with returned tourists on the internet. hence, repeat tourists may act as unpaid sales people who can influence potential tourists to visit discovering destinations. additionally, it is important to note that some thai and chinese tourists interviewed indicated that they were neutral toward considering ghosts as their travel barrier in visiting the tsunami-hit-destinations but do not deny the existence of ghosts. those who were neutral said ''there is no objection to organizing religious ceremonies to dispel ghosts at disaster-hit destinations, as such activities relieve ghost fear.'' another commended that ''if ghosts really exist, such religious ceremonies, it is felt, would make the place safe from ghosts.'' when asked how long it takes before the destination is safe from ghosts, most respondents perceived that ''it would take two to three years, depending on the crowding of the destination.'' others believed: ''as the destination becomes more crowded, ghosts no longer haunt the destination. hence, it is safe to travel there again.'' however, several inbound chinese tourists interviewed were reluctant to share their beliefs in ghosts, saying that ''during chinese new year, people must only talk about good things to ensure good luck throughout the year.'' it could be extrapolated from this that they, in fact, simply didn't want to talk about ghosts for fear of bringing bad luck. while most of the thai and chinese respondents in a 2005 survey (rittichainuwat, 2006) perceived that phuket, khoa lak, and phang nga were haunted by ghosts during the first year of the destination recovery, the 2010 interviews reported in this paper show that, with the passage of five years, most thai tourists were no longer worried about ghosts at those places. however, while ghosts had mysteriously ''disappeared'' when these destinations became crowded, most thai tourists interviewed indicated that they continue to believe in the existence and potential presence of ghosts and that for those who are killed under tragic circumstances and thus unprepared for death, their souls remain or haunt the place where they died, causing problems to tourists at night, such as bothering them while sleeping. ghost beliefs as a travel barrier. many people from thai and chinese cultures, have a strong belief in ghosts and so perceived the tsunamihit destinations as haunted by ghosts during the early stages of destination recovery. moreover, news reports on ghost stories strengthen the perceived risks of ghosts at the tsunami-hit destinations. hence, once a 'ghost story' becomes widely known, it dissuades people from visiting such places (comaroff, 2007) . ghost stories surrounding the tsunamihit destinations may be the community's mechanism for coping with the traumatic effects of a natural disaster. as cashman and cronin (2008) stated, individuals tend to explain the phenomena by integrating it with supernatural beliefs to make sense of the disaster. moreover, news attention to catastrophes and negative stories make ghost stories hot discussion issues for both news reports and for rumor (milo & yoder, 1991) . although in the modern world belief in ghosts is gradually vanishing, it has not completely disappeared. it still serves as a mean to manage individuals' anxiety and stress caused by uncertainty (hofstede, 1980; hofstede, 2001; kim, 1999; reisinger & mavondo, 2005; schü tte & ciarlante, 1998) . cultural differences on beliefs in ghosts. similar to studies by cohen (1990 cohen ( , 1991 , inglis and holmes (2003), long (1987) , reisinger (2003) , reisinger and turner (2002) , and sjödin (1995) , secularization in christianity, norms and values toward scientific rationalism encourage disbelief in ghosts among westerners. while american and british people separate the physical and the spiritual world and believe in a reality that can be objectively tested, instead of accepting unproven superstitious ''evidence,'' (reisinger, 2003) , the chinese and thai live in cultures where most people hold strong beliefs in ghosts, which conform to collective norms (formoso, 2001; komin, 1991; summala, 1996; tambiah, 1970 tambiah, , 1984 terwiel 1994; yang et al., 2008) . such beliefs continue to be strongly held in chinese and thai cultures even in modern times. more importantly, beliefs in ghosts are not only individually held but also socially shared. additionally, while american, british and german tourists consider the progress of destination recovery, thai and chinese tourists focus on the past tragedy at the destinations: whether or not the place is haunted. as reisinger (2003) and reisinger and turner (2002) note, western cultures are future time oriented while asian cultures are past oriented. hence, when asian tourists visit with the assumption that the destination is safe, service providers should not cause them worry by informing their guests about a past tragedy at the site (tarlow & santana, 2002) . this is because asian tourists tend to be sensitive to negative messages, which might be exaggerated and lead to negative repercussions (kim & wong, 2006) . furthermore, while the asian (thai and chinese) tourists are concerned about both physical and psychological safety, most western (american, british, and german) tourists pay more attention to the physical recovery. hence, western tourists should be the primary target markets of the destinations that suffer from ghost panic by asian tourists. once the destinations are crowded with western tourists, it will be perceived as physically and psychologically safe for chinese and thai tourists to visit those places. nevertheless, an efficient warning system must be installed at the destinations to ensure physical safety, which is the major concern of both western and asian tourists (rittichainuwat, 2008) . this study highlights the fact that cultural beliefs and norms should be understood as essential considerations in crisis management and destination recovery so that marketers integrate such beliefs and norms in effectively planning marketing communication after a disaster. according to thai and chinese norms, religious ceremonies can be seen as a means of transforming malevolent ghosts into the benevolent dead so that they can take rebirth and dispel ghosts from possessed people (burnard et al., 2006; cohen, 1990 cohen, , 1991 formoso, 2001; tambiah, 1970 tambiah, , 1984 terwiel, 1994) . to assure psychological safety, it is necessary to organize ceremonies by various religions to dispel ghosts and to allow potential tourists who hold such beliefs to feel at ease and restore their confidence in visiting such places. additionally, country leaders and politicians are important opinion leaders who can influence the modification of the image by being at special events such as an assembly of religious leaders of different religions to give auspice to newly disaster-recovered destinations. moreover, newsletters on religious ceremonies to dispel ghosts at the disaster-hit destinations should not be treated as irrational. furthermore, in the aftermath of a disaster, such messages should be released frequently with a focus on chinese and thai markets during the early destination recovery period. however, rather than calling such ceremonies 'dispelling ghost ceremonies,' they should be called 'auspicious ceremonies' to highlight the positive aspect of the place and eliminate the negative word ''ghost''. it can be seen that, the fear of ghosts at a particular destination can result in a short-term ''ghost panic'' impact on the recovering destination. however, once the destination has become crowded, such fear disappears, especially if tragedy does not repeat itself at the same place, as confirmed by beirman (2006) , pizam (2002) , mansfeld (1999 mansfeld ( , 2006 and tarlow (2006) . according to the studies by durocher (1994) , faulkner (2001) , henderson (2005) , huang and min (2002) , and rittichainuwat (2006) , a destination takes more than a year to fully recover from natural disaster. hence, promotional messages should highlight the recovery progress that has been made at the destinations. during the early stage of destination recovery, the beauty of nature can be used to motivate tourists in visiting the tsunami hit-destinations by highlighting the quality of the sea water, the beaches, and the improvements in landscape and infrastructure (henderson, 2005; ichinosawa, 2006; rittichainuwat 2006; rittichainuwat 2008 ). in addition, since tourist-generating tour operators would not promote a destination unless it is safe due to liability for their customer safety (cavlek, 2002; wilks & page, 2003) , destination marketers must boost safety confidence not only with potential tourists but also with tour operators. additionally, since repeat tourists are the first group of customers to return to a destination after recovery (beirman, 2006; mansfeld, 2006) , special promotions should focus on this market, in order to encourage them to visit the destination so that they can spread positive wordof-mouth news about the destination recovery. moreover, travel writers (who tend to report positive news about destinations) and international news reporters, whose reports are often on catastrophes (castelltort, in press) , should be invited to join familiarization trips to witness destination recovery. likewise, marketing communications should focus not only on international english news agencies but also on local television stations and newspapers, as they report in local languages and focus on local circulation, making them more accessible to local markets. finally, once a natural disaster has occurred, it leaves behind not only physical damage but also psychological damage. thus, destination recovery requires more than physical recovery. it also requires psychological recovery, which has lagged behind and has slowed down destination recovery. nevertheless, 'ghost panic' is a short-term effect. once a destination becomes crowded, it is no longer perceived as haunted by ghosts. however, for people who hold strong beliefs in ghosts or have experienced trauma, the destination continues to be a place of mourning unless all corpses are discovered and properly buried, and appropriate religion ceremonies have been held. hence, marketing communications on destination recovery should highlight the fact that the destination is psychologically safe. when strong beliefs in ghosts become a major travel barrier, local authorities and service providers must ask for media assistance to discourage reports of ghosts in order to assist the local people in recovering from the consequences of 'ghost panic'. furthermore, the aftermath of the 2004 tsunami called for governments of host destinations to find a counterbalance between tourism income and tourist safety (kivela, 2006; plog, 2006) . specially, there is a demand for safety measures such as tsunami warning systems at the tsunami-hit tourist destinations (rittichainuwat, 2006) , which is regarded as one component of a crisis management system to establish confidence and prevent tragedy. this study contributes to the theoretical development in tourist decision making on the importance of culturally-held beliefs in ghosts. while previous destination recovery studies suggest destination marketers communicate the extent of the physical recovery, this study suggests that such efforts should be made simultaneously with messages confirming that the destination is also psychologically safe. in other words, while most marketing efforts during destination recovery deliver messages about physical recovery of infrastructure and hotels and offer incentives to stimulate tourist arrivals, they fail to create confidence that would ensure the psychologically safety of the destinations. destination marketers can not deny the fact that psychologically perceived risk regarding ghosts is another real factor that delays destination recovery. more importantly, the travel barriers revolving around collective beliefs takes more time to overcome than physical risks from wreckage and debris. thus, although significant discounts might interest those who do not believe in ghosts, it would not attract those who do. since belief in ghosts is a sensitive issue, some participants might not have shown their true attitudes in order to avoid being considered strange or uneducated. because of this, it can take time to elicit from some respondents their beliefs in ghosts. to illustrate, some respondents initially answered that they did not believe in ghost, but the content of their responses indicated that they were not certain. similar responses were found among northern hindu indian respondents in a study by freed and freed (1990) and a study by burnard et al. (2006) , where some respondents give indirect responses to questions about beliefs in ghosts: denying the beliefs at the beginning but then acknowledging such beliefs. as bloom, venard, harden, and seetharaman (2007) and peltzer and renner (2003) note, although superstition has continued to be a topic of interest for researchers for nearly 60 years, it is difficult to capture actual attitudes due to participants' tendency to answer in a socially desirable way that may, in fact, appear to contradict their superstitious beliefs. future studies on this issue would be beneficial to tourism literature. moreover, due to the small sample size of less than 100 subjects from asian and western tourists from china, uk, usa, and germany, the findings may not be generalized to the general population of these samples. in addition, as all western and asian cultural groups do not necessarily share the same cultural dimensions, the analysis in this study is not generalized to other western and asian 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hampton court palace: psychological variables and magnetic fields belief in ghost month can help prevent drowning deaths: a natural experiment on the effects of cultural beliefs on risky behaviors refereed anonymously. coordinating editor: gianna moscardo available online at www acknowledgements-this research is funded by dr. pornchai mongkhonvanit, president of siam university' s research funding. the author would also like to thank assistant professor donald sandage for his tremendous helps and guidance in writing this paper. key: cord-309997-iwueedmm authors: chan, c.h.; tiwari, a.; fong, d.y.t.; ho, p.c. title: post-traumatic stress disorder among chinese women survivors of intimate partner violence: a review of the literature date: 2010-03-19 journal: int j nurs stud doi: 10.1016/j.ijnurstu.2010.01.003 sha: doc_id: 309997 cord_uid: iwueedmm background: post-traumatic stress disorder is one of the most prevalent mental health sequelae of intimate partner violence, and as a result, it has been extensively documented in western literature. however, whether abused women from non-western cultures experience similar post-traumatic responses to intimate partner violence is less documented. objectives: the objectives of this paper were (1) to review the literature for information about post-traumatic stress disorder among chinese women survivors of intimate partner violence; (2) to provide a synthesis of the literature on post-traumatic stress disorder among abused chinese women; and (3) to identify implications for practice and to suggest directions for research relating to post-traumatic stress disorder among abused chinese women. design: a systematic review of the literature. data sources: following a systematic search for relevant literature in computerized databases and manual searches of english and chinese language publications, five papers reporting on four studies conducted in china, taiwan, malaysia, and the united states were included in the review. review methods: abstracts meeting the inclusion criteria were reviewed independently by two of the authors and any discrepancies were resolved by discussion. full papers for selected abstracts were then retrieved and assessed independently by the same reviewers. results: the present literature review revealed a paucity of information relating to post-traumatic stress disorder symptoms or diagnoses in abused chinese women. nevertheless, a link between post-traumatic stress disorder and intimate partner violence was demonstrated by the reviewed papers. conclusions: caution should be exercised when making comparison of the findings across the four studies because of the inherent methodological differences. also, as the assessment tools have not been validated for culture-bound interpretation of trauma and symptom manifestation, comparisons of findings for chinese women to women in western literature should be undertaken with due consideration. implications for practice and recommendations for future research are discussed. a universal post-traumatic reaction to intimate partner violence cannot be assumed. cultural beliefs may influence abused women's interpretation of trauma and their expression of posttraumatic stress disorder symptoms. there is a paucity of information relating to posttraumatic stress disorder symptoms or diagnoses in abused chinese women. this review highlights the need for ethno-cultural and qualitative research in order to facilitate culture-bound interpretations of trauma, symptom expression, and coping in abused chinese women. the review identifies suggestions for providing culturesensitive care in relation to intimate partner violence and post-traumatic stress disorder in the chinese context. intimate partner violence (ipv), also known as domestic violence, is one of the most common forms of violence against women. ipv consists of any one, or combination of, the following acts: physical violence, psychological abuse, sexual assault, controlling behaviors such as limiting resources or social contacts, intimidation, or creation of emotional dependence where the perpetrator is a current or former intimate partner (saltzman et al., 1999) . ipv is a global problem. the world report on violence and health found that between 10% and 69% of women had been physically assaulted by an intimate partner at some time in their lives in 48 population-based surveys world-wide (krug et al., 2002) . ipv occurs across social, economic, religious and cultural boundaries. even in cultures that emphasise social harmony, such as the chinese culture, ipv against women is pervasive. for example, prior year prevalence of ipv victimization was reported to range from 16% to 26% in china (chan et al., 2008) . not only is ipv pervasive, it is also a major public health problem, with negative physical and mental health consequences (campbell, 2002) . specifically, ptsd has been recognized as one of the most prevalent mental health sequelae of ipv (silva et al., 1997; coid et al., 2003) . ptsd, an anxiety disorder which develops after traumatic exposure, is characterized by distressing memories or emotions about the trauma, avoidance of trauma reminders and elevated arousal (green and kimerling, 2004) . golding (1999) , in a meta-analysis of the prevalence of mental health problems among women with a history of ipv, reported a pooled prevalence of 63.8% in 11 studies of ptsd, compared to estimates of lifetime prevalence of 1.3% to 12.3% in general populations of women (resnick et al., 1993; kessler et al., 1995) . a dose-response relationship was also suggested, as severity or duration of ipv was associated with the prevalence or severity of ptsd (golding, 1999) . in recent studies conducted in north america, ptsd was found to mediate the association between intimate partner aggression and physical health symptoms (taft et al., 2007; wuest et al., 2009) while ptsd avoidance symptoms predicted physical health problems in women abused by an intimate partner (woods et al., 2008) . the current body of knowledge related to trauma and ptsd is mainly based on research conducted in western nations (bedard et al., 2004) . it is not so clear whether people from non-western societies have similar reactions compared to those of their western counterparts (tang, 2007) . there is even an argument that ptsd is a euro-american culture-bound syndrome that does not apply to those in traditional cultures (summerfield, 2004) . although these views are expressed about reactions to trauma in general, the same considerations could also apply to women's reactions to ipv, long recognized as a traumatic event (houskamp and foy, 1991) . it is important, therefore, not to assume a universal post-traumatic reaction to ipv. instead, there is a need to understand ipv and ptsd in culturally sensitive ways so that appropriate interventions can be developed for ipv survivors in culturally diverse populations. this paper aims to contribute to the development of increased awareness by presenting a comprehensive review of the literature on ptsd among chinese women survivors of ipv. for the purpose of this review, ptsd includes the diagnosis of ptsd and ptsd symptoms. the objectives of this paper are as follows: 1. to review the literature for information about ptsd among chinese women survivors of ipv (hereafter known as abused chinese women). 2. to provide a synthesis of the literature on ptsd among abused chinese women. 3. to identify implications for practice and to suggest directions for research relating to ptsd among abused chinese women. the authors conducted a systematic search for relevant english language publications in computerized databases (pubmed, medline, psychinfo, cinahl, embase and google scholar) using the keywords intimate partner violence, domestic violence, partner violence, sexual abuse, physical violence, abused women, battered women, posttraumatic stress disorder, ptsd, ptsd symptoms, trauma, traumatic stress, post-traumatic responses, mental disorder, and chinese or asian, with date restrictions from 1900 to june 2009. an electronic search of websites of government departments, and women's health or domestic violence organizations in mainland china, hong kong, and taiwan, was undertaken for relevant materials or citations. manual searches of reference lists of relevant articles found in the primary search were also performed. in addition, a search for chinese-language papers in the china journals full-text database was conducted using the above keywords. the authors contacted the corresponding authors of relevant research studies in order to obtain more information or check for possible omissions. papers were included for full review if the main focus of the study was on ptsd (diagnoses and/or symptoms) among chinese women abused by an intimate partner. the authors also included articles in the review if abused chinese women were part of a diverse cultural group of participants. abstracts of articles found were reviewed in accordance with the inclusion criteria, that is, reports on ptsd diagnoses and/or symptoms related to chinese women with a history of abuse by an intimate partner. the abstracts were reviewed independently by two of the authors (chc and at). discrepancies between the review authors were resolved by discussion. consensus was achieved after two meetings. full papers for selected abstracts were retrieved. each of the articles was assessed independently by the same review authors against the inclusion criteria. there were no disagreements between the reviewers about the appropriateness of a paper for inclusion in this review. a flow chart of studies from search to inclusion is shown in fig. 1 . of the 74 potentially relevant abstracts retrieved, 5 papers were eventually included in this review. two of the five included papers reported on different aspects of the same study (hou et al., 2003 (hou et al., , 2005 . the reason for the large number of studies being excluded was that many of them addressed either ptsd or ipv but not both ipv and ptsd. the five papers are summarized as follows. 3.1. post-traumatic responses to domestic violence in taiwan (hou et al., 2003 (hou et al., , 2005 hou, wang, and chung assessed the post-traumatic responses of 109 chinese women to domestic violence in a cross-sectional survey. the women were recruited from the kaohsiung area of taiwan and were included if they had suffered physical, psychological, and/or sexual abuse from their husband, ex-husband, or former or current intimate heterosexual partner within the last year. a 15item post-traumatic response scale (ptrs), a chinese version translated from horowitz et al.'s (1979) impact of event scale (ies), was used to measure the subjective impact of marital violence on abused women within the past week. in their 2003 paper, hou et al. reported that most (93.6%) of the participants had scores of 19 indicating a high level of post-traumatic response. they also found that the standardized mean score of the intrusion subscale of the ptrs was higher than that of the avoidance subscale. the significance of the high intrusion score was compared to an earlier study by houskamp and foy (1991) in which ptsd was predicted by high intrusion reaction. based on this observation, hou and colleagues concluded that the women in their study had a higher rate of developing ptsd. in their 2005 paper, hou et al. reported that most (89%) of the women faced life-threatening situations in their abusive intimate relationships. also, the more dangerous the life-threatening situations faced by the women, the greater their overall post-traumatic response scores, a finding similar to those reported in western literature (houskamp and foy, 1991) . (huang et al., 2006) in a study of 471 chinese female prisoners randomly selected from the hunan female prison in china, huang, zhang, momartin, cao and zhao used structured psychiatric interviews and a clinician-administered ptsd scale (caps) (blake et al., 1997) to arrive at a diagnosis of ptsd as specified by the dsm-iv. a history of ipv was reported by 24.6% of the participants and was found to be one of the most predictive factors for ptsd. specifically, survivors of ipv in the younger age group were nearly five times more likely to develop lifetime ptsd while those in the older age group were twice as likely to develop lifetime ptsd. despite their high exposure to traumatic events, which included ipv, the lifetime and current rates of ptsd for this chinese sample of female prisoners, at 15.9% and 10.6% (chandra et al., 2009; leahy et al., 2004; yoshihama and horrocks, 2003; yoshihama and horrocks, 2005) . respectively, were much lower than those found in western literature (cauffman et al., 1998; ruchkin et al., 2002) . differences between the chinese and western study subjects were suggested as a possible reason for the discrepancy in the prevalence of ptsd, although the researchers did not elaborate on the differences. interestingly, not only were the rates of ptsd lower than those in western literature, they were also lower than those reported in colleagues' (2003, 2005) study of women in a community in taiwan. what may have accounted for the apparent difference in ptsd scores between female prisoners in mainland china and community-dwelling women in taiwan? could this be due to differences in coping strategies or personality hardiness that may have insulated the female prisoners from developing ptsd? as huang et al.'s study did not elaborate on the participants' coping strategies or personality hardiness, it was not possible to draw a conclusion. 3.3. cross-cultural assessment of post-trauma reactions among abused women (phillips et al., 2006) chinese women seeking refuge in a domestic violence shelter in malaysia were included in a study conducted by phillips, rosen, zoellner, and feeny, to examine posttraumatic reactions in abused women from non-western cultures. seventeen female residents at a domestic violence shelter, consisting of 10 indian, 5 malay and 2 chinese, completed semi-structured interviews and standardized measures for the assessment of post-trauma psychological morbidity. the 17-item ptsd-sr symptom scale-self-report (pss-sr, foa et al., 1997) and the 15-item revised impact of events scale (ries, sundin and horowitz, 2002) were administered. a majority (82.4%) of the women met the criteria for ptsd symptoms on the pss-sr, and 76.5% of the women also met, or exceeded, a recommended cut-off score of 35 on the ries. additionally, the participants' reports of post-trauma reactions were comparable to those of a sample of women in the united states who experienced partner violence. in their discussion of the findings, phillips and colleagues identified several limitations of the study including the small sample size, the use of the western construct of ptsd in non-western cultures and the omission of comorbidity. specifically, they raised their concern about imposing western ptsd symptomatic criteria on the participants in their study whose cultural experience of trauma might be different to trauma victims in the west. also, although phillips and colleagues did not elaborate on the issue of comorbidity, they nevertheless highlighted the importance of including comorbidity when assessing the psychological status of trauma victims. 3.4. effects of social support and coping strategies on ipv and psychological outcomes in asian and caucasian women in this study, the potential mediating effects of social support and coping strategies on the relationship between ipv and psychological outcomes of ptsd symptoms and depression were investigated. a sample of 100 caucasian women and 61 asian women were recruited from nine domestic violence agencies located in texas and california. the asian women consisted of 25 chinese, 22 vietnamese and 14 koreans. the ptsd checklist-civilian version (pcl-c; weathers et al., 1993) , the perceived social support scale (pss; norris and kaniasty, 1996) , and the revised ways of coping checklist (wccl; vitaliano et al., 1985) were used to measure ptsd symptoms, perceived social support, and coping efforts, respectively. analysis of the combined caucasian and asian groups revealed that there was an indirect effect of the level of violence on psychological outcomes via the mediating variables of perceived social support and passive coping strategies. however, ethnic group comparisons indicated differences between caucasian and asian women. specifically, in the asian group, the effect of ipv on the women's psychological distress was entirely direct. thus, the higher the levels of ipv experienced, the more severe the ptsd and depression symptoms. neither social support nor coping mediated the impact of ipv on the asian women's psychological health. based on the findings, lee et al. suggested that asian women may be more vulnerable to adverse psychological outcomes following ipv. as the results were drawn from a diverse group of asian participants, they should be interpreted with caution with regard to generalizability. the present review demonstrated a paucity of information on ptsd among abused chinese women. this is consistent with the current state of ptsd research in chinese societies that, to date, has mainly focused on the post-traumatic impact of natural disasters such as earthquakes and flooding (for example, zhang and zhang, 1991; zhao et al., 2001; liu et al., 2006) . however, relatively little is known about the post-traumatic impact of human-instigated disasters. additionally, caution should be exercised when making comparisons across the reviewed studies because of the methodological differences. for example, the use of different assessment tools could account for the variability in the rates of ptsd across the studies. specifically, the differences may be due to measuring ptsd diagnosis versus severity scores or the use of self-reports versus clinician-administered measures. for instance, the use of the clinician-administered ptsd scale (caps) in huang et al.'s (2006) study to measure the diagnosis of ptsd could have led to lower rates of ptsd because the caps is not a self-report measure and the participant has to answer questions face-to-face. it is possible that some of the participants may be reluctant to admit psychological difficulty to another person, but would have more highly endorsed mental health problems on a self-report measure. despite the variability, a link between ptsd and ipv was demonstrated in the reviewed studies. the studies included in this review used measurement instruments developed in the united states to assess abused chinese women's ptsd (symptoms and/or diagnosis). evaluation of the translated measurement instruments was described in one of the papers (hou et al., 2003) , which focused only on surface validity and reliability. none of the papers provided adequate evidence regarding the scientific rigor with which the translated instruments were evaluated and revised in the chinese context. indeed, phillips et al. (2006) expressed their concern about imposing the western construct of ptsd in non-western cultures. such concern is consistent with that expressed by tang (2007) about the widespread use of translated instruments from the west in an imposed-etic approach when measuring ptsd in chinese trauma survivors. also, by assuming that ptsd is a relevant and meaningful construct in chinese culture, researchers conducting ptsd research in abused chinese women could fail to recognise omissions of emic constructs that are central to chinese ways of conceptualizing life adversity, expressing symptoms of post-trauma reactions, and coping with life's vicissitudes. therefore, future research should adopt more rigorous validation procedures when translated instruments are used. for example, back-translation should be used to ensure that the underlying meaning of the original wording is preserved after translation. further, the translated version of the instrument should be reviewed and agreed by a committee of bilingual members who have not participated in the translation process. validation efforts should also include testing the translated instrument with a sample made up of members of the target culture as well as submitting it to a full psychometric evaluation (polit and beck, 2008) . the expression of ptsd by the participants in the reviewed studies should be contextualized in the traditional chinese health beliefs. this is because, unlike western medicine, there is no clear distinction between physical disorders and mental disorders in chinese medicine. as such, internal organs are viewed as centers for combined physiological and psychological functions and vital organs such as the heart, lungs and kidneys are often used by chinese people for colloquial expression of feeling states (lin, 1982) . it has been suggested that such beliefs, together with the stigma associated with mental illness in chinese societies, may be responsible for chinese patients presenting with somatic symptoms (e.g. headache, back pain) rather than expressing their mental health problems (e.g. depression) (tang, 2007) . interestingly, in hou and colleagues' (2005) study, somatization was the fourth most common symptom expressed by the participants. in huang et al.'s (2006) study, where the prevalence of ptsd in chinese female prisoners was found to be lower than that in the western studies of female prisoners, somatization was not assessed. to what extent was the apparent lower prevalence of ptsd an artifact of the chinese women prisoners' health beliefs? in other words, could some of the participants have expressed their ptsd in the form of somatic symptoms? such a question cannot be answered because the measures in huang et al's study did not include somatization. this shows the need for future research to include the assessment of somatic symptoms when studying ptsd in abused chinese women previous studies on the psychological status of trauma survivors in western populations have identified the need to consider the issue of comorbidity (boudreaux et al., 1998; stein and kennedy, 2001) . specifically, stein and kennedy have found major depressive and post-traumatic stress disorder comorbidity in female victims of ipv. despite this, with the exception of phillips et al. (2006) , none of the reviewed studies have identified the need to address comorbidity when assessing psychological responses of chinese ipv survivors. interestingly, studies on natural disasters in china and taiwan have found comorbidity of ptsd and other mental health problems (mainly depression) among adult community survivors (lai et al., 2004; wu et al., 2006) , long-term survivors (zhang and zhang, 1991; zhang et al., 2002) and rescue workers (chang et al., 2003) . in addition, comorbidity of ptsd and depression, as a result of the severe acute respiratory syndrome (sars) outbreak, was also found among patients in china (yan et al., 2004) , health care workers in taiwan (chong et al., 2004) , and survivors of sars in hong kong (cheng et al., 2004) . in light of such findings, future research should also consider psychiatric comorbidity when investigating the psychological responses of abused chinese women. since ipv is still considered to be a private matter and victim-blaming attitudes are still prevalent in asian communities (yoshioka et al., 2000) , it is important to educate the community as a first step in the promotion of primary prevention of ipv. nurses can, through public education programs, teach members of chinese communities that ipv reflects the community's normative acceptance of violence against its members, which goes against the confucian teachings of respect and harmony. furthermore, the psychological damage caused by ipv, not only to the survivor but also to the family and the community as a whole, should be emphasized. by raising public awareness of the problem of ipv and by promoting community involvement in the prevention of ipv, nurses can help to ensure that abused chinese women are not revictimized when they seek assistance from their informal social networks. as identified by hou et al. (2005) , chinese women survivors of ipv are at risk of developing ptsd if no support or intervention is provided. thus, detection of ipv is an important step to prevent deterioration of these women's mental health. in view of the fact that ipv is considered to be a family shame in the chinese culture and would not be disclosed to outsiders (tang et al., 1999) , nurses should be sensitive to chinese women's reluctance to discuss their abusive relationships, and their reluctance to accept help from formal services. earlier studies have found that, in a safe and trusting environment, chinese women were prepared to disclose their abuse experiences to nurses who had been trained to elicit such sensitive information (tiwari et al., 2005 (tiwari et al., , 2007 . it is, therefore, important that culture-sensitive training on screening for ipv be provided if nurses are to conduct assessment for ipv in chinese women. in the cases of abused chinese women with physical problems, their mental health should also be assessed because somatic symptoms may be reported instead of psychological symptoms (tang, 2007) . although none of the studies reviewed focused on the relationship between psychological abuse and ptsd in chinese women, an earlier study of japanese-american women found that those women who had experienced emotional, but not physical, violence reported increased post-traumatic stress symptoms relative to those with no history of partner violence (yoshihama and horrocks, 2002) . previous studies of ipv among chinese women have found a predominance of psychological abuse, in the absence of physical or sexual violence (leung et al., 1999 (leung et al., , 2002 tiwari et al., 2005 tiwari et al., , 2007 , but no assessment for ptsd was conducted in these cases. in light of yoshihama and horrocks' findings, consideration should be given to screening chinese women, who have experienced psychological intimate partner abuse, for the possibility of ptsd as well. in their analysis of the apparent vulnerability of asian women to adverse psychological outcomes (ptsd being one of them) after exposure to ipv, lee et al. (2007) suggested that the existing social support systems, that were not consistent with asian cultural beliefs, might not be helpful to asian women. reluctance to utilise formal services was not only confined to abused chinese women, but it was also noted that chinese survivors of natural disasters were also reluctant to seek outside help. for example, only 18-25% of those who reported ptsd symptoms after the chi-chi earthquake in taiwan in 1999 used the available mental health services (kuo et al., 2003) . when offering assistance to abused chinese women, nurses should be aware that these women may be hesitant to accept help from individuals outside their families, especially if they perceive that such help would bring shame to their family reputation or threaten their family unity. thus, reassurance should be given in a culturally appropriate manner. also, as chinese women are more likely to seek help from informal social networks, nurses may consider collaborating with such networks in providing abused chinese women with social support. when deciding which of the interventions would be appropriate for abused chinese women at risk for developing ptsd, nurses should ensure that the chosen intervention is evidence-based as well as culturally appropriate. a recent review of advocacy interventions for abused women provided comprehensive information about the effects of advocacy interventions in reducing post-traumatic stress (ramsay et al., 2009) . if advocacy interventions are to be used for chinese women, it is crucial for nurses to recognise that ''empowerment'' is a socially constructed term and may not be compatible with the traditional chinese values of sacrificing one's needs for the greater good of the family (yick, 2001) . care should be taken not to encourage the women to end their abusive relationships. instead, time and effort should be spent to assist them to resolve their self-blaming attitudes, and to acknowledge their dilemma of wishing to end the abuse, yet wanting to keep their family together (yick et al., 2003) . furthermore, nurses can empower abused chinese women by affirming their coping behaviors and supporting them in developing their own resources. research conducted in developed nations has shown that ipv is associated with ptsd in women survivors (resnick et al., 1993; kessler et al., 1995) . for chinese women, as demonstrated in this review, relatively little is known about the post-traumatic impact of ipv. even though trauma research has a relatively short history in chinese societies and the research focus is mainly on natural disasters, there is already an accumulation of evidence of ptsd within chinese survivors (tang, 2007) . future ptsd research should broaden the scope to include not only the mental health impact of ipv but also the possible differential relationship between types of ipv (e.g. psychological abuse, physical violence, or sexual assault) and ptsd symptoms or diagnoses. additionally, the use of cross-sectional design precludes an examination of causality between ipv and ptsd in chinese women. by adopting a longitudinal approach within the chinese context, a more reliable conclusion can be drawn regarding the causal process (if any) from ipv to ptsd. the use of convenience samples in the studies reviewed has restricted the generalization of the results to other abused chinese women. in order to enhance representativeness of the sample, stratified probability sampling should be considered. as well, the ethnic makeup within the asian participants in two of the reviewed studies (phillips et al., 2006; lee et al., 2007) may be too diverse, thus confounding the overall results. for example, in lee et al.'s study, chinese, korean and vietnamese women made up the asian group. china has not seen warfare or combat for more than half a century, whereas vietnam's experience of warfare is more recent. therefore, it should not be assumed that traumatic life events for the chinese and vietnamese women are similar. although it is often assumed that korean, vietnamese and chinese people are influenced by confucian beliefs, in fact, because of the different political, social and economic conditions in these countries, the actual confucian influence may not be the same. thus, future research should clearly delineate the post-traumatic impact of ipv on different ethnic groups. as discussed earlier, the studies in this review adopted an imposed-etic approach (berry, 1980) by using translated assessment tools from the west. cross-cultural differences in terms of psychometric properties or interpretation have not been considered. thus, the assessment instruments may be appropriate for the culture where they were developed but may not be appropriate in a different culture where they may be applied. indeed, tang (2007) has argued for the need to obtain emic constructs that are appropriate for chinese societies when conducting trauma research among chinese people. future research should consider using ethno-cultural or qualitative approaches in order to collect, interpret and compare perceptions of, and reactions to, the same traumatic life events from chinese and non-chinese survivors. it is hoped that using ethnocultural or qualitative approaches will facilitate culturebound interpretations of trauma, symptom expression, and coping, in the chinese context. in recent western studies, people who report ptsd symptoms, but who do not necessarily meet the diagnostic criteria, have been found to have impaired functioning (grubaugh et al., 2005; jeon et al., 2007) . in some cases, the reporting of ptsd symptoms has been shown to be a predictor of delayed onset ptsd (carty et al., 2006) . there is a need to validate whether the findings of impaired functioning also apply to chinese people and to assess how such information may inform the choice of interventions for abused chinese women. finally, there is a need to investigate the role played by ptsd in mediating the relationship between ipv and physical health problems among abused chinese women. despite an increased understanding about the relationships between ipv, physical health problems, and ptsd (wuest et al., 2009; woods et al., 2008) , the specific relevance for abused chinese women remains unknown. this needs to be addressed so that appropriate preventive strategies for chinese women can be instituted in a timely manner. a search of the existing literature has identified five papers reporting on ptsd symptoms or diagnoses in abused chinese women. the studies were conducted in china, taiwan, malaysia and the united states, with chinese women being the sole participants, or participants as part of a mixed asian group. interview schedules and/or rating scales utilized to assess the women for ptsd at diagnostic or symptomatic levels, were exclusively developed in western countries. the present review has revealed a paucity of information about ptsd among abused chinese women, and has also highlighted the methodological differences across the studies. furthermore, the studies utilized assessment tools that have not been validated for culture-bound interpretation of trauma and symptom expression; therefore, comparing the findings with those in the western literature should be undertaken with care. implications for practice and suggestions for future research are discussed. none. international publication trends in the traumatic stress literature introduction to methodology clinician-administered ptsd scale for dsm-iv, current and lifetime version criminal victimization, posttraumatic stress disorder, and comorbid psychopathology among a community sample of women health consequences of intimate partner violence delayed-onset ptsd: a prospective study of injury survivors posttraumatic stress disorder among female juvenile offenders understanding violence against chinese women in hong kong: an analysis of risk factors with a special emphasis on the role of in-law conflict women reporting intimate partner violence in india: associations with ptsd and depressive symptoms posttraumatic distress and coping strategies among rescue workers after an earthquake psychological distress and negative appraisals in survivors of severe acute respiratory syndrome (sars) psychological impact of severe acute respiratory syndrome on health workers in a tertiary hospital abusive experiences and psychiatric morbidity in women primary care attenders the validation of a selfreport measure of posttraumatic stress disorder: the posttraumatic diagnostic scale intimate partner violence as a risk factor for mental disorders: a meta-analysis trauma and health: physical health consequences of exposure to extreme stress subthreshold ptsd in primary care: prevalence, psychiatric disorders, healthcare use, and functional status impact of event scale: a measure of subjective stress post-traumatic responses of abused women to marital violence domestic violence against women in taiwan: their life-threatening situations, post-traumatic responses, and psycho-physiological symptoms: an interview study the assessment of posttraumatic stress disorder in battered women prevalence and characteristics of trauma and posttraumatic stress disorder in female prisoners in china partial versus full ptsd in the korean community: prevalence, duration, correlates, comorbidity, and dysfunctions posttraumatic stress disorder in the national comorbidity survey world report on violence and health. world health organization prevalence of psychiatric disorders among bereaved survivors of a disastrous earthquake in taiwan full and partial ptsd among earthquake survivors in rural taiwan perpetrator methodology as a predictor of traumatic symptomatology in adult survivors of childhood sexual abuse intimate partner violence and psychological health in a sample of asian and caucasian women: the roles of social support and coping domestic violence and postnatal depression in a chinese community the prevalence of domestic violence against pregnant women in a chinese community an epidemiologic study of posttraumatic stress disorder in flood victims in hunan china traditional chinese medical beliefs and their relevance for mental illness and psychiatry received and perceived social support in times of stress: a test of the social support deterioration deterrence model a cross-cultural assessment of posttrauma reactions among malaysian and us women reporting partner abuse nursing research: generating and assessing evidence for nursing practice advocacy interventions to reduce or eliminate violence and promote the physical and psychosocial well-being of women who experience intimate partner abuse. cochrane database of systematic reviews prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women violence exposure, posttraumatic stress, and personality in juvenile delinquents intimate partner violence surveillance: uniform definitions and recommended data elements, version symptoms of post-traumatic stress disorder in abused women in a primary care setting cross-cultural perspectives on the medicalisation of human suffering impact of event scale: psychometric properties major depressive and post-traumatic stress disorder comorbidity in female victims of intimate partner violence posttraumatic stress disorder and physical health symptoms among women seeking help for relationship aggression assessment of ptsd and psychiatric comorbidity in contemporary chinese societies breaking the silence: violence against women in asia identifying intimate partner violence: comparing the chinese abuse assessment screen with the chinese revised conflict tactics scales a randomised controlled trial of empowerment training for chinese abused pregnant women in hong kong the ways of coping checklist: revision and psychometric properties the ptsd checklist (pcl): reliability, validity, and diagnostic utility. paper presented at the annual convention of the international society for traumatic stress studies physical health and posttraumatic stress disorder symptoms in women experiencing intimate partner violence survey of quality of life and related risk factors for a taiwanese village population 3 years post-earthquake abuse-related injury and symptoms of posttraumatic stress disorder as mechanisms of chronic pain in survivors of intimate partner violence survey on mental status of subjects recovered from sars feminist theory and status inconsistency theory: application to domestic violence in chinese immigrant familes partner violence, depression, and practice implications with families of chinese descent posttraumatic stress symptoms and victimization among japanese american women the relationship between intimate partner violence and ptsd: an application of cox regression with time-varying covariates relationship between emotional numbing and arousal symptoms in american women of japanese descent who experienced interpersonal victimization asian family violence report: a study of the cambodian, chinese, korean, south asian and vietnamese communities in massachusetts. asian task force against domestic violence long-term effects of tangshan earthquake on psychosomatic health of paraplegic sufferers psychological consequences of earthquake disaster survivors prevalence and correlated factors of ptsd in adolescents 17 months after earthquake this review was supported by a small project funding (#200807176148) from the university of hong kong. key: cord-273941-gu6nnv9d authors: chandran, uma; mehendale, neelay; patil, saniya; chaguturu, rathnam; patwardhan, bhushan title: chapter 5 network pharmacology date: 2017-12-31 journal: innovative approaches in drug discovery doi: 10.1016/b978-0-12-801814-9.00005-2 sha: doc_id: 273941 cord_uid: gu6nnv9d abstract the one-drug/one-target/one-disease approach to drug discovery is presently facing many challenges of safety, efficacy, and sustainability. network biology and polypharmacology approaches gained appreciation recently as methods for omics data integration and multitarget drug development, respectively. the combination of these two approaches created a novel paradigm called network pharmacology (np) that looks at the effect of drugs on both the interactome and the diseasome level. ayurveda, the traditional system of indian medicine, uses intelligent formulations containing multiple ingredients and multiple bioactive compounds; however, the scientific rationale and mechanisms remain largely unexplored. np approaches can serve as a valuable tool for evidence-based ayurveda to understand the medicines’ putative actions, indications, and mechanisms. this chapter discusses np and its potential to explore traditional medicine systems to overcome the drug discovery impasse. drug discovery, the process by which new candidate medications are discovered, initially began with random searching of therapeutic agents from plants, animals, and naturally occurring minerals (burger, 1964) . for this, they depended on the materia medica that was established by medicine men and priests from that era. this was followed by the origin of classical pharmacology in which the desirable therapeutic effects of small molecules were tested on intact cells or whole organisms. later, the advent of human genome sequencing revolutionized the drug discovery process that developed into targetàbased drug discovery, also known as reverse pharmacology. this relies on the hypothesis that the modulation of the activity of a specific protein will have therapeutic effects. the protein that the drug binds to or interacts with is also referred to as a "target." in this reductionist approach, small molecules from a chemical library are screened for their effect on the target's known or predicted function (hacker et al., 2009) . once the small molecule is selected for a particular target, further modifications are carried out at the atomic level to ameliorate the lock-and-key interactions. this one-drug/onetarget/one-therapeutic approach was followed for the last several decades. the information technology revolution at the end of 20th century metamorphosed the drug discovery process as well (clark and pickett, 2000) . advancements in omics technologies during this time were used to develop strategies for different phases of drug research (buriani et al., 2012) . computational power was implemented in the discovery process for predicting a drug-likeness of newly designed or discovered compounds and ligandprotein docking for predicting the binding affinity of a small molecule with a protein three-dimensional structure. in silico tools were developed to predict other pharmacological properties of the drug molecules such as absorption, distribution, metabolism, excretion, and toxicity-abbreviated together as admet (van de waterbeemd and gifford, 2003; clark and grootenhuis, 2002) . the technological advancements triggered discovery efforts in a direction to discover more specific magic bullets that were completely against the holistic approach of traditional medicine. this magic bullet approach is currently in decline phase. the major limitations of this drug discovery approach are side effects and the inability to tackle multifactorial diseases. this is mainly due to the linearity of this approach. during the peak, historical time of drug discovery and development of natural productsàbased drugs had played a significant role due to their superior chemical diversity and safety over synthetic compound libraries (zimmermann et al., 2007) . currently, it is estimated that more than one hundred new, natural productàbased leads are in clinical development (harvey, 2008) . many active compounds (bioactives) from traditional medicine sources could serve as good starting compounds and scaffolds for rational drug design. natural products normally act through modulation of multiple targets rather than a single, highly specific target. but in drug discovery and development, technology was used to synthesize highly specific mono-targeted molecules that mimic the bioactives from natural compounds rather than understanding the rationale behind their synergistic action and developing methods to isolate the bioactives from natural resources. researchers understand that most diseases are due to dysfunction of multiple proteins. thus, it is important to address multiple targets emanating from a syndrome-related, metabolic cascade, so that holistic management can be effectively achieved. therefore, it is necessary to shift the strategy from one that focuses on a single-target, new chemical entity to one of a multiple-target, synergistic, formulation-discovery approach . this tempted the research world to go back and extensively explore natural sources, where modern pharmacology had begun. this renewed research focus indicates the need to rediscover the drug discovery process by integrating traditional knowledge with state-of-the-art technologies (patwardhan, 2014a) . a new discipline called network pharmacology (np) has emerged which attempts to understand drug actions and interactions with multiple targets (hopkins, 2007) . it uses computational power to systematically catalogue the molecular interactions of a drug molecule in a living cell. np appeared as an important tool in understanding the underlying complex relationships between botanical formula and the whole body berger and iyengar, 2009) . it also attempts to discover new drug leads and targets and to repurpose existing drug molecules for different therapeutic conditions by allowing an unbiased investigation of potential target spaces (kibble et al., 2015) . however, these efforts require some guidance for selecting the right type of targets and new scaffolds of drug molecules. traditional knowledge can play a vital role in this process of formulation discovery and repurposing existing drugs. by combining advances in systems biology and np, it might be possible to rationally design the next generation of promiscuous drugs (cho et al., 2012; hopkins, 2008; ellingson et al., 2014) . np analysis not only opens up new therapeutic options, but it also aims to improve the safety and efficacy of existing medications. the postgenomic era witnessed a rapid development of computational biology techniques to analyze and explore existing biological data. the key aim of the postgenomic biomedical research was to systematically catalogue all molecules and their interactions within a living cell. it is essential to understand how these molecules and the interactions among them determine the function of this immensely complex machinery, both in isolation and when surrounded by other cells. this led to the emergence and advancement of network biology, which indicates that cellular networks are governed by universal laws and offer a new conceptual framework that could potentially revolutionize our view of biology and disease pathologies in the 21st century (barabási and oltvai, 2004) . during the first decade of the 21st century, several approaches for biological network construction were put forward that used computational methods, and literature mining especially, to understand the relation between disease phenotypes and genotypes. as a consequence, lmma (literature mining and microarray analysis), a novel approach to reconstructing gene networks by combining literature mining and microarray analysis, was proposed (li et al., 2006; huang and li, 2010) . with this, a global network was first derived using the literatureàbased, cooccurrence method and then refined using microarray data. the lmma biological network approach enables researchers to keep themselves up to date with relevant literature on specialized biological topics and to make sense of the relevant large-scale microarray dataset. also, lmma serves as a useful tool for constructing specific biological network and experimental design. lmmaàlike representations enable a systemic recognition for the specific diseases in the context of complex gene interactions and are helpful for studying the regulation of various complex biological, physiological, and pathological systems. the significance of accumulated-data integration was appreciated by pharmacologists, and they began to look beyond the classic lock-and-key concept as a far more intricate picture of drug action became clear in the postgenomic era. the global mapping of pharmacological space uncovered promiscuity, the specific binding of a chemical to more than one target (paolini et al., 2006) . as there can be multiple keys for a single lock, in the same way, a single key can fit into multiple locks. similarly, a ligand might interact with many targets and a target may accommodate different types of ligands. this is referred to as "polypharmacology." the concept of network biology was used to integrate data from drugbank (re and valentini, 2013) and omim (hamosh et al., 2005) , an online catalog of human genes and genetic disorders to understand the industry trends, the properties of drug targets, and to study how drug targets are related to disease-gene products. in this way, when the first drug-target network was constructed, isolated and bipartite nodes were expected based on the existed one-drug/one-target/onedisease approach. rather, the authors observed a rich network of polypharmacology interactions between drugs and their targets (yildirim et al., 2007 ). an overabundance of "follow-on" drugs that are drugs that target already targeted proteins was observed. this suggested a need to upgrade the singletarget single-drug paradigm, as single-protein single-function relations are limited to accurately describing the reality of cellular processes. advances in systems biology led to the realization that complex diseases cannot be effectively treated by intervention at single proteins. this made the drug researchers accept the concept of polypharmacology which they previously thought as an undesirable property that needs to be removed or reduced to produce clean drugs acting on single-targets. according to network biology, simultaneous modulation of multiple targets is required for modifying phenotypes. developing methods to aid polypharmacology can help to improve efficacy and predict unwanted off-target effects. hopkins (hopkins, 2007 (hopkins, , 2008 observed that network biology and polypharmacology can illuminate the understanding of drug action. he introduced the term "network pharmacology." this distinctive new approach to drug discovery can enable the paradigm shift from highly specific magic bulletàbased drug discovery to multitargeted drug discovery. np has the potential to provide new treatments to multigenic complex diseases and can lead to the development of e-therapeutics where the ligand formulation can be customized for each complex indication under every disease type. this can be expanded in the future and lead to customized and personalized therapeutics. integration of network biology and polypharmacology can tackle two major sources of attrition in drug development such as efficacy and toxicity. also, this integration holds the promise of expanding the current opportunity space for druggable targets. hopkins proposed np as the next paradigm in drug discovery. polypharmacology expands the space in drug discovery approach. hopkins had suggested three strategies to the designers of multitarget therapies: the first was to prescribe multiple individual medications as a multidrug combination cocktail. patient compliance and the danger of drugàdrug interactions would be the expected drawbacks of this method. the second proposition was the development of multicomponent drug formulations. the change in metabolism, bioavailability, and pharmacokinetics of formulation as well as safety would be the major concerns of this approach. the third strategy was to design a single compound with selective polypharmacology. according to hopkins, the third method is advantageous, as it would ease the dosing studies. also, the regulatory barriers for the single compound are fewer compared to a formulation. an excellent example of this is metformin, the first-line drug for type ii diabetes that has been found to have cancerinhibiting properties (leung et al., 2013) . the following years witnessed the application research of np by integrating network biology and polypharmacology. a computational framework, based on a regression model that integrates human proteinàprotein interactions, disease phenotype similarities, and known geneàphenotype associations to capture the complex relationships between phenotypes and genotypes, has been proposed. this was based on the assumption that phenotypically similar diseases are caused by functionally related genes. a tool named cipher (correlating protein interaction network and phenotype network to predict disease genes) has been developed that predicts and prioritizes disease-causing genes (wu et al., 2008) . cipher helps to uncover known disease genes and predict novel susceptibility candidates. another application of this study is to predict a human disease landscape that can be exploited to study the related genes for related phenotypes that will be clustered together in a molecular interaction network. this will facilitate the discovery of disease genes and help to analyze the cooperativity among genes. later, cipher-hit, a hitting-time-based method to measure global closeness between two nodes of a heterogeneous network, was developed (yao et al., 2011) . a phenotypeàgenotype network can be explored using this method for detecting the genes related to a particular phenotype. a net-workàbased gene clustering and extension were used to identify responsive gene modules in a conditionàspecific gene network aimed to provide useful resources to understand physiological responses (gu et al., 2010) . np was also used to develop mirnaàbased biomarkers (lu et al., 2011) . for this, a network of mirna and their targets was constructed and further refined to study the data for specific diseases. this process integrated with literature mining was useful to develop potent mirna markers for diseases. np was also used to develop a drug geneàdisease comodule (zhao and li, 2012) . initially, a drug-disease network was constructed by information gathered from databases followed by the integration of gene data. the gene closeness was studied by developing a mathematical model. this network inferred the association of multiple genes for most of the diseases and target sharing of drugs and diseases. these kinds of networks give insight into new drug-disease associations and their molecular connections. during the progression period of network biology, natural products were gaining importance in the chemical space of drug discovery, as these have been economically designed and synthesized by nature for the benefit of evolution (wetzel et al., 2011) . researchers began analyzing the logic behind traditional medicine systems and devised computational ways to ease the analysis. a comprehensive herbal medicine information system that was developed integrates information of more than 200 anticancer herbal recipes that have been used for the treatment of different types of cancer in the clinic, 900 individual ingredients, and 8500 small organic molecules isolated from herbal medicines (fang et al., 2005) . this system, which was developed using an oracle database and internet technology, facilitates and promotes scientific research in herbal medicine. this was followed by the development of many databases that serve as a source of botanical information and a powerful tool that provides a bridge between traditional medicines and modern molecular biology. these kinds of databases and tools made the researchers conceive the idea of np of botanicals and their formulations to understand the underlying mechanisms of traditional medicines. we refer to such networks as "ethnopharmacological networks" and the technique as "network ethnopharmacology (nep)" (patwardhan and chandran, 2015) . shao li pioneered this endeavor and proposed this network as a tool to explain the zheng (syndrome of traditional chinese medicine (tcm)) and the multiple-targets' mechanism of tcm (li, 2007) . li et al. tried to provide a molecular basis for 1000-year-old concept of zheng using a neuro-endocrine-immune (nei) network . zheng is the basic unit and key concept in tcm theory. it is also used as a guideline in disease classification in tcm. the hot (hans zheng in mandarin) and cold (re zheng) are the two statuses of zheng which therapeutically directs the use of herbs in tcm. chinese herbs are classified as hotàcooling and are used to remedy hot zheng and coldàwarming herbs that are used to remedy cold zheng. according to the authors, hormones may be related to hot zheng, immune factors may be related to cold zheng, and they may be interconnected by neurotransmitters. this study provides a methodical approach to understand tcm within the framework of modern science. later they reconstructed the nei network by adding multilayer information including data available on the kegg database related to signal transduction, metabolic pathways, proteinàprotein interactions, transcription factor, and micro rna regulations. they also connected drugs and diseases through multilayered interactions. the study of cold zheng emphasized its relation to energy metabolism, which is tightly correlated with the genes of neurotransmitters, hormones, and cytokines in the nei interaction network ma et al., 2010) . another database, tcmgenedit, provides information about tcms, genes, diseases, tcm effects, and tcm ingredients mined from a vast amount of biomedical literature. this would facilitate clinical research and elucidate the possible therapeutic mechanisms of tcms and gene regulations (fang et al., 2008) . to study the combination rule of tcm formulae, an herb network was created using 3865 collaterals-related formulae . they developed a distance-based, mutual-information model (dmim) to uncover the combination rule. dmim uses mutual-information entropy and "between herb distance" to measure the tendency of two herbs to form an herb pair. they experimentally evaluated the combination of a few herbs for angiogenesis. understanding the combination rule of herbs in formulae will help the modernization of traditional medicine and also help to develop a new formulae based on the current requirement. a network targetàbased paradigm was proposed for the first time to understand the synergistic combinations , and an algorithm termed "nims" (network tar-getàbased identification of a multicomponent synergy) was also developed. this was a step that facilitated the development of multicomponent therapeutics using traditional wisdom. an innovative way to study the molecular mechanism of tcm was proposed during this time by integrating the tcm experimental data with microarray gene expression data (wen et al., 2011) . as a demonstrative example, si-wu-tang's formula was studied. rather than uncovering the molecular mechanism of action, this method would help to identify new health benefits of tcms. the initial years of the second decade of the 21st century witnessed the network ethnopharmacological exploration of tcm formulations. the scope of this new area attracted scientists, and they hoped nep could provide insight into multicompound drug discoveries that could help overcome the current impasse in drug discovery (patwardhan, 2014b; . nep was used to study the antiinflammatory mechanism of qingfei xiaoyan, a tcm . the predicted results were used to design experiments and analyze the data. experimental confirmation of the predicted results provides an effective strategy for the study of traditional medicines. the potential of tcm formulations as multiple compound drug candidates has been studied using tcm formulations based np. tcm formulations studied in this way are listed in table 5 .1. construction of a database containing 19,7201 natural product structures, followed by their docking to 332 target proteins of fda-approved drugs, shows the amount of space shared in the chemical space between natural products and fda drugs (gu et al., 2013a) . molecular-docking technique plays a major role in np. the interaction of bioactives with molecular targets can be analyzed by this technique. molecular dockingàbased nep can be a useful tool to computationally elucidate the combinatorial effects of traditional medicine to intervene disease networks (gu et al., 2013c ). an approach that combines np and pharmacokinetics has been proposed to study the material basis of tcm formulations (pei et al., 2013) . this can be extrapolated to study other traditional medicine formulations as well. in cancer research, numerous natural products have been demonstrated to have anticancer potential. natural products are gaining attraction in anticancer research, as they show a favorable profile in terms of absorption and metabolism in the body with low toxicity. in a study all of the known bioactives were docked for their property to interact with 104 cancer targets (luo et al., 2014) . it was inferred that many bioactives are targeting multiple ejiao slurry regulates cancer cell differentiation, growth, proliferation, and apoptosis, and shows an adjuvant therapeutic effect that enriches the blood and increases immunity xu et al. (2014b) xiao-chaihu decoction and da chaihu-decoction xchd treats diseases accompanying symptoms of alternating fever and chills, no desire for food or drink, and dry pharynx, while dchd treats those with symptoms of fullness, pain in abdomen, and constipation. dragon's blood used in colitis and acts through interaction with 26 putative targets xu et al. (2014a) protein targets and thus are linked to many types of cancers. np coupled to sophisticated spectroscopical analysis such as ultra-performance liquid chromatographyàelectrospray, ionizationàtandem mass spectroscopy (uplc-esi-ms/ms) is a useful approach to study the absolute molecular mechanism of action of botanical formulations based on their constituent bioactives (xu et al., 2014a) . bioactiveàtarget analysis has shown that some of the botanical formulations are more effective than their corresponding marketed drugàtarget interactions . this indicates the potential of np to better understand the power of botanical formulations and to develop efficient and economical treatment options. the holistic approach of botanical formulations can be better explained by np. a study has reported this property by exemplifying a tcm formulation against viral infectious disease . not only does the formulation target the proteins in the viral infection cycle, but it also regulates the proteins of the host defense system; thus, it acts in a very distinctive manner. this unique property of formulations is highly efficient for strengthening the broad and nonspecific antipathogenic actions. thus, network-based, multitarget drugs can be developed by testing the efficacy of the formulation, identifying, and isolating the major bioactives and redeveloping a multicomponent therapeutic using the major bioactives based on synergism (leung et al., 2013) . np also serves to document and analyze the clinical prescriptions of traditional medicine practitioners . a traditional medicine network that links bioactives to clinical symptoms through targets and diseases is a novel way to explore the basic principles of traditional medicines (luo et al., 2015) . the network-based approaches provide a systematic platform for the study of multicomponent traditional medicine and has applications for its beneficial modernization. this platform not only recovers traditional knowledge, but it also provide new findings that can be used for resolving current problems in the drug industry . this section explains a handful of ethnopharmacological networks that were developed to understand the scientific rationale of traditional medicine. dragon's blood (db) tablets, which are made of resins from dracaena spp., daemonorops spp., croton spp., and pterocarpus spp., is an effective tcm for the treatment of colitis. in a study, an np-based approach was adopted to provide new insights relating to the active constituents and molecular mechanisms underlying the effects of db (xu et al., 2014a) . the constituent chemicals of the formulation were identified using an ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry method. the known targets of those identified 48 compounds were mined from literature and putative targets that were predicted with the help of computational tools. the compounds were further screened for bioavailability followed by the systematic analysis of the known and putative targets for colitis. the network evaluation revealed the mechanism of action of db bioactives for colitis through the modulation of the proteins of the nod-like receptor signaling pathway (fig. 5.1) . the antioxidant mechanism of zhi-zi-da-huang decoction as an approach to treat alcohol liver disease was elucidated using np an and feng, 2015 ). an endothelial cell proliferation assay was performed for an antiangiogenic alkaloid, sinomenine, to validate the network targetàbased identification of multicomponent synergy (nims) predictions. the study was aimed at evaluating the synergistic relationship between different pairs of therapeutics, and sinomenine was found to have a maximum inhibition rate with matrine, both through the network and in vitro studies. the discovery of bioactives and elucidation of the mechanism of action of the herbal formulae, qing-luo-yin and the liu-wei-di-huang pill, using np, has given insight to the design validation experiments that accelerated the process of drug discovery . validation experiments based on the network findings regarding cold zheng and hot zheng on a rat model of collagenàinduced arthritis showed that the cold zhengàoriented herbs tend to affect the hub nodes in the cold zheng network, and the hot zheng-oriented herbs tend to affect the hub nodes in the hot zheng network . np was used to explain the addition and subtraction theory of tcm. two decoctions: xiao chaihu and da chaihu were studied using np approach to investigate this theory. according to the addition and subtraction theory, the addition or removal of one or more ingredients from a traditional formulation resulted in a modified formula that plays a vital role in individualized medicine. compounds from additive herbs were observed to be more efficient on diseaseàassociated targets (fig. 5.2) . these additive compounds were found to act on 93 diseases through 65 drug targets (li et al., 2014a) . experimental verification of the antithrombotic network of fufang xueshuantong (fxst) capsule was done through in vivo studies on lipopoly-saccharideàinduced disseminated intravascular coagulation (dic) rat model. it was successfully shown that fxst significantly improves the activation of the coagulation system through 41 targets from four herbs (sheng et al., 2014) . np analysis of the bushenhuoxue formula showed that six components-rhein, tanshinone iia, curcumin, quercetin and calycosin-acted through 62 targets for the treatment of chronic kidney disease. these predictions were validated using unilateral ureteral obstruction models, and it was observed that even though the individual botanicals showed a significant decrease in creatinine levels, the combination showed lower blood creatinine and urea nitrogen levels (shi et al., 2014) . the antidiabetic effects of ge-gen-qin-lian decoction were investigated using an insulin secretion assay, and an insulinàresistance model using 13 of the 19 ingredients showed antidiabetic activity using np studies (li et al., 2014b) . to confirm the predictions of the network of liu-wei-di-huang pill, four proteins-pparg, rara, ccr2, and esr1-that denote different functions and are targeted by different groups of ingredients were chosen. the interactions between various bioactives and their effect on the expression of the proteins showed that the np approach can accurately predict these interactions, giving hints regarding the mechanism of action of the compounds (liang et al., 2014) . experimental results confirmed that the 30 core ingredients in modified simiaowan, obtained through network analysis, significantly increased huvec viability and attenuated the expression of icam-1 and proved to be effective in gout treatment (zhao et al., 2015) . the role of anthraquinone and flavanols (catechin and epicatechin) in the therapeutic potential of rhubarb in renal interstitial fibrosis was examined using network analysis and by conventional assessment involving serum biochemistry, histopathological, and immunohistochemical assays (xiang et al., 2015) . in silico analysis and experimental validation demonstrated that compound 11/12 of fructus schisandrae chinensis targets gba3/shbg . np is a valuable method to study the synergistic effects of bioactives of traditional medicine formulation. this was experimentally shown on the sendeng-4 formulation for rheumatoid arthritis (fig. 5.3 ). data and network analysis have shown that the formulation acts synergistically through nine categories of targets (zi and yu, 2015) . another network that studied three botanicals, salviae miltiorrhizae, ligusticum chuanxiong, and panax notoginseng for coronary artery disease (cad), displayed their mode of action through 67 targets, out of which 13 are common among the botanicals (fig. 5.4) . these common targets are associated with thrombosis, dyslipidemia, vasoconstriction, and inflammation . this gives insight to how these botanicals are managing cad. another approach using np is the construction of networks based on experimental data followed by literature mining. this method is very effective for large space data analysis, which will help to derive the mechanism of action of the formulation. a network of qishenyiqi formulation having cardioprotective effects, constructed based on the microarray data and the published literature, showed that 9 main compounds were found to act through 16 pathways, out of which 9 are immune and inflammation-related (li et al., 2014c) . the mechanism of action for the bushen zhuanggu formulation was proposed based on lc-ms/ms standardization, pharmacokinetic analysis, and np (pei et al., 2013) . the efficacy of shenmai injection was evaluated using a rat model of myocardial infarction, genome-wide transcriptomic experiment, and then followed by a np analysis. the overall trends in the ejection fraction and fractional shortening were consistent with the networkàrecovery index (nri) from the network . in order to develop an ethnopharmacological network, exploring the existing databases to gather information regarding bioactives and targets is the first step. further information such as target-related diseases, tissue distribution and pathways are also to be collected depending on the type of study that is going to be undertaken. the universal natural products database (unpd) (gu et al., 2013a ) is one of the major databases that provides bioactives information. other databases that provide information regarding bioactives include cvdhd (gu et al., 2013b) , tcmsp (ru et al., 2014) , tcm@taiwan (sanderson, 2011) , supernatural (banerjee et al., 2015) , and dr. dukes's phytochemical and ethnobotanical database (duke and beckstrom-sternberg, 1994) . the molecular structures of bioactives are usually stored as "sd" files and chemical information as smiles and inchkeys in these databases. any of these file formats can be used as inputs to identify the targets in protein information databases. binding database or "binding db" (liu et al., 2007) and chembl (bento et al., 2014) are databases for predicting target proteins. binding db searches the exact or similar compounds in the database and retrieves the target information of those compounds. the similarity search gives the structurally similar compounds with respect to the degree of similarity as scores to the queried structure. the information regarding both annotated and predicted targets can be collected in this way. this database is connected to numerous databases, and these connections can be used to extract further information regarding the targets. the important databases linked to binding db are uniprot (bairoch et al., 2005) , which gives information related to proteins and genes; reactome, a curated pathway database (croft et al., 2011) ; and the kyoto encyclopedia of genes and genomes (kegg), a knowledge base for systematic analysis of gene functions and pathways (ogata et al., 1999) . therapeutic targets database (ttd) (zhu et al., 2012) gives fully referenced information of targeted diseases of proteins, their pathway information, and the corresponding drug directed to each target. disease and gene annotation (dga), a database that provides a comprehensive and integrative annotation of human genes in disease networks, is useful in identifying the disease type that each indication belongs to (peng et al., 2013) . the human protein atlas (hpa) database (pontén et al., 2011) is an open database showing the spatial distribution of proteins in 44 different normal human tissues. the information of the distribution of proteins in tissues can be gathered from hpa. the database also gives information regarding subcellular localization and protein class. an overall review of the methods to implement np for herbs and herbal formulations is also available, including a systematic review of the databases that one could use for the same (kibble et al., 2015; lagunin et al., 2014) . integration of knowledge bases helps data gathering for network pharmacological studies, and its knowledge base shows the inter-relationships among these databases (fig. 5 .5) . the counts of entities, such as bioactives, targets, and diseases, can vary based on the knowledge bases that are relied on for data collection. an integration of knowledge bases can overcome this limitation. another factor that affects the counts of these entities is the time frame for data collection. this change occurs due to the ongoing, periodic updates of the databases. a network is the schematic representation of the interaction among various entities called nodes. in pharmacological networks, the nodes include bioactives, targets, tissue, tissue types, disease, disease types, and pathways. these nodes are connected by lines termed edges, which represent the relationship between them (morris et al., 2012) . building a network involves two opposite approaches: a bottom-up approach on the basis of established biological knowledge and a top-down approach starting with the statistical analysis of available data. at a more detailed level, there are several ways to build and illustrate a biological network. perhaps the most versatile and general way is the de novo assembly of a network from direct experimental or computational interactions, e.g., chemical/gene/protein screens. networks encompassing biologically relevant nodes (genes, proteins, metabolites), their connections (biochemical and regulatory), and modules (pathways and functional units) give an authentic idea of the real biological phenomena (xu and qu, 2011) . cytoscape, a java-based open source software platform (shannon et al., 2003) , is a useful tool for visualizing molecular interaction networks and integrating them with any type of attribute data. in addition to the basic set of features for data integration, analysis, and visualization, additional features are available in the form of apps, including network and molecular profiling analysis and links with other databases. in addition to cytoscape, a number of visualization tools are available. visual network pharmacology (vnp) , which is specially designed to visualize the complex relationships among diseases, targets, and drugs, mainly contains three functional modules: drug-centric, target-centric, and disease-centric vnp. this disease-target-drug database documents known connections among diseases, targets, and the usfda-approved drugs. users can search the database using disease, target, or drug name strings; chemical structures and substructures; or protein sequence similarity, and then obtain an online interactive network view of the retrieved records. in the obtained network view, each node is a disease, target, or drug, and each edge is a known connection between two of them. the connectivity map, or the cmap tool, allows the user to compare gene-expression profiles. the similarities or differences in the signature transcriptional expression profile and the small molecule transcriptional response profile may lead to the discovery of the mode of action of the small molecule. the response profile is also compared to response profiles of drugs in the cmap database with respect to the similarity of transcriptional responses. a network is constructed and the drugs that appear closest to the small molecule are selected to have better insight into the mode of action. other software, such as gephi, an exploration platform for networks and complex systems, and cell illustrator, a java-based tool specialized in biological processes and systems, can also be used for building networks . ayurveda, the indian traditional medicine, offers many sophisticated formulations that have been used for hundreds of years. the traditional knowledge digital library (tkdl, http://www.tkdl.res.in) contains more than 36,000 classical ayurveda formulations. approximately 100 of these are popularly used at the community level and also as over-the-counter products. some of these drugs continue to be used as home remedies for preventive and primary health care in india. until recently, no research was carried out to explore ayurvedic wisdom using np despite ayurveda holding a rich knowledge of traditional medicine equal to or greater than tcm. our group examined the use of np to study ayurvedic formulations with the wellknown ayurvedic formulation triphala as a demonstrable example (chandran et al., 2015a, b) . in this chapter, we demonstrate the application of np in understanding and exploring the traditional wisdom with triphala as a model. triphala is one of the most popular and widely used ayurvedic formulations. triphala contains fruits of three myrobalans: emblica officinalis (eo; amalaki) also known as phyllanthus emblica; terminalia bellerica (tb; vibhitaka); and terminalia chebula (tc; haritaki). triphala is the drug of choice for the treatment of several diseases, especially those of metabolism, dental, and skin conditions, and treatment of cancer (baliga, 2010) . it has a very good effect on the health of heart, skin, eyes, and helps to delay degenerative changes, such as cataracts (gupta et al., 2010) . triphala can be used as an inexpensive and nontoxic natural product for the prevention and treatment of diseases where vascular endothelial growth factor aàinduced angiogenesis is involved . the presence of numerous polyphenolic compounds empowers it with a broad antimicrobial spectrum (sharma, 2015) . triphala is a constituent of about 1500 ayurveda formulations and it can be used for several diseases. triphala combats degenerative and metabolic disorders possibly through lipid peroxide inhibition and free radical scavenging (sabu and kuttan, 2002) . in a phase i clinical trial on healthy volunteers, immunostimulatory effects of triphala on cytotoxic t cells and natural killer cells have been reported (phetkate et al., 2012) . triphala is shown to induce apoptosis in tumor cells of the human pancreas, in both in vitro and in vivo models (shi et al., 2008) . although the anticancer properties of triphala have been studied, the exact mechanism of action is still not known. the beneficial role of triphala in disease management of proliferative vitreoretinopathy has also been reported (sivasankar et al., 2015) . one of the key ingredients of triphala is amalaki. some studies have already shown the beneficial effect of amalaki rasayana to suppress neurodegeneration in fly models of huntington's and alzheimer's diseases (dwivedi et al., 2012 (dwivedi et al., , 2013 . triphala is an effective medicine to balance all three dosha. it is considered as a good rejuvenator rasayana, which facilitates nourishment to all tissues, or dhatu. here we demonstrate the multidimensional properties of triphala using human proteome, diseasome, and microbial proteome targeting networks. the botanicals of triphala-eo, tb, and tc-contain 114, 25, and 63 bioactives, respectively, according to unpd data collected during june 2015. of these, a few bioactives are common among the three botanicals. thus, triphala formulation as a whole contains 177 bioactives. out of these, 36 bioactives were score-1, based on binding db search carried out during june 2015. eo, tb, and tc contain 20, 4, and 20 score-1 bioactives, respectively ( fig. 5.6 ). the score-1 bioactives that are common among three plants are chebulanin, ellagic acid, gallussaeure, 1,6-digalloyl-beta-d-glucopiranoside, methyl gallate, and tannic acid. this bioactive information is the basic step toward constructing human proteome and microbial proteome targeting networks. thirty-six score-1 bioactives of triphala are shown to interact with 60 human protein targets in 112 combinations (fig. 5.7) . quercetin, ellagic acid, 1,2,3,4,6-pentagalloylglucose and 1,2,3,6-tetrakis-(o-galloyl)-beta-d-glucose are the four bioactives that interact with the maximum number of targets: 21, 16, and 7, respectively. the other major bioactives that have multitargeting property include catechin; epicatechin; gallocatechin; kaempferol; and trans-3,3',4',5,7-pentahydroxylflavane. the major protein targets of triphala include alkaline phosphatase (alpl); carbonic anhydrase 7 (ca7); coagulation factor x (f10), dna repair protein rad51 homolog 1 (rad51); gstm1 protein (gstm1); beta-secretase 1 (bace1); plasminogen activator inhibitor 1 (serpine1), prothrombin (f2); regulator of g-protein signaling (rgs) 4, 7, and 8, tissue-type plasminogen activator (plat); and tyrosineprotein phosphatase nonreceptor type 2 (ptpn2). the 60 targets of triphala are associated with 24 disease types, which include 130 disease indications (fig. 5.8) . the major disease types in which triphala targets are associated include cancers, cardiovascular diseases, nervous system diseases, and metabolic diseases. analysis of existing data indicates that targets of triphala bioactives are involved in the 40 different types of cancers making it the largest group of diseases, involving triphala targets. this linkage is through the interaction of 25 bioactives and 27 target proteins in 46 different bioactiveàtarget combinations. the types of cancers which are networked by triphala include pancreatic, prostate, breast, lung, colorectal and gastric cancers, tumors, and more. quercetin, ellagic acid, prodelphinidin a1, and 1,2,3-benzenetriol are the important bioactives; and rad51, bace1, f2, mmp2, igf1r, and egfr are the important targets that play a role in cancer. triphala shows links to 18 indications of cardiovascular diseases through 12 bioactives and 11 targets. the cardiovascular diseases that are covered in the triphala network include atherosclerosis, myocardial ischemia, infarction, cerebral vasospasm, thrombosis, and hypertension. the bioactives playing a major role in cardiovascular diseases are quercetin, 1,2,3,4,6-pentagalloyoglucose, 1,2,3,6-tetrakis-(o-galloyl)-beta-d-glucose, bellericagenin a1, and prodelphinidin a1, whereas the targets playing an important role are serpine1, f10, f2, and fabp4. triphala's network to nervous system disorders contains 13 diseases in which the significant ones are alzheimer's disease, parkinson's disease, diabetic neuropathy, and retinopathy. in this subnetwork, 14 bioactives interact with 11 targets through 21 different interactions. quercetin, 1,2,3,4,6-pentagalloyoglucose, 1,2,3,6-tetrakis-(o-galloyl)-beta-d-glucose, and epigallocatechin-3-gallate are the most networked bioactives whereas the most networked targets are bace1, serpine1, plat, aldr, ca2. the association of triphala with metabolic disorders is determined by six bioactives that interact with seven targets. the major metabolic diseases come in this link are obesity, diabetic complications, noninsulin-dependent diabetes, hypercholesterolemia, hyperlipidemia, and more. the bioactives having more interactions with targets are ellagic acid, quercetin, and bellericagenin a1, whereas the highly networked targets are igf1r, fabp5, aldr, and akr1b1. triphala bioactives are also linked to targets of other diseases comprising autoimmune diseases, ulcerative colitis, mccuneàalbright syndrome, psoriasis, gout, osteoarthritis, endometriosis, lung fibrosis, glomerulonephritis, and more. the proteome-targeting network of triphala, thus, shows its ability to synergistically modulate 60 targets that are associated with 130 disease indications. this data is generated with the available information that included only one-fifth of the total number of bioactives. further logical analysis and experimental studies based on the network result are needed to explore the in-depth mechanism of action of triphala. for researchers in this area, these kind of networks can give an immense amount of information that can be developed further to reveal the real mystery behind the actions of traditional medicine. triphala is also referred to as a "tridoshic rasayana," as it balances the three constitutional elements of life. it tonifies the gastrointestinal tract, improves digestion, and is known to exhibit antiviral, antibacterial, antifungal, and antiallergic properties (sharma, 2015; amala and jeyaraj, 2014; sumathi and parvathi, 2010) . triphala mashi (mashi: black ash) was found to have nonspecific antimicrobial activity, as it showed a dose-dependent inhibition of gram-positive and gram-negative bacteria (biradar et al., 2008) . hydroalcoholic, aqueous, and ether extracts of the three fruits of triphala were reported to show antibacterial activity against uropathogens with a maximum drug efficacy recorded by the alcoholic extract (bag et al., 2013; prasad et al., 2009) . the methanolic extract of triphala showed the presence of 10 active compounds using gc-ms and also showed potent antibacterial and antifungal activity (amala and jeyaraj, 2014) . triphala has been well studied for its antimicrobial activity against gram-positive bacteria, gram-negative bacteria, fungal species, and different strains of salmonella typhi (amala and jeyaraj, 2014; sumathi and parvathi, 2010; gautam et al., 2012; srikumar et al., 2007) . triphala showed significant antimicrobial activity against enterococcus faecalis and streptococcus mutans grown on tooth substrate thereby making it a suitable agent for prevention of dental plaque (prabhakar et al., 2010 (prabhakar et al., , 2014 . the application of triphala in commercial antimicrobial agents has been explored. a significant reduction in the colony forming units of oral streptococci was observed after 6% triphala was incorporated in a mouthwash formulation (srinagesh et al., 2012 ). an ointment prepared from triphala (10% (w/w)) showed significant antibacterial and wound healing activity in rats infected with staphylococcus aureus, pseudomonas aeruginosa, and streptococcus pyogenes (kumar et al., 2008) . the antiinfective network of triphala sheds light on the efficacy of the formulation in the simultaneous targeting of multiple microorganisms. also, this network provides information regarding some novel bioactiveàtarget combinations that can be explored to combat the problem of multidrug resistance. among the bioactives of triphala, 24 score-1 bioactives target microbial proteins of 22 microorganisms. the botanicals of triphala-eo, tb, and tccontain 19, 3, and 8 score1 bioactives respectively which showed interactions with microbial proteins. they act through modulation of 35 targets which are associated with diseases such as leishmaniasis, malaria, tuberculosis, hepatitis c, acquired immunodeficiency syndrome (aids), cervical cancer, candidiasis, luminous vibriosis, yersiniosis, skin and respiratory infections, severe acute respiratory syndrome (sars), avian viral infection, bacteremia, sleeping sickness, and anthrax ( fig. 5.9 ). the microorganisms captured in the triphala antiinfective network includes candida albicans, hepatitis c virus, human immunodeficiency virus 1, human papillomavirus type 16, human sars coronavirus leishmania amazonensis, mycobacterium tuberculosis, staphylococcus aureus, plasmodium falciparum, and yersinia enterocolitica. in mycobacterium tuberculosis, dtdp-4-dehydrorhamnose 3,5-epimerase rmlc is one of the four enzymes involved in the synthesis of dtdp-l-rhamnose, a precursor of l-rhamnose (giraud et al., 2000) . the network shows that triphala has the potential to modulate the protein through four bioactives such as punicalins, terflavin b, 4-o-(s)-flavogallonyl-6-o-galloylbeta-d-glucopyranose, and 4,6-o-(s,s)-gallagyl-alpha/beta-d-glucopyranose. research on new therapeutics that target the mycobacterial cell wall is in progress. rhamnosyl residues play a structural role in the mycobacterial cell wall by acting as a linker connecting arabinogalactin polymer to peptidoglycan and are not found in humans, which gives them a degree of therapeutic potential (ma et al., 2001) . triphala can be considered in this line to develop novel antimycobacterial drugs. the network shows the potential of gallussaeure and 3-galloylgallic acid to modulate human immunodeficiency virus type 1 reverse transcriptase. inhibition of human immunodeficiency virus at the initial stage itself is crucial and thus, targeting human immunodeficiency virus type 1 reverse transcriptase, at the preinitiation stage is considered to be an effective therapy. protein e6 of human papillomavirus 16 (hpv16) prevents apoptosis of figure 5.9 the microbial proteomeàtargeting network of triphala. dark green verus are the botanicals of triphala and oval green nodes are the score1 bioactives. targets, diseases, and microorganisms are represented by blue diamond nodes, red triangle nodes, and pink octagon nodes, respectively. infected cells by binding to fadd and caspase 8 and hence being targeted for development of antiviral drugs (yuan et al., 2012) . kaempferol of triphala is found to target protein e6 of hpv16, which is a potential mechanism to control the replication of the virus. the network also shows triphala's potential to act on plasmodium falciparum. enoyl-acyl carrier protein reductase (enr) has been investigated as an attractive target due to its important role in membrane construction and energy production in plasmodium falciparum (nicola et al., 2007) while the parasite interacts with human erythrocyte spectrin and other membrane proteins through protein m18 aspartyl aminopeptidase (lauterbach and coetzer, 2008) . trans-3,3',4',5,7-pentahydroxylflavane, epigallocatechin, and epicatechin can modulate both while epigallocatechin 3-gallate can regulate enoyl-acyl carrier protein reductase and, quercetin and vanillic acid can act on m18 aspartyl aminopeptidase. epigallocatechin 3-gallate can also target 3-oxoacyl-acyl-carrier protein reductase which is a potent therapeutic target because of its role in type ii fatty acid synthase pathway of plasmodium falciparum (karmodiya and surolia, 2006) . epigallocatechin 3-gallate and quercetin are the bioactives that have shown maximum antimicrobial targets interaction. while epigallocatechin 3-gallate shows interaction with 3-oxoacyl-(acyl-carrier protein) reductase, cpg dna methylase, enoyl-acyl-carrier protein reductase, glucose-6phosphate 1-dehydrogenase, hepatitis c virus serine protease, ns3/ns4a and yoph of plasmodium falciparum, saccharomyces cerevisiae, and spiroplasma monobiae; quercetin acts on 3c-like proteinase (3cl-pro), arginase, beta-lactamase ampc, glutathione reductase, m18 aspartyl aminopeptidase, malate dehydrogenase and tyrosine-protein kinase transforming protein fps of escherichia coli, fujinami sarcoma virus, human sars coronavirus (sars-cov), leishmania amazonensis, plasmodium falciparum, saccharomyces cerevisiae, and thermus thermophiles. np has gained impetus as a novel paradigm for drug discovery. this approach using in silico data is fast becoming popular due to its cost efficiency and comparably good predictability. thus, network analysis has various applications and promising future prospects with regard to the process of drug discovery and development. np has proven to be a boon for drug research, and that helps in the revival of traditional knowledge. albeit there are a few limitations of using np for nep studies. this is because the bioactives form the foundation of any traditional medicine network. 2. absorption, distribution, metabolism, excretion, and toxic effects (admet) parameters associated with the bioactives/formulation when they are administered in the form of the medicine need to be considered in order to extrapolate in silico and cheminformatics data to in vitro and in vivo models. in silico tools that offer the prediction of these parameters can be depended on for this. but traditional medicines are generally accompanied by a vehicle for delivery of the medicine. these vehicles, normally various solvents-water, milk, lemon juice, butter, ghee (clarified butter), honey-that alter the solubility of the bioactives, play a role in regulating admet parameters. experimental validation studies are required to evaluate this principle of traditional medicine. 3. target identification usually relies on a single or a few databases due to the limited availability of databases with free access. this can occasionally give incomplete results. also, there may be novel targets waiting to be discovered that could be a part of the mechanism of action of the bioactives. to deal with this discrepancy in the network, multiple databases should be considered for target identification. integration of databases serving similar functions can also be a solution for this problem. in addition to this, experimental validation of the target molecules using proteinàprotein interaction studies or gene expression studies will provide concrete testimony to the network predictions. 4. a number of traditional medicines act through multiple bioactives and targets. synergy in botanical drugs helps to balance out the extreme pharmacological effects that individual bioactives may have. the interactions of bioactives with various target proteins, their absorption into the body after possible enzyme degradation, their transport, and finally their physiological effect are a crucial part of traditional medicine (gilbert and alves, 2003) . however, in vitro assays or in silico tools are unable to give a clear idea as to the complete and exact interactions in a living organism. np is only the cardinal step toward understanding the mechanism of bioactives/formulations. but this gives an overview of the action of traditional medicine which can be used to design in vivo experiments and clinical trials. this saves time and cost of research and inventions. 5. it is observed that formulations are working by simultaneous modulation of multiple targets. this modulation includes activation of some targets and inhibition of other. in order to understand this complex synergistic activity of formulation, investigative studies regarding the interactions of ligands with targets are to be carried out. this can be achieved by implementing high-throughput omics studies based on the network data. network pharmacological analysis presents an immense scope for exploring traditional knowledge to find solutions for the current problems challenging the drug discovery industry. nep can also play a key role in new drug discovery, drug repurposing, and rational formulation discovery. many of the bioactiveàtarget combinations have been experimentally studied. the data synthesis using np provides information regarding the mode of action of traditional medicine formulations, based on their constituent bioactives. this is a kind of reverse approach to deduce the molecular mechanism of action of formulations using modern, integrated technologies. the current network analysis is based on the studies that have been conducted and the literature that is available. hence, the data is inconclusive as a number of studies are still underway and novel data is being generated continuously. despite its limitations, this still is a favorable approach, as it gives insight into the hidden knowledge of our ancient traditional medicine wisdom. np aids the logical analysis of this wisdom that can be utilized to understand the knowledge as well as to invent novel solutions for current pharmacological problems. determination of antibacterial, antifungal, bioactive constituents of triphala by ft-ir and gc-ms analysis antibacterial potential of hydroalcoholic extracts of triphala components against multidrug-resistant uropathogenic bacteria--a preliminary report triphala, ayurvedic formulation for treating and preventing cancer: a review super natural ii--a database of natural products network biology: understanding the cell's functional organization the chembl bioactivity database: an update network analyses in systems pharmacology exploring of antimicrobial activity of triphala mashi-an ayurvedic formulation. evidence-based complement 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blood stasis syndrome computational pharmacological comparison of salvia miltiorrhiza and panax notoginseng used in the therapy of cardiovascular diseases triphala and its active constituent chebulinic acid are natural inhibitors of vascular endothelial growth factor-a mediated angiogenesis computational identification of potential microrna network biomarkers for the progression stages of gastric cancer systems pharmacology strategies for anticancer drug discovery based on natural products multiscale modeling of druginduced effects of reduning injection on human disease: from drug molecules to clinical symptoms of disease drug targeting mycobacterium tuberculosis cell wall synthesis: genetics of dtdp-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dtdp-glucose to dtdp-rhamnose bridging the gap between traditional chinese medicine and systems biology: the connection of cold syndrome and nei network analysis and visualization of biological networks with cytoscape discovery of novel inhibitors targeting enoyl-acyl carrier protein reductase in plasmodium falciparum by structure-based virtual screening global mapping of pharmacological space rediscovering drug discovery network ethnopharmacology approaches for formulation discovery integrative approaches for health: biomedical research, ayurveda and yoga material basis of chinese herbal formulas explored by combining pharmacokinetics with network pharmacology the disease and gene annotations (dga): an annotation resource for human disease significant increase in cytotoxic t lymphocytes and natural killer cells by triphala: a clinical phase i study. evid. based complement alternat the human protein atlas as a proteomic resource for biomarker discovery evaluation of antimicrobial efficacy of herbal alternatives (triphala and green tea polyphenols), mtad, and 5% sodium hypochlorite against enterococcus faecalis biofilm formed on tooth substrate: an in vitro study evaluation of antimicrobial efficacy of triphala (an indian ayurvedic herbal formulation) and 0.2% chlorhexidine against streptococcus mutans biofilm formed on tooth substrate: an in vitro study potent growth suppressive activity of curcumin in human breast cancer cells: modulation of wnt/beta-catenin signaling tcmsp: a database of systems pharmacology for drug discovery from herbal medicines anti-diabetic activity of medicinal plants and its relationship with their antioxidant property databases aim to bridge the east-west divide of drug discovery cytoscape: a software environment for integrated models of biomolecular interaction networks network pharmacology analyses of the antithrombotic pharmacological mechanism of fufang xueshuantong capsule with experimental support using disseminated intravascular coagulation rats a network pharmacology approach to understanding the mechanisms of action of traditional medicine: bushenhuoxue formula for treatment of chronic kidney disease triphala inhibits both in vitro and in vivo xenograft growth of pancreatic tumor cells by inducing apoptosis aqueous and alcoholic extracts of triphala and their active compounds chebulagic acid and chebulinic acid prevented epithelial to mesenchymal transition in retinal pigment epithelial cells, by inhibiting smad-3 phosphorylation evaluation of the growth inhibitory activities of triphala against common bacterial isolates from hiv infected patients antibacterial efficacy of triphala against oral streptococci: an in vivo study antibacterial potential of the three medicinal fruits used in triphala: an ayurvedic formulation dissection of mechanisms of chinese medicinal formula realgar-indigo naturalis as an effective treatment for promyelocytic leukemia a network study of chinese medicine xuesaitong injection to elucidate a complex mode of action with multicompound, multitarget, and multipathway phytochemical and pharmacological review of da chuanxiong formula: a famous herb pair 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involving the integration of chemical analysis, adme prediction, and network pharmacology study on action mechanism of adjuvant therapeutic effect compound ejiao slurry in treating cancers based on network pharmacology alternative medicine. intech network pharmacological research of volatile oil from zhike chuanbei pipa dropping pills in treatment of airway inflammation navigating traditional chinese medicine network pharmacology and computational tools modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network small molecule inhibitors of the hpv16-e6 interaction with caspase 8 an integrative platform of tcm network pharmacology and its application on a herbal formula network understanding of herb medicine via rapid identification of ingredient-target interactions dbnei2.0: building multilayer network for drug-neidisease systems pharmacology dissection of the anti-inflammatory mechanism for the medicinal herb 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traditional medicine that would hopefully get resolved in the future. the major limitations and possible solutions are listed:1. nep currently relies on various databases for literature and bioactive mining. databases, though curated, may show discrepancies due to numerous sources of information, theoretical, and experimental data. moreover, the botanicals that undergo certain preparatory procedures during the formulation of the medicine may have its constituents that have chemically changed due to the procedures; like boiling, acid/ alkali reactions, interactions between the bioactives, etc. a way to navigate around this problem is to make use of modern, high-throughput chemical identification techniques like ultra-performance liquid chromatogra-phyàelectrospray ionizationàtandem mass spectroscopy (uplc-esi-ms/ms). this technique will help to identify the exact bioactives or the chemical constituents of the formulation, and will enrich the subsequent key: cord-303107-f5k686pg authors: yang, yifan; chen, xuechen title: globalism or nationalism? the paradox of chinese official discourse in the context of the covid-19 outbreak date: 2020-09-16 journal: j chin polit sci doi: 10.1007/s11366-020-09697-1 sha: doc_id: 303107 cord_uid: f5k686pg by employing discourse-historical approach and corpus linguistics, this paper examines media reports to analyze the chinese official discourse in the context of the covid-19 outbreak. the results demonstrate that a paradox of globalism and nationalism has been simultaneously reflected when reporting the global pandemic. based on a polarizing discursive construction of positive “self” and negative “others,” on many occasions, the globalist and nationalist arguments have been closely intertwined and complement each other to reinforce the legitimacy of the ruling party at home and the international reputation of china under the leadership of the ruling party. the future of globalization has been overshadowed by the coronavirus outbreak in the early 2020s as has changed the landscape of world politics in opposing directions. on the one hand, global leaders are calling for more cooperation on global health while, on the other hand, they exacerbate nationalist sentiment for tighter border control against globalization. although not the only case, china is frequently in the spotlight due to the china-centered global supply chains and their growing impact on globalization at a time when the us-led western world refrains from assuming global responsibility [39] . china was the first country that reported the confirmed cases of coronavirus to the world health organization (who) and has pioneered in promoting global cooperation after the declaration of a global pandemic. this is consistent with china's longstanding diplomatic discourse on globalism after the 2008-2009 global financial crisis, evident in its official discourse on the "community of shared destiny for mankind" and "global community of health for all." chinese top leaders publicly emphasize the importance of international cooperation against covid-19, to protect global public health by proactively collaborating with multilateral institutions such as the united nations, the who, and other g20 countries and providing funding and clinical support for developing countries affected by the global pandemic [60] . chinese officials argued that leading global cooperation, upholding multilateralism, supporting vulnerable regions, and strengthening macro policy coordination are essential in chinese foreign policies in response to the covid-19 outbreak [63] . however, nationalist sentiment had also been rising after covid-19 spread was successfully curbed in mainland china in less than 3 months. chinese mass media that has long been serving as the mouthpiece of the chinese communist party (ccp) [54] frequently hailed the superiority of chinese political system and praised president xi jinping's leadership when reporting anti-epidemic efforts. this is evident in the news reports that self-congratulate the nation's containment of the pandemic and downplay other nations' performances. this nationalist sentiment encourages the chinese population to actively promote "positive energy" while ignoring dissenting opinions disclosing the mishandling of the crisis during the early days of the covid-19 outbreak [33] . some media accounts even pointed out with pride that western countries can only learn from beijing's experience and "copy china's homework"to implement the same measures to contain the epidemic [17] . it seems that chinese mass media send contradictory messages to the world: supporting globalism and upholding nationalism in the same contexts. at first sight, these two contradicting positions in the spectrum of chinese national identity discourse are easily explained. as explained by shambaugh, globalist discourse at one extreme of the spectrum has been highlighted when talking about china's interaction with globalzaization, and nationalist discourse at the opposite end when highlighting china's domestic stability [50] . however, as this paper argues, the chinese official discourse is seemingly paradoxical when reporting the covid-19 outbreak, as it jointly promote both globalism and nationalism at the same time and constructs its globalist discourse in a nationalist manner. the result is a polarizing discursive construction of "us" and "them." ironically, the paradox between the two extremes of nationalism and globalism in the chinese official discourse seems to harmonize the two discourses as they now complement each other to better serve the interests of china and the domestic legitimacy of the ruling party. to explain this paradox within chinese political discourse, discourse analysis is an entry point. the core of this study is the chinese official discourse in the mass media that engages in "othering" when representing western countries as "them" or "others" relative to china as "us" or "the self," leading to "heteronomization" or discursive construction of an outgroup and a threatening stranger that is different from the constructed "in-group" [38] . to study the chinese official discourse, this paper will utilize discourse-historical approach (dha, a major variant of critical discourse analysis) and corpus linguistics (cl). these approaches were chosen because, critical discourse analysis as a qualitative approach studies discourse as a circular process in which social practices (language use) influence texts by shaping the context and mode in which they are produced, and in turn, texts influence society by shaping the attitudes of those who read or otherwise consume them [21] . in addition, corpus linguistics (cl) is a quantitative approach to examining collocational and other recurrent patterns associated with specific lexical items [2] . combining these two approaches (that will be elaborated later) together, this paper examines the news reports targeting domestic and international readers of the top five official media outlets in china on the covid-19 outbreak. in doing so, it firstly identifies how the paradox of chinese official discourse has been represented in news reports and why it is represented in this manner. secondly, it discusses the discourse's effects on chinese international relations. moreover, looking at chinese official discourse in the context of covid-19 outbreak will contribute to the understanding of china in global health governance. on the one hand, it will shed light on china's attitude towards multilateral institution in global health governance and global governance more widely and provide insight into china's attempts to change global covid-19 narrative [57] . on the other hand, to what extent the chinese experience of controlling the epidemic may be applied to other countries is debatable, but promoting this line of global policy learning is invaluable in global health governance [28] . the reminder of this paper consists of four parts. the first part will look at the relationship between mass media, national identity and identity discourse, which is followed by a discussion on globalism and nationalism as two extremes in chinese official discourse. by analyzing the top five official media outlets (three in chinese and two in english), the third part will look at how globalist discourse and nationalist discourse have been intertwined and approve that these two paradoxical discourses can be complementary to serve the same objectives. the fourth part is a short discussion and conclusion. this study adds to the debate on globalism and nationalism, and also contributes to a larger body of academic literature on public health and global governance [14, 24, 31, 56, 58] . an identity is whatever makes a thing what it is in the philosophical sense, but identity is too ambiguous for discussion when it applies to an object such as a nation. notably, national identity has been widely studied in different disciplines. it is a theoretical object that can be understood as a type of variable with explanatory power; something shaped by various social conditions external to it in structural terms; or something structured through institutions, individuals, and "discourse" within an "imagined community" from a constructivist perspective [29] ; it is rooted in what all its members share not individually but collectively, not privately but publicly, and has an inescapable institutional focus [47] ; it revolves around the past, present, and futurethe three temporal axes of a nation [59] . national identity can be differentiated between internal identity and external identity [36] . when studying the international behaviors of a nation-state and predicting its policy directions, internal and external identities must be considered in conjunction, since internal identities are the root of external identities and cannot be separated from each other. accordingly, this paper does not distinguish external identities from internal identities because they both help project a nation-state as an international actor in world politics. however, considering that identities, either individual or collective, develop from drawn-out processes of both internal and external interaction over a long period, they do not change within a short time [10] . consequently, in this paper, we assume national identities are relatively stable constructs when using them within concrete domestic and international occasions. what is essential in the political discourse of national identity are the maintenance of a boundary and the dichotomization between members and outgroups, because they lead to a sense of belonging by closing out others, by which self-esteem and internal solidarity is to be built [27] . arguably, there are twoone symbolic and one behavioral dimensions of the construction. in addition, there is also a boundary and the continuous dichotomization between insiders and outsiders. in terms of the former, the cognitive notion of "us" and "them" has been created through discourselanguage in use in spoken and written form; regarding the latter, social closure occurred through discrimination of members of the other group, which can be coupled with a symbolic dimension [32] . equating the nation-state to a unitary actor when discussing identity formation is problematic, but a nation-state is analogous to a "group self, capable of group-level cognition." humanizing the nation-state has been commonly applied in studies of collective identity [8] . in this sense, applying discursive construction of the self-other dialectic has been meaningful in studies of national identity. in this context, what role do mass media play in the construction of national identity? although many factorsstate related (or more specifically its administers and officials), political, institutional, media, and everyday social practicesare contributing to the formation of national identity [59] , it is a common practice nowadays that news making in the media outlets plays a vital role in the formation and expression of modern national consciousness [25, 26] . admittedly, while travels within nations and across borders are increasing, much of the contact and experience that individuals gained on populations and cultures of other nations are through media texts. because nations are a political community of large dimensions and structural diversity, the prevalence of media outlets that can approach large audiences are the ideal distributor and multiplier of pro-national information. during this process, media outlets satisfy the needs of a mass audience in virtue of conveying positive media representation of the audience groups and devaluating the stereotyping foreign nations. this not only leads to a stronger identification with the own nation at the individual level and an increase in cohesion as a political community at the societal level but also to another side effect: the othering of foreign nations and ethnicities [44] . nevertheless, the rapid development of information and communication technologies has changed the ecology of mass media to such extent that a variety of news sources on the internet are available for information seeking. consequently, the role of traditional mass media as integrators of nations or more specifically governments has been eroded [19] . an examination of the impact of internet communication on information, power, and freedom distribution in democratic and authoritarian countries indicates that power distribution and freedom distribution work together to neutralize and regulate the influence of information distribution [41] . in other words, the internet as a tool has been domesticated by social and individual predispositions from the perspectives of the social construction of technology, helping consolidate national identity. as a result, state authorities can employ mechanisms to control the internet that originally seem uncontrollable and self-expanding, making the internet gradually reproduce the features of traditional media and join national media systems [19] . accordingly, müller [44] views national identity building as a mediated process, which also works in the age of internet communication. nevertheless, media exposure encourages readers to observe the world in national terms and think about their nation in patriotic terms. cda is commonly considered a point of entry into the user's identity. it uncovers how a polarizing discursive strategy is employed to highlight the negative characters of the other and the positive aspects of the self while marginalizing the positive attributes of the other and the negative behaviors of the self [38] . discourse, when defined widely, includes language, encompassing for example, signs, semiotics, and gestures, but also refers to how the world is ordered through social practice [20] . thus, discourse-based understandings of identity allow the understanding of how identities are maintained, reproduced, and normalized in everyday texts and practice of interaction [7] . for mass media, media representations are a reconceptualization of observable linguistic markers based on the specific intentions of those involved in media production. regarding the dual role that mass media play in the formation and expression of national identity, madianou [42] suggests top-down and bottom-up approaches to study the relationship between mass media and national identity: the top-down approach highlights how mass media is manipulated to create a sense of national identity among the masses, and the bottom-up approach indicates how cultures and identities as lived and performed in discourse, which has been reflected in mass media. in the context of the relationship between mass media and national identity, media discourse is understood in terms of its content and as an intention that reorganizes and regulates other discursive practices into a new order [40] . this paper equates media discourse to political (official) discourse, but the complicated relationship between government and mass media in china cannot be overlooked. notably, the ccp allows news outlets (e.g., newspapers, magazines, television programs) to compete for market share instead of relying on government financing; thus, the ccp has relinquished its monopoly in the provision of information to the public [51] . however, the increased marketization does not result in fewer political constraints because the content production of news outlets remains under strict state control, putting the production of meaning under the dual-pressure of state control and the market [26] . by following the political rules exercised by the ruling party, media coverage has been largely determined by the official response to the event being covered, which further strengthens self-censorship and increases the homogeneity of the news content. in summary, because news narratives on mass media play a vital role in establishing political consensus, national identity can be articulated in terms of principles of "us" and "them" by identifying their differences [15] . therefore, mass media help the discursive construction and symbolic representation of national identity by drawing on the logic of "the self" and "the other" or "us" and "them." accordingly, analyzing media discourse on national identity can facilitate an understanding of political (official) discourse in china, particularly in terms of identity performance in during a global public health crisis such as the covid-19 outbreak. political discourse on china's national identity: between "nationalism" and "globalism" china as an emerging power pays more attention than other states to its discourse power strategy. how it defines its perspectives and expresses itself has a decisive influence on its relationship with established powers in international politics and the world structure [65] . however, the political discourse on china's national identity can range from nationalist tendencies on the left to globalist tendencies marked by the full engagement in multilateral institutions and global governance on the right. again other discourses on national identity progress from a more realistic to a more liberal orientation in between the two extremes [50] . in china, the complicated relationship between nationalism and globalism continues to be highly debated, in particular in regard to whether nationalist ideology and the role of nation-states in world politics will be strengthened or whether globalism will gradually dominate at the expense of nationalism. nationalism matters in chinese official discourse. according to smith [52] , nationalism is "a sentiment or consciousness of belonging to the nation," among the range of meanings associated with it. in the early years after the p. r. china was founded, chinese nationalism is constructed by emphasizing china as a victim of foreign invasion and ill-treatment through western countries' economic, political and ideological power [57, 67] . more recently, by praising china's performance and achievements under the leadership of the ruling party and criticizing western countries' interference, the chinese government/party-state counters criticism of western countries and sustains the legitimacy of the ruling party at home [67] . since the early 1990s, nationalism has become another vision of ideology employed by the ccp to legitimize the ruling party to counter the belief vacuum arising fromthe decline in the maoist faith and the so-called "intrusion of western ideology" [13, 66] . chinese nationalism has been promoted through a top-down approach in an instrumentalist fashion, which involves blatant fabrication of facts and selective remembering and partial forgetting of the nation's historical and cultural legacy [64] . by contrast, globalist discourse also rises in recent years in china. globalism starts from "where human beings assume obligations toward the world as a whole, where they expose values which take the globe as their frame or reference point" [1] . this has been further developed into a "the dominant ideology and subjectivity associated with different historically-dominant formation of global extension" [30] . globalism's most obvious expression is in the worldwide green movement and sustainable development and penetrates such areas as health, gender equality, and human rights more generally [1] . nye [46] posits that globalism -understood as the density of networks of interdependence -does not imply universality but that different relationships of interdependence intersect more deeply at more different points. hence, globalists realize the limits of sovereignty in managing non-traditional challenges across national borders and embrace multilateral institutions [50] . moreover, globalism is viewed as the spatial extension of social relations worldwide and associated with globalization due to capitalist expansion [30] . however, it is also of political nature because the political tasks of the nation-states are being increasingly globalized because of global problems that cannot be managed by nation-states alone, including the united states, the most powerful nation in the world. consequently, managing global problems and the high speed of globalization should be differentiated from government-centered values through advocating globalism and respecting values and ideas [11] . according to çınar [16] , "globalism is a product of nationalism," meaning globalism makes sense in national discourse because global-local dichotomization can be understood as the relationship between "them" and "us." therefore, globalism is about how to produce and project a particular image of the world in the local context when portraying "us" against the "global-other" to empower a particular national identity. for zheng [66] , nationalism seems to serve as a strong power against globalization, especially globalization characterized by westernization. in this sense, nationalism and globalism seem to be in tension. however, these two concepts do not necessarily contradict each other, not because nationalism produces globalism, but because globalism augments nationalism [12, 50] . also, these two extremes can be complementary when they both are constructed through an "us" versus "them" dichotomization in political discourse to serve the same objectives. whether examining the chinese official discourse of nationalism and globalism in general or these two ideologies reflected in the context of the covid-19 outbreak in particular, both views seem to be reasonable explanations. despite benefiting from economic globalization, china's globalism aims to find an alternative means to access the global market in order to maintain its economic development at a high speed without merging into the western-based international system. with its increasing strength and capability, china also intends to reassure its influence proportional to its growing power in global governance under the leadership of the ruling party [62] . the first driver behind china's intention to join world politics is to "reform within" the current system in order to better serve the interests of china as an emerging power [6] , seeming to imply china as an outward-looking country. however, china is basically an inward-looking rather than an outward-looking country [12] , as china still has plenty of problems at home influencing its further development. a great challenge faced by the ruling party is to deepen the reform to accommodate the new and diverse changes in economy, politics and society without losing its control at home [23] . albeit a growing number of western countries are encouraging china to take on more responsibilities commensurate with china's growing economic power in international politics, china is not complying. admittedly, china would like to be regarded as a responsible international actor on the world stage but not as a domineering leader, as maintaining internal stability still comes first. the covid-19 outbreak has strengthened nationalism and globalism, as demonstrated in china's political discourse. the nationalist discourse in chinese mass media results from fear and confidence. in the early days of the covid-19 outbreak, china was blamed for its botched response in the initial stages of combating this new type of coronavirus because reports indicate that covid-19 spread from a seafood market in wuhan, in central china [57] . either calling for an inquiry into the origin of the virus or finding a scapegoat for their failure to contain the spread of the contagion or both, western countries blame china for its bad governance, insufficient transparency, and unwillingness to share information and are demanding reparations [18] . these can threaten china's standing in world affairs and jeopardize the legitimacy of the ccp at home as the influx of foreign news reports about the covid-19 outbreak deteriorates domestic public opinion and reduces public support for the governmental directives. consequently, chinese foreign affairs departments have taken an increasingly strident tone against criticism from western countries, irrespective of their reasons. the "wolfwarrior diplomacy" seems to be a new normal for chinese diplomacy [68] . being the first country to have successfully contained the virus, self-congratulations for its achievements and downplaying the attempts of other countries to contain the virus has been added to china's nationalist discourse. however, this is done without considering whether the measures such as the fierce lockdown and impositions on freedom of movement can be deployed in other countries of different political systems [9] . from fear to confidence, chinese nationalist sentiment has been changing from refusing criticism from western countries to criticizing western countries. in the context of the covid-19 outbreak, the chinese official discourse of globalism has been increasing, also reflecting a polarizing discursive strategy. the side effects of globalization, such as the global pandemic, call for cooperation among actors in a world without a central authority. in a newly published paper, zhang [63] states that covid-19 can spread to any person in any country and that china provided extra time for all other countries by building a crucial line of defense. therefore, beyond providing a model for containing the spread of covid-19, china has leveraged its role as the global manufacturing hub by exporting personal protective equipment and ancillary medical equipment as a public good. it has also been a responsible power relative to the us-led western world by providing necessary funding to developing countries and multilateral institutions such as who, and offering medical aid to countries in need [55] . this has allowed china to boost its image as a global leader in this crisis. however, globalist discourse is reflected by highlighting china's willingness to cooperate and contribute to global public goods. it is upholding the discourse of a "community of shared community for mankind", in comparison with western countries' insufficient efforts to deliver effective measures domestically and to commit to multilateral institutions internationally. chinese official media outlets widely cover the stories about a growing number of the confirmed cases in america as a "new epicenter", the coldblooded "herd immunity" and the widespread "political virus" jeopardizing international cooperation in fighting against the covid-19. to be more specific, the globalist discourse has been constructed in a nationalist manner by praising china and downplaying western countries. when looking at the news reports regarding the covid-19 outbreak, globalism and nationalism as the two extremes of china's national identity co-exist. on the one hand, the globalist discourse is favored in official discourses as demonstrated below, but it has been constructed in a nationalist manner. it highlights china's support for international cooperation but might generate more suspicion of western countries if chinese official media outlets keep downplaying the anti-pandemic efforts made by western countries. on the other hand, nationalism and globalism complement each other to sustain the legitimacy of the ruling party at home. the nationalist discourse selfcongratulates china on containing the virus and globalist discourse marked by projecting china as a model of global governance of the worldwide pandemic. both discourses criticize the western countries' demonization of china by highlighting its performance relative to the failure of western countries, demonstrating how mass media acts as the mouthpiece of authority in guiding public opinions [61] . in this case, nationalism and globalism in the media and the official discourses have been constructed based on the same logic of the "us" and "them" dichotomization and harmonized in sustaining the legitimacy of the ccp at home. therefore, the following empirical section will illustrate how the seemingly paradoxical discourses between globalism and nationalism that have been studied before have been complementing each other in mass media reports about the covid-19 outbreak in china. to examine the media representation of the covid-19 outbreak in china, we draw on an integrative combination of methodological approaches associated with cda and cl. cda can be broadly defined as an academic movement or a method of conducting discourse analysis from a critical perspective [5] . cda has been widely adopted to explore concepts such as power, ideology, and domination [2, 5] and is particularly suited for understanding the role of language in the construction of power relations, exclusion, values, and identities in news texts [53] . we are aware of the many cda approaches with their different research focuses and adopt the discourse-historical approach (dha)-a major variant of cda primarily concerned with identifying the themes of a given discourse, adopting detailed analysis of linguistic and discursive strategies, and examining how these discursive practices contribute to shaping particular social relationships and identity constructions [59] . in the context of this research, dha entails a two-dimensional process. the first step of dha aims to identify the key content, themes, or topics of a given corpus. as explained later, combined with keyword analysis, the first phase of dha provides an overview of a news story and an understanding of the dominant discursive topics in the corpora. dha also helps reveal the extent to which nationalism and globalism are prominent frames in the press coverage of the covid-19 outbreak. the second step investigates discursive strategies and linguistic means deployed in the news texts. the empirical analysis in this step examines how three discursive strategies (i.e., nomination, predication, argumentation) are used in the corpora to construct a globalist and/or nationalist stance in china's media representation of the covid-19 outbreak (table 1) . furthermore, we use another methodological approach-cl-to complement dha. cl is an approach for conducting quantitative research on a large volume of text [4] , allowing researchers to explore collocational and other recurrent patterns associated with specific lexical items [2] . therefore, cl can be used to examine sematic patterns, discursive functions, and collocational environments by analyzing keywords, frequency of lexis, collocations, and concordance lines in a large amount of language data [5] . cl has been adopted to effectively study discourse across various social domains, including the media and politics [5, 22, 48] . notably, proponents of cda in general and dha in particular have been eager to draw on multi-method research designs to address the frequently raised criticism of cda. for instance, traditional cda often used qualitative research to examine small samples, undermining the cda's validity and generalizability [35] . adopting cl methods enables researchers to use a larger volume of samples and thus increase the level of rigor in data analysis [5] . in this paper, cl is deployed in parallel with dha and is a complementary tool throughout the two-step process of dha analysis. to be specific, we adopt cl to analyze three aspects of the corpora: keyness, collocation, and concordance [3] . keyness is analyzed on the basis of the high frequency of particular words (also termed keywords). as aforementioned, keyword analysis can be used in conjunction with dha to identify terms that are significantly more frequent in texts and can contribute to establishing the key discursive themes. collocation refers to the co-occurrence of two words when the frequency of the co-occurrence is above the chance that is statistically determined. collocation analysis provides information on the most salient characteristics associated with a word (or a selected group of words). furthermore, concordance analysis shows a list of a given word or word cluster with its co-text on either side [3] . this research entails two corpora of news texts comprising 1,058,665 tokens. 1 the english language corpus is retrieved from prequest and contains at least one of the following search terms ("new coronavirus," "covid-19") published in china daily and beijing review. the chinese language corpus is downloaded from cnki and includes at least one of the following search words ("新冠肺炎", "新冠疫情") published in people's daily, guangming daily, and xinhua daily news. the english and chinese corpora were published between january 1 and may 15, 2020. two important reasons are behind the selection of these five newspapers. first, these newspapers are leading national newspapers that play a significant role in shaping the news agendas and influence the contour of public opinion. therefore, media coverage on these newspapers has a high representativeness of chinese official discourse. second, these newspapers contain the largest volume of news texts concerning the covid-19 outbreak at the national and global levels based on the keyword search at prequest and cnki (table 2) . above all, in line with the first step of dha, we draw on multiple cl tools to establish the key content, themes, and discursive topics in the chinese and english corpora. specifically, the text analysis tool kh coder [34] is used to identify the topfrequency keywords and create the co-occurrence networks of words in the english and chinese corpora. before processing the data, we identify a list of stop words (e.g. common words occurring in all kinds of sentences such as substantive verbs) in both chinese and english corpora and remove them from kh coder analysis. additionally, a chinese language text analysis tool, ringdata, 2 is used to create a phrase cloud in the chinese corpus. the aforementioned cl techniques enable us to identify and compare the most important themes and topics in the english and chinese corpora. they also contribute to evaluating the relative significance of globalist and nationalist stances in the construction of discursive topics. with regard to the second phase of dha, our primary goal is to evaluate how the discursive construction of nationalism and globalism is realized through the use of different discursive strategies. in particular, our analysis focuses on three discursive strategies-nomination, predication, and argumentation-and their relevant linguistic means. for the nationalist and globalist narratives in the news texts, we first select various identity labels-"china/中国," "us/美国," "europe/欧洲," and "international or global community/国际社会"-as the "node" of text analysis. given that the discursive constructions of nationalism and globalism are closely intertwined with the process of constructing the boundary between "us" and "them", we expected that analysing the lexical patterns associated with these identity labels can provide an insight into how chinese mass media sees the relationships between china and the international community, as well as the relationships between china and the west. we then use kh coder to scrutinize the top-frequency collocates and concordance lines associated with these identity labels to examine whether nomination, predication, and argumentation strategies are in place and how these discursive strategies are used to construct china's nationalist and/or globalist stances. in the first step of dha, two observations are made. first, by adopting the function of co-occurrence networks of words-to the chinese and english corpora, we find a high degree of similarity between the chinese and english texts in the key themes and discursive topics (figs. 1 and 2) . in other words, when reporting the covid-19 outbreak, the chinese and english newspapers have focused on similar issues and thus constructed common themes such as "pandemic control," "patients treatment in hubei province," "medical supplies," "president xi and central government," and "international cooperation/global community." second, the first step of dha tends to reveal that the frames of globalism appear to be more prominent than nationalism. as mentioned earlier, the primary objective of the first step of dha is to identify the key content and topics of a given corpus, which provides an overview of the dominant discursive themes in the news texts. according to charts 1 and 2, an examination of high-frequency words shows a tangible globalist stance. specifically, "world/世界," "global/全球," and "international/国际" are among the top 20 frequency words in both chinese and english corpora. this observation implies that china's news coverage attaches great importance to the covid-19 outbreak at the global level. additionally, we adopt kh coder to create the cooccurrence network of words in each corpus which enables us to draw a network diagram which demonstrates the words with similar appearance patterns (i.e., with high degree of co-occurrence, connected by lines, as shown in figs. 1 and 2) . as can be seen from figs. 1 and 2 , the co-occurrence networks of words created by kh coder illustrate that "international, global, cooperation, community, [and the] world health organization" are close to each other and connected with lines. as a result, these words constitute a key linguistic cluster or a main discursive theme in the english and chinese corpora. in other words, international cooperation based on multilateralism stands out as a key discursive theme in both the english and chinese news texts, reflecting a strong globalist stance. moreover, by adopting the tool ringdata, we create two phrase clouds for the chinese news corpus, illustrating the top 30 two-word phrases and three-word phrases (figs. 3 and 4) . a similar pattern can be observed: the phrases "international society (国际社会)", "human destiny (人类命运)", "who (世卫组织/世界卫生组织)", "a community with a shared future for humanity(人类命运共同体)," and "values of the community with a shared future for humanity (人类命运共同体理念)" have the highest frequency of key phrases in the chinese language news corpus, which suggests that chinese corpus highlights the significance of international cooperation, the role of who, and the idea of a community with a shared future for humanity. these terms indicate that chinese news coverage has a salient globalist vision. although the aforementioned observations reveal a strong globalist sentiment, there is a lack of explicit evidence concerning the construction of a binary "self-versus-other" relationship at this initial stage of dha. whilst the first stage of dha did not explicitly reveal a construction of a binary "self-versus-other" relationship, in the second step of dha, which examines the deeper linguistic structures and discursive strategies, a more complex picture emerges. we have examined the discursive strategies and linguistic patterns associated with a selected group of identity labels (table 3) in both corpora to disentangle the processes through which nationalism or/and globalism have been discursively constructed. during the second stage of dha, we observe that the discursive constructions of globalism and nationalism went hand in hand with each other in both corpora. next, we show that the ultimate objective of the globalist accounts is to reinforce the legitimacy of the ruling party and strengthen the logic of the "us" and "them" dichotomization between china and the west. a combination of nomination, predication, and argumentation discursive strategies are used to establish china as a model in combating the covid-19 pandemic and construct china as a benign, cooperative, and responsible member of the international community. nomination the examination of the noun collocates associated with the label "china/ 中国" reveals a prominent globalist stance. the nomination of china as a successful model in fighting the global pandemic is observed in the chinese and english corpora. specifically, china is frequently referred to as "a great and responsible power /负责任 fig. 1 co-occurrence network of words in the english corpus 大国" and a source of "智慧(wisdom)", demonstrating the fitness for a global leadership role. the news texts also emphasize that many "lessons" and "experiences/经验" can be learned by how china is managing covid-19. furthermore, the label "international society/国际社会" is frequently collocated with "a community with a shared future for humanity/人类命运共同体"-a concept introduced at the 18th national congress of the ccp in 2012 and subsequently codified as an integral component of president xi's thought on socialism with chinese characteristics for the new era. in both corpora, china is constructed as a firm proponent of "international cooperation/国际合作" and "multilateralism /多边主义," fighting with covid-19 with the spirit of "building a community with a shared future for humanity /建立人类命运共同体的精神力量." predication for the predication strategy, scrutiny of adjective collocates attached to the label "china/中国" shows that both corpora tend to attribute positive traits and characteristics to china to portray china as a cooperative, benign state willing to support the global community. overall, china is described as an "important /重要," "effective/有 效," "responsible/负责任," and "strong/强大" actor in containing the pandemic. the news texts highlight that china has managed the crisis in a "timely/及时," "open and transparent /公开透" manner. moreover, because china's achievement in covid-19 prevention is outstanding (出色/了不起), the chinese and english corpora stress that beijing is ready and is willing to cooperate with all parties in the international community to overcome the covid-19 outbreak. argumentation in addition to nomination and predication, the argumentation strategy has been used to construct and reinforce china's globalist stance in the newspapers. by analyzing the concordance lines associated with the labels "china" and "international/ global community" in a qualitative manner, we find that the english and chinese news (table 4 ). in particular, the topos of reality, usefulness, and opportunity were used to strengthen globalist arguments. for instance, the topoi of reality stressed that china's active cooperation with multilateral institutions and the wider international community in fighting covid-19 is acknowledged as a "fact" that is "obvious to all." additionally, the topoi of usefulness were adopted to support the claim that international cooperation and multilateralism is useful for overcoming the global pandemic. for example, the news texts considered "multilateral efforts" and the establishment of "a community with a shared future for mankind" as a precondition for achieving "common health and well-being and a better development prospect." furthermore, the topoi of opportunity were used to support the argument that china can offer extra time in the global fight against covid-19. specifically, the news texts emphasized that china's economy would become improve after the pandemic, resulting in "development opportunities" for the global community. additionally, the media reports assumed that china's experiences in controlling the covid-19 would enable other countries to "seize the opportunity to control the epidemic. " 6800 2878 2496 2284 1935 1852 1722 1632 1627 1625 1593 1444 1388 1345 1335 1321 1293 1273 despite the salient attitude of globalism, china's media representation of the covid-19 outbreak is characterized by a deliberate construction of a positive selfrepresentation and a negative other-representation based on a binary or antagonistic opposites of us versus them. similar to the construction of globalism, a combination of nomination, predication, and argumentation strategies is adopted to realize the discursive construction of nationalism in the news corpora. the following paragraphs show how discursive strategies are used to establish the polarizing "self-versus-other" relationship between china and other countries. in particular, the examination of the corpora's data reveals two distinct, interrelated processes of discursive construction through which china attempts to create an antagonistic relationship between a positive self and a negative other: first, the news texts accentuate china's self-congratulations on its success in containing the pandemic while heavily criticizing western countries' ineffective responses and the west's demonization of china; second, the news corpora portray china as an altruistic international actor in the global fight against the virus while describing the west-especially the united states-as irresponsible actors that undermine the solidarity of the international community. nomination nomination strategy is a technique to describe china's response to the covid-19 outbreak in a positive, appreciative manner. nomination is used to establish a negative "other" by labeling western countries deprecatorily. scrutiny of the noun collocates and the corresponding concordance lines of "china/中国," "us/美国," and "europe/欧洲" reveals evidence of the discursive construction of polarized images of china and the west. for example, when reporting china's measures of pandemic prevention and control, noun collocates such as "achievements /成就," "success /成功," "victory /胜利," "contribution /贡献," and "sacrifice/牺牲" are frequently used to praise china's efforts and sacrifices regarding covid-19, whereas collocates such as "failure /失败," "失控(loss of control)," and "new epicenters of the outbreak /新震中" are used to depicts the us and european responses. predication for the predication strategy, the examination of adjective collocations and relevant concordance lines of the same identity labels reveals similar polarized portraits of china and the west. whereas china was praised for its "effective/有效," "strong/强 大," and "timely/及时" measures of pandemic control and its "enormous(巨大)" sacrifice in the fight against covid-19, the united states and europe are referred as the worst-hit, worst-affected, or hardest-hit regions, where the number of cases has sharply "剧烈(sharp)" increased. additionally, the united states and europe are criticized for their slow responses and "ineffective/不力", "erratic" management of the crisis. the at present, china's economy is gradually returning to the right track, and it is believed that china's economic development after the epidemic will be healthier. china's goal of building a well-off society in an all-round way will not only bring development opportunities to the economies of all countries, but also make a major contribution to the innovation of global governance models (people's daily, 13 march 2020). china as a "generous/慷慨" donor making every effort to assist all parties in the world while portraying other countries (especially those in the west, including the united states) as pursuing "selfish/自私" crisis management measures based on geopolitical and strategic calculations. table 5 offers a summary of the top-frequency adjective collocates associated with china, the united states, and europe in both corpora. argumentation for the argumentation strategy, topos were used to establish an antagonistic relationship between china and the west. in table 6 , the news corpora relied on the topos of threat, uselessness, irresponsibility, and illegality to realize the discursive construction of a negative other. specifically, the press coverage used the topoi of threat to portray the us actions as a threat to "the overall public health and safety situation." additionally, the topoi of uselessness and that of irresponsibility stressed that western countries' responses to the pandemic were generally ineffective; therefore, their ineffectiveness should be blamed. for instance, the media coverage stated that "the us government reacted too slowly to contain the covid-19" and that "the incompetence of the governments of the us and some european countries is to blame for the high numbers of positive cases and deaths." last, the topoi of illegality were used to consolidate the media's argument that western countries-especially the united states-tended to demonize china unlawfully. although the aforementioned analysis confirms our assumption that in china's media representation of covid-19 outbreak, globalism neither contradicts national sovereignty nor is a blanket rejection of national units and commitments. instead, nationalism and globalism co-exist in both news corpora. next, we examine the relationships between china's nationalist and globalist stances in the context of this research. based on a closer examination of the concordance lines and paragraphs associated with the key identity labels, we observed that on many occasions, the globalist and nationalist arguments were closely intertwined and complement each other to reinforce the legitimacy of the ccp at home. excerpt 1 represents a telling example of how globalism and nationalism are closely linked and serve a similar purpose of portraying china as a powerful, responsible state in the international community. in excerpt 1, the globalist stance is obvious because the news texts emphasized china's capability and willingness to provide assistance to the global community. nevertheless, the paragraph also reveals a strong nationalist stance by discursively constructing the logic of positive "self" and negative "other." excerpt 1: at present, i am quite disappointed with the performance of the united states in this epidemic. since world war ii, the united states has been recognized globally, not only because of its strong economic and military strength, but also because it provided a lot of public goods in previous crises, but this time it did not, because the united states is still under the influence of the "american priority theory" and unilateralism. china can do more in this regard, demonstrating the style of great powers. recently, china donated 1,000 ventilators to new york state, usa. the american people are grateful that china has the ability to provide assistance within its ability to more countries in crisis. the united states has problems in this regard. (16 april 2020, guangming daily, translated by the authors) we observe a similar pattern in excerpt 2, in which globalism and nationalism are detected. on the one hand, globalism was evidenced in the paragraph, which accentuated china's active role in providing material support to the us in its fight against the virus. on the other hand, we observe nationalism in the news coverage's portrayal of the united states as a negative "other". the ultimate objective of the globalist and nationalist discursive practices is to strengthen the ccp's domestic legitimacy and promote china's international reputation on the global stage. excerpt 2: despite the us administration's continuous and organized attacks on it, china has never ceased providing assistance to the country. as of last week, china had provided the us with about 2.5 billion face masks, and 5,000 ventilators, making it the largest material supporter of the us in its fight against the virus. to save lives must be its priority. with one-third of the world's infections and one-fourth of the world's deaths caused by the virus being recorded on us soil, those advisers, who feel no qualms about earning money from trying to keep the us administration in its comfort zone, should be ashamed that they are in effect taking blood money (china daily, 27 april 2020). by employing dha and cl, this paper has examined the chinese media representation of the covid-19 outbreak and found both globalism and nationalism in china's official media discourse. a globalist stance is more evident in newspapers published in chinese and english, since the chinese official media highly support international cooperation in combating the covid-19. meanwhile, nationalism as a sentiment or consciousness of belonging to the nation is presented by in chinese media discourse as well praising china, blaming the us and lecturing the eu when reporting the covid-19 outbreak. in particular, it firstly seems that a paradox of globalism at one extreme and nationalism at the opposite extreme co-exist in official discourse. secondly, the globalist discourse has been constructed in a nationalist manner. these findings suggest china, on the one hand, supports international cooperation but, on the other hand, might generate more suspicion vis-à-vis the west by criticizing western countries who are supposed to be cooperated with. due to the media ecology in china, the official media outlets portray china as a cooperative, responsible power in combating the global pandemic relative to some irresponsible, incapable western powers such as the united states, which has been reflected in both globalist and nationalist discourses in the context of the covid-19 outbreak. while the simultaneous promotion of globalism and nationalism appears to be paradoxical at first, the discursive constructions of globalism and nationalism go hand in hand with each other [37, 43] , as both are constructed based on the same logic of the "us" and "them" dichotomization and harmonized in sustaining the legitimacy of the ccp at home and enhancing the international reputation of china under the leadership of the ccp on the world stage [53] . while the existing literature suggests that that audience design influences and determines the choice of concepts and words familiar to the target audience [45] , the chinese english-language media has never intended to address the distinctiveness of international audiences because the discursive content in the english corpus is merely a mirror of the chinese news texts. in other words, as an inward-looking country, dealing with internal problems without losing the control of the ccp and enhancing the legitimacy of the ruling party at home has been prioritized in china's official media outlets. this is particularly the case during public health crises that might lead to the loss of credibility of the government and the legitimacy of the ccp. therefore, on the one hand, a globalist discourse is evident in stressing multilateralism/global governance in comparison with the conservative and even selfish behaviors of western countries. on the other hand, nationalist stances are reflected in the discourse of selfcongratulations relative to the inefficiency and incapacity of western countries. both are targeting the domestic audience rather than international readers. however, this is not to exclude china's active participation in global governance. china's growing dissatisfaction with the current international system has been further increased by some western countries' accusations and demonization of china and its political system when combating the global pandemic. this has been attributed to china's weakness in discourse rights in international politics. by portraying china as a defender of multilateralism and global governance and a cooperative, responsible international player through official media outlets, it to some extent shows china's intention to reassure its influence proportional to its growing power. consequently, the global age: state and society beyond modernity critical discourse analysis in analysing european union foreign policy discourses of refugees and asylum seekers in the uk press using collocation analysis to reveal the construction of minority groups a useful methodological synergy? regionalism, globalism and complexity: a stimulus towards global ir? discourse and identity china's global identity politics and science: the case of china and the coronavirus national identity and the limits of constructivism in international relations theory global governance and state governance capturing china's international identity nationalism, internationalism and chinese foreign policy mainstream ir theoretical perspectives and rising china vis-à-vis the west: the logic of conquest, conversion and socialisation political discourse in the news: democratizing responsibility or aestheticizing politics? globalism as the product of nationalism: founding ideology and the erasure of the local in turkey. theory china's story about covid-19: china to praise, america to blame, europe to learn. china media watch by central european institute of asian studies access global backlash builds against china over coronavirus, the new york times national identity in new media. procedia-social and behavioral science introduction critical discourse analysis: the critical study of language a bilingual corpus-assisted discourse study of the construction of nationhood and belonging in quebec china's rise: inward-looking or expansionist? npr.org access global justice index report the mass media, cultural identity and perceptions of national character lucky cloud" over the world: the journalistic discourse of nationalism beyond china in the beijing olympics global torch relay domestic troubles, national identity discourse, and china's attitude towards the west crisis governance, chinese style: distinctive feature of china's response to the covid-19 pandemic ethnomethodology and national identity globalism, nationalism, tribalism: bringing theory back in extreme inequality and state capture: the crisis of liberal democracy in the united states how can i feel belgian if belgians don't accept me?": ethnic boundary perception and national identity among turkish belgians the chinese people step up to enforce china's nationalist propaganda. the diplomat access kh coder, open source software computer applications in critical discourse analysis national identity: inside and outside nationalism and its effects on attitudes about trade, cooperation and immigration othering in chinese official media narratives during diplomatic standoffs with the us and japan the coronavirus is killing globalization as we know it. foreign policy access intertextuality and national identity the internet as a context: exploring its impacts on national identity in 36 countries mediating the nation: news, audiences and the politics of identity the cornerstone of economic nationalism: national self-image national identity building as a mediated process media discourse on globalization in china globalism versus globalization. the globalists access discourse on national identity using automated semantic tagging in critical discourse analysis the discourse-historical approach (dha) coping with a conflicted china changing media, changing china nationalism: theory, ideology, history the news prism of nationalism versus globalism: how does the us, uk and chinese elite press cover 'china's rise remote control: how the media sustain authoritarian rule in china the covid-19 global inflection point and europe's predicament us-china trade war: is winter coming for global trade china's "mask diplomacy" to change the covid-19 narrative in europe from economic cooperation to strategic competition: understanding the us-china trade disputes through the transformed relations methods for critical discourse analysis fighting covid-19 through solidarity and cooperation, building a global community of health for all. statement by h.e. xi jinping, president of the people's republic of china at virtual event of opening of the 73rd world health assembly, ministry of foreign affairs of the people's republic of china access looking inward: how does chinese public diplomacy work at home? chinese views of global economic governance dispel clouds of pandemic through cooperation chinese nationalism and its international orientations china's rise and its discursive power strategy globalization and state transformation in china performance legitimacy" and china's political adaptation strategy wolf-warrior diplomacy": china's new normal? think china access he holds a phd degree in international political economy from king's college london, and his research lies in the field of chinese foreign policy, eu-china relations and the impact of icts on chinese politics/society. his academic papers have appeared in british journal of politics and international relations she recently passed her phd thesis at king's college london. her research interests lie in the field of eu-asia pacific relations covid-19 may be an opportunity for chinese statecraft in managing with internal and external challenges. key: cord-284946-3y16j3ts authors: addo, isaac yeboah title: double pandemic: racial discrimination amid corona virus disease 2019 date: 2020-10-20 journal: nan doi: 10.1016/j.ssaho.2020.100074 sha: doc_id: 284946 cord_uid: 3y16j3ts the emergence of the covid-19 pandemic has seen an escalation of racial discrimination against non-citizens and people of colour in many places around the world. while this covid-19-related racial discrimination against non-citizens and people of colour has drawn much attention in the media space, the issue has been less discussed in academia. given that racial discrimination has a significant impact on human relations, mental health, and general well-being, it is important to address the rising racial discrimination problem amid the covid-19 pandemic. this paper discusses some of the emerging stories of racial discrimination associated with covid-19 and presents viewpoints on why people are being abused and the socio-economic implications associated with the abuse. the paper concludes with few suggestions on how to address the covid-19 related racial discriminations as the world continues to fight against the double pandemic. for more than a half-century, racial discrimination against non-citizens and people of colour has persisted as an intractable social problem in several parts of the world [1] . while the origin of racial discrimination seems to be contestable in the critical race literature [2] , it is widely recognised that race-related discrimination can be traced as far back as the ancient period of colonialism and slavery [3] . between the 16th and 18th centuries, for instance, racial discrimination was known to be prevalent in europe's american colonies (e.g. virginia). amerindians were stereotypically regarded as inferior to europeans and africans were viewed as useful for slave labour [4, 5] . racial discrimination can be defined as "any distinction, exclusion, restriction, or preference based on race, colour, descent, or national or ethnic origin that has the purpose or effect of nullifying or impairing the recognition, enjoyment or exercise, on an equal footing, of human rights and fundamental freedoms in the political, economic, social, cultural or any other field of public life" [6] . declaration of human rights have been introduced by the un to commit its members to eliminate all forms of racial discrimination [7] [8] [9] . following that, the 2001 ground-breaking world conference against racism, racial discrimination, xenophobia, and related intolerance was held in durban, south africa to promote a global discussion on how to eliminate all forms of racial discrimination [10] . the un has also pegged march 21 st of every year as the international day for the elimination of racial discrimination to promote greater global awareness of the racial discrimination problem. additionally, an agenda spanning from 2015 to 2024 has been framed by the un to address racial discrimination against persons of african descent who are considered as one of the greatly affected racial victims in the world [1] . institutions have been formed in many countries to protect human rights, including the promotion of inter-racial acceptance [11] . the forming of such institutions has also influenced the passing of several laws that criminalise racial discrimination in some countries [11] . for instance, racial offenders in the united kingdom (uk) under the public order act 1986 face up to seven years imprisonment for "using, displaying, publishing, showing or distributing any words, images or j o u r n a l p r e -p r o o f behaviour which are threatening, abusive or insulting" and which are intended or likely to spark race-related hatred. in canada, offenders of racial discrimination also face two years imprisonment (or five years for advocating a genocide) [12] . through advocacies, civil societies and movements, such as the global black lives matter movement have also protested against racial injustice in several communities globally [13] . as the un, human rights institutions, governments, and civil society groups and movements continue to promote greater acceptance of people from different racial categories and encourage greater respect for human rights across the globe, the numerous reports of racial discrimination against non-citizens and people of colour in the fight against the corona virus disease 2019 (covid-19) demonstrate that more work is needed to achieve the un's goal of eliminating all forms of racial discrimination. in almost every continent, there have been widespread reports of racial discrimination against non-citizens and people of colour in relation to the covid-19 pandemic [14, 15] . several cases of racial discrimination against non-citizens and people of colour have received much attention on numerous media platforms. for instance, in the uk and the us, media reports have shown that covid-19 morbidities and mortalities were disproportionately high among people of colour by the end of may 2020 [16] . however, the issue has been less discussed within academia and raceaggregated data is virtually non-existent in many countries. this appears to be a major limitation to recognising the negative implications of government policies against people of colour and visible minorities. using news reports from credible media outlets as evidence, this paper discusses some of the unfolding racial discrimination stories associated with the covid-19 pandemic and examines the implications of this disease-related racial discrimination for the future. the covid-19 pandemic has been associated with a series of racial discrimination, especially, against people of east asian and southeast asian appearance [17] . the surfacing of racial discrimination amid the covid-19 pandemic warrants serious attention bearing in mind that the reported cases in the various media outlets and this paper are likely just a fraction of actual encounters. it is also important to be reminded that racial discrimination can be subtle resulting in underreporting of cases [18] . reports of racial discrimination against people of asian (especially chinese) appearance have, however, been noted in several news channels as it was being conveyed that covid-19 originated from wuhan in china [17] . in australia, for instance, a dispute was j o u r n a l p r e -p r o o f caught on camera showing a woman verbally abusing asian telstra workers at miranda in sydney [19] . the furious woman threatened one of the men of chinese appearance that his entire family "would be deported" and shouted at the man to "go back to china". there have been similar reports of anti-asian racism in several other places, including india, the united kingdom, the united states, israel, jordan, the philippines, and some african countries [17] . in the united states, for example, the 'stop aapi hate' forum has recorded more than 1,100 instances of anti-asian abuse since late march 2020 [19] . in the north-eastern states of india, people of chinese appearance have been facing racially motivated discrimination and have been blamed for bringing covid-19 to india [20] . in an interview organised by deutsche welle (dw) news, one victim and his daughter were allegedly denied entry into their apartment on march 16 as the administrator of the building claimed they may be incubating covid-19 [20] . on 10 march 2020, an egyptian driver was also arrested in egypt after a video showed the driver compelling a chinese passenger to get out of his car at a highway in cairo on an unfounded reason that the passenger has covid-19 [21, 22] . as covid 19 has triggered anti-asian racism in various places around the world, interestingly, it is being reported that the reverse is happening in china as the country experienced new waves of covid-19 cases [17] . the chinese government after declaring control of the pandemic has increasingly emphasised the threat of imported cases. china's national health commission reported that there had been few domestically transmitted cases of covid-19 and that the new cases were largely from overseas [23] . following these announcements in china, there have been several reports of racial discrimination against noncitizens and people of colour [17] . as businesses reopened in the country, racial discrimination against non-citizens and people of colour took an economic dimension as some chinese shops and restaurants allegedly banned non-chinese people from using their services. an australian woman was reportedly attacked in china after attempting to breach this anti-foreigner abuse [24] . in guangzhou, china, there have been reports of abuse against people of african appearance [17] . chinese residents of african appearance were being evicted from their homes by landlords and prevented from entering public accommodations based on suspicion that they are incubating covid-19, despite many claiming that they have had no recent travel overseas or come into contact with any covid-19 patient [25] . in an interview between cable news network (cnn) and a number of the african immigrants in china, many shared their experiences on how they have been evacuated from their homes, been subjected to selective testing for covid-19, and been selectively quarantined for 14 days, despite having no symptoms or contact with known covid-19 patients [25] . another incident believed by many as racially motivated appeared on several international social media platforms when videos of two french doctors openly agreed on live television that the first vaccine trials for covid-19 should be tested in africa. in the video, one of the doctors said: "if i can be provocative, shouldn't we be doing this study (testing of vaccine) in africa, where there are no masks, no treatments, no resuscitation?" "a bit like as it is done elsewhere for some studies on aids. in prostitutes, we try things because we know that they are highly exposed and that they do not protect themselves." this idea came after the other doctor had earlier questioned whether the study would work as planned on healthcare workers in europe and australia because they had access to personal protective equipment to prevent them from contracting the virus [26] . the remarks from the two doctors received backlashes from social media users in the following days who condemned the comments as racist. the remarks from the two doctors also drew criticism from a highranking figure in the world health organization who described the comments as a "hangover from a colonial mentality" [27] . while emphasizing that racial discrimination should not be encouraged for any reason, it is important to recognise why it occurs to elicit a better understanding of how to address the problem. factors associated with the racial discrimination against non-citizens and people of colour during this pandemic are complex and may include post-colonial perception of racial superiority, fear of covid-19 infection, 'inflammatory' comments by significant public figures, vengeance for fellow citizens who have experienced abuse elsewhere, and perception of differences in covid-19 susceptibility due to differences in phenotypic physical features. history has shown that the human population has long been divisive with perceptions that people of different appearances have different abilities and natural dispositions [28] . this form of reasoning in the pre-civil rights era has motivated unequal treatments of people across different racial categories with evidence showing that rights and privileges have, for a long period, been distributed unequally as in the 'nazi crisis' as well as the apartheid systems that existed in south africa, australia, israel, and the united states [29] [30] [31] [32] . colonisation and slavery in the early 1800s, particularly, in africa, asia, australia, and the southern pacific are other classic examples of the past associated with racial discrimination [33] . notably, there was a massacre of tasmanians (in australia) and the maori population (in new zealand) in the late 18th and early 19th centuries [33] . by 1850, robert knox (a famous english anatomist) falsely declared that race and intelligence are linked and concluded that j o u r n a l p r e -p r o o f people of colour were intellectually inferior [33] . the studies of knox and others influenced the eugenics movement in the 20th century but it was later revealed that his conclusion was based on the autopsy of only one man of colour [33] . between the 19th and 20th centuries, more than 600 distinctive legislations against the rights and privileges of asians were passed in europe which prevented asians from obtaining citizenship and somewhat allowed for the murder of asians with impunity [33] . these ancient colonial ideas of racial superiority for particular groups of people may still be internalised by perpetrators of racial discrimination today. in correspondence with the report of devakumar, shannon [14] , fear of covid-19 may also be contributing to the racial discrimination problem. instances of regional discrimination against wuhan natives in other provinces of china, such as people being refused entry into hotels, have been noted in some media reports [17] . given this example, it is tempting to simplistically assume that perpetrators of racial discrimination against noncitizens and people of colour do so to prudently protect themselves from covid-19 infection. it is however important to bear in mind that the vast majority of victims of racial discrimination in china were people of colour rather than citizenry [17] . as covid-19 spreads across borders, some social media users, media personalities, celebrities, and political leaders have made comments that may have encouraged racial discrimination against non-citizens and people of colour. for example, a former deputy prime minister of italy attributed the early spread of covid-19 in italy to asylum seekers of african descent [14, 34] . in another instance, a president of a nation referred to the covid-19 pandemic as the 'chinese virus', linking the health threat to foreign policy and trade negotiations [35] . at one point in time, two un human rights experts had to appeal to the bulgarian government to stop hate speech and racial discrimination against the roma minority in its response to covid-19 [36] . the world health organisation (who) has also underscored that the names of new diseases should not be tagged with people or places where it was first detected [17] . some cases of racial discrimination may have been motivated by a desire for vengeance for fellow citizens or people of the same racial category who have reported racial abuse elsewhere. for instance, there have been reports of growing tensions between chinese people in nairobi and kenyan citizens due to the abuse of kenyans and some other african nationals in china [37] . another factor that may be associated with the racial discrimination against noncitizens and people of colour during this pandemic is the differences in phenotypic physical j o u r n a l p r e -p r o o f features across racial categories [28] . as humans have distinct phenotypic physical features of the face and body, such as skin colour, hair colour, and eye colour, these differences in physical appearance may have triggered some thoughts of differences in covid-19 susceptibility, transmissions, and incubation periods across different racial categories [28] . the covid-19 pandemic and its ramifications of racial discrimination continue to have a serious socio-economic impact on victims and societies. globally, millions of people have been infected with the virus, hundreds of thousands have died, countries have closed their borders, cities have been put on lockdown, businesses have stalled, jobs have been lost, schools have been closed, and social life has been disrupted [14] . the racial discrimination associated with the covid-19 pandemic has intensified existing health vulnerabilities of non-citizens and people of colour [14, 38] . highly infectious diseases, such as covid-19 often increase pressure on limited health care resources [14] . in the presence of a biased society that often favours citizens of a country, non-citizens and people of colour face a higher risk of infection and mortality from covid-19. a typical example is the case in america where communities inhabited mostly by people of colour emerged as the 'hotspots' and zones for covid-19 transmission and deaths [39] . the risk of infection and death from covid-19 may even be higher for undocumented immigrants who are likely to avoid medical attention as they face an additional risk of detention and deportation [38] . moreover, an experience of racial discrimination in this pandemic period can exacerbate mental health distress associated with the fear of contracting covid-19 [40] . victims of racial discrimination in this pandemic era are likely to express feelings of sadness, anger, depression, and constant fear [40, 41] . these negative energies which are often associated with an experience of racial discrimination can lead to lifelong hatred and intolerance towards people of different racial categories [41] . period has the potential to also disrupt global trade and economic ties. before the emergence of the covid-19 pandemic, several countries had arranged trade agreements [42] . as non-citizens and people of colour often provide essential hard labour and income to host countries. studies have shown that this category of people often earn a low income, face labour exploitations, and do not have access to citizenry benefits, such as paid leave, and access to income support [43] [44] [45] . in this pandemic era, several policies have been imposed by many governments that have put migrant communities and people of colour in devastating conditions. in australia, for instance, an extensive survey conducted in march and april 2020 has shown that 65% of overseas visa holders lost their jobs during this pandemic, 43% were skipping meals regularly, 34% have become homeless, and 39% did not have enough money for daily upkeep, and yet, were neglected and advised to go back to their countries of origin by the government [46] . these problems were accompanied by escalated racial discrimination against them, and the risk of unemployment and economic hardships may increase among this vulnerable group of people. to some extent, governments imposing discriminatory policies against non-citizens and people of colour may also lose financial benefits gained through income taxes [15] . racial discrimination has no place in society, and certainly, not in this time of covid-19 pandemic. as the epicentre of the disease outbreak continues to shift from place to place, urgent measures need to be developed to reduce the increasing cases of racial discrimination. the un, human rights institutions, governments, and citizens of countries should increase advocacies against racial discrimination. it needs to be understood that this pandemic is a global problem and that discriminating against non-citizens and people of colour will only worsen existing vulnerabilities for people. as some citizens are likely to continue propagating anti-migrant sentiments during this disease outbreak, people (particularly, other citizens) need to stand against such sentiments, especially, when they occur in their presence. a good example has been noted in egypt where an egyptian was admonished for abusing a man of chinese appearance. some egyptians visited the chinese man in his hotel and expressed an apology to him for the incident, and condemned the act as bullying and racist [21, 22] . criminalisation of racial discrimination and associated penalties should be promoted and intensified in countries by political leaders and existing powers. this can assist with j o u r n a l p r e -p r o o f reducing both overt and subtle display of racial superiority and discrimination against noncitizens and people of colour [47] . considering the possibility that racial discriminatory behaviour can be learned and unlearned [48] , promotion of racial tolerance and acceptance among children in schools can be a useful long-term approach for eliminating racial discrimination against people of colour and ethnic minorities. places of social gatherings, such as work, hospitals, sports avenues, can intensify advocacies against racial discrimination. it is important to always understand that our differences should complement rather than reprove one another. expression of love, understanding, patience, and tolerance towards one another will make the world a better place to live in. the author declare that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 1 dear editor-in-chief, a big thanks to you and the reviewers for your recommendations. i have addressed all the comments from the reviewers as shown in 'red' below: reviewer 1: thank you for submitting your revisions. i have no substantive comments to add, save for a few minor edits/corrections which may be added in the editing/proofing stage: on page 1, the international bill of rights is composed of the iccpr, the icescr and the udhr (so three instruments -not two, as currently listed). the components of the international bill of rights have been changed from two to three on page 2 as recommended by the reviewer: "the international convention on the elimination of all forms of racial discrimination and the international bill of human rights which comprises the international covenant on civil and political rights (iccpr), the international covenant on economic, social and cultural rights, and the universal declaration of human rights have been introduced by the un to commit its members to eliminate all forms of racial discrimination [7] [8] [9] ." it would also be useful to list the year of the world conference against racism in durban. the year the world conference against racism in durban occurred has now been included on page 2 as follows: "following that, the 2001 ground-breaking world conference against racism, racial discrimination, xenophobia, and related intolerance was held in durban, south africa to promote a global discussion on how to eliminate all forms of racial discrimination [10] " the black lives matter movement is also not so much civil society as it is an entire movement (so suggest changing to: "civil societies and movements such as the global black lives matter movement..." the phrase has been extended to include movements as shown on page 2: "through advocacies, civil societies and movements, such as the global black lives matter movement have also protested against racial injustice in several communities globally [13] ." on page 2, i suggest changing the word "far-fetched" -it implies that the change is intrinsically difficult to achieve, when it really shouldn't be, if principles of equality were respected globally. j o u r n a l p r e -p r o o f 2 the word 'fat-fetched' has been deleted and the sentence has been rephrased on page 3 as follows: "as the un, human rights institutions, governments, and civil society groups and movements continue to promote greater acceptance of people from different racial categories and encourage greater respect for human rights across the globe, the numerous reports of racial discrimination against non-citizens and people of colour in the fight against the corona virus disease 2019 (covid-19) demonstrate that more work is needed to achieve the un's goal of eliminating all forms of racial discrimination" on page 5, i'd recommend changing "factor(s) associated with the racial discrimination against non-citizens and people of colour during this pandemic is complex" to simply "factors associated...are complex" (more streamlined for readers). the sentence on page 5 has been streamlined for readers as suggested by the reviewer: "factors associated with the racial discrimination against non-citizens and people of colour during this pandemic are complex and may include post-colonial perception of racial superiority, fear of covid-19 infection, 'inflammatory' comments by significant public figures, vengeance for fellow citizens who have experienced abuse elsewhere, and perception of differences in covid-19 susceptibility due to differences in phenotypic physical features" also on page 5, the following sentence "it is however important to bear in mind that the vast majority of victims of racial discrimination have been people of colour rather than citizenry" could be clarified. are you referring to china in this sentence? if so, should add this to sentence. the sentence, which can now be seen on page 6, has been clarified by the inclusion of china as follows: "it is however important to bear in mind that the vast majority of victims of racial discrimination in china were people of colour rather than citizenry [17] ." on page 7, "people" can be removed in the reproduced sentence, as the next sentence clarifies the subject (i.e., victims): "moreover, racial discrimination amid the risk of covid-19 infection can lead to double mental health distress [for people]". just to clarify, does the source actually quantify the distress (i.e., is it really double) or do you mean it aggravates the mental health distress that is already there? if the latter, would clarify as such. the word people has been deleted and the sentence has been clarified on page 7 to imply that experience of racial discrimination can aggravate mental health distress associated with fear of contracting covid-19: "moreover, an experience of racial discrimination in this pandemic period can exacerbate mental health distress associated with the fear of contracting covid-19 [40] ." united nations, international decade for people of african descent race, periodicity, and the (neo-) middle ages. modern language quarterly the old world background to european colonial slavery. the william and mary quarterly the origins debate: slavery and racism in seventeenth-century virginia. the virginia magazine of history and biography international convention on the elimination of all forms of racial discrimination, defining racial discrimination the international covenant on civil and political rights international covenant on economic, social and cultural rights the international bill of human rights world conference against racism, racial discrimination, xenophobia and related intolerance global alliance of national human rights institutions, global alliance of national human rights institutions australian human rights commission, an international comparison of the racial discrimination act building bridges: social movements and civil society in times of crisis. voluntas: international journal of voluntary and nonprofit organizations racism and discrimination in covid-19 responses. the lancet disproportionate impact of the covid-19 pandemic on immigrant communities in the united states how is race affecting covid-19 outcomes? list of incidents of xenophobia and racism related to the 2019-20 coronavirus pandemic the sociology of discrimination: racial discrimination in employment, housing, credit, and consumer markets. annual review of sociology go back to china... i was born here!' disgusting moment woman who calls herself 'queen of australia' racially abuses a telstra workers -because she was asked questions to ensure coronavirus safety chinese-looking' indians targeted in racist attacks driver jailed for dumping chinese man on highway over virus fears in egypt racist': outrage after egyptian driver kicks out asian passenger over corona panic chinese mainland reports 6 new confirmed covid-19 cases, in xinhua as coronavirus sparks anti-chinese racism, xenophobia rises in china itself. abc news in abc news africans in guangzhou are on edge, after many are left homeless amid rising xenophobia as china fights a second wave of coronavirus two doctors spark criticism for discussing in a tv show the idea of testing a vaccine for the coronavirus in africa, in aljazeera french doctor apologizes after suggesting africa for coronavirus tests in the hill news discrimination and the 'fear of difference', in community cohesion: a new framework for race and diversity the rise and fall of apartheid -the rise and fall of apartheid american apartheid: segregation and the making of the underclass speaking unspoken memories: remembering apartheid racism in australia south africa and the 'one-state solution': the case for an apartheid analysis. politikon the construction of race and racism, in dismantling racism project salvini attacks italy pm over coronavirus and links to rescue ship trump's new fixation on using a racist name for the coronavirus is dangerous united nations human rights office of the high commissioner, bulgaria/covid-19 response coronavirus brings 'sinophobia' to africa in voice of america the coronavirus pandemic could be devastating for the world's migrants covid-19 is hitting black and poor communities the hardest, underscoring fault lines in access and care for those on margins ethnic-racial socialization, and crime: a micro-sociological model of risk and resilience feeling the pain of my people: hurricane katrina, racial inequality, and the psyche of black america economic development in africa report 2019: made in africa: rules of origin for enhanced intra-african trade wage theft as a neglected public health problem: an overview and case study from san francisco's chinatown district. american journal of public health gender and the social rights of citizenship: the comparative analysis of gender relations and welfare states migration, immigration controls and the fashioning of precarious workers i will never come to australia again': new research reveals the suffering of temporary migrants during the covid-19 crisis', in the conversation bias in the law: a definitive look at racial prejudice in the u.s. criminal justice system the following sentence "these negative energies which are often associated with an experience of racial discrimination can lead to lifelong hatred and intolerance towards people of different racial categories" may need a reference (if not already covered in prior citation). a citation has been provided as advised by the reviewer: "these negative energies which are often associated with an experience of racial discrimination can lead to lifelong hatred and intolerance towards people of different racial categories [41] in the conclusion, i would remove first part of first sentence ("although desperate times call for desperate measures") --this seems to indicate that racial discrimination may be justified on some level. i believe most would agree that it cannot be justified. would just start at "racial and discrimination...has no place in society, and most certainly not in this time of covid-19 pandemic"thank you for this excellent observation. the sentence on page 8 now reads: "racial discrimination has no place in society, and certainly not in this time of covid-19 pandemic"in the final sentence, i would suggest removing this part, as it implies that being of a certain skin colour is inherently undesirable "no one is responsible for his/her racial category". it would suffice to say that our differences should complement rather than reprove one another (as already written).as advised by the reviewer, the phrase has been deleted and the sentence now starts as follows: "it is important to always understand that our differences should complement rather than reprove one another." j o u r n a l p r e -p r o o f 4 reviewer 3 reviewer 3: this is a useful and ambitious commentary that captures some of the diverse manifestations of racial discrimination in the response to the pandemic, and provides insight into some of the causes behind it. the paper's attention to forms of discrimination outside the united states and europe should be commended, as should its willingness to examine different possible drivers of this discrimination. thank you! to improve, the paper could provide more precision and detail on the historical context behind the ideas of racial superiority and racial threat it identifies in the present pandemic. this does not need to be a large addition, but a case of adding a couple of sentences describing context and suggesting specific historical examples. in my comments below i have highlighted where these additions could be made.p.2 the first line says that racial discrimination has existed for more than half a century, but the early paragraphs only address history post-1945 -it would be good to emphasise that race is entangled with long histories of slavery, colonialism etc, before focussing in on un definition of racial discrimination. this is especially important given the mention of a 'hangover from a colonial mentality' on p.4 and the 'pre-civil rights era' on p.5a brief historical context of racial discrimination before 1945 has been included on page 2 as follows:"for more than a half century, racial discrimination against non-citizens and people of colour has persisted as an intractable social problem in several parts of the world [1] . while the origin of racial discrimination seems to be contestable in the critical race literature [2] , it is widely recognised that race-related discrimination can be traced as far back as the ancient period of colonialism and slavery [3] . between the 16th and 18th centuries, for instance, racial discrimination was known to be prevalent in europe's american colonies (e.g. virginia). amerindians were stereotypically regarded as inferior to europeans and africans were viewed as useful for slave labour [4, 5] ." p.2 maybe replace 'several reports' with 'widespread reports' to better capture scale of racial discrimination in relation to covid-19 the phrase 'several reports' has been replaced with 'widespread reports' as follows: "in almost every continent, there have been widespread reports of racial discrimination against non-citizens and people of colour in relation to the covid-19 pandemic [14, 15] " j o u r n a l p r e -p r o o f 5 p.3 there is some confusion in the description of the incidents between the terms anti-chinese and anti-asian -i'd suggest anti-asian is more appropriate as a catch-all term given that this racism is not solely intended for chinese nationals, nor solely directed at them, and given the uncertainty of what constitutes 'chinese appearance.' on page 4, anti-chinese has been replaced with anti-asian as follows: "as covid 19 has triggered anti-asian racism in various places around the world, interestingly, it is being reported that the reverse is happening in china as the country experienced new waves of covid-19 cases [17] " however, the term 'chinese appearance' has been reserved in certain contexts where the racial discrimination occurred in an asian country to avoid confusing readers, as shown in the following example: "in the north-eastern states of india, people of chinese appearance have been facing racially motivated discrimination and have been blamed for bringing covid-19 to india [20] " p.5 in the second paragraph, it would be good to maybe take two examples of historical events and explain how they are related to the development of race (e.g slavery in the united states and french colonialism in africa), this would help explain where ideas of racial superiority come from three historical events have been added on pages 5 and 6 as suggested by the reviewer: "notably, there was a massacre of tasmanians (in australia) and the maori population (in new zealand) in the late 18th and early 19th centuries [33] . by 1850, robert knox (a famous english anatomist) falsely declared that race and intelligence are linked and concluded that people of colour were intellectually inferior [33] . the studies of knox and others influenced the eugenics movement in the 20th century but it was later revealed that his conclusion was based on the autopsy of only one man of colour [33] . between the 19th and 20th centuries, more than 600 distinctive legislations against the rights and privileges of asians were passed in europe which prevented asians from obtaining citizenship and somewhat allowed for the murder of asians with impunity [33] ." p.7 replace 'frowned upon' with something stronger -e.g condemned, rejected. the phrase 'frowned upon' has been deleted and the sentence which can now be found on page 8 has been rephrased as follows:"racial discrimination has no place in society, and most certainly not in this time of covid-19 pandemic" x the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.â��the authors declare the following financial interests/personal relationships which may be considered as potential competing interests:declarations of interest: none j o u r n a l p r e -p r o o f key: cord-310856-9dc9bqv8 authors: bardhan, pranab title: the chinese governance system: its strengths and weaknesses in a comparative development perspective date: 2020-06-30 journal: china economic review doi: 10.1016/j.chieco.2020.101430 sha: doc_id: 310856 cord_uid: 9dc9bqv8 abstract this is an overview paper focusing on the organizational aspects of the chinese governance system and their relation to development. compared to other developing countries like india, it has special positive features of career incentives promoting growth at the local level, the ability to take long-term decisions relatively quickly, and a unique blend of political centralization and decentralization of economic power and responsibility, that is conducive to central guidance and local business development. on the other hand, with a lack of sufficient downward (as opposed to upward) accountability and absence of institutionalized systems of scrutiny and challenge from below, mistakes or abuse of power are more difficult to check and correct quickly, political loyalty may often get a premium over performance at the upper levels, and there are insufficient checks on collusion between business and officials. the over-all organizational system is prone to over-reaction in times of crisis and thus only weakly resilient compared to systems where information flows from below are less controlled or choked. the governance system is an essential part of the so-called china development model, and yet somewhat less frequently discussed than the other aspects of this model, and when it is discussed in the general literature on comparative governance, the emphasis outside china has been more on the simplistic authoritarianism-democracy distinction. as briefly discussed in bardhan (2013) , authoritarianism is neither necessary nor sufficient for some of the distinctive features of chinese governance, both positive and negative -and their roots actually go long back in history-just as some of the recently observed dysfunctionality of governance in usa or india is not inherent in their democratic process. in this overview paper i shall focus particularly on the following three aspects of chinese governance, from the point of view of economic development, and occasionally draw comparison with governance features in india, the second largest developing country: i. internal organization of government ii. abuse of governance and corruption. iii. decentralized structures and practices. it is often pointed out that unlike in most authoritarian countries china has a political meritocracy. china's dramatic economic success has now convinced even some western scholars-see for example the book by bell (2016)not to speak of the members of the chinese elite, that in terms of performance chinese political meritocracy can achieve as well as (or even better than) a multi-party democracy: an issue of special urgency at a time when there is widespread shakiness of confidence in liberal democracy. not merely are officials in china selected on the basis of an examination system that goes way back in imperial history, their career promotion depends on how well the local economy performs. this works better than in, for example, democratic india's top administrative system, where promotion is based more on seniority than on performance, even though recruitment is on the basis of civil service examinations. an immediate question that arises is: in the political system who defines what is 'meritorious' and what is not? it is possible that what may look like meritorious performance to the chinese party elite and its central organization department, zhongzubu, may not be considered so by many others in the general population, particularly in a large country with inevitable diversities and conflicts of objectives; not to speak of the outlying regions where performance by centrally appointed provincial leaders considered meritorious by the party may not be judged so by many in the ethnic groups like tibetans or uighurs. in general, how do we know what people consider as meritorious without institutions of downward accountability? one of the distinctive features of democracy is that the criteria of meritorious performance arise out of open public discussion. thus how much of a political leadership's performance is meritorious may include considerations of pluralism and inclusiveness in the decision process itself. democratic performance emphasizes the process as much as outcome. in this process citizens in a democracy are not treated as children: what is good for them is not decided by a patrimonial leadership, as is the case much too often in china (or singapore). this is valid even when the latter leadership is very wise and benevolent. also, in a democracy the performance criteria are much more multi-faceted reflecting the pluralist agenda-it is uncommon to reward an official mainly on the basis of the growth rate of the local economy-and thus the incentives get diluted and are less effective. the same thing is happening in china now when other criteria (like environmental goals) enter performance evaluation. the general understanding is that career concerns of top officials act as a key determinant of economic growth at the local level, particularly the county and prefecture levels. and job rotation of officials at that level provides useful on-the-job training at diverse localities. 1 of course such performance incentives sometimes also generate plenty of side income or rent-earning opportunities (for example, from sales of local government land and mining rights), which while helping local revenue also used to enable private illicit income for officials. what about the large numbers of the rank and file of public employees, who mostly remain in one place and for whom career incentives through promotion are not that relevant? they used to help themselves to all kinds of supplemental compensations, perks and benefits making up for low salaries. in other authoritarian countries such systems of supplemental compensation sometimes degenerate into local loot and plunder-the proverbial extreme case is that of zaire under mobutu, where soldiers and bureaucrats were not paid but left to fend for themselves (this tradition largely continues in the democratic republic of congo even today). it is likely that in china this system for the low-level officials was constrained from being excessive by the career concerns of the top local leaders. but a less well-known factor about chinese promotion system is that as one climbs up the political ladder, to the provincial levels and beyond, performance factor seems to diminish in importance in career prospects, and the factor of political connections assumes significance-this is suggested, for example, by landry, lu, and duan (2017) from an analysis of a comprehensive dataset of political appointments at the provincial, prefectural and county levels. they find that the link between economic performance-in terms of gdp and revenue growth-and promotion is the strongest for county officials, significant for municipal officials, and insignificant for provincial officials. similarly, from a comprehensive biographical database of all provincial leaders from 1978 until 2012 and an analysis of their promotion patterns, su, he, and tao (2016) find no evidence supporting the claim that competence has played much of a role in the central personnel decisions. instead links with the politburo members or family connection with senior party leaders are more important. there are also quid pro quo transactions. using data for over a million land transactions during 2004-16 chen and kung (2019) have shown o that provincial party secretaries in selling local government land gave firms linked with politburo members nearly 60% price discounts compared to others (an even more substantial discount to the firms of members of the top standing committee of the politburo) o in return such discount-givers were estimated to be 23% more likely to be promoted to positions of national leadership (in general the larger the discount the higher was the chance of promotion). the recent crackdowns have somewhat reduced the chances for such promotions. in any case such a general system of promotion has at least one important implication compared to other countries: since performance incentives operate at least at the lower levels, higher-level leaders, even when they are selected on the basis of their loyalty to the current leadership at the top, are likely to have some measure of field-tested competence and experience. 2 this balance of performance and loyalty over an official's career path leads to a major advantage that china enjoys in the quality of its bureaucracy, compared to many other countries (including, say us or india), not to speak of many authoritarian countries where loyalty rules over minimum competence. of course, this also means that competent officials who are not sufficiently well-connected to the top current leadership in china may reach a 'glass ceiling'. some of them may then turn to alternative ways of earning rewards (including some corrupt ways). these corrupt ways have now been substantially curbed in the recent anti-corruption campaigns. there is even some evidence that highperformers connected to previous top leaderships were particularly likely to be investigated, although the campaigns have gone much beyond merely penalizing rival power groups. in india meritocratically recruited bureaucrats are manipulatively transferred. the threat of transfer to unattractive departments or locations acts to ensure loyalty to their political masters. the lure of post-retirement plum jobs for ex-bureaucrats assigned by political leaders also work to keep the former pliant. this often means that junior officers under-invest in acquiring expertise, and one hears about corrupt deals between indian politicians and bureaucrats in the process of 'transfers and postings'. there are also stories about vertical corrupt transactions in buying and selling of positions in the chinese bureaucracy, some of which have been revealed in the recent anti-corruption campaigns-from the data one finds vertical correlation between corruption indictments at higher and lower levels across provinces. in india such corruption may be somewhat more subject to public scrutiny by media, social movements, and investigative agencies, which are usually more open and intense than in china. in uk such manipulative transfers are less common. the system in usa, on the other hand, is characterized by high turnover of senior civil servants (long before firing by twitter under the current president). the political-bureaucratic distinction particularly at higher levels is, of course, blurred in china, as the party is supreme. but even in western democracies the political control over senior appointments and promotions in public service has increased over time. even in the uk, the insulation of career civil service has declined somewhat, and this insulation has always been much weaker in usa than in uk (or denmark or new zealand). the issue of political control pertains not just to the civil service, but also to the various regulatory bodies that any complex economy requires-like the entities that regulate public utilities (e.g. electricity, civil aviation, telecommunication, etc.) and apex bodies regulating monetary or environmental policy or financial markets. decisions in such regulatory bodies need special expertise and some insulation from the day-to-day political pressures and some independence from political interference. such independence is often completely lacking in the chinese system-commitment to independence even when earnestly announced by the political leadership is not ultimately credible. but even in democracies the balance between autonomous experts and the need for periodic public review of their decisions to ensure accountability has been difficult to achieve. in india there are very few genuinely independent regulatory bodies (even apart from the problem of their capture by generalist indian administrative service officers). even the semi-independence of the reserve bank of india has been under some stress. in both china and india the police and bureaucracy are often deliberately incapacitated and made to serve short-term political goals of leaders. in terms of the governance capacity to foster technological innovations, china has advanced much more than most developing countries, particularly in terms of r&d as percentage of gdp (though public r&d support often neglects small and medium enterprises), restructuring and upgrading of elite universities, and measures of progress in science and technology. china, of course, has been very successful in the 'catching-up' process of development, of learning and imitating off-the-shelf technology. in some day-to-day application and enhancement of existing technology (mobile payment, e-commerce, transport, etc.) china is now more advanced than the us. the major technological race between china and the west is currently in areas like artificial intelligence, chip-making, and bio-technology. but in any future advances beyond the existing technological frontier china has a major advantage and a major disadvantage. the advantage follows from the large size of the population and of the domestic market. innovations (like those involving artificial intelligence and machine learning) that thrive on economies of scale, network externalities and big data feedback loops will find hospitable ground in china. the disadvantage for china follows from the lack of an open system that could encourage free spirit, critical thinking, challenging of incumbent organizations and methods, and diversity rather than conformity-these are necessary ingredients of many types of creative innovations. the current system of state promotion and guidance of globally successful large private technological 2 on the basis of city-level panel data jiang (2018) even shows that city leaders with informal ties to incumbent provincial leaders display better performance in terms of growth. also, political loyalty plays an important role in bureaucratic promotion in democracies as well. but in the latter in view of possible electoral consequences, politicians at all levels are a bit more sensitive to the well-being of diverse interest groups. enterprises (alibaba, tencent, etc.) is worth examining from this point of view. on the one hand, the state wants them to be 'national champions', on the other hand, it does not want them to be autonomously powerful enough to be outside the ambit of its control, supervision, and surveillance. will the chinese state allow the full forces of 'creative destruction' that schumpeterians associate with innovations? (in 2017 the total no. of annual insolvency cases was smaller in china than even romania, not to speak of the advanced industrial countries). will an autonomously successful firm be considered too 'independent' for the comfort of the party? are today's successful incumbent firms (private or public) 'too big to fail', or in the case of clusters, 'too many to fail'? will the party consider a major commercial failure or a prolonged stock market slump as a sign of lack of confidence in the all-powerful party? what will be the role of venture-capital funds? (there are inherent problems of state-run or -controlled venture-capital funds). it also depends on the nature of future innovations. some innovations are of the 'disruptive' kind that challenge incumbent firms (which the us private innovators in collaboration with venture capitalists are good at and a politically-connected large entrenched organization usually is not). other innovations are of the steady 'incremental' kind that adds up to significant gains (the japanese call it kaizen), in which some large organizations in germany, japan and south korea have excelled. it is likely that the chinese system is more conducive to this incremental kind of innovations. • upward vs. downward accountability even though at the top level between the provincial and the central leadership in china there is some degree of reciprocal accountability, as provincial officials constitute about half of the central committee of the party that elects politburo members, it is probably correct to say that the chinese system is by and large one of upward accountability. downward accountability provides more political legitimacy to democratic governments, but such accountability can sometimes degenerate into pandering to short-run interests and pressure groups, particularly at election time. short-run cyclical official behavior before the party congress is not unknown in china, but in general it is much easier for leaders to take long-run decisions under the chinese governance system. but a severe flaw of the upwardly accountable chinese system is that mistakes in such top-level decisions or outright abuses of power (in collaboration with crony business interests) take longer to detect and to correct (as the flow of information upward is tortuous or choked and the tendency to cover up is often too strong). the recent abolition of term limits for the president and the decline of the collective leadership that deng xiaoping had put in place will make this problem more acute. in multi-party democracies the open adversarial relation between the government and opposition parties and the free media usually uncovers the mistakes and abuses much sooner, and corrections are prompted by public protests, agitations, and ultimately electoral sanctions. this also means that the information problem that even well-meaning bureaucrats in the chinese system face is less severe in multi-party democracies-in china, unlike in many authoritarian countries, the information problem is partly relieved through decentralization (more on this in section iii). one concern about the chinese governance system is about the mechanism through which a system that can go off-equilibrium on account of various kinds of political or economic shocks is restored to equilibrium. in the face of a crisis the chinese state often tends to over-react, suppress information and act heavy-handedly, thereby sometimes magnifying the dimensions of the crisis. 3 this also generates low tolerance for short-run economic volatility and the rush to reckless fiscal policies that exacerbate the staggering problems of capital misallocation that china faces. the institutional mechanisms for structural reform have now become particularly weaker, as the resolution of internal governance conflicts is now more dependent on personalized channels. there also remains the larger institutional issue that china has faced throughout history: how to institutionally guarantee the rule of a 'good emperor', as opposed to a 'bad emperor', or that of a good emperor not turning bad. the recent disruption in the conventions of collective leadership and the acceleration of the cult of personality in leadership can only worsen this problem. as the economy becomes more complex and social relations become more convoluted and intense, the absence of transparent and accountable processes and the attempts by a 'control-freak' leadership to force lockstep conformity and discipline will generate acute tension, conflicts, and informational inefficiency. in india, despite all the recent ominous signs of a democracy sliding into a form of a majoritarian overreach, it is probably still correct to say that the system structurally remains somewhat more resilient than in china. over the last quarter century, there has been a tight, often collusive, relationship between business and politicians in china. this is evident from (a) frequent interchanging of positions between executives in public sector companies and the party's central committee; (b) some of china's richest private businessmen are members of the national people's congress (china's parliament) and the people's political consultative conference, an important advisory body; (c) the average net worth of the richest 70 members of the national people's congress in china is several times that for the richest 70 members of the us congress or the indian lok sabha (lower house of parliament)-there are even accounts of large "donations" made before such businessmen are selected for these bodies in china. all this is apart from the influence of the top political families ("princelings") who have long been in lucrative business. the ownership of many private companies is so murky and intertwined with the public-sector companies that it is often difficult to keep track of the boundaries of the business-politics nexus. there have also been cases of successful private companies "persuaded" to invest billions of dollars' worth in backing state-owned companies. the business-politician nexus is, of course, quite common in india. of the current ruling party members of parliament in india about half are businessmen, the corresponding percentage for mp's of all parties taken together is about a quarter. (there is also evidence that people from other occupations, once elected, often turn to business, particularly of the kind that thrive on political connections and networks). the businessmen bring their own money for election campaigns and other political expenditure, and company donations to party funds for election are large, and now, under the anonymous election bond system, openly non-transparent. both countries have similar patterns of rampant influence-peddling, policy manipulation, politically connected firms getting favors in loans from public banks and access to prize real estate, monopoly mining rights, etc. china being more involved in construction and infrastructure activities, which are usually "rent-thick", there is more scope for corruption, as seems to be suggested by both anecdotal and empirical evidence. fisman and wang (2014) detected corruption in state asset sales by comparing the prices of publicly traded assets to those of non-publicly traded assets. even to take an example from a different area, like public health: drug prices are usually much higher in china than in india, even though the single-payer system in chinese health care should have given the government more bargaining advantage vis-a-vis the drug companies. people attribute this to the more entrenched kickback system between drug companies and doctors, hospitals, and officials in china. it is likely that the business-politician collusion in governance is somewhat more subject to public scrutiny in india than china, and the courts are more independent in india (though clogged and corrupt, particularly at the lower levels). the scrutiny of collusive behavior by indian media is now under some shadow with the concentration of its business ownership. also, it should be mentioned that the relation with the all-powerful party is somewhat precarious for the chinese business tycoons, as political disloyalty or even suspected 'independence' is punished more harshly than in india. indian politicians may be a bit more dependent on businessmen particularly in view of election funding. chinese political centralization (in the imperial authority in the past and in that of the party in recent decades) has been historically tempered by a unique blending of political centralization with economic and administrative decentralization-another distinctive feature of the chinese governance system. xu (2011) has described the system as 'regionally decentralized authoritarianism', in contrast with most authoritarian systems that are highly centralized. india in some sense is the obverse-combining political decentralization (regional power groupings have been quite strong in recent decades) with economic centralization (the vertical fiscal imbalance, for example, is quite severe). china has much better modes of management of infrastructure financing and construction at the local level. for example, urban infrastructure there is constructed, operated, and maintained by separate companies set up by the city government, whereas in india the municipal government itself does it through its own departments. the latter are financially strapped, as they do not have much taxation power and are perpetually dependent on the state government for funds. in general, even after the centralizing reforms since 1994, the fiscal system is much more decentralized in china, where sub-provincial levels of government tend to spend more than half of total government budgetary expenditure, compared to about 3% in india (this is not including the large off-budget revenue-raising and expenditure of local governments in china). the much worse performance of sub-provincial local bodies in india in the last-mile delivery of public services and facilities is partly attributable to this (even though chinese local governments have also much larger responsibility for infrastructure-building and public services). in india the emphasis has been more on fiscal transfers to local governments than on local tax autonomy. 4 in both china and india decentralization tends to accentuate regional inequality, though in india the constitutional body of the finance commission tends to partially compensate for this by allocating redistributive transfers to poorer regions. in comparison with other developing countries the chinese local government is much more involved in local business development, not just in public services delivery. a few years back when the private automaker, zhejiang geely holding group, bought up the swedish car company volvo in a widely publicized move, much of the money was actually provided by the local municipal government-something unthinkable, for example, in india. jurisdictional competition for mobile resources and business and regional competition in growth rates influencing career promotion of officials have usually played a much more important role in chinese local development. but in recent years the pace of experimentation and trial-and-error pilot projects in local areas, which characterized the early reform period, has slowed down. the current regime's more centralized and personal loyalty-based leadership has made experimentation even more difficult. this is on top of the policy paralysis of a bureaucracy made nervous by the massive anticorruption campaigns. a growing literature in decentralization all over the world has pointed to the problem of capture of local governments by the elite (including officials and intermediaries) and the frequent diversion of benefits and resources to non-target groups. 5 in india there is plenty of evidence of landed interests undermining decentralized welfare programs for the poor, apart from state political administration and legislators hampering devolution of power to the village or municipal authorities. china's more egalitarian land use rights distribution after de-collectivization may have prevented the rise of a landed oligarchy that has often captured local governments in parts of rural india. however, in recent decades chinese decentralization has not been able to avoid the problem of serious local elite capture. chinese local business in collusion with local officials has been at the root of problems of arbitrary land acquisition, toxic pollution, and violation of safety standards in food and in work for factories and mines. such collusion is much more rampant in china than, say, in india, primarily because china has fewer checks from below on abuse of power. on safety standards, for example, chinese coalmine death rates are reported to be 15 times higher than that in india. on the basis of provincial-level panel data on key state coal mines in china from 1995 to 2005, jia and nie (2015) provide evidence that decentralization makes collusion between official regulators and firms more likely (in the chinese media such collusion is called guanmei goujie) and is correlated with increases in coal-mine fatality rates. this is also consistent with the general finding of fisman and wang (2015) that politically connected firms in china have higher rates of workplace fatalities, based on firm-level data collected from different industries between 2008 and 2011. (while jia and nie focus on the characteristics of regulators, fisman and wang focus on those of firms.) there is also suggestive evidence in the jia and nie paper that media exposure can act as a deterrent against collusion. martinez-bravo, qian, and yao (2014) provide evidence, on the basis of village panel data, that local officials are better controlled by local elections than by central monitoring. there are also fewer checks on debt-fueled over-investment and excess capacity in local government-controlled or politically connected firms (currently a source of major macro-economic problems in china). china's central leadership is now trying to rein in the debt problem of local governments and their dependence on the shadow banking system. thus in this paper we have looked at some positive and negative features of the organizational system of chinese governance and put them in some comparative perspective. such overviews need to be complemented by more in-depth studies at the micro-level of governance, in comparison with micro institutions in other developing countries. decentralization of governance and development awakening giants, feet of clay: assessing the economic rise of china and india busting the "princelings": the campaign against corruption in china's primary land market decentralization, incentives, and tax enforcement decentralization, collusion, and coalmine making bureaucracy work: patronage networks, performance incentives, and economic development in china does performance matter? evaluating political selection along the chinese administrative ladder sponsored human capital: bureaucratic transfer and economic performance. national school of development, peking university meritocracy and patronage in state building: evidence from provincial leaders in china key: cord-330674-enq6kgab authors: yu, jung-sheng; ho, chung-han; hsu, yao-chin; wang, jhi-joung; hsieh, ching-liang title: traditional chinese medicine treatments for upper respiratory tract infections/common colds in taiwan date: 2014-06-12 journal: eur j integr med doi: 10.1016/j.eujim.2014.06.003 sha: doc_id: 330674 cord_uid: enq6kgab introduction: traditional chinese medicine (tcm) has been used to treat upper respiratory tract infections/common colds (urtis) in asian countries for over 2000 years. however, chinese medicine doctors (cmds) follow the traditional treatment rules to select or administer these diverse chinese medicine formulae. the main purpose of our study was to explore data on the frequency of medication and medication habits by cmds for the treatment of urtis with chinese herbs and chinese medicine formulae. methods: the tcm treatments for patients consulting with an urtis were analyzed from the national health insurance research database using the appropriate codes from the international classification of diseases, ninth revision, clinical modification diagnoses for taiwan in 2009. a data mining and association rules, were used to analyze co-prescriptions of tcm for patients with urtis. results: for 472,005 patients who sought the treatment of urtis, a total of 46,805 patients with urtis received tcm treatments, of these 29,052 patients sought both tcm and western medication treatments. of the urtis patients who had received a tcm treatment, 79% presented with an acute common cold, 9% had influenza, and 9% had acute upper respiratory infections. furthermore, 53.89% of the sample were aged between 20 and 49 years, and 62.84% were women, 3.56% of the patients used yin-qiao-san and 2.76% used jie-geng. yin-qiao-san and ma-xing-gan-shi-tang were the most commonly combinations of prescriptions for patients with urtis. conclusions: the patients experiencing urtis were more likely to request tcm treatment if their symptoms were mild and they were women. the chinese medicine doctors treating urtis generally followed tcm theory. a coding system for tcm diagnostic classifications could improve evaluations of tcm treatments. traditional chinese medicine (tcm) has been used to treat upper respiratory tract infections/common colds (urtis) in asian countries for over 2000 years. urtis-related symptoms, complications, treatment methods, and principles were thoroughly recorded in shanghanzabinglun, which was written by zhang zhongjing during the han dynasty in china (150-219 a.d.) [1] . as part of the long-term development of urtis treatment theories, wen bing theory advocated by wu jutong was published during the qing dynasty http://dx.doi.org/10.1016/j.eujim.2014.06.003 1876-3820/© 2014 elsevier gmbh. all rights reserved. (1758-1836 a.d.) because febrile diseases, including infectious diseases such as encephalitis, were added to the texts [2] . to the best of our knowledge, the current principles of the tcm treatments used for diseases, such as urtis remain diverse. therefore, this study employed a database analysis to investigate the basis of chinese medicine doctors' (cmd) treatments. several reports have described how tcm treatments for urtis and related diseases, including influenza, can alleviate symptoms with fewer side effects [3, 4] . the efficacy of tcm possibly results from the antibacterial and antiviral effects of the chinese herbs and formulae [5] . many articles mention chinese herbal medicines may shorten the symptomatic phase in patients with the common cold and treat or prevent seasonal influenza. however, these articles are weak owing to the lack of high quality tcm trials. well-designed clinical trials are required [6] [7] [8] . in spite of this, many extracts of medical herbs have been found to have the potential to treat urtis and prevent colds [9, 10] . some chinese herbs have even been recommended as a treatment to prevent severe acute respiratory syndrome (sars) [11] . the same chinese herbs or formulae may be used to treat many diseases, and cmds may use a single chinese herb or a mixture of herbs, depending on their experience. nevertheless, how cmds follow the treatment rules to select or administer these drugs or chinese medicine formulae remains diverse [12] . this required further investigation. to the best of our knowledge, there are no population based pharmacoepidemiologic studies of tcm for the treatment of urtis. the main purpose of our study was to explore the data on the frequency of medication and medication habits by cmds for the treatment of urtis with chinese herbs and chinese medicine formulae. taiwan's national health insurance system was established in 1995 and covers 99% of inpatient and outpatient medical benefit claims for taiwan's 23 million residents. the detailed clinical information for each patients for each visit includes the date of diagnosis, diagnostic codes, payments for consultations and prescriptions, and is contained in this claims data [13, 14] . traditional chinese medicine is also covered in taiwan's national health insurance program. the prescriptions are written by cmds for treating various disorders that are recorded by the international classification of diseases, ninth revision, clinical modification (icd-9-cm) codes [15] . we used a cohort database from the nhird that comprises of a million randomly sampled individuals who were alive in 2000. the tcm claims database for 2009 was analyzed in this study. the 2009 ambulatory file (cd2009) and corresponding prescription file (oo2009) were included in the tcm claims data. encrypted personal identifications were used to protect patient privacy for avoiding the possibility of the ethical violation. ethical approval and exemption was obtained from the institutional review board of chi mei medical center (irb no. 10202-e09). urtis patients were identified from the 2009 ambulatory file (cd2009) and corresponding prescription file (oo2009) based on the icd-9cm codes 460 (acute nasopharyngitis [common cold]), 462 (acute pharyngitis), 463 (acute tonsillitis), 465 (acute upper respiratory infections of multiple or unspecified sites), and 487 (influenza). patients received either both western and tcm medication, or only tcm treatment or western medication in this study. the mean (standard deviation) and frequency (percentage) were presented as continuous variables and discrete variables, respectively. the frequency of each variable category according to age group and tcm prescription patterns of a single herb or herbal formulae were shown as distributions among the urtis patients. for exploring the prescription patterns of the single tcm herbal drugs or formulae among the urtis patients, a data mining method, association rule, was used to analyze individual patterns and combinations to determine the most common prescription patterns [16] . the method of association rule was often used in large databases for finding frequent item sets which are the lists of commonly displayed together or finding the strong relationships between two items [17, 18] . this method has been used extensively in various published studies using the taiwan nhird [19] [20] [21] [22] . each single herb or chinese medicine formula was set as an independent fixed prescription to estimate the support probability of all of the prescriptions in the data set containing the fixed prescription in order to measure how frequently the association rule occurred in the data set. the minimum level of support was 0.4%. statistical software r (version 2.13.2) and its package a rules were employed to perform all the statistical analyses. in our study, 472,005 patients sought the treatment of urtis, including; 425,200 for the western medication only, 29,052 for western medication and tcm, and 17,753 for the tcm only. a total of 46,805 (9.92%) urtis patients sought the tcm treatment, which accounted for 17.04% of the 274,662 patients underwent tcm treatment. those 46,805 urtis patients receiving tcm treatment as an outpatient, included; the common cold (79%), influenza (9%), acute upper respiratory infections of multiple or unspecified sites (9%), acute pharyngitis (2%), and acute tonsillitis (1%) (fig. 1) . the results showed that the most patients who suffered from urtis mainly sought western medicine treatment. the common cold was a most common condition for patients who sought treatment of tcm treatment. the age distribution of the 46,805 patients with urtis showed that most of all (19.07%) were aged between 40 and 49 years, and 18.78% were between 30 and 39. the use of tcm to treat urtis among women (62.84%) exceeded that for men (37.16%); the usage ratio for women to men was approximately 1.69:1 ( table 1 ). the main seasons of morbidity from urtis were december and january (fig. 2) . the results indicated that the distribution was between 30 and 49, with females more likely than males consulting for tcm if they had a urti. there were 6075 (12.98%) patients who also presented with comorbidity of gastroenteritis, 4054 (8.66%) with hypertension, 3097 (6.62%) with allergic rhinitis, 1586 (3.39%) with diabetes mellitus, and 1108 (2.37%) with urinary tract infections. other comorbid conditions such as: mental disorders, cancer, chronic kidney disease, and cerebrovascular accidents for each accounted for less than 2% ( table 2 ). the results showed that the most common comorbidity was gastroenteritis in these urtis patients. a total of 596,801 tcm prescriptions to treat urtis were issued in taiwan in 2009. there were 21,260 (3.56%) prescriptions for yin-qiao-san, the most popular tcm prescription, followed by 16,087 (2.70%) for xin-yi-qing-fei-tang, 14,566 (2.44%) for ma-xing-gan-shi-tang and 13,909 (2.33%) for chuan-xiong-cha-tiao-san (table 3) . jie-geng (radix platycodi) was the most popular chinese herb and was included in 16,465 (2.76%) prescriptions of the total 596,801. this was followed by yu-xing-cao (herbahouttuyniae) with 11,852 (1.99%), and bei-mu (bulbus fritillaria) with 10,659 (1.79%) ( table 3) . overall, 3224 (0.54%) prescriptions contained combinations of yin-qiao-san and ma-xing-gan-shi-tang, followed by 3191 (0.53%) with yin-qiao-san and ban-lan-gen (radix isatidis) and 3085 (0.52%) with yin-qiao-san and xin-yi-qing-fei-tang (table 4 ). in summary, according to the tcm principle of clearing heat for the common cold, the tcm pattern of wind-heat was a common trend for urtis in taiwan during 2009 the yin-qiao-san, xin-yi-qing-fei-tang and ma-xing-gan-shi-tang formula, and ban-lan-gen belong to cold characteristics. this study was a database analysis of the taiwanese population who used tcm to treat urtis. a total of 46,805 patients with urtis received tcm treatment in 2009. the primary reason for using tcm among people in taiwan was the belief that chinese herbs are natural products and, consequently, their associated side effects are less than those of western drugs [23] . of the urtis patients, 79% presented with a common cold. the majority reported mild cold symptoms including nasopharyngeal inflammation [24] , running and/or stuffy nose, oropharyngeal irritation or discomfort, cough, and fever [25] . tcm treatment of patients with influenza, acute pharyngitis, acute tonsillitis, or acute upper respiratory infections was relatively rare. symptoms and signs of these diseases included a severe sore throat, tonsillar exudate, fever, and cervical lymphadenopathy [25, 26] . our results indicated that most patients with urtis treated with tcm ranged between 30 and 49 years of age. people in this age group are generally healthy; thus, their urtis symptoms were milder compared to those in older or younger age groups. our results also indicated that the percentage of clinical visit for urtis female patients receiving tcm treatment was higher than for males (1.69:1). this result was very similar to the reports of chen et al., who found the tcm utilization ratio was higher for females than males in taiwan between 1996 and 2001 [15] , but the real reasons still remain unclear and need further study. in 2009, the period with the highest frequency of tcm treatment of urtis was from october to april, and the main month of morbidity from urtis was january. during the winter and spring, the weather is colder and the incidence of urtis corresponds to the weather [27] . although lowen et al. concluded that both cold and dry weather favor transmission of the influenza virus [28] , and the annual influenza epidemic season is the winter [20] , the results of this study did not provide sufficient evidence to support their conclusion because the 9% influenza rate in 2009 was low. the most likely connection between gastroenteritis and urtis is the common mucosal immune system for the respiratory and gastrointestinal tracts. in this immune system, secretory iga plays a critical role because it originates from the lymphoid tissue of the gastrointestinal and respiratory tracts, forming the first line of defense in these tracts [29] . numerous patients had comorbid of hypertension. one study has reported that the coxsackie virus is related to hypertension because it can cause cardiovascular disease and myocarditis [30] . we contend that this is unlikely because urtis development resulting from coxsackie viral infections is uncommon. a more probable suggestion is that hypertension is the underlying disease and a urtis may cause rhinitis and sinusitis, resulting in obstructive sleep apnea and a lack of oxygen, which then leads to increased blood pressure [31] . allergic rhinitis is another type of urtis. one study reported that 42.55% of pre-school children had a history of allergic rhinitis and often experienced urtis; they assumed that this association was because of an immunity deficiency [32] . a large environmental study suggested that a humid climate and airborne mold could easily induce multiple respiratory tract diseases including asthma, bronchitis, respiratory infections, common colds, and allergic rhinitis [33] . in other words, allergic rhinitis and urtis can occur concurrently because of environmental factors. in addition, these two diseases may produce several similar symptoms, such as allergic rhinitis, a sore throat, coughing for longer durations, and a runny nose because of external environmental factors [34] . a number of chinese herbs have been used to treat urtis. tcm treatment of disease in taiwan is generally in accordance with tcm theories and the personal experience of the cmds. our results showed that yin-qiao-san was the most popular tcm formula that was used to treat urtis. yin-qiao-san first appeared in the record of wenbingtiaobian (1798-1836 a.d.) and remains a common tcm prescription for treating seasonal influenza [35] , as well as the common cold, fever, cough, and other respiratory tract diseases [36] . yin-qiao-san is comprised of the following 9 herbs: jin-yin-hua (flos lonicerae), lianqiao (fructus forsythiae), niu-bang-zi (fructus arctii), jing-jie (herba schizonepetae), bo-he (herba menthae), dan-do-chi (semen sojae praeparatum), zhu-ye (herba lophatheri), lugen (rhizoma phragmitis), and gan-cao (radix glycyrrhizae). based on the theory of tcm, yin-qiao-san can be used to treat a cough or sore throat resulting from warm-heat diseases (febrile disease). one study reported that lian-qiao (fructus forsythiae) had antiviral, antibacterial, anti-inflammatory, and antioxidant effects, and that jin-yin-hua (flos lonicerae) had anti-inflammatory, anticancer, and immune-boosting effects [37] . the second most popular chinese medicine formula for treating urtis was xin-yi-qing-fei-tang. xin-yi-qing-fei-tang is comprised of the following 10 chinese herbs: xin-yi (flos magnoliae), bai-he (bulbus lilii), zhi-mu (rhizoma anemarrhenae), shi-gao (gypsum fibrosum), pi-pa-ye (folium eriobotryae), sheng-ma (cimicifuga foetid), mai-dong (radix ophiopogonis), zhi-zi (fructus gardeniae), huang-qin (radix scutellariae), and gan-cao. one study reported that xin-yi-qing-fei-tang was the most commonly prescribed formula for treating allergic rhinitis [38] . xin-yi is primarily used to treat allergic rhinitis, sinusitis, and headaches in tcm. another study found that xin-yi had anti-allergic and anti-inflammatory effects, and that these effects resulted from the inhibition of histamine, prostaglandin e2 (pge2), platelet active factor (paf), nitric oxide (no), pro-inflammatory cytokine interleukin-1␣ (il-1␣), and tumor necrosis factor-␣ (tnf-␣) [39] . in tcm, ma-xing-gan-shi-tang is used mainly for the treatment of urtis with a fever, cough, and yellow phlegm. the primary ingredients are the following 4 herbs: ma-huang (herba ephedrae), xing-ren (semen armeniacae amarum), gan-cao, and shi-gao (gypsum fibrosum). an animal study found that ma-xing-gan-shi-tang was an excellent antipyretic agent because of its antiviral and t-cell regulation effects. therefore, ma-xing-gan-shi-tang can inhibit the proliferation of influenza a [35] . jie-geng has long been employed in asian countries for the treatment of urtis, including the common cold, coughs, sputum, tonsillitis, and even asthma [40] . furthermore, a number of studies have found that jie-geng has an immune regulatory effect and can inhibit the production of inflammatory substances, such as il-6, pgd2, ltc4, and cox-2 protein, by mast cells; thus, it may reduce allergic reactions [40] . jie-geng is also an expectorant that can prevent secondary respiratory tract infections [41] . in tcm, yu-xing-cao is considered to have heat-clearing and detoxifying actions, although this has seldom been investigated [42] . yu-xing-cao (herbahouttuyniae) has also been suggested to have weak antibacterial efficacy [43] ; however, it has been employed to treat severe acute respiratory syndrome (sars) [44] . bei-mu (bulbus fritillaria) is commonly used to treat urtis because it is an expectorant. in actuality, bei-mu is divided into zhe-beimu (bulbus fritillariae thunbergii) and chuan-beimu (bulbus fritillariae cirrhosae), and chuan-beimu is further divided into fritillaria unibracteato, fritillaria przewalskii, and fritillariadelavay [45] . chuan-beimu is considered the best antitussive and expectorant in tcm. zhe-beimu contains a cholic acid-verticinoneester that may regulate central opioid receptors; thus, its excellent antitussive and expectorant effects are believed to be superior to those of codeine phosphate [46] . extant studies had shown that ban-lan-gen (radix isatidis) possesses anti-helicobacter [47] , anti-e. coli [48] , and anti-endotoxic effects [49] . thus, we can conclude that the common chinese herbs used to treat urtis have antitussive and/or expectorant properties. the cmd treating disease is accordance with the principles of tcm, treating cold with heat and treating heat with cold. the yin-qiao-san, xin-yi-qing-fei-tang and ma-xing-gan-shi-tang formula, and ban-lan-gen are belong to cold in character. therefore, we suggested the most common type of urtis in taiwan belonged to the tcm wind-heat pattern. although the results of this research investigated the prescription patterns of tcm for patients with urtis, there are several limitations to this study: (1) some patients with urtis may buy chinese herbs from pharmacies by themselves, so the frequency of tcm treatment may be underestimated. however, the nhi program has the encyclopedic coverage of all population, so this selection biases may have been minimized by the large sample size; (2) the cmd prescribes a treatment according to the patient's clinical manifestations, which is, symptoms, the color and quality of the tongue, and the various pulse formations that comprise the so-called 4 examinations of tcm. these methods differ from the etiological diagnoses of western medicine. therefore, when selecting herbs for the treatment of disease, patient symptoms, such as appetite, thirst, and mood, play a crucial role [1] ; (3) the study did not use condition probability to explore the relationship between herbs and diseases and further analysis the different patterns of herb or herb combination; (4) the study did not record the usage of western medication, so therefore, information for common polypharmacy was unavailable; (5) the study is limited to the use tcm theory to explain the simple descriptive statistics. but the logistical regression analysis could not be carried out or that there was no statistical relationship. in the future research, developing a suitable coding system for tcm diagnostic classifications could improve evaluations of tcm and link the western medicine for increasing the efficacy of tcm. the results suggested that patients experiencing urtis 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extract platycodin d and d3 increase airway mucin release in vivo and in vitro in rats and hamsters antimicrobial and antioxidant activities of cortex magnoliae officinalis and some other medicinal plants commonly used in south-east asia susceptibilities of mycoplasma hominis to herbs symptom combinations associated with outcome and therapeutic effects in a cohort of cases with sars herbological study for the beimu categorical chinese medicine on the original plants addictive evaluation of cholic acid-verticinone ester, a potential cough therapeutic agent with agonist action of opioid receptor screening test for anti-helicobacter pylori activity of traditional chinese herbal medicines thermochemical studies on the quantity -antibacterial effect relationship of four organic acids from radix isatidis on escherichia coli growth the anti-endotoxic effect of o-aminobenzoic acid from radix isatidis this study is based in part on data from the national health insurance research database provided by the bureau of national health insurance, department of health and managed by national health research institutes. the interpretation and conclusions contained here in do not represent those of bureau of national health insurance, department of health or national health research institutes. all authors were involved in the design and writing of the study, and chh conducted the statistical analysis. all authors approved the submitted version of the manuscript. no current external funding sources for this study. the authors declare that they have no conflict of interest. key: cord-305747-h17l3rt6 authors: sznajderska, anna; kapuściński, mariusz title: macroeconomic spillover effects of the chinese economy date: 2020-04-24 journal: rev int econ doi: 10.1111/roie.12479 sha: doc_id: 305747 cord_uid: h17l3rt6 the slowdown of economy and widening of domestic imbalances in china bothers economists and politicians across the globe. we estimate the influence of a negative output shock in china on a number of different economies. we concentrate on china's neighboring countries. we compare the results from the global var model and from the bayesian var models. also using bayesian model averaging we search for determinants of chinese spillovers for the global economy. we find that spillovers are stronger to economies with less flexible exchange rates, a higher share of manufacturing in gross value added and to economies which are larger. sznajderska and kapuściński that the negative output shock in china has the largest effect on less-diversified commodity exporters and asean-5 countries (indonesia, malaysia, singapore, and thailand-without the philippines). following a 1 p.p. decrease of the real gdp growth in china, global growth decreases by 0.23 p.p. in the short term, and oil prices fall by 2.8 p.p. in the long term. similarly, sznajderska (2019) by estimating a different gvar model shows that a 1 p.p. negative china gdp shock reduces global output by 0.22 p.p. in the short run, leading to a maximum 1 p.p. decrease in the global output in the longer term. blagrave and vesperoni (2018) show that spillover effects are largest for countries with tighter trade links to china, particularly those in asia. they analyze demand shocks for chinese secondary and tertiary sectors separately. they apply a panel var model with china's demand shocks, identified outside the model, as exogenous variables. authors show that shocks to china's secondary sector have much larger effects on partner export countries than shocks to china's tertiary sector. in our study we do not take into account the tertiary sector, because we measure links between countries using dots statistics. also the chinese stock market crash (2015) (2016) shows that china is becoming more integrated with the regional financial markets. abdullahi and rui (2019) , for instance, by investigating daily data between 2015 and 2016, show strong shock spillover effects from china to most asia-pacific stock markets (except new zealand). it is important to note that chinese financial linkages are smaller than linkages through trade channels. capital flows in and out of china are restricted legally. despite capital controls, financial integration of china is de facto non-negligible (see dieppe et al., 2018) . dieppe et al. note that the share of china and hong kong's global gross asset and liability position in 2015 was approximately 8% (to compare with 10% share in global imports or 22% share in global energy consumption in 2015 4 ). based on the data from bis locational international banking statistics we may notice that the highest financial flows are between china and hong kong, 5 followed by the euro area, the united states, the united kingdom, japan, taiwan, 6 korea, australia, and canada, in descending order (see figure a1 in the appendix). the important question is why some economies are affected more and some are less by china's spillovers. we try to answer this question by looking at structural characteristics of the economies. georgiadis is the author of two papers in which he shows that differences within the monetary transmission mechanism depend on the differences in the structural characteristics of the economies. he applies gvar methodology with sign restrictions. in his first paper, georgiadis (2015) studies the transmission of the common euro area monetary policy across the individual euro area economies. the euro area countries in which a share of sectors with the demand sensitive to interest rate changes in the accumulated industry is bigger exhibit a stronger monetary transmission to real economic activity. similarly, stronger transmission is observed in the countries with more real wages rigidities and/or fewer unemployment rigidities. in his second paper, georgiadis (2016) studies spillover effects from the u.s. economy. the results of the study suggest that policymakers could mitigate the u.s. spillover effects by encouraging trade integration, financial market development, flexibility of exchange rates and by reducing labor market rigidities. moreover, other policies, such as slowing the process of financial integration and industrialization or participation in the global value chains, could also reduce the spillover effects, but would probably decrease the level of long-run economic growth as well. we analyze the factors which explain differences in spillovers similarly as georgiadis (2015 georgiadis ( , 2016 , by regressing maximum point impulse responses on structural characteristics of respective economies. however, due to having a large number of candidate characteristics compared to the number of observations, we have used bayesian model averaging. a similar approach was used, for example, by havranek and rusnak (2013) in order to analyze the transmission lags of monetary policy. in contrast to their analysis, we do not carry out a meta-analysis of existing studies. we use the global vector autoregressive model to investigate the impact of the chinese economy on other economies. 7 the gvar model is estimated within two steps (see dees, mauro, pesaran, & smith, 2007; pesaran, schuermann, & weiner, 2004) . first, let us consider the varx (p i , q i ) models for each country (i = 1, … n; n is the number of countries), where p i and q i are lags lengths selected by sbc. x it , is a vector of domestic variables, x * it , is a vector of foreign variables, t , is a vector of dominant unit model variables (here: oil prices). note that t is treated as a foreign variable in the gvar model and shares the same lag order as foreign variables. foreign variables are calculated as a weighted average of domestic variables: and ij are weights calculated on the basis of bilateral trade flows ( ∑ n j=0 ij = 1). k i is the number of domestic variables and k * i is the number of foreign variables in ith country (here k * i = 2). following other studies we estimate the error correction form (vecmx (p i , q i ) models) of the varx (p i , q i ) specification for each country (cf. backé, feldkircher, & slacík, 2013; bussière, chudik, & sestieri, 2012; dees, holly, pesaran, & smith, 2007; inoue et al., 2015; pesaran et al., 2004) : ect are error correction terms and r i is the number of cointegrating relations. most of the variables are nonstationary with stationary first differences. the usage of vecm models allows as to capture long-run relationships that exists among the domestic and the country-specific foreign variables. the dominant unit is modeled as: where x t are feedback variables, constructed as a weighted average of variables included in the models for non-dominant units (see smith and galesi (2014) for details). in the second step, the corresponding varx models (equation 1) are recovered from the estimated vecmx models. then the individual country models are stacked into one model: (1) (2) link matrix for ith country defined by trade weights ij , so that: when solving the gvar model equations (1) and (2) are written in one equation, which is solved recursively. next we calculate the generalised impulse response functions (girfs), that were developed in koop, pesaran, and potter (1996) and pesaran and shin (1998) , and we calculate 90% bootstrap confidence bands. because of the large number of variables in the gvar model we cannot use the standard impulse response functions (irfs) that assume orthogonal shocks. girfs do not depend on the ordering of the variables. girfs show how changes in chinese gdp affect the other variables in the gvar over time regardless of the source of the change. we do not know whether such a shock stems from a shift in the demand or supply of output in china or in other countries. the baseline gvar model includes five variables for each country: these are real gdp, cpi, stock price index, reer, and short-term interest rate. furthermore, it includes oil prices as a global variable and real gdp and short-term interest rate as a foreign variable (see equation 1). the model uses a time-varying matrix of trade flow (imf dots). also, we include a dominant unit to model oil prices with two feedback variables (real gdp and short-term interest rate). we obtained a stable gvar model, meaning convergent persistent profiles, 8 eigenvalues lying in the unit circle, and non-explosive girfs. to arrive with a stable gvar we reduced the number of cointegrating relations for argentina from 5 to 1 relation. also we decided to remove from the sample three economies that faced episodes of very high inflation, namely venezuela, turkey, and bulgaria. when we included the three economies in the sample, many results were statistically insignificant. the order of the varx* models as well as the number of cointegration relationships are presented in table a1 in the appendix. the cointegration results are based on the trace statistic, which has better small sample power results compared to the maximum eigenvalue statistic. we apply the bayesian var models to check the robustness of the results from the gvar model. bvar models are estimated for each country separately. 9 we estimate the models on first differences (all variables except of interest rate are in first differences) to ensure maximum comparability to gvar model. x t is a vector of endogenous variables, z t is a vector of exogenous variables, and it corresponds to foreign variables and the dominant unit in the gvar model, t ∼ n (0, σ) is a vector of residuals. we identify shocks using the cholesky decomposition, which is easier to reasonably implement within the bvar framework, than within the gvar framework. the specification of the bvar models is chosen to be as similar to the gvar model as possible. the endogenous variables are as follows: chinese gdp (y china ), chinese interest rate (i china ), domestic gdp (y), domestic price level (p), domestic interest rate (i), domestic stock price index (s), and domestic real effective exchange rate (r). the order of variables for the cholesky identification is as written above. the exogenous variables are foreign gdp (without china) (y foreign ), foreign price level (without china) (p foreign ), and oil price level (oil). the choice of variables is similar to peersman and smets (2001) . the number of lags is 4. note that in the models for algeria, croatia, saudi arabia, and romania, stock price indexes are not included due to the unavailability of data. we use minnesota prior with parameters presented in table 1 . auto-regressive coefficient is equal to 0.8, because our variables are known to be stationary (see dieppe, van roye, & legrand, 2016) . the rest of the hyperparameters are chosen on the basis of suggestions in canova (2007) . we implement block exogeneity to create partial exogeneity within our set of endogenous variables. we want domestic variables (y, p, i, s, r) to have no impact on chinese variables (y china , i china ) (see table 2 ). next after computing gdp responses in respective economies to china's gdp impulse from both gvar and bvar models, we attempt to explain them by the countries' structural characteristics. in principle, we estimate the parameters of the following linear regression models: note: the value of 1 in row i and column j of the table means that variable i has no effect on variable j. where y i is an impulse response (either from the gvar or from the bvar model), x i is a vector of structural characteristics for each economy, is a vector of coefficients and i is an error term. as a dependent variable, we take the maximum effect within 20 quarters (5 years) after an impulse. we consider as many as 18 (16-17 at the same time) structural characteristics 10 within the following groups: • the structure of international trade (shares of: agriculture, fuels and mining products, and manufacturing in trade with china), • the structure of gva (shares of: agriculture, industry, manufacturing and services in gva), • financial openness (chinn-ito index, where the higher the value, the higher the capital account openness), • the size of international investment position (the sum of international investment position assets and liabilities to gdp ratio), • distance (between capitals of respective economies and beijing), • exchange rate regime (according to the classification of klein and shambaugh (2008) , where 1 indicates a fixed and 0-a flexible exchange rate), • trade openness (the sum of exports and imports to gdp ratio), • size (gdp in ppp, constant prices), • development (gdp per capita in ppp, constant prices), • participation in global value chains (gvc)-with china and total, • tariffs (weighted average). as we describe in the next section, we consider 40 economies, so if we included all the above mentioned variables in linear regression models at the same time we would be left with just above 20° of freedom, which does not appear to be acceptable. we could estimate a model with each structural characteristic separately, but that would put us at risk of getting biased estimates (due to the omittedvariable bias). therefore, we decided to use the bayesian model averaging approach, where first we estimate linear regression models with different sets of independent variables, and then we average parameters over models, with weights proportional to posterior probabilities of respective models being correct (assuming one of them is correct). 11 formally, a model-averaged bayesian point estimator is the following: where e[ 1 |d] is the posterior distribution of a parameter 1 , ̃ (k) 1 is the posterior mean of the parameter 1 under model m k , and p(m k |d) is the posterior probability that m k is the correct model, given that one of the models considered is correct. for more details on bayesian model averaging see, for example, raftery, painter, and volinsky (2005) . when interpreting the results we focus on posterior inclusion probabilities of each variable being in the model. finally, it should be noted that, on top of using two variants of the dependent variable (either from the gvar or from the bvar models), we also try two sets of regressors: one with a weight in trade with china, and one with proxies for it based on the gravitational model of trade-gdp in ppp and distance. the latter specification does not directly include any deterministic relationship between responses and trade weights due to the construction of the gvar model itself. the remaining variables are used in both sets. in the baseline model we explain responses from the gvar model by the set of variables including gdp in ppp and distance, while the remaining three variants make up a sensitivity analysis. our sample consists of 59 economies, where the 19 euro area countries are grouped into one economy. we use quarterly observations. the data span from 1995q1 to 2017q4. the primary data source for gdp, price level (cpi), and short-term interest rate was the imf ifs. if for any country these data were not available we used the oecd mei database. if the data were still not available we used national sources of data, and next annual data from the imf weo (with chow-lin interpolation). in cases of data on stock market indexes the primary data source was msci. if the data were not available we used the data sources listed above. the data on real effective exchange rates (reer) for each country was taken from the bank of international settlements (bis). the monthly data were aggregated to quarterly frequency. an increase in the reer index indicates an appreciation. detailed data sources for each country are presented in table 3 . 12 real gdp, cpi, stock market indexes, and reer are 2010 indices (2010 = 100). these variables are in logarithms. oil prices were taken from fred, as an average from brent, west texas intermediate and dubai fateh indexes. we used the world economic outlook database of the imf for construction of the country-specific ppp-gdp weights. we took the average from 1995 to 2017 from the annual data on purchasing power parity in billions of international dollars. the matrixes of trade flows were constructed on the basis of international monetary fund statistics, namely the direction of trade statistics (dots). these are annual data, so they allow the construction of trade flows matrix for each year separately and subsequent estimation of the model with time-varying link matrixes. it is important to note, that the data for chinese taipei as a reporting country were not available. the data for chinese taipei were available only as a counterpart country. thus, we made the symmetry assumption here (meaning that, for example, the value of export and import from china to taipei equals the value of export and import from taipei to china). also there were no data for south africa from 1995 to 1997 and we decided to replace the empty spaces using data from 1998. we took data on the structure of international trade from the wto. the structure of gva, measures of trade openness, size, development and tariffs were taken from the world bank. we used the updated versions of databases from chinn and ito (2006) , and klein and shambaugh (2008) for financial openness and exchange rate regimes, respectively. the size of international investment positions was taken from the imf, distances were from the distance calculator webpage (www.dista nceca lcula tor.net) and the participation in global value chains-from the oecd. we computed an average over the period 1995-2015 for each variable. due to the large number of missing observations in data on structural characteristics we removed algeria, the euro area, israel, and taiwan from the bma analysis. these economies, however, were included in the gvar and bvar models. in this section we describe the influence of negative demand shock in china on a set of economies. we report output elasticities for specific countries following a 1% negative gdp shock in china. figure 1 presents the negative demand shock in china from the gvar model, which is equal to 1 p.p. decrease in chinese gdp on impact, and an average response of the whole global economy and an average response of southeast asia and oceania. the negative demand shock in china is standardized to 1 p.p. (figure 1a ).the shock is permanent. the presented girfs are bootstrap mean estimates with the associated 90% bootstrap error bounds. the maximum response of the whole global economy to 1 p.p. negative demand shock in china is equal to −0.157 p.p. after 7 quarters. the maximum response of southeast asia and oceania to 1 p.p. negative demand shock in china is −0.262 p.p. after 4 quarters. thus, the response of neighboring countries is much stronger and faster than the average response of other economies. concerning southeast asia and oceania, according to the results from the gvar model, the strongest response of domestic gdp to negative gdp shock in china is observed in chinese taipei (−0.505 p.p. after 6 quarters). next we list the countries from the most to the least affected: the strongest response of domestic gdp is observed in singapore (−0.430 p.p. after 4 quarters), indonesia (−0.383 p.p. after 8 quarters), thailand (−0.317 p.p. after 3 quarters), hong kong (−0.280 p.p. after 3 quarters), japan (−0.269 p.p. after 9 quarters), malaysia (−0.259 p.p. after 4 quarters), philippines (−0.246 p.p. after 5 quarters), and south korea (−0.188 p.p. after 2 quarters). hong kong, singapore and taipei have strong financial linkages with china (see figure 5 ). it is worth noting that chinese taipei is a smaller financial centre than hong kong and singapore, but it has greater trade links with the mainland. this may be the reason for its strong gdp reaction. indonesia is a major exporter of coal and industrial metals to china. whereas thailand, malaysia, the philippines, and south korea are major exporters of industrial supplies (including base metals) and capital goods to china. japan is the main chinese export market. a similar result is found by inoue et al. (2015) , who found that negative chinese gdp shock impacts commodity exporters, like indonesia, to the greatest extent, and also export dependent economies, like japan, malaysia, singapore, and thailand. they find a counterintuitive reaction for philippines. within the studied region the weakest reaction is observed in new zealand (−0.144 p.p. after 6 quarters) and australia (−0.099 p.p. on impact). it may be a bit surprising, because australia has about a third of its exports headed for china (see figure a3 in the appendix). the output reaction is statistically significant in chinese taipei, hong kong, japan and, south korea (see figure 2) . the obtained results are in line with cashin et al. (2016) , who reported that negative output shock has a large and statistically significant impact on all asean-5 countries (except for the philippines), with output elasticities ranging between −0.23% and −0.35%. also bussière et al. (2012) show that asian countries benefit the most from a positive shock to chinese imports. they reported that a one-standard-error shock to chinese imports, which is an increase of 1.9% at the time of the impact, has an economically significant effect on other asian countries, with real output increase in korea, singapore, and thailand by 0.4% after 1 year, and a lower but still considerable real output increase in japan and new zealand by 0.2%. in order to check the robustness of our results we estimate a series of bvar models. specification of the models is described in section 2.2. we check whether the difference between the irfs obtained from the gvar model and the irfs obtained from the bvar model for each country separately is statistically significant. to do so we subtract the irfs and the confidence bands obtained from the two models. the results are presented in table 4 . it appears that there are considerable differences between maximum responses and maximum response horizons across the economies between the two types of models. we find out that there are statistically significant differences between the irfs for 8 out of the 37 analyzed economies, that is for 22% of analyzed economies (8th column of table 4 ). however, if we omit the first quarter (the reaction on impact), for the following quarters the difference between the reaction obtained from the gvar model and the reaction obtained from the bvar model is statistically different for 4 out of 37 analyzed economies, that is for 11% of the analyzed economies (9th column of table 4 ). this is a good result, that seem to indicate that the results from bvar models confirm the results from the gvar model. nevertheless the comparison of the two models is a bit problematic and should be analyzed with caution. first, the confidence bands are quite wide (see figure 3) . second, the gdp shock is different within the two models (compare, for example, figures 1a and 4) . the shock is very similar for each of the 37 estimated bvar models (see figure 4 ). but the chinese gdp shocks in bvar model are much stronger than the chinese gdp shock in gvar model. it is important to note, however, that the shocks are equal on impact, we standardize them so that they are equal to 1 p.p. on impact. for example, for australia the chinese gdp shock stabilizes at the level of 1.56 p.p. in the bvar model, whereas the shock stabilizes at the level of 1.01 p.p. in the gvar model. note that the shocks are permanent in both specifications. the maximum response of domestic gdp in australia is stronger in the bvar model (−0.17 p.p.) than in the gvar model (−0.99 p.p.). therefore, the differences between the irfs obtained from the two models do not necessarily stem from a different reaction of domestic gdp, but may be the result of differences in the trajectories of chinese gdp shock. concerning southeast asia and oceania, according to the results from the bvar models, the strongest response of domestic gdp to negative gdp shock in china is observed in chinese taipei (−1.40 p.p.) , and next in singapore (−1.03 p.p.), thailand (−0.85 p.p.), malaysia (−0.57 p.p.), indonesia (−0.48 p.p.), hong kong (−0.26 p.p.), and australia (−0.17 p.p.). according to the results the irfs from the bvar model are statistically significant on impact. if we omit the first quarter, the gdp reaction becomes statistically insignificant for hong kong, japan, new zealand, the philippines, and south korea. in japan the reaction is very weak. in the philippines we find a counterintuitive positive reaction of domestic gdp to negative chinese gdp shock. thus, both the gvar and bvar models show that chinese taipei is the most affected economy by negative gdp shock in china. the results for japan from the gvar model and from the bvar model are very different. both specifications point to very weak and statistically insignificant output reaction in new zealand. figure 5 shows posterior inclusion probabilities of each structural characteristic being in the model from the baseline bma analysis (based on results from gvar, without the weight in trade with china among regressors). 13 they are the highest for the exchange rate regime (94.5%), gdp in ppp (98.0%), the share of manufacturing in international trade (81.1%), the size of international investment position (78.5%), and the share of manufacturing in gva (80.0%). t hailand figure 6 shows the results in a different way. rows correspond to variables and columns correspond to models. the wider the column, the higher the probability of a given model. models are ordered so that the first one has the highest probability. if a variable enters a given model, it is in red (a positive impact) or in blue (a negative impact) in a cell. otherwise--it is in white. when interpreting the results it should be noted that responses are to a negative impulse. the relationship between the strength of the response to a china gdp impulse is negatively related with the exchange rate regime (the less flexible the exchange rate, the stronger the response), gdp in ppp and the size of international investment position, and positively related with the share of manufacturing in international trade. table a2 f i g u r e 6 graphical results of bma analysis-baseline. abbreviations are explained in table a2 | 19 figures 7-10 show the results from the remaining variants of the bma analysis (responses from gvar with the weight in trade with china among regressors, responses from bvars with or without the weight in trade). some of them give a high probability of being in the model for participation in gvc with china (a negative relationship), and measures of trade and financial openness (a negative and a positive relationship, respectively). averaging over the results above, among the most important factors differentiating responses to a china gdp impulse are: the exchange rate regime, the structure of the economy and its size, with more rigid exchange rates, higher shares of manufacturing in gva and larger sizes of the economy associated with stronger spillovers. below we try to interpret these results. the economies with floating exchange rates should be more resistant to a decrease in china's gdp, because if it leads to a decrease in domestic gdp, then domestic currency should depreciate leading to a later increase in domestic gdp. the share of industry in china's value added was about 41% in 2015, whereas the average for all other countries in our sample was 31%, similarly the share of manufacturing in china's value added was about 83% in 2015, whereas the average for all other countries in our sample was 67%. it means that manufacturing is the most important component of china's trade, thus, the slowdown of chinese economy transmits more strongly to economies with higher shares of manufacturing in gva. it appears that the size of economy correlates with the weight in trade with china. it means that china trades more with larger economies. therefore, larger economies are more affected by negative demand shocks from china. in this study we develop the gvar model to investigate how a slowdown in chinese economy may affect other economies. we use a novel data set that spans from1995q1 to 2017q4 and covers 59 economies. we apply time-varying trade weights. also, we estimate a set of bvar models to check the robustness of the results. we decided to concentrate on southeast asia and oceania, because this region seems to be the most dependent from china. indeed, our results show that the maximum response of the whole global economy to 1 p.p. negative demand shock in china is equal to −0.157 p.p. after 7 quarters, while the maximum response of southeast asia and oceania is equal to −0.262 p.p. after 4 quarters. thus, the response of neighboring countries is much stronger and faster than the average response of other economies. according to our results from both the gvar and the bvar models chinese taipei is the most affected economy by negative gdp shock in china. also indonesia, singapore, hong kong, thailand, and malaysia are strongly affected. australia seems to be also affected but to a lesser degree. we find a weak gdp response to china gdp shock for new zealand and the philippines. the response of gdp in south korea and japan is quite significant, but only according to the results from the gvar model. thus, our results suggest that there exist strong economic linkages between the asian economies. bussière et al. (2012) , for example, also confirm the presence of a strong asian business cycle and an increased vertical specialization in international trade among asian economies. the results from the bvar models seem to confirm the results from the gvar model. we find out that there are statistically significant differences between the irfs in 22% of analyzed economies, but if we omit the first quarter the differences appear only in 11% of the analyzed economies. but there are considerable differences between maximum responses and maximum response horizons across the economies between the two types of models. in the final step of our analysis, we used bayesian model averaging in order to check how structural characteristics may explain the differences in the response of the analyzed economies to a negative chinese gdp shock. we found that spillovers are stronger to economies with less flexible exchange rates, a higher share of manufacturing in gva and to economies which are larger. impacts of china's crash on asia-pacific financial integration: volatility interdependence, information transmission and market co-movement economic spillovers from the euro area to the cesee region via the financial channel: a gvar approach the implications of china's slowdown for international trade modelling global trade flows: results from a gvar model, globalization and monetary policy institute (working paper no. 119) chapter 10: bayesian vars. methods for applied macroeconomic research china's slowdown and global financial market volatility: is world growth losing out? (imf working papers no. 16/63) what matters for financial development? capital controls, institutions, and interactions exploring the international linkages of the euro area: a global var analysis long run macroeconomic relations in the global economy the transition of china to sustainable growth-implications for the global economy and the euro area the bear toolbox examining asymmetries in the transmission of monetary policy in the euro area: evidence from a mixed cross-section global var model determinants of global spillovers from us monetary policy transmission lags of monetary policy: a meta-analysis the impact of china's slowdown on the asia pacific region: an application of the gvar model the dynamics of exchange rate regimes: fixes, floats, and flips impulse response analysis in nonlinear multivariate models inflation dynamics in asia: causes, changes, and spillovers from china the monetary transmission mechanism in the euro area: more evidence from var analysis modeling regional interdependencies using a global error-correcting macroeconometric model generalized impulse response analysis in linear multivariate models bma: an r package for bayesian model averaging gvar toolbox 2.0. cambridge: university of cambridge the role of china in the world economy: evidence from a global var model the data that support the findings of this study are openly available in mendeley at https://data.mende ley.com/datas ets/jr8n8 hnrw9 /draft ?a=9fecc a2f-5853-4058-9117-2e1d2 3f744d3. https://orcid.org/0000-0002-5604-1229 endnotes 1 investment slowed from over 17% in 2000 (12) to 3% in 2015, while private consumption slowed from 13% in 2000(12) to 9% in 2015. 2 china consumed about 50% of copper and aluminium (2016), 60% of iron ore, and 12% of oil (2015), produced globally. sznajderska and kapuściński 3 it appears that the level of inflation is most strongly affected in indonesia and next in malaysia, india, philippines, thailand, singapore, and korea. while hong kong, new zealand, australia, and japan are less affected. key: cord-024111-7yrftdp4 authors: zhang, runzhi; gao, xi; bai, hong; ning, kang title: traditional chinese medicine and gut microbiome: their respective and concert effects on healthcare date: 2020-04-22 journal: front pharmacol doi: 10.3389/fphar.2020.00538 sha: doc_id: 24111 cord_uid: 7yrftdp4 advances in systems biology, particularly based on the omics approaches, have resulted in a paradigm shift in both traditional chinese medicine (tcm) and the gut microbiome research. in line with this paradigm shift, the importance of tcm and gut microbiome in healthcare, as well as their interplay, has become clearer. firstly, we briefly summarize the current status of three topics in this review: microbiome, tcm, and relationship of tcm and microbiome. second, we focused on tcm's therapeutic effects and gut microbiome's mediation roles, including the relationships among diet, gut microbiome, and health care. third, we have summarized some databases and tools to help understand the impact of tcm and gut microbiome on diagnosis and treatment at the molecular level. finally, we introduce the effects of gut microbiome on tcm and host health, with two case studies, one on the metabolic effect of gut microbiome on tcm, and another on cancer treatment. in summary, we have reviewed the current status of the two components of healthcare: tcm and gut microbiome, as well as their concert effects. it is quite clear that as the holobiont, the maintenance of the health status of human would depend heavily on tcm, gut microbiome, and their combined effects. with the rapid advancement of research in traditional chinese medicine (tcm) and gut microbiome, studies involving both fields have significantly accelerated around the world. tcm and gut microbiome are closely related to human health. therefore, exploring the relationship between tcm and gut microbiome is essential for healthcare. the microbiome is a novel research field related to human health, bioenergy, agriculture, and the environment. it has recently emerged as a crucial factor in human physiology and disease. taking the microbiome into consideration, human beings could be considered "super organisms," with around 10% human cells and 90% microbial cells, most of which can be found in the gut (lederberg, 2000) . the human gut is a biological niche, home to a variety of microbes that affect nearly all aspects of human biology through their interactions with their hosts (blaser, 2014) . the human intestinal flora is a complex micro-ecosystem, containing approximately 10 14 microbes from more than 1,000 microbial species, of which the phyla firmicutes, bacteroidetes, and actinobacteria (gill et al., 2006) account for more than 90% of the species above. in addition, the genetic factors, dietary habits, and various environmental factors of the host lead to the diversity and the specificity of the human intestinal flora, while human intestinal flora in turn would play important roles in exerting host's physiological functions, such as metabolism, energy intake, and immune regulation. under normal circumstances, the intestinal flora is in a state of homeostasis. environment, drugs, and the other factors that destroy the structure of intestinal flora will cause dysbiosis, which may influence human health. recent studies have already accumulated ample evidences that the gut microbiome plays pivotal roles in many forms of chronic diseases. for example, inflammatory bowel disease (ibd) is a chronic bowel disease with clinical symptoms of abdominal pain, diarrhea, and unknown etiology, it includes ulcerative colitis and crohn's disease (cd) . the fecal microbiome of cd patients contains a significant reduction of firmicutes diversity, and it's worth mentioning that the clostridium leptum phylogenetic group has less abundance in cd patients than healthy (manichanh et al., 2006) . constipation is a common health problem with high mortality, as well as a predisposing factor for many conditions. bifidobacterium adolescentis exhibited strain-specific effects in alleviation of constipation . obesity is a global problem in that nearly 12% of the people worldwide are obese. obese mice had 50% fewer bacteroidetes and more correspondingly firmicutes than their lean littermates (ley et al., 2005) . besides, they reached similar conclusions for obese people (ley et al., 2007) . dietary interventions might lead to the modulation of gut microbiome, which will contribute to weight loss, enhance the integrity of the intestinal barrier, and reduce the antigenic load in the circulation, ultimately improving the inflammatory and metabolic phenotypes (xiao et al., 2014) . type 2 diabetes (t2d) is a complex disorder affected by genetic and environmental components (wellen and hotamisligil, 2005; risé rus et al., 2009) , and become a major public health problem on a global scale. a protocol has been developed for the metagenome-wide association study (mgwas) and a two-phase approach has been taken based on high-throughput sequencing of the intestinal microbiome of 345 chinese individuals. mgwas analysis revealed that the intestinal microbiome of patients with t2d was mal-regulated, which was manifested by the decrease in the abundance of certain universal butyrate-producing bacteria and the increase of pathogenic bacteria in various conditions (qin et al., 2012) . metformin is a widely used drug in the treatment of t2d. a recent study discovered the mechanism of metformin by regulating the composition of gut microbiome (wu et al., 2017) , indicating a close relation between the gut microbiome and t2d. human gut microbiome are structurally dynamic over time and plastic under different conditions, as the bacterial composition as well as the collection of genes varied with xenobiotics and the environment (zhao et al., 2012) . due to the close relevance between the microbiome and the human genome, the taxonomic and functional composition changes of the intestinal microbiome inevitably regulate gene expression and host immunity, which may lead to the occurrence of diseases, in particular, chronic diseases. in recent years, with the launching of various international projects on human microecology [e.g., hmp: http://www. hmpdacc.org/, metahit: http://www.metahit.eu/ and ihmp (proctor et al., 2014) ], gut microbiome have become the hotspot research between chronic diseases and the gut microbiome has steadily increased, promoting the most significant paradigm shifts in modern medicine. tcm is in constant development and inheritance along the long chinese traditional culture. it has been developed in clinics over thousands of years and has accumulated abundant clinical experience, forming a field with unique experiences and specific theories. the tcm system is complex, as it contains components of natural plants, animals, and mineral materials. tcm uses therapeutic herbs to treat the disease and restore the balance of physical function according to the patient's syndrome, based on the combination principle of "king, vassal, assistant and delivery servant" (yi and chang, 2004) . each prescription combination of these herbs is called a tcm preparation or prescription, such as liuweidihuangwan (lwdhw) pills. many chinese herbal medicines are known for their therapeutic effects compared to chemical and biological agents (chan, 1995; corson and crews, 2007; qiu, 2007) , which contain not only bioactive components but also various nutrients such as proteins and polysaccharides. for example, glycyrrhiza uralensis fisch., also called "gan-cao" in china, as a health-preserving and therapeutic agent, it has been widely utilized for more than 2,000 years. it is one of the most broadly used ingredients in tcm preparations in china, exerting a wide range of pharmacological efficacies. glycyrrhiza uralensis fisch. contains many bioactive ingredients, including glycyrrhizin, glycyrrhetinic acid, glycyrol, coumarin, and alkaloids. in addition, previous studies have shown that glycyrrhiza uralensis fisch. has a variety of pharmacological effects, including antitumor (shibata et al., 1991) , antiviral (nakashima et al., 1987) , and anti-inflammatory effects (kimura et al., 1988) . the traditional discovery pathway for most new drugs is to identify or design pharmacologically effective agents that specifically stimulate or inhibit a specific set of target receptors. nevertheless, the influence of the gut microbiome on humans has been largely ignored in this process. therefore, the pharmacological effects of these single target drugs on chronic diseases are limited. in contrast, since one of the characteristics of tcm is oral administration, the drug will interact with the intestinal flora inevitably. previous studies have proven that tcm is conductive to maintain the homeostasis of the intestinal flora (chang et al., 2015; zhou et al., 2016) , and the gut microbiome could also exert pharmacological effects of the tcm on host (park et al., 2006) , which render tcm a potential new drug in the western markets. thus, research about relationship between tcm and gut microbiome is significant, which helps researchers to further study the pharmacological effects of tcm on the human body and the causal links among intestinal microbiome with disease. in this review, we summarize the current status of microbiome, tcm, relationship of tcm and microbiome, as well as the therapeutic effects of tcm and gut microbiome's mediation roles. among them, databases and tools that contribute to the molecular understanding of tcm and the role of the gut microbiome in diagnosis and treatment are also presented. finally, we introduce the impacts of gut microbiome on tcm and host health, with two case studies, one on the metabolic effect of gut microbiome on tcm, and another on cancer treatment (figure 1 ). an increasing number of studies have been conducted on tcm, gut microbiome, and their interplay. statistics on the published papers in "public medicine (pubmed)" (https://pubmed.ncbi. nlm.nih.gov) and "china national knowledge infrastructure (cnki)" (https://www.cnki.net) showed that the number of literature on tcm and gut microbiome continued to rise in recent years ( figure 2 ). most importantly, due to the standardization of tcm, research on tcm and gut microbiome has received more and more attention around the world, and the tcm-related research outputs have shown explosive growth in 2019. to maintain the health of humans under various physiological conditions and environments, tcm and the gut microbiome must coordinate with each other to cope with the challenges. the interactions between tcm and the gut microbiome can mainly be categorized into four types ( figure 3 ): the regulatory effects of tcm on gut microbial communities are mainly reflected in treatment of dysbiosis to restore homeostasis of the intestinal flora. ganoderma lucidum (g. lucidum), called "ling-zhi" in china, has been widely used as a health-preserving and therapeutic agent. a water extract of g. lucidum has antiobesogenic effects, as it could modulate the taxonomical composition of the gut microbiome (chang et al., 2015) . the water extract of g. lucidum mycelium can reverse high-fat diet (hfd)-induced gut dysbiosis, indicated by the decreased firmicutes-bacteroidetes ratios and endotoxin-bearing proteobacteria levels. it can also maintain intestinal barrier integrity and reduce metabolic endotoxemia. in addition, it can reduce the expression and secretion of the proinflammatory cytokines tumour necrosis factor (tnf), interleukin-1-beta (il-1b), and interleukin-6 (il-6). the glucose tolerance and insulin sensitivity are improved by the extract as well. these effects are especially mediated by the gut microbiome, as it has already been observed from experiments on mice that the weight loss effect induced by g. lucidum is transmissible via transfer of feces from g. lucidum-treated mice to hfd-fed mice. the study has also demonstrated that the antiobesogenic effect of the g. lucidum water extract is mainly owing to its high molecular weight polysaccharide fraction (>300 kda). g. lucidum polysaccharide can inhibit colon expansion of colorectal cancer (crc) mice and reduce mortality by 30%, by alteration of reduced the relative abundance (ra) of cecal oscillospirawhich was first observed in crc mice, and down-regulation of four cancer-related genes (acaa1b, fabp4, mgll, and scd1) expression of colonic epithelial cells (luo et al., 2018) . gegen qinlian decoction (gqd), a traditional prescription, could effectively alleviate t2d by modulating the gut microbiome (xu et al., 2013) . in their study, compared to the patients with a low dose gqd and the placebo, patients who received high dose and moderate dose gqd showed remarkable reductions in adjusted mean changes from baseline fasting blood glucose (fbg) and glycated hemoglobin (hba1c). faecalibacterium prausnitzii was a species enriched significantly by gqd; the species was negatively correlated with hba1c and fbg, while 2-h postprandial blood-glucose levels were positively correlated with homeostasis model assessment of b-cell function, which suggests that the structure of gut microbiome was changed by gqd. furthermore, the amounts of beneficial bacterium, such as faecalibacterium spp., could be enriched by gqd treatment. it has been reported that another tcm, polygonatum kingianum, is effective in the treatment of diabetes and related diseases (deng et al., 2012) . a phytochemistry investigation demonstrated that the major types of active chemical constituents of p. kingianum were total saponins (tspk) and total polysaccharides (pspk). tspk and pspk could prevent the increase of fasting blood glucose after oral administration, and tspk could increase the content of fasting insulin. since tspk and pspk improved the intestinal microecology by increasing the abundance of firmicutes and decreasing that of bacteroidetes and proteobacteria, tspk and pspk could prevent t2d by changing the regulation of the gut microbiome (yan et al., 2017) . huang-qin decoction (hqd) is widely used to alleviate gastrointestinal disorders such as inflammatory bowel disease. hqd significantly inhibited the weight loss, tissue damage, colon shortening, and inflammatory cytokine changes caused by dextran sulfate sodium (dss). the relative abundance of lactococcus in the dss + hqp group was higher than that in the dss group, while desulfovibrio and helicobacter were decreased, indicating that hqd can improve dss-induced inflammation through its regulation in the gut microbiome. in addition to tcm directly acting on gut microbiome to ameliorate diseases, some tcms exert indirect effects on the intestinal flora . ginsenosides and polysaccharides in du-shen-tang made from panax ginseng are used to investigate their pharmacological effects on acute cold stress and overfatigue. it was demonstrated that the intestinal metabolism and absorption of certain ginsenosides were improved by polysaccharides. in addition, in recovery of the disordered gut microbiome, polysaccharides especially boost the growth of two important probiotics, lactobacillus spp. and bacteroides spp. (zhou et al., 2016) . glycyrrhiza uralensis fisch., also named licorice, has been commonly used for sore throat and gastrointestinal diseases. after administering different doses of licorice aqueous extracts to mice, they found that the proportion of bacteroides gates decreased significantly, and the proportion of phylum firmicutes increased and became dominant. bacteroides was reported to be associated with iga in humans and may cause colitis, and more phylum firmicutes than bacteroides lead to more efficient absorption of food calories. therefore, it is speculated that licorice aqueous extract can promote intestinal absorption, anti-inflammatory effect, and treatment of abdominal pain . diammonium glycyrrhizinate (dg), the main component of licorice root extracts, is a compound of the natural bioactive pentacyclic triterpenoid glycoside, can protect against nonalcoholic fatty liver disease (nafld) in mice through the decreasing of firmicutes-to-bacteroidetes ratio and endotoxin-producing bacteria such as desulfovibrio, and elevate the abundance of probiotics such as proteobacteria and lactobacillus. dg can also augment the levels of short-chain fatty acid (scfa)-producing bacteria such as ruminococcaceae to promote scfa production, and restoration of intestinal barrier . the regulation of tcm on human health can also be reflected in other microbial communities, including saliva and tongue coating (jiang et al., 2012; liang et al., 2014; li, 2015) . for figure 2 | number of published papers related to tcm-gut microbiota in pubmed and cnki. papers in pubmed were searched using keywords "gut/intestinal microbiota," "chinese," and "medicine"; papers in cnki were searched by chinese name of "tcm" and "gut microbiota/microbiome." the red bar chart represents the papers in chinese; the blue bar chart represents the papers in english. instance, through a network pharmacology approach (li, 2015) , the tongue coating microbiome have been found to be associated with various diseases including colorectal cancer (liang et al., 2014) and "cold-disease" (jiang et al., 2012) . therefore, the regulation of tcms can be reflected in microbial communities of various human body habitats, including gut and oral habitats, indicating quite diverse microbial-based approaches for noninvasive probing of human health status. in recent years, with the widespread use of synthetic and semisynthetic antibiotics, the problem of bacterial resistance has become increasingly serious in clinical fields. pathogenic bacterial infections are critical factors that may affect the development and severity of the disease. tcm was reported to possess a broad-spectrum antibacterial effect. therefore, systematic study on the antibacterial activity of tcm and the further development of new drugs have become the focus of more and more researchers. currently, more and more research indicate that tcm has antibacterial effect ( table 1) . in the long history of tcm treatment, diet has always been considered as an important category of resources. development of the research of gut microbiome involves not only the drug and tcm but also the daily diet of humans. recently, a rapidly increasing number of studies have indicated the crucial role of the diet for the treatment of disease (leboeuf et al., 2020; li et al., 2020b; moayyedi et al., 2020; naudin et al., 2020; yu et al., 2020) . in addition, studies about the close relationship between the diet and the intestinal flora have gradually aroused attention, which may offer us some new perspective for disease prevention. carbohydrates are important components of the daily diet and include monosaccharides, disaccharides, and polysaccharides. both fructooligosaccharide (fos) and polyphenols can be transferred directly into the large intestine of mammals alone, reshaping the composition of gut microbiome, which is beneficial to human health. the combination of different phenolic compounds and fos had a distinct impact upon the host, and gut microbiome improved by using prebiotics can delay the onset of senescencerelated health problems (zheng et al., 2017; tanabe et al., 2019) . adding catechin to an fos diet could inhibit firmicutes and enhance bacteroidetes. in addition, it turns out that antibiotic treatment influences the diversity and composition of the gut microbial community. furthermore, the use of probiotics or prebiotics to modulate antibiotic-induced gut microbiome destruction has been considered a desired treatment or prophylaxis (bron et al., 2011) . cefixime can reduce the diversity of the microbial community and lead to a significant decrease in the relative abundance of firmicutes. the composition of gut microbiome of lactobacillus and fos probiotic mixture treatment group was much more diverse than that of the natural recovery group, indicating a better recovery effect of the probiotic cocktails on the gut microbiome (shi et al., 2017) . moreover, the composition of the gut microbiome significantly changed in the hfd + fructose (hff)-fed and the hfd + sucrose (hfs)-fed rats compared with the control diet (c)-fed rats; body-fat mass, metabolic inflexibility, glucose intolerance, lipopolysaccharide (lps), insulin, renal reactive oxygen species (ros), malondialdehyde (mda), nadphox, and srebp-1 were significantly higher, and antioxidant enzymes and lean body masses were significantly lower in the hfs group with respect for the hff group (rosas-villegas et al., 2017) , indicating the harmful effect on the hfs group and the hff group on gut microbiome as well as the health of humans. carrageenan, agarose, and alginate are algae-derived undigested polysaccharides that have been used as food additives for hundreds of years. bacteroides uniforms l8 could degrade agarose completely, and the major enzyme secreted was b-agarase. the enzyme produced by isolate 38f6 (bacteroides xylanisolvens and escherichia coli), which degrades k-carrageenan oligosaccharides, is b-carrageenase, and alginate, guluronic acid oligosaccharides, and mannuronic acid oligosaccharides could be degraded by two enzymes from bacteroides ovatus g19 . vitamin d is an important pro-hormone for optimal intestinal calcium absorption for mineralization of bone (khazai et al., 2008) , which is common in high-fat food such as cream and salmon. vitamin d deficiency is a disease caused by air pollution, insufficient sunlight exposure, and altered dietary composition, which have also been associated with other diseases, including autoimmune diseases, hepatitis, and cancer (holick et al., 2011) . the functionality of the vitamin d-vitamin d receptor (vdr) axis in up-regulating and the activation/process of ileal a-defensins was identified. conversely, dietary vitamin d deviancy resulted in the loss of paneth cellspecific a-defensins, which may consequently lead to intestinal dysbiosis and endotoxemia, indicating that vitamin d is essential for the homeostasis of intestinal flora (su et al., 2016) . acetate has been widely distributed in nature, such as in fruits or vegetable oils. a recent study showed that acetate produced by protective bifidobacteria could improve intestinal defense that is mediated by epithelial cells, and this could protect the host against negative infection (fukuda et al., 2011) . in addition, moderate consumption of wine has shown the potential to delay the onset of neurodegenerative diseases: after drinking, microbial metabolites may effectively protect neuroblastoma cells from nitrosative stress injury (esteban-fernandez et al., 2017) . with the application of network pharmacology and related databases and tools, the research on tcm and gut microbiome has been further developed (figure 4) . commonly used databases of tcm gut microbiome research include the tcm database [tcm-mesh , tcmsp (ru et al., 2014) , tcmid , and hit (ye et al., 2011) ], as well as pathogen-host databases [phi-base (winnenburg et al., 2006) and ehfpi ]. tcm-mesh has integrated information about tcm ingredients, compound-protein interactions, as well as protein-disease relationships, to establish the largest resource for tcm target genes and diseases. based on the biological databases and clinical trial results, a researcher can analyze the "tcm-host-gut microbiome" interaction network from a holistic perspective. virtual metabolic human database (noronha et al., 2018) contains information on human and gut microbial metabolism, which is linked to hundreds of diseases and nutritional data by mathematical models. many tools are usually used for analysis and visualization as well. for example, qiime (caporaso et al., 2010 ) is a software that provides an open-source bioinformatics pipeline for performing microbiome analysis from raw dna sequencing data. it includes demultiplexing, quality filtering, operational taxonomic units (otu) picking, taxonomic assignment, phylogenetic reconstruction, diversity of analyses and visualizations. picrust (langille et al., 2013) is designed to predict microbiome functional content from marker gene (e.g., 16s rrna) surveys and full genomes. metaphlan (segata et al., 2013 ) is a computational tool for microbial communities analysis based on metagenomic sequencing data, in which the data were compared with the markers of each species obtained from the known database to determine the species category. muscle (edgar, 2004) and clustalw (thompson et al., 1994) are two algorithms used for multiple sequence alignments; muscle is a computer program for creating multiple alignments of protein sequences. mega (kumar et al., 2016 ) is a computer program package for estimating evolutionary distances, reconstructing phylogenetic trees, and computing basic statistical quantities from molecular data. additionally, itol (letunic and bork, 2016) is an online tool for visualization, annotation, and management of phylogenetic trees. furthermore, with the development of deep learning, many methods have been used for studying the gut microbiome and diseases. for example, a model was constructed to predict responses to anti-integrin biologic therapy for inflammatory bowel diseases through gut microbiome function (ananthakrishnan et al., 2017) . although many approaches are not currently used in tcm study on gut microbiome, related methods will become a future trend. therefore, additional investigations are warranted. furthermore, interactive visualization tools are of equal importance. cytoscape is an open-source platform that could be used for complex network analysis and visualization (shannon et al., 2003) , which is useful for analyzing the network in network pharmacology studies. similar functions are also offered by the web services of many databases. the involvement of the gut microbiome in maintaining the health status of every person will undoubtedly affect the effectiveness of drug treatments, including tcm treatment. here, we provide two case studies to illustrate this, one on the metabolic effect of gut microbiome on tcm, and the other on cancer treatment, to illustrate the mediation role of the gut microbiome in medicinal treatment in general. previous studies have found that many of the chemical constituents of tcm can be transformed and metabolized by the intestinal flora, making it easier for the body to absorb. in other words, the gut is like a processing factory of tcm. the effects of the intestinal flora on different kinds of chemical constituents vary: flavonoids represent a major class of secondary metabolites of plants and can be classified into 12 subclasses: anthocyanins, chalcones, dihydrochalcones, flavanols, flavanones, flavones, flavonols, isoflavones, flavan-3-ols, flavan-3,4-diols, aurones, and proanthocyanidins (crozier et al., 2009) . the effects of these polyphenols in the prevention of cancer, cardiovascular disease, t2d, and cognitive dysfunction are supported by an increasing number of studies (del et al., 2013; rodriguez-mateos et al., 2014) . to exert their effects, flavonoids are metabolized by the gut microbiome, and the resulting compounds may have bioactivity. such bacterial conversion and potential health consequences for the human host (chiou et al., 2014) are hardly unique: baicalin, puerarin, and daidzin, which are widely found in tcm prescriptions, can also be metabolized by gut microbiome (kim et al., 1998) . as baicalin is difficult to be absorbed in the gut, it has to be hydrolyzed by gut microbiome to baicalein to exert its effect. metabolism of baicalin was hardly detected in germ-free rats compared to conventional rats, indicating that gut microbiome play a key role in the metabolism of baicalin (akao et al., 2001) . (mochizuki et al., 1995; sun et al., 2008; shi et al., 2013) . ginsenoside compounds k (ck) is one of the metabolites of ginsengoside, which exerts various pharmacological effects, including antiallergic (shin and kim, 2005) , antidiabetic (kim et al., 2014) , anticarcinogenic (zhou et al., 2010; zhang et al., 2013) , anti-inflammatory (joh et al., 2011; chen et al., 2014) , and antiaging effects (kim et al., 2004) . the occurrence of ck in rat plasma is required for intestinal bacterial hydrolysis after oral administration of ginsengosides (akao et al., 1998) . when human intestinal flora was cultured anaerobically with ginsengosides rb1, rb2, and rc, these ginsengosides were metabolized into ck, where the transformation of rc is conducted by the concert efforts of bacteroides spp., eubacterium spp., and bifidobacterium spp. (bae et al., 2000; bae et al., 2002) . in addition, intestinal bacterial metabolism of ginsengosides was mainly dependent on the composition of intestinal flora, such as bacteroides spp., ruminococcus spp., and bifidobactetium spp. (kyung-ah kim et al., 2013) . additionally, the metabolism of panax notoginseng saponins (pnss) was influenced by gut microbiome, of which proteobacteria may have an effect on the deglycosylated metabolism of pnss by regulating the activities of glycosidases (xiao et al., 2016) . up-regulation of bacteroidetes may increase the activity of redox metabolic enzymes in intestinal flora and accelerate the redox metabolism of pnss (xiao et al., 2016) . oxymatrine and matrine are two main alkaloids in the radix sophorae flavescentis, and oxymatrine could be transformed into matrine by intestinal bacteria when taken orally, and both can be absorbed by the blood . scopolamine was incubated with rat intestinal flora in vitro under limited oxygen conditions, and scopolamine was transformed by gut microbiome into scopine (chen et al., 2006) . anthraquinones have widespread applications throughout industry and medicine, and are naturally distributed in many plants, including rheum officinale baill., fallopia multiflora (thunb.) harald., catsia tora linn., folium sennae, and aloe vera (linn.) n. l. burman var. chinensis (haw.) berg. through a chemical constituent study on the metabolism of rhubarb extract by rat intestinal bacteria, a total of 14 components, including emodin-o-glucosides, aloe-emodin-o-glucosides, physcion-oglucosides, chrysophanol-o-glucosides, and their aglycones were found to be biotransformed by rat intestinal bacteria. twelve major metabolites were identified in the incubation sample, suggesting the importance of the intestinal flora during the metabolism of anthraquinones (song et al., 2011) . carcinogenesis may be mediated by microbiome influencing cellular metabolism, inflammation, and proliferation (zitvogel et al., 2017) . the microbiome regulate cancer at the level of predisposing conditions, initiation, genetic instability, susceptibility to host immune response, progression, comorbidity, and response to therapy. several examples are as follows: there is an increasing number of studies involving mice and humans on the role of intestinal flora in cancer treatments. in mice, the procarcinogenic phenotype expressed by genetically mutated mice has been shown to be transferred to wild-type mice by microbiome transfer (garrett et al., 2009; couturier-maillard et al., 2013; hu et al., 2013) , and transfer of fecal microbiome from patients who are sensitive to cancer treatment into germfree mice has been found to endow these animals with an ability to respond efficiently to therapy (vetizou et al., 2015) , indicating that changes in the composition of intestinal flora indirectly affect carcinogenesis and response to cancer treatment through lifestyle and host genetic. furthermore, the intestinal flora affects anticancer activity, toxicity, as well as pharmacokinetics of drugs at various levels (dzutsev et al., 2015; spanogiannopoulos et al., 2016) . several anticancer drugs have experimentally been shown to be affected by the intestinal flora , including the hydrolysis of methotrexate, the nitroreduction of misonidazole, and the deconjugation of irinotecan. in germfree mice or mice in which gut commensals were exhausted by broad-spectrum antibiotics, the antitumor effect of cisplatin or oxaliplatin treatment on subcutaneous transplantable tumors was decreased evidently (lida et al., 2013) . probiotics lactobacillus acidophilus in antibiotic-treated mice restored cisplatin-induced inflammatory gene expression (gui et al., 2015) , indicating the mediation role of gut microbiome on drug efficacy. additionally, oral administration with bifidobacterium bifidum and l. acidophilus, a probiotic combination, was found to prevent intestinal toxicity in cancer patients who were treated with both cisplatin and radiotherapy (chitapanarux et al., 2010) . in addition to the direct effects on the enzymes and microbiome on the absorption and metabolism of drugs (maurice et al., 2013; feng et al., 2015; montassier et al., 2015) , the indirect effects of gut microbiome on the metabolism of drugs were reported to occur through regulation of gene expression and the physiological function of the local mucosal barrier and of distant organs, such as the liver (bjorkholm et al., 2009; selwyn et al., 2015; selwyn et al., 2016) . radiotherapy is one of the traditional methods for cancer treatment. because radiotherapy alters the microbiome composition and destroys the intestinal barrier (barker et al., 2015) , pathobionts can easily access the intestinal immune system (belkaid and hand, 2014) . with the development of research on cancer and microbiome, probiotics have been reported to be beneficial in prevention of radiation-induced enteropathy in some clinical studies. for example, patients 2 | recent studies on the close relationship between colorectal cancer (crc) and the gut microbiome. year reference fecal metabolomic signatures are associated with gut microbiome and colorectal cancer pathogenesis: (1) the levels of polyunsaturated fatty acids and sphingolipids are further increased in patients with crc, which may represent early changes in crc. (2) regardless of disease status, age, or gender, there is a strong overall correlation between microbiome and metabolomics data, and the correlation is higher in women than in men. (3) the abundance of multiple bacteria in firmicutes, actinobacteria, and bacteroides is strongly correlated with elevated metabolite pathways in patients. 2020 (kim et al., 2020) non-nucleatum fusobacteria common in southern chinese populations are associated with colorectal cancer: (1) irrespective of crc disease status, the prevalence, relative abundance, and diversity of fusobacterium in southern chinese populations are higher than those in other regions. (2) in addition to non-nucleatum fusobacteria, fusobacterium varium and fusobacterium ulcerans and other fusobacterium groups are also enriched in crc patients. (3) several non-nucleatum taxa possess fada homologues and were enriched in crc cohorts. 2020 (yeoh et al., 2020) a pathological imbalance of the gut microbiome (dysbiosis) is present in colorectal cancer patients: (1) bacteria affect crc directly or indirectly, by secreting metabolites, by invading tissues, and by modulating the host immune response. (2) fusobacterium, peptostreptococcus, porphyromonas, prevotella, parvimonas, bacteroides, and gemella are among the most prominent crc-associated bacteria. 2020 (ternes et al., 2020) changes in gut microbiome can reduce the carcinogenic effect of colitis-related colorectal cancer: (1) enterobacter strains are associated with molybdenum-dependent metabolic pathways in the colitis model. oral sodium tungstate can inhibit the activity of e. coli molybdenum and reduce the colonization of e. coli in the intestine. (2) limiting the growth of enterobacteriaceae can control intestinal inflammation and reduce the incidence of colorectal cancer. (3) oral sodium tungstate treatment can reduce intestinal inflammation and inhibit tumorigenesis caused by colicin. 2019 (zhu et al., 2019) colorectal cancer can be diagnosed by lachnoclostridium as a marker: (1) metagenomic analysis identified "m3" from a lachnoclostridium sp., fusobacterium nucleatum (fn), and clostridium hathewayi (ch) to be significantly enriched in crc. (2) the combination of m3 with fn, ch, bacteroides, and fit can diagnose crc most accurately. 2019 (liang et al., 2019) intestinal fungal disorders in colorectal cancer, expected to be used for diagnosis: (1) crc intestinal fungal disorders, increased ratio of basidiomycetes/ascomycetes, increased malassezia, decreased yeast and pneumocystis, 6 genus enrichment, 38 species abundance changes. (2) the co-occurrence association between fungi and the mutual exclusion of bacteria-fungi in crc increased, and the positive interaction between proteobacteria and ascomycota became mutually exclusive in crc. 2019 (coker et al., 2019) different intestinal flora species increased or decreased the effectiveness of drugs: (1) bacterial nucleotide metabolism genes in caenorhabditis elegans affect drug efficacy. (2) 5-fluorouracil and 5-fluoro-2'-deoxyuridine act through bacterial ribonucleotide metabolism to exert their cytotoxic effects in c. elegans rather than by thymineless death or dna damage. two-way bacterial mediation effects of fluoropyrimidine on host metabolism may contribute to drug efficacy: (1) microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin b 6 , b 9 , and ribonucleotide metabolism. (2) disturbances in bacterial deoxynucleotide pools amplify 5-fu-induced autophagy and cell death in host cells. 2017 (scott et al., 2017) levels of p. anaerobius are higher in human colon tumor tissues and adenomas compared with nontumor tissues; this bacterium increases colon dysplasia in a colorectal cancer mouse model. p. anaerobius interacts with tlr2 and tlr4 in colon cells to increase the abundance of reactive oxidative species, which promotes cholesterol synthesis and cell proliferation. 2017 (tsoi et al., 2017) f. nucleatum plays a key role in colorectal carcinogenesis through suppression of the hosts' immune response to tumor. a diet rich in whole grains and dietary fiber is associated with a lower risk of f. nucleatum-positive colorectal cancer. 2017 (mehta et al., 2017) key microbial markers are critical in the classification of crc cases and are commonly used in the diagnosis of disease. 2017 (shah et al., 2017) (1) aim2-deficient mice are hypersusceptible to colonic tumor development. (2) susceptibility of aim2-deficient mice to colorectal tumorigenesis is enhanced by dysbiotic gut microbiome compared with healthy wildtype mice. 2015 (man et al., 2015) zhang et al. with head and neck cancer received lactobacillus brevis cd2 lozenges during chemotherapy and radiation, and the incidence of treatment-induced mucositis decreased while the treatment completion rate increased (sharma et al., 2012) . immunotherapy is another approach that has shown potential in treating solid cancers and hematopoietic (couzin-frankel, 2013) . the proliferation and antitumor cytotoxic activity of transferred t cells in the tumor were increased by the total-body irradiationinduced translocation of intestinal flora into the mesenteric lymph nodes (paulos et al., 2007) . moreover, many studies have revealed the crucial role of intestinal flora in colorectal cancer treatment recently ( table 2) , indicating the close relationship between gut microbiome and cancer treatment. in recent years, with the modernization of tcm and the development of systems biology, our understanding of tcm has been significantly advanced. tcm has gradually transformed from an experience-based approach to an evidence-based medicinal system, of which chinese scientists have made great contributions. we modify this sentence to "for example, it was discovered that arsenic induces the degradation of a key leukemogenic protein and exerts a pharmacological effect on the treatment of acute promyelocytic leukemia (zhang et al., 2001) . youyou tu, the nobel prize winner, has also focused on tcm research and research on the combination of western medicine and tcm for many years (tu et al., 1981; tu et al., 1982) . the trend has become clear that more and more tcm researches use molecular biology approach. however, with the systems biology approach enabled, the potential of tcm studies at the molecular level remains to be better exploited. on the other hand, research about the microbiome, in particular the gut microbiome, has made enormous progress during recent years. with the launch of various international projects on the human microbiome, research on the gut microbiome has become a hot research area. studies have proven that tcm could be used as a perfect agent to treat many kinds of diseases, many of which were mediated by gut microbiome. therefore, combination of the research of tcm and gut microbiome is important to maintain the healthy status of the host-microbiome holobiont. in addition, with the advancement of biological big data research, databases can now provide a more holistic perspective for tcm research and intestinal flora research. however, with the regulation or mediation principles of gut microbiome on human health still lacking except for a few diseases, more microbiome experiments, sequencing data, and analytical methods have yet to be conducted, collected, or developed to better understand these principles. it has become urgent that several problems remain to be solved for both tcm and gut microbiome research areas, especially in the era of biological big-data. with the constant increase in research in related fields, various experimental data have been generated. these all require better ways to curate, analyze, and interpret the concerted effects of tcm and the microbiome on human health. first, a more comprehensive database on tcm and gut microbiome is needed, which should not only include the interaction between the tcm and the gut microbiome but should also represent the advantages of tcm databases and microbiome databases in accelerating the application of tcm on a global scale. second, analytical methods must keep pace with the rapid development of modern systems biology. a more powerful data mining tool is required to investigate the complex and multi-scale "tcm-hostmicrobiome" network. third, investigations on the mechanisms of mutual regulation between tcm and gut microbiome are limited. how do various tcms regulate dysbiotic microbiome in concert? what kinds of enzymes produced by gut microbiome are responsible for metabolizing tcm and exerting the effect of tcm? these only represent a few questions that are to be answered. fourth, the microbiome has been indicated as a precision medicine frontier (kuntz and gilbert, 2017) , as interindividual differences in microbiome patterns have been reported, even between co-raised twins. finally, it is only when enough time-series samples are collected can we answer questions about dynamic patterns for the "tcm-host-microbiome" network. such dynamic pattern is the basis for the "shelf life" and "personalized medicine" for the microbiome-mediated tcm treatment, and could push for the modernization of tcm. in summary, researchers might take advantage of tcm and microbiome for better health care and treatment, as both possess the great potential in health care. this might lead to another paradigm shift: from genome-centric precision medicine to systems biology approach enabled holobiont-centric precision medicine. kn and hb conceived and proposed the idea. kn, hb, and rz jointly designed the main idea of this work. kn, rz, and xg contributed to the interpretation of data for the work. kn, hb, xg and rz drafted the manuscript, kn, hb, xg, and rz revised it critically for important intellectual content. all authors read and approved the final manuscript to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. drug metabolism: intestinal bacterial hydrolysis is required for the appearance of compound k in rat plasma after oral administration of ginsenoside rb1 from panax ginseng balicalin, the predominant flavone glucuronide of scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases constitutive beta-glucosidases hydrolyzing ginsenoside rb1 and rb2 from human intestinal bacteria metabolism of ginsenoside r(c) by human intestinal bacteria and its related antiallergic activity the in vitro growth-inhibitory effect of euphorbia humifusa willd. 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purification, partial characterization, and bioactivity of polysaccharides from panax ginseng impact and consequences of polyphenols and fructooligosaccharide interplay on gut microbiota in rats studies on the preparation, crystal structure and bioactivity of ginsenoside compound k gut microbiotainvolved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer anticancer effects of the microbiome and its products the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 zhang, gao, bai and ning. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-308431-l4sv28hj authors: schindler, seth; jepson, nicholas; cui, wenxing title: covid-19, china and the future of global development date: 2020-08-04 journal: nan doi: 10.1016/j.resglo.2020.100020 sha: doc_id: 308431 cord_uid: l4sv28hj abstract tensions between the united states and china have been escalating in recent years, and the covid-19 pandemic has intensified their competition. if sustained, china's more effective public health response and economic restart will burnish its leadership credentials in the field of global development. this article lays out the origins and distinctive features of china's development policies and vision, and argues that in a post-covid world these may constitute an appealing alternative to the us-led development paradigm for many developing countries. we contrast the universalism and rigidity of contemporary development orthodoxy with china's emphasis on bilateral and pragmatic forms of development cooperation borne out of its domestic experience. while chinese development assistance and loans enhance its soft power, partner countries are offered significant autonomy and flexibility. we conclude by outlining three factors which may impact the future of chinese leadership in the field of global development; a reconciliation of global financial governance and china's development lending, the outcome of the upcoming american presidential election and domestic discontent within china over the belt and road initiative. j o u r n a l p r e -p r o o f aides (bbc, 2020) . china's response to the crisis and its aftermath was effective by comparison. 1 to recap events, chinese authorities reported an outbreak of pneumonia cases of unknown origin in wuhan to the world health organization on december 31, 2019. by january 7 th chinese officials had identified a novel coronavirus as the cause and its genetic sequence was shared with the who on january 12 th (who, 2020a) . by late-july china had reported 4,659 covid-19 related deaths to the who (2020b). the us government and usbased researchers have charged that the actual number of deaths in china is in the neighbourhood of 36,000 (he et al., 2020) and this controversy is unlikely to be resolved. what is indisputable, however, is that minor outbreaks in china have been contained and at the time of writing, life has returned to normal in most of china. meanwhile, the us registered its first case of covid-19 on january 20. by february 26 fifty-eight people had tested positive for the virus and donald trump assured the public that "you have 15 people , and the 15 within a couple of days is going to be down to close to zero." community transmission of covid-19 accelerated in the us in march, and by the second week of april new york state had registered more cases of covid-19 than any country. new infections levelled off for a brief period, but then accelerated in july, particularly in southern and western states. by late-july florida was registering more new cases than any country on a daily basis. 2 as this article goes to print about 147,000 people have died as a result of covid-19, and to put it in perspective, that's equivalent to nearly fifty september 11 terror attacks and american casualties in 2.5 vietnam wars. animosity between the us and china intensified in the midst of the pandemic. trump began to refer to covid-19 as a "chinese virus" in march, while his aides called it the "kung flu." american and british officials have repeatedly charged that china inhibited a concerted global response by withholding important information about covid-19. meanwhile a narrative began to circulate widely in china that covid-19 was brought there by members of the american military. this is not beijing's official line, but it has been repeated by officials and media outlets close to the government (scarborough, 2020) . western media have also questioned the official version of events, such as a british tabloid that interrupted coverage of quarantined celebrities to report that covid-19 may have leaked from a us-backed virus research laboratory in wuhan (mulraney and owen, 2020) . not to be outdone, trump countered that the novel coronavirus actually originated in a lab in wuhan, although he claimed he could not share the evidence publicly (sevastopulo and manson, 2020) . tension escalated further when washington closed the chinese consulate in houston, and in a tit-fortat move beijing closed the american consulate in chengdu. this dispute will not be settled in press briefings, diplomatic communiques or on social media. instead, the narrative will fall into place in the wake of covid-19's epidemiological curve. covid-19 is sweeping across the us from coast to coast, and american leadership will be eroded if the death toll runs into the hundreds of thousands. a recent global survey confirmed that the vast majority of people around the world think that china's response to covid-19 has been far more effective than the united states' (wintour, 2020) . if china manages to contain further outbreaks and restart its economywhich is by 1 it is important to note that china is not the only country that responded effectively to limit the spread of covid-19. for example, other commendable policy responses were implemented by governments in vietnam, south korea, the state government of kerala. 2 for data on covid-19 in the us see: https://www.nytimes.com/interactive/2020/us/coronavirus-us-cases.html j o u r n a l p r e -p r o o f no means assuredits leadership credentials will be burnished, and the enhancement of chinese leadership will be evident in the field of global development. in the remainder of this essay we explain why covid-19 differs from the 2008 financial crisis in which similar predictions were made surrounding the inexorable rise of china. we then explain in brief the origins of the notion of 'development' in china and we explore the implications of chinese leadership for the field of global development. this paradigm outlined by horner and hulme (2019) accounts for emergent patterns of wealth distribution and wellbeing in the 21 st century, and the emphasis is on increasing inequality within countries while there is a convergence among countries. this leads to the rejection of "a clear spatial demarcation between first and third worlds, 'developed' and 'developing', or rich and poor, countries" (ibid., p. 349) , in favour of the recognition of the global scope of civilizational challenges (e.g. global health pandemics and climate change). it is in this context that the world has taken note of china's response to covid-19 and we conclude with future scenarios in which china's leadership is cemented, or challenged by a renewed pax americana. american foreign policy guru henry kissinger (2020) proclaimed that covid-19 threatens to "set the world on fire" and it may ultimately upend the global order. implicit is an assumption that china will replace, or at least challenge, american supremacy. in some sense, of course, we've been here before and predictions of china's unstoppable rise sound all too familiar. the 2008 financial crisis, with its origins on wall street, prompted a slew of obituaries for highly financialised us capitalism. the era of unrestricted capital flows and unregulated markets seemed a thing of the past as the world's economic and geopolitical centre of gravity appeared to move both east and south. china emerged from the crisis relatively unscathed and of sufficient economic heft to play a central role in dragging the world economy out of the mire through a huge and decidedly non-neoliberal stimulus programme (tooze, 2018) . although talk of china's global hegemony was premature at minimum, its sustained economic growth lifted hundreds of millions of people out of poverty. crucially, china employed a pragmatic and eclectic mix of policies which ran counter to orthodox development policy promulgated by the likes of the world bank and the international monetary fund. one enduring impact of the 2008 crisis has been a gradual hollowing out of the neoliberal edifice. this did not turn out to be the simple return to keynesianism which some predicted at the time, and the neoliberal 'zombie' shuffled on (peck 2010) . but in much of the oecd, neoliberal ends are increasingly sustained via means antithetical to the paradigm's intellectual foundations (not least in juicing the stock market via quantitative easing). many neoliberal regimes had previously fused corporate welfare with austerity for everyone else, but these practices became so apparent after 2008 that the sense of a coherent project with the potential to deliver broad-based progress has been lost. few now believe in neoliberalism's promises, and the missionary zeal with which these were pursued during the reagan and clinton eras now seems bizarrely anachronistic. this disintegration of neoliberal ideology almost went unnoticed in the us because american hegemony remained unchallenged. importantly, however, it was no longer sustained by faith in free markets and global economic integration, but by the expansive policies of the us treasury and federal reserve under the resolute leadership of barack j o u r n a l p r e -p r o o f obama. indeed, while the eu fumbled its response to the crisis, the us provided a host of central banks with dollars and maintained global liquidity. this decisive action at once prevented a financial collapse while simultaneously compounding the dysfunctions of global finance. the injection of massive amounts of liquidity into the world economy by the fed (joined by the banks of japan, england and later the european central bank) encouraged a build-up of debt by corporations and individuals. stock market bubbles were inflated and the financial sector's dislocation from the real economy deepened. that profound cleavage is one of the most important legacies of 2008. it is handily illustrated by the performance of the the s&p 500 index, which as of 8 june 2020 had made net gains over the year so far, despite a global pandemic and shutdown of activity in most major economies (winck 2020; krugman, 2020) . this crisis differs from 2008 in three very important ways. first, the scale and scope of the impending economic crisis will require unprecedented state intervention that will be even more difficult to reconcile with neoliberal ideology. on this point the economist (2020) and new left review (brenner, 2020) are in agreement. we have already seen countries move to impose capital controls, bail out private corporations, roll out basic income grant schemes and expand social welfare programs. some countries may have little choice but to nationalize failing companies and manage production of essential goods. second, china was an engine of growth after the 2008 crisis but its global presence was modest in comparison to today. since the announcement of its signature belt and road initiative in 2013, china has ramped up its activity abroad and significantly enhanced its soft power. finally, the us has scorned multilateralism under donald trump's banner of america first, and even long-time allies are weary of washington's transactional diplomacy. meanwhile, the murder of george floyd at the hands of minneapolis police officers unleashed pent up rage across the us that exposed deep rifts in american society (cobb, 2020) . the us department of homeland security deployed troops to portland, oregon, and they have used unmarked vehicles and detained protestors without warrants (green, 2020). the result is that the us government faces a crisis of legitimacy at home and abroad, and its leadership has not been this tenuous in the post-war era. the us will enjoy certain advantages as long as the dollar is the world's primary reserve currency. this is not necessarily apparent when times are good because managing the world's reserve currency does come with costs that can make it seem like a burden (pettis, 2011) . however, it affords the us tremendous agency in times of crisis because it can borrow vast sums at the very moment when other countries are trying to stem capital flight. indeed, control over the world's common unit of account and largest asset class has emerged in this crisis as perhaps the main remaining weapon in the american hegemonic arsenal. no serious challenger to the dollar looks likely to emerge in the medium term, barring a complete collapse of world financial systems (in which case, all bets are off). while chinese authorities are cautiously promoting renminbi internationalisation, its current lack of convertibility means it has a great distance to travel before even entering the conversation as a possible global reserve currency. in 2009, then people's bank of china governor zhou xiaochuan called for imf reform in order to position the special drawing rights (sdrs) as a possible alternative to the dollar (zhou 2009). sdrs are based on a basket of five currencies and are issued by the imf to member as a form of foreign exchange reserve asset. the imf's control over the sdrs makes any use of it to undermine dollar hegemony highly unlikely so long as the us retains its veto at the fund. recently, for example, the us has scuppered an imf plan j o u r n a l p r e -p r o o f to issue new sdrs to members, which was intended as a quick fix for countries' liquidity needs (birdsall 2020) . instead, the us prefers to work directly, unilaterally and selectively in providing liquidity through the fed. favoured states have been granted dollar swap lines, while others are afforded much more limited assistance (johnson 2020) . the choice to restrict assistance in this way is causing disquiet among those left out, including key developing countries like turkey, indonesia, south africa and nigeria. thus, maintaining global liquidity through the selective provision of access to dollar swap lines will not be enough to shore up american leadership, which will be eroded in the absence of a convincing ideology or guiding principle beyond self-interest. the dollar is likely to remain the global reserve currency by default, but as countries grapple with the health impacts and economic fallout from covid-19, many will turn to china for leadership given the effectiveness of its response. chinese leaders are well aware that they may be able to steal a march against the us. the chinese government and chinese firms recently began donating protective medical equipment to countries around the world. this was met with derision by the eu's leading representative for foreign policy, who warned that "there is a geopolitical component including a struggle for influence through spinning [the narrative] and the 'politics of generosity'" (lau, 2020) . lowand middle-income countries will be disproportionately impacted by the looming economic crisis (goodman et al., 2020) , and they are unlikely to be offended by the politics of generosity. in contrast, the us has provided approximately $100 million to developing countries "to support virus prevention, detection, and control" (pompeo, 2020) but it cannot be used to purchase personal protective equipment (eg masks and gowns for frontline healthcare workers) in order "to ensure there would be enough ppe for the u.s." (gharib, 2020) . in a stunning plot twist, the us was accused by a german official of "modern piracy" after intercepting a shipment of n95 respirators bound for berlin and redirecting them to the us (willsher et al., 2020) . we argue that developing countries will be less offended by the politics of generosity than they will by modern piracy, and we anticipate that china will become the primary development partner for many countries as a result. china's assertiveness in the field of global development poses a direct challenge to traditional donors, such as the us and uk, as well as international financial institutions such as the world bank (mawdsley, 2019) . one common misconception is that the norms, objectives and practices of global development are agreed upon, and that china is elbowing its way into the crowded group of countries and institutions that provide aid and expertise. on the contrary, china is beginning to shape the very notion of development, and this raises the question: what is the meaning of 'development' according to china? to answer this question, it is necessary to understand how the concept of 'development' evolved from earlier understandings of state-induced change on a grand scale. the us government launched a raft of measures designed to 'reconstruct' the southern states whose economies were ravaged by the country's brutal civil war (1861-1865). in the late-19 th century american policy makers turned their attention overseas to their quasi-colonies. american exceptionalism and technological mastery were meant to catalyze the modernization of stagnant primitive societies. development became a cornerstone of american efforts to halt the spread of communism after the second world war. the ussr and the us competed for client states during the cold war, yet their development aid programs were strikingly similar in terms of their objectives and practice. both were informed by the experience of colonizing a vast internal frontier, and both leveraged the command of technology and a rationalized organizational structure to foster industrialization. large-scale investments in turnkey projects in remote areas, such as dams and steel plants, were designed to have ripple effects and result in the growth of industry and the enhancement of productivity in agriculture. historian michael adas (2006, p. 276 ) explained that this served to limit the policy space of recipient countries: the underlying similarities in the developmentalist ideologies and policies advanced by the rival superpowers in the cold war meant that the options available to leaders and planners in post-colonial societies were much more limited than currently prevailing interpretations of the era, which stress superpower differences and competition, would suggest. china remained aloof from debates surrounding mainstream development policy advocated by the americans and the soviets throughout the cold war. china's irrevocable split with the ussr in the late-1950s led to the departure of soviet technical advisors (lã¼thi, 2010). one result was that the chinese communist party's reputation was never tarnished by its association with stalinism. in contrast, revelations of stalinism's excesses led to the collapse of mass support for communist parties in western europe. communist ideology advanced by organized parties was replaced by a distrust of metanarratives and it gave way to a preference for relativism, difference and local particularisms that inhibited a coordinated resistance to the rolling back of keynesian welfare states in the 1980s. neoliberalism became the ideological foundation of development in the 1980s, and according to colin leys (1996, p. 24) , "the only development policy that was officially approved [by the washington consensus] was not to have one." the human and environmental costs of neoliberal restructuring were increasingly apparent as the 1980s wore on, yet opposition remained convulsed by conflict that pitted marxists, who had regrouped under a banner of critical political economy, against adherents of post-development who were committed to identity politics. china avoided the ideological battles that characterized development studies in the west throughout the 1980s and 90s. china was never forced to accept a loan from the international monetary fund under duress, and the political autonomy it has enjoyed as a result sets it apart from other brics countries. most importantly, chinese policy makers have had the time and policy space to experiment with an eclectic mix of pragmatic reforms. to this end, five special economic zones were established in the mid-1980s and served as policy laboratories where western institutions were tested (yeung et al., 2009; chen, 2019) . political reforms were decidedly abandoned after 1989, but economic experimentation and reforms continued apace. while sectors of china's political economy became increasingly market-oriented, it avoided the radical shock therapy implemented in other developing countries and the state remained sovereign vis-ã -vis markets. policy makers pursued a set of objectives strikingly similar to what western theorists outlined in 'modernization theory,' that is, broad-based structural transformation from an agrarian society to a center of advanced techno-industrial production and innovation that exhibits an increasingly sophisticated j o u r n a l p r e -p r o o f division of labour. hundreds of millions of people were lifted out of poverty and living standards improved for the vast majority, which explains why the chinese government enjoys a high level of trust and legitimacy among its citizenry (tang, 2018) . this hybrid and pragmatic approachrather than a universally applicable policy framework informed by ideology -informs china's understanding of development. in the years after 2008, a conversation emerged in academic and development circles around the potential for countries to follow the example of an alternative 'china model.' after an initial wave of interest, though, these debates subsided for two main reasons. first, the identification of a 'beijing consensus' surrounding development policy proved elusive. it was impossible to identify the parameters of a concrete set of ideologically-informed policies in the manner of john williamson's (2004) original washington consensus. second, china's post-1978 economic miracle was the result of very particular circumstances that developing countries could not hope to replicate. most important was china's virtually unlimited supply of cheap but relatively productive labour, whose integration with east asian value chains was mediated by the chinese diaspora. for countries used to adhering to an economic orthodoxy that has too often wrought instability and crisis, the absence of an ideologically informed policy framework is precisely what makes china an appealing development partner. for the most part, china's development cooperation is not conditional upon domestic policy reforms. the most notable exception is the chinese leadership's sensitivity towards perceived support for separatism or 'splitism.' for example, mongolia's attempt to secure chinese loans was temporarily derailed as a result of a 2016 visit by the dalai lama to ulan bator (wong, 2016) . critics maintain that china's official policy of non-interference is a defensive manoeuvre aimed at pre-empting foreign criticism of politics surrounding taiwan, hong kong, tibet and xinjiang 3 regardless of china's motives, many governments find it easier to meet this condition than to implement the suite of reforms demanded by neoliberal institutions that act as custodians of mainstream development policy such as the imf and world bank. china's growing economic and political entanglements abroad, particularly in east asia and africa, have necessitated a gradual de facto shift away from non-interference. in the aftermath of south sudan's independence, for example, china leaned on the juba government to end conflicts with both khartoum and rebels which threatened chinese oil interests. nevertheless, chinese envoys have cultivated relationships with ruling and opposition parties in numerous countries. and when friendly governments have been ousted by elections or coups, chinese diplomats have courted their replacements (holslag, 2011) . in general, china j o u r n a l p r e -p r o o f has been happy to lend to democracies and autocracies alike, as well as both us allies and socalled rogue states. chinese development assistance incorporates spatial planning strategies that are a legacy from the post-reform period when china's slumbering interior was activated through its integration with entrepot cities along its south-eastern coast. plans tend to emphasize the importance of inter-city, regional and even transnational connectivity via expansive corridors (mayer and zhang, 2020) . the realization of these ambitious plans requires significant investments in infrastructure such as regional energy grids, railways, highways and ports (schindler and kanai, 2019) . chinese planners consider this turnkey infrastructure a necessary precondition for economic growth, and countries are encouraged to finance construction through loans. most loans for large-scale infrastructure projects are issued by the china development bank and china exim bank, and neither institution has shown any interest in reforming the domestic economic policies or institutional structures of borrowers. while project-specific conditions are common (the insistence that chinese firms are the lead contractors, for example), pragmatism and flexibility remain the guiding principles of china's overseas development policy (lee, 2017) . the trump administration has promoted the idea of chinese 'debt trap diplomacy' (schindler, 2019) . the charge is that china is acting as a kind of international loan shark by deliberately lending countries unsustainable amounts, then using debt as leverage to force borrowing governments to accept chinese domination or relinquish strategic infrastructure in exchange for debt relief. proponents of this narrative often cite the example of hambantota port in sri lanka, which was handed over to china in 2016. there is speculation that hambantota will eventually become a chinese naval base. the reality is rather different. the port was a loss-making venture and associated with the previous government's national development plans. the new government in colombo struck a deal to sell a 70% share to china merchants port for $1.12 billion. it is certainly true that sri lanka was struggling with a heavy debt burden at the time, but only 10% of its outstanding debt was owed to china. the idea that beijing engineered a debt crisis in sri lanka in order to take possession of hambantota does not bear scrutiny (sautman and hairong, 2019; brautigam, 2020) . as china has expanded its lending portfolio some states have indeed struggled to repay their loans. china's responses highlight its preference for bilateral negotiations and pragmatic solutions over multilateral engagement. ordinarily, governments seeking debt relief must deal with the paris club. it is a grouping of the major lending states that act in concert to establish a common negotiating position. getting a paris club deal, in turn, depends on a country agreeing to an imf program, that typically includes policy reforms designed to ensure outstanding debt is repaid. china is not a member of the paris club. instead, it conducts its own separate talks with governments in debt distress, and again, china appears to approach these negotiations on a case-by-case basis. some small debts have been written off entirely (kratz et al., 2019) , other loans have been restructured and expanded or amortized over a longer period to ease the immediate burden (south china morning post, 2019; white, 2020) . finally, in some cases the cost of planned infrastructure projects has been revised downward (mitchell and woodhouse, 2019) . rather than a model with universal applicability, china's development assistance is goal oriented. first and foremost, chinese development assistance appears designed to reorient the global economy in ways that strengthen sino-centric production networks (hung, 2017) . according to zhang (2019, p. 321 ) the belt and road initiative "could entrench sino-j o u r n a l p r e -p r o o f centric networks of trade, investment, and infrastructure in east asia, southeast asia, eurasia and beyond, echoing japan's 'flying geese' model, but on a much more expansive geographic dimension, and in a more complicated, diverse and multi-scalar manner." this entails unbundling existing value chains driven by lead firms within china and offshoring certain segments. to this end, china builds hard infrastructure first (eg ports, railways, energy grids), firms locate production facilities in proximate industrial parks and officialdom subsequently exerts soft power if necessary. this is a marked difference from washington consensus institutions which, throughout the 1980s and 1990s first exerted soft power to open markets, and then allowed market forces to determine whether hard infrastructure was built. china's approach has proven attractive to many developing countries, which is evident from the number of countries that have agreed to participate in the belt and road initiative. shortages of basic medical equipment in advanced-industrial countries has led to a realization that they are entirely dependent on china. the us and japan have made initial moves to decouple their domestically-anchored value chains from china, while china is simultaneously seeking to unbundle its domestic value chains. if these trends continue they could radically re-shape economic geography in the 21 st century, and at the very least, we anticipate an expanded role for china in the field of global development. the true scale of covid-19's impact on the global economy is impossible to assess at present. the imf currently predicts that 2020 will see the worst recession since the 1930s, though the damage could be even greater if the pandemic persists into the second half of the year (gopinath, 2020) . developing countries face capital flight, currency crises and cratering export revenues, and many are only beginning their battle against the virus. this situation has already made it difficult for countries to meet repayments on debts owed to governments, international organisations and private creditors. the world bank backed a g20 initiative to suspend debt repayments from developing countries (malpass, 2020) , and china urged the world bank to "lead by example" and do the same (lawder, 2020) . debt relief in the short term will provide many countries with necessary reprieve. however, a long-term solution will be far more difficult to engineer because the us retains a dominant position at the world bank and imf and insists that no assistance from either institution be used to pay off debts to china (lawder and crossley, 2020) . this is an attempt to slow china's economic expansion overseas, but it also reflects an incompatibility between china's lending and washington consensus principles. up until now, this impasse has been managed by borrowing countries first reaching bi-lateral debt relief deals with china, before then turning to the imf. this is a slow but feasible workaround for individual countries, but it cannot work if dozens of countries require debt relief at the same time. any sustainable solution will require china to be fully integrated into the multilateral debt system of the paris club and imf, yet doing that successfully will mean accommodating china's very different lending philosophy. this would require an overhaul that would lead many g20 countries to balk, not least the us. if an accommodation is not reached between china and the paris club, developing countries may find themselves in a position where they have to choose between defaulting on either chinese loans or paris club and imf debt. at present this impasse is far from being resolved (parkinson et al., 2020) , and one result of a prolonged struggle surrounding debt could be the emergence of two distinct economic blocs j o u r n a l p r e -p r o o f reminiscent of the cold war. there are signs this is already be happening. for example, after the us withdrew from the nuclear deal with iran and sanctions were re-imposed. european countries balked at us intransigence but they were unable to piece together a program to mitigate american sanctions. rather than forcing the iranians to the bargaining table, however, this drove them into a $400 billion deal with china (cohen, 2020) . second, if trump is elected to a second term in november we can expect more of the same. american policy will remain jingoistic and self-serving, while incompetence will continue to characterize the us government's operations at home and abroad. in this scenario china would continue to be harassed by the us in ad hoc ways that beijing would likely be able to parry. developing countries would continue to hedge their bets (see kuik, 2020) and avoid alienating the us but many would look to china for leadership and stability. if joe biden wins the us election in november the situation will become more complicated for china. while biden's approach to china would surely be more civilized in tone than trump's, issues such as the balance of trade and intellectual property rights would nevertheless have to be resolved before relations could be reset. the countries would remain competitors, yet unlike trump, biden could go on a global charm offensive and marshal support among traditional american allies. even before the covid-19 pandemic european companies were seeking to reduce their dependence on china (rapoza, 2020) while the eu has soured on a trade deal with china (bermingham, 2020). similarly, japan followed suit by providing support in its covid-19 stimulus package for the repatriation of supply chains from china (nakazawa, 2020) . more recently, tensions flared between china and india over disputed territory in the himalayas (agrawal, 2020) , and the united kingdom has ruled that huawei hardware must be removed from its 5g infrastructure by 2027 (kelion, 2020) . a biden victory in november could signal the revival of a pax americana whose primary purpose would be to limit beijing's disruption of global systems (e.g. trade, finance, production, etc.). the prospect of a revived pax americana draws attention to the importance of the geopolitical context that will shape global development. thus far we have noted that japan may attempt to decouple its value chains from china, while the eu seeks to manage its current and future member states' relations with china, but many other countries will influence geopolitics. the pace, scope and terms of eurasian integration will be influenced by russia, which is intent on regaining influence in former soviet republics (plokhy 2014; dutkiewicz and sakwa, 2015) . a host of so-called 'rising powers' across eurasia bolster geopolitical claims with historical narratives of their supposed greatness (onar, 2013) , while the indian ocean is subject to competing visions (fanell, 2019). these geopolitical visions and strategies will influence the extent to which the developmental components of americanled neoliberal globalization or the belt and road initiative are rolled out, maintained and realized. additionally, the post-covid-19 economic crisis could jeopardize the bri. there are already rumblings within the chinese state and society that label it a wasteful extravagance (æµ·å¤�ç½�, 2017) . given its close association with xi jinping and its inclusion in china's constitution, the bri enjoys ideological reverence among chinese officialdom and it has become common sense that it is the framework through which china will engage other countries. while this is unlikely to change, beijing may prefer to scale back the bri than face internal dissent. a more modest version of the bri would probably focus on strategic largescale projects undertaken by central government state-owned enterprises (see liu et al., j o u r n a l p r e -p r o o f 2020). the gwadar port in pakistan, for example, is an example of a project whose strategic importance far outweighs its potential to generate returns. mining is another strategic priority which may see a post-pandemic boost. with worries over security of supplies rising along with geopolitical tensions, greater bri financing for mining ventures in iron ore, copper and coal appears likely in order to reduce china's dependence on australian resource imports in particular. in contrast, small-scale entrepreneurial initiatives whose strategic value is not readily apparent may be curtailed. these projects tend to be undertaken by private firms, state-level or municipal soes, and many are already in financial trouble given the current economic crisis (russel, 2020) . projects of this sort may struggle to get approval from beijing in a post-covid-19 bri-lite. in broader terms, questions have long been raised regarding the sustainability of china's economic model, and the covid-19 pandemic has brought these into sharper focus. chinese leadership has declined to set a gdp growth target for 2020, breaking with decades of tradition and signalling an end to the economy's unbroken thirty-year run of breakneck economic expansion (feng and bermingham, 2020) . with the country's total debt now exceeding 300 percent of gdp, recently announced stimulus measures are understandably somewhat more cautious than those seen in 2008, at least in gdp terms (shen 2020) . it is unlikely that china will be able to serve as a lighthouse in the coming economic storm in the manner seen twelve years ago. despite the weakness of its own position in comparison with 2008, china seems likely to emerge with a relative advantage in a situation where all major economies are taking a battering. the oecd projects, for example, that china's gdp will shrink between 2.6 and 3.7 percent in 2020, compared to equivalent figures of between 7.3 and 8.5 percent for the us (as well as 9 and 11 percent for eurozone economies) (oecd 2020). also in china's favour is its relative insulation from volatile global financial markets. so long as the country can avoid its own domestic financial meltdown, which is by no means a given, china's centrality to the global economy only looks set to grow. in conclusion, the covid-19 pandemic is the context that will shape the ongoing competition between china and the us. it will not be decided by policy makers in beijing and washington alone, however, because both the us and china will have to calibrate their global development policies in response to widespread demands 'from below,' in particular for coordinated action to mitigate climate change. chinese policy makers are not particularly adept at responding to demands from below, but beijing will enjoy a reputation as an effective development partner for the time being given its effective handling of covid-19. the notion of 'development' in china has unique originswhile it adheres to an understanding of development that is strikingly similar to modernization theory, the development policies it advocates are characterized by pragmatism and flexibility. thus, china is an attractive development partner for many countries, but the durability of its leadership is dependent on us elections, and its ability to continue to support the bri while also responding to demands from below. india and china step back from the brink-for now dominic cummings: did he break lockdown rules new sdrs? that pesky 85 percent approval 2020) a critical look at chinese 'debt-trap diplomacy': the rise of a meme escalating plunder change and continuity in special economic zones: a reassessment and lessons from china an american spring of reckoning: in death, george floyd's name has become a metaphor for the stacked inequities of the society that produced them china and iran approach massive $400 billion deal deng xiaoping wenxuan (selected works of deng xiaoping) protecting china's overseas interests: the slow shift away from non-interference, spiri policy paper no. 41 eurasian integratoin -the view from within. abingdon: routledge china gdp: beijing abandons 2020 economic growth target, premier li keqiang confirms at npc. south china morning post the u.s. is giving vast sums of money to fight covid-19 abroad in world's most vulnerable countries, the pandemic rivals the 2008 crisis the great lockdown: worst economic downturn since the great depression homeland security was destined to become a secret police force top economist: us coronavirus response is like 'third world' country. the guardian cremation based estimates suggest significant under-and delayed reporting of covid-19 data in wuhan and china china and the coups: coping with political instability in africa from international to global development: new geographies of 21st century development the china boom: why china will not rule the world dollar liquidity measures leave some countries out in the cold huawei 5g kit must be removed from uk by 2027. bbc news the coronavirus pandemic will forever alter the world order new data on the "debt trap" question. rhodium group market madness in the pandemic: why are investors rushing to buy junk hedging in post-pandemic asia: what, how, and why? the asian forum eu fires warning shot at china in coronavirus battle of the narratives. south china morning post china urges world bank to suspend debt payments for poorest countries mnuchin says imf and world bank funds won't repay debts to china the specter of global china: politics, labor, and foreign investment in africa the rise and fall of development theory demystifying chinese overseas investment in infrastructure: port development, the belt and road initiative and regional development u.s. and china turn coronavirus into a geopolitical football world bank group president malpass: remarks to the development committee south-south cooperation 3.0?: managing the consequences of success in the decade ahead theorizing china-world integration: sociospatial reconfigurations and the modern silk roads malaysia renegotiated china-backed rail project to avoid $5bn fee revealed: u.s. government gave $3.7million grant to wuhan lab at center of coronavirus leak scrutiny that was performing experiments on bats from the caves where the disease is believed to have originated. daily mail online xi fears japan-led manufacturing exodus from china oecd economic outlook historical legacies in rising powers: toward a (eur)asian approach the logic of contingency in china's insistence on the noninterference principle as africa groans under debt, it casts wary eye at china zombie neoliberalism and the ambidextrous state an exorbitant burden: why keeping the dollar as the world's reserve currency is a massive drag on the struggling the last empire: the final days of the soviet union additional u.s. foreign assistance builds upon u.s. leadership in the global covid-19 response europe joins u.s. companies moving out of china the coronavirus will not be fatal for china's belt and road initiative but it will strike a heavy blow the truth about sri lanka's hambantota port, chinese 'debt traps' and 'asset seizures china falsely telling arab world u.s. behind coronavirus how china is driving america's new africa strategy getting the territory right: infrastructure-led development and the re-emergence of spatial planning strategies trump says he is confident covid-19 came from wuhan lab a thawing arctic is heating up a new cold war china's stimulus sceptics need not fear side-effects this time china agrees to restructure republic of congo's debt, african nation says the "surprise" of authoritarian resilience in china rich countries try radical economic policies to counter covid-19 crashed: how a decade of financial crises changed the world the death of american competence china extends us$500mn to sri lanka in covid-19 support who (2020a) pneumonia of unknown cause -china. world health organization situation report -188 a short history of the washington consensus accused of 'modern piracy' after diversion of masks meant for europe here's how much each sector jumped after the coronavirus sell-off only three out of 53 countries say us has handled coronavirus better than china. the guardian mongolia, with deep ties to dalai lama, turns from him toward china china's special economic zones at 30 chinese capitalism and the maritime silk road: a world-systems perspective key: cord-304021-e0zj7apb authors: tang, haitao; huang, wenlong; ma, jimei; liu, li title: swot analysis and revelation in traditional chinese medicine internationalization date: 2018-01-25 journal: chin med doi: 10.1186/s13020-018-0165-1 sha: doc_id: 304021 cord_uid: e0zj7apb traditional chinese medicine (tcm) is currently the best-preserved and most influential traditional medical system with the largest number of users worldwide. in recent years, the trend of tcm adoption has increased greatly, but the process of tcm internationalization has suffered from a series of setbacks for both internal and external reasons. thus, the process of tcm internationalization faces formidable challenges, although it also has favourable opportunities. using swot analysis, this paper investigates the strengths, weaknesses, opportunities and threats for tcm. these findings can serve as references for tcm enterprises with global ambitions. at present, the pace of the expansion of traditional chinese medicine (tcm) into the overseas market continues to accelerate. both the chinese government and chinese medicine enterprises are making efforts to promote tcm as it moves into the overseas market. however, particular issues associated with tcm, such as its complex composition, various effects of its actions, insufficient systematic studies during its internationalization, etc., hinder the adoption of specific tcm drugs in the internationally recognised pharmaceutical market. in this study, we use the swot method to analyse the current situation of tcm internationalization, and the analysis is divided into four aspects. there are many strengths of tcm in the treatment of diseases which are not found in western medicine (table 1) . first, tcm and western medicine are two different medical theoretical systems with different modes and substantial differences in such aspects as theoretical foundations, methods of thinking, as well as diagnostic and treatment approaches. in the latter, the treatments are partial; in the former, symptoms and root causes are treated simultaneously. tcm has a unique theory as well as diagnostic and treatment techniques and methods. compared with modern western medicine, which focuses on detailed molecular targets, tcm thought takes an overall approach and pays attention to syndrome differentiation based on an overall analysis of the illness and the patient's condition. tcm adopts multiple levels (dimensions) and a multi-targeted method to make overall adjustments and restore the human body to achieve the goal of treating both the manifestation of the disease and its cause. second, tcm can be used to treat various diseases and especially has advantages for treating incurable diseases and chronic diseases [1, 2] . berberine exhibits beneficial anti-inflammation effects for the inflammatory bowel diseases, it also differentially modulates the activities of erk, p38 mark, and jnk to suppress th17 and th1 t cell differentiation indicating that it could be a potential therapeutic drug to treat type 1 diabetes mellitus (dm) [3] . even for a disease without an obvious clinical manifestation according to western medicine principle, tcm treatment can use its theoretical advantages of syndrome differentiation and effective timing to relieve the disease and make up for the deficiencies of modern western medicine [4, 5] . for example, in management of metabolic syndrome, tcm is an excellent representative in alternative and complementary medicines with a complete theory system and substantial herb remedies. ginseng, rhizoma coptidis (berberine, the major active compound) and bitter melon were discussed for their potential activities in the treatment of metabolic syndrome [6] [7] [8] [9] [10] [11] . recently, a search of active ingredient(s) from some commonly used tcm has revealed a wide variety of compounds that are biologically active with therapeutic potentials. about 62% of the 240 species were found to contain chemical compounds with pharmacological procies were found for the treatment of at least one disease and 53% of them for two or more diseases [12] . virtual mapping between databases of chinese herbal ingredients and molecular targets of diseases is likely to offer a new avenue for drug discovery [13] . third, some new tcm drugs are being successfully developed based on many years of clinical practice; these drugs can generally have precise effects and have only less adverse side effects [14] . only minimal adverse effects were reported for chinese medicines used in treating type 2 dm indicating certain advantages in the prevention of diabetes and delay of its complications [15] . at the same time, combined traditional chinese and western medicine has good effect in the treatment for patients which is beneficial to improve patients' quality of life [16] . for example, tcm in combination with insulin exhibited better clinical effect in the treatment of gestational diabetes [17] . in present-day society, the concept of healthy living has undergone tremendous changes, and people are increasingly pursuing improved health and quality of life. the unique effects of tcm are not only valued by domestic intellectuals but have also attracted the attention of the international community. correspondingly, the demand for natural botanical medicine is also increasing. compared with the research and development (r&d) of tcm, there are some problems in r&d of chemical medicine. first, the process of chemical drug discovery is long and arduous that it begins from the search of a potential candidate to the development of a marketable drug. the course could be as long as more than a decade [18] . second, the r&d cost for a new drug can be, in average, more than 800 million usd in the united states (us) [19] . third, the development of new chemical drugs remains very a low rate of success. among thousands chemical compounds only a few candidates could reach their first markets as new drugs in recent years. finally, synthetic chemical drugs are often associated with undesirable side effects in patients. it is now clear that the need of therapeutic intervention in many clinical conditions cannot be satisfactorily met by synthetic chemical drugs. since the research and development of new chemical drugs remain time-consuming, capital-intensive, safety issues, and undesired side effects, much effort has been put in the search for alternative routes for drug discovery in china [20] . tcm has a long history of use, with extensive literature and clinical applications covering thousands of years. such as berberine, an active ingredient from coptis chinensis franch, is widely used for the treatment of infectious diseases in china [21] . as tcm has the advantages of treatment of special diseases safety, and so on, there are many countries and regions begin to study it. at present, more than 150 countries and regions [22] have established natural botanical institutions, and pharmaceutical companies are increasingly focusing on research and development of botanicals, paying attention to the construction of traditional botanical studies and development teams, and focusing on the search for effective natural medicines to replace chemical treatments. furthermore, there are over 1300 medicinal plants used in europe [23] . as safe and healthy treatments are associated with a return to nature, tcm can make up for the shortcomings of western medicine in many areas. we can find the solutions to different kinds of diseases that are hard to cure by using the innovations and developments of tcm. tcm displays a distinctive curative effect for different diseases that are hard to cure and for technological difficulties that are recognized worldwide, such as tumours [24] , chronic liver disease [25] and chronic kidney disease [26] . china has rich natural medicine resources, with the world's largest treasure of chinese herbal medicine, and [27] . at present, domestic cultivation is a widely used and generally accepted practice in china. cultivation provides the opportunity to use new techniques to solve problems encountered in the production of medicinal plants, such as toxic components, pesticide contamination, low contents of active ingredients, and the misidentification of botanical origin. cultivation under controlled growth conditions can improve the yields of bioactive components and obtain improved yields of target products [28] . china has a number of large-scale tcm enterprises with strong scientific research abilities. chinese tcm enterprises are strengthening their research and development abilities while continuing to conduct studies of listed products and move forward with adaptions for the international market. at the same time, drug regulatory authorities continue to promote chinese production and quality management systems in connection with international standards and to improve the good manufacturing practice (gmp) management level. chinese tcm enterprises should achieve the gmp requirements and make efforts to connect to the international production management system. they have increased their investment in technological transformation so that the tcm production quality management level has reached a historical new height through the improvement of the production environment and conditions as well as the promotion of staff quality and production quality management. in addition, in recent years, upstream and downstream enterprises and industries related to tcm, such as chinese herbal planting, research and development; the manufacture and marketing of pharmaceutical equipment; tcm transportation; and many other supporting industries, have continued to grow and develop through the promotion and rapidly expanding development of the tcm industry. thus, the development of the tcm industry can also advance the development of supporting industrial chains, forming a favourable interaction. we have analyzed the strengths of the internationalization of tcm, but we should also realize that many unfavourable factors are also related to the internationalization of tcm. chinese medicine theory has many ancient chinesebased terms that cannot be expressed in objective and modern scientific language and evidence, so that many chinese medicine terms, such as yin-yang and the five elements, assistant and guide and other traditional theories and terms, are not understood and accepted by the international community [29] . tcm is a medical system developed on the basis of taoist philosophy. the theory of tcm was first documented in an ancient chinese book, huangdi neijing (yellow emperor's inner classic). the book proposes that the human body contains yin and yang. a disease is a consequence of disbalance of yin and yang. qi (air) and blood serve as mediators in communication between yin and yang. the primary aim in the treatment of illness is to restore the balance, and replenish qi or blood. herbal medicines, acupuncture, and massage are often used to restore the balance in the clinical practice in tcm [2, 30] . eastern and western cultures are different not only in language systems but also in values, ways of thinking, etc. chinese medicine and pharmacy are a huge, complex system of long-term experience based practice, emphasizing an overall view that is totally different from the perspective of western medicine and pharmacy. in the tcm theory, diabetes is considered a result of yin deficiency with dryness-heat. the treatment of diabetes should be focused on replenishing yin (fluid) and evacuating fire (heat) from the body [31] . however, for western medicine, such as metformin is commonly used in the treatment of diabetes. it acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis [32] . chinese medicine is based on a holistic approach, while western medicine is based on a reductionistic approach. for example, in the treatment of cancer, western medicine often take the tumor mass reduction as the ultimate goal, regardless of normal cells; while the tcm in addition to tumor inhibition, but also intend to alleviate the symptoms, strengthen the body resistance, improve the quality of life, prolong the survival time of cancer patients for the therapeutic purpose [32, 33] . in the cultivation of herbs, the quality of chinese medicinal herbal products directly affects the quality of tcm. however, most of the cultivation, harvesting and processing management procedures of chinese herbal medicinal materials are extensive. there is a lack of relevant technological innovations, the production process is not well scientifically based, the yield per unit area is low, the quality of the herbs is uneven, and the classification of species is not strictly enforced. there are no effective means to manage and resolve the problems of pesticide residues during pest control, and heavy metal residues occur through the process of planting, leading to the existence of unwanted chemicals in the herbs [34] . there are only a few quality control indicators for most of chinese medicinal materials, and some of them have no quantitative indicators and even no qualitative indicators. currently, the majority of the existing chinese medicinal materials quality control specifications are not effectively to ensure the stable quality of chinese medicinal materials, and the medicinal ingredients in these materials, which are the most direct causes for the unstable quality of tcm and the unevenness of its clinical efficacy [34] . tcm is more complex and comprehensive than western medicine in terms of finished product quality, whether for a single drug prescription (prescriptions consisting of a single medicinal material) or a compounded chinese medicine (prescriptions consisting of two or more medicinal materials). there is a lack of studies on material basis, active ingredients, and mechanism of action and no scientific and reasonable quality control indicators and methods [35] . therefore, the uniformity, safety and effectiveness of inter-assay stability for tcm products cannot be guaranteed. the implementation periods required by chinese good clinical practice (gcp), good laboratory practice (glp), gmp and other specifications are shorter than the international standards for pharmacology, toxicology, standardization, gmp construction, etc. the foundation is weak, various research data have not yet gained acceptance in international communities, and there is still a long way to go before tcm can harmonize with international standards [36] . most tcm enterprises commonly experience the following problems: there is not enough application of advanced technology, and there is a large gap between tcm practices and international advanced technologies [37] . although the implementation of a new version of the gmp forced out some non-standard enterprises, some chinese medicine enterprises still use outdated hardware and facilities, including outdated technologies for extraction, concentration and purification of chinese herbal medicines; therefore, some key parameters are unclear and cannot be effectively controlled. there is a large gap between china and developed countries in terms of the extraction process and production technology of natural medicine. regardless of specific national drug regulations there is an international consensus that all tcm drugs must meet stipulated high quality standards focusing on authentication, identification and chemical composition [38] . chinese herbal medicine and tcm itself have complicated components that change constantly during the production of tcm, especially in the extraction process. some components are not originally from chinese herbal medicine itself but are transformed during the process of extraction and concentration, leading to difficulty in the identification of tcm components. in addition, tcm emphasizes mutual synergy, so it cannot simply use one or several indicators to fully represent the effect of tcm products. tcm consists of many chemical ingredients, and these ingredients play synergistic roles in human body [39] , thus, the active medical ingredients are not clear. tcm adopts multi-target, multi-functional method to make overall adjustments and restore the human body to achieve the goal of treating both the manifestation of the disease and its cause. tcm is difficult to be clearly expressed by the chemical compositions in accordance with the requirements of chemical drugs, where the compositions are clearly expressed in chemical formulas. at present, many enterprises and research institutions are committed to the pharmacology and composition of traditional chinese medicine research. advances in phytochemistry, high throughput screening, dna sequencing, systems biology, and bioinformatics can reveal the chemical composition and molecular mechanisms of tcm [39] [40] [41] . in the tcm hospital bad kã¶tzting, 171 tcm drugs underwent an analytical quality proof including thin layer as well as high performance liquid chromatography [38] . as from now mass spectroscopy will also be available as analytical tool. the findings are compiled and will be published one after another. the main issues of the analytical procedure in tcm drugs like authenticity, botanical nomenclature, variability of plant species, as well as medicinal parts processing are pointed out and possible ways to overcome them are sketched [38] . at present, the construction of chromatographic fingerprints plays an important role in the quality control of complex herbal medicines [42] . many companies utilize advanced technologies to develop multi-component determination technics and chromatographic fingerprint analysis for qualitative and quantitative assessments. these assays will create a complete monitoring and evaluation system to ensure the efficacy, consistency, and inter-batch stability of the product. it is possible to clarify the role of the composition of tcm in the future. in recent years, europe, the us, japan, south korea and many other developed countries and regions have adopted modern research methods and techniques to increase the development of traditional botanical drugs, the screening and confirmation of active ingredients, the establishment of international advanced quality standards and the development of new formulations [43] . most domestic chinese enterprises and research institutes make relatively less investment in the r&d of tcm. insufficient r&d investment leads to a lack of competitiveness of the enterprise products. chemical drugs and biological products enjoy obvious competitive advantages, seriously affecting the growth rate of the market share of tcm. tcm products feature more impurity or low purity and a lack of innovation in dosage forms; traditional dosage forms still hold a dominant position. the development and application of quick-acting, long-term, efficient and convenient emergency dosage forms and other new dosage forms are still in the beginning stage. the production and application of new pharmaceutical excipients are insufficient and have a large gap with the mainstream trend of international drugs, directly affecting the competitiveness of tcm in the international market [43] . with the progress of society and changes in the human disease spectrum, the medical model has undergone tremendous changes; people are not simply seeking disease treatment but are focusing on the comprehensive management of disease prevention, treatment and health protection [44] . people are inclined to treat disease with natural medicine due to the obvious toxic and side effects of chemical drugs, and chinese medicine is aligned with this development tendency [45] . in addition, many national governments have gradually accepted and attached importance to tcm and natural herbal medicine because of the high bio-pharmaceutical r&d costs, medical costs, long-term costs and other issues. the international community continues to accept natural medicine, and market demand will continue to grow. more than 90 countries and regions are introducing laws and regulations for the registration of chinese herbal medicine [46] . tcm herbal drugs are increasingly used in many countries of the eu [47] . in europe, it is very good to know that european pharmacopeia (ph eur) is working on tcm herbal drug quality monographs. the european directorate for the quality of medicines (edqm) has established two groups of experts in pharmacognosy, who elaborate monographs on herbal drugs and herbal drug preparations. since 2007 a special working group has been established with the elaboration of monographs on traditional chinese medicinal plants and preparations [48] . till now, a working program, existing of 75 monographs was established by the commission of ph eur, out of which almost 50 new tcm herbal drug monographs have been implemented for the ph eur so far [49] . the standards put forward in these monographs not only define the quality of these products, but also eliminate dangerous counterfeit, substandard, adulterated and contaminated (traditional) herbal medicinal products [48] . with many tcm herbal drug monographs are implemented in the ph eur, this will be a significantly contribution to the acceptance of tcm worldwide [50] . all aspects relevant to the quality parameters have to be achieved in an adequate manner, requiring a broad range of analytical methods to be applied for new herbal drug monographs in the ph eur [47] . first, due to the equivalent access for world trade organization (wto) members, china's admission to the wto gave it more opportunities to participate in international exchanges and cooperation, to promote the wider spread of chinese medicinal culture, and to recommend tcm products with minimal side effects and high efficiency in treating both symptoms and causes of disease, which will establish a good foundation for popularizing tcm in the international community [25] . second, chinese medicine is becoming more popular for treating and preventing many diseases, especially incurable diseases and chronic diseases, in many countries due to the poor efficacy and obvious side effects of western medicine. third, due to a decline in tariffs [51] , many enterprises are more able and more willing to introduce foreign advanced technologies and equipment into china, which will speed up the production technology and accelerate the internationalization of traditional chinese medicine. in recent years, china has introduced a series of new policies and regulations to support the development of chinese medicine, while increasing the support for international cooperation in chinese medicine, indicating that the development of chinese medicine has risen to a strategic governmental level. china attaches great importance to the inheritance and innovation of chinese medicine, which will greatly promote the entry of chinese medicine into the international market. in addition, the implementation of the national strategy "one belt and one road" will create a new historical opportunity for chinese medicine to move into the international community [52] . the development strategy of "one belt and one road", utilizes the ancient "silk road" historical symbols, actively develops economic cooperation partnerships along with the countries with geographical proximity and cultural similarities to create great opportunities for the development of chinese medicine industry [52] . with the "one belt and one road" strategy, we can promote the communication of tcm cultures. through constantly tcm cultural exchange, we can bridge the gap between eastern and western medical systems to enhance the tcm internationalization. at the same time, the advantages of tcm and the international market demand provide great possibilities for tcm under the "one belt and one road" strategy. tcm has the feature of both humanity and medical sciences, therefore, its great resource in the economy, cultural and health care, should be regarded as one of the best mediums of cultural exchanges and international cooperations between china and the countries along the "one belt and one road". moreover, "one belt and one road" strategy also provides the platform for inheritance and innovation of tcm, which will promote the further development of chinese traditional medicine [53] . during this period, we can make full use of related resources and strengthen the international exchange and cooperation related to tcm. cooperation and exchange include enhancing the policies and regulations for traditional medicine, improving herbal medicine quality standards and control indicators, and establishing administration regulations. there will be more exchanges between the chinese government and international organizations, and the cooperation with foreign universities, research institutions, and hospitals as well, to co-establish academic and clinical research centres or groups to let more academic authority institutions accept and recognize tcm. the unique role of tcm has been widely recognized by the international community in the process of severe acute respiratory syndrome (sars) prevention and control and has been highly praised by the world health organization. chinese medicine can effectively reduce the mortality rate of sars patients and the sequelae in the process of treating the sars virus, and the treatment costs are significantly reduced. the specific function and significance of chinese herbal medicine in treating sars have been recognized by who experts and have also helped reduce prejudice against the supposed inaccurate efficacy of tcm in the international community [54, 55] . a researcher at the china academy of chinese medical science, tu youyou, was awarded the 2015 nobel prize in physiology or medicine for the development of artemisinin. tu youyou made an exploratory investigation of tcm and found that the components extracted from the plant artemisia annua are effective in the treatment of malaria. by referring to ancient books and many studies, tu youyou found the best extraction method for artemisinin. artemisinin is the invention not only of tu youyou but also of china and is an achievement of tcm heritage and innovation, which deserve popularization. this important invention created a sensation in the world [14] . due to differences between chinese and western cultures, china's tcm theory cannot be accepted by the international community [56] . tcm theories advocate "discontinuing medication when the patient is cured", oppose the long-term medication. long-term medication or even increase of dose to several times of standard dose may inevitably lead to side effect [57] . this also exposes the differences between chinese and western cultures. chinese medicine emphasizes the principle of syndrome differentiation. however, from western medicine perspective the concept of tcm is hardly understood and accepted, therefore tcm is not well positioned and accepted [5] . the officially entering of tcm to europe union (eu) market is at a slow rate, and there are only four products produced by chinese enterprises registered in the eu; no real tcm is sold in the us; and the tcm industry is facing enormous challenges. china's botanical drugs have only a small share, less than 5%, of the international botanical market, 2% in the united kingdom and the us, and 0.2% in germany [58] . as natural medicine has been recognized by the international community, tcm and natural medicine have become the target of many large multinational companies. the international herbal medicine market is highly competitive. at present, japan, south korea and other countries are competitive with china in the international herbal medicine market and pose a great threat to china's exports. in addition, a large number of foreign tcm companies based in japan, south korea and india have impacted the tcm market in china. china is the world's largest tcm market, and its demand for natural medicine is also very large. in recent years, due to the continuous opening of china's pharmaceutical market, many large-scale foreign pharmaceutical enterprises have entered the chinese market, and approximately 40 types of natural medicine manufactured in more than 10 countries and regions are successfully registered and listed in china [59] . the practice standards of china's tcm industry remain in the progress of standardization. after entering the wto, china had to align its standards with international standards. however, many countries and regions in the world, especially the western developed countries, restrict foreign products entering their territory through various administrative measures and requirements, high-tech trade barriers and the "green trade barriers" threshold, including measures for medication safety and protection to strengthen the supervision of imported drugs; develop or improve relevant technical requirements, such as quality standards for heavy metal residues, pesticide residues, aflatoxin and others; standardize the technology of plant extracts and environmental standards; and so on [42] . chinese medicine has a 5000-year history in china, and in a traditional comprehensive theoretical system, the related intellectual property should belong to china. however, the implementation of patent protection and technical protection of the novel tcm drugs in china began late, and there is a lack of study of protection of tcm intellectual property rights; therefore, most chinese medicine enterprises lack experience in patent applications in foreign countries and are not ready to protect their intellectual property. most tcm can easily be imitated or limited by patents in foreign countries; thus, many valuable chinese medicine product technologies and knowledge are under threat of advanced applications for patents by foreign enterprises. the developed countries, which have rich experience in drug patents, can not only obtain for tcm intellectual property rights but also compete for other resources related to chinese medicine by using intellectual property advantages. with the swot analysis of the internal and external environments, we can observe the advantages, disadvantages, opportunities and threats of tcm during the internationalization process (table 2) . overall, the advantages outweigh the disadvantages, and the opportunities outweigh the threats. to deal with these disadvantages and threats, we can provide some recommendations. first, we can strengthen the international communication on chinese culture. we should make full use of related resources at home and strengthen the international exchange and cooperation related to tcm, thereby promoting the development of tcm culture. we should strengthen the exchange between the chinese government and the leadership of international organizations; strengthen the cooperation with foreign institutions of higher educations and hospitals and co-establish clinical research centers or groups to make more academic authority institutions accept and recognize tcm. second, we can increase the input into tcm research. to align the foreign regulations concerning natural medicines, tcm can start with each individual medicinal materials. enterprises can take some multi-herbal formula of tcm with specific curative effects, and take the effective part as an "effective body", then control the composition and contents of the "effective body", and gradually reach the purposes of "safe, effective, controllable, and stable". the "effective body" in individual medicinal material can also be analyzed and summarized with the "assistant and guide" theory of tcm. we should explore and investigate the traditional formulas and carry out secondary development with modern innovative technologies to develop and produce new products. third, we can enhance the standardization and modernization of tcm quality. we should issue tcm product quality standards that are applicable to both china and the world as soon as possible and establish strict management of planting and production, to ensure that the consistency of tcm quality can be controlled. we should regulate each step of the tcm industrial process, apply high and new technologies, use advanced equipment and adopt strict standards to transform the tcm production and reach the goals of modernizing the technologies for the extraction, formulation, and quality control of tcm based on related conventional theories. finally, we must carry out intellectual property protection training among the practitioners of the tcm industry and enhance the awareness of the whole industry regarding the protection of intellectual property. we must learn the domestic and international regulations on the protection of intellectual property. we may also achieve effective protection through the core technologies, trademarks, essence and inventions in tcm intellectual property. in the process of the internationalization of tcm, we must emphasize the advantages to avoid the disadvantages, seize the opportunity to overcome the threats, carry out specific internationalization processes, 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traditional chinese medicine in views of system science and system complexity study on the influencing factors and preventive methods of toxic and side effects of chinese herbal medicine the challenge to china's pharmaceutical enterprises after wto entry export of chinese medicine: difficult to develop not applicable. ht, wh, jm and ll conceived and designed the review. ht, jm and ll wrote the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests. not applicable. all of authors consent to publication of this work in chinese medicine. not applicable. not applicable. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. submit your next manuscript to biomed central and we will help you at every step: key: cord-296717-ay4wcmk3 authors: long, wen; zhao, manyi; tang, yeran title: can the chinese volatility index reflect investor sentiment? date: 2020-10-20 journal: nan doi: 10.1016/j.irfa.2020.101612 sha: doc_id: 296717 cord_uid: ay4wcmk3 the volatility index is the implied volatility calculated inversely from the option prices. this study investigates whether the official chinese volatility index, ivx, can represent investor sentiment. in order to describe investor sentiment comprehensively, we build a three-dimensional investor sentiment measurement system composed of macro, meso and micro level, and decompose ivx into three components to obtain short-term, medium-term fluctuations and long-term trend by eemd method. the relationships between ivx, its components and sentiment indexes at each level have been analyzed separately, and the empirical results reveal all components of ivx can reflect the investor sentiment at the corresponding level but to which extent they can reflect are not the same. further we introduce the mixed-frequency dynamic factor analysis to extract the common sentiment factor, which shows stronger correlation with contemporaneous ivx, compared with the sentiment indexes at each level. the adl model in robustness check also demonstrates the results. our findings confirm ivx can represent the common sentiment and expectations of chinese investors in different time scales. since the stock came into being, its risk characteristics have been the focus of investors. risk refers to the uncertainty of return, which is generally defined as volatility. according to different calibers and methods, volatility can be categorized into historical volatility, predicted volatility, and implied volatility. historical volatility is calculated as the average deviation from the average price of a financial instrument in the given time period. predicted volatility is the volatility estimated based on asset conditions, economic situation, historical experience, etc. when calculating the option price, it is brought into the option pricing formula to obtain the price. implied volatility is the volatility inversely derived by putting the market price of the option and other known parameters except volatility into the black-scholes option pricing model. investor sentiment refers to a belief formed by the expectation of future cash flows and investment risks of assets, which yet does not fully reflect the existing facts (wurgler and baker, 2006) . this kind of belief is not only influenced by the fundamentals of assets and the information transmission of capital market, but also strongly related to the education, personal experience and personal preference of investors. therefore, for the same asset, different investors will hold different beliefs, namely sentiment. herd effect and other phenomena show that sentiment is contagious, which will lead to consistent actions among people. due to this irrational behavior, if limited arbitrage exists, asset prices will have systematic bias. in 1993, chicago board options exchange (cboe) delivered the world's first volatility index vix, which is the implied volatility calculated using the s&p 500 index. in 2016, shanghai stock exchange of china also announced the first official certain advantages in vix futures pricing. kanniainen et al. (2014) price s&p500 index options based on the garch model and the vix index. basher at el. (2016) compare the effects of hedging market risks with indicators such as vix index and oil prices. some researchers also study the volatility index in other stock markets (siriopoulos and fassas, 2012; badshah i. et al., 2018) . due to the late release of the chinese volatility index ivx, there are few studies on ivx. the related researches mainly focus on three aspects: the prediction ability of ivx (qiao et al., 2019) , the relationship between ivx and the yield, including the "leverage effect" yue et al., 2019) , and the inclusion of volatility index as an indicator in the sentiment index construction system (xu and zhou, 2018) . in order to measure the expectation of investor, scholars put forward the concept of investor sentiment index. previous methods for obtaining investor sentiment indicators can be divided into three categories: (1) investor sentiment index composed of questionnaires and interviews. american studies mainly use the university of michigan consumer survey sentiment index, while chinese indexes mainly include "cctv watch index", good and bad index by stock market trend analysis weekly, -long and short polls‖ by huading, consumer confidence index et al. (lemmon, 2006; schmeling, 2009) . although the survey method aims to directly quantify investor sentiment, its operation cost is high, the data frequency of constructing sentiment index is relatively low, and the time span is relatively short. (2) indirect indicators obtained from the historical data of the stock market. this method mainly uses historical data of several proxies that can be observed on the stock market to synthesize the investor sentiment index. at present, the academic community mainly adopts the method proposed by baker and wurgler (2007) . they use principal component analysis to extract a sentiment index from six variables of the stock market, including closed-end fund discount, nyse share turnover, the number and average first-day returns on ipos, the equity share in new issues, and the dividend premium. although the approach of using indirect indicators in the stock market is more time-saving and labor-saving than survey and interview, it is limited by some conditions such as index selection and synthesis methods. furthermore, using market j o u r n a l p r e -p r o o f variables as proxies for investor sentiment may not only reflect investor sentiment, but also reflects the equilibrium results after the interaction of sentiment and other economic factors (da et al., 2014; qiu and welch, 2004) . (3) analysis of information on the internet. many researchers start with the internet information and apply text analysis to analyze the information released by investors on social platforms or searched content to get the investor sentiment. this method avoids the shortcomings of the first two methods, but is susceptible to network noise information. text data mainly includes yahoo finance posts (antweiler and frank, 2004; das and chen, 2007; kim and kim, 2014; tsukioka et al., 2018) , wechat (shi et al. 2018) , weibo platform (checkley et al., 2017; renault, 2017) , twitter (behrendt and schmidt, 2018; li et al., 2017) and google search (da et al., 2014; gao et al. 2019) , etc. the purpose of this paper is to investigate the ability of the chinese volatility index ivx to represent investor sentiment. since ivx is computed given the option prices and the prices reflect the expectations of the stock market by the investors, thus ivx reveals the investors' predictions towards future of the stocks. and the predictions reflect the investors' sentiment. therefore, ivx can simultaneously represent the investors' sentiment in theory. li et al. (2019) find that ivx is negatively associated with the price and return of shanghai 50etf separately, which indirectly proves that ivx could reflect investors' panic sentiment, but did not directly measure the sentiment. regarding the sentiment representation of the vix created by cboe, most of the researches take it as the known facts and conduct research on this basis (pan, 2018; smales, 2017; yang et al., 2016) . however, there is little literature that confirms vix has this effect. some of them indirectly proves it by analyzing the negative correlation between vix's change and the return rate of the underlying index (smales,2016; whaley, 2000; whaley, 2009) . the researches which directly prove it only involve the relationship of volatility index on sentiment index based on news, social media or other single-level sentiment (pineiro et al., 2016; smales, 2014; zhang, 2011) . in order to obtain fluctuations on different time scales, this paper will use ensemble empirical mode decomposition (eemd) to decompose ivx. eemd provides a j o u r n a l p r e -p r o o f feasible way to deal with non-linear and non-stationary data. it consists in a local and fully data-driven separation of a signal in fast and slow oscillations (torres et al., 2011) . it has been widely used in industry and resources (wang et al, 2014; wang et al.,2013; lei and zuo, 2009) . meanwhile, zhang (2008 ) and yu et al. (2008 have successfully applied this idea to the field of social science, and prove that the integrated empirical mode decomposition method is a useful approach for financial time series analysis. the contributions of this paper include the following three aspects: (1) this study seeks to examine systematically on whether ivx has the ability to represent sentiment, and analyze it at the macro, meso and micro levels, while previous studies rarely discuss this issue, especially for the newly released and short-lived chinese volatility index ivx. (2) this paper constructs a three-dimensional comprehensive measurement system of investor sentiment, which is composed of three levels: macro-economy, stock market and individual opinions. the frequency is monthly, weekly and daily, respectively, including rational and irrational components, so our measure system can capture more information about the investor attitudes. however, most of the previous studies only focus on one level of sentiment, such as micro-blog sentiment from the micro perspective. (3) by employing dynamic factor analysis on different sentiment indexes with mixed-frequency to extract the common factor, we investigate whether ivx can comprehensively represent investor sentiments at different time scales. the remaining of the article is organized as follows. section 2 introduces ivx and compiles sentiment indexes at different levels. section 3 decomposes ivx by eemd to get three components and analyzes their representation on investor sentiment at different levels. section 4 applies mixed-frequency dynamic factor analysis to obtain a common sentiment factor, and discuss its relationship with ivx. section 5 is the robustness test. finally, this study concludes with a few remarks. j o u r n a l p r e -p r o o f chinese volatility index ivx, released by the shanghai stock exchange, can be traced back to february 9, 2015, and was suspended on february 22, 2018 for unknown reasons. using model-free methodologies similarly to vix, the ivx is estimated from the bid and ask prices of the underlying options for shanghai 50etf. this paper collects all the data during the ivx release period, with 740 effective observations from the wind database. and 50etf's variation δ50etf in the sample period, respectively. it is clearly visible from the graphs that when the chinese stock market falls sharply in mid-2015, ivx rises to a historical peak of 63.79, which suggests ivx is negatively related to the underlying assets to a certain extent. the left vertical axis depicts δivx and the right depicts δ50etf. (excel format , 1-column fitting image)， table 1 reports the summary statistics for ivx and δivx. the mean value of ivx is 23.879 and δivx is approximately zero. the two are both positively skewed. δivx presents excess kurtosis while ivx does not. the above two points suggest that big positive changes of ivx occur more frequently than large negative changes and vice versa. the reported first-order autocorrelations show that ivx is highly persistent, but δivx is not. the augmented dickey fuller (adf) and pp tests on the levels, reject the null hypothesis of unit root for δivx, while accepts for ivx. hypothesis at the 1%, 5% and 10% significance levels, respectively. investor sentiment reflects the expectation of investors for the future economy and stock market. this paper builds a three-dimensional measurement system of investor sentiment, which depicts sentiment from three levels: macro, meso and micro. among them, macro level quantifies investor sentiment towards the whole economy; meso level measures investor sentiment towards the stock market; and micro level shows investor sentiment towards each individual stock. the three levels of sentiment index are monthly, weekly and daily data separately. in order to reflect the latest situation of economic development in time, taking into account the representativeness of china's macroeconomic cycle variables and the availability of data, this paper uses the purchasing manager index (pmi) and production price index (ppi) on the production side, the consumer satisfaction index (si) , consumer price index (cpi) and total retail sales of consumer goods (rscd) on the consumer side, and the consistent index of business climate index (cbci) indicating the economic boom and bust issued by the china economic prosperity monitoring center, to form a composite macro-level index of sentiment. these data are monthly and from wind database. (excel format , 1-column fitting image)， further, considering the fact that some variables take longer to reveal the same sentiment (baker and wurgler, 2006) , if the variables are synthesized directly in the same period, the composite index will not effectively reflect the market sentiment movement. referring to baker and wurgler (2006) , this paper uses the following two (excel format , 1-column fitting image)， the formation of the investor sentiment index at the meso level is mainly based on the method of wurgler (2006, 2007) . the six proxy variables they selected are: the closed-end fund discount, nyse share turnover, the number and average first-day returns on ipos, the equity share in new issues, and the dividend premium. however, compared with the us stock market, the chinese stock market has its own particularities, mainly containing the following three points: (1) almost every ipo will hit a daily limit on the first day of listing, which means the average value for first day's earnings is almost 44%. among the above variables, in theory, the price of closed-end funds should be consistent with the value of the unit net assets of the stock portfolio. however, in reality, closed-end funds often trade at a discount (lee et al., 1991) . it is generally believed that the higher the absolute value of the discount rate, the less optimistic view investors take about the market outlook. since fddr is negative in normal conditions, it is positively correlated with investor sentiment. to signifies market liquidity. under the restrictions of market short selling and the participation of irrational investor, high liquidity is often accompanied by overvaluation, which has positive correlation with investor sentiment. in addition, pe and nia are also positively associated with sentiment. in order to control the impact of fund size, we adopt the following criteria for fund table 4 reports that there is a certain degree of association between the four sentiment agent variables. j o u r n a l p r e -p r o o f (excel format , 1-column fitting image)， we use the same method as section 2.2.1 to select the proxies or their lags, and then perform principal component analysis to calculate the meso-level sentiment index. the selected terms are to t-1 , pe t , nia t-1 , and fddr t . taking of the sample variance respectively, thus the two factors with cumulative rate of 81.351% capture much of the common variation. therefore, we take weighted average of the first and second principal components as meso sentiment index, without the macro influence. the resulting sentiment index mesi is shown in eq. (2), and its variation throughout the sample period is shown in fig. 6 . the index falls sharply in the mid-2015, after then appears to be less volatile. (excel format , 1-column fitting image)， based on investors' online opinion posts on the internet social media, the investor sentiment at micro level is extracted and analyzed from massive text data. in terms of data acquisition, we use web crawler tools to grab the information on the east money stock forum, which has a considerable number of visits and influence among the stock forums in china. according to ranking of visitor volume by alexa's website and baidu weight rankings, east money stock forum currently ranks first in the major there are usually two types of sentiment classification, based on sentiment dictionary or classifier, respectively (liu et al. 2012) . it is hardly possible to meet the professional needs in the field of finance by using a general sentiment dictionary in natural languages, and empirical evidence has shown that the classification results obtained by the latter are better than the former (wu et al., 2014) . therefore, on the grounds of previous research, we adopt machine learning algorithm and choose svm classifier to identify investor sentiment and calculate the micro sentiment index. considering that online posts contain a great deal of noise, we use two-step classifier for sentiment analysis (shi et al., 2018) . the first step is to get rid of noise by separating the text into noise and non-noise, and the second step is to divide non-noise text into bullish and bearish ones. we use several technologies including data cleaning, text representation, feature extraction and classification, to compute investor sentiment index with individual sentiments, which will be applied into following study. (1) data cleaning the posts on the online stock forum involve a lot of punctuation, noise, etc. which cannot be directly used to sentiment analysis. therefore, in the data cleaning process, we first remove the punctuation and gibberish, and then operate word segment. (2) text representation in order to enable the computer to read text, words must be changed into digital j o u r n a l p r e -p r o o f data for computer processing. in this paper, word2vec, which is commonly used in academia, is applied to represent words. it can calculate word vectors according to the context of words, fully capture the semantic information of the context, and has good performance in text classification (lilleberg et al., 2015; wolf et al., 2014) . then we use tf-idf (term frequency-inverse document frequency) algorithm to compute the weight of words in short text, and provide weighted word2vec text vector. word2vec is a tool based on deep learning and released by google in 2013 . this neural network includes two architectures: continuous bag-of-words model (cbow) and skip-gram. the former predicts the current word based on the context, while the latter predicts surrounding words given the current word (mikolov et al., 2013) . compared with the cbow model, skip-gram has higher semantic accuracy, higher computational complexity, and longer model training time. in this paper, the skip-gram model is used to predict words through context, the mathematical representation (3) is as follows: where the input is a word in the corpus. the main idea of tf-idf is if a word or phrase appears frequently in one article and rarely in other articles, we infer that this word or phrase shows good performance on distinguishing different text information. formula (4) shows tf-idf is the product of tf term frequency and idf reverse document frequency. where , is the number of times that the word appears in the file , while the denominator ∑ , is the sum of number of times that all the words appear in the file , |d| represents the total number of files in the corpus, and |{ : ∈ }| represents the number of files containing . by adding the weighted word2vec vector of words in document, we get the new j o u r n a l p r e -p r o o f vector r( ) of document : where 2 ( ) is the word2vec vector of word . (3) classifiers for sentiment identification we use support vector machine (svm) to identify investor sentiment, which has already become an important approach for classification due to its outstanding performance (cortes and vapnik, 1995; deng et al., 2012) . in the first step of "noise elimination" identification, non-noise data is labeled with +1 and noise data with -1. in the second step of "bullish-bearish" identification, bullish sentiment is labeled with +1 and bearish sentiment with -1. through the procedures of classifying the text, we can identify the investors' attitudes towards individual stock. table 4 reports the classification accuracy rate obtained by the 10-fold cross validation method. it indicates that the classification accuracy and recall rate based on the svm algorithm have reached more than 70%. after identifying individual investor sentiment, we can combine the views of all individual investors into micro investor sentiment index. in accordance with the method in previous literatures (antweiler and frank, 2004; kim and kim, 2014; wu et al., 2014) , we define as total bullish posts in time interval t, and as total bearish posts in time interval t. the calculation for sentiment index is: eq. (6) is used to compose the csi 800 daily micro investor sentiment index, named as micsi, which can reflect the comparison of investors' long or short views. the higher the investor sentiment index, the more investors hold positive expectation on the future stock market. average, investor sentiment is towards bearish, which demonstrates the viewpoint of investors' irrational biases in behavioral finance (odean, 1998) . (excel format , 1-column fitting image)， the u.s. volatility index vix has the ability of reflecting investor sentiment, thus it is known as "the investor fear gauge". in order to study whether the chinese volatility index ivx possess this capability, we conduct the following research. first, we decompose ivx into short-term, medium-term and long-term fluctuations, considering macro-level sentiment is the investor's sentiment towards the market, which lasts for a long time, and the persistence of meso level and micro level sentiment decreases in turn. then we explore the relationship between the decomposed ivx and corresponding sentiment respectively. compared to that, the relationship between the ivx and sentiment is also examined on each level. with the above process, we can verify whether ivx is a proper representation of investor sentiment. previous studies show short-term volatility clustering (gray,1996; cont, 2007) and long-term mean reverting of the volatility (bollerslev and mikkelsen, 1996; arav et al.,2018) , which indicates the characteristics of stock market on different time scales are not consistent. in order to obtain the fluctuations on different time scales, we need to decompose ivx. since the duration of three levels of sentiment is different, if ivx has the ability of representing sentiment, the short-term with high frequency, medium-term fluctuations with low frequency and long-term trend obtained after decomposition should have a relationship with corresponding sentiment at the level of macro, meso and micro. we use eemd to operate decomposition. compared with wavelet analysis, it can avoid the instability of the result caused by manual selection of wavelet function. moreover, compared with fast fourier transform, it can realize the analysis of high-frequency data volatility. therefore, eemd is chosen to decompose ivx. (1) eemd model the eemd algorithm can be summarized as follows: step 1. initialize the number of realizations and amplitudes of added white noise. set m equal 1. step 2. perform the mth emd decomposition. 1)add white noise ( ) with the given signal ( ). ( ) = ( ) + ( ) j o u r n a l p r e -p r o o f where ( ) is the white noise added at the mth time, and ( ) is the signal containing white noise at the mth time. 2)after employing emd to decompose the signal ( ), we get a group of imf , ( = 1,2, ⋯ , ), where , is the nth imf in the mth decomposition. 3)if m<m, then go back to step 1) and let = + 1. repeat steps 1) and 2) until m equals m. step 3. compute the population mean in the mth decomposition. step 4. take n imfs in the mth decomposition, i.e. ( = 1,2, ⋯ , ) as the final imfs. (2) fine-to-coarse reconstruction in practice, fine-to-coarse reconstruction is used to get short-term, medium-term fluctuations and the long-term trend of the original signal (zhang et al., 2008) . the algorithm is as follows: step 1. except for the residue, calculate the mean of the sum of 1 to for each component. step 2. identify for which i the mean departs from zero significantly. step 3. if i is identified as a significant change point, partial reconstruction with imfs from this to the end is identified as the medium-term fluctuations, the partial reconstruction with other imfs is identified as the short-term fluctuations and the residue as the long-term trend. we get five the imfs and residue by decomposing ivx, of which the variations are depicted in fig. 8 . shows the average of imfs as a function of imfs index k. it can be observed that the average of the fine-to-coarse reconstruction departs significantly from zero at imf4. furthermore, we use t-test to demonstrate the result (the significance value is set at 0.05). therefore, we take the partial reconstruction with imf1, imf2 and imf3 as short-term fluctuations and the partial reconstruction with imf4 and imf5 as medium-term fluctuations. short-term fluctuations have the characteristics of small amplitudes, and each steep rise or fall in medium-term fluctuations corresponds to a significant event. the residue retains as long-term trend which is slowly varying around the long-term mean. the variation of three components including hivx, livx, tivx is shown in fig. 10 . in this section, we plot the scatter diagrams of sentiment index and ivx or its components on the level of macro, meso and micro respectively. then we calculate their correlation coefficients, and analyze the sentiment representation of ivx at different levels. j o u r n a l p r e -p r o o f in the above discussion, we decompose ivx into three components with different characteristics, and then study the sentiment representation of different components on each level. it is concluded that only the component at the macro level has a strong ability to reflect sentiments. however, the weekly and daily data account for the majority of the research of financial market, to which the corresponding levels are meso and micro. according to our study, the correlations between ivx or its components and sentiment index are low at the meso and micro levels (the maximum absolute values are about 0.2 and 0.4), which is not enough to prove that ivx can reflect investor sentiment. but meanwhile, it is noted that the correlations between the components of ivx at different levels and the corresponding sentiment index are almost stronger than those between ivx and the sentiment index, which suggests that ivx also reflects the sentiments and expectations of investors at different levels to some degree. therefore, it is necessary to combine the sentiment indexes of different levels together to test how the volatility index ivx represents the investor sentiment. the dynamic factor model is mainly used in the modeling and analysis of macroeconomics. in recent years, it has received more and more attention. its theoretical basis can be traced back to lucas (1977) . he finds that a single macro variable is not enough to reflect all the characteristics of economic fluctuations, and the evolution of fluctuations accompanies with the interaction and coordinated j o u r n a l p r e -p r o o f movement of many macro variables. the main advantage of the dynamic factor model is that it can extract dominating factors from a variety of macro data through metrological methods, that is, assuming that the mutual movement of many macro variables can be explained by an unobservable common random factor, which can better reflect the variation and characteristics of economic (bańbura and rünstler, 2007; koopman and harvey, 2003) . in this paper, we think that all levels of sentiment are influenced by not only specific factors but also common sentiment factors. section 3.2 shows that ivx has different correlations with the sentiment index at three levels, hence it should also have potential relationship with the common sentiment factors. therefore, the dynamic factor model is employed on the extraction of common sentiment factors. considering that the frequencies of sentiment indexes at three levels are different, we further combine the mixed-frequency modeling method (aruoba et al., 2009) , and build the mixed-frequency dynamic factor model to extract the common sentiment factor. the frequencies of sentiment indexes at macro, meso and micro level are monthly, weekly and daily, respectively. in order to construct a high-frequency daily common sentiment factor, denotes the unobservable common sentiment factor at day t, which evolve daily with ar(p) dynamics, where is a white noise innovation with unit variance. interested in tracking and forecasting real activity, we use a single-factor model, i.e. is a scalar. denotes the sentiment index at day t, which depends linearly on and also on lags of , and i represents the level of sentiment index, which equals 1, 2, and 3 in the case of micro, meso and macro, respectively. where coefficient for , reflects the effect of the common sentiment factor on the sentiment index . where 3, is missing for t ∈ a and 2, is missing for t ∈ b. based on eq. (13), eq. (11) is transformed into the following form: where is a 3×3 identity matrix when there is no missing value in observed vector , is a 2×3 matrix deleted ith row when the ith value in is missed, and is a 1×3 matrix when two of values in is missed. in eq. (14), there is no problem with missing data. hence for the state space model composed of eq. (12) and eq. (14), the maximum likelihood estimation based on kalman filter is used to obtain the consistent estimators, and simultaneously, kalman filter and smoothing estimators of state variable can be calculated. since eq. (12) and eq. (14) demand the variables in state space model should be stationary, we first take the adf test on three sentiment indexes of different levels. table 6 reports macsi is non-stationary, whereas the other two are opposite. in an attempt to maintain the data properties, we take first difference of the variables with trend. finally, all variables are standardized eliminating the influence of dimension. j o u r n a l p r e -p r o o f table 6 also gives some descriptive statistics of three sentiment indexes. according to aic、bic, we set p equals 1. hence the measurement and transition equations become on the basis of the optimal estimation of unobserved state vector, table 7 gives the estimation values of related parameters. the estimates are all significant, and those of β1, β2, and β3 are positive, which suggests the effects of the common sentiment factor on the three sentiment at different levels are consistent. ρ is significantly positive, indicating the first-order common sentiment factor has a positive effect on the current one, i.e. investor sentiment is influenced by inertia, which will lead to conservatism bias in behavioral finance: investors' insufficient response to new information, resulting in short-term momentum effect. according to the estimations of the common sentiment factor obtained by kalman smoothing, fig. 12 represents its time series. we calculate the correlation coefficients between the common sentiment factor and ivx as shown in table 8 . in comparison with table 5 , the three correlation coefficients show a significant negative correlation between the common sentiment factor and ivx. the absolute values are larger than the correlation coefficients between the meso and micro level sentiment indexes and the corresponding ivx component, and also significantly larger than the correlation coefficients between the two sentiment indexes and ivx. it suggests that compared with the sentiment index of each level, the common sentiment factor we extract is more closely related to ivx. therefore, we believe that ivx represents more a mutual portion of all levels of sentiments than the diversity. besides, compared with lags ranging from 1 to 3, ivx has the strongest correlation with the contemporaneous common sentiment factor, indicating that ivx can reflect the current mutual sentiment. in the previous section, we use three correlation coefficients to discuss the sentiment representation of ivx. in this section, we will further investigate the relationship of ivx and sentiment based on econometric model. according to the formula of ivx, it is affected by risk-free rate, option prices and strike prices. here we take shibor 1-year rate as the risk-free rate and average strike price of all near-term and next-term options as the strike prices. as for option prices, except for investors' sentiment, it can be influenced by other factors. therefore, the explanatory variables will include lagging ivx or its component. the polynomial order is decided by maximum of residual sum of squares divided by degrees of freedom, recommended by mitchell and speaker (1986) . at the macro level, all monthly variables, including ivx (mivx), average strike price (msp), shibor 1-year rate (msr) and macsi are tested non-stationary, while their first differences (which are denoted as dmivx, dmsp, dmsr and dmacsi, respectively) are the opposite. the results are shown in table 9 . the estimations are presented in table 11 . for equation (21), current sentiment has significantly strongest negative impact on mtivx, compared with other periods. for equation (22), the results suggest current sentiment influence ivx most strongly. these inferences indicate ivx and its low-frequency component can reflect investors' sentiment simultaneously. note: ***, **, and * denote rejection of the null hypothesis at the 1%, 5% and 10% significance levels, respectively. at the meso level, we test weekly ivx (wivx), average strike price (wsp), shibor 1-year rate (wsr) and their first differences (which are denoted as dwivx, dwsp and dwsr, respectively), as well as mesi and weekly livx(wlivx). table 12 reports summary statistics for the variables. table 13 reports the estimations. it shows that current sentiment cannot effectively affect ivx or its component. for both wlivx and ivx, first-order lagging sentiment has the significantly negative impact. thus, ivx and its medium-frequency component represent previous sentiment, consistent with our conclusions. note: ***, **, and * denote rejection of the null hypothesis at the 1%, 5% and 10% significance levels, respectively. we define the regression model as the following way: we estimate the equations, as shown in table 15 . for equation (25), only 0 1 is significantly negative among 1 , which suggests ivx reveals more the current j o u r n a l p r e -p r o o f sentiment. although 2 1 and 3 1 are significantly positive, but the sum of all the coefficients on sentiment is negative, which means ivx can reflect investor sentiment. for equation (26), 0 2 is negatively larger than 1 2 . note: ***, **, and * denote rejection of the null hypothesis at the 1%, 5% and 10% significance levels, respectively. after discussing ivx and investors' sentiment at different levels, we analyze its representation of common sentiment factor (csf). the factor is tested stationary with adf test of -6.625 and pp test of -6.427. the other variables have been tested during the previous investigation. then we run the following regression model: note: ***, **, and * denote rejection of the null hypothesis at the 1%, 5% and 10% significance levels, respectively. table 16 shows that our conclusions hold, and only the current sentiment can significantly negatively impact ivx. therefore, the application of adl confirms our findings on ivx' s representation to investor sentiment, for different levels or the common sentiment factor. in this paper, we investigate whether chinese volatility index ivx can represent investor sentiment. most of the previous researches treat the sentiment representation of the volatility index as a known fact, or only analyze a certain level of sentiment. however, we construct a three-dimensional investor sentiment measurement system, and use eemd method to decompose ivx into three components, i.e. short-term fluctuations, medium-term fluctuations and long-term trend. we study the relationship of ivx and micro, meso and macro sentiments respectively. further, in the framework of dynamic factor model, with mixed-frequency data, a common sentiment factor is constructed to verify the representation of ivx to mutual sentiment. finally, we use adl to test our results. our findings mainly include the following aspects: first, the ivx's components at the macro, meso, and micro levels all have certain ability to represent sentiment. among them, the ivx decomposition component at the macro level has the strongest ability to represent the current sentiment; the one at the meso level reflects the first-order or second-order lagging sentiment; the one at the micro-level can represent the current sentiment, but the effect is weak. overall, ivx tends to more reflect the macro sentiment, yet has a weaker ability to represent sentiment at meso and macro levels. second, this paper finds that compared with the sentiment index at each level, the common sentiment factor has a stronger relationship with ivx. this fact implies that j o u r n a l p r e -p r o o f ivx more represents the mutual composition of sentiment at different levels, and ivx has the strongest correlation with the current common sentiment factor. hence, we believe that ivx can represent mutual sentiment of all levels to a certain extent. the underlying asset of ivx is shanghai 50etf option, and the pricing of option should theoretically reflect the expectations and sentiments of investors. that is confirmed to be effective, for we have verified the ability of ivx to represent sentiment in this paper. since chinese volatility index ivx is still in its infancy, the empirical evidence of this paper would contribute to providing a theoretical basis for the development of ivx. our results show ivx can comprehensively reflect the sentiment and expectations of investors on different time scales. the measurement of investor sentiment is complicated from the macro level to the micro level, while ivx can be calculated at high frequency. thus, we strongly recommend resuming the release of ivx. it will help investors better understand the overall financial market situation, allocate asset portfolios, and perform risk management, and is also beneficial for regulatory authorities to deepen their understanding of changes in the domestic financial market and effectively conduct financial supervision, so as to achieve the healthy and sustainable development of the financial market and ensure the stable operation of the macroeconomic system. hedging emerging market stock prices with oil, 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a new approach for crude oil price analysis based on empirical mode decomposition estimating the impact of extreme events on crude oil price: an emd-based event analysis method sentiment analysis key: cord-323261-1of5ertf authors: lo, catherine yuk-ping title: securitizing hiv/aids: a game changer in state-societal relations in china? date: 2018-05-16 journal: global health doi: 10.1186/s12992-018-0364-7 sha: doc_id: 323261 cord_uid: 1of5ertf background: china has experienced unprecedented economic growth since the 1980s. despite this impressive economic development, this growth exists side by side with the human immunodeficiency virus/acquired immune deficiency syndrome (hiv/aids) and severe acute respiratory syndrome (sars) crises and the persisting deficiencies in public health provision in china. acknowledging the prevailing health problems, the chinese government has encouraged the development of health non-governmental organizations (ngos) to respond to the health challenges and address the gaps in public health provision of the government. hiv/aids-focused ngos have been perceived as the most outstanding civil society group developed in china. considering the low priority of health policies since the economic reform, the limitation of the “third sector” activity permitted in authoritarian china, together with the political sensitivity of the hiv/aids problem in the country, this article aims to explain the proliferation of hiv/aids-focused ngos in china with the usage of the securitization framework in the field of international relations (ir). methods: the research that underpins this article is based on a desk-based literature review as well as in-depth field interviews with individuals working in hiv/aids-focused ngos in china. face-to-face interviews for this research were conducted between january and may in 2011, and between december 2016 and january 2017, in china. discourse analysis was in particular employed in the study of the security-threat framing process (securitization) of hiv/aids in china. results: this article argues that the proliferation of hiv/aids-related ngos in china is largely attributed to the normative and technical effects of hiv/aids securitization ushered in by the united nations security council (unsc) and supported by the global fund to fight aids, tuberculosis, and malaria (hereinafter global fund) observed in china. despite depicting a positive scenario, the development of hiv/aids-focused ngos in china generated by the international securitization efforts is largely limited. an internal and external factor was identified to verify the argument, namely (1) the reduction of international financial commitments, as well as (2) the fragmentation of hiv/aids-focused ngo community in china. conclusions: this article shows that international securitization weakened with the rise of chinese commitment on hiv/aids interventions. in other words, hiv/aids-related responses delivered by the national government are no longer checked by the global mechanism of hiv/aids; thus it is unclear whether these ngos would remain of interest as partners for the government. the fragmentation of the hiv/aids community would further hinder the development, preventing from ngos with the same interest forming alliances to call for changes in current political environment. such restriction on the concerted efforts of hiv/aids-related ngos in china would make achievement of the sustainable development goals (sdgs) to foster stronger partnerships between the government and civil society difficult, which in turn hindering the realization of ending hiv/aids in the world by 2030. china has experienced remarkable economic growth since the initiation of the economic reform in the 1980s. the average gdp growth in china was 9.6% annually during the first two decades of the economic reform [1] . the rising nation became the world's leading manufacturing power in 2011, and it surpassed the united states as the world's largest trading country [2] . jakovljievic further predicted that the economic growth in china would continue at least up to the middle of the 21st century [3] . despite such impressive economic performance, the provision of public health and the control of infectious diseases have been marginalized. between the late 1980s and 2003, the chinese national government public health spending as a proportion of total health spending plunged from 30% to just over 15% [4] , despite the fact that china has outperformed other developing countries, such as other brics members, regarding the public health spending in nominal terms [5] . as argued by yip and mahal, chinese political leaders in the abovementioned period of time simply perceived health as "a consumption activity rather than a productive good and therefore was given lower priority in government funding" [4] . in this regard, the chinese authorities deliberately curtailed the level of public health expenditures so that economic development could be pursued and the legitimacy of the one-party authoritarian regime bolstered. acknowledging the economic success in the past decades, hiv/aids nevertheless emerged as one of the "negative externalities" of public health threats brought about by the 1980s economic reform. hiv/aids was first discovered in china during the mid-1980s, the same period when the economic reform was just beginning. the epidemic was exacerbated in china in the 1990s mainly because of government-supported blood plasma selling, which did not follow adequate sterilization procedures. this lack of regulation resulted in the emergence of so-called aids villages (aizibing cun) in henan and its outlying provinces, where a large percentage of rural residents were infected with hiv/aids [6] . having little benefit from the economic reform in ways that coastal provinces did during the 1980s, many residents in the central plains had little choice but to engage in the blood-plasma industry to improve their standard of living. since 2000, hiv/aids has become a politically sensitive issue in china because of the international condemnation of the henan blood scandal. according to the latest figures released by the joint united nations program on hiv/aids (unaids), 660,000 people were estimated to have hiv/aids in china in 2016 [7] . the country has the second largest hiv/aids population in asia after india. the chinese government started addressing the hiv/ aids problem after years of denial and underestimation of the hiv/aids prevalence in the country, especially among the most-at-risk populations (marps) including injecting drug users (idus), female sex workers (fsw), and men who have sex with men (msm) [8] . however, national hiv/aids policies in the early years were very much driven in a top-down manner with government institutions (i.e. mainly the chinese centers for disease control and prevention [china cdc hereinafter] ) playing a leading role and with limited engagement of the "third sector" [9, 10] . given the association of the disease with behaviors that are legally or socially unacceptable in the country (i.e., commercial sex work, injecting drug use, and men having sex with men), hiv/aids high-risk individuals refrain from using the related services provided by the government agencies because they wish to avoid being seized or humiliated by public security officials or by thugs hired by local officials [11] . in this regard, gåsemyr claimed that the emergence of hiv/aids-focused non-governmental organizations (ngos) 1 in china during the early 1990s could fill the capacity gap of the government by implementing national hiv/aids policies and providing the related services for those marps that are hard to reach by the authorities [12] . considering the low priority of health policies since the economic reform, the limitation of the "third sector" activity permitted in authoritarian china, together with the political sensitivity of the hiv/aids problem in the country, it is believed that the involvement of hiv/aids-related ngos in china would be largely limited. this is however not the case. over the last 15 years there has been a dramatic increase in the number of hiv/aids-focused ngos operating in china. while gåsemyr argued that the growth of hiv/ aids-related ngos is mainly attributed to the devastating health crisis of sars in china and the new chinese leadership in 2003 [12] , the previous work cannot explain why a high degree of political recognition was observed in solely hiv/aids ngos, instead of other health ngos, such as tb or cancer ngos in china. this article aims to fill this research gap with regard to the proliferation of hiv/aids-focused ngos in china with the use of the securitization framework in the field of ir. the research that underpins this article is based on desk-based literature review as well as in-depth field interviews with individuals working in hiv/aids-focused ngos in china. discourse analysis was in particular employed to study the securitization of hiv/aids in china. potter argued that "discourse analysis has an analytic commitment to studying discourses as texts and talks in social practice…the focus is…on language as… the medium for interaction…one theme that is particularly emphasized here is the rhetorical or augmentative organization of talk and texts" [13] . silverman pointed out that the intellectual ancestor of discourse analysis is john langshaw austin, the original inventor of the idea of speech acts that later became the core element in securitization theory [14] . concerning discourse analysis and speech acts share the austinian concern with the rhetorical structure of talk and texts, the founding scholars of securitization theory, buzan, waever and wilde explicitly stated, "the obvious method [to study securitization] is discourse analysis, since we are interested in when and how something is established by whom as a security threat" [15] . the authors also noted that the technique of employing discourse analysis to securitization studies is to "read[ing], looking for arguments that take the rhetorical and logical form defined here as security" [15] . the meaning of security is constructed when the political leaders (securitizing actors) frames an issue as an existential threat to the referent objects, 2 claiming the issue as having an absolute priority on the government agenda, thereby invoking a right to handle such an issue with extraordinary/emergency measures to ensure the survival of the referent objects [16] . in this research, public speeches (in written form) related to hiv/aids problems, which were delivered by the top-level political leaders, were examined. a specific rhetorical structure had to be located in their discourses, consisting of either one or all of the following elements: (1) the existence of an existential threat; and/or (2) the perceived threat is challenging the survival of the states or people in the states (referent objects), and/or which it requires to (3) be urgently dealt with by new political measures of the respective country. an array of documents ranging from official documents, reports, newspaper articles was initially identified via the search engines of google scholar and proquest with the keywords of "hiv/aids", "security threat", and "china". nine key articles were consequently singled out to identify the textual discourses related to hiv/aids threat/ security nexus in china, published or released between 1987 and 2011 (table 1) . a total of 47 semi-structured interviews were conducted along with the discourse analysis. apart from the background information of the respective ngos, the interview questions used in this study are categorized into three main dimensions: (1) the priority of hiv/aids on the government agenda; (2) the perceptions on the changing international and national financial commitment on hiv/aids interventions; and (3) civil society involvement and coordination in national hiv/aids policies. the first dimension aimed to ensure that the ngos respondents were knowledgeable about the changing national government perceptions and policy priority towards hiv/aids in china, therefore, the researcher could rule out those comments given by unknowledgeable respondents so as to enhance the internal validity of the data collected. the second dimension was included to study their perceptions on the level of hiv/aids funding and effect (if any) on the service provision. the third dimension aimed to discover the actual level of involvement of ngos in national hiv/aids interventions as well as the level of coordination and cooperation between different ngos working on hiv/aids. two types of non-probability sampling-purposive sampling, including "theoretical sampling" and snowball sampling-were employed in the selection process of key informants. for purposive sampling method, samples were selected based on the "logic" or "commonsense" of the researcher in terms of the target population, its elements, and the purpose of the study. in this study, the target population consisted of the individuals working in hiv/aids-related ngos at global, national, and grassroots levels. in the course of the data collection, "theoretical sampling" was also applied to understand the subjects from a theoretical perspective. hence, academic scholars who have conducted research on hiv/aids policies in china were also included in the interviewee list. interviewees were also recruited via snowball sampling. the researcher collected data on the few members, and each respondent was asked to suggest people whom the respondent believed to be the most influential for interviewing. interviews for this research were undertaken between january and may in 2011, and between december 2016 and january 2017 with leaders or senior officers working on hiv/aids in china, including 15 international ngos, nine self-help groups, four gongos, five advocacy groups, two national ngo, one independent consultant, two academia, and two networks (see table 2 ). twenty-six respondents were pinpointed based on the civil society (minjian shehui) 3 was not considered as part of the political system in the pre-modern era; the emergence of a relatively independent civil society is a product of modern china. the changing socio-economic relations brought about by "open door policy" resulted in the recognition and growth of civil society for the first time in the chinese history [17] . despite the early emergence of civil society, the 1999 falung gong incident showcased the destructive power of civil society in the eyes of the chinese government, worrying a robust, well-organized, and out-of-control civil society could overthrow and replace the ccp ruling position. meanwhile, the authorities realized the supplementary role ngos could perform in policy implementation. the chinese government has thus resolved such dilemma by adopting a "state-led" approach to manage civil society in china. based on frolic's concept of "state-led civil society", civil society is created by and belong to the state, thus the independence and autonomy of civil society are at all time bounded by the state [18] . the state has the role of legitimating social organizations, demanding a disciplined partnership. accordingly, antagonism inherited in the western concept of civil society is not allowed to exist in the state-society relations in chinese authoritarian regime; any alternative force to the state is considered as an attempt to curtail or overturn its political legitimacy and power. accordingly, the state apparatus has managed the numbers and restricted the growth of both international and grassroots ngos via various legislative means, thereby allowing ngos to operate openly but at the same time keep the organization growth in check [19, 20] 4 despite these regulations, the chinese authorities had relatively given more autonomy to ingos than grassroots ngos operating in its territory, since the government could access international expertise and tap foreign money to tackle with the emerging social problems in china [22] . such degree of autonomy is nevertheless problematic after the promulgation of foreign ngos management law (jingwai fei zhengfu zuzhi guanli fa) in april 2016. the 2016 law stipulates that ingos operating in china must register with public security officials, and must not engage in political or religious activities that damage "china's national interests" or "ethnic unity". international community and western governments perceived the new law as a reinforcement of restriction of the numbers and scopes of foreign entities operating in the authoritarian regime. grassroots ngos are regulated by the regulation on registration and administration of social organizations (shehui tuanti dengji guanli tiaoli). according to the 1998 regulation (amended in february 2016), a ngo must possess a minimum asset of 100,000 yuan and have a "professional management unit" (zhuguan danwei) that acts as a supervisory body to the organization in order to register under the ministry of civic affairs (moca). 5 fulfilling these two requirements is very formidable for grassroots ngos. the financial situation is problematic in many grassroots ngos because of the limited source of funding. on the one hand, most grassroots ngos receive limited financial support from the government, as they usually do not have political ties with the government. grassroots ngos also seldom receive donations from local communities because (1) newly developed ngos do not have good track records that enable them to win the trust of the locals, and (2) donors cannot receive tax breaks for their donation to unregistered ngos [23, 24] . in addition, most government departments simply reject their applications due to fear of consequences of taking responsibilities for grassroots ngos. many grassroots ngos are hence often unregistered or registered as business entities with the ministry of industry and commerce (moic) [25] . 6 in addition to the abovementioned restrictions, the regulation also bans "similar organizations" coexisting at the various administrative levels [21] , facilitating the management and even control the legal status of grassroots ngos in china. 7 having official registration, to certain extent, is sine qua non to the survival of organizations as the legal status entitles ngos as official recognized entities to receive legal and financial supports from the government; unregistered ngos are officially perceived as illegal that would be subjected to prosecution and coercion by the state apparatus. 8 considering a restrictive engagement of grassroots ngos in china, instead of grassroots ngos, early hiv/ aids-related responses at societal level were largely conducted by gongos [26] , 9 [27] . considering the low priority of health policies since the economic reform, the limitation of the "third sector" activity permitted in authoritarian china, together with the political sensitivity of the hiv/aids problem in the country, it is intriguing to uncover the reasons for the growth of hiv/aids-focused ngos in china since 2003. gåsemyr argued that the growth of hiv/aids-related ngos is mainly attributed to the devastating health crisis of sars in china and the new chinese leadership in 2003 [12] . having said that the chinese government realized the impacts health problems or infectious diseases could have on its economic and social development, the previous work cannot explain why a high degree of political recognition was observed solely in hiv/ aids ngos, instead of other health ngos, such as tb or cancer ngos in china. considering the regime type of the government, allowing the growth of local ngos would in turn potentially attenuate the supremacy of the chinese communist party (ccp) in ruling the country or erode the autonomy of the state, why the chinese government tolerated, allowed, or even encouraged the growth of ngos in fixing hiv/aids problems, especially the epidemic has been viewed as a politically sensitive issue in china? how can one account for and understand the phenomenon? answering the key question with an ir perspective, this article argues that the rapid development of hiv/ aids-related ngos in china is attributed to the effects of hiv/aids securitization at the international level since 2000. considering one of the most influential theories developed in the field of ir, securitization describes the process of defining an issue as a security threat (speech acts) and the corresponding political responses to block the adverse development of the perceived threat (emergency measures). this article particularly pinpoints the unsc and the global fund, which provide normative and technical supports, to study this endeavor. normative influences in this article refer to the effects of security-threat discourses, primarily resolution 1308 of the unsc, on the national government's perception on hiv/aids problems, whereas technical influences refer to the effects of global emergency measures, in particular the global fund, on the funding and management of hiv/aids-related policies at the state level [28] . this article aims to demonstrate the ways in which international hiv/aids securitization has served as a game changer in altering state-society relations in china. drawing on literature reviews and fieldwork materials, this article further argues that the proliferation of hiv/aids-focused ngos in china generated by the international securitization efforts is nevertheless largely limited owing to the reduction of international financial commitments. the fragmentation of hiv/aids-focused ngo community is another factor hindering the development of a full-fledged third sector in the country. securitization in the ir discipline is a model outlining the process of framing an issue as a security threat and the corresponding political reactions to block the adverse development of the perceived threat. employing the theory, one is required to look for three criteria to determine whether an issue is a threat to the country and its people, including 1) discourses uttered by toplevel political leader (securitizing actor) declaring a particular referent objects as an existential threat to security; 2) acceptance by the targeted audience convinced of its potential to be an existential threat (audience acceptance); and also 3) redirections of existing financial resources, new policies, or practices (emergency measures) are implemented to address the issue following the security-threat claim [15] . in other words, the resolution of the "existential threat" posed by "x" takes precedence over other problems [29] . numbers of security studies scholars believed that hiv/aids is the first infectious disease being securitized by the international institutions and national governments as the abovementioned criteria were all fulfilled in the case of hiv/aids [9, [30] [31] [32] . speech acts concerning hiv/aids as a security threat were first identified in a unsc meeting in january 2000. 10 in july of the same year, the unsc passed resolution 1308, acknowledging the urgent need to address hiv/aids, which threatens the stability and security if left unchecked [33] . it is perceived that the particular security framing of hiv/aids gained acceptance by the national governments (audience of the hiv/aids security-threat claim) since 189 countries unanimously adopted and signed the declaration of commitment on hiv/aids in 2001. the urgency of addressing hiv/aids problems was reinforced in the special united nations general assembly special session (ungass) devoted to hiv/aids that has taken place every 5 years since 2001 [34] [35] [36] [37] . the abovementioned events are significant because they represented the first time that the unsc general assembly devoted an entire session to a single disease, and the first time that the international political authorities framed hiv/ aids as a global health threat to national and international security instead of solely as a developmental or public health problem [38] . 11 the 2000 rhetorical act was backed by operational emergency responses in terms of the augmentation of the global hiv/aids spending since 2000. the amount was exponentially surged from about us$900 million in 1999 to us$16 billion by 2009; and to an estimated us$19 billion in 2013 [39] . several hiv/aids-related funding agencies and health programs formulated after 2000, also referred to global health initiatives (ghis), brought in additional monetary resources for hiv/aids [40] . 12 perceiving as the most prominent ghis, the global fund pledges to accelerate the end of the three epidemics, [hiv/]aids, tuberculosis, and malaria by providing financial support (us$4 billion annually) for low-income countries to respond to the three diseases [41] . undoubtedly, the introduction of the abovementioned ghis has brought about unprecedented levels of funding for diseases, in particular hiv/aids, in countries that have insufficient resources, whether because of poor socio-economic development or lack of political will, to orchestrate appropriate responses to the intractable disease. acknowledging international securitizing efforts on hiv/aids, this article illustrates the normative effects of resolution 1308 of the unsc and the technical influences of the global fund on national-level hiv/aids responses. china is selected as a case study to investigate this endeavor. china's response to the hiv/aids problem changed from an ignorance of "global evidencebased policy recommendations and international advice" into "one of our success stories [in global hiv/aids fight] during this past 15 years," as claimed by michel sidibe, executive director of the unaids [42, 43] . the subsequent sections demonstrate the ways in which the securitization effort in the international level acted as a game changer for hiv/aids-focused ngos in participating in national hiv/aids undertakings in china. chinese case study discourse analysis: normative influences and the role of the unsc in china, many of the first cases of hiv/aids since 1985 occurred among foreigners and homosexuals. therefore, the official discourses at that time promoted the idea that hiv/aids only affected non-local chinese people and foreigners, asserting "drug taking, alcoholism, robbery, homicide, suicide, divorce, prostitution, homosexuality, syphilis, aids…these kinds of western social ills come from their ideology", and also claiming "china had no sources of hiv/aids" [44, 45] . the rhetorical acknowledgement of hiv/aids as a health security threat to the chinese population was largely absent during the early period of time. ramiah also pinpointed that the chinese leadership was extremely reluctant to acknowledge hiv/aids as a problem and securitize hiv/aids in china prior to the 2000s [46]. one probable reason for the resistance to hiv/aids securitization is economic: the period of early hiv/aids outbreak coincided with the initial years of open door policy and economic reform (gaige kaifang) of china to the outside world. the thirst for economic growth and performance preceded the urgency of disease management: local authorities feared their respected jurisdictions would lose external or foreign investment if the full extent of the problem were known, or that they would be punished by superiors for failing to prevent the hiv/aids spread. the "cover-up" practice also ocin response to the designated targets, the securitythreat framing of hiv/aids has been fully adopted in the official discourses of chinese leaders and in official documents since 2003. previously viewing hiv/aids as a "western disease" or "non-chinese disease", executive vice minister of health gao qiang stated in the hiv/ aids high-level meeting of the un general assembly that "hiv/aids is a common enemy of the whole mankind as it seriously threatens public health and safety. the chinese government has attached great importance to hiv/aids prevention and treatment and has treated it as a strategic issue for social stability, economic development, national prosperity and security, making it a first priority of the government work" [emphasis added] [47] . the chinese president hu jintao once claimed in a 2003 public speech that "hiv/aids prevention, care and treatment is a major issue pertinent to the quality and prosperity of the chinese nation"; whereas premier wen likewise asserted that "dealing with hiv/aids as an urgent and major issue is related to the fundamental interests of the whole chinese nation" [emphasis added] [47] . the ideas in the speeches were restated in the official document entitled state council notice on strengthening hiv/aids prevention and control (guowuyuan guanyu qieshi jiangqiang aizibing fangzhi gongzuo de tongzi). this 2004 document explicitly demonstrated the determination of the chinese authorities in grappling with the disease and stated that "hiv/aids prevention and control is linked to economic development, social stability, and national security and prosperity. long-term commitment to respond to hiv/aids is hence necessary" [emphasis added] [48] . china's hiv/ aids prevention and control policies were further strengthened in the state council notice on further strengthening hiv/aids prevention and control (guowuyuan guanyu jinyibu jiangqiang aizibing fangzhi gongzuo de tongzi) in late 2010, claiming that "the prevention and control of hiv/aids is related to the people's physical health and social and economic development, as well as to national security and the rise and fall of the nation. the party central committee and the state council have always attached great importance to the prevention and treatment of hiv/aids" [emphasis added] [49] . based on the discourse analysis of the official documents and newspaper articles, it is argued that chinese national leaders followed suit the international move (i.e. unsc resolution 1308) to securitize hiv/aids in the country, framing hiv/ aids as a threat with social, political, economic, and security implications. such an alteration in perception toward the epidemic brought about the political recognition of the hiv/ aids-focused ngos, which has also been highlighted by multiple statements delivered by various top-level government officials since 2003. in 2004, vice premier wu yi stated, "we should mobilize all the partners in society to participate in the fight against hiv/aids. we need to improve our policies and strategies to build a better environment for the society to participate in the response, and try our best to facilitate the involvement of all sectors" [49] . in 2011, vice minister of health yin li publicly proclaimed "civil societies play an indispensable role in effective hiv/aids interventions led by the government" [50] . premier li keqiang even promoted tax break for ngos specializing in hiv/aids prevention, claiming the role of ngos in hiv/aids prevention "is an irreplaceable and unique force" [51] . to a certain extent, these aforementioned statements demonstrate the state's recognition of ngos' works and its willingness to engage with ngos in national hiv/aids interventions, although the political space of involvement is by and large bounded by the state [52] . the previous section illustrates the change in the perception of the chinese government toward the hiv/ aids problems: from denial to the acceptance of the threats that could be posed by the disease on the country and its people. such threat recognition also brought about the acknowledgement that the government alone could not resolve the hiv/aids problems because of the complicated nature of the epidemic; the involvement of civil society groups was a globally recognized recommendation leading to the successful containment of the epidemic. nevertheless, verbal recognition is not sufficient to enhance the engagement and development of hiv/aids-focused ngos, especially in the preexisting authoritarian government structure; the governance and funding mechanism for hiv/aids responses requires alternation in china. as illustrated in the following section, this was the mechanism of the global fund that enhanced the funding for hiv/aids-focused ngos, facilitating the involvement of civil society groups in translating the rhetorical acts into emergency responses of hiv/aids in china. among the international funding agencies emerging after the hiv/aids securitization launched by the unsc, the global fund was the most renowned major contributor to the hiv/aids interventions in china. the global fund finally accepted the first proposal submitted by the chinese government on hiv/aids interventions in late 2003, after the previous proposals being turned down twice in 2002 [52] . between 2003 and 2012, the chinese government has received over us$8 billion in grants from the global fund; approximately us$324 million were disbursed to hiv/aids intervention programs [41] . further information regarding the global fund on hiv/aids in china is illustrated in table 3 . intervention of the global fund's funding mechanism was deemed to transform the primary hiv/aids governance in china [53] . the global fund required the governments to set up a country-level country coordination mechanism (ccm) to construct the grant proposals in line with the national hiv/aids-related strategies, manage the use and distribution of grants, and also oversee the implementation of successful applications. as per the requirement of the global fund, ccm should consist of a broad representation from the government, ngos, multilateral and bilateral agencies, and private sector [54] . in the existing government structure in china, grassroots ngos have limited channels to participate in policymaking and implementation processes. thus, the multi-sectoral structure of ccm contributed to enhancing the government's commitment to involve ngos in national hiv/aids prevention and control measures [55] . two among the 22 seats in chinese ccm were reserved for the representatives of hiv/ aids-related grassroots ngos and people living with hiv/aids are a case in point [56] . considering the existing government structure does not allow the full involvement of ngos in china, the ccm provided valuable opportunities for civil society groups to engage in hiv/aids-related policymaking. the involvement of ngos in national hiv/aids programs was notably highlighted in round 6 of the global fund in china, since the theme of the grant proposal submitted by the ccm was directly linked to the development of civil society groups (refer to table 3 ). in the course of the interview, a director of a hong kongbased ngo commented on the profound influence of the round 6 on the ngo development: "round 6 of the global fund acts as a pushing force for the government to involve more grassroots ngos in hiv/aids interventions" (national ngo-1). in line with the respondent's opinion, kaufman argued the round 6 in particular "was seen by many as a further mechanism to institutionalize hiv/[aids] ngos roles in china's [hiv]/aids response [42] ." in addition to the increase in participation, financial support for ngos working on hiv/aids-related programs surged through the global fund. as the principal recipient (pr) of the country, the chinese government (i.e., china cdc or the nhfpc) was required to disburse a designated portion of the grants to hiv/aids-related ngos (in the form of sub-recipients) operating in the country [41] . following the instruction, 20% of the total grant was allocated to support ngos in round 3 and 4, whereas 50% of its grant was distributed to ngos in round 5 of the global fund [56] . in line with the theme of round 6 entitled "mobilizing civil society to scale up hiv/aids control efforts in china" proposed by the chinese ccm, the proportion granted to hv/aids-related ngos reached 100% [52] . owing to the constructive political atmosphere and promising financial resources in the country, a burgeoning number of individual-organized hiv/aids-focused ngos was established in china; over 43% of the number of grassroots ngos increased in china between 2003 and 2004 [57] . the suspension of the global fund in 2011 demonstrated that the funding mechanism to some extent held the chinese government accountable for the financial supports of hiv/aids-focused ngos. the global fund once suspended its funding to chinese hiv/aids programs in early 2011 because the chinese ccm failed to allocate 35% of the us$283 million hiv/aids grant to grassroots ngos as pledged; less than 11% was distributed to hiv/aids-focused ngos [58] . a program officer of a ngo mentioned the failure of ccm to allocate the right portion of the global fund grant to grassroots ngos: "government officials and representatives from gongos dominate the ccm. only a few representatives are from grassroots ngos and civil society" (advocacy group-1). the improper management and use of the global fund was even admitted by a senior government official in the shanghai cdc in times of the interview: first, the global fund required at least 25 percent to 30 percent of the grant should be given to grassroots ngos. however, the government failed to achieve this requirement. second, the management fee in some provinces was too high. third, one of the elements in the rcc program was related to budget aggregation (i.e., monetary contribution by both the national government and the global fund). however, the chinese government did not allocate enough money for the aggregated budget (ccdc/nhfpc-1). the determination of the chinese government to resolve the suspension of the global fund was observed in the course of fieldwork research. during a face-to-face interview inside the office building of the ministry of health (renamed national health and family planning commission in 2013) in may 2011, the respondent told the investigator "the representatives of the chinese government and the global fund representatives are meeting upstairs to negotiate for the resumption of the 2011 grants" (ccdc/nhfpc-2). the dispute was eventually resolved; the chinese government promised to allocate at least 25% of the global fund grant to ngo work [59] . in this regard, the global fund mechanism contributed to the political and financial supports of ngos, thereby resulting in the proliferation of hiv/aids-specific grassroots ngos in china, and also the proactive involvement of ngos in national hiv/aids undertakings. in other words, international securitization altered the hiv/aids policy in china, allowing numerous grassroots-level ngos working on hiv/aids to grow in a prevailing political system with "bounded autonomy". an injecting drug use self-help group leader believed the upsurge in the involvement of civil society also resulted in the improvement of state-societal relations, stating, "in the past, the relationship with the government was not good, but it becomes much better now. the government sent officials to visit our center to learn the management strategy of our organization" (self-help group-1). another ngo interviewee in beijing also claimed that "an increase in the acceptance of the government, especially the ministry of health, on grassroots ngos, [is observed in china] . the ministry of health does open the opportunity for ngos to cooperate with the government" (advocacy group-2). having said that the improvement of state-societal relations, it is noted that the chinese state is not a monolithic actor, but a conglomeration of departments and officials with competing and sometimes conflicting agendas in the national and sub-national levels [22] . a beijing ngo leader pinpointed this phenomenon, stating, "the ministry of health is fine to cooperate with those ngos that can help, regardless of whom. however, state security bureau usually holds a relatively hostile view on the existence of grassroots ngos since the bureau is concerned about social stability" (advocacy group-2). considering hiv/aids as a health threat to the country and its people, the recognition and involvement by the central government and the nhfpc and other related government agencies is of particular vital to the proliferation of hiv/aids-focused ngos in a statedominated society in the current political regime. despite depicting a positive scenario, this article further illustrates that the development of hiv/aids-focused ngos in china generated by the international securitization efforts is largely limited. in other words, the growth of the number of ngos working on hiv/ aids in china would be ceased or even decreased in long term, and also the political space for grassroots to involve in hiv/aids policy making and implementation would be further restricted. an internal and external factor was identified to verify the argument, namely (1) the reduction of international financial commitment, as well as (2) the fragmentation of hiv/aids-focused ngo community in china. external factor: the reduction of international financial commitment china resembles some developing countries in that it has faced the problem of decreasing international hiv/ aids financial commitments in supporting its national hiv/aids responses [60] . given the 2008 global financial crisis and the continuous economic boom in china, international and bilateral funding agencies argue that china should be the donor instead of the recipient of international hiv/aids-specific grants and loans [52] . owing to a lack of international and national hiv/ aids funding, the number of ngos working on hiv/ aids was drastically reduced; many ngos and cbos were simply closed down, only a few of them could barely survive with the support by other funding sources (national ngo-2). the retreat of the global fund has subsequently created a policy vacuum for the chinese government in taking the lead in managing the development of hiv/ aids-related ngos in china. mimicking the funding mechanism of the global fund, the state council launched the china aids fund for non-governmental organizations (cafngo) (shehui zuzhi canyu aizibing fangzhi jijin), providing financial resources for hiv/ aids-related ngos via the submission of grant proposal starting from 2017 [61] . the reduction of the chinese government's reliance on the global fund implies that the hiv/aids-related responses delivered by the national government are no longer checked by the external mechanism. the authoritarian regime is probably the only agency defining/restricting the political space that ngos could work in. explaining the interaction between the chinese authorities and ngos, a university professor in beijing suggested: "in normal circumstances, local cdc staff hand over treatment delivery work to grassroots ngos. nonetheless, cdc officials intend to keep these ngos small, giving them just enough money to run the programs, so that they will not grow too strong to pose potential threats to the government" (academic-1). along with the weakening of international securitization efforts and the rise of chinese government's involvement in managing ngos in the post-global fund era, the continuous proliferation of ngos is further complicated by the fragmented nature of hiv/aids-focused civil society groups in china. it is argued that the existing ngo registration system, as previously mentioned, has brought about a fragmented ngo community in china. apparently, governmentorganized non-government organization (gongo) and registered ngos working on hiv/aids are included in hiv/aids national policy implementation processes, whereas excluding unregistered grassroots ngos that are perceived as illegal or "anti-government" organizations. based on the nature of services that individual hiv/ aids-focused ngos provided, service providers are preferred by the state, whereas ngos serving as advocates of human rights and agencies providing legal services for hiv/aids-infected people would be subjected to prosecution and coercion. a hiv/aids specialist working in an international ngo in beijing stated, "during a 2011 hiv/aids ngo meeting, the chinese government clearly claimed that the authorities would like to work with ngos/cbos conducting service delivery, but not with those working on hiv/aids-related human rights or gender issues" (ingo-1). to further illustrate this point, the chinese political leaders publicly praised a guangxi-based ngo named aids care china, recognizing the work the organization had been done in hiv/aids prevention, meanwhile stifling numbers of hiv/aids activists through imprisonment, house arrest, or assault. dr. wang yanhai and dr. gao yaojie were two of the prominent chinese hiv/aids activists that fled to the united states in 2009 and 2010, respectively, due to the recurrent pressure and disturbance exerted by chinese authorities owing to their advocacy work. in june 2015, a hiv/aids-related legal aid ngo, beijing yirenping, was raided, and two of its activists were detained. in this regard, the continuous inclusion/exclusion selection process would weaken unregistered or advocacy groups that conceived as threats to the legitimacy of the authoritarian regime [62] , while preserving ngos that are willing to under control by the state apparatus and prepared to accept the regime's policy measures. for the sake of reaching a modus vivendi, these ngos usually display self-limiting behaviors, avoiding actions that would be interpreted as threats to the regime [20] , such as having close relationship or cooperation with ngos being "excluded" by the state apparatus. while a formal local network for hiv/aids-related ngos or civil society groups has been established in many countries in asia, such coordination mechanism between non-state actors is largely absent in china. 13 the fragmentation of hiv/aids ngo community is likewise observed in the course of interview sessions. amongst the interviewees, the majority of the ngo respondents believed that cooperation dramatically increased between the government and ngos working on hiv/aids, especially in the areas of treatment, care, and prevention. only a few of them nevertheless stated that communication and coordination occurred amongst ngos in policy implementation. a national-wide ngo respondent claimed that "we seldom cooperate with other ngos or ingos; we have our own teams to do the work" (national ngo-3). some grassroots ngo respondents in shanghai and kunming expressed their unwillingness to cooperate with so-called "unauthentic" ngos or ngos having so-called "government background": few ngos have cooperative relationship. there are lots of "fake" ngos in china. the cdc found some patients to set up grassroots ngos and then through the name of such ngo to apply for the global fund. after they received the money, cdc would become the one who controlled the funding (self-help group-2). eighty-five percent of the hiv/aids-focused ngos in yunnan have government background…for those ngos that are funded by the global fund or china-bill gates projects, these are organizations with the government background…or if you read their introduction saying "with the help and support of government", you will know these are ngos with the government background (self-help group-3). a "we-they" distinction has apparently prevailed amongst the hiv/aids ngos community in china, reinforcing the atomization of hiv/aids-focused ngos, discouraging the proliferation of civil society in china. horizontal relationship amongst ngos working on hiv/aids is relatively weak and ill-organized, thereby avoiding these organizations joining hand to call for favorable political environment or monetary supports to continue their operation in china. owing to the reduction of international financial commitments, as well as the fragmentation of hiv/aids-focused ngo community in china, the proliferation of hiv/aids-focused ngos in china generated by the international securitization efforts is nevertheless largely limited in long run. such restriction on the concerted efforts of hiv/aids-related ngos will inevitably pose challenges to china to fulfill the pledge of the 2030 agenda to end hiv/aids as one of the targets of the sustainable development goals (sdgs) [63] . hiv/aids was officially announced as a security issue in 2000 by the unsc resolution 1308, which claimed that the pandemic could pose security threats if left unchecked. the rhetorical security-threat claim resulted in the burgeoning number of ghis organized by the international and bilateral organizations operating at the state level. this article illustrates the ways in which the unsc resolution 1308 and the global fund influencing the hiv/aids governance in china. rhetorically acknowledged the hiv/aids problems and the irreplaceable role of hiv/aids-focused ngos in combating the disease by the chinese government, the monetary and technical supports by the global fund enabled hiv/aids-focused ngos to participate in the national policymaking process, facilitating the proliferation and development of civil society in china. this success nevertheless does come with concerns regarding sustainability. this article shows that international securitization weakened with the rise of chinese commitment on hiv/aids interventions. in other words, hiv/aids-related responses delivered by the national government are no longer checked by the global mechanism of hiv/aids; thus it is unclear whether these ngos would remain of interest as partners for the government [64] . the fragmentation of the hiv/aids community would further hinder the development, preventing from ngos with the same interest forming alliances to call for changes in current political environment. such restriction on the concerted efforts of hiv/ aids-related ngos in china would make achievement of the sdgs to foster stronger partnerships between the government and civil society (goal 17) difficult, which in turn hindering the realization of ending hiv/aids in the world by 2030 (goal 3). this research has several limitations. firstly, there is a lack of available information regarding the operation of local or grassroots hiv/aids-specific ngos that are in particular helping marps in china, owing to the political sensitivity of hiv/aids, the unregistered status of ngos working on hiv/aids, the increasing restrictive environment for ngos operating in china especially under the xi administration, together with the social stigma attached to their service objects as well as the ngos themselves as the service providers. secondly, it is difficult to conduct longitudinal study on the development of hiv/aids-specific ngos in china. the researcher realized that many of the ngos that had been interviewed in 2011 were no longer under operation in the follow-up fieldwork in 2017, either because these ngos could not secure sustainable funding, or they were cracked down by local authorities for advocating hiv/aids-related human rights or gender equality, or having very close links to foreign (western) organizations. further research therefore needs to be conducted to remedy these technical weaknesses. it is suggested that comparative research could be conducted on the effects (if any) of the regime types, such as china and thailand, and the level of socio-economic development of the country, such as china and singapore, on the effects of international hiv/aids securitization in the national levels. endnotes 1 here ngos does not include government-organized non-governmental organizations (gongos). 2 referent objects refer to "things that are seen to be existentially threatened and that have a legitimate claim to survival." see buzan b et al., security: a new framework for analysis, p. 36. 3 "civil society" is often translated as "minjian shehui", "shiming shehui" and "gongming shehui" in chinese. in fact, the three different chinese terms do not have the same meaning. many scholars actually use these different chinese terms of civil society simultaneously. "minjian shehui" is used in this article because the term is widely used in the academic research in china's modern civil organizations. "civil society" in this article refers to a sphere that is conceptually separable from the state and government. 4 at the same time the state council abolished the jijin guanli banfa stipulated in 1988. 5 the chinese and english versions of the revised regulation (2016) can be found in chinalawinfo. "regulation on registration and administration of social organizations (2016) (shehui tuanti dengji guanli tiaoli). 6 nevertheless, grassroots ngos registered under the moic also encounter problems with regard to the amount and source of funding. as registered commercial entities, grassroots ngos are required to pay a 5 % tax on any revenue, even for funding received for non-profit purposes. 7 in recent years, the abovementioned legislative hurdle in ngo registration has been relaxed in some parts of china, first in shenzhen and then in beijing. the local government in these two cities relaxed its ngo registration rule, and allowed ngos in the fields of business, charity, welfare, and social services to register directly with the moca. such a move can also be observed at the national level. in early 2011, the national government started planning to revise the regulations on ngo registration and management. if the revised version is passed by the state council, the individual-organized or grassroots ngos can directly register with the moca without seeking a supervisory body prior to the registration. 8 it is noted that the author is fully aware of the arguments put forward by timothy hildebrandt, stating chinese ngos could be favored or cracked down by the state apparatus irrespective of registration status. the author is argued that unregistered ngos are comparatively easier to be targeted and cracked down by the government officials in the name of "unlawful organizations". for hildebrandt's argument, see hildebrandt, t. the political economy of social organization registration in china. the china quarterly. 2011;208:970-89. 9 gongos are composed of three types of organizations existed in the 1950s and 1960s: (1) private organizations from the "old china"; (2) friendship associations for the promotion of trade, and cultural exchange agencies; and (3) people's organizations and mass organizations. 10 in the course of the meeting, us vice president al gore claimed that hiv/aids was a security threat because "it threatens not just individual citizens, but the very institutions that define and defend the character of a society. the disease weakens workforces and saps economic strength. hiv/aids strikes at teachers, and denies education to their students. it strikes at the military, and subverts the forces of order and peacekeeping". 11 mcinnes and rushton (2010) argued that the hiv/ aids securitization in 2000 was not a successful or complete securitization. however, this article does not intend to examine whether the international hiv/aids securitization has been fully accepted by the target audience. it intends to examine the influences of the hiv/ aids international securitization on the national and sub-national levels in china. 12 in 2003, the bush administration launched the president's plan for emergency aids relief (pepfar), pledging us$15 billion from 2003 to 2008 to "turn the tide against hiv/aids." the who launched the "3 × 5" campaign that targets getting 3 million people on antiretroviral treatment by 2005, while the multi-country hiv/aids program of the world bank provided more than us$1.3 billion for grants and concessional loans to help governments respond to hiv/aids issues. 13 examples included the indian network of people living with hiv/aids, thai network of people living with hiv/aids, asia pacific council of aids service organization in malaysia, and also action for aids singapore, economic reform and growth in china routledge handbook of chinese security. london: routledge bric's growing share of global health spending and their diverging pathways the health care systems of china and india: performance and future challenges evolving health expenditure landscape of the brics nations and projections to 2025 rural china, a steep price of poverty: dying of aids: new york times unaids data china's pragmatic approach to aids hiv/aids in china and india: governing health security geopolitics in health: confronting obesity, aids, tuberculosis in the emerging brics economies unleash civil society in china to save lives. human rights watch twenty years of mobilizing around aids in china: the main actors and influences behind organizational growth discourse analysis as a way of analyzing naturally-occurring talk interpreting qualitative data: methods for analyzing talk, text and interaction security: a new framework for analysis. usa: lynne rienner publishers security, insecurity and asecurity in the west european non-war community civil society, corporatism and capitalism in china the civil society in china social organizations and the authoritarian state in china ngos in china: an overview. international community foundation is china's new overseas ngo management law sounding the death knell for civil society? maybe not china's evolving civil society: from environment to health china's rapidly growing non-governmental organizations. eai background brief no. 514 from spectators to implementers: civil society organizations involved in aids programs in china defining chinese nongovernmental organizations. volunt int j volunt nonprofit org globalization and its methodological discontents: contextualizing globalization through the study of hiv how is health a security issue? politics, responses and issues securitizing infectious disease should hiv/aids be securitized? the ethical dilemmas of linking hiv/ aids and security where are the links? council on foreign relations on the responsibility of the security council in the maintenance of international peace and security: hiv/aids and international peace-keeping operations. united nation security council united nations general assembly united nations general assembly political declaration on hiv/aids: intensifying our efforts to eliminate hiv/ aids. united nations general assembly united nations general assembly aids and security: where are we now? hiv/aids and securitization theory the global fund to fight aids, tuberculosis, and malaria china's evolving aids policy: the influence of global norms and transnational non-governmental organizations china among success stories in global hiv/aids fight: unaids chief. xinhua. 2015 peking daily cautions against western threats of aids, drugs: the associated press leexisnexis newspapers 46. ramiah i. securitizing the aids issue in asia gao qiang, at the hiv/aids high-level meeting of the un general assembly. permanent mission of the people's republic of china to the un state council notice on strengthening hiv/aids prevention and control. ncaids, china cdc 国务院关于进一步加强艾滋病防治工作的通知 [state council notice on further strengthening hiv/aids prevention and control.] 国发48号 [state council document no red ribbon forum redoubles aids fighting bid. china daily keqiang wants tax break for ngos specializing aids/hiv work. south china morning post china after the global fund investment in hiv/ aids programs: does it help strengthen health systems in developing countries? glob health the global fund: managing great expectations china country coordinating mechanism secretariats. the global fund to fight aids, tuberculosis, and malaria people's republic of china: national center for aids/std control and prevention aids funds frozen for china in grant dispute global fund lifts china grant freeze. the body china aids fund for non-governmental organizations making turkey's transformation possible: claiming "securityspeak"-not desecuritization! southeast european and black sea studies estimates of global, regional, and national incidence, prevalence, and mortality of hiv, 1980-2015: the global burden of disease study the political economy of social organization registration in china this work is supported by a hong kong university research council general research fund grant #144913. the author would like to thank 2 anonymous reviewers for their useful suggestions. the author would also like to express the appreciation to dr. nicholas thomas for his comments on an earlier version of the manuscript. all errors and omissions are the author's responsibility alone. the author declares that she has no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. the author read and approved the final manuscript. key: cord-310232-n10ciwy6 authors: cheung, wing; ip, wan-yim; chan, dominic title: maternal anxiety and feelings of control during labour: a study of chinese first-time pregnant women date: 2007-06-30 journal: midwifery doi: 10.1016/j.midw.2006.05.001 sha: doc_id: 310232 cord_uid: n10ciwy6 abstract objective to explore and examine the relationship between maternal anxiety levels and feelings of control during labour among hong kong chinese first-time pregnant women. design an exploratory descriptive correlation design. data were collected on three occasions: during latent phase of labour, during active phase of labour and within 24–48 hrs after delivery. setting an obstetric unit of a public teaching hospital in hong kong. participants a convenience sample of 90 hong kong chinese first-time mothers. measurements and findings the labour agentry scale (las) is a self-report scale designed to measure feelings of control during childbirth. a visual analogue scale for anxiety (vas-a) was used to measure women's self-reported level of anxiety during labour. pearson product moment correlation coefficient test indicated a significant negative relationship between the feelings of control and maternal anxiety during labour. no statistical relationships were detected between women's attendance at antenatal classes and feelings of control during labour. key conclusions the study showed a significant negative relationship between maternal anxiety and feelings of control during labour. implications for practice midwives should work with women to enhance their personal control during labour and satisfaction with their birth. the insignificant relationship between attendance at antenatal classes and feelings of control suggests the need to evaluate the content of childbirth education in order to empower women's control during labour. traditionally, maternity services have mainly focused on reducing perinatal and infant mortality rates, whereas women's feelings and experience of the childbirth process have tended to be neglected (martin, 1990) . in the past decade, growing recognition of the importance of woman-centred maternity care has shifted the emphasis of the importance of care to promote pregnant women's psychosocial health (lavender et al., 1999) . recent studies have suggested that feelings of control during labour are one of the important factors contributing to maternal childbirth satisfaction (gibbins and thomson, 2001) , and women should be empowered through knowledge of what to expect from accurate information received about the birth process. as studies exploring the concept of feelings of control during labour and the relationship with maternal physical and psychological labour outcomes are limited, the present study was undertaken to look at these issues in more detail. childbirth is a stressful event, and maternal anxiety is known to be associated with a less positive experience and lower satisfaction with the birth (waldenstrom et al., 1996) . anxiety was found to rise concomitantly with the level of pain experienced throughout labour in women of all personality types (connolly et al., 1978) . spiby et al. (2003) stated that a hierarchy of methods, mainly focusing on coping with labour pain, might seriously limit women's psychosocial needs. wuitchik et al. (1990) showed that anxiety could persist even after adequate pain relief was achieved. morgan et al. (1977) concluded that, although analgesia was effective for pain relief, it could provoke anxiety and affect the birth experience. various methods have been suggested to reduce the level of anxiety and labour pain. these include childbirth education (brewin and bradley, 1982) , nonpharmacological and pharmacological pain-relief methods (moir, 1973; schuiling and sampselle, 1999; hodnett, 2002; lowe, 2002) , music therapy (browning, 2002) , support from midwives (sigridur and sigfridur, 1996) and significant others (tarkka and paunonen, 1996) . however, the effectiveness of these methods remain inconclusive. lowe (1996) has explained that how women express, manage and cope with labour discomfort is individual and dependent on a variety of factors. recently, gibbins and thomson (2001) pointed out that maternal feelings of control during labour could be the most vital predictor of an enjoyable birth, and may help in decreasing the level of anxiety during pregnancy. the definition of feelings of control in the maternity context was given by hodnett and simmons-tropea (1987) on the basis of the refined work of tiffany et al.'s (1969) model of control. they defined feelings of control as the sense of mastery over internal and environmental forces by personal initiation of choice that was self-actualising, active, responsible, creative and controlling one's own density. recently, green and baston (2003) categorised the senses of control into three dimensions: control of what health-care professionals are doing, control of one's own behaviour and control during a contraction. it seems that this categorisation of control provides a more specific and measurable way for women and caregivers to evaluate control during labour. some investigators have suggested that feelings of control are positively related to the childbirth experience and satisfaction with this (berg and dahlberg, 1998; cheung, 2002) . in evaluating the expected and experienced feelings of control of women during labour, hodnett et al. (1997) found no significant difference in experienced control between women having expectant management of pre-labour rupture of their membranes and those who had their labour induced. however, women had significantly higher labour agentry scale (las) scores when they experienced continuous caregiver support (hodnett and osborn, 1989) , spontaneous birth without continuous fetal heart monitoring (hodnett, 1982) and decreased usage of pharmacological pain-relief measures (hodnett and abel, 1986) . moreover, green et al. (1990) noticed that feelings of control during labour enhanced women's emotional well-being after labour, and these positive experiences persisted even though they were different from their expectation. feelings of control have also been linked to various variables related to the childbirth experience. brewin and bradley (1982) found childbirth preparation was positively associated with women's perceptions of personal control over the discomforts experienced during childbirth, such as anxiety and pain. gibbins and thomson (2001) reported that information giving during labour and participation in decision-making were crucial in helping women achieve feelings of control. brown and lumley (1994) and jacoby (1987) found that medical intervention during the labour period was negatively related to overall maternal satisfaction and feelings of being in control. however, other researchers (blanche et al., 1998; gibbins and thomson, 2001) claimed that labouring women who received medical intervention still found they experienced a sense of control as long as they were fully informed of events during their labour. previous studies have reported inconsistent findings in chinese women's perceptions towards their feelings of control and participation in decisions about their pregnancy and birth. woollett and dosanjh (1995) indicated that chinese women who lived in east london perceived personal involvement in decision-making as very helpful, and were more committed to seeking childbirth information than non-asian women. in investigating the difference in choice and control as experienced by chinese and scottish childbearing women in scotland, cheung (2002) found that chinese women preferred to give birth without medical intervention and to be well informed during labour. in contrast, a recent study (ip et al., 2003) revealed that chinese pregnant women had a strong expectation about the level of social support that should be provided by their nurses and partners during labour; however, their expectations of their own responsibilities towards how they coped with childbirth were relatively low. previous studies investigating the relationships between maternal feelings of control and levels of anxiety during labour are limited. in the present study, we investigated the relationship between hong kong chinese first-time pregnant women's anxiety levels and their feelings of control during labour. the relationships among the women's sociodemographic characteristics and physiological variables of labour and their feelings of control were also investigated. it was envisaged that the results of this study could (1) increase understanding of the psychological parameters of chinese women in childbirth; (2) help in explaining women's unspoken high anxiety level and its relationship with their feelings of control during labour; and (3) help midwives to develop appropriate strategies to enhance positive childbirth experience for their clients. an exploratory descriptive correlation design was used to examine the level of maternal anxiety and feelings of control during labour among hong kong chinese first-time pregnant women, and to examine the relationship between level of maternal anxiety and feelings of control reported by the women. a convenience sample of primigravid women in their latent phase of labour was recruited from the labour ward of a public teaching hospital in hong kong. they were chinese, aged 18 years or over, could read and speak cantonese and had not developed complications during pregnancy. of the 94 women recruited, four were excluded from the study as one required emergency caesarean section because of suspected fetal distress, and three required epidural analgesia for pain control, giving a final sample of 90 (96% response rate). according to cohen (1992) , this was the recommended minimal sample size to determine study relationships with a medium effect size (r ¼ 0.3) at 5% level of significance and a power of 0.8. the study was carried out in the obstetric unit of a public teaching hospital in hong kong during the period of the severe acute respiratory syndrome (sars) endemic. as a precautionary measure, no visitor was allowed to enter the hospital. the dominant model of care in the unit was medical and supported the active management of labour. this meant that most women had their labour induced or augmented; all women in labour abstained from food and drink, and received continuous electronic fetal monitoring. in addition, each woman was required to have 4-hourly and 2-hourly vaginal examinations, respectively, during the latent and active phases of their labour. the use of continuous fetal monitoring restricted women to a lateral position on the labour ward bed, and to give birth in the lithotomy position. moreover, episiotomy was routinely carried out for every primigravida. women at low risk were classified as a midwifery case according to the hospital protocol; this meant that women in labour were cared for by midwives without the involvement of an obstetrician unless a complication was detected. one midwife usually took care of more than one woman in labour at any given time. about 2 hrs after giving birth, women were transferred to a postnatal ward where a new team of midwives took care of them and their babies. the las was developed by hodnett (1982) . it is a self-report scale designed to measure feelings of control during childbirth. the las consists of 29 short affirmative statements (e.g. 'i felt confident' and 'i felt tense'). respondents were asked to rate each statement on a seven-point likert scale from 1 (representing rarely) to 7 (representing almost always). possible total scores for the las range from 29 (indicating feelings of control rarely) to 203 (reflecting feelings of control almost always). the reported internal consistency of the las ranges from 0.91 to 0.98 (hodnett and abel, 1986) . hodnett and simmons-tropea (1987) claimed that las scores remained stable at 2 weeks, 1 month and 3 months postpartum. in the present study, the chinese version of las (c-las) was used, which has demonstrated high internal consistency with a cronbach's alpha of 0.87, comparable to the previous findings reported by law (2003) . women's self-reported levels of anxiety during labour were measured with a 10 cm vas, with chinese verbal anchors at either end ranging from 0 (not at all) to 10 (very much so). women indicated their response by adjusting the pointer on the vas-a ruler. the intensity of anxiety was calculated in centimetres by measuring from zero end of the ruler to the woman's mark. the criterion-related coefficients for measuring anxiety in childbirth are 0.42-0.91 (guiffre, 1983) . a demographic sheet was used to record the woman's socio-demographic data and information on their attendance at antenatal classes. obstetric data collected included mode of vaginal delivery, duration of labour, types of analgesia used and medical intervention. ethical approval was obtained from the ethics committees of the institutions concerned. a pilot study was conducted with five women in the obstetric unit of the target hospital. revisions and refinements were made to the instrument and data collection procedure before the main study. minor corrections were made to the instrument to achieve a better understanding by the women. women who met the inclusion criteria were invited to participate in the study. each woman was provided with a consent form along with an information sheet outlining the purpose of the study, the right to refuse or withdraw at any time and assurance of confidentiality of the collected data. data were collected by the researcher in the labour and postnatal wards between june 2003 and december 2003 on three occasions: (1) during the latent phase of labour when cervical dilatation was within 1-3 cm with effaced cervix (bennett and brown, 1999) ; (2) during the active phase of labour when the cervical dilatation was within 4-7 cm (bennett and brown, 1999) ; and (3) within 24-48 hrs after the delivery. on the first two occasions, women were asked to rate their anxiety levels at the respective state of labour by adjusting the pointer of the vas-a ruler when they were able to respond during the period of uterine relaxation. the last set of data was collected in the postpartum ward where women were asked to recall and rate their overall level of anxiety and feelings of control during labour, using the vas-a ruler and c-las, respectively. women were not asked to rate their anxiety levels during the transitional phase when cervical dilation was within 8-10 cm (bennett and brown, 1999) , as they were likely to be suffering from the most intensive pain during this phase and would have found it difficult to respond to the questions attentively (niven and murphy-black, 2000) . data were analysed using the statistical programme for quantitative data analysis, spss for window version 11.0. descriptive and inferential statistics were performed on variables. frequencies, means and standard deviations were used to describe the characteristics of samples. pointbiserial formula was used to correlate c-las with dichotomous variables, such as antenatal class attendance, marital status, mode of delivery and obstetric intervention. interval and ratio data, including maternal age, vas-a and c-las scores, were analysed using pearson product moment correlation coefficient. the relationship between c-las and those ranking data, including educational level and family income, were analysed using spearman's rho test. all correlation tests were two-tailed, with a value of po0.05 considered significant (bryman and cramer, 1994) . three pairwise comparisons were made by using a paired t-test to determine if women differed in their mean anxiety score in the three time slots, with bonferroni correction made to the level of significance of 0.017 (0.05/3) (munro, 2001) . data completed on 90 women were included in the analysis. the mean age of women was 26 years (sd ¼ 5.1), and the mean gestational age of their pregnancy was 39.1 weeks (sd ¼ 7.3). most women were married (92%), 59% reported to have planned their pregnancy, 85% had attended antenatal classes, 90% had completed secondary education and 78% claimed to have no religious belief. financially, 46% of women reported that their monthly family incomes were less than hk$10,000, lower than the territory's average of hk$18,705 (census and statistics department of hksar, 2001). the mean duration of labour was 7.23 hrs (sd ¼ 13.8). most women had normal vaginal delivery (88%). in the area of pain relief, 51% received pethidine and entonox inhalation, 48% required augmentation of labour that included aminotomy or oxytocin infusion, and 39% of women did not require any medical intervention. the mean scores of maternal anxiety reported at the latent phase (anxiety 01) and active phase (anxiety 02) were 6.5 (sd ¼ 2.8) and 7.8 (sd ¼ 2.5), respectively; the mean score of the recalled overall anxiety during labour (anxiety 03) was 7.6 (sd ¼ 2.2). pearson's product moment correlation analysis showed that anxiety 03 was positively and significantly related to anxiety 01 (r ¼ 0.6, po0.01) and anxiety 02 (r ¼ 0.7, po0.01). furthermore, anxiety 01 was related significantly to anxiety 02 (r ¼ 0.9, po0.01). according to the paired t-tests, a significant difference was found between anxiety 01 and anxiety 02 (po0.001). another significant difference was also found between anxiety 01 and anxiety 03 (po0.001). however, no significant difference was found between anxiety 02 and anxiety 03 (p40.05). the c-las scores reported by the 90 women in the postnatal ward ranged from 89-187, with a mean score of 131.5 (sd ¼ 22.9). pearson's product moment correlation analysis revealed a statistically significant negative relationship between feelings of control and maternal anxiety during the latent phase (r ¼ 0.3, po0.01), active phase (r ¼ 0.3, po0.01) and recalled overall anxiety during labour (r ¼ 0.2, po0.05). pearson's product moment correlation analysis revealed no significant relationship between maternal age (p40.05) and feelings of control. pointbiserial formula showed no significant relationship between women's feelings of control, planned pregnancy, religious belief, attendance of antenatal class or marital status (p40.05). spearman rho analysis revealed no significant relationship between women's feelings of control, educational level and family income (p40.05). pearson's product moment correlation revealed no significant relationship between the duration of labour and feelings of control (p40.05). pointbiserial formula showed no significant relationship between feelings of control, usage of analgesia, mode of delivery and obstetric intervention (p40.05). the convenience sampling method and the small sample size suggest that the findings of the current study cannot be generalised to the total population. maternal feelings of control and anxiety during labour are soft phenomenon that may change over time from the birth as women become 'wrapped up' with their baby (mccrea and wright, 1999) . this may affect the accuracy of the recalled information. moreover, the vas is used as the selfreport tool and may overestimate or underestimate the anxiety experienced by the women during labour. a replicated study of anxiety and feelings of control with a larger sample size is recommended. as expected, the retrospective measure of the overall anxiety level during labour correlated highly with the measures taken at the time of labour. the insignificant differences between the recalled overall anxiety scores and anxiety scores during the active phase of labour may shed some light on the use of retrospective measures in studies that have difficulties in gaining access to the labour ward. some previous investigators (simkin, 1992; mccrea and wright, 1999) have argued that the recall of labour experience might be subject to the 'halo' effect, as this was a recall of negative aspects of childbirth. notwithstanding, redelmeier and kahneman (1996) suggested that it was impossible to retain every aspect of pain episode in memory, and the retention of a memory of pain at its worst may be maximally efficient. this theoretical explanation could be extended to recall anxiety level, and, as such, the postnatal assessed anxiety could represent a measure of anxiety at its most intense. more studies about anxiety of diverse cause are necessary before one can conclude that postnatally assessed anxiety does represent a measure of anxiety at its most intense. hodnett and abel (1986) concluded that the mean las scores of homebirth primigravida (160.81, sd ¼ 20.29) were higher than those who gave birth in hospitals (142.89, sd ¼ 22.01). the mean c-las score reported by the chinese primigravida in the current study was 131.47 (sd ¼ 22.94), which is comparatively lower than the mean las scores reported in hodnett and abel's (1986) study. this suggests that the environment of birth might affect the woman's feelings of control. women who had a home birth indicated that they anticipated greater control over decision-making, greater commitment to non-medicalised childbirth, more freedom of mobility and avoidance of intrusive medical procedures (hodnett and abel, 1986 ). in addition, hodnett and abel (1986) reported that those women who gave birth in hospitals were allowed to ambulate until delivery. in contrast, the hong kong chinese women were confined to bed and positioned laterally, with continuous fetal heart monitoring throughout their entire labour. in an earlier study, hodnett (1982) reported that women with continuous fetal heart monitoring reported lower las scores than those without continuous fetal heart monitoring. women claimed that the external electronic monitor interfered with their movement and ability to attain a comfortable position during labour, and they consequently required more analgesia (hodnett, 1982) . previous randomised-controlled trials have revealed no significant differences in the labour outcome between low-risk women during labour receiving intermittent auscultation and those with continuous electronic fetal heart monitoring (feinstein et al., 2000) . in this study, one caregiver usually took care of more than one woman during labour at any given time. besides environmental influences, the support of the caregiver is vital to the feelings of control in the women during labour. this was reinforced by hodnett and osborn (1989) who studied labouring women receiving continuous one-to-one caregiver support during labour. hodnett and osborn (1989) reported higher las mean score (151.3 sd ¼ 26.4) than the chinese women during labour in the current study. this suggested that there would have been room for improvement in the current midwifery practice in hong kong, with the objectives for balancing economic constraints while providing quality care. heavy reliance on a technological and medicalised approach to birth at the study unit may reflect that the administrative health policies do not value or understand the time intensiveness of being with women, and this may influence women's satisfaction and their postnatal health and well-being. midwives are encouraged to initiate dialogue with obstetricians to look for ways of improving women's birth environment. waldenstrom et al. (1996) emphasised that the sense of control during childbirth came from the opportunity to receive support from significant others or caregivers. gibbins and thomson (2001) added that the perceived partner's support during labour was identified by the women during labour as a crucial factor in helping them maintain control and cope with the challenge of labour. as the current study was conducted during the sars endemic in hong kong, when husbands were not permitted to accompany labour, the influence of husband's support on women's sense of control could not be explored. it would be worthwhile replicating the study with the husbands present during labour in future. nevertheless, numerous studies have suggested that women might gain a greater sense of control by relinquishing decision-making rights to their entrusted caregivers whom they perceive to know and provide the best care (bluff and holloway, 1994; halldorsdottis and karlsdottir, 1996; green, 1999) . miller (1979) went further and asserted that when an individual believed another person possessed a more reliable control response than her own, the individual would prefer not to have any control (miller, 1979) . midwives were always held in high regard by women during labour in hong kong (holroyd et al., 1997) . their attitudes and the care provided play an important role in helping women to get through the long, intense and tumultuous childbirth (page, 1993) . it was apparent that the mean c-las score reported by the hong kong chinese women during labour was comparatively lower than that reported in western countries. the differences in the cultural background among these women in labour should also be taken into consideration. in a study on the perception of choice and control by chinese and scottish childbearing women in scotland, cheung (2002) found that chinese women tended to focus on the safety of their babies and themselves, and they required encouragement to have self-control over their behaviour in coping with labour pain. on the other hand, scottish women were more concerned about what had happened and what was done to them (cheung, 2002) the findings suggested a negative relationship between the feelings of control and maternal anxiety. in other words, women in labour who perceived better personal control over the labour process reported a reduction in the level of anxiety. this is echoed by mineka and kelly (1989) who reported that the person that preferred to take control found it effective in lowering anticipatory anxiety as well as reducing the effect of aversive events. the insignificant relationship between maternal feelings of control and use of pain relief during labour found in this study was consistent with findings reported by ip et al. (2003) that chinese women have low expectations of their own ability to cope with pain. moreover, results from the current study were also consistent with the findings reported by green and baston (2003) that the duration of labour was not related to feelings of control and that there were no significant relationship between the type of obstetric intervention and article in press the feelings of control. evidently, obstetric procedures may not decrease a woman's feelings of control. stark (1997) reported that a mature primigravida may have greater confidence in her ability to maintain control and cope with labour, as her life experience and knowledge would enable her to face the challenges of childbirth. mercer (1986) asserted that women aged 30 years and older had greater flexibility and personality integration than younger mothers. however, no significant relationship was found between maternal age and feelings of control in the present study. one possible explanation was that most participants were below 30 years and younger mothers under the age of 18 years were excluded from the study. no statistical relationship was detected between participants' attendance to antenatal class and feelings of control. it is contrary to the findings reported by brewin and bradley (1982) that childbirth preparation was positively related to personal perceived control. although most of the women in the present study claimed to have attended antenatal classes (84.4%), the number of attendances and the content of information obtained were beyond the control of the study. accordingly, evaluative studies on childbirth education regarding the empowerment of personal control over childbirth are recommended. in this study, we found a significant negative relationship between maternal anxiety and feelings of control during labour. a sense of control is an important predictor to a positive childbirth experience (green et al., 1990; gibbins and thomson, 2001; green and baston, 2003) . childbirth preparation is crucial to enhance women's confidence towards labour and thus her personal control (thompson, 1981) . the lack of a relationship between women's attendance at antenatal classes and feelings of control suggests the need to evaluate the content of traditional childbirth education to enhance women's control, and inform ways in which midwives could work with women to attain satisfactory childbirth. a phenomenological study of women's experiences of complicated childbirth dysfunctional labour: a randomized trial they know best: women's perception of midwifery care during labour and childbirth perceived control and the experience of childbirth satisfaction with care in labour and birth: a survey of 790 australian women using music during childbirth quantitative data analysis for social scientists. routeledge, london. census and statistics department of hksar choice and control as experienced by chinese and scottish childbearing women in scotland a power premier 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method, evidence and theory the relationship between anxiety, lack of control and loss of control pain relief in labour effectiveness of pain relief in labour: a survey of 1000 mothers statistical methods for health care research memory for labour pain: a review redefining the midwife's role: changes needed in practice patients' memories of painful medical treatment: real time and retrospective evaluations for two minimally invasive procedures comfort in labour and midwifery art journey through labour and delivery: perceptions of women who have given birth just another day in woman' life? part 2: nature and consistency of women's long-term memories of their first birth experiences selected coping strategies in labour: an investigation of women's experiences psychosocial adjustment during pregnancy: the experience of mature gravidas social support and its impact on mothers' experiences of childbirth will it hurt less if i can control it? a complex answer to a simple question a model of control the childbirth experience: a study of 295 new mothers the ideas and experiences of pregnancy and childbirth of asian and non-asian women in east london relationships between pain, cognitive activity and epidural analgesia during labour key: cord-342852-8wlqbwdi authors: chen, jie; liu, xinghuang; wang, dongke; jin, yan; he, miao; ma, yanling; zhao, xiaolong; song, shuangning; zhang, lei; xiang, xuelian; yang, ling; song, jun; bai, tao; hou, xiaohua title: risk factors for depression and anxiety in healthcare workers deployed during the covid-19 outbreak in china date: 2020-09-10 journal: soc psychiatry psychiatr epidemiol doi: 10.1007/s00127-020-01954-1 sha: doc_id: 342852 cord_uid: 8wlqbwdi purpose: this study was conducted to evaluate the status of depression and anxiety of healthcare workers and to explore the risk factors during the outbreak of covid-19 in china. methods: a cross-sectional study was designed using convenience sampling to obtain a sample of healthcare workers. a structured questionnaire was designed to collect the information of the basic characteristics, workload, and the health condition. burnout, coping style, anxiety, and depression were measured by specific scales. multiple logistic regression model was performed to explore the risk factors of anxiety or depression. results: there were 902 questionnaires received between february 9, 2020 and february 11, 2020. the proportion of healthcare workers with symptoms of moderate/severe anxiety and moderate/severe depression were 16.63% and 18.29%, respectively. there were 24.50% healthcare workers experiencing moderate/severe anxiety and depression at the same time. the increased workload, respiratory symptoms, digestive symptoms, having done specific test(s) related to covid-19, having family member needs to be taken care of, negative coping style, and job burnout were the independent risk factors of anxiety. furthermore, the increased workload, respiratory symptoms, digestive symptoms, having done specific test(s) related to covid-19, negative coping style, and job burnout were the independent risk factors of depression. conclusion: more attention should be paid to the mental health of frontline healthcare workers at the outbreak of covid-19 in china. taking steps to reduce the intensity of the work and burnout will be effective to stabilize the mental state of them. electronic supplementary material: the online version of this article (10.1007/s00127-020-01954-1) contains supplementary material, which is available to authorized users. a novel coronavirus, which was named sars-cov-2 by the international committee on taxonomy of viruses (ictv), broke out in wuhan, hubei province, china [1] . by march 4, 2020, the virus had infected at least 80,270 people in china, 2981 of them died. in hubei province alone, 67,332 people have been diagnosed with the virus [2] . by february 20, 2020, 476 hospitals across the country had reported 2,055 laboratory-confirmed cases among healthcare workers, mostly from hubei province (88%) [3] . this is the largest outbreak of the virus in china since sars in 2003. thousands of healthcare workers are fighting the virus across the country, especially in hubei province. healthcare workers in such circumstances are faced with multiple sources of stress, including work intensity, workplace changes relative to daily work, as well as family responsibilities, which may affect mental health [4, 5] . moreover, personal coping style and the presence of jobrelated burnout might also have an important impact on levels of anxiety and depression among healthcare workers [6] [7] [8] . it is believed that preventing the negative effect on psychological state should be an important objective to defend the disasters [9, 10] . however, the impact on healthcare workers at the outbreak of covid-19 was not clear. we felt it important to explore the risk factors associated with psychological problems in healthcare staff in order to provide evidence to support an appropriate intervention program. therefore, we conducted this cross-sectional study to evaluate the prevalence of symptoms of anxiety and depression of healthcare workers during covid-19 epidemic and to identify associated risk factors. we conducted a cross-sectional survey of psychological state on chinese healthcare workers by delivering online questionnaires through wechat platform (https ://www. wecha t.com/en/), a chinese app for communication among friends and colleagues, between february 9 and february 11, 2020. data were collected by designed online questionnaires containing demographic characteristics, working and health conditions of participants, as well as four self-rated psychological scales. the purpose and use of this research were explained at the beginning of the online questionnaire. all the participants agreed the online informed consent before entering the online questionnaire. only one response to the questionnaire per person was permitted. the questionnaire was filled out voluntarily and the personal information was kept confidential. this study was approved by the ethics committee of union hospital, tongji medical college. a structured questionnaire was designed to collect information on the basic characteristics, workload, and health condition. subjective assessment of workload was evaluated by asking the question "how do you evaluate your workload in recent days? 5 = significantly higher than before, 4 = higher than before, 3 = the same as before, 2 = lower than before, 1 = significantly lower than before" [4] . if participants chose answers 5 and 4, then workload (subjective) would be evaluated as increased workload, and if they chose answers 3, 2, and 1, it would be evaluated as non-increased workload. objective assessment of workload is working hours per week. respiratory symptoms in the study included runny nose, cough, expectoration, dyspnea, and chest pain. systemic symptoms include fatigue, muscle aches, headaches, sleep disturbances and others. meanwhile, gastrointestinal symptoms include acid reflux, diarrhea, constipation, abdominal discomfort, bloating, abdominal pain and other. even if the respondents were medical professionals, the explanation of those symptoms was added to the questionnaire. specific tests related to covid-19 included chest computed tomographic (ct) scans and realtime reverse transcription polymerase chain reaction assay (rt-pcr) for sars-cov-2 rna of nasopharyngeal swab. the results were considered as positive if chest ct images showed bilateral patchy shadows or ground glass opacity in the lungs, with or without positive result of rt-pcr for sars-cov-2 rna [11] . by definition, the frontline working environment included fever clinics and isolation wards. the 15-item chinese version of maslach burnout inventory (cmbi) was used to assess job burnout in health care workers participated in this study. the cmbi scale consists of three dimensions of burnout: emotional exhaustion (5 items), depersonalization (4 items), and personal accomplishment (6 items). each item scores from 1 (never) to 7 (every day) and items of personal accomplishment are reverse-scored. the cmbi scale has satisfying reliability and validity in chinese population [12] [13] [14] [15] . cronbach's alpha for the total scale is 0.816, and cronbach's alpha for three dimensions are 0.871, 0.807, and 0.787, respectively [14] . the cut-off scores of the three dimensions were larger than 25, 11, and 16, respectively, and no burnout is defined as all three dimensions under the cut-off scores [12, 14] coping style the 20-item trait coping style questionnaire (tcsq) was employed in this study to evaluate the coping style-positive coping (pc) or negative coping (nc) of participants. there are 10 items for each coping style, and each item scores from 1 to 5. the chinese version of tcsq was proved to be valid and reliable in chinese population, with cronbach's alpha for each coping style dimension at 0.790 and 0.776, respectively [14, 16] . the highest scoring between positive and negative coping style indicates a person's more usual coping style [12, 14] . the generalized anxiety disorder 7-item scale (gad-7) was applied to evaluate participants' anxiety symptoms in the last 2 weeks. with each item ranging from 0 to 3, the total score of gad-7 can be divided into four severity levels: severe (˃ 14), moderate (10) (11) (12) (13) (14) , mild (5) (6) (7) (8) (9) , and no (≤ 4) anxiety [17] . this study employed the chinese version of gad-7, which has been proven to have good reliability and validity in chinese population [18, 19] . cronbach's alpha coefficient of gad-7 was 0.898 and kappa value was 0.825 [18, 19] . statistical analyses were done between moderate/severe and none/mild anxiety distinguished by the recommended cut-off value (total score = 10) [18] [19] [20] . depression symptoms in the last 2 weeks were assessed by the 9-item patient health questionnaire (phq-9) with each item ranging from 0 to 3. according to the total score, the severity of depression is defined as follows: severe (˃ 20), moderate to severe (15) (16) (17) (18) (19) (20) , moderate (10) (11) (12) (13) (14) , mild (5) (6) (7) (8) (9) , and no (≤ 4) depression [17, 21] . the chinese version of phq-9 applied in this study has high reliability and validity in general chinese population, whose cronbach's alpha equals to 0.86 [21, 22] . statistical analyses were done between moderate/severe and none/mild depression distinguished by the recommended cut-off value (total score = 10) [20] [21] [22] . difference in each characteristic described in our online questionnaire according to anxiety and depression status was evaluated by the chi-square (χ 2 ) test or student's t test. multiple logistic regression was done to eliminate the interference of confounding factors and find the independent risk factors of anxiety and depression. and the odds ratios (ors) of anxiety and depression status were also calculated by step-by-step multiple logistic regression model. the c statistic (the area under the receiver operating characteristic (roc) curve) was calculated to evaluate the discrimination of the logistic model. and a value larger than 0.7 is considered as clinically useful [23] . all statistical analyses in this study were performed by r 3.6.0 (https ://www.r-proje ct.org/). and double-tailed p value < 0.05 was considered as statistically significant. there were 902 questionnaires received in total by convenience sampling, all of which were completed and included in the final statistical analysis. questionnaires were filled by 902 healthcare workers: 543 (60.20%) doctors, 311 (34.48%) nurses, and 48 (5.32%) other occupations including the administrative and management staff of the hospital. among all the participants, there were 619 (68.63%) females and 283 (31.37%) males. the information of titles of occupation were asked among doctors and nurses, and 532 (62.30%) of them had primary titles of occupation (interns, residents, attending doctors, junior nurses and primary nurses), while 322 (37.70%) with senior titles (associate chief physician/ associate professor, chief physician/professor, nurse-incharge, deputy chief nurse, and senior nurse). there were 417 (46.23%) of participants assessed their workload as increased. however, only 247 (27.38%) healthcare workers fought on the front line (fever clinic, isolation ward or other work area with direct contact with patients of covid-19), and rest 655 (72.62%) of them worked on second line (general clinics and wards or other places that do not have direct contact with the patients). there were 254 (28.16%) participants had done specific test(s) related to covid-19 and 648 (71.84%) of them had not. positive results of specific test(s) related to covid-19 were detected in 14 (5.51%) participants. in total, 681(75.50%) healthcare workers had none/mild anxiety and depression, and 221(24.50%) had moderate/ severe anxiety and depression ( fig. 1 ). according to the gad-7 score, 274 (30.38%) healthcare workers experienced mild anxiety, while 150 (16.63%) experienced moderate/ fig. 1 distribution of anxiety and depression. most healthcare workers had none/mild anxiety or depression. about a quarter of healthcare workers had moderate/severe anxiety and depression. anxiety and depression can be independent or combined in participants. number of participants with both of anxiety and depression was more than those with the single severe anxiety. on the other hand, there were 274 (30.38%) healthcare workers with mild depression and 165 (18.29%) with moderate/severe depression based on the score of phq-9. the remaining 330 (36.59%) healthcare workers were free from anxiety and depression symptoms. anxiety and depression were significantly concomitant in our respondents, since 291(32.26%) healthcare workers had anxiety and depression at the same time. the univariate analysis showed that some variables did have effects on anxiety and depression to different extend ( table 1 ). the occurrence rates of moderate/severe anxiety and depression were significantly higher in those who experienced increased workload (χ 2 test, 23.74% vs. 10 then, step-by-step multiple logistic regression was performed to establish the best regression model and find the independent risk factors of anxiety and depression (tables 2 and 3 ). these two models were clinically useful according to c statistic (0. 815 the comparison between different working environments (front line or second line) was performed (fig. 2) . feeling of increase in workload was more common in front line than second line (χ 2 our study, a nationwide, observational study, was conducted from february 9 to february 11, 2020, which was the peak period since covid-19 outbreak. we found that self-rated increase in workload, having respiratory symptoms, having digestive symptoms, having done specific test(s) related to covid-19, negative coping style, and job burnout were independent risk factors for both anxiety and depression. we call that attention should be paid to the psychological state of healthcare workers. when people are faced with a pressure source, they need to adapt or cope with it. when their coping ability cannot meet this need, they will produce a stress response, causing changes in physiology, psychology, and behavior [24] . the pathogen causing this new type of pneumonia is very similar to sars, whose mortality rate is as high as 9.6% [25] [26] [27] . covid-19, as a stress source, inevitably causes anxiety and tension among healthcare workers. in our study, we also found that healthcare workers in this outbreak were more prone to anxiety and depression, especially those in the front line. we have shown that in the battle against covid-19, moderate percentages of healthcare workers experience anxiety and depression. social support is the core of psychological intervention. studies have shown that social support is important resources for stress coping [25] . in studies that have investigated the correlates of these psychological outcomes, social support is found to be one of the most reliable factors associated with fewer negative and more positive outcomes [28, 29] . we suggest that healthcare managers should pay full attention to the response of healthcare staff in the face of stress events and provide more social supports and resources to help them [10, 30] . they need to be able to acutely detect signs of psychological injury in healthcare staff, such as avoidance, moody, guilty, and help staff go through mental distress. professional and evidence-based psychological care is needed, if the distress is severe and persistent [31] . in our survey, there was a positive association between anxiety or depression and job burnout, as well as with coping style. healthcare workers who tend to have negative coping style or job burnout are more likely to develop anxiety and depression. a similar phenomenon has been found in many studies [6] [7] [8] . so, it is reasonable to believe that taking certain measures to help alleviate job burnout and guide healthcare workers from negative coping to positive coping will effectively improve the psychological state of them. from the result of step-by-step multiple logistic regression, we can get that working hours per week did not affect the incidence of anxiety and depression, while the subjective feeling of increase in workload did. it may support that the feeling of increase in workload during the outbreak can increase the occurrence of both anxiety and depression. thus, our survey data indicate reducing the risk of anxiety and depression in health care workers by reducing the intensity of work per unit of time. specific measures may include maximizing the number of healthcare workers involved in the disaster and batch management based on the patient's basic condition and severity of symptoms. usually, people who have illness or afraid of getting infected are more likely to have adverse psychological reactions. this phenomenon is in line with the findings in our study that the presence of respiratory and gastrointestinal symptoms, as well as having done specific test(s) related to covid-19 was independent risk factor for anxiety and depression. interestingly, fever, which is considered a very important first symptom of covid-19 [11] , did not affect the occurrence of anxiety or depression. we suspect this may be due to the small sample size of participants with fever (n = 26), resulting in statistical instability. above all, we speculate that the fear of getting infected with the virus might cause anxiety and depression in healthcare workers. we agree that healthcare managers should provide detailed and comprehensive information about this epidemic and pay more attention to the protection of healthcare staff who worked on front line, such as providing effective and adequate personal protective equipment (ppe) [31] . based on the univariate analysis (table 1) , working environment (front line or second line) had an influence on moderate/severe anxiety or depression, while it was not thought to be an independent predictor factor for moderate/ severe anxiety or depression according to step-by-step multiple logistic regression (tables 2 and 3 ). this indicated that the effect of working environment on anxiety or depression might be eliminated by other factors in the multiple logistic regression analysis. according to the comparison between front line and second line (fig. 2) , an appropriate explanation is that the significant difference in the occurrence of moderate/severe anxiety or depression between front line and second line might be due to differences in certain factors between them, such as workload, respiratory symptoms, digestive symptoms, and whether specific test(s) related to covid-19 had been performed. we measured the intensity of the acute traumatic impact of the covid-19 outbreak on hospital workers, as a higher proportion of healthcare workers on the front line did specific test(s) related to covid-19. 2-5 there was no significant difference in coping styles between the front line and the second line. there was no significant difference in job burnout between the front line and the second line characterized by anxiety, and depression. some characteristics (sex, age, occupation, and titles of occupation) had been shown not to be factors that contribute to anxiety or depression in healthcare workers in this study (not included in step-by-step multiple logistic regression). coincidentally, all these factors could not be affected by the outbreak of the virus. the indirect implication is that anxiety or depression in healthcare workers was more likely due to exposure to the risk of infection. this study is an urgently needed original study investigating risk factors for depression and anxiety in healthcare staff working during the peak period of the sars cov-2 outbreak and providing evidence in support of the need for steps to be taken to protect the psychological wellbeing of staff. however, there are some limitations about this study: firstly, considering that it is difficult to directly investigate participants during the pandemic, we choose convenience sampling via online questionnaire. so, there is selection bias in this network research. furthermore, it was impossible to define any characteristics of non-respondents due to the limitation of this method. but despite this, we found some independent risk factors, and the regression model has a good fitting degree. secondly, although causality is uncertain in cross-sectional studies, we believe anxiety and depression are more likely to be the result, since there were evidences that stressful life events are very likely to lead to these mental states [32] [33] [34] . finally, due to the lack of knowledge about the prevalence of anxiety and depression in this population before the outbreak, it is difficult to say with certainty to what extent these findings can be attributed to working circumstances during the coronavirus pandemic, although some risk factors of anxiety and depression mentioned in this study do have association with the outbreak of covid-19, such as self-rated increase in workload, having respiratory and digestive symptoms. multiple factors, including having respiratory or digestive symptoms, having done specific test(s) related to covid-19, self-reported increase in work intensity, negative coping style, and job burnout, participate in the anxiety or depression of healthcare workers. taking steps to reduce work intensity and burnout will be effective to stabilize the mental state of them, especially for whom with negative coping style. more attention should be paid to the mental health of frontline healthcare workers at the outbreak of covid-19 in china. author contributions jc, xl, dw, and tb were responsible for draft writing, conceived the idea for the article, analyzed the data of this study and wrote the final manuscript. yj, xz, mh, ym and ss contributed to data collection in the fieldwork and gave suggestions for data analysis. xx, ly, js, tb and xh contributed to the study design, supervised and checked the analyses, and critically reviewed the manuscript. all authors contributed to this study have approved the final report. funding urgent projects of scientific and technological research on covid-19 funded by hubei province (2020fca014) supported this work. availability of data and material the original data have been uploaded as electronic supplementary material. code availability r 3.6.0 (https ://www.r-proje ct.org/). conflict of interest on behalf of all authors, the corresponding author states that there is no conflict of interest. ethics approval this study was approved by the ethics committee of union hospital, tongji medical college. this study was performed in accordance with the ethical standards laid down in the 1964 declaration of helsinki and its later amendments consent to participate all the participants agreed the online informed consent before entering the online questionnaire. the questionnaire was filled out voluntarily. all authors have seen the manuscript and approved to submit to your journal. a novel coronavirus outbreak of global health concern national health commission of the people's republic of china (2020-03-04) daily briefing on novel coronavirus cases in china report of the who-china joint mission on coronavirus disease 2019 (covid-19 severe acute respiratory syndrome (sars) in hong kong in 2003: stress and psychological impact among frontline healthcare workers the mental health of medical workers in wuhan, china dealing with the 2019 novel coronavirus dynamics of a stressful encounter: cognitive appraisal, coping, and encounter outcomes the relationship between burnout, depression and anxiety: a systematic review and meta-analysis 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probable sars cases with onset of illness from1 the process and mechanics of social support distinctions that matter: received social support, perceived social support, and social embeddedness after disasters psychological outcomes in disaster responders a systematic review and meta-analysis on the effect of social support managing mental health challenges faced by healthcare workers during covid-19 pandemic causal relationship between stressful life events and the onset of major depression the role of life events and hpa axis in anxiety disorders: a review key: cord-339864-rv5zw972 authors: reihani, hamidreza; ghassemi, mateen; mazer-amirshahi, maryann; aljohani, bandar; pourmand, ali title: non-evidenced based treatment: an unintended cause of morbidity and mortality related to covid-19 date: 2020-05-06 journal: am j emerg med doi: 10.1016/j.ajem.2020.05.001 sha: doc_id: 339864 cord_uid: rv5zw972 nan nonevidence-based remedies are spreading across different populations and endangering the lives of individuals, particularly those with low health literacy. for example, given the sacredness of cows in india, some hindus are drinking cow urine to prevent covid-19, a practice backed by government officials [4] . in iran, social media accounts circulated false stories of curing covid-19 by drinking high-proof alcohol, poisoning over 2,000 people due to the inadvertent consumption of methanol with bleach to hide its color [5] . the quick spread of misinformation regarding nonevidence-based treatments for covid-19 may be due to feelings of fear, helplessness, and hope. because there is no definitive treatment for covid-19, people j o u r n a l p r e -p r o o f seek remedies based on their level of knowledge and personal or popular beliefs, which is detrimental to both their own health and the public's health. in the united states, president donald trump suggested the possibility of injecting a disinfectant into patients with sars-cov-2 infection or treating them with ultraviolet rays [6] . these remarks are not only dangerous because disinfectants are poisonous when mishandled, but when these statements are circulated to populations with low health literacy, people may poison themselves from self-administration. of note, even before this statement, there had been a 20% increase in calls to u.s. poison centers related to disinfectants and cleaning products compared to last year [7] . while some of these calls are related to accidental pediatric exposures, others involve inadvertent misuse of the product [7] . there were notable increases in inhalational exposures, as well as exposures to bleach products and alcohol-based sanitizers [7] . even though chloroquine derivates are not approved treatments for covid-19, president trump has tweeted and publicly suggested the therapeutic benefit of the drugs. due to the media attention surrounding chloroquine, an arizona man died after ingesting chloroquine phosphate (an additive to household products meant to treat fish parasites) in an effort to prevent himself from getting infected with coronavirus. [8] . in madagascar, president andry rojoelina launched an herbal coronavirus "cure" produced from the artemisia plant, yet the who stated that the tonic is not evidence-based and is potentially toxic [9] . touting unproven covid-19 treatments will only worsen the current healthcare crisis, as people will certainly experiment with these remedies. as a result, health care systems will become overwhelmed with many critically ill patients, from both covid-19 and those with toxicity from nonevidence-based treatments. there has also been increased media coverage for "alternative" remedies to prevent and treat sars-cov-2 infection. for example, the chinese government encourages the use of herbal j o u r n a l p r e -p r o o f plants to fight the virus including jinhua qinggan capsules, lianhua qinwen capsules, and shufeng jiedu capsules [10] . these herbal formulas contain a combination of many herbs and the exact proprietary mixture is not available, posing a major health risk to patients due to their potential toxicity, contamination, or adulteration [10] . although traditional medicine techniques were widely used during past epidemics such as severe acute respiratory syndrome (sars) and h1n1 influenza, a cochran review found that chinese herbs combined with western medicine did not decrease mortality versus western medicine alone [11] . use of chinese herbal products for treating viruses is not guided by viral pathology, rather herbs are prescribed by herbalists according to chinese diagnostic patterns (inspection, listening, smelling, inquiry, and palpitation) [12, 13] . the implications of medicating with herbal-based formulas is serious and dangerous because there is no scientific evidence suggesting that these alternative remedies can prevent or cure covid-19. there are several adverse effects noted with herbal medications, such as hepatotoxicity, and there have been numerous reports of toxic contaminants, including pesticides and heavy metals [14] . furthermore, although supplementing with vitamins and minerals may improve immune function, there is no evidence to suggest that the use of any supplement will prevent or cure covid-19. similarly, "cures" spread by iranian social media accounts (which include gargling vinegar and rosewater or salt, and drinking concoctions of mint or white willow with saffron, turmeric, and cinnamon) are not evidence-based, though they may have other nutritional benefits [15] . medicating with these herbal formulas or supplements may lead to adverse health effects due to imprecise dosing of the supplement or herb, inherent toxicity of the herb itself, or toxicity of the contaminants in the product, thus complicating the clinical picture. the spread of nonevidence-based covid-19 treatments or cures will undoubtedly worsen the magnitude of the pandemic. as people turn to traditional and nonevidence-based therapeutic options for covid-19 patients a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 are patients with hypertension and diabetes mellitus at increased risk for covid-19 infection? hindu group offers cow urine in a bid to ward off coronavirus [internet]. reuters iran, false belief a poison fights virus kills hundreds public broadcasting service trump suggests 'injection' of disinfectant to beat coronavirus and 'clean' the lungs nbcuniversal news group cleaning and disinfectant chemical exposures and temporal associations with covid-19 -national poison data system fearing coronavirus, arizona man dies after taking a form of chloroquine used in aquariums cable news network coronavirus: caution urged over madagascar's 'herbal cure china is encouraging herbal remedies to treat covid-19. but scientists warn against it nbcuniversal news group chinese herbs combined with western medicine for severe acute respiratory syndrome (sars) in silico screening of chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus traditional chinese herbal medicine for treating novel coronavirus (covid-19) pneumonia: protocol for a systematic review and meta-analysis toxicities by herbal medicines with emphasis to traditional chinese medicine misinformation and false medical advice spreads in iran risk communication: epi-win world health organization. world health organization key: cord-341436-apcueljv authors: zhai, yusen; du, xue title: mental health care for international chinese students affected by the covid-19 outbreak date: 2020-03-19 journal: lancet psychiatry doi: 10.1016/s2215-0366(20)30089-4 sha: doc_id: 341436 cord_uid: apcueljv nan , responsible for covid-19. they also face discrimination and isolation in some countries due to being deemed as potential sars-cov-2 carriers. 1 some media outlets have used derogatory headlines, perpetuating stereotypes and prejudices about chinese people. this coverage fuels public fear, alienation, and discrimination. consequently, such students are at risk of hate crimes, especially when individuals consider them contagious. this situation can lead to mental health problems, such as denial, stress, anxiety, and fear. 2 hence, we urgently need to address the mental health needs of international chinese students. some universities have sent messages of solidarity to international chinese students, offering support and resources to respond to the crisis. although these universities provide counselling services, such centres are often understaffed, and long waiting times might aggravate students' mental health problems. mental health care for international chinese students requires improvement. first, a walkin triage system can assist university counselling centres in differentiating urgent and routine problems; 3 meanwhile, the triage coordinator needs to be aware of international chinese students' specific mental health concerns involving covid-19. second, counselling training clinics are essential assets because they present avenues for collaboration with university counselling centres to address pressing understaffing issues. 4 free counselling services in training clinics can also ease anxiety among international chinese students experiencing distress. third, departments such as student affairs, international programmes, and student health centres should rally to support affected students by advocating for non-discrimination and coordinating the health response to the crisis. advice services provided by these departments can help students address academic and financial issues, and other concerns causing distress. education is also needed to inform the public about the facts of covid-19 to protect international chinese students from hate crimes. care and advocacy serve a crucial role in promoting mental health. 5 thus, building institutional and societal awareness of international chinese students' needs for mental health care can be the lynchpin of supporting them. with the experience attained working with these students in this crisis, universities and communities should be well positioned to provide timely appropriate mental health care for other students experiencing natural or ecological disasters if required, in the future. british-chinese people tell of 'discrimination' and hate as fears rise over coronavirus the mental health of medical workers in wuhan, china dealing with the 2019 novel coronavirus walk-in triage systems in university counseling centers we declare no competing interests. department of educational psychology, counseling, and special education (yz) and department of food science (xd), the pennsylvania state university, university park, pa 16802, usa key: cord-327502-za6x4reh authors: tian, lin; liu, nian cai title: inward international students in china and their contributions to global common goods date: 2020-03-11 journal: high educ (dordr) doi: 10.1007/s10734-020-00522-5 sha: doc_id: 327502 cord_uid: za6x4reh this study identifies the (global) common goods produced and augmented by inward student mobility and its relevance to national policies and strategies in china by interviewing 27 policy-makers, university leaders, and academics, as well as international students. most importantly, it develops a new framework for interpreting inward student mobility through the lens of (global) common goods, with benefit, influence, and balance as the three key elements. the findings of this study indicate that inward international students contribute to global common goods in the aspects of cultural diversity, global talents, improved policies, and practices, etc. (benefit). key policies related to inward international students are generally supportive, and meanwhile compatible with these global common goods to a large extent (influence). though some problems and tensions are observed in this study, constructive solutions have already been proposed by both the chinese government and heis (balance). under the influence of globalization since the beginning of the twenty-first century, the internationalization of higher education has become an unstoppable and irresistible trend. international student mobility, in its multiplicity of forms, continues to be a high priority of internationalization, which refers to students moving from a country of origin to a country of education for study in a limited time (knight 2012) . more specific, inward student mobility is viewed from the perspective of the chosen country of study (that is, the favorite destinations), which brings a potential "brain-gain" (murphy-lejeune 2008) . there were about 5.3 million international students pursuing higher education overseas in 2017, comparing with 3.3 million in 2008 (oecd 2019). they have the potential to bring significant academic and economic implications, and their numbers are expected to grow continuously (knight 2012) . however, perhaps as important as the rising numbers of international students is the fact that the traditionally dominant destination countries for international students (e.g., the usa, the uk, australia, etc.) face growing competition from newly industrialized countries like china, russia, singapore, and malaysia. these countries, which once sent large numbers of students abroad, are gradually becoming recipients of international students, as a result of their efforts in promoting inward student mobility (de wit et al. 2013; abdullah et al. 2017) . for instance, in 2017, china sent 608,400 students to study abroad while at the same time hosted 489,200 international students (ministry of education of china, 2018) . in the same year, according to oecd (2019), russia took the fourth largest market share of international education globally, with a percentage of 5%, following the us (18%), uk (8%), and australia (7%). the primary motives for these countries' push on inward student mobility can be summarized as: enhancing international influence, promoting international exchanges, accelerating the process of building leading universities, and potentially generating economic gains (cao et al. 2016; abdullah et al. 2017; choudaha 2017) . though the economic benefit of inward international student flows is not a main focus for certain countries (e.g., china) , it is the primary pursuit for many developed countries including the uk and australia. therefore, when imaging inward international students, the notions of "global education market" and "global student market" are often used, which underpin the commercial value of inward student mobility and ignore its function as cooperation and a "win-win" (marginson 2016a) . in fact, inward student mobility is not solely market-driven. it brings various academic and social benefits not only to the host country but to other countries, including the countries of student origin. in light of this, (global) common goods can be a more inclusive lens to understand inward student mobility, since this concept highlights collective endeavor, shared participation/engagement, diversity, inclusion, and responsibility (unesco 2015) . the idea of "common goods" is of significance in describing (higher) education, as (higher) education requires active participation and collective endeavor in the process, which is compatible with the definition of common goods (unesco 2015; tian and liu 2019) . although closely related to the idea of public goods, the concept of common goods has its own specific meaning and implications 1 (see table 1 ). common goods can be defined as goods that are characterized by a binding destination and necessary for the realization of the fundamental rights of all people, irrespective of any public or private origin (unesco 2015, p.77) . "the good realized in the mutual relationships in and through which human beings achieve their well-being" (hollenbach 2002, p.81) , which is inherent to the relationships that exist among the members of a society tied together in a collective endeavor (unesco 2015, p.78) . these goods are necessarily grounded in the cultural and social dimensions of a specific community and are identified for their contribution to the "general interest", also to conditions of justice and well-being (locatelli 2018a) . deneulin and townsend (2007) argue that a celebratory dinner, an orchestral, or a team sport can be thought as common goods. they then take the orchestra as an example to illustrate how a common good is produced and how its benefits can be enjoyed. the good itself, an orchestra, cannot exist without each musician playing their respective parts and performing collectively for the whole audience. in other words, the good exists in the shared action which generates it. also, benefiting from such good is by participating in it, whether in the orchestra or audience. hence, the shared action is both intrinsic (without the various musicians' participation and performance, the orchestra cannot exist at all) and instrumental (it is necessary, efficient, and convenient to perform as an orchestra) to the good itself, and its benefits (an orchestra; beautiful music; excellent performance) are generated from the course of that shared action. such kinds of goods are intrinsically common in their production and their benefits, reflecting the distinct characteristics of intrinsic value and shared participation (deneulin and townsend 2007; unesco 2015) . in other words, the benefits and burdens for the realization of common goods are intrinsically shared among all participants, thus the common quality of these goods is not preexisting but is dynamic and contingent, emphasizing a process of participatory democracy (locatelli 2018a) . however, common goods may have a boundary and be confined to a given group/ community, since it is often socially embedded. their creation and production are processes of collective participation. people who participate in these processes can benefit from them, and these participants form a community with common interest (tian and liu 2019) . in light of this, global common goods are related to all people worldwide, highlighting the participation can be enjoyed as individual goods necessarily shared, both regarding production and benefits non-excludable and non-rivalrous in terms of consumption of a commodity non-excludable and non-rivalrous in terms of participation and generation of the goods themselves the public quality is predetermined the common quality is dynamic and not pre-existing governance public governance justified on the basis of externalities which extend to all shared governance justified on the basis of the cultural and social value of a specific good result of the action of public institutions result of the interaction of the different components of society top-down approach bottom-up approach passive role of those who benefit active role of those who benefit value global public goods are quasi-universal in terms of accessibility to countries, people and generations global common goods imply the empowerment of all actors in a world society who have a right to a fully informed and critical participation instrumental, can be treated as economic resources cannot be reduced to economic resources or to factors of production because of intrinsic social and relational value source: adapted based on locatelli (2018b) of all persons in a diverse and differentiated, yet solidaristic and collaborative, world society (deneulin and townsend 2007, p. 29) , and perhaps fostering social inclusion, integration, tolerance, equality, and human rights at a global level (unesco 2015; tian and liu 2019). thus, higher education itself can be regarded as a (global) common good, because receiving higher education can be seen as a specific activity, and heis, educators, students, and other stakeholders involved in the process could jointly reap the benefits through shared participation (tian 2019) . broadly speaking, the notion of common goods suggests the transformation of heis through greater engagement of communities, civil society, and other non-state actors in the decision-making and practices in order to build a more democratic educational system (locatelli 2018a; boyadjieva and ilieva-trichkova 2019) . apart from this, higher education as a common good is closely related to such concepts as equity, justice, solidarity, and inclusion (walker and mclean 2013, marginson 2016b) . also, the idea of common goods in higher education is especially important in the process of globalization and internationalization, because it refuses to be closed and conservative, encouraging global universities and educators to collaborate jointly and participate actively (tian 2019) . the previous literature draws a picture of the general situation of the internationalization of higher education, but it does not give as much attention to inward student mobility from a common goods lens, and the (global) common goods which are created and increased by it are rarely spelled out. through semi-structured interviews, this study aims to explore the (global) common goods generated and augmented by inward student mobility in china as well as relevant policies, regulations, and practices. this paper begins with the broad literature on the history and development of inward student mobility in china as well as relevant policies and strategies. then, it presents the research method, procedures, and empirical data. the paper concludes by linking the findings to the previous literature, to deepen and extend the understanding of this topic. inward student mobility in china: history, development, and key policies the recruitment of education for international students in china began in 1950 and went through a 70-year history, which falls into the following five periods with relevant national policies (see table 2 ). until now, china has educated a group of people who understand and respect the chinese culture, and at the same time expand china's international influence, helping to enhance its international image (jiang 2010b) . it can be assumed that before the reform and opening-up in 1978, the recruitment of and education for international students in china mainly served as a diplomatic tool for international exchanges and assistance. after the reform and opening-up, policies for international students studying in china gradually moved from closed to open, and the decision to accept and educate international students in china shifted from government to heis. meanwhile, more than a few heis began to recruit self-funded international students, and the number of these students rose rapidly (jin 2012) . later in the 1990s, several improvements were made in the international education system. for instance, in 1992, the hsk (hanyu shuiping kaoshi, which is a standard chinese language proficiency test) was used as a standard test for evaluating the language ability of international students. in 1996, the ministry of education established the china scholarship council, which specialized in organizing, funding, and managing chinese students studying abroad and international students studying in china. during the present period, policies for international students studying in china are more comprehensive, and efforts related to promoting inward student mobility yield positive results (cheng and huang 2008; fang and wu 2016) . the number of international students in china has increased markedly, and their study in china is greatly supported by a number of policies. china (1950-present) periods changes and development i: initial practice (1950) (1951) (1952) (1953) (1954) (1955) (1956) (1957) (1958) (1959) (1960) (1961) (1962) (1963) (1964) (1965) • china conducted more international exchanges with socialist countries in the former soviet union and developing countries in asia and africa. as a duty to fulfill international aid, china actively accepted a large number of international students from third world countries of asia, africa, and latin america. china regulations on recruiting self-financed international students (1989) iv: establishing a new system (1990) (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) • with the formation of a self-operation system under the guidance of the government, international education in china entered the first period of rapid development. three hundred thirty-nine heis in china accepted 234,691 international students from 164 countries, an increase of more than 15 times compared to the previous period. in 2018, the number of international students studying in china was 492,185, about 11 times when compared with 44,711 in 1999 (see fig. 1 ). china has entered the 10 highest-ranked destination countries in the world of international education, with the majority of international students coming from south korea, thailand, and pakistan in 2018 (see table 3 ). in terms of policies, the administrative measures for the enrolment and cultivation of international students by schools issued in 2017 clarified various aspects of inward student mobility, concerning degree certificates, training methods, curriculums, and so on, further improving the management system for international students studying in china. in october 2018, china published the first and latest quality standards of higher education for international students studying in china, expecting to improve the quality and management of international education in china. knight (2012), riaño et al. (2018) consider that international student mobility has brought diverse and plentiful benefits to students, home and host institutions, communities, and countries, for instance, international students can be portrayed as precious human capital to boost the host country's economy and also as sources of income for the higher education sector. specifically, in the chinese context, fang and wu (2016) consider that international students improve the level of internationalization of chinese higher education. also, they assume that international students not only increase the direct economic benefits but also stimulate the growth of related service industries such as catering, transportation, and tourism. similarly, jiang (2010a) notes that international students studying in china have the potential to create economic benefits, though this has not received sufficient attention in china and it lacks reliable official statistics. han (2014) , ma and zhou (2018) agree that international education in china has cultivated a large number of professional talents and develop fig. 1 the increase of international students in china (1999 china ( -2018 source: ministry of education of china (2000 china ( -2019 higher education table 3 the top 10 countries of sending students studying in china (1999 china ( -2018 year rank source: ministry of education of china (2000 china ( -2019 cooperative relations with other countries. moreover, in recent years, under the background of belt and road initiative, chen and wen (2018) suggest that international students play a central role in improving diplomatic relations and these students are human resources for chinese enterprises overseas. however, research touches little on the common good(s) of inward student mobility in china, though some chinese scholars have put forward that higher education contributes to (global) common goods in four respects: research outputs; public services; cultural inheritance and innovation; and talents (with global perspectives) (tian and liu 2019) . the mobility of these global talents and cultural exchanges are conducive to building a community of shared future for humanity (ren lei ming yun gong tong ti) (yang 2018) . in summary, the previous research has explored the history, development, and benefits of international students studying in china. this prior research lays a foundation for the present project. however, most research on inward students in china is theory-based, with less emphasis on empirical investigation; though some relevant research is policy-based and data-based, both the policies and data are out of date; also, there is an absence of attempts to explore inward student mobility and relevant policies in china through a lens of common goods, which would generate both theoretical and practical contributions. hence, in order to deeply understand the inward student mobility in china and (global) common goods, we formulated the following research questions: (1) what are the (global) common goods of inward student mobility in china? (2) how do the key policies, strategies, and regulations concerning inward international students relate to (global) common goods in china? according to kehm and teichler (2007) , institutions, people, and knowledge are the core elements of internationalization in higher education, and there is also a strong political undercurrent in the form of institutional strategies and national policies embedded in internationalization activities. accordingly, in order to have a better understanding of inward student mobility in china, which is a key to higher education internationalization, the research method for this project mainly involves semistructured interviews (people-concerned), while at the same time focuses on policy documents related to international students mentioned by interviewees (policy-focused). learning through policy texts from interviewees is a form of "lesson drawing", which can be defined as the voluntary act of transfer by rational actors working in specific political contexts (benson and jordan 2011) . this project adopted a purposive sampling to identify participants who were directly involved in inward student mobility. they were invited by the researchers through email. twenty-seven chinese people from the government and universities participated in the research. they were divided into four groups according to their affiliated institutions and positions (see table 4 ) to ensure coverage of all relevant groups of people who might have a good understanding of inward international students and common goods in china. the study chose two universities at two different levels in china: a top research university that is also a "double first-class" 2 university in china, with a higher level of internationalization (s university 3 ) and a local university with a lower level of internationalization (z university 4 ), with participants from different disciplines. admittedly, these two cases cannot represent the whole of china, but the investigation of perspectives from them can enable us to make a comparison of the policies, strategies, regulations, and relevant practices (e.g., management) about international students between universities at two different levels. due to the differences of the participants, there were four sets of interview questions for the above-listed participants in the study. interview questions for each group were slightly different, but they can be generally divided into the following three broad topics: (1) policies and strategies related to inward international students; (2) management and regulations of international students; and (3) each interview lasted between 30 and 70 min, depending on the interest of the participants and the natural pace with which the interview moved. interviews were conducted in both chinese and english (according to the respondents' requirements) and then transcribed into written form by researchers. participation in this research was on a voluntary basis, and participants were guaranteed anonymity and confidentiality. universities and conducted a wide range of research cooperation with overseas partners (source: university website). 4 z university is a comprehensive research university with international connectedness and a strong regional mission. it is a provincial university, being listed in the 301-400 in the arwu and 50-60 in the best chinese universities ranking. by the end of 2018, the percentage of international students in z university is about 2.4%. z university also has exchange programs and research cooperation with overseas universities in certain fields (source: university website). nvivo12.0 qualitative software and qualitative content analysis (qca) were used to analyze the interview data. qualitative content analysis, also called thematic analysis, is one of the most commonly used methods for analyzing qualitative data, with the focus on working with categories (codes) and developing a category system (coding frame) (mayring 2014 ). transcripts were coded according to participants' responses to each question and to the most salient categories (also called themes) emerging across the set of interviews. an initial list of main categories corresponding to the questions asked in the interview was formed deductively; then, as a second step, data were coded with the main categories (e.g., policies and strategies; global common good contributions). next, compiling text passages of the main categories and forming subcategories inductively on the material; assigning text passages to subcategories (e.g., "scholarship policy" was a subcategory under "policies and strategies"). last, all categories were refined under more general headings related to the research questions, and a category system was formed. in the paragraphs that follow, participants in the interviews were referred to by different code names, for the purposes of both ensuring anonymity and facilitating tracing references from the data (see examples of code names for participants in table 5 ). considering the contributions made by inward student mobility to (global) common goods, participants suggested that, academically, it cultivates human resources, retains high-level talents (serving local society), and improves international cooperation; politically, it accelerated international exchanges, which improves mutual understanding and respect; scientifically, it strengthens international scientific research cooperation; and economically, it can be seen as a potential economic growth point (though china has not yet achieved this result) and may expand the influence of destination countries and cities. in general, based on marginson's (2018) global goods framework, the individualized and common goods at both national and global levels can be summarized in table 6 . specifically, for the host country, international students promote cultural exchanges, and they could become cultural ambassadors in the future. for students' home countries, they can bring back advanced knowledge and research outputs, and students studying abroad can also the second participant in s university, who is a university leader. the third participant in z university, who is an academic. the fifth participant in z university, who is an international student. notes: p, participants; ga, participants from the government; s, s university (a top research university with a higher level of internationalization); z, z university (a local university with a lower level of internationalization); l, university leaders; a, academics; s, international students be regarded as role models for other students who hoped to study abroad. eight international students interviewed expressed their willingness to stay for employment or continue further studies in china. i have a lot of things that i owe china…i probably will stay here, at least for several years, but that depends on whether china will accept me, but of course, i don't take this education for granted, and i hope there is a chance i can make a contribution to china. most participants suggested the advantages brought by inward student mobility outweigh the disadvantages. however, university leaders and academics considered the potential disadvantages of inward student mobility include: (1) problem of unfairness (n = 4), since international students occupy the opportunities for domestic students, excessively consuming the energy of the administrators as they often pay more attention to international students rather than the domestic students; (2) brain drain of the source countries (n = 1). in contrast, two government officials believed that inward student mobility could promote social equity, as it advances the sharing of educational resources, and helps some backward countries' educational development. i believe inward student mobility in china promotes social equity rather than damages it, because it is good for the sharing of educational resources, and it is also a way to help some countries with less-developed education. (pga4) also, most international students (n = 7) did not consider it to be unfair for people like them to access to the experiences and benefits of international education, because the selection of candidates to study in china depends on the ability of the applicants, and the opportunity for international education is on a global basis, and it is beneficial for all. at the national level, government officials mentioned that china's strategic goal is to host 500,000 international students by 2020. meantime, most participants (n = 18) mentioned that the funding policy oriented to international students studying in china are very supportive (e.g., chinese government scholarships and provincial funding). in these years, under the framework of "people-to-people exchange", the belt and road initiative as well as other important policies includes international students studying in china as a strategic part (n = 7). our strategic goal is to recruit 500,000 international students by 2020… this was stated in the plan of studying in china… the policies, especially the funding policy, are quite supportive… the belt and road initiative also includes international students studying in china as a strategic part. (pga1) eight participants mentioned the decree no. 42, i.e., the administrative measures for the enrolment and cultivation of international students by schools issued in 2017, which covers all aspects of international student management. in addition, the assimilative management of international students studying in china becomes a trend, which implies heis encourage chinese and international students to live together thereby increasing mutual respects and understandings (n = 10). by doing so, china hopes to have more students who have better knowledge about china, become friends to china, and are on intimate terms with china. china is now much closer to the centre of the world stage than ever before… we hope more students come to china so as to better understand china, become familiar with china, and finally form friendly relationship with china. (pga2) at the university level, policies are more specific, that is, increasing the support for international students; conducting assimilation management to avoid isolation; introducing new types of scholarship; and opening bilingual courses (n = 10). s university's current working guidelines for international students are: expanding size, optimizing structure, improving management, and ensuring quality. as a "double first-class" university in china, internationalization is a key component in the development of s university (n = 6). z university focuses on increasing the number of international students and the recruitment of these students from the belt and road countries (n = 4). in 2015, z university introduced an internationalization strategy, and highlighted international postgraduate students' recruitment (n = 3). since there is no government scholarship in z university, it plans to set up its own scholarship for international students. our policy and strategy are definitely conforming to the strategy of national development... we pay much attention to belt and road countries, so we are now working on attracting students from these countries... we will also establish some additional scholarships. (pzl5) the majority of government officials and university leaders (n = 10) pointed out that the government strategically guides the internationalization of heis, and heis serve the national goal of attracting international students. all officials and university leaders (n = 14) considered relevant policies and strategies to be effective, achieving the expected results. the most frequently mentioned policies and strategies by the interviewees are the administrative measures for the enrolment and cultivation of international students by schools (2017) (n = 6); belt and road initiative (n = 5); and the plan of studying in china (n = 5). at the national level, all four government officials agreed that all international students who are accepted by chinese heis do not have any difficulties in their first entry, and it is necessary for all international students to abide by national laws and regulations. the latest requirement in the decree no. 42 allows work-study experiences for international students during their study period, and they are encouraged to have internships in china and spend part of their study time to learn more about chinese society. after graduation, students need to go through certain procedures to obtain a work visa, or they must return home immediately. participants mentioned that china has relatively tight regulations on foreign nationals' long-term residence, but it welcomes high-level talents to stay (n = 5). undergraduate students cannot stay in china after graduation, and they cannot obtain work permits. the policy for postgraduate students is relatively flexible, and students can obtain an employment visa in free trade zones 5 in some coastal metropolitan cities (n = 9). however, some international students (n = 4) are still concerned about the employment issues in china: we have an information group and the teacher promptly provides relevant employment information... but this is not enough for us, we still face a lot of problems in finding a good job in china. (pss5) international students do have some influence on policy-making, for example, the right of residence, entry and exit, and employment, and they play a positive role in promoting policy reforms (n = 6). three interviewees pointed out that when international students are studying and living in china, they are involved in a series of issues related to medical care, social insurance, and other public services; thus, when formulating policies, it is reasonable for the government to consider the needs of international students for their daily life. international students do have an impact on some policies, for example, the right of residence, entry and exit, and employment issues, and they have played a positive role in promoting these reforms, which is a positive sign. (pga4) at the university level, both universities have regulations and requirements on international students based on national policies (n = 12). for international students' first entry, they need to have a student visa and go through medical examinations; for in-university supervision, they must obey relevant laws and regulations (n = 14). most international students in our study thought they had favorable experience in chinese universities which matched their expectations (n = 8). is this a good place? i must say this place can be described as heaven… i find out that china has already entered the modernized stage… there are so many things we can learn… i guess china goes far beyond my expectations... (pss1) both universities offer specific courses and services for international students. each international student dormitory has an assistant, and there are also online information groups specifically for international students (n = 9). all nine interviewed students received generous scholarships from the chinese government or the universities. they considered both the chinese government and universities to be very supportive to international students. basically, international students have few problems on campus, though some of them (n = 3) encountered minor problems, for example, they think the administrative procedures are too complicated, and the accommodation is poor in z university. all nine students put forward that they have never faced issues related to welfare, human rights, personal agency, and dignity, and they feel safer and more comfortable in china than other places. i don't feel marginalized or disempowered, because i believe "ru xiang sui su" (do in rome as rome does), and i am obeying the laws of china and trying to see the world through chinese people' eyes … in many ways, i am freer, safer and happier here, which i've never felt in my home country… (pss3) discussion framework for inward student mobility from a common goods lens the objective of the current research is to identify the (global) common goods produced and augmented by inward student mobility and its relevance to national policies and strategies in china. the findings of this study illustrate that inward student mobility contributes to (global) common goods, and meanwhile policies are compatible to these perceived global common goods to a large extent. although some problems and tensions among policies, practices, and (global) common goods are observed in this study, measures have been taken by both the chinese government and heis. as inward student mobility involves different participants (host countries and universities, sending countries, university staff, international students, etc.) simultaneously, and its benefits flow to places at different levels (individual, institutional, local, national, and global) ; by using the common goods lens, we can interpret inward student mobility within at least the following three sets of relations (see also table 7 ): (1) common and individual. this term (common goods) may differentiate the common and individual benefits accruing from inward student mobility; (2) governmental and institutional. this term is useful to explain policies and initiatives in the national context, thus government's influences, support, regulations on heis can be reflected; (3) national and global. this concept is multidimensional, and it is helpful to explore the balance, consistency, and tensions between policies and practices concerning inward student mobility at different levels (deneulin and townsend 2007; unesco 2015; marginson 2018; tian and liu 2019) . as we have defined in this paper, common goods are multilevel, including local, national, and global common goods. based on the research findings, inward student mobility in china contributes to (global) common goods in the following five aspects, which are highly valued by interviewees from both the government and heis: (1) talents with global perspectives and respect to other cultures. through international education, international students will become global citizens who care for the whole world and make contributions to form a more inclusive, tolerable, and equal world. (2) the wider sharing of educational resources. inward student mobility intensifies educational cooperation between different countries and accelerates the process of mutual recognition of credit and certificate, which boosts the sharing of educational resources. (3) increased cultural exchanges, deeper mutual understandings, and diverse campus culture. international students help to form a more diverse and inclusive campus culture, and they can also be portrayed as cultural ambassadors to press ahead cooperation and exchanges between the host country and their home countries. (4) the improvement of policies and practices. the presence of international students may shape higher education policies and practices to be more efficiency-, service-, and reputation-driven. (5) the potential economic growth point. inward student mobility can be regarded as economic agent or driver of knowledge and eventually of economic growth. for some universities, recruiting international students is an alternative source of revenue to ensure their financial sustainability. in fact, the economic aspect of inward student mobility is particularly strong among anglo-saxon countries (geddie 2015) and extensively studied as the "marketization approach" to international education (findlay et al. 2017 ). however, our results suggest that china gives less weight to the economic aspect of inward student mobility at this moment, agreeing with jiang (2010b) that the economic benefits of international students are not a focus of higher education in china. nevertheless, chinese interviewees highlight the increased soft power brought by inward student mobility, which can be regarded as a national common good within a national boundary. inward student mobility intensifies academic and scientific exchanges which are central to soft power theory, and this can also be inspired by observations of how the us has gained friends among political elites of hostile countries by means of student exchanges (nye 2004; ma and zhou 2018) . this theory suggests that international students with pleasant firsthand experiences of studying abroad will admire the host country's academic, social, and political system and, in turn, nudge or steer cooperation between their home countries and the host country, push education, society, and politics at home in the direction desired by the country they studied and lived in (haugen 2013 ). this is not only an opportunity for chinese language and culture to enter the global platform but also for soft power expansion. in general, these are the perceived potential national and global common goods created by inward student mobility in china, which undoubtedly reveal the unique value of inward international students. despite that, the research findings suggest that attracting and educating international students in china is never a pure business transaction with only market and economic orientations, as both the chinese government and heis attach great importance to the development and welfare of international students who desire educational, social, personal, and professional development that underpins the process of "becoming" and "self-formation" (marginson 2014; tran 2016) . therefore, international education in china tends to be a practice of reciprocity, within the concept of the "ethics of care" (blackburn 1997; abdullah et al. 2017) , which suggests both parties (international students and heis) should ensure each party is involved in the benefits of internationalization from their interaction and have genuine concern over the well-being of each other in the provision of international education. in this sense, international education in china could be viewed as a global common good itself, since both parties need each other to achieve their intended goals, which thinks highly of collective endeavor, shared participation/engagement, inclusion, and responsibility, meshing with unesco's (2015) definition of global common goods. hence, international students should never be simply treated as "cash cows" and their desire to have a life-changing experience (through international education) should be valued. in turn, the cared for (international students) should acknowledge the energy and efforts invested by the carer (heis) to enhance the value of the relationship between both parties. in light of this, the narrative of ethical caring could build a conducive intercultural ecosystem to support the internationalization activities, boosting greater learning between students and university staff, and ensuring mutuality in strategies developed for cooperation and collaboration with foreign partners, which is a key virtue in internationalization from the outset (blackburn 1997; abdullah et al. 2017) . the results of this study show that in the chinese context, inward student mobility has not only emerged as a significant favorable pull factor for the internationalization of higher education but also contributes significantly to both national and global common goods. by examining various recent national policies and university strategies, it is easy to conclude that the inward student mobility has been given a special priority in the chinese context. this reflects the positive attitude of both the chinese government and heis, and contradicts the idea that the emphasis laid on international students is less in china, and the view that international students are less important to chinese universities, because they are not seen as human resources due to their generally low academic performance (jokila 2015) . however, some researchers believe that the chinese government's efforts to promote inward student mobility are only to achieve the policy objectives of diplomacy and education, while ignoring the contributions of international students in culture, politics, and economy (cheng et al. 2013) . obviously, this comment is not objective, because the findings of this study provide evidence that promoting mutual understandings and improving the quality of higher education through international education is an established strategy for the development of higher education in china, and this strategy does not exist in isolation. it falls in line with china's development goals of improving national soft power and cultural influence (wang et al. 2014) . also, the neoliberals believe that china's efforts for educational improvement are characterized by export (zheng 2010) . this comment seems to simply equate the internationalization of higher education with a commercial trade activity, overlooking the internationalization of chinese higher education contains unique cultural appeal. chinese culture advocates "harmony in diversity" and believes that different value systems should coexist harmoniously. according to our research findings, the dissemination of chinese culture through international education is currently an important tool for china to build better political and economic relations with other countries, and the "bridge" is the international students who understand and respect chinese culture, show kindness to china, and are on intimate terms with china. this is aligned with schulte's (2012) idea that chinese education actually takes place at the interface of global ideas and national strategies. internationalization and nationalism are not necessarily in conflict with each other in china; instead, special cultural aspects could benefit from international relations (gu 2001) . specifically, this study uncovers the different policies and strategies of internationalization between the two case universities. due to the different institutional needs and developmental goals in the process of internationalization, the university with lower degree of internationalization lays more emphasis on the quantity of international students, while the university with higher level of internationalization has shifted its focus from merely increasing the number of international students to improving the quality of international students as well as diversifying students' source countries. this strategy is supported by wang et al.'s (2014) study, which propose that the effectiveness international education strategy mainly hinges on the quality, not the number, of international students. tellingly perhaps, the research results also illustrate that z university gives close attention to attracting students from the belt and road countries. on the one hand, this is due to z university's geographic location (it is located near the southern chinese border) which makes it have a unique advantage to attract international students from neighboring nsr countries; on the other hand, this reflects that countries working with china on the belt and road initiative are likely to see more opportunities in educational cooperation and involvement (chen and wen 2018) . however, there are some problems and tensions among the policies, practices, and (global) common goods that can be observed in the results and findings, for example, the employment issue. though both the chinese government and heis endeavor to attract more international students studying in china and build a global talent pool, the employment mechanism is not in place, failing to retain talents who hope to work and stay in china. but very recently, a few coastal metropolitan cities in china have re-tailored their policies on international student employment (but only for postgraduate students) to secure highly skilled international graduates, and potentially, these policies may be expanded to the whole country within the coming years. the present research is both people concerned and policy focused, addressing issues by investigating perspectives from people directly involved in the process and examining some key policy documents related to inward international students in china. the findings of this study reveal that inward student mobility brings benefits to china and contributes to global common goods flowing worldwide, which can also be regarded as a reason for the supporting of national and institutional policies and strategies on international students. though there are also some tensions in the policies and practices for international students (e.g., employment and management issues), relevant efforts have been exerted to address them. most importantly, this study suggests that international education in china, as an essential part of higher education internationalization, can be seen as a global common good, which emphasizes collective endeavor, shared participation, inclusion, and responsibility. nevertheless, the current coronavirus (covid-19) threat may cast a shadow over booming international education in china and affect china's ability to attract more international students in a certain period. this puts forward new requirements for both countries and universities (not only china and chinese universities) to raise awareness of the need for risk management and crisis response strategies to ensure sustainability that highlighted by unesco (2015) as an indispensable role and responsibility of diverse stakeholders in the collective quest for the common good. what are the policies and strategies of your institution in relation to inward student mobility? 2. in your hei's internationalization strategy, what priority do you place on inward student mobility? how internationalized is your hei? what is the profile of international students in your institution at present? how does this compare to other institutions? has it changed over time? 4. [only for those leaders responsible for detailed administration of international students] what are the requirements of migration policy and national security as they directly affect inwardly mobile cross border students, including (1) initial entry, (2) regulation during the student sojourn are there other areas of government policy, apart from policies on education, migration, and national security, which, in your opinion, affect inwardly mobile cross border students? 6. how have policy changes in recent years impacted the student profile, and the student experience? looking at inward student mobility as a whole, not just your hei, to what extent are inward student mobility policies and strategies implemented successfully, given the policy objectives what are the benefits of student mobility and risks/disadvantages for the hei? 8. what are the main global common goods, benefits flowing not just to your country but to other countries, including the countries of student origin, that are created or augmented by inward student mobility in your nation? what are the experiences of inwardly mobile international students in the country of education, in relation to issues of welfare, human rights, personal agency and dignity? what problems and limitations face these students? 11. [only for selected leaders likely to tackle the question effectively] what are the benefits of a degree from your institution, when students return to their home countries? what do they learn at your institution, or gain in other ways, that is not available in their home country? do graduate cross-border students keep in touch with your institution after they leave? 12 the stories they tell: understanding international student mobility through higher education policy what have we learned from policy transfer research? dolowitz and marsh revisited internationalization: some ethical challenges from conceptualization to measurement of higher education as a common good: challenges and possibilities. higher education a survey of the influencing factors for international academic mobility of chinese university students three waves of international student mobility (1999-2020). studies in higher education yi dai yi lu" chang yi xia lai hua liu xue sheng jiao yu: shi ming, tiao zhan he dui ce [international education under the belt and road initiative: missions, challenges and solutions lun lai hua liu xue sheng jiao yu li shi fen qi wen ti strategic choices of development of china international education in the early twenty-first century public goods, global public goods and the common good international student mobility: european and us perspectives. perspectives: policy and practice in higher education gao deng jiao yu lai hua liu xue sheng de bian hua qu shi yan jiu-ji yu jin shi wu nian tong ji shu ju de fen xi marketization, marketing and the production of international student migration policy mobilities in the race for talent: competitive state strategies in international student mobility education in china and abroad: perspectives from a lifetime in comparative education jing ji quan qiu hua shi jiao xia de guo ji ren li zi yuan guan li wen ti yan jiu-ji yu lai hua liu xue sheng jiao yu guan li de si kao [a study on international human resource management from the perspective of economic globalization-based on the education management of international students in china china's recruitment of african university students: policy efficacy and unintended outcomes. globalization, societies and education the common good and christian ethics lai hua liu xue sheng jiao yu de ping jing wen ti ji jie jue cuo shi [the bottleneck problems and solutions of lai hua liu xue sheng jiao yu de zhan lue ding wei: ji yu duo yin su de fen xi gai ge kai fang yi lai zhong guo gao deng jiao yu guo ji hua zheng ce de shan bian: ji yu shu ju yu zheng ce de lian jie [the evolution of china's higher education internationalization policies since reform and opening up: based on the connection of data and policies the internationalization of higher education with chinese characteristics: appadurai's ideas explored research on internationalization in higher education student mobility and internationalization: trends and tribulations education as a public and common good: reframing the governance of education in a changing context higher education as a public and common good yi dai yi lu" yan xian gao duan liu xue sheng mian lin de tiao zhan ji qi dui ce [the challenges and solutions for high-level student self-formation in international education the outline of project 1.2: internationalization of he as a public good. london: centre for global higher education higher education and the common good world higher education under conditions of national/global disequilibria, cghe working paper 42 qualitative content analysis: theoretical foundation, basic procedures and software solution concise statistics for international students in china. beijing: department of international cooperation and exchange in the ministry of education the student experience of mobility soft power: the means to success in world politics new directions in studying policies of international student mobility and migration. globalization, societies and education world culture with chinese characteristics: when global models go native world-class universities: towards a global common good and seeking national and institutional contributions rethinking higher education in china as a common good mobility as 'becoming': a bourdieuian analysis of the factors shaping international student mobility rethinking education: towards a global common good? paris: unesco retrieved professional education, capabilities and the public good: the role of universities in promoting human development quan qiu hua bei jing xia de guo ji xue sheng liu dong yu zhong guo zheng ce xuan ze [international student mobility and china's policy choice under the background of globalization gai ge kai fang 30 nian de lai hua liu xue sheng jiao yu tui dong gao deng jiao yu quan qiu liu dong jian she ren lei ming yun gong tong ti [promoting the global mobility in higher education and building a community of shared future for mankind neoliberal globalization, higher education policies and international student flows: an exploratory case study of chinese graduate student flows to canada publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments this study was partly funded by the esrc (economic and social research council) and hefce (higher education funding council for england) (grant number: es/m010082/1). interview questions for university leaders key: cord-294167-58ti0m1l authors: kelley, keith w.; peng, yu-ping; liu, quentin; chang, hui-chih; spencer, sarah j.; hutchinson, mark r.; shimada, atsuyoshi title: psychoneuroimmunology goes east: development of the pnirs(china) affiliate and its expansion into pnirs(asia-pacific) date: 2020-04-15 journal: brain behav immun doi: 10.1016/j.bbi.2020.04.026 sha: doc_id: 294167 cord_uid: 58ti0m1l the psychoneuroimmunology research society (pnirs) created an official chinese regional affiliate in 2012, designated pnirs(china). now, just eight years later, the program has been so successful in advancing the science of psychoneuroimmunology that it has expanded to the whole of asia-oceania. in 2017, pnirs(china) became pnirs(asia-pacific). between 2012 and 2019, this outreach affiliate of pnirs organized seven symposia at major scientific meetings in china as well as nine others in taiwan, japan, south korea, australia and new zealand. this paper summarizes the remarkable growth of pnirs(asia-pacific). here, regional experts who have been instrumental in organizing these pnirs(asia-pacific) symposia briefly review and share their views about the past, present and future state of psychoneuroimmunology research in china, taiwan, australia and japan. the newest initiative of pnirs(asia-pacific) is connecting asia-pacific laboratories with those in western countries through a simple web-based registration system. these efforts not only contribute to the efforts of pnirs to serve a truly global scientific society but also to answer the imperative call of increasing diversity in our science. expenditures in biomedical research and development (r&d) are a reliable indicator of not only a country's wealth but of the importance it places on the health of its citizens. it is challenging to estimate global research and development expenditures and compare those results across countries. the two major issues are obtaining health care data from each country and using a common currency conversion over time (young et al, 2015) . despite these important challenges, chakma et al (2014) made a legitimate effort to do just that, sourcing data from global biomedical agencies, governments and statistical bureaus and rendering those data into us dollars for legitimate comparisons. according to this analysis, in 2012 the usa spent the most on health care research, amounting to us $48.9 billion by public institutions and us $70.4 billion by private industry. the whole of europe spent us $81.8 billion. all of the countries in asia-oceania spent half the amount of the biomedical research increased at a faster pace in asia-oceania than in the united states as well as canada and europe. in accord with this rising biomedical investment, psychoneuroimmunology research is now growing in the entire asia-pacific region. the increase in biomedical r&d research expenditures in all the countries of asia-oceania did not go unnoticed by academia and private industry. there was an increase in competition among countries for recruiting and retaining the best biomedical research talent. this increase in health spending meant more opportunities for asian-oceanian scientists to return home to their native country to work and prosper. and, after they returned, many developed productive collaborative research programs with western scientists where they received their advanced training. it also meant that graduate students, post-docs and professors from countries outside of asian-oceania had more employment opportunities in foreign countries. stated simply, increased funding for biomedical r&d in asia increased opportunities not only for asian-pacific investigators but for scientists around the entire world. the end product has been simply the result of supply and demand. the beneficiaries of this greater investment in biomedical r&d in the entire asia-pacific region were not only the investigators but all of us because of the biomedical discoveries that they produced. highlighting a potential challenge with global collaboration, the recruitment efforts of one asia-oceania country, china, have recently come under scrutiny in the usa based upon economic and national security concerns (anonymous, 2019a) . this development challenges two key features of biomedical research: openness in sharing data and global collaboration. and, this umbrage might spread to all countries in asia-oceania. as highlighted by the current pandemic with sars-cov-2, this is a time when biomedical scientists and pharmaceutical companies around the world are working together to find both treatments and a vaccine for this very contagious coronavirus (apuzzo and kirkpatrick, 2020) . indeed, the former director of the national institutes of health, elias zerhouni, pointed to the substantial contributions of foreign-national scientists. he noted that foreign nationals have contributed greatly to both patents and scientific discoveries in the usa. he wrote, "no members of any community should be targeted because of their origins….the united states should not risk losing critical intellectual assets such as productive foreign-born scientists and engineers to global competitors…" (zerhouni, 2019) . this cautionary message was more recently reiterated by the editorial staff of the leading journal, biological psychiatry: "the mission of biological psychiatry is to publish impactful scientific communications. to further that mission, we promote diversity in all aspects of the publication process, including authorship, reviewing, and editing. our diversity efforts aim to increase participation among individuals of underrepresented racial, ethnic, and gender identities; from underrepresented countries or disadvantaged backgrounds; and those with disabilities." (leibenluft, 2020) . biomedical research in china and that in western countries has proceeded relatively independently. however, as noted above, that focus changed dramatically early in the 21st century. the psychoneuroimmunology research society (pnirs) is a global nonprofit society that was formed in 1993. its primary goal is to promote the study of interactions between the nervous and immune systems and the relationship between behavior and health. pnirs has a rich history of promoting basic research that can be translated to the clinic (kelley and mccusker, 2014; kelley, 2020) , and this extends to asia. as early as 2002, christopher coe, ph.d., organized a symposium at the annual pnirs meeting that was held in madison, wisconsin. the speakers discussed both traditional chinese medicine (tcm) and tai chi (anonymous, 2002) . ten years later, the society "got ahead of the curve" by recognizing the growing importance of biomedical research in china by forming the chinese branch of pnirs, designated pnirs china , as its official regional affiliate in that country. this pnirs china affiliate began by serendipity. yu-ping peng, m.d., ph.d., invited professor virginia sanders at the ohio state university to present lectures at nantong medical university in 2012. professor sanders, who was an associate editor of brain, behavior, and immunity at the time, was unavailable. as such, she recommended that professor peng invite the then editor-in-chief of brain, behavior, and immunity. professor kelley readily accepted the ensuing invitation from professor peng to lecture in nantong. he went on to lecture in dalian and beijing. during that trip, lots of brainstorming occurred about the idea of forming liaisons between china, brain, behavior, and immunity and pnirs (fig. 1 ). the possibility of creating an eastern affiliate like pnirs china , as had previously been done in the west with germany (german-endocrine-brain-immune-network (gebin; anonymous, 1997) , was considered. mind-body relationships have been studied for centuries by indian, greek and egyptian physicians. the practice of tcm has been, and continues to be, used by billions of people in the sinosphere. the k.w. kelley, et al. brain, behavior, and immunity xxx (xxxx) xxx-xxx essence of tcm is the balance of body and mind (fig. 2) , which is considered to be linked by communication between the brain, neuroendocrine and immune systems. professor cobol su, m.d., ph.d., at the china medical university in taiwan recently eloquently summarized this concept with a simple sentence: "psychoneuroimmunology has been long stemmed in ancient medicine (su, 2019) ." as such, it seemed logical to develop a plan that would establish more formal relationships with chinese scientists. this would not only promote a better understanding of psychoneuroimmunology but also serve to contribute to improvement of world-wide health care. furthermore, sharing western science with chinese investigators made sense in order to articulate and better understand if and how tcm aligns with western scientific principles (anonymous, 2007) . perhaps the pnirs affiliate of china would promote development of knowledge about mind-body techniques practiced in other eastern countries like taiwan, japan and south korea. a summary of these discussions was shared with the president of the pnirs at that time, professor manfred schedlowski in essen, germany. following discussions of these and other ideas with the pnirs executive officers, professor schedlowski formally recognized this affiliation on november 26, 2012, in a letter to quentin liu, m.d., ph.d., stating: "please accept this letter as an official formal acceptance and recognition of the regional network of chinese scientists/physicians engaged in research of direct interest to the pnirs and its official scientific journal, brain, behavior, and immunity. your china branch of pnirs (pnirs china ) will be recognized as an official regional affiliate of pnirs." (fig. 3) . professor schedlowski hoped that creation of the regional affiliate of pnirs china would someday permit pnirs to enjoy its first annual meeting in china. in 2013, professor quentin liu was (and remains) vice-president of dalian medical university and director of their institute of cancer stem cells. dalian medical university was one of the first universities in china to focus on clinical integrative medicine. this is a curriculum that combines teaching, practice and research in both traditional and western medicine. following creation of pnirs china , professor liu moved quickly to establish and organize the first official meeting of this new pnirs affiliate (anonymous, 2016) . the participating organizations were dalian medical university, nantong university, jining medical university and sun yat-sen university. importantly, professor liu enlisted the input of bo bai, m.d., ph.d., the president of jining medical university. this academic forum was held in conjunction with the dalian psychoneuroimmunology medical society. a broad goal was developed that aimed to embrace, learn and share knowledge about psychoneuroimmunology with chinese colleagues. at the opening ceremony of the first pnirs china meeting on april 23, 2013, professor liu outlined three specific goals for the new pnirs affiliate: (1) conduct basic research that can be translated into clinically relevant health applications; (2) promote the growth of interrelationships among scientists of different scientific and medical disciplines; and (3) build a platform of academic communication for researchers engaged in psychoneuroimmunology research and teaching. the pnirs china affiliate would help scientists in china develop an international perspective, to identify and cultivate emerging outstanding young investigators and organize academic forums and experience exchanges among laboratories. professor kelley, other scientists and university leaders made presentations during the ceremony. this 2013 meeting was well-attended with 250 registrants. professor liu formally presented professor kelley with a plaque recognizing the formal creation of pnirs china (fig. 4) . professor liu extended the opening of pnirs china by organizing meetings at jining medical university and sun yat-sen university in guangzhou. the integrative aspects of psychoneuroimmunology research were emphasized at all these meetings. indeed, the call for expanding the knowledge of integrative medicine in continuing medical education programs, as assessed by the accreditation council for continuing medical education, has recently been highlighted (ring et al., 2020) . following formal creation of pnirs china , pnirs established a new committee, designated pnirs china . this committee aimed to organize symposia and other outreach approaches that would embrace, learn and share knowledge about psychoneuroimmunology with chinese colleagues. the approach used was simple and cost-effective. leading psychoneuroimmunology scholars from around the world were invited to participate in symposia submissions to major scientific meetings held in mainland china. even though no travel funds were available to support expenses, nearly all of the invited experts willingly agreed to pay their own travel. since the formal opening ceremony in dalian, there have been six more pnirs asia-pacific -sponsored symposia in shanghai, wuzhen, beijing, zhanjiang, tianjin and nanchang (fig. 5) . a summary of the scientific content, as well as the names and photos of all the fig. 2 . traditional chinese medicine psycho-behavioral interventions improve quality of life for cancer patients. the psycho-behavioral interventions were acupuncture, chinese massage, traditional chinese medicine five elements musical intervention, traditional chinese medicine dietary supplement, qigong and tai chi. (tao et al, 2015) . julie mcmahon at the university of illinois urbana-champaign is credited for preparing this figure. speakers, is available online at the pnirs home page (https://pnirs. org/pnirschina/index.cfm). each of these meetings attracted around 120 scientists or more. the audience was actively engaged, as assessed by both the number and quality of questions. it was clear to the organizers and speakers that chinese scientists were interested in learning more about psychoneuroimmunology, pnirs and brain, behavior, and immunity. in 2000, brain, behavior, and immunity became the official journal of pnirs (kelley, 2020) . its impact factor has been around 6 since 2013. and for the past 15 years, the journal has been ranked in the top 15% of all world-wide journals published in the category of neuroscience as well as immunology. it was recently ranked in the top 10% of all psychiatry journals. this has led to the designation of brain, behavior, and immunity as, "the best immunology journal in the neurosciences" (kelley, 2017) . as such, it is an appropriate surrogate for describing the progress of psychoneuroimmunology research throughout asia. prior to 2005, only 8 manuscripts with corresponding chinese authors were submitted for publication to brain, behavior, and immunity. scientists from the united states were the major contributors to the journal. only eleven years later, 17% of all submissions to brain, behavior, and immunity originated in china, making china the second leading country to submit papers to the journal (kelley, 2017) . since k.w. kelley, et al. brain, behavior, and immunity xxx (xxxx) xxx-xxx the first issue of the journal appeared in 1987, there have been 609 cumulative papers from the asia-pacific region published in the journal (fig. 6 ). the rise in annual publications from china since 2015 is particularly impressive, with australia publishing the second largest number of papers. more importantly, the quality of published papers is high, as shown by the skyrocketing increase in citations of papers originating in both china and australia. of note, these citation data have not been adjusted for factors like the number of submissions or the population of each country. however, of the top ten most highly 2014 papers that were cited between 2015 and 2016, three of them were from laboratories in china. it is especially noteworthy that the most highly cited paper in the journal in 2015/2016 was published by bing ruan, m.d., ph.d., whose laboratory is at the first affiliated hospital, school of medicine at zhejiang university in hangzhou, zhejiang . this pnirs award-winning paper was highlighted in brain, behavior, and immunity by dinan and cryan (2019). beginning in 2000, it seemed that research and high-quality publications in psychoneuroimmunology were increasing throughout australia, japan and south korea. following the successful organization of seven symposia in mainland china, it was therefore natural to expand these activities to the whole of asia-oceania. in addition to east k.w. kelley, et al. brain, behavior, and immunity xxx (xxxx) xxx-xxx asian countries (e.g., china, hong kong, macau, japan, the koreas), these include north (e.g., siberia), south (e.g., india, pakistan, afghanistan, bangladesh, bhutan) and southeast (e.g., malaysia, indonesia, cambodia, vietnam, thailand, singapore, philippines, myanmar, laos) asia. oceania countries are plentiful, including australia and its territories, new zealand, and all the islands of melanesia, polynesia and micronesia. the idea of expanding the presence of pnirsasia was presented to the pnirs board of directors. in 2017, they agreed to this proposal and changed the official name of pnirs china to pnirs asia-pacific (anonymous, 2017) . the charge was to expand the successful activities of pnirs china to other countries in asia-oceania. since then, the pnirs asia-pacific affiliate has sponsored nine successful symposia at meetings of scientific societies outside mainland china. these included taiwan, australia, japan, south korea and new zealand (fig. 5 ). at the end of 2019, 69 expert scientists had participated in the 13 official meetings of the pnirs asia-pacific affiliate. gender of the speakers was equivalent, and all of these scholars generally paid their entire travel expenses. as a result of these meetings, the official journal of the japanese society for neuroimmunology published a special issue on a pnirs asia-pacific symposium that was accepted for presentation at the 2019 meeting of the japan neuroscience society in niigata, japan (kelley and shimada, 2020) . a second publication was accepted by brain, behavior, and immunity as a special issue (kelley and reaux-le goazigo, 2020) . this pnirs asia-pacific symposium was selected for presentation at the 2019 meeting of the federation of the asian-oceanian neuroscience societies in daegu, south korea. the names and photographs of these speakers, as well as a short summary of the scientific content of all these symposia, are also available online (https:// pnirs.org/pnirschina/index.cfm). since its founding in 1993, pnirs has focused its science on research in the usa and western europe. every three years since that time, the pnirs has held its annual meeting in western europe. but clearly, scientists all over the world are trying to understand interactions between the nervous and immune systems and their effects on behavior and health. unfortunately, even now very few western scientists spend time working in asia, as assessed by post-doc training, collaborative studies and scientific meetings. this issue was addressed at the 2019 meeting of the pnirs that was held in berlin. members of the pnirs asia-pacific committee recommended that an approach be developed that would facilitate connecting psychoneuroimmunology laboratories in the asia-pacific rim with others throughout the world. based on the outreach success of the pnirs asia-pacific in organizing symposia, an entirely new program was launched in the fall of 2019. this initiative was entitled pnirs asia-pacific global research connections. it was implemented by creating a website since that time, six more symposia have been held on the mainland. nine more pnirs asia-pacific symposia have been held in asia-oceania. the next one will be held in late october 2020 in taichung, taiwan. that allows interested scientists to join this initiative by simply providing their name, country of origin, a link to their laboratory website, email address and specialty interest (https://pnirs.ansc.illinois.edu/#). the goal of this program is to bring together asia-pacific psychoneuroimmunology investigators with other laboratories around the world. it will also promote collaborations of scientists within countries in the asia-pacific region. as a result, biomedical scientists from both china and australia have already traveled to other countries to conduct collaborative research. the following sections contain four "perspectives" from productive scientists engaged in psychoneuroimmunology research in china, taiwan, australia and japan. at least one pnirs asia-pacific symposium has been organized in each of these countries. these "perspectives" provide an overview regarding how psychoneuroimmunology research in east asia has developed over the years. there have been several chinese scientists who have been awarded nobel prizes in categories that include peace, literature, chemistry and physics. but it was not until 2015 that a chinese academic was honored with the nobel prize in physiology or medicine. professor tu youyou was selected for her research that ultimately culminated in a novel therapy against malaria, thereby preventing millions of deaths throughout the tropics of the world. her interest and training in chinese herbal medicine led to discovery of a compound extracted from a plant known as artemisinin. she found that artemisinin is an effective treatment against the protozoan plasmodium falciparum that is responsible for the majority of malaria cases. professor youyou was also the first female chinese nobel laurate. increased spending in medical r&d research by china has now vaulted it to the second leading country that publishes in top-ranked scientific journals and third in life sciences publications, as assessed by the nature index (anonymous, 2020) . this well-respected indicator summarizes institutions and countries that publish papers in 82 leading academic journals. it is noteworthy that the chinese academy of sciences was the fifth most prestigious institution in the world (anonymous, 2020) . as quoted from the nature index, "the chinese academy of sciences and harvard university have maintained the highest positions in the nature index for four consecutive years, but the university of chinese academy of sciences made the most impressive gains." (anonymous, 2019b) . when it comes to the neuroimmunology research in china, most of the credit goes to professor shao-guang fan, late dean of the medical school at beijing university. professor fan initiated neuroimmunology research in china in the early 1980s. he organized and chaired the international neuroimmunology conference in 1997 and 1999, respectively, in china. professor fan dedicated his entire academic research career to understanding the relationships between stress and immune system. he discovered a serum factor, a protein with a large molecular weight induced by restraint stress in mice and rats, and demonstrated this serum factor suppresses lymphocyte function (zha et al., 1992) . the groundbreaking research and leadership of professor fan contributed greatly to the initiation and development of neuroimmunology research during the last century in china. china has one of the world's oldest medical systems. tcm aims to maintain harmony in the body and employs a variety of mind and body approaches. some of these practices are exercise (tai chi), dietary therapy (herbal medicine), acupuncture, meditation, cupping therapy, massage and gua sha (literally to "scrape sand" for skin treatment). (26); new zealand (15) and singapore (10). in addition to these data, 4 papers were published from hong kong and one each from vietnam, the philippines and malaysia. b. number of citations of papers published in brain, behavior, and immunity, using the same time frame as part a. although not universally accepted by many chinese physicians, tcm is by its very nature an integrative approach to medicine that has long recognized the connections between mind and body. yet, despite the rich history of tcm that dates back for centuries, the concept of "neuroimmunology" and "psychoneuroimmunology" has not been familiar to chinese scientists. as such, prior to the turn of the 21 century, this research field was not very large in china. that is at least partially caused by the very same trend towards increased scientific specialization that occurred in the 20th century (kelley, 2020) . immunologists collaborated with immunologists and neuroscientists did the same with other neuroscientists. cross-talk and collaborative efforts between these two disciplines were not well accepted. training graduate students and post-docs in integrative approaches to biomedical research took a back seat to formal training in specialized disciplines. all this has changed during the first two decades of this century, during which time there has been a consistent deepening and expansion of psychoneuroimmunology research in china. increasing evidence has established that immune disorders are involved in many nervous system diseases and that neuroregulatory abnormalities can result in immune dysfunction. today, more and more chinese scientists recognize the significance of neuroimmunology and psychoneuroimmunology research in human health and disease therapy and are being attracted to this research field. the establishment of pnirs china in 2013 was a hallmark development that is already rapidly promoting psychoneuroimmunology research in china. by using data from the official scientific journal of pnirs, this fact is made clear (fig. 7a ). prior to 2016, there were fewer than 100 papers per year submitted to brain, behavior, and immunity. now, research papers submitted by mainland scientists to this journal amount to nearly 400 per year. more importantly, the quality of these papers has increased substantially, as assessed by the rapid rise in scientific citations. it is also clear that during the past five years, chinese scientists have greatly increased their collaborative research efforts with laboratories outside of the mainland, which now includes the united states, all of europe and australia (fig. 7b) . during this decade, most studies on psychoneuroimmunology in china have focused on interactions between immune disorders mediated by microglia and nervous system diseases. excessive microglial activation is involved in the pathogenesis of many mental health and central nervous system (cns) disorders, including stress, depression, ischemic or traumatic brain injury and neurodegenerative diseases. in turn, psychological and cns disorders often cause microglial activation. inhibition of microglial excessive activation or promotion of microglial polarization from an m1-like towards an m2-like phenotype may help to alleviate some of these disorders. several relevant studies from china on these topics have been published in brain, behavior, and immunity. microglial activation is involved in stress-induced depressive behavior (lian et al., 2017; wang et al., 2018) . importantly, anti-depressive treatment can be implemented by modulation of microglial phenotypes . 2. microglia and ischemic or traumatic brain injury. nitidine, a benzophenanthridine alkaloid, restricts reactive microgliosis and promotes cns repair following traumatic injury (yuan et al., 2015) . suppression of microglial activation by let-7c-5p overexpression is neuroprotective and ameliorates ischemic damage (ni et al., 2015) . specific deletion of the protein kinase mst1 in microglia mitigates stroke-induced brain injury (zhao et al., 2016) . 3. microglia and neurodegenerative diseases. trem2 promotes microglial polarization from an m1-like towards an m2-like phenotype and thereby reduces neuroinflammation in alzheimer's disease and ameliorates its development . trans-cinnamaldehyde, a primary bioactive component derived from the stem bark of cinnamomum cassia, suppresses neuroinflammatory responses by diminishing microglial activation and levels of pro-inflammatory mediators. this reduces memory deficits in mice with alzheimer's disease (zhao et al., 2019) . gut microbial dysbiosis is involved in parkinson's disease pathogenesis, and fecal microbiota transplantation can protect affected mice by suppressing neuroinflammation and reducing tlr4/tnf-α signaling in microglia (sun et al., 2018) . galectin-1 reduces neurodegeneration in a parkinson's disease model by modulating the microglial mapk/iκb/nfκb axis (li et al., 2020) . it is important to note that the triptolide (t10), a chinese herb, protects against neurotoxicity in parkinson's disease by inhibiting microglial activation with metabotropic glutamate receptor 5 mediating its effect . thus, as was highlighted by nobel laurate professor tu youyou, exploring more chinese herbs and their mechanisms underlying suppression of microglial activation provide an opportunity for chinese scientists to develop novel therapeutic strategies for targeted psychological and cns diseases. in addition to microglial involvement in nervous system disorders, recent evidence has established that the adaptive immune system, particularly t lymphocytes, participates in the processes of neuronal injury and repair. helper t (th)17 cells, a subset of cd4+ t lymphocytes, have strong pro-inflammatory properties and are essential in pathogenesis of many inflammatory diseases. regulatory t (treg) cells, the foxp3-expressing cd4+ cd25+ t lymphocyte population, were originally termed "suppressor cells" and are pivotal in suppressing autoimmunity and maintaining immune tolerance. some findings from china on this important topic have also been published in brain, behavior, and immunity. brain parenchyma in parkinson's disease through a lesioned brainblood barrier and cause neurotoxicity by both promoting glial activation and directly injuring neurons. the inflammatory cytokine interleukin (il)-17a released from th17 cells accelerates this neurodegeneration in models of parkinson's disease, depending on microglial activation. supporting this conclusion is the fact that il-17a deficiency or anti-il-17a-neutralizing antibody treatment alleviates microglial activation, blood-brain-barrier disruption and parkinson's disease-like manifestations . on the other hand, treg cells protect dopaminergic neurons against 1-methyl-4-phenylpyridinium (mpp) neurotoxicity by a cell-to-cell contact mechanism. tgf-β1 secreted by treg cells exerts an indirect protective effect by inhibiting excessive microglial activation (liu et al., 2016) . cerebral ischemia increases the number of treg cells in the bone marrow of mice, which contributes to stroke-induced immunosuppression . the fasl mutation inhibits both recruitment of peripheral inflammatory cells (neutrophils) and activation of resident glial cells (microglia and astrocytes), and drives the th1/th2 balance towards th2 in the brain and peripheral blood following cerebral ischemia (niu et al., 2012) . 6. t cells also infiltrate the spinal cord with an imbalance of th17/treg towards th17 during the development of bone cancer pain. in turn, this promotes microglial activation and further increases pain, while neutralizing il-17/il-17a in the spinal cord ameliorates bone cancer pain (huo et al., 2019) . in addition to the th17/treg imbalance, a th1/th2 imbalance also occurs in the brain and peripheral blood following cerebral ischemia (niu et al., 2012) . the anti-inflammatory cytokine il-4 derived from th2 cells may alleviate neuropathic pain and contribute to other neuropsychiatric disorders (nie et al., 2018) . thus, blocking proinflammatory immune responses or applying anti-inflammatory cytokines may offer a potential and novel therapeutic strategy for some psychological and nervous system diseases. asia and the pacific region are home to 60% of the world's population. unfortunately, biomedical research, particularly psychoneuroimmunology medicine, is underdeveloped in this region. this could be due to barriers of communication, differences in medical theories and diagnostic systems, lack of a common ground for clinical research design or cultural differences. indeed, psychopathology manifestations are sensitive to cultural influences (guinart et al, 2019) . furthermore, immunological status is arguably different regarding significant backgrounds of genomic constitution, dietary patterns and life styles. it is therefore strongly urged that more exploratory, rather than replicated, translational brain research from the east be valued and promoted. this approach is needed to turn empirical practices into precision medicine that is based on innovative and integrative science (su, 2019) . psychoneuroimmunology is an emerging field in neuroscience and immunology. research on this crosstalk between east and west is now happening in taiwan. according to data available for brain, behavior, and immunity, there have been 33 published papers by authors from taiwan during the past 33 years (fig. 6) . remarkably, 13 were published in the past two years, supporting the conclusion that translational brain-immune research is rising. in 2017, professor keith w. kelley from the pnirs was invited as the plenary keynote speaker at the mind-body interface (mbi) international symposium held in taiwan. with a mutual interest and a common and achievable goal, this led to an affiliate of pnirs, pnirs asia-pacific , to propose co-organizing future mbi symposium. the mbi and pnirs asia-pacific teams have been working together since then. in 2018, professors keith kelley, chris coe and carmine pariante called for a dozen pnirs scholars to propose a thematic session for the forthcoming mbi symposium. it was here that the entire organization of pnirs and brain, behavior, and immunity was officially introduced and promoted to scientists in taiwan. the following year, professor deborah hodgson and another 10 pnirs scholars presented a pnirs asia-pacific symposium at the 2019 mbi meeting. the next mbi meeting is scheduled to be held in october 2020, and the theme is "the mind maze -early life experiences that shape adult health of mind and body." with the support from president julie bower and the pnirs asia-pacific affiliate, michael irwin, m.d. has been chosen to be the plenary keynote speaker at this 2020 mbi symposium. his lecture will be complimented by another formal pnirs asia-pacific symposium in taiwan, which will be four consecutive years in a row. influential scientists gather in taiwan every year to share cuttingedge research discoveries in translational neuroscience. organized annually by taiwanese society for nutritional psychiatry research (tsnpr), the mbi international symposium has been held annually since 2010. this society vigorously promotes a global agenda of translational medicine by encouraging interdisciplinary research and integrating biomedical discoveries focused on patients. the meeting features a broad range of topics, including immunology, metabolic processes and molecular science, psychopharmacology, psychology and biological processes that underlie links between diet, nutrition and mental health. furthermore, there is a strong focus on the use of novel technology, artificial intelligence, big data, neuroimaging, personalized medicine, lifestyle intervention and population studies in brain disorders. due to the heterogeneity of clinical manifestations and etiological complexity of mental disorders, as well as a paucity of brain research with east asian subjects, translational approaches bridging bench and bedside are gaining substantial interest. however, the current psychiatric classification system, dsm-v, is not sufficient for clinical studies on mental disorders despite its feasibility for health care practitioners (chang et al., 2014) . furthermore, there is a fundamental difference in theory between western and eastern medicine. eastern medicine views mind-and-body as inseparable as a meridian system rather than an anatomical structure. practices include dietary intervention, herbal medicine, acupuncture, massage, meditation or tai chi. these treatments aim to bring harmony and alignment back to the mind-and-body as a whole. the benefits of this holistic approach is gaining attention nowadays with robust findings from biomedical research. however, the therapeutic effect of one single life-style intervention is expected to be much smaller and difficult to detect than that with an expensive randomized controlled trial. this is the gold standard for examining the effects of treatments such as anti-depressants on subjects with confirmed diagnoses like major depressive disorders (su, 2019) . it is therefore crucial to advocate for translational brain research in the east with good practices in clinical trials using advanced science. as but one example, new technologies of wearable devices for continuous data collection of brain activities can now be used and summarized with algorithms for these types of big data. there is no doubt that the mbi symposium and pnirs asia-pacific affiliate have now provided a platform for scientists in this region to network with one another, to be inspired and to establish research and teaching collaborations. each year, meeting registrants exceed 150 people from countries worldwide, including australia, canada, china, estonia, france, germany, hong kong, italy, india, japan, macau, netherlands, south korea, russia, united kingdom, united states and taiwan. friendship and partnerships between international societies that share common goals are built to promote good science side by side. australia has had a strong niche role in psychoneuroimmunology research from the beginning of the field. the very first edition of brain, behavior, and immunity, published in 1987 carried an article by professor kusnecov and colleagues, which has since been cited 64 times. in this work, the authors revealed a role for β-endorphin in enhancing lymphocyte reactivity to concanavalin a (kusnecov et al, 1987) . at that time, publications in the journal were dominated by laboratories from the united states (5 articles of the 10 in the first issue). since then, psychoneuroimmunology research in australia has gone from strength to strength (fig. 8a) , with a particular boost in 2017 when the pnirs china initiative was broadened to encompass the rest of asia and the pacific. australians now have the 6th most submissions to brain, behavior, and immunity annually, after the united states, china, brazil, germany and the united kingdom (data for 2017 courtesy of elsevier). these publications are at least as high quality and impactful as those from other countries. the most recent data published in nature index noted that between 2017 and 2018, contributions of australian scientists to the highest quality journals in the life sciences increased by 8.2% (anonymous, 2020) . australia now contributes approximately the fourth most published articles in brain, behavior, and immunity (after the united states, china, united kingdom and equal to canada). in 2019, 16 papers were published in brain, behavior, and immunity with australian first or senior authors. an additional four had australian collaborators and at least ten employed diverse internationally collaborative research teams. importantly, many of those articles are examples of the truly global nature of current psychoneuroimmunology research. several featured upwards of five nations in the author list, integrating technologies, ideas, personnel and student experiences towards research outcomes that could not be achieved by one group alone (fig. 8b) . these papers covered such diverse research topics as chlamydia and alzheimer's disease (woods et al, 2020) to microglial morphology in post-traumatic stress disorder (smith et al., 2019) to aging and traumatic brain injury . in addition to publication outputs, australians are now an embedded part of the global psychoneuroimmunology community. as of 2019, there are two australian associate editors at brain, behavior, and immunity (as well as one from taiwan). in 2019, pnirs elected its first australian president, professor deborah hodgson. around 10% of the pnirs membership is australian. the few years since the 2017 incorporation of australia along with the rest of asia and the pacific region into the pnirs asia-pacific affiliation have also witnessed an explosion of internationally collaborative meetings and symposia showcasing australian psychoneuroimmunology research. professor mark hutchinson organized a symposium in sydney in 2014. three years later, professor hutchinson teamed with dr. luba sominsky to organize a psychoneuroimmunology satellite workshop to australia's premiere neuroscience meeting, the australasian neuroscience conference. the 2019 international brain research organization showcased key australian elements of the pnirs asia-pacific initiative, along with professor suzi hong from the pacific side of the united states at their meeting in daegu, south korea. in 2019, there was also a pnirs asia-pacific symposium integrated into the queenstown winter conference on brain research week in queenstown, new zealand. this symposium highlighted research from investigators with experience from australia, canada, japan, new zealand, south korea and the united states and amply illustrates how far the pnirs has now come as a global scientific community. going forward into 2020 and beyond, we expect to witness even more globalization, integration and transdisciplinary psychoneuroimmunology research incorporating australia and the rest of the asia-pacific region. however, we also expect to see psychoneuroimmunology research becoming more specialized to embrace the specific psychoneuroimmunology needs of different international communities. for instance, the psychoneuroimmunology consequences of endemic diseases like malaria or dengue might be of key relevance for south-east asia. china may benefit from an individualized response to novel coronaviruses. australia and the united states are now investing heavily in space exploration, making psychoneuroimmunology research important in this context for these countries. air pollution may have important psychoneuroimmunology implications all over the world, but the types of pollution may differ. on the other hand, historically different approaches to our understanding of psychoneuroimmunology among different communities worldwide may bring important advances to all of us. the holistic integration of body and mind that is the cornerstone of traditional medicine in china is revolutionizing western medicine and popular approaches. likewise, the strong social support networks of indigenous communities have key implications for stress and mental health management for everyone. thus, globalizing psychoneuroimmunology research does not just mean more of the same in new countries, but a true advance in our approach to understanding how the world we live in affects our brains and bodies. for the period between 1987 and the end of 2019, there were 92 papers published in brain, behavior, and immunity with a primary corresponding author from japan (fig. 6 ). this placed japan as the 13th country in the world with the highest number of publications in the journal. in addition, there were 231 japanese authors that contributed to papers. the number of japanese members in pnirs is only four at the present time. although these data might make it appear as though japanese investigators do not have a strong interest in psychoneuroimmunology, a growing number of japanese scientists are performing research related to this field. the japanese society for neuroimmunology was established in 1988 by physicians who specialize in intractable neurological diseases, such as multiple sclerosis, guillain-barré syndrome and the paraneoplastic syndrome. these physicians are interested not only in clinical treatments, but also in the basic mechanisms underlying the interactions between the nervous and immune systems. when pnirs asia-pacific organized a symposium for the first time in japan at the 2019 annual meeting of the japan neuroscience society, the japanese society for neuroimmunology published a record of this symposium in its official journal (shimada, 2020; pal et al., 2020; kelley and shimada, 2020) . collaborations between the executive board members of the society and pnirs asia-pacific are currently in the works, and the japanese society for neuroimmunology and pnirs asia-pacific hope to hold joint symposia in the near future. in addition, the national institute of neuroscience at the national center of neurology and psychiatry has one of the most active laboratories that perform research related to neuroimmunology and neuroinflammation (yamamura et al, 2019) . a group of japanese psychologists was inspired by the groundbreaking book "psychoneuroimmunology" (ader, 1981) , and in 2004, they launched the psychoneuroendocrinoimmunology (pnei) research group, which was sponsored by the japanese psychological association. these psychologists are interested in the interrelationships among stress, changes in the autonomic nervous system and endocrine system, and alterations in immune responses. they have been holding meetings once or twice every year since 2004. in the history of modern immunology, japanese immunologists have made outstanding achievements using molecular biological techniques to elucidate the fundamental principles of immunology. the most recent example is from the famous laboratory of tadamitsu kishimoto, m.d., from osaka university. his life work led to development of a humanized monoclonal antibody against the interleukin-6 receptor (kishimoto, 2005) . this antibody, known as tocilizumab, is used for treatment of rheumatoid arthritis. because of its immunosuppressive properties that inhibit the cytokine storm, it has recently been approved for late stage clinical trials in both china and the usa as treatment for sars-cov-2. professor susumu tonegawa was awarded the nobel prize in 1987 for his work showing that genetic material rearranges itself to form millions of different antibodies (tonegawa, 1983) . his discovery revealed the mechanism of the adaptive immune system, which had been the central question of immunology for over 100 years. professor tasuku honjo established the basic conceptual framework of class switch recombination through his discovery of dna deletion (honjo and kataoka, 1978) and activationinduced cytidine deaminase (aid) (muramatsu et al, 2000) . other leading japanese immunologists have also contributed to the identification of cytokines, their receptors and signaling pathways, including interferon α, interferon β, interleukin (il)-4, il-5, il-6, il-18, il-8/ cxcl8, cxcl12, cxcr4, fas receptor and fas ligand (kumanogoh and ogata, 2000 for a review). the contributions of japanese research to the field of innate immunity include identification of ligands for most of the toll-like receptors (akira and takeda, 2004) . professor honjo was awarded the nobel prize in 2018 for his discovery of program cell death 1 (pd-1), a negative co-receptor of the effector phase of the immune response. anti-pd-1 immunotherapy is now approved in the united states, european union and japan, and it has revolutionized the treatments for cancer (chowdhury et al, 2018) . pd-1 could also be a novel key molecule in psychoneuroimmunology. augmented t cell responses in pdcd1−/− mice, which lack the inhibitory receptor pd-1, induce a systemic decrease in tryptophan and tyrosine levels. this leads to a substantial deficiency in brain serotonin and dopamine, resulting in anxiety-like behavior and exacerbated fear responses (miyajima et al, 2017) . the contributions of japanese biochemists in uncovering the molecular mechanisms of inflammation can be illustrated by the purification of cyclooxygenase (miyamoto et al, 1976) , the key enzyme in the biosynthesis of prostanoids, and by the cloning of the receptors for platelet-activating factor (honda et al, 1991) , leukotriene b 4 (yokomizo et al, 1997) and thromboxane a 2 (hirata et al, 1991) , among others. at the forefront of early molecular neuroscience, japanese biochemists determined the protein-coding sequence of the adrenocorticotropic hormone (acth) precursor gene (nakanishi et al, 1980) . researchers from the same group cloned the primary structures of different families of receptors and channels, including nicotinic and muscarinic acetylcholine receptors, sodium and calcium channels (hayaishi, 1992) and n-methyl-d-aspartate (nmda) and metabotropic glutamate receptors moriyoshi et al, 1991) . achievements from japanese laboratories of experimental pathology include the discovery of regulatory t cells (treg cells) as a homeostatic regulator of immune responses (sakaguchi et al, 2008] as well as development of senescence-accelerated mouse (sam) strains as a model for aging research (takeda, 1999) . the samp10 mouse strain exhibits microglial dystrophy from a young age and lacks the ability to construct a neuroprotective cytokine-mediated glia-neuronal network. this causes the mice to be vulnerable to age-related cognitive impairments (hasegawa-ishii et al, 2011) . japanese pathologists also invented a novel bone marrow transplantation method called intra-bone marrow-bone marrow transplantation (ibm-bmt) (kushida et al, 2001) , which led to the determination of the intracranial histological architecture supporting brain-immune cell-cell interactions (hasegawa-ishii et al, 2013) . in addition to those mentioned above, there are many other welltrained biomedical scientists and top laboratories in japan that pioneered research in molecular immunology, neurobiology and pathology. a growing number of scientists, especially those of the younger generation, have become interested in psychoneuroimmunology, and they have started numerous collaborative studies (furuyashiki et al, 2019) . it is therefore an opportune time for the ministry of education, culture, sports, science and technology (mext) of japan to launch a new grant program starting in fiscal year 2020 under the name of "grant-in-aid for transformative research areas." this new grant program aims to promote the creation of novel research areas by young investigators through co-creative and interdisciplinary efforts between researchers in diverse fields that will lead to radical transformation and changes in the existing framework of academic disciplines. through these efforts, japanese scientists of new generations will make significant contributions to the emerging field of psychoneuroimmunology. pnirs asia-pacific answers the important and pressing call of increasing diversity in science (leibenluft, 2020) . by all accounts, in less than 10 years, this pnirs affiliate has been very successful in bridging the gap between eastern and western scientists interested in psychoneuroimmunology research. this advance is evidenced by the rapid growth in both the number and citations to high-quality manuscripts published in brain, behavior, and immunity by countries throughout the asia-pacific region. beginning in 2019, the pnirs asia-pacific committee furthered global collaboration in this field with the creation of a program that promotes scientific exchanges of faculty, post-docs and graduate students between laboratories in the east and west: pnirs asia-pacific global research connections. biomedical research today is a global enterprise that is becoming more and more integrative in nature. age-old practices from the east, including meditation/mindfulness, exercise and dietary interventions, are now becoming accepted in the west. it is the continuing goal of the pnirs asia-pacific affiliate to promote crosstalk between biomedical scientists in the east and west. toll-like receptor signalling converging perspectives: east meets west, anonymous. pnirs annual meeting brief history of the development of pnirschina pnirschina committee grows into pnirsasia-pacific threats to the u.s. research enterprise: china's talent recruitment plans. permanent subcommittee on investigations united states senate the fastest rising institutions by country for scientific researchthese are the ones to watch anonymous 2020 covid-19 changed how the world does science, together asia's ascentglobal trends in biomedical r&d expenditures view on dsm from taiwan: transition from iv to 5 combination therapy strategies for improving pd-1 blockade efficacy: a new era in cancer immunotherapy gut microbes and depression: still waiting for godot role of multiple lipid mediators in stress and depression is transcultural psychiatry possible? defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse selective localization of bone marrowderived ramified cells in the brain adjacent to the attachments of choroid plexus shosaku numa 1927-1992 cloning and expression of cdna for a human thromboxane a 2 receptor cloning by functional expression of k.w. kelley, et al. brain, behavior, and immunity xxx (xxxx) xxx-xxx platelet-activating factor receptor from guinea-pig lung organization of immunoglobulin heavy chain genes and allelic deletion model triptolide up-regulates metabotropic glutamate receptor 5 to inhibit microglia activation in the lipopolysaccharide-induced model of parkinson's disease imbalanced spinal infiltration of th17/treg cells contributes to bone cancer pain via promoting microglial activation altered fecal microbiota composition in patients with major depressive disorder brief history of the development of pnirs china to boldly go where no one has gone before from psychoneuroimmunology to immunopsychiatry: an historical perspective getting nervous about immunity neuroinflammation and the blood-brain-interface: new findings in brain pathology dialing in the dialogue between inflammation and the brain interleukin-6: from basic science to medicine-40 years in immunology the study of cytokines by japanese researchers: a historical perspective intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in mrl/lpr mice in vivo effects of beta-endorphin on lymphocyte proliferation and interleukin 2 production increasing diversity in science: it begins with all of us galectin-1 attenuates neurodegeneration in parkinson's disease model by modulating microglial mapk/iκb/nfκb axis through its carbohydrate-recognition domain ds-hmgb1 and fr-hmgb induce depressive behavior through neuroinflammation in contrast to nonoxid-hmgb1 transforming growth factor-β1 acts via tβr-i on microglia to protect against mpp(+)-induced dopaminergic neuronal loss il-17a exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of parkinson's disease sequence and expression of a metabotropic glutamate receptor metabolic shift induced by systemic activation of t cells in pd-1-deficient mice perturbs brain monoamines and emotional behavior purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes molecular cloning and characterization of the rat nmda receptor class switch recombination and hypermutation require activation-induced cytidine deaminase (aid), a potential rna editing enzyme the protein-coding sequence of the bovine acth-beta-lph precursor gene is split near the signal peptide region microrna let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation akap150 involved in paclitaxel-induced neuropathic pain via inhibiting cn/nfat2 pathway and downregulating il-4 targeted mutation of fas ligand gene attenuates brain inflammation in experimental stroke meningeal lymphatic network keeping integrative medicine continuing medical education on the cutting edge -and compliant regulatory t cells and immune tolerance principles of neuroanatomical architecture supporting brain-immune cell-cell interactions microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of ptsd are we all the same? the critical role of translational brain, behavior, and immunity research in east asia aged rats have an altered immune response and worse outcomes after traumatic brain injury neuroprotective effects of fecal microbiota transplantation on mptp-induced parkinson's disease mice: gut microbiota, glial reaction and tlr4/tnf-α signaling pathway senescence-accelerated mouse (sam): a biogerontological resource in aging research practice of traditional chinese medicine for psycho-behavioral intervention improves quality of life in cancer patients: a systematic review and meta-analysis somatic generation of antibody diversity hmgb1 mediates depressive behavior induced by chronic stress through activating the kynurenine pathway cerebral ischemia increases bone marrow cd4+cd25+foxp3+ regulatory t cells in mice via signals from sympathetic nervous system assessment of evidence for or against contributions of chlamydia pneumoniae infections to alzheimer's disease etiology trial of satralizumab in neuromyelitis optica spectrum disorder a g-protein-coupled receptor for leukotriene b 4 that mediates chemotaxis global trends in health research and development expenditures -the challenge of making reliable estimates for international comparison neuroprotective effects of nitidine against traumatic cns injury via inhibiting microglia activation brain, behavior, and immunity xxx (xxxx) xxx-xxx suppress alzheimer's disease by elevating trem2 chinese scientists and security salvianolic acid b promotes microglial m2-polarization and rescues neurogenesis in stress-exposed mice serum factor(s) induced by restraint stress in mice and rats suppresses lymphocyte proliferation hippo/mst1 signaling mediates microglial activation following acute cerebral ischemia-reperfusion injury trans-cinnamaldehyde improves neuroinflammation-mediated nmda receptor dysfunction and memory deficits through blocking nf-κb pathway in presenilin1/2 conditional double knockout mice key: cord-322575-3goj00ej authors: karl, julie a.; bohn, patrick s.; wiseman, roger w.; nimityongskul, francesca a.; lank, simon m.; starrett, gabriel j.; o’connor, david h. title: major histocompatibility complex class i haplotype diversity in chinese rhesus macaques date: 2013-07-01 journal: g3 (bethesda) doi: 10.1534/g3.113.006254 sha: doc_id: 322575 cord_uid: 3goj00ej the use of chinese-origin rhesus macaques (macaca mulatta) for infectious disease immunity research is increasing despite the relative lack of major histocompatibility complex (mhc) class i immunogenetics information available for this population. we determined transcript-based mhc class i haplotypes for 385 chinese rhesus macaques from five different experimental cohorts, providing a concise representation of the full complement of mhc class i major alleles expressed by each animal. in total, 123 mamu-a and mamu-b haplotypes were defined in the full chinese rhesus macaque cohort. we then performed an analysis of haplotype frequencies across the experimental cohorts of chinese rhesus macaques, as well as a comparison against a group of 96 indian rhesus macaques. notably, 35 of the 51 mamu-a and mamu-b haplotypes observed in indian rhesus macaques were also detected in the chinese population, with 85% of the 385 chinese-origin rhesus macaques expressing at least one of these class i haplotypes. this unexpected conservation of indian rhesus macaque mhc class i haplotypes in the chinese rhesus macaque population suggests that immunologic insights originally gleaned from studies using indian rhesus macaques may be more applicable to chinese rhesus macaques than previously appreciated and may provide an opportunity for studies of cd8(+) t-cell responses between populations. it may also be possible to extend these studies across multiple species of macaques, as we found evidence of shared ancestral haplotypes between chinese rhesus and mauritian cynomolgus macaques. macaque monkeys are used extensively to model and understand human diseases. historically, rhesus macaques (macaca mulatta; mamu) of indian origin have been preferred for such research. however, exportation of rhesus macaques from india was halted in 1978 (southwick and siddiqi 1994) . as it became more difficult to obtain indian rhesus macaques, researchers turned to other sources, including chineseorigin rhesus macaques. chinese rhesus macaques have been used to study infectious diseases including simian immunodeficiency virus/ human immunodeficiency virus, avian influenza, malaria, plague, and severe acute respiratory syndrome, as well as studies of xenotransplantation, stem cell therapies, reproduction, and neurobiology (shen et al. 2007; chen et al. 2009 chen et al. , 2011 chen et al. , 2012 choi et al. 2011; liu et al. 2011; tian et al. 2011; wei et al. 2011; hutnick et al. 2012; li et al. 2012b; ling et al. 2013; mumbauer et al. 2013 ). yet comparatively little is known about the immunogenetics of these animals. the genome of a single chinese rhesus macaque was sequenced in 2011, but whole-genome sequencing technology struggles to accurately characterize highly polymorphic, duplicated regions such as the major histocompatibility complex (mhc) loci and killer immunoglobulin receptor loci (fang et al. 2011) . the mhc is an exceptionally polymorphic region of the genome responsible for presentation of peptides to t cells (bontrop 2006) . because of its pivotal role in immune response, understanding mhc genetics is essential for infectious disease research. our group and others have shown that the repertoire of mhc class i alleles expressed by chinese rhesus macaques is largely distinct from that observed in indian rhesus macaques (otting et al. 2007 (otting et al. , 2008 karl et al. 2008; copyright © 2013 karl et al. doi: 10.1534 /g3.113.006254 manuscript received march 28, 2013 accepted for publication may 14, 2013 this is an open-access article distributed under the terms of the creative commons attribution unported license (http://creativecommons.org/licenses/ by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. supporting information is available online at http://www.g3journal.org/lookup/ suppl/doi:10.1534/g3.113.006254/-/dc1. sequence data from this article have been deposited with the embl/genbank data libraries under accession nos. kc205288-kc205396 for novel mamu mhc alleles. 1 otting et al. ; wu et al. 2008; ma et al. 2009; wiseman et al. 2009; naruse et al. 2010; doxiadis et al. 2011) . consequently, we inferred mhc class i2restricted cd8 + t-cell responses in these two populations would be unlikely to target many of the same epitopes. here we reconsider the relationship between mhc class i genetics of chinese-and indian-origin rhesus macaques by focusing on mhc class i transcript2defined haplotypes inherited together, rather than simply analyzing individual allelic variants. most studies that currently control for the complex rhesus macaque mhc class i region only account for the presence of one or a few widely studied alleles (mamu-a1 ã 001, etc.), with no regard for the majority of alleles expressed by the animal. analysis on a haplotype level as presented here provides a more global view of the mhc class i alleles transcribed by each animal, creating the potential for a greater degree of allele matching between animals within a study. to define haplotypes with high resolution, we deep sequenced complementary dna (cdna) amplicons spanning most of exons 224 of mamu-a and mamu-b genes, the most polymorphic area of mhc class i corresponding to the peptide binding region. a total of 385 chinese-origin rhesus macaques from five different experimental cohorts were examined, as well as 96 indian-origin rhesus macaques from two distinct sources. unexpectedly, we discovered that 35 of 51 of the mamu-a and mamu-b haplotypes observed in indian rhesus macaques also were expressed by a significant majority of chinese rhesus macaques. conservation of these haplotypes suggests that functional cd8 + t-cell immunity to pathogens may be more similar between chinese-and indian-origin rhesus macaques than previously appreciated. whole blood and peripheral blood mononuclear cell samples from 385 chinese rhesus macaques were obtained over the span of 5 yr from five different sources, including battelle biomedical research center, etubics corporation, the national institute of allergy and infectious diseases/national institutes of health, and harlan laboratories, inc. cohorts are detailed in table 1 . the core set of 51 chinese rhesus macaque samples included 45 samples from cohort chrh #1 and six samples from cohort chrh #4. the expanded set of 334 chinese rhesus macaque samples included an additional 142 animals from these two cohorts, as well as 192 animals from the three other sources. it is unknown from which provinces in china the animals or their ancestors were initially obtained, or any degree of relation between the animals sampled. whole blood samples from 96 indian rhesus macaques were obtained from the wisconsin national primate research center (wnprc) and new england primate research center (neprc) breeding colonies. the wnprc cohort was selected to be unrelated based on pedigree records whereas the neprc cohort was taken from active adult breeding stock. macaques at the wnprc were cared for according to protocols approved by the university of wisconsin-madison graduate school animal care and use committee, whereas macaques housed at the neprc were maintained in accordance with standards of the association for assessment and accreditation of laboratory animal care and the harvard medical school animal care and use committee. rna isolation, cdna synthesis, and polymerase chain reaction (pcr) amplification (normalization and pooling) rna was isolated from whole blood or peripheral blood mononuclear cell samples using the roche magna pure instrument and rna high performance kit (roche, indianapolis, in), following manufacturer's protocols (supporting information, file s1). synthesis of cdna and pcr amplification were performed as previously described, generating either a 248-bp or 638-bp genotyping amplicon (the shorter amplicon dates back to studies performed before roche/454 sequencing technology advanced to~500-bp read lengths) (wiseman et al. 2009; fernandez et al. 2011 ). the amplicons for each sample were tagged during primary pcr with a multiplex identifier sequence, a unique 10-bp tag for each sample (file s1). amplification was confirmed by running pcr products on a flash gel (lonza group ltd, basel, switzerland), and bead-based purification was performed using ampure xp spri beads (agencourt bioscience corporation, beverly, ma) to remove primer dimers. quantification of purified products was performed using the quant-it dsdna hs assay kit and a qubit fluorometer (invitrogen, carlsbad, ca). products were then normalized to 0.3 ng/ml and pooled in equal volumes. sequencing for all amplicons was performed using roche/454 secondgeneration methods following manufacturer's protocols for emulsion pcr and pyrosequencing (roche, indianapolis, in). the core set of 51 chinese rhesus macaques and 96 indian rhesus macaques were sequenced in a total of five runs on a gs junior pyrosequencing instrument. the expanded set of 334 chinese rhesus macaques were sequenced on a combination of gs junior and gs flx platforms; both platforms utilize the same basic chemistry, differing only in scale of the run (a single gs junior run is~1/8 the scale of a full gs flx run). for the core set of 51 chinese-origin and 96 indian-origin rhesus macaques, sequences were analyzed by trimming all sequences from the 39 end to fixed 430-bp lengths, binning sequences into separate animal groups by parsing for the unique multiplex identifier tags, then creating uni-directional contigs of sequence reads assembled at 100% n stringency using the program geneious pro (biolegend, san diego, ca). fasta format sequences of all contigs for each sample were then exported, and bidirectional reads were assembled at 100% stringency using codoncode aligner (codoncode, dedham, ma). bidirectional contigs were interrogated against a curated database of known rhesus macaque mhc class i alleles using the basic local alignment search tool (i.e., blast), and novel alleles were submitted to genbank (kc205288-kc205396). putative haplotypes were inferred by looking for combinations of shared alleles between animals (file s1). analyses of the mamu-a and mamu-b regions were performed independently, since these gene clusters are separated by~1.2 million base pairs and recombination is relatively common at the population level (daza-vamenta et al. 2004) . once putative haplotypes were defined, a simpler workflow was used to assign haplotype designations to the additional 334 chinese rhesus macaque samples from the expanded set. all individual sequence reads obtained for each sample were directly compared against our rhesus macaque mhc class i allele database using blast-like analysis tool (i.e., blat) in a local instance of galaxy (penn state, state college, pa; emory, atlanta, ga), following the data analysis workflow detailed in figure s1 . haplotypes were assigned by identifying groups of shared major alleles from the previously defined putative haplotypes. the unparalleled complexity of the nonhuman primate mhc class i region makes it difficult to describe simply the full diversity of class i alleles expressed by an animal. macaques may encode as many as 30 distinct mhc class i transcripts expressed at widely differing steady state levels in peripheral blood. however, combinations of distinct alleles are inherited together on a chromosome as haplotypes, making it possible to assign a simplified name (i.e., haplotype a007) to each specific combination of alleles. here, unique haplotypes were defined on the basis of transcriptionally abundant "major" mamu-a and mamu-b alleles; an example of this simplification for the a007 haplotype is illustrated in figure 1 . our operational criterion for defining a "major" allele is that it must exceed a 4% transcript abundance relative to all class i transcripts identified per animal. we previously showed that cd8 + t-cell responses are principally restricted by highly transcribed major mhc class i alleles expressed in macaques, so we believe functionally defining haplotypes based on configurations of major alleles is appropriate for assessing conservation of mhc alleles involved in antigen presentation to cd8 + t cells (budde et al. 2011) . to further streamline haplotype definitions, only lineage level allele names were considered (commonly referred to as two-digit resolution in human hla genotyping, e.g., all mamu-a1 ã 007 allelic variants were grouped with the designation mamu-a1 ã 007; figure 1 ). alleles are named by the nonhuman primate immuno polymorphism database-mhc group based on similarity to other known macaque mhc class i alleles, such that alleles sharing a common lineage level designation are identical or nearly so within the peptide binding regions. a total of 123 unique haplotypic configurations were defined in the full cohort of 385 chinese rhesus macaques, consisting of 53 distinct mamu-a haplotypes and 70 mamu-b haplotypes (table s1 ). names were assigned to each haplotype based on the presence of what we call a "diagnostic major" allele. mamu-a region haplotypes typically contained a single major allele, usually from the mamu-a1 locus, so that allele was considered the "diagnostic major." a few of the mamu-a haplotypes and most of the mamu-b haplotypes expressed two or more major alleles; for these haplotypes, the most transcriptionally abundant allele expressed on the haplotype was typically considered the "diagnostic major" allele. occasionally the "diagnostic major" allele was selected based on known biological significance. for instance, even though the mamu-b ã 017 allele was not typically the most abundant transcript, it was considered the "diagnostic major" due to its known association with spontaneous control of siv (yant et al. 2006) . different versions of a base haplotype, denoted with a lowercase letter following the haplotype name (for instance, b001a and b001b), were designated to indicate differences in the complement of major transcripts accompanying a shared diagnostic allele. by this method of haplotype definition, four simple haplotype names represent the full complement of mhc class i major alleles expressed by each macaque (table s2 ). because the geographical source of macaques within china has been indicated as a factor in frequency of specific mhc class i alleles, we wanted to explore the differences in chromosomal haplotype frequencies between our five experimental cohorts (li et al. 2012a; liu et al. 2013) . after identifying the 20 most common chinese rhesus macaque mamu-a and mamu-b haplotypes across the data set as a whole, we examined the differences in the frequencies for those haplotypes between the five cohorts ( figure 2 ). frequencies were calculated based on the total number of chromosomes examined (770 chinese rhesus macaque chromosomes), to account for each animal expressing pairs of mamu-a and mamu-b haplotypes. some haplotype frequencies, such as a019, a018a, and b056a, were relatively consistent across the cohorts; however, some frequencies varied greatly from cohort to cohort. one example is the a004 haplotype, which was observed in~18% of the total chromosomes examined for cohort chrh #5, but only~5% for cohort chrh #2. overall, frequency differences between cohorts were more pronounced for the mamu-b haplotypes, and some cohorts did not contain one or more of the 20 most common mamu-a and mamu-b haplotypes. this finding is not unexpected for cohort chrh #5, because it only contained 11 macaques. the remaining cohorts each contained at least 46 macaques, minimizing the effect of sample size on observed frequencies in these cohorts. these results emphasize the point that not all research figure 1 simplification of mhc class i allele calls from full allele down to haplotype designation. schematic representation of reducing the a007 haplotype observed in chinese-origin rhesus macaques, from full allele name to major alleles to lineage designation to final haplotype call. cohorts of chinese rhesus macaques are equal from the standpoint of mhc class i diversity, as the complement of major mhc class i alleles expressed by chinese rhesus macaques can vary greatly between different sample groups. however, despite frequency differences, common haplotypes can still be identified across all five cohorts. we next performed mhc class i haplotype analysis on a group of 96 indian rhesus macaques, allowing for haplotype comparison between the two geographically isolated populations. in total, 51 haplotypes were identified in the indian rhesus macaque cohort, including 21 mamu-a haplotypes and 30 mamu-b haplotypes. interestingly, only 16 haplotypes (four mamu-a and 12 mamu-b haplotypes) were unique to indian rhesus macaques in this comparison (figure 3) . these findings indicate that although the allelic variation between chinese-and indian-origin rhesus macaques is largely distinct (table s3) , the two populations frequently inherit shared combinations of closely related allelic variants. overall, 35 of the 51 mhc class i haplotypes present within indian rhesus macaques have closely related homologs in the chinese population. the frequencies of these 35 shared haplotypes in each population are shown in figure 4 ; frequencies were again based on total number of chromosomes examined. although several of these shared haplotypes were not among the most abundant in this study, there were four haplotypes (a004, a019, b001a, and b015b) observed at a chromosomal frequency of at least 3% in each population. remarkably, 85% of the chinese rhesus macaques in this study express at least one of the 35 shared mamu-a or mamu-b haplotypes (64% carry at least one of the 17 shared mamu-a haplotypes, and 62% carry one or more of the 18 shared mamu-b haplotypes). likewise, 99% of the indian rhesus macaques in this cohort express at least one haplotype shared with chinese-origin animals ( figure 5 ). therefore, there is a high likelihood that these shared haplotypes were present in prior studies using indian-origin rhesus macaques that researchers might reproduce or expand upon today using chinese-origin rhesus macaques. mhc class i genotyping would need to be performed to confirm presence of shared haplotypes between populations for any specific studies. we also compared our 139 chinese-and indian-origin rhesus macaque haplotypes against the well-characterized panel of mauritian cynomolgus macaque (macaca fascicularis; mafa) haplotypes to explore possible ancestral haplotype sharing between the two species (wiseman et al. 2007; budde et al. 2010) . mauritian cynomolgus macaques exhibit extremely limited mhc class i diversity, as the population arose from a small group of founder cynomolgus macaques deposited on the island in the 1500s (lawler et al. 1995) . the mhc class i diversity of mauritian cynomolgus macaques is effectively described by five mafa-a and seven mafa-b haplotypes (one mafa-a haplotype is commonly associated with three distinct mafa-b haplotypes) (wiseman et al. 2007; budde et al. 2010) . three of our mamu-a haplotypes (a033, a060, and a063) and two of our mamu-b haplotypes (b045a and b150) were homologous to mauritian cynomolgus macaque haplotypes (table s1 ). four of these haplotypes were observed exclusively in chinese rhesus macaques; the fifth haplotype (b045a) was detected in both chinese-origin and indian-origin rhesus macaques. it has previously been shown that the specific mhc class i alleles expressed by chinese-and indian-origin rhesus macaques are largely distinct, and those distinctions were thought to equate to an unfathomable mhc class i diversity between the two geographically divided populations (otting et al. 2007 (otting et al. , 2008 karl et al. 2008; wu et al. 2008; ma et al. 2009; wiseman et al. 2009; naruse et al. 2010; doxiadis et al. 2011) . however, our model of defining mhc class i haplotypes of coinherited highly expressed major alleles provides a novel approach for assessing putatively functional similarities between macaque populations. most notably, more than two thirds of the haplotypes observed in indian rhesus macaques were shared with chinese rhesus macaques. this indicates that ancestral haplotypes were retained in both populations after the split from their most recent common ancestor~162,000 years ago, despite subsequent shrinking and expansion of the indian and chinese rhesus macaque populations, respectively (hernandez et al. 2007) . although chinese rhesus macaques overall display a greater repertoire of mhc class i haplotypes private to the population than indian rhesus macaques, 85% of the chinese rhesus macaques in this study express at least one of the shared ancestral mamu-a or mamu-b haplotypes described here ( figure 5 ). these homologous haplotypes may provide a valuable resource for cross-population studies of functional cd8 + t-cell immune response to pathogens. does conservation of mhc class i haplotypes correspond to conservation of cd8 + t-cell immune responses? though this remains to be tested at the haplotype level, a previous study demonstrated that it was possible to create mamu-b ã 017:03 (a chinese rhesus macaquespecific allelic variant of the mamu-b ã 017 lineage) monomers and tetramers with the siv nef 165-173 peptide iw9 (ouyang et al. 2009 ). this amino acid sequence was characterized as a ctl epitope restricted by mamu-b ã 017:01 in indian rhesus macaques, an allele that has been associated with control of sivmac239 viral replication (mothe et al. 2002; yant et al. 2006) . mamu-b ã 017:03 differs from mamu-b ã 017:01 by four amino acids, three of which occur in the peptide binding domain encoded by exons 2-3. these amino acid substitutions did not appear to alter the ability of mamu-b ã 017:03 to bind siv nef 165-173 peptide iw9 (ouyang et al. 2009 ). if the highly similar allelic variants expressed on homologous haplotypes are also able to bind the same peptides, it is very likely those haplotypes would mount similar cd8 + t-cell responses in both chinese-and indianorigin rhesus macaques. to extend these observations, class i alleles of specific interest sharing a lineage designation would need to be analyzed for predicted binding preferences as well as the functional ability to present specific peptides. there is also early evidence that sharing of homologous haplotypes may be a pan-macaque phenomenon. comparison of the rhesus macaque haplotypes identified in this study to an established panel of mauritian cynomolgus macaque haplotypes revealed a total of five putative orthologous haplotypes, including three of the five mafa-a haplotypes. interestingly, the cynomolgus macaque haplotypes with putative rhesus macaque orthologs account for more than 62% and 20% of the mafa-a and mafa-b diversity, respectively, in mauritian cynomolgus macaques (budde et al. 2010) . it may therefore be possible to also explore whether rhesus and cynomolgus macaques with conserved ancestral mhc class i haplotypes mount similar cd8 + tcell immune responses. additional haplotype similarities are also likely to exist between rhesus macaques and cynomolgus macaques of other geographic populations, or between rhesus macaques and other macaque species, but a current lack of defined haplotypes for these other populations make comparisons difficult. overall, this study provides the first large-scale description of mhc class i transcript-based haplotypes in rhesus macaques. it begins to explore some of the variability of haplotypes observed between independent experimental research cohorts of chinese rhesus macaques, and provides a valuable chromosomal haplotype frequency survey for groups looking to study high-frequency chinese rhesus macaque alleles. importantly, it highlights the unexpected sharing of indian rhesus macaque haplotypes with rhesus macaques from china, which may facilitate comparisons of mhc class i2mediated response to pathogens across populations. comparative genetics of mhc polymorphisms in different primate species: duplications and deletions characterization of mauritian cynomolgus macaque major histocompatibility complex class i haplotypes by high-resolution pyrosequencing transcriptionally abundant major histocompatibility complex class i alleles are fundamental to non-human primate siv-specific cd8+ t cell responses pathological lesions and viral localization of influenza a (h5n1) virus in experimentally infected chinese rhesus macaques: implications for pathogenesis and viral transmission variability of bio-clinical parameters in chinese-origin rhesus macaques infected with simian immunodeficiency virus: a nonhuman primate aids model the available time window for embryo transfer in the rhesus monkey (macaca mulatta) efficacy of pig-to-rhesus lamellar corneal xenotransplantation genetic divergence of the rhesus macaque major histocompatibility complex genomic plasticity of the mhc class i a region in rhesus macaques: extensive haplotype diversity at the population level as revealed by microsatellites genome sequence and global sequence variation map with 5.5 million snps in chinese rhesus macaque screening and confirmatory testing of mhc class i alleles in pigtailed macaques demographic histories and patterns of linkage disequilibrium in chinese and indian rhesus macaques an optimized siv dna vaccine can serve as a boost for ad5 and provide partial protection from a high-dose sivmac251 challenge identification of mhc class i sequences in chinese-origin rhesus macaques mitochondrial dna of the mauritian macaques (macaca fascicularis): an example of the founder effect preliminary observations of mhc class i a region polymorphism in three populations of chinese-origin rhesus macaques characterization of peripheral blood t lymphocyte subsets in chinese rhesus macaques with repeated or long-term infection with plasmodium cynomolgi effect of combination antiretroviral therapy on chinese rhesus macaques of siv infection epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques mamu-b genes and their allelic repertoires in different populations of chinese-origin rhesus macaques identification of 17 novel major histocompatibility complex-a alleles in a population of chinese-origin rhesus macaques characterization of the peptide-binding specificity of mamu-bã17 and identification of mamu-bã17-restricted epitopes derived from simian immunodeficiency virus proteins efficient mucosal transmissibility but limited pathogenicity of r5 shivsf162p3n in chinese origin rhesus macaques diversity of mhc class i genes in burmese-origin rhesus macaques mhc class i a region diversity and polymorphism in macaque species a snapshot of the mamu-b genes and their allelic repertoire in rhesus macaques of chinese origin construction of soluble mamu-bã1703, a class i major histocompatibility complex of chinese rhesus macaques, monomer and tetramer loaded with a simian immunodeficiency virus peptide cue-invariant detection of centresurround discontinuity by v1 neurons in awake macaque monkey population status of nonhuman primates in asia, with emphasis on rhesus macaques in india histopathological observation of immunized rhesus macaques with plague vaccines after subcutaneous infection of yersinia pestis derivation of rhesus monkey parthenogenetic embryonic stem cells and its microrna signature simian immunodeficiency virus sivmac239 infection of major histocompatibility complex-identical cynomolgus macaques from mauritius major histocompatibility complex genotyping with massively parallel pyrosequencing allelic diversity within the high frequency mamu-a2ã05/mane-a2ã05 (mane-aã06)/mafa-a2ã05 family of macaque mhc-a loci the high-frequency major histocompatibility complex class i allele mamu-bã17 is associated with control of simian immunodeficiency virus sivmac239 replication we thank battelle biomedical research center, etubics corporation, the national institute of allergy and infectious diseases/national institutes of health, and harlan laboratories, inc., for providing us with chinese rhesus macaque samples, and the new england primate research center for providing an independent source of indian rhesus macaque samples. we also thank the staff of the w.m. keck center for comparative and functional genomics at the university of illinois at urbana-champaign for performing roche/454 gs flx sequencing. this work was supported by the national institute of allergy and infectious diseases (hhsn266200400088c, hhsn272201100013c), the national center for research resources (p51 rr000167), and the office of research infrastructure programs (p51 od011106) of the national institutes of health. this research was conducted at a facility constructed with support from the research facilities improvement program (rr15459-01, rr020141-01). key: cord-338901-1kzy7rts authors: li, heng; yang, li; liu, fei-fei; ma, xin-na; he, pei-lan; tang, wei; tong, xian-kun; zuo, jian-ping title: overview of therapeutic drug research for covid-19 in china date: 2020-06-17 journal: acta pharmacol sin doi: 10.1038/s41401-020-0438-y sha: doc_id: 338901 cord_uid: 1kzy7rts since the outbreak of novel coronavirus pneumonia (covid-19) in december 2019, more than 2,500,000 people worldwide have been diagnosed with sars-cov-2 as of april 22. in response to this epidemic, china has issued seven trial versions of diagnosis and treatment protocol for covid-19. according to the information that we have collected so far, this article provides an overview of potential therapeutic drugs and compounds with much attention, including favipiravir and hydroxychloroquine, as well as traditional chinese medicine, which have been reported with good clinical treatment effects. moreover, with further understanding of sars-cov-2 virus, new drugs targeting specific sars-cov-2 viral components arise and investigations on these novel anti-sars-cov-2 agents are also reviewed. in december 2019, a new type of unexplained pneumonia appeared in the south china seafood wholesale market in wuhan, hubei province, but its source has not yet been found. to confirm the cause, whole-genome sequencing of samples from patients with this unexplained pneumonia revealed a betacoronavirus that had never been seen before, which was different from sars-cov and mers-cov [1] . after the alert of this new pathogen, china quickly took measures to completely block off hubei province and implemented a quarantine policy nationwide to keep the outbreak under control. this efficient process was also recognized by the international who. this highly contagious new coronavirus was initially named 2019-ncov. on feb 11, 2020, the international committee on taxonomy of viruses introduced the name "severe acute respiratory syndrome coronavirus 2" (sars-cov-2) to refer to the virus, and the who named the related pneumonia coronavirus pneumonia . this article will go through basic virology of sars-cov-2 and review mainly the drugs used in the battle against covid-19 in china. by genome sequencing, it was found that sars-cov-2 has 82% sequence similarity with sars-cov [2, 3] , and through phylogenetic tree analysis, it has 96% homology with bat coronaviruses at the genome level, for which reason bats were inferred to be the host for sars-cov-2 [4] . the genome structure of sars-cov-2 is shown in fig. 1 . sars-cov-2 is a single-stranded positive-sense rna virus and is classified in the order nidovirales, coronaviridae, and coronavirus [5] . coronaviruses are a large class of viruses that can infect mammals and birds and can cause many diseases, such as respiratory, intestinal, liver, and nervous system diseases [6] . coronaviruses are divided into four groups: alpha-, beta-, gamma-and delta-coronaviruses [7] , and all known human pathogenic coronaviruses are beta-coronaviruses. the single-stranded rna genome of sars-cov-2 is 29891 nucleotides in size. the genes of sars-cov-2 from 5′ to 3′ are a 5′ untranslated region, including 5′ leader sequences; and open reading frame (orf) 1a/b; structural proteins, including the envelope glycoprotein spike (s), envelope (e), membrane (m) and nucleoprotein (n); accessory proteins, such as orf3, 6, 7a, 7b, 8, and 9b; and a 3′ untranslated region [3] . orf1a/b occupy two-thirds of the viral genome, and they encode two polyproteins, pp1a and pp1ab [8] . these two polyproteins can be hydrolyzed into 16 nonstructural proteins (nsps), including papain-like protease (plpro), 3c-like protease (3clpro), rna-dependent rna polymerase (rdrp), helicase, and exonuclease [6] . the enveloped glycoprotein spike (s) forms a layer of glycoproteins protruding from the envelope and is closely related to virus infection of cells [9] . there are multiple sequence segments in the receptor-binding domain of the s protein, which have high homology with sars-cov sequences, and some studies have confirmed that sars-cov-2 can bind to the ace2 receptor on the cell surface, similar to sars-cov [1, 3, 10] . two additional transmembrane glycoproteins, envelope (e) and membrane (m), are incorporated into the virion. nucleoprotein encapsulates the viral (+) rna genome in the form of a spiral in the envelope to prevent degradation. accessory proteins do not participate in viral replication, but they interfere with the host innate immune response or have other unknown functions [10] . the sars-cov-2 possible life cycle begins when the spike glycoprotein on the envelope binds to the ace2 receptor, and membrane fusion occurs either directly with the host cell membrane or with the endosome membrane. after membrane fusion, the viral rna genome is released into the cytoplasm, and the uncoated rna is translated into two polyproteins. the polyproteins are cleaved by the protease encoded by orf1a into the 16 nsps, which can form an rna replicase-transcriptase complex [6, 10] . this complex drives the production of negative-sense rna, which is used as a template for the full-length (+) rna genome. during transcription, subgenomic rnas are produced by discontinuous transcription and then transcribed into subgenomic (+) mrna, which is translated into different structural proteins. the newly formed structural protein and viral genomic rna combine to form a nucleocapsid. the viral particles bud into the er-golgi intermediate compartment (ergic), and then the primary virion is released from the infected cells [10] . a diagram of sars-cov-2 life cycle is shown in fig. 2 . due to the sudden emergence of sars-cov-2, no specific antiviral agents are available. however, many drugs under development are believed to have potential anti-sars-cov-2 activity due to common biological processes in the virus life cycle. currently, there are~200 domestic clinical trials of covid-19 drugs from the chinese clinical trial registry (chictr) as of 10 march, and most are for chemical drugs, chinese patent medicines, and combinations. all of these clinical trials were registered in 2020, after the outbreak of covid-19 [11] . among those covid-19 treatment-related clinical trials, a total of 155 registered covid-19 treatment drug-related interventional studies were obtained from the chictr database (www.chictr.org. cn) with ethics committee approval and informed consent signed by 10 march. statistic information of these registered trials are shown in fig. 3 . the study phase of each trial was extracted, and nearly 25% of these clinical trials were registered as phase 4 studies, which were stated as "postmarketing drugs" or "phase iv clinical trials" by the chictr definition. in phase four studies, many domestically approved chinese patent drugs and chemical agents are being used to treat covid-19 patients. with so many clinical trials registered in such a short period of time, we can see that china has responded to the epidemic in a timely manner and hopes to find sars-cov-2-specific medicines to end the epidemic as soon as possible. this urgent need propelled china's drug research ability to its full power, and this motivation involved many academic institutions, hospitals, and companies. this approach has also led to concerns about this phenomenon. excessive research and drug trials can create the problem of squeezing each other for limited medical resources or even wasting them. this phenomenon and its impact on our medical system, as well as possible improvement in our medical administration, need thorough review and discussion at an appropriate time in the future. in these 155 pooled clinical trials, a number of approved chemical and biomacromolecule drugs have been used in covid-19 treatment clinical trials for drug repurposing, most of which are nucleotide analogs and protease inhibitors against other viral pathogens, including influenza virus, hiv and hcv. comprehensive information about the chemical agents used in covid-19 drug clinical trials is shown in the table below (table 1) . although the mortality rate of sars-cov-2 is not as high as that of sars-cov and mers-cov, sars-cov-2 is more contagious, and studies have shown that it can be transmitted during the incubation period [12] . to date, there are no specific vaccines or antiviral drugs against covid-19. for the treatment of patients, isolation and symptomatic supportive care are currently recommended, including oxygen therapy, water, and dielectric balance, nutritional interventions and fluid management to reduce symptoms and prevent end-organ dysfunction [13, 14] . for the treatment of severe pneumonia, extracorporeal membrane oxygenation therapy is a new type of adjuvant treatment technology [15] , and gas exchange through cardiopulmonary bypass technology can reduce ventilator-related damage and oxygen toxicity damage to promote early patient recovery. however, the needs for specific technical skill and high expense limit its usage. a number of nonspecific antiviral agents have been recommended in the latest 7th trial version of the "diagnosis and treatment protocol for novel coronavirus pneumonia". table 2 shown below lists important information about currently available anti-sars-cov-2 drugs ( table 2 ). type i interferons, including ifn-α and ifn-β, have broad-spectrum antiviral effects [16] . ifn-α can directly inhibit virus replication or can achieve antiviral effects by activating innate or adaptive immunity [17] . many studies have proven that ifn-α has an antiviral effect on sars-cov [18] , and other experts discovered that ifn-α can prevent mers-cov infection and effectively inhibit the virus in the early stages of infection [19] . because it is also a coronavirus and highly homologous to sars-cov, ifn-α is recommended for the treatment of sars-cov-2 infection. according to the latest new "diagnosis and treatment protocol for novel coronavirus pneumonia", ifn-α at a dose of~5 million u or equivalent dose each time for adults is added to 2 ml of sterile water, and it is aerosolized and inhaled twice a day [13] . lopinavir/ritonavir lopinavir was first approved in the united states in 2000 for the treatment of hiv infection [20] . it is a protease inhibitor and is usually used in combination with ritonavir to increase its half-life through the inhibition of cytochrome p450 [21] . in vitro studies have shown that lopinavir/ritonavir can inhibit the replication of mers-cov and sars-cov and exert antiviral effects [22] [23] [24] [25] . at present, the drug has been used in the clinical treatment of covid-19 at a dose of 400 mg/100 mg for adults twice daily, and the course of treatment does not exceed 10 days [13] . however, this treatment has certain toxic and side effects on the treatment of covid-19. therefore, its safety and effectiveness require further research. recently, some clinical studies have shown that lopinavir/ritonavir treatment has no significant effect [26, 27] . ribavirin is a purine nucleoside analog with a broad-spectrum antiviral effect [28] . it is used mainly to treat respiratory syncytial virus infection [29] and in combination with interferon for hepatitis c [30] . ribavirin was widely used in 2003 to treat sars-cov infection, but when used alone, it seemed to have no effect and caused significant hemolysis in many patients [31] [32] [33] [34] . when ribavirin was combined with ifn-β, it had good antiviral activity in in vitro studies [35] . some studies have shown that in patients with severe mers-cov infection, ribavirin combined with ifn-α-2a treatment can significantly improve patient 14-day survival [36] . preliminary in vitro test results demonstrate that ribavirin can inhibit sars-cov-2 in a human cell line. in the latest "diagnosis and treatment protocol for novel coronavirus pneumonia", it is recommended to use ribavirin at a dose of 500 mg each time for adults and in combination with interferon or lopinavir/ritonavir, with 2-3 intravenous infusions daily. the course of treatment does not exceed 10 days [13] . chloroquine phosphate chloroquine phosphate is an antimalarial drug that has been on the market for many years, and it also has a potential broadspectrum antiviral effect [37, 38] . it can increase the ph of lysosomes to prevent virus fusion with the cell membrane and then block virus entry and infection [39] . some studies have found that the spike glycoprotein on the virus envelope binds to the ace2 receptor to mediate sars-cov-2 infection [9, 40] . chloroquine phosphate has been reported to interfere with the glycosylation of the ace2 receptor, thereby inhibiting the binding of sars-cov to cells and achieving therapeutic goals [41] . therefore, chloroquine phosphate is used to treat covid-19, and in vitro experiments show that chloroquine phosphate does inhibit sars-cov-2 and that its ec 50 is 1.13 μm [39] . apart from the above antiviral mechanism, chloroquine phosphate can continue to exert antiviral effects after sars-cov-2 invades cells, and it also has immunomodulatory activity to strengthen the antiviral effect [42] . therefore, chloroquine phosphate has been included in the "diagnosis and treatment protocol for novel coronavirus pneumonia" and is undergoing clinical trials. chloroquine phosphate is used for the treatment of covid-19 in adults aged 18-65 years. those who weigh more than 50 kg will receive 500 mg twice daily for 7 days, while those who weigh less than 50 kg will receive 500 mg twice daily on days 1 and 2 and 500 mg once daily on days 3-7 [13] . arbidol is a non-nucleoside broad-spectrum antiviral drug for upper respiratory tract infections caused by influenza a and b viruses, and it was first approved in russia [43] . it can inhibit the adhesion of viruses to host cells and prevent them from invading human cells [44] . at the same time, it can promote the synthesis of interferon, which can prevent influenza virus invasion and treat influenza virus infection [45] . some studies have confirmed that arbidol has a good effect against sars-cov and mers-cov infections [46, 47] . chinese scientists found in in vitro cell experiments that compared with a drug-untreated control group, 10-30 μm arbidol can effectively inhibit sars-cov-2 up to 60 times and significantly inhibit the pathological effects of the virus on cells [48] . as described in the latest "diagnosis and treatment protocol for novel coronavirus pneumonia", arbidol is used at a dose of 200 mg for adults three times daily, and the course of treatment does not exceed 10 days [13] . it has been reported that some patients have improved symptoms after receiving arbidol [49] . favipiravir is a nucleoside analog [50, 51] with an ability to inhibit rna-dependent polymerase [52] and was approved for marketing in japan in 2014. it is used for antiviral treatment of influenza a and b [52] and can effectively inhibit ebola virus, yellow fever virus [53] , etc. in vitro experiments have shown that favipiravir is effective for covid-19 and that its ec 50 is 61.88 μm [39] . to date, some clinical trials of favipiravir in the treatment of covid-19 have been carried out in china. recent clinical studies have found that compared with the antiviral drug arbidol, the clinical effect of favipiravir is more significant. nucleic acid positive-to-negative time, mean antipyretic time and cough remission time were all better than those of the arbidol group [27] . remdesivir(gs-5734) remdesivir was first used to treat ebola virus, and it has completed phase 2 clinical trials [54] . as a nucleoside analog, it can interact with rdrp [55, 56] , and the triphosphate form of remdesivir will compete with adenosine triphosphate, leading to delayed chain termination and inhibiting viral replication and transcription [57] . a number of in vitro studies have shown that remdesivir has inhibitory effects on a variety of human and animal coronaviruses [58, 59] . an in vivo study of remdesivir against sars-cov showed that remdesivir can reduce virus levels in the lungs of mice infected with sars-cov and reduce lung function damage caused by the virus [60] . moreover, some studies have found that the antiviral effect of remdesivir against mers-cov is better than that of lopinavir/ritonavir combined with ifn-β [21] . according to the above evidence, remdesivir has been used to treat sars-cov-2, and in vitro experiments showed that remdesivir has a good inhibitory effect on sars-cov-2, with an ec 50 of 0.77 μm [39] . recently, the first covid-19 patient in the united states was treated with remdesivir on the 7th day of hospitalization, and their clinical symptoms were improved significantly [61] . at present, a phase three clinical trial of remdesivir for covid-19 has been officially launched in china, and a total of 761 patients are planned to be enrolled in the study, which will be randomized, double-blind and placebo-controlled [62] . as a derivative of chloroquine, hydroxychloroquine has similar efficacy and few adverse reactions. based on its characteristics of immunomodulation, antithrombotic activity, and improved inflammation, hydroxychloroquine has been used in the clinical treatment of systemic lupus erythematosus [63] . hydroxychloroquine has been shown to have anti-sars-cov activity in vitro [64] , and it is clinically safer than chloroquine [65, 66] . some clinical studies have found that after treatment with hydroxychloroquine, the viral load significantly decreases or even disappears, and azithromycin can enhance the antiviral effect [67, 68] . traditional chinese medicine has played an important role in the treatment of previous outbreaks of viral infectious diseases, so it has once again received attention during this epidemic of covid-19 [69, 70] . in response to the outbreak, chinese medicine experts provided different chinese medicine prescriptions and proprietary chinese medicines for selection at different stages of the clinical treatment period of diagnosed patients according to the principle of tcm syndrome differentiation. for example, for patients with fatigue and fever during the medical observation period, jinhua qinggan granules, lianhua qingwen capsules (granules) and shufeng jiedu capsules (granules) can be used, while for patients with fatigue and gastrointestinal discomfort, the chinese patent medicine huoxiang zhengqi capsules (pills, liquid, and oral solution) can be used [13] . lianhua qingwen capsules contain many chinese herbal ingredients with antiviral effects, such as licorice. glycyrrhizic acid, an extract of licorice, has been shown to inhibit virus replication and has been used clinically to treat hcv infection [71] . glycyrrhizic acid has been reported to inhibit the replication of sars-cov in vitro [72] . for the reasons above, lianhua qingwen capsules have been used in the clinic and have a certain effect on improving clinical symptoms because they can obviously alleviate the symptoms of cough, fever, and fatigue in patients with covid-19, reduce the proportion of severe cases, and shorten fever time [73] [74] [75] . in addition, lung cleansing and detoxifying decoction is also recommended for the treatment of confirmed cases in the latest "diagnosis and treatment protocol for novel coronavirus pneumonia" [13] . in addition to traditional chinese medicine prescriptions, some traditional chinese medicine ingredients also have certain potential for the treatment of sars-cov-2. baicalin is a flavonoid compound isolated from the root of scutellaria baicalensis and has been confirmed to inhibit sars-cov in vitro [76] . ginsenoside improves human immunity and has a curative effect on viral infection [77] . therefore, traditional chinese medicine can also be used as an option to treat covid-19. many clinical trials have been launched to further analyze the safety and effectiveness of traditional chinese medicine, and the traditional chinese medicines mentioned above have been recommended in the latest "diagnosis and treatment protocol for novel coronavirus pneumonia" [13] (table 3) . chinese patent medicine chinese patent medicine is herbal medicines in traditional chinese medicine modernized into a ready-to-use form, such as tablets, oral solutions, or dry suspensions. chinese patent medicine has played very important roles in the domestic battle against covid-19 in china, and many clinical investigations have started to more precisely evaluate its effects on covid-19 patient treatment. chinese patent medicine, as well as many herbal medicines, has been very useful in improving symptoms such as coughing, weakness, and digestive system disorders, as well as alleviating anxiety. reports announced that up to 90% of covid-19 patients in china have been given chinese patent medicine or tcm prescriptions. a list of chinese patent medicine currently undergoing covid-19 clinical trials is shown below (table 4) to present an overall message about chinese patent medicine in covid-19 treatment research (table 2) . spike protein some studies have confirmed that sars-cov-2 infects cells through endocytosis via the ace2 receptor on at2 alveolar epithelial cells in the lungs [78, 79] . at present, the protein structure of the s protein and ace2 interaction has been solved, providing reliable guidance for vaccine and drug design [80] . aiming at the mutual use of the s protein and ace2 protein necessary for sars-cov-2 to enter host cells, multiple domestic research teams have discovered a variety of potential ace2papain-like protease (plpro) plpro is a multifunctional protein with protease and phosphatase activity that is involved in viral replication and ifn antagonism [81] . plpro of sars-cov-2 and sars-cov have only 83% sequence similarity [82] . however, the high-level structure of the protein that forms the active site is not altered in the two plpro proteins [83] . there are already domestic teams working to find potential inhibitors of plpro through virtual screening, which needs to be confirmed by experiments. the 3clpro of sars-cov-2 and sars-cov have an amino acid sequence similarity of up to 96%, and the structure of 3clpro in sars-cov-2 has been solved [82] . 3clpro is a key protein of the virus, and the virus needs to use it to replicate rna. therefore, finding sars-cov-2 3clpro inhibitors can provide a more effective way to fight covid-19. rna-dependent rna polymerase (rdrp) as an rna virus, sars-cov-2-encoded rdrp plays a key role in the virus's rna replication. rdrp inhibitors can be used as broadspectrum antiviral drugs against rna viruses. the rdrp protein structure has a large and deep groove structural region as the active center of rna synthesis. the sequence similarity of the rdrp proteins of sars-cov-2 and sars-cov is as high as 96%, and structural differences exist outside the active center [82] . therefore, high sequence conservation allows the development of rdrp inhibitors against sars-cov to be applied to the development of anti-sars-cov-2 drugs. tmprss2 (serine protease) a recent study showed that in addition to the use of the sars-cov receptor ace2 to enter the cell, sars-cov-2 has two other proteins, cathepsin b and l(catb/l) and tmprss2, that activate the s protein, help sars-cov enter the cell, and play a key role in the process of invasion of normal cells by sars-cov-2 [84] . when a tmprss2 inhibitor is used in combination with a catb/l inhibitor, they can completely inhibit the invasion of sars-cov-2. therefore, tmprss2 may be a potential antiviral target. this article provides an overview of published information on domestic research and the development of coronavirus-related therapeutic agents. the drug-repurposing effort summarized in this article focused primarily on agents currently known to be active against other rna viruses, including sars-cov, mers-cov, influenza, hcv, and ebola, as well as anti-inflammatory drugs. this information provides a strong intellectual groundwork for support of current and future research and development for the discovery and development of therapeutic agents for the treatment of covid-19 and coronavirus-related diseases. however, there are still no officially approved specific antiviral drugs or vaccines for sars-cov-2, and supportive care remains a key to treatment. tcm has accumulated thousands of years of experience in the treatment of pandemic and endemic diseases. complementary and alternative treatments are still urgently needed for the management of patients with sars-cov-2 infection, and experiences in tcm are certainly worth examining. many antiviral chinese patent medicines, such as shuanghuanglian oral solution and others, have been declared to have the effect of heat clearing and detoxifying, which could help clear viral respiratory pathogens and relieve symptoms according to tcm theory. chinese patent medicine has been used in many historic epidemics, such as the previous two coronavirus outbreaks (sars-cov in 2013 and mers-cov in 2012) and seasonal epidemics caused by influenza viruses and dengue virus. fighting against current epidemics also provides an opportunity to test the true value of tcm in treating emerging contagious diseases. it is encouraging that controlled clinical studies to evaluate the efficacy of tcm in the treatment of sars-cov were conducted and reported. we believe that specific and efficient antiviral drugs and therapy will arise from these ongoing and developing drugs, especially from the rich tradition of herbal medicines in china. competing interests: the authors declare no competing interests. evolution of the novel coronavirus from the ongoing wuhan outbreak and 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antiviral compounds combined adjuvant effect of ginseng stem-leaf saponins and selenium on immune responses to a live bivalent vaccine of newcastle disease virus and infectious bronchitis virus in chickens structure of the sars-cov-2 spike receptor-binding domain bound to the ace2 receptor structural basis of receptor recognition by sars-cov-2 cryo-em structure of the 2019-ncov spike in the prefusion conformation the sars-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-ncov nucleotide analogues as inhibitors of viral polymerases sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor key: cord-316181-ccauw70y authors: yang, fude; dong, xiaoxv; yin, xingbin; wang, wenping; you, longtai; ni, jian title: radix bupleuri: a review of traditional uses, botany, phytochemistry, pharmacology, and toxicology date: 2017-05-16 journal: biomed res int doi: 10.1155/2017/7597596 sha: doc_id: 316181 cord_uid: ccauw70y radix bupleuri (chaihu) has been used as a traditional medicine for more than 2000 years in china, japan, korea, and other asian countries. phytochemical studies demonstrated that this plant contains essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids, and sterols. crude extracts and pure compounds isolated from radix bupleuri exhibited various biological activities, such as anti-inflammatory, anticancer, antipyretic, antimicrobial, antiviral, hepatoprotective, neuroprotective, and immunomodulatory effects. however, radix bupleuri could also lead to hepatotoxicity, particularly in high doses and with long-term use. pharmacokinetic studies have demonstrated that the major bioactive compounds (saikosaponins a, b(2), c, and d) were absorbed rapidly in rats after oral administration of the extract of radix bupleuri. this review aims to comprehensively summarize the traditional uses, botany, phytochemistry, pharmacology, toxicology, and pharmacokinetics of radix bupleuri reported to date with an emphasis on its biological properties and mechanisms of action. radix bupleuri, also called "chaihu" in chinese, is derived from the dried roots of bupleurum chinense dc. and bupleurum scorzonerifolium willd. [1] . as a traditional herbal medicine, radix bupleuri has been used widely for the treatments of influenza, fever, inflammation, malaria, menstrual disorders, and hepatitis in china, japan, korea, and other asian countries [2, 3] . according to ancient chinese medical literatures, radix bupleuri is capable of regulating the exterior and interior metabolisms, dispersing evil heat from the superficies, soothing the liver, and promoting yang and qi (representing "life energy" or "life force" in tcm theories). in recent decades, investigations of radix bupleuri have focused on its biological activities, including its anti-inflammatory [4, 5] , anticancer [6, 7] , antipyretic [8] , antimicrobial [9] , antiviral [10] , hepatoprotective [11] , and immunomodulatory effects [12] . in addition, radix bupleuri also exhibited significant effects on membrane fluidity [13] . these studies have resulted in the isolation of essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids, and sterols from this plant [14] . among them, triterpenoid saponins are known to be the major bioactive compounds [15, 16] . saikosaponins a and d are commonly used as chemical standards for quality evaluation of radix bupleuri in the current chinese pharmacopoeia and recent publications. however, an increasing number of recently published studies have reported adverse effects of radix bupleuri. the purpose of this review is to provide updated, comprehensive information on the traditional uses, botany, phytochemistry, pharmacology, toxicology, and pharmacokinetics of radix bupleuri based on scientific literatures in the past few decades. this study will facilitate exploring the therapeutic potential of this plant and evaluate future research opportunities. radix bupleuri, which is characterized by a wide spectrum of biological and pharmacological effects, has been used as a famous traditional chinese medicinal herb with a history of medical use in china. according to tcm theory, radix bupleuri is thought to regulate the exterior and interior curing rhinitis and nasosinusitis bioactive compounds owing to their antifungal and antiinflammatory activities [37, 38] . in one study, the essential oils in radix bupleuri were extracted by steam distillation and solvent extraction and then analyzed by gc/ms; 78 peaks were identified. among these peaks, the major volatile compounds were 3-methylbutanal (7.24%), pentanal (5.74%), hexanal (20.11%), furan-2-carbaldehyde (25.23%), and heptanal (12.07%) [39] . however, in another study, the results showed that e-2-heptanal, furan, 2-pentyl, and e-2-nonenal were some of the main compounds of the oil [40] . triterpenoid saponins are the main active components of radix bupleuri, which exhibit a broad spectrum of biological and pharmacological effects, including analgesic, immunomodulatory, hepatoprotective, immunomodulatory, anti-inflammatory, antitumor, and antiviral activities [3, [41] [42] [43] . currently, approximately 35 saponins have been isolated from radix bupleuri ( figure 2 ) [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] . among them, saikosaponins a, c, and d are the major bioactive constituents found in radix bupleuri; however a variety of minor saikosaponins have also been isolated [16] . the cytotoxic and antiproliferative effects of saikosaponins a and d have been attracting much interest in recent years [55] . additionally, more information about the intimate relationship between the structural characterization of saikosaponins and their cytotoxic evaluations is very necessary. radix bupleuri have been identified, including (2z,8z,10e)pentadecatriene-4,6-diyne-1-ol ( ), (2z,8e,10e)-pentadecatriene-4,6-diyne-1-ol ( ), (2z,8z,10e)-heptadecatriene-4,6-diyne-1-ol ( ), and bupleurynol ( ) ( figure 3 ) [56, 57] . radix bupleuri exerts a great variety of pharmacological activities due to its complexbioactive compounds. an overview of the pharmacological studies on radix bupleuriis presented in detail in the following sections. widely used for the treatment of several types of chronic inflammatory diseases. the crude polysaccharides (80 mg/kg) isolated from the roots of bupleurum chinense dc. significantly attenuated lung injury by inhibiting the level of myeloperoxidase (mpo), tumor necrosis factor-(tnf-), and serum nitric oxide (no) [66] . chun et al. reported that saikosaponins from radix bupleuri exhibited anti-inflammatory activity on inflammatory processes including inhibition of inflammatory exudation, capillary permeability, inflammatory mediators release, migration of white cells, connective tissue hyperplasia, and a variety of allergic inflammation [67] . ma et al. was the first to show that saikosaponins exerted anti-inflammatory activity on paw edema mainly via regulating the nicotinate and nicotinamide metabolism and arachidonic acid metabolism [5] . zhu et al. found that saikosaponin a (ssa) exhibited an inhibitory effect on proinflammatory cytokines in lps-stimulated macrophages. the mechanism of these actions involved the regulation of mapk and nf-b signals pathways [68] . in another study, ssa dose-dependently inhibited the production of ros, tnf-, il-8, cox-2, and inos in lps-stimulated human umbilical endothelial cells (huvecs) by upregulating of the lxr -abca1 signaling pathway [69] . moreover, lee et al. showed that saikosaponin c (ssc) was also shown to inhibited lps-induced apoptosis in huvecs via inhibition of caspase-3 activation and caspase-3-mediated-fak degradation [70] . zhao et al. showed that ssa also suppressed tnf-and il-6 concentrations in the intestines of septic rats through the inhibition of the nucleotide-binding oligomerization domain 2 (nod2)/nf-b signaling pathway [71] . saikosaponin d (ssd) has been reported to inhibit pge 2 production and intracellular free ca 2+ concentration ([ca 2+ ]i) in a concentration-dependent manner with an ic 50 value of 3 m in c6 rat glioma cells [72] . in addition, several studies showed that a wide range of radix bupleuri preparations also exhibited antiinflammatory effects in in vitro and in vivo model. li et al. showed that saireito and its active components (ssd) could suppress the proliferation of mesangial cells and expansion of the mesangial matrix in the rat glomerulonephritis model [73] . in experimental chronic pancreatitis rats model, "chai-hu-shu-gan powder" exerted anti-inflammatory and antifibrotic effects by inhibiting the expression of nuclear factor-b (nf-b) and tnf-mrna in the pancreas [74] . furthermore, it also reduced the abnormally high plasma level of cholecystokinin, improved the gastric movement, and avoided nausea and flatulence [75] . in another experiment, a chinese herbal formula called "rcm-101" (containing flos magnoliae, radix bupleuri, radix glycyrrhizae, radix angelicae sinensis, etc.) inhibited the no production and inos protein expression in lps-stimulated rat aorta and raw 264.7 macrophages [76] . radix bupleuri also possessed anticancer/antitumor effect. the acetone extract of bupleurum scorzonerifolium could inhibit the proliferation of a549 human lung cancer cells in a dose-dependent manner via causing cell cycle arrest in the g2/m phase, increasing microtubule stabilization, suppressing telomerase activity, activating erk 1/2 and caspase-3/9 in a549 cells [77] [78] [79] . saponins isolated from radix bupleuri also exhibited significantly anti-proliferative activity in human non-small cell lung cancer a549 cells through fas-dependent apoptotic pathway [80] . su et al. found that the water extracts of radix bupleuri could enhance 5-fluorouracil-induced cytotoxicity in hepg2 hepatoma cells through cell arrest at the late g1/early s phase, while protecting normal blood lymphocytes [6] . ssd showed very potent activity against the hepg2 cell line with an ic 50 value of 12.5 mg/ml. the mechanism of cytotoxicity was attributed to the induction of apoptosis through activation of caspase-3 and caspase-7, which subsequently resulted in poly-adp-ribose polymerase (parp) cleavage [81] . sarcoplasmic/endoplasmic reticulum ca 2+ atpase (serca), leading to the increase of intracellular calcium ion levels and activating the ca 2+ /calmodulin-dependent kinase kinase--(camkk -) amp-activated protein kinase-(ampk-) mammalian target of rapamycin (mtor) signaling cascade, endoplasmic reticulum (er) stress, and unfolded protein responses (upr) [43] . several chinese medicine preparations containing radix bupleuri also have been traditionally used in the treatment of tumors and cancer. the water extracts of "long dan xie gan wan" exerted a significant growth inhibitory effect in hl60 and ht29 cancer cell lines, indicating that this formulation may possess some chemotherapeutic potential [83] . treatment with "xiao-chai-hu decoction" exhibited a significantly lower incidence of hepatocellular carcinoma and reductions in cancer pain and tumor size. the underlying mechanism of the antitumor activities is based on stimulation of the reticuloendothelial system (res) and is closely related of tnf production [84] [85] [86] . wen et al. reported that the acetone extract of radix bupleuri possessed a significant antivirus effect on acute respiratory tract infections with h1n1 virus infection and suppressed influenza a virus-induced rantes secretion in h1n1-infected a549 cells at a concentration of 100 and 200 g/ml, suggesting that radix bupleuri might be beneficial for the treatment of chronic inflammatory conditions followed by viral infection [10] . ssc has been reported to show effective anti-hbv activity through inhibiting dna expression of hbsag, hbeag, and hbv [81] . treatment with "xiao-chai-hu decoction" (20 g/ml, 3 days; 20 g/ml, 6 days) could inhibit the production of hbv ( < 0.0001) and the expression of hbeag. moreover, crude saponins of bupleurum chinense dc. could inhibit the replication of hbv ( < 0.0001) [87] . similarly, in another study, yin et al. showed that ssd isolated from the meoh extract of bupleurum chinense dc. exhibited significant bioactivity in inhibiting dna replication of hbv [88] . the antiviral activity of saikosaponins (a, b 2 , c, and d) and their mode of actin were examined. the results showed that all saikosaponins exerted antiviral activity on human coronavirus-229e at concentrations of 0.25-25 m, and the strongest activity was observed for saikosaponin b 2 with an ic 50 of 1.7 m. this mechanism might involve interference in the early stage of viral replication, such as absorption and penetration of the virus [89] . the water extract of radix bupleuri was reported to exert its antipyretic effect on dry yeastinduced high fever rats. the mechanism is related to the adjustment of synthesis and exudation of cyclic adenosine monophosphate (camp) and arginine vasopressin (avp) [90] . a novel in situ gel system for nasal delivery of the essential oil from radix bupleuri was prepared. the results suggested that radix bupleuri in situ gel can be more effective than the solution in the treatment of fever [91] . a similar study showed that the essential oil extracted from the herb exhibited dose-dependent antipyretic capacity on both fevered rabbits and rats [92] . the ethanol extract of bupleurum chinense dc. exerted a remarkable bacteriostatic effect on gram-negative microorganism helicobacter pylori. the bioactive minimum inhibitory concentration (mic) value was 60 mm [93] . saikosaponins isolated from radix bupleuri have been reported to exhibit antibacterial activity, particularly against pseudomonas aeruginosa and listeria monocytogenes. the protective effect was attributed to the immunomodulatory action on macrophages [94] . "chaihu injection" has also been tested for possible antimicrobial activity in vitro. the results demonstrated that mild inhibition of staphylococcus aureus was observed but no effects were observed against staphylococcus albus, neisseria gonorrhoeae, diplococcus pneumoniae, haemolytic streptococcus, or pseudomonas aeruginosa [95] . the liver protective effects against ccl 4 induced liver injury were investigated after treatment of mice with raw and vinegar-baked radix bupleuri (5 g/kg/day) for 14 days. the results showed that both raw and processed radix bupleuri showed liver protective effects against ccl 4 induced liver injury, and the vinegar-baked radix bupleuri exerted better effects than that of raw radix bupleuri [96] . pretreated with saikosaponins, especially ssa or ssd, showed remarkable inhibition of d-galactosamineinduced hepatic injury through decreasing the activity of glucose-6-phosphatase and nadph-cytochrome c reductase and increasing 5 -nucleotidase activity [97] . similarly, bupleurosides iii, vi, ix, and xiii and saikosaponin b 3 isolated from bupleurum scorzonerifolium willd. were also found to exhibit protective effect on the d-galactosamineinduced cytotoxicity in primary cultured rat hepatocytes [98] . further studies also demonstrated that the protective effects of saikosaponins isolated from bupleurum chinense dc. could prevent hepatocyte injury through regulating intracellular calcium levels [99] . in a rat model with ccl 4 induced acute hepatic injury, the hepatic enzyme levels (got, gpt, and alp) and the lipid peroxidation in the liver were significantly reduced by the administration of ssd [100] . additionally, ssd significantly reduced collagen i deposition and alanine aminotransferase level on liver fibrosis rats and decreased the concentration of transforming growth factor 1 (tgf-1). moreover, ssd was able to alleviate hepatocyte injury from oxidative stress. the effect of ssd on liver fibrosis may be related to its ability to reduce lipid peroxidation [101] . the effects of radix bupleuri on spontaneous lymphatic vessel activity. the results indicated that radix bupleuri significantly increased the amplitude of spontaneous activity of lymphatic vessels in a concentration-dependent manner, and the mechanisms of this effect seem to be independent of endothelial function [102] . eugenin ( ) and saikochrome a ( ) isolated from the meoh extracts from bupleurum scorzonerifolium possessed immunosuppressive effect on human peripheral blood t cells via inhibiting cd28-costimulated activation [62] . ssd (10 mg, intraperitoneally) significantly activated peritoneal macrophages in terms of enhancement of phagocytic activity, increased level of cellular lysosomal enzyme, and suppressed the response of plaque-forming cells to heterologous erythrocytes by stimulating t and b cells in a dose-dependent manner [103] . moreover, ssd modulated lymphocyte activity through suppressing the t cell response and increasing the b cell response to different mitogens and the interleukin-(il-) 2/il-4 production through a receptor-bypassed pathway [41, 104, 105] . in another experiment, wong et al. found that ssd was shown to inhibit okt3/cd28-costimulated human t cell proliferation and pma, pma/ionomycin, and con a-induced mouse t cell activation in vitro. the underlying mechanisms involved downregulation of nf-kb signaling by suppression of ikk and akt activities [106] . autophagy is a complex process in cells, which occurs through the formation of doublemembrane vesicles (autophagosomes), which are engulfed by cytoplasmic molecules. then, the autophagosome fuses with the lysosomes, leading to degradation of long-lived proteins, aggregated proteins, and damaged organelles [107] [108] [109] . moreover, autophagy might be triggered by hypoxia, nutritional deprivation, radiation, chemical drugs, and other stimulants [110] . autophagy contributes to the pathogenesis of diverse diseases, such as neuronal degeneration, inflammatory bowel disease, aging, and cancer [111, 112] . in the previous study, law et al. demonstrated that the protective pharmacological effects of radix bupleuri might be attributed to its autophagy induction. the autophagic effect of radix bupleuri played an important role in relieving liver disease-related symptoms through anti-inflammatory, organ-protective, and aggregate removal functions. furthermore, the anticancer effects of radix bupleuri could be attributed to its autophagy induction. radix bupleuri has been found to be an effective treatment against depression by regulating metabolite, hormone, and neurotransmitter levels via autophagy-mediated lipid metabolism [113] . the effect of the ethanol extract from radix bupleuri on cytochrome 450 isoform activities using a six-drug cocktail approach was evaluated; the results demonstrated that radix bupleuri had strong induction activity on the cyp2e1, cyp2d6, and cyp3a4, which may lead to potential plant drug-drug interactions [114] . radix bupleuri was shown to be the inhibitor ofglucuronidase. the inhibition rate of radix bupleuri extracts rb1 (high molecular weight polysaccharides), rb2 (ethanol soluble/water insoluble component), rb3 (extracted by nbutanol, soluble in water), and rb4 (low molecular weight water soluble parts) on the activity of -glucuronidase was found to be 45.15%, 33.94%, 24.94%, and 34.54%, respectively [115] . in pentylenetetrazol (ptz) induced epilepsy rats model, ssa isolated from radix bupleuri significantly reduced seizure severity and duration while it markedly elevated seizure latency and downregulated the cytokines expression of p-mtor, p-70s6k, l-1 , and tnf-through inhibiting mtor signaling pathway [116] . he et al. demonstrated that ssa obviously reduced lipoprotein uptake to block foam cell formation and the expression of lox-1 and cd36, boosted cholesterol efflux, and the expression of abca1 and ppar through inhibiting pi3k/akt/nf-b/nlrp3 signaling pathway [117] . in another experiment, ssc exerted a potent effect on inducing human umbilical vein endothelial cells (huvecs) viability and growth. furthermore, ssc also induced endothelial cells migration and capillary tube formation. the underlying mechanisms might be related to the gene expression or activation of matrix metalloproteinase-2 (mmp-2), vascular endothelial growth factor (vegf), and the p42/p44 mitogenactivated protein kinase (mapk, erk) [118] . in addition, ssc was shown to exhibit inhibitory activities against alzheimer's disease (ad) via suppressing the secretion of a peptides and abnormal tau hyperphosphorylation-mediated microtubule depolymerization. moreover, ssc suppressed a peptideinduced brain endothelial apoptosis, indicating that ssc might be a novel therapeutic tool for treating human ad and other neurodegenerative diseases [119] . it was shown by liu et al. for the first time that four polyacetylenes ( -) from radix bupleuri potently exhibited an antidepressant activity by inhibiting the reuptake of serotonin, norepinephrine, and dopamine. the mechanism might be mediated by increasing the level of monoamines, particularly 5-ht and ne [56] . zhu et al. suggested that ssa and ssd exhibited the anthelmintic activity against dactylogyrus spp. infecting goldfish. the effective concentration (ec 50 ) values for ssa and ssd were 1.46 and 0.74 mg â��1 , respectively [120] . bupleuri possesses a wide spectrum of pharmacological effects, including anti-inflammatory effect, anticancer effect, antiviral effect, antipyretic effect, antibacterial effect, hepatoprotective effect, and immunomodulatory effect (table 3 ). based on these pharmacological effects, we can conclude that the extracts and the compounds from this plant can prevent or treat certain diseases, such as cancer, fever, malaria, hepatitis, and ad. however, there is not enough systemic data of these chemical compounds and their pharmacological effects. thus, in the future, the pharmacological effects and the possible molecular mechanisms of the pharmacological activities of radix bupleuri must be urgently explored on our modern understanding of these diseases' pathophysiologies. radix bupleuri has been used for thousands of years as an important traditional herb in china. however, the toxic effects of radix bupleuri in clinical applications have been gradually reported. several studies have found that the liver is the main organ affected by toxicity, particularly in longterm use. major symptoms of liver injury induced by radix bupleuri included transaminase lifts, hepatitis, and jaundice. however, liver functions can return to normal levels after a specific period [121] . radix bupleuri has been reported to exhibit acute hepatitis and acute hepatic necrosis. the mean total daily dose was 18.0 â± 33.5 g, which was more than the chinese pharmacopoeia recommended range of 3 to 10 g [122] . moreover, radix bupleuri had been implicated in multiple cases of acute hepatitis both as an ingredient alone and within a particular formulation "xiao-chai-hu-tang" (also known as syo-saiko-to in japanese) [123] . lee et al. demonstrated that two chinese herbal products containing radix bupleuri might increase their risks of liver injury in hbv-infected patients. however, further mechanistic research on the hepatotoxicity of radix bupleuri in the presence of hbv infection is warranted [124] . in addition, the essential oil of radix bupleuri induced acute hepatotoxicity with asynchronous state, higher heart rate, and fast breathing [125] . the total saponins isolated from radix bupleuri could also cause evidently liver damage in dose-dependent manner manifested as hepatocyte organic lesion and liver function changes, as well as hepatocyte death [126] . a selective and sensitive lc-ms/ms method was developed and validated for simultaneous determination of ssa, b 2 , c, and d in rat plasma afteroral administration of the ethanolwater (50 : 50, v/v) extract of radix bupleuri for the first time. the results demonstrated that ssa, c, and d were absorbed rapidly with max less than 30 min [127] . in another pharmacokinetics experiment of rats, liu et al. was the first to develop an uplc-pda-ms method to determine the pharmacokinetics of four polyacetylenes after i.g. administration of 95% ethanol extract of radix bupleuri. the results showed that compounds and were not detected in rat serum, whereas compounds and exerted a fast distribution phase followed by a relatively slow elimination phase ( 1/2 , 4-7 h) [56] . in traditional chinese medicine, radix bupleuri has long been used regulate the exterior and interior metabolisms, disperse evil heat from superficies, sooth the liver, and promote yang and qi. it has been widely used to treat various diseases in china, japan, korea, and other asian countries for many centuries. a total of 74 compounds including essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids, and sterols have been isolated and identified from radix bupleuri . pharmacological studies have revealed that radix bupleuri possesses a variety of biological effects, including anti-inflammatory, anticancer, antiviral, antipyretic, antibacterial, antiobesity, immunomodulatory, hepatoprotective, neuroprotective, and autophagic effects . however, there are some aspects that need to be further investigated. radix bupleuri is an ingredient of many patent medicines or prescriptions. although modern experiments have confirmed that this drug alone exhibits multiple pharmacological activities, it is important to investigate the molecular mechanisms of radix bupleuri combined with other herbs based on traditional uses. furthermore, the pharmacological effects of only a few of the ingredients, such as saikosaponins, flavonoids, and the essential oils, have been investigated. some polyacetylenes, lignans, and sterols have not been sufficiently researched in terms of their pharmacological effects. radix bupleuri shows both hepatoprotection and in vitro [89] antipyretic effect dry yeast-induced high fever rats adjusts the synthesis and exudation of camp and avp in vivo [90] turpentine-induced fever rabbits decreases body temperature the essential oil in vivo [91] turpentine-induced fever rabbits and rats the essential oil in vivo [92] antibacterial effect in vivo [113] hepatotoxicity, which appears to be contradictory. this phenomenon is similar to that of polygonum multiflorum thunb. [128] . based on the literature, the main reasons are likely the administration dosage and delivery time. high doses and long-term drug delivery are more likely to result in liver toxicity, whereas low doses and short-term drug delivery might result in liver protection. therefore, this issue needs further study. in conclusion, this review summarized the traditional uses, botany, phytochemistry, pharmacology, and toxicology of radix bupleuri. moreover, it has provided a new foundation for further research on its mechanism of action and the development of better therapeutic agents employing radix bupleuri in the future. it is anticipated that the comprehensive and detailed research on toxicity, pharmacodynamics, pharmacokinetics, and molecular mechanism are necessary to be explored to develop its bioactive compounds as effective drugs. the authors have declared that there are no conflicts of interest regarding the publication of this paper. fude yang and xiaoxv dong contributed equally 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inhibiting the mapk and nf-b pathways in lps-stimulated raw 264.7 cells saikosaponin a inhibits lipopolysaccharide-oxidative stress and inflammation in human umbilical vein endothelial cells via preventing tlr4 translocation into lipid rafts saikosaponin c inhibits lipopolysaccharide-induced apoptosis by suppressing caspase-3 activation and subsequent degradation of focal adhesion kinase in human umbilical vein endothelial cells saikosaponin a protects against experimental sepsis via inhibition of nod2-mediated nf-b activation dual effect of saikogenin d: in vitro inhibition of prostaglandin e 2 production and elevation of intracellular free ca 2+ concentration in c6 rat glioma cells suppressive effects of saireito on monoclonal antibody 1-22-3-induced glomerulonephritis: analysis of effective components therapeutic effects and mechanisms of chaihushugan decoction in experimental chronic pancreatitis rats effect of chaihu shugan pulvis on dysfunction of pancreatic exocrine secretion in 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with chinese herbal products containing radix bupleuri in 639, 779 patients with hepatitis b virus infection acute toxicity of volatile oil from bupleurum chinense in rats and mice dose-time-toxicity" relationship study on hepatotoxicity caused by multiple dose of total bupleurum saponin crude extracts to rats analysis of saikosaponins in rat plasma by anionic adducts-based liquid chromatography tandem mass spectrometry method traditional usages, botany, phytochemistry, pharmacology and toxicology of polygonum multiflorum thunb.: a review this work was financially supported by the collaborative innovation construction plan of beijing university of chinese medicine (no. 2013-xtcx-03). key: cord-299007-5m6lk409 authors: paterson, r. russell m. title: cordyceps – a traditional chinese medicine and another fungal therapeutic biofactory? date: 2008-05-31 journal: phytochemistry doi: 10.1016/j.phytochem.2008.01.027 sha: doc_id: 299007 cord_uid: 5m6lk409 abstract traditional chinese medicines (tcm) are growing in popularity. however, are they effective? cordyceps is not studied as systematically for bioactivity as another tcm, ganoderma. cordyceps is fascinating per se, especially because of the pathogenic lifestyle on lepidopteron insects. the combination of the fungus and dead insect has been used as a tcm for centuries. however, the natural fungus has been harvested to the extent that it is an endangered species. the effectiveness has been attributed to the chinese philosophical concept of yin and yang and can this be compatible with scientific philosophy? a vast literature exists, some of which is scientific, although others are popular myth, and even hype. cordyceps sinensis is the most explored species followed by cordyceps militaris. however, taxonomic concepts were confused until a recent revision, with undefined material being used that cannot be verified. holomorphism is relevant and contamination might account for some of the activity. the role of the insect has been ignored. some of the analytical methodologies are poor. data on the “old” compound cordycepin are still being published: ergosterol and related compounds are reported despite being universal to fungi. there is too much work on crude extracts rather than pure compounds with water and methanol solvents being over-represented in this respect (although methanol is an effective solvent). excessive speculation exists as to the curative properties. however, there are some excellent pharmacological data and relating to apoptosis. for example, some preparations are active against cancers or diabetes which should be fully investigated. polysaccharides and secondary metabolites are of particular interest. the use of genuine anamorphic forms in bioreactors is encouraged. too much about cordyceps is unsubstantiated. this literature is written to sell so-called medicines to potentially vulnerable people with serious diseases. on the other hand, there is convincing scientific information that indicates significant pharmacological properties which are worth assessing (see table 1 ). the present large review undertakes this task and deals with papers that use the name cordyceps sometimes in its most general sense, especially when the revision of sung et al. (2007) is considered. there follows an extended introduction to the topic. the title relates to another in this journal concerning the fungal traditional chinese medicine (ftcm), ganoderma (paterson, 2006) . in that case, the fungus was indeed a biofactory in the sense that numerous compounds have been reported from the fungus. what is the situation with another ftcm, cordyceps? the immediate answer is that the state of the art is considerably less developed (see table 2 for a list of secondary metabolites). there is a general impression that this fungus is being used in a modern context, before the benefits, and even what is being used, have been determined scientifically. cordyceps is one of a growing number of ftcm being considered as cures for modtable 1 medically related purported effects of various cordyceps taxa (or preparations) as described by various authors ern human diseases. many commercial products are available in the market (e.g. didanosine from cordyceps militaris). these nutraceuticals are considered to relieve the ''stress for humans of living in technologically developed societies" by stimulating basic and secondary responses of the immune system (lakhanpal and rana, 2005) . the fungus represents a genus of perithecial ascomycetes (phylum ascomycota) classified in the clavicipitaceae, a monophyletic group included in the order hypocreales. the genus contains over 400 species and the anamorphs of most are unknown. paecilomyces is considered traditionally to host the anamorphs but this has been disputed. sung et al. (2007) should be consulted for an up-to-date revision (and see later). cordyceps are parasites of insects or fungi, often exhibiting a high degree of host specificity (fig. 1) . however, the cordyceps species associated with lepidopteran hosts do not represent a monophyletic group. there is even a high degree of genetic variation within cordyceps sinensis which creates difficulties in verifying samples. a taxonomic review of the fungus is now available (see later section) a similar review is required for ganoderma (e.g. see paterson, 2006 . larval infection via meiotic and/or mitotic spores/conidia and multiplication within the insect is from yeast-like budding. however, the fungus grows through the insect by hyphae. the accumulation of the biomass eventually kills the host (and/or a toxin(s) may be involved). it would be interesting to determine the biochemical parameters that cause these changes but this is not reported in the literature. the fungus ruptures the host body following over wintering and forms the sexual perithecial stroma that are connected to the dead larva below ground which grow upward to emerge above the soil surface (fig. 1) . the complete insect/fungus combination is used traditionally, but not exclusively, for medicinal purposes. the present reviewer has seen no reports of the insect per se being given as a treatment. c. sinensis (berk.) sacc., is one of the most famous traditional chinese medicines (tcm) and health foods. the fungus parasitises larvae of moths (lepidoptera), especially hepialus armoricanus (and thitarodes), and converts each larva into a sclerotium, from which the stroma and fruitbody grows. the complex (including the larva body) has been used as a health food and traditional medicine to ''invigorate the lung and nourish the kidney" in china for hundreds of years, and at least from the 17th century (dong and yao, 2007; kuo et al., 1994) . although what these preparations actually represented is impossible to determine given the difficulties in taxonomy of even modern times (burnett, 2003; korf, 2005 ; and see sung et al., 2007) . understandably, conservation and sustainable harvest are important issues. there is need for (a) research on biological screening, (b) a better understanding of the status in natural habitats, and (c) artificial cultivation of the fungus. cordyceps and products are available in ''western" countries as over-the-counter medicine/tonics which advertise them as chinese herbs with anti-aging, ''pro-sexual", anti-cancer and immune boosting effects, although with poor supporting scientific evidence. the believe is that c. sinensis (cs) has various beneficial effects on humans, including those of a psychological nature. the ftcm, is also called dong chong xia cao in chinese (=winter worm summer grass) (li et al., 2006a) . primarily it is prescribed as a tonic for body strengthening after serious disease. more recently other treatments have been claimed such as for (a) respiratory, renal, liver, nervous system and cardiovascular diseases, and (b) tumours, aging, hyposexuality and hyperlipidemia (kuo et al., 2006; chen et al., 2006; wang and shiao, 2000) . it has been officially classified as a drug in the chinese pharmacopoeia since 1964. furthermore, the outbreak of the severe acute respiratory syndrome (sars) in china in 2003 has increased use considerably. this would have been an excellent opportunity to have determined how effective it was. however, this does not appear to have been undertaken. the market demand for cs is growing sharply in many countries (dong and yao, 2007) . they would surely be hailed as medical breakthroughs if the efficacy of any of these treatments were confirmed. nevertheless, the identities of active components have not been determined (in all cases) (li et al., 2006b) . research has shown that at least some of the traditional uses ''may" relate to pharmacological activities (zhu et al., 1998a,b) (if not pharmacological activities then what?). herbs have been used throughout history to enhance physical performance, but scientific scrutiny with controlled clinical trials has only recently been used to study such effects (bucci, 2000) . the authors mention that cordyceps remain untested which is surprising given the interest in the fungus. the fungus is endemic to the alpine habitats of the tibetan plateau above 3000 m in south-western china, and there has been large-scale harvesting of the wild material from nepal and india more recently. it is agreed generally table 2 example of the range of species and some of the low molecular-weight secondary metabolites from cordyceps secondary metabolites c. sinensis cyclic peptides, h1-a c. militaris cyclic peptides, cordycepin, 10-membered macrolides, cepharosporolides c, e and f, pyridine-2,6-dicarboxylic acid and 2carboxymethyl-4-(30-hydroxybutyl) furan, dipicolinic acid c. pseudomilitaris bioxanthracenes c. brunnearubra cordyformamide c. sinclairii (2s,3s,4r)-(e)-2-amino-3,4-dihydroxy-2hydroxymethyl-14-oxoeicos-6-enoic acid c. cicadae ergosterol peroxide c. nipponica cordypyridones a and b c. ophioglossoides ophiocordin, glycoprotein containing nacetylgalactosamine c. heteropoda cicadapeptins i and ii, myriocin the number of compounds is small compared to that for ganoderma (paterson, 2006) . to have been over-harvested. furthermore, the price of natural products of cs is over us$ 12,000 kg à1 (2006 prices) for only ''average quality" (how this is determined is not clear) in the market and increasing (sharma, 2004) . so one can understand the pressures on supply. the socioeconomic implications of the ftcm are highly significant to the regions where it is harvested. the fungus has officially been classified as an endangered species by cites management authority of china and china customers and this scarcity is of considerable concern to all. consequently, living strains have been isolated from natural cs and cultivated in large quantity by bioreactor technology which is a promising method to meet the needs of human consumption and to reduce the pressure on natural resources of the species (dong and yao, 2007) . in vitro culture of the fungus has been employed increasingly and yang et al. (2005) state, ''it is generally accepted that its cultivated cs fungi possess the same functions as cs natural ''herbs" (sic)". some other issues that require addressing are that natural c. militaris is not readily available and is costly. thus, a growing number of socalled cordyceps products that derive from mycelial cultures of the asexual forms of these fungi have become commercially available (hamburger, 2007) . mycelia cultivation has resulted in establishing a number of cultures derived from the holomorphic cs. these are referred to by the anamorphic names paecilomyces hepiali and cephalosporium sinensis, although the anamorph of cs appears to be hirsutella sinensis (and see later). however, the situation is confused with some taxonomist using outdated names. to paraphrase buenz et al. (2004 buenz et al. ( , 2005 : while these strains undoubtedly support ecologically sustainable use of cs, the actual similarities between the wild fungus and the cultures are not clear. the consumption of complimentary medicine has increased dramatically, with over 42% of people in the united states of america reported as ''users". sales were us$ 3.3 billion in 1999 (buenz et al., 2005) . an important factor was the passage of the dietary supplement health and education act in 1994 in the usa which opened the market for tcm (cooper and chang, 2001) . one can appreciate how journals advocating these have increased concomitantly. why have they not been developed by big pharmaceutical companies and made available to the public in pure compound form? no doubt there could be many reasons why this has not happened (e.g. not enough profit, ''sticky" intellectual property rights issues (see paterson, 2008) , difficulty in mass production or synthesis, etc.)apart from the possibility that they simply may not be effective. buenz et al. mention that ''one of the most interesting supplements is the not yet well-characterized c. sinensis (berk.) sacc.". cs has attracted much research interest for anti-oxidant activity and there is considerable evidence of this from the fungus as a treatment of a wide range of diseases. however, unauthenticated material has been used in some cases. for example, a polysaccharide was isolated which can protect pc12 cells against hydrogen peroxide-induced neuronal cell toxicity, but the cordyceps mycelia used was from the wan fong pharmaceutical factory (zhejiang, china) and derived from ce. sinensis chen sp. nov. this is a nomenclaturally illegitimate fungal name, which raised doubts as to its relationship to cs. in fact, it was later proved to be a different species (dong and yao, 2007) and this is a specific example of a general problem in the field. an example of another problem is cordymax cs-4, a commercial mycelial fermentation product that lowered fasting plasma levels of glucose and insulin, improved oral glucose tolerance and increased the glucose-insulin index, which measures insulin sensitivity, in rats (zhao et al., 2002) . however, the following statement is given on the web site of the product, ''these (health-related) statements have not been evaluated by the food and drug administration. this product is not intended to diagnose, treat, cure or prevent any disease". extracts from artificially cultivated fruit-bodies of cs from the xinhui xinhan artificial cordyceps factory (guangdong, china) could scavenge ros by inhibiting malondialdehyde formation by the peroxynitrite generator sin-1. these results have been since referred to uncritically (e.g. buenz et al., 2004 buenz et al., , 2005 li et al., 2003) . however, the fungal material may have been unauthentic, because reports exist that cultivation of fruit-bodies of this fungus was not repeatable and that the manufacturer is actually selling c. militaris. furthermore, li et al. (2001) compared the anti-oxidant activities of natural cs and cultured cordyceps mycelia from different sources and were able to show the similar effects of the cultured mycelia to the natural products. however, the cultured material used was derived from a wide range of strains, and not from a valid cs. some of these were products from the chinese medicine factory of jiangxi and hebei boding pharmaceutical factory. in addition, the ftcm are boiled in water or soaked in alcohol to drink for medications/health foods. obviously, the various solvents and temperatures may have resulted in different compounds (dong and yao, 2007) . nevertheless, guo et al. (2007) state that the ongoing exploration of cs has shown that the species can produce ''many" bioactive compounds, and the medicinal benefits of cs have been demonstrated extensively. in addition, there is (unbelievably for scientific journals) the use of words such as ''yin" and ''yang" as a basis for undertaking scientific research on material activities. canney (2006) discusses kidney ''yang" and one needs to ask what this is from a scientific perspective. why include this word when it has no scientific currency? the fungus is also referred to as a herb and indeed the title of the piece asks, ''c. sinensis animal, vegetable or both?", whereas it is neither. various bioactive constituents from cordyceps species have been reported. these include cordycepin and other anti-bacterial and anti-tumour adenosine derivatives, ophicordin, an anti-fungal agent, and l-tryptophan. recent reports have indicated that cs contains polysaccharides exhibiting anti-oxidant activity and nucleosides that inhibit platelet aggregation (wu et al., 2005) . the bioactive compounds involved in the activities claimed include polysaccharides, modified nucleosides, and cyclosporin-like metabolites which are produced by this fungus and related species. the beneficial effects on (a) renal and hepatic function and (b) immunomodulation-related anti-tumour activities are most promising and deserve great attention. an increasing number of studies have used cultured mycelia in investigations. more mechanism-based, disease-oriented pharmacological studies are required to ensure clinical efficacy for particular diseases. however, pang et al. (2002) state revealingly that studies have demonstrated repeatedly that many natural products marketed as nutraceuticals or health food do not deliver the health benefit as claimed and are inconsistent from batch to batch. in the popular mind, cs first gained worldwide attention when it was revealed that several chinese runners who broke world records in 1993 had included this fungus in their diet as part of their training program. although scientist need to desist from quoting such reports as they are unsubstantiated and far-fetched. purported and unsubstantiated effects of the fungus include use as an aphrodisiac, analgesic, immune modulator, and free radical scavenger. a review of the literature uncovers the predictable collection of general papers concerning medical mushrooms some with a distinctly ''alternative" flavour. i have no concerns about being alternative but are they scientific? these overviews often are written in breathless, overblown and unscientific terms; others are well balanced. dasilva (2005) talks about ''novel mushroom-based healthcare products and therapeutics licensed for medical use can contribute to the good health status and feeling of the povertystricken strata of urban societies and populations. indeed, mushroom cultural practices and medicines are being widely accepted as the integral skeins in the fabric of the human society of tomorrow". a valid response to this situation of a wide range in the quality of papers would be to only review those papers that have a high impact factor (or any impact factor). temporarily putting the debate about the value of impact factors to one side, the reader may find it beneficial to concentrate only on those journals reviewed herein that do indeed have such ratings. of course, the disadvantage is that valuable information may be missed. it may be worth mentioning that, asian nations on the world stage have realised that biomedicine offers a unique chance to develop new industries and markets. universities in singapore, korea, hong kong and china are appearing concomitantly in world tables for the best and citations data suggest they are producing well-regarded papers (ince, 2007) . the following review concentrates on the biological activity of various preparations of cordyceps spp. (the name as used in the essentially non-taxonomic papers) because of the quantity of data and importance of medicinal claims, at the expense of taxonomic and quality control issues. the various pure compounds, extracts, whole fungus and other preparations as they relate to pharmacological activities are discussed next, as these divisions are considered to be most relevant to a biochemical/phytochemical perspectives of the topic. data from pure compounds are the most revealing in terms of determining effects of the fungus/insect. it is noted that these reports are scarce. some compounds from cordyceps (as defined here) are not particularly unusual. ng and wang (2005) review the chemical constituents and pharmacological properties. the chemical constituents include (a) cordycepin (3 0 -deoxyadenosine) and its derivatives, (b) ergosterol, (c) polysaccharides, (d) a glycoprotein and (e) peptides containing a-aminoisobutyric acid. the activities ascribed to the fungus are anti-tumour, antimetastatic, immunomodulatory, anti-oxidant, anti-inflammatory, insecticidal, anti-microbial, hypolipidaemic, hypoglycaemic, anti-aging, neuroprotective and renoprotective effects: so a vast a range of properties from a narrow spread of compounds. polysaccharides account for the anti-inflammatory, antioxidant, anti-tumour, anti-metastatic, immunomodulatory, hypoglycaemic, steroidogenic and hypolipidaemic effects. cordycepin contributes to the anti-tumour, insecticidal and anti-bacterial activity. ergosterol (a universal fungal compound) exhibits anti-tumour and immunomodulatory activity. finally, a dnase has been characterized. these are not particularly novel compounds and one wonders why there are so many reports of the effects of crude extracts rather than much more work on the effects of novel pure compounds. cordycepin (fig. 2) , 3-deoxyadenosine, is a derivative of the nucleoside adenosine differing from the latter by the absence of oxygen in the 3 0 position of its ribose entity. as such is may be quite common. initially, it was extracted from cordyceps; however, it is now produced synthetically. some enzymes do not discriminate between adenosine and so it can participate in certain reactions. for example, it can be incorporated into rna molecules causing premature termination of its synthesis. it is classified as an anticancer compound. cordycepin inhibited the growth of clostridium paraputrificum and clostridium perfringens, but had no effect on bifidobacterium spp. and lactobacillus spp. (ahn et al., 2000) . in addition, larvicidal activity against plutella xylostella after 2-4 days of treatment was observed . it is interesting that cordycepin, a compound originally isolated from c. militaris as much as 60 years ago (cunningham et al., 1950) , is known to exert cytotoxic effects through nucleic acid methylation (kredich, 1980) , with possible implications for the pcr of these fungi (see paterson, , 2008 . if it is a truly useful compound it is surprising that it is not a well-known pharmaceutical by now. the presence of cordycepin in cs has been difficult to confirm, although it has been confirmed by nmr (chen and chu, 1996) . however, other groups have not been able to detect this compound . it is clearly important to confirm the presence of the compound in cs in terms of determining the active components of the fungus and ultimately for chemotaxonomic purposes. cho et al. (2007) state that cordycepin is isolated from c. militaris and is (claimed to be) an ingredient in tcm which is prescribed for various diseases, such as cancer and chronic inflammation (again note how vague this verbatim statement is). in this study, the novel effect of cordycepin inhibiting collagen-induced platelet aggregation was reported. the data suggests that the inhibitory effect of cordycepin might be associated with the down-regulation of [ca 2+ ]i and the elevation of camp/cgmp production. this result has obvious significance for prevention of thrombus formation. finally, cordycepin inhibited the growth of b16 melanoma cells inoculated subcutaneously into right murine footpads (yoshikawa et al., 2004) . cordyheptapeptide a (fig. 3) , a novel cycloheptapeptide, was isolated from a strain of cordyceps together with four known bioxanthracenes. there were only two previous reports on the isolation of cyclic peptides from this genus and these were from c. militaris and cs. the metabolite exhibited anti-malarial activity against plasmodium falciparum and cytotoxicity to vero cell lines. also, the anti-malarial and cytotoxic activities of the bioxanthracenes were reported (rukachaisirikul et al., 2006) . in an extensive and impressive report, compounds designated as es-242s, were isolated from a verticillium strain and identified as bioxanthracenes (isaka et al., 2007a) . these compounds were known to exhibit potent activity as n-methyl-d-aspartate (nmda) receptor antagonists. in addition, five novel es-242 analogues were isolated with nine known compounds from a cordyceps strain. a closely related strain provided cordyheptapeptide a, cordyheptapeptide b, and known es-242s. the structures of the novel bioxanthracenes were 6 0 -o-desmethyl analogues of the compounds described. furthermore, cordyheptapeptide b has an n-methyl-l-phenylalanine residue in place of the n-methyl-l-tyrosine. the isolation, structure elucidation, and anti-malarial activity of es-242s and their analogues from the insect pathogenic fungus cordyceps pseudomilitaris (from a lepidoptera larva) were reported previously. cycloheptapeptide, cordyheptapeptide a, and some known es-242s were isolated from a cordyceps strain from an elaterid larva. in a continuing search for bioactive compounds from insect pathogenic fungi it was noticed that culture extracts of six cordyceps strains, collected in the same location (from coleoptera larvae, at doi innthanon national park, chiang mai province, thailand), showed similar 1h nmr spectra. this suggested the presence of bioxanthracenes (es-242s) and cordyheptapeptide a as major constituents. two of these strains were subjected to mass fermentation (15 l) and chemical investigation. as a result, five new es-242 analogues and nine known compounds and cordyheptapeptide a were isolated from an undefined strain. cordyheptapeptide b, was isolated, together with other known compounds. some of these were tested for activity against p. falciparum and cytotoxicity to kb cells (oral human epidermoid carcinoma), bc cells (human breast cancer), nci-h187 cells (human small cell lung cancer), and noncancerous vero cells (african green monkey kidney fibroblasts). cordyheptapeptide a exhibited antimalarial activity, while cordyheptapeptide b was inactive and both cyclic peptides showed moderate cytotoxicity. furthermore, cordyformamide is a plausible biogenetic precursor of xanthocillin y, and was isolated from a culture broth of cordyceps brunnearubra bcc 1395. cordyformamide was found to exhibit activity against p. falciparum, whereas it showed weak or no cytotoxicity (isaka et al., 2007b) . production of the nonribosomal peptides cicapeptins i and ii (fig. 4) were reported by krasnoff et al. (2005) which was the first report from fungi of consecutive hyp or pro residues in a nonribosomal linear peptide. the compounds exhibited anti-bacterial and anti-fungal activity. a novel immunosuppressant was isolated from the culture broth of isaria sinclairii, the anamorph of c. sinclairii, and characterized as (2s,3s,4r)-(e)-2-amino-3,4-dihydroxy-2-hydroxymethyl-14-oxoeicos-6-enoic acid, which was identical to anti-fungal substances, myriocin and thermozymocidin (fujita et al., 1990) . the suppressive activity was found to be equal to, or higher than cyclosporin a which is used clinically. the activities of the 10 derivatives were also examined, indicating the following relationships between structure and activity -the: (a) lactone formation between the carboxy group at c-1 and the hydroxy group at c-4, and the reduction of the carbonyl group at c-14 to the hydroxy group do not affect the suppressive activity; (b) hydrogenation of the double bond at c-6 resulted in activity; and (c) acetylation of the amino group and the thioketalization on the carbonyl group at c-14 ''drastically" reduced the suppressive activity. also, the compound suppressed the production of anti-bodies to sheep red blood cells and induction of cytotoxic lymphocyte t cells more strongly than cyclosporin a. obviously, this is an important lead compound and hence one of the more satisfactory papers. chen et al. (1999) isolated a pure compound (h1-a) from cs and investigated whether autoimmune disease progression in mice was affected by administration of the metabolite. the authors are vague as to what the compound is and state that, ''it is a kind of ergosterol and looks like testosterone". the authors also provide a chemical structure which confirms that it is a common sterol and a systematic name could have been provided. their results demonstrated that mice treated daily exhibited a progressive reduction in anti-ds-dna production. in clinical presentation, the treated group had a reduction in lymphadenopathy, a delayed progression of proteinuria, and an improvement in kidney function. histological analysis of kidney tissue indicated that h1-a inhibited mesangial proliferation that was evident in lupus nephritis. however, there was no change in immune complex deposition. h1-a ''may be" useful for treating systemic lupus erythematosus in human patients. however, more work is required. h1-a was claimed to be effective in the treatment of autoimmune disorders (yang et al., 2003) . results demonstrated inhibition of cell proliferation and promotion of apoptosis of activated human mesangial cells in vitro: the activities were not a result of cytotoxicity. in addition, h1-a inhibited tyrosine phosphorylation of human mesangial proteins. these findings suggest that h1-a modulated some (unspecific) subcellular signal-transduction pathways and changed the balance between proliferation and apop-tosis of mesangial cells in vitro and in vivo. the conclusions were that h1-a may be effective in the management of autoimmune disorders, and the modulation of the signal-transduction proteins may represent a target for future pharmacologic interventions. more correctly, they probably do represent a target, and such vague statements should be avoided. in an older report, hi-a alleviated immunoglobulin a nephropathy (berger's disease) with histological and clinical improvement . hi-a inhibited the proliferation of human mesangial cells and promoted apoptosis by suppressing tyrosine phosphorylation of bcl-2 and bcl-xl (yang et al., 2003) and reduced antids-dna production and lymphadenopathy, delayed progression of proteinuria, improved kidney function and inhibited mesangial proliferation . moving on to more interesting compounds, cordypyridones a and b were detected from the uncommon species, c. nipponica. these are atropisomers, and demonstrated potent anti-malarial activity in vitro (isaka et al., 2001b) . shin et al. (2001) state that, ''in an effort to evaluate the pharmacological effects, including the anti-aging effect" of the fruiting bodies of the cultivated paecilomyces japonica fungus, ''a new type" of cordyceps sp. was investigated. two pure compounds were isolated as active principles from low molecular-weight fractions, and a protein-bound polysaccharide that showed a marked increase in the liver enzyme activities, and a significant inhibition of lipid peroxidation was found. boros et al. (1994) reported that ophiocordin, an anti-fungal antibiotic from cordyceps ophioglossoides (kneifel et al., 1977) and balanol from verticillium balanoides are structurally identical. this may indicate a particularly close taxonomic relationship between the two taxa. the structure of ophiocordin was falsely assigned and balanol was the compound of interest. balanol was under development as an anti-cancer agent as it established to be a selective inhibitor of protein kinase c (see paterson, 2008) . it is more common for pure compounds to be tested in the fields of anti-bacterial, anti-fungal, anti-malarial and insecticidal activity which is to be recommended more generally. ophiocordin is an anti-fungal antibiotic isolated from submerged cultures of c. ophioglossoides. however, it is devoid of anti-bacterial activity (kneifel et al., 1977) . bioxanthracenes (see also previously) were isolated from c. pseudomilitaris (isaka et al., 2001a; jaturapat et al., 2001) and appear to be anti-malarial. ten-membered macrolides, cepharosporolides c, e and f, cordycepin, pyridine-2,6-dicarboxylic acid and 2-carboxymethyl-4-(30hydroxybutyl) furan were reported from c. militaris by rukachaisirikul et al. (2004) . however, only cordycepin was anti-malarial. krasnoff et al. (2005) reported cicadapeptins i and ii (nonribosomal peptides containing aminoisobutyric acid), which were anti-bacterial and antifungal, and myriocin (anti-fungal) from c. heteropoda isolated from an australian cicada. finally, a glycoprotein containing n-acetylgalactosamine was isolated from c. ophioglossoides but activity data are not available (kawaguchi et al., 1986 ). an inhibitor of the prophenoloxidase activation was isolated from a culture filtrate of c. militaris and identified as dipicolinic acid (dpa). the production of dpa in a range of clavicipitaceae fungi was examined. entomogenous fungi that produce dpa were integrated into one group by a phylogenetic analysis based on 18s rdna. interestingly, it was suggested that the group acquired an ability to produce dpa during its evolution from plant pathogenic fungi to entomogenous fungi (watanabe et al., 2006) . in a useful comparison of crude extracts and pure compound, the anti-diabetic effect of various fractions of c. militaris, ccca (crude cordycepin containing adenosine), cmess (ethanol soluble supernatant), and cordycepin were evaluated in diabetic mice (yun et al., 2003) . cmess showed a potent inhibitory activity of 34.7% in starchloaded mice: cmess reduced blood glucose level by 35.5%. however, ccca, and cordycepin showed no difference. after 7 days administrations of these drugs, cmess, and cordycepin dramatically reduced blood glucose level. ccca with a high concentration of cordycepin did not reduce blood glucose level. proliferation of t-lymphocyte was significantly decreased; while no production was increased more than two-fold in the cordycepin-administered group. the proliferation of macrophages and no production were significantly decreased in the cmess administered group. cmess and cordycepin may be (a) useful tools in the control of blood glucose level in diabetes and (b) promising new drugs as an anti-hyperglycemic agent without the defects of lowered immune responses and other side effects, the authors suggest. furthermore, cordycepin, 3 0 -amino-3 0 -deoxyadenosine, homocitrullyl aminoadenosine, adenine, cordycepic acid and d-mannitol have been reported from cordyceps spp. (cunningham et al., 1950; chatterjee et al., 1957; kredich and guarino, 1961; guarino and kredich, 1963; kaczka et al., 1964; liu et al., 1989) . ergosterol peroxide isolated from c. cicadae inhibited phytohaemagglutinin-induced t cell proliferation, and arrested the progression of activated t cells from g1 to s phase of the cell cycle. early gene transcripts, in particular those of cyclin e, interferon, and interleukins were suppressed (kuo et al., 2003) . the glycosylated form of ergosterol peroxide from cs was more potent than the aglycone in inhibiting proliferation of tumour cells (bok et al., 1999) . however, ergosterol peroxide is widespread in fungi and cordyceps does not offer any particular advantage in its preparation. it is worth noting that eight different cordyceps species (cs. c. militaris, c. cicadae, c. ophioglossoides, c. heteropoda, c. pseudomilitaris, c. nipponica, c. sinclairii) are listed in the above paragraph indicating the extent of the possible diversity involved in the biology and activity (tables 1 and 2) . although whether they are distinct species is open to question. water-soluble crude polysaccharides were obtained from the fruiting bodies of cultured c. militaris by hotwater extraction followed by ethanol precipitation. the polysaccharides were successively purified by chromatography giving three polysaccharide fractions. in the in vitro anti-oxidant assay, p70-1 was found to possess hydroxyl radical scavenging activity. the polysaccharide is a heteropolysaccharide and is occasionally branched. the fundamental information obtained from this work is beneficial to the interpretation in the relationship of polysaccharide structure and its biological functions. this provides the ''experimental evidence and scientific explanation for the folkloric uses of c. militaris as a substitute for cs" (yu et al., 2007a) . the effect of an exopolysaccharide fraction (epsf) from anamorphic strains of cs on the immunocyte activity of tumour-bearing mice was investigated. epsf significantly inhibited the h22 tumour growth, and elevated the activity of immunocytes. it enhanced the phagocytosis capacity of peritoneal macrophages and proliferation ability of spleen lymphocytes. epsf promoted (a) tnf-a expression of macrophages, (b) the cytotoxicity of spleen lymphocytes, and (c) tnf-a and ifn-c mrna expression of splenic lymphocytes . cs possesses anti-tumour, anti-oxidation and stimulation of the immune system activities . however, the identity of active component(s) has not been determined . towards this end, a polysaccharide was isolated from cultured cordyceps mycelia which had strong anti-oxidation activity, and which contained glucose, mannose and galactose. the pre-treatment of the isolated polysaccharide on cultured rat pheochromocytoma cells demonstrated strong protective effect against hydrogen peroxide (h 2 o 2 )-induced insult. treatment prior to h 2 o 2 exposure significantly elevated the survival of pc12 cells in culture. this was the first report that identified a polysaccharide from cordyceps, which protected against the free radical-induced neuronal cell toxicity. a water-soluble polysaccharide fraction, a poorly water-soluble polysaccharide, and a protein fraction stimulated steroidogenesis (huang et al., 2001b) . interestingly, galactomannans isolated from the insect portion of c. cicadae demonstrate potent hypoglycaemic activity in mice (kiho et al., 1990) . in an investigation into a polysaccharide from cs mycelium hypocholesterolaemic and hypotriglyceridaemic activity in mice was exhibited (kiho et al., 1996) . chen et al. (1997) studied a polysaccharide fraction from cs as to its effect on the proliferation and differentiation of human leukaemia cells using an in vitro culture system. the conditioned medium had an activity that significantly inhibited proliferation. differentiated cells also possessed phagocytosis functions and supported superoxide production. antibody neutralization studies further revealed that the tumouricidal and differentiating effects of the compounds were mainly derived from the elevated cytokine concentrations. finally, galactosaminoglycan from c. ophioglossoides reacted with sera from patients with certain collagen diseases and its use as an index of serological activity is thus of diagnostic value (ikeda et al., 1993) . an aqueous extracted polysaccharide from cultured c. militaris demonstrated general anti-inflammatory activity (yu et al., 2004a) as did ethanolic extracts of cultured fruiting bodies and mycelia of c. militaris applied topically in the croton oil-induced ear oedema test in mice. the fact that in vitro fruiting bodies were employed rather than in vivo is interesting as most papers report using fruiting bodies in vivo and/or in vitro biomass. however, the paper is flawed as the details of the cultivation of the fruiting bodies were not provided. antioxidant activity in the xanthine oxidase, haemolysis and lipid peroxidation assay systems was demonstrated by li et al. (2001a) from water extracts, and a polysaccharide fraction, of cultured cs mycelia. interestingly, the fruiting body and the caterpillar parts of cs are claimed to be similar in chemical composition and hence anti-oxidant activity, because the fungus had presumable replaced the insect constituents with fungal . it would be interesting to determine (a) how this occurs in terms of insect substrate utilisation and optimisation of yields of bioactive fungal components, (b) when the preparation is at the correct stage for use as a medicinal treatment, and (c) if these data could be extrapolated to in vitro culture. an ambiguous statement is made by shin et al. (2001) , ''cordyceps is negative for its many biological activities and a tonic for restoring vital functions in traditional chinese medicine". it proceeds to state that p. japonica is a new type of cordyceps species, which is incomprehensible. it also mentions that p. japonica is (or produces) mushrooms. paecilomyces is considered to be an anamorph of cordyceps and so this appears to be incorrect and, what appear to be mushrooms, may be synnemata (compacted conidiophores). however, it is unwise to speculate what the material actually is as descriptions are vague. a protein-bound polysaccharide that inhibited lipid peroxidation and increased the activity of anti-oxidant was described from the fungus. finally, phaeochromocytoma cells were protected against h 2 o 2 -induced injury by a 210-kda polysaccharide from cs mycelium . yamada et al. (1984) reported that a water-insoluble extracellular glucan isolated from the culture filtrate of c. ophioglossoides suppressed potently the growth of sarcoma 180 solid-type tumours. remarkably, a protein-bound polysaccharide fraction from c. ophioglossoides extended the life of mice bearing ehrlich carcinoma or a syngeneic tumour . also, ohmori et al. (1989a,b) isolated a galactosaminoglycan that inhibited the proliferation of sarcoma 180 cells and the growth of a syngeneic solid tumour in vivo: it exhibited cytotoxicity against cancer cells in vitro. chen et al. (1997) observed that medium from blood mononuclear cells stimulated with the polysaccharide fraction from cs inhibited the proliferation of human leukaemic cells, and induced approximately 50% to differentiate into mature monocytes/macrophages expressing non-specific esterase activity and certain surface antigens. the anti-proliferation and differentiating effects were demonstrated to be caused by an elevated production of cytokines, i.e. a tumour necrosis factor and an interferon. the exopolysaccharide fraction of cs inhibited metastasis of melanoma cells and down-regulated concomitantly the levels of bcl-2 protein into the lungs and the liver . the exopolysaccharide fraction of cultivated cordyceps stimulated peritoneal macrophages to take up neutral red and splenic lymphocytes to proliferate . crude and neutral polysaccharides of cs exerted hypoglycaemic activity in normal mice. however, the polysaccharide did not affect the circulating insulin level in normal mice (kiho et al., 1993) . the compound lowered the plasma glucose level in diabetic mice (kiho et al., 1996) . another unspecific polysaccharide from a hot-water extract of mycelia also lowered the plasma glucose level in normal, adrenaline-induced hyperglycaemic and diabetic mice (kiho et al., 1999) . some cordyceps-like strains have been isolated from the fruiting bodies of wild cs that have been reported to show the same properties as the natural product. however, care in interpretation is required as these could conceivably be contaminants (see later). an exopolysaccharide fraction was prepared from cultivated cs . the results showed that it enhanced significantly the neutral red uptake capacity of peritoneal macrophages and spleen lymphocyte proliferation in melanoma-bearing mice. the metastasis of b16 melanoma cells to lungs and livers was significantly inhibited. moreover, the levels of bcl-2 in the lungs and livers were decreased. the results suggest that the polysaccharide has an immunomodulatory function and anti-tumour activity. however, yang et al. (2005) state that although certain polysaccharides from cs are bioactive, the anti-tumour effect has not been confirmed. the authors investigated the effects of the exopolysaccharide fraction of cultivated cs fungus on c-myc, c-fos, and vascular endothelial growth factor (vegf) expression of tumour-bearing mice. the expression in the lungs and livers of treated mice were found to be significantly lower than those of untreated mice. the authors suggest that the fraction had inhibited tumour growth in the lungs and livers of mice, and that it is an adjuvant in cancer therapy. in addition, yu et al. (2004a,b) isolated four polysaccharides from c. militaris, cps-1 was shown to possess a significant anti-inflammatory activity and suppressed the humoral immunity in mice but had no significant effects on cellular immunity and non-specific immunity. in a previous study using anti-oxidant activity-guided fractionation csp-1 from cultured cordyceps, mycelium was isolated. the hypoglycemic effect of csp-1 on mice and rats was demonstrated. csp-1 increased circulating insulin level in diabetic animals, which suggests that the compound(s) may stimulate pancreatic release of insulin and/ or reduce insulin metabolism. chen et al. (2006) undertook further work on the biological activity of the isolate: the polysaccharide from fungus and its anti-oxidant activity on h22-tumour bearing mice was investigated. the h22 tumour growth was inhibited and sod activity of liver, brain and serum and gsh-px activity of liver and brain in tumour-bearing mice were enhanced. in general, beneficial effects were observed in the liver and brain of tumourbearing mice. finally, four exopolysaccharides with different molecular masses ranging from 50 to 2260 kda were reported from c. militaris by kim et al. (2003b,c) as part of yield optimisation studies. an extracellular polysaccharide extracted from the mycelia of cs with hot-water indicated that this d-glucan consisted of a backbone composed of (1 ? 3)-b-d-glucosyl residues and carried a single (1 ? 4)-b-linked d-glucosyl residue: sugar residues were linked with b-glycosidic bonds (wu et al., 2005) . a lectin from c. militaris exhibited hemagglutination activity in mouse and rat erythrocytes, but not in human abo erythrocytes (jung et al., 2007) . however, the n-terminal amino acid sequence differed greatly from those of other lectins. it exhibited mitogenic activity against mouse splenocytes. the following section concerns solvent extraction of the fungi. in effect, this is often how the preparations will be consumed as a tcm. the significance of tests on extracts is much reduced compared to those of pure compounds. there is a great deal of data. in general, this type of work needs to be deemphasised in favour of that of pure compounds. reports on the metal chelating and reducing power from cs are not available in the scientific literature. therefore, there is a demand to obtain an overall measure of the anti-oxidant activity of extracts using reliable fungal material because of increasing interest in the relationship between anti-oxidants and diseases. the anti-oxidant activities from natural and cultured mycelia of cs were investigated in vitro. optimal effects were demonstrated on the inhibition of linoleic peroxidation. the results suggested that the cultured and natural mycelia have direct and potent activities and that the cultured mycelia could be used for the anti-oxidant activity which would tend to reduce the pressures on the natural fungus, which is, after all, an endangered species (dong and yao, 2007) . the anti-oxidant efficiency of c. militantis extract (cme) and cs extract (cse) in protecting lipid, protein, and lowdensity lipoprotein (ldl) against oxidative damage was reported (hui et al., 2006) . however, this study provoked a strong response from hamburger (2007) which was subsequently rebutted by one of the original authors (duh, 2007) . this is something of an unexpected bonus to a reviewer of the literature such as myself as another opinion is obtained. the questions are, what biological material is being worked with, and can other scientists obtain it to repeat the experiment? the current author has encountered this before (paterson, 2005) where commercial interests are involved. the hamburger response can be applied in a general sense to some of the other work cited in the present review. cme and cse showed weakly inhibitory effect on liposome oxidation. the inhibitory effect of cme on protein oxidation was inferior to that of cse. cme and cse showed inhibition of ldl oxidation. the contents of the bioactive ingredients cordycepin and adenosine in cme were higher than those of cse; however, cordycepin and adenosine showed no significant anti-oxidant activity. in addition, a polysaccharide present in cme and cse displayed anti-oxidant activity. the authors concluded that the protective effects of cme and cse against oxidative damage of biomolecules are a result of their free radical scavenging abilities. however, the experimental data and some of the conclusions need a critical comment (hamburger, 2007) . the author criticised the report on the bases of poor taxonomy, biochemistry and extrapolation of data to imply possible cures of diseases. in particular, the authors' claims of a potential treatment for human disease on the basis of in vitro data are called into question. the rebuttal by duh simply confirms that appropriate information about the strains was not provided; the comments on the inadequate analytical procedures are largely accepted. and there is no doubt that the conclusions could have been rewritten to indicate that the results were preliminary. hamburger (personal communication, 2007) stated that the rebuttal was evasive, an assessment with which i agree. kuo et al. (2005) describe the effects of cs against group a streptococcus infection in mice. the preparation protected by decreasing bacterial growth ''and dissemination", thereby increasing mouse survival rate. il-12 and ifn-gamma expression and macrophage phagocytic activity also increased. kuo et al. (2007) claim to demonstrate that cs increased phagocytosis in human monocytic cells and abrogated inhibition of phagocytosis by causing cytokine production. these two reports are sound and in good journals. however, the fungus used was from a company called simpson biotech and very few or no details are supplied about how the material was collected, identified, maintained, and grown. of course, this is unsatisfactory. shahed et al. (2001) refer somewhat unusually to cs as a ''black blade" fungus. their results showed that cs improved renal function and reduced the expression of inflammatory and apoptotic genes in rats. the authors make the very conditional statement that, cs extract may play a potential therapeutic role in renal transplantation"; on the other hand it may not play an actual role. after all, precision in what is written in such important areas of medicinal research is crucial. the authenticity of the fungal material can be questioned: it was obtained from a company from the united states of america and there is little indication about the standards of collecting, purity, identities and maintenance of the materials. basically, what level of accreditation applies to such organizations? a c. militaris inhibited the growth of human umbilical vein endothelial cells (huvec) and ht 1080 cells. it down-regulated, in dose-and time-dependent manners, bfgf gene expression in huvec cells and mmp-9 gene expression in ht 1080 cells. the growth of melanoma cells in mice was suppressed. in addition, anti-angiogenic activity was manifested (yoo et al., 2004) . it is gratifying that adequate details of the fungal material are provided in this chinese journal, which acts as a model for others generally. chiou et al. (2000) observed a hypotensive effect of cs in anaesthetized rats and a vaso-relaxant effect in isolated aorta. the fungus counteracted arrhythmia in rats and increased the dosage of ouabain required to produce arrhythmia in guinea-pigs. in addition, the heart rate in anaesthetized rats and the contractility of isolated papillary muscle or atria in guinea-pigs were decreased (mei et al., 1989) . cultured fruiting bodies of cs prevented deposition of cholesterol in the aorta of atherosclerotic mice by inhibiting free radical-mediated ldl oxidation in an investigation into hypolipidaemic activity (yamaguchi et al., 2000a) . a hot-water extract of mycelia (a) lowered the total cholesterol concentration, (b) reduced the concentration of cholesterol carried by ldl and very-low-density lipoprotein, and (c) elevated the high density lipoprotein (hdl)-cholesterol concentration in the serum of mice fed a cholesterol enriched diet (koh et al., 2003a) . water extracts of cs: increased survival time of mice inoculated with carcinoma cells or syngeneic fibrosarcoma cells (yoshida et al., 1989) ; inhibited spontaneously liver metastasis of carcinoma cells and melanoma in syngeneic mice and results suggested that the activity was not attributable to cordycepin (nakamura et al., 1999a) ; prolonged the survival period of mice inoculated with b16 melanoma cells when coadministered with methotrexate (nakamura et al., 2003) and caused apoptosis of melanoma cells (nakamura et al., 1999b ). an orally administered cs was considered to be ''quite" safe based on body weight gain, and liver/kidney weights of mice (nakamura et al., 1999a,b) . the authors concluded the extract could inhibit aortic cholesterol deposition in atherosclerotic mice by scavenging free radicals in vivo. these extracts ''may have" beneficial effects on the process of atherogenesis and aging with few side effects (yamaguchi et al., 2000a) . this is good news but surely more evidence is required. towards these ends, tsai et al. (2001) also demonstrated the hydroxyl radical scavenging activity of cs. whereas reduced lipid peroxidation in rats was demonstrated by shen and chen (2001) . antioxidant activity in the xanthine oxidase, haemolysis and lipid peroxidation assay systems was reported from water extracts, and a polysaccharide fraction, of cultured cs mycelia (li et al., 2001a) . as mentioned previously, the fruiting body and the caterpillar parts of cs are claimed to be similar in chemical composition and hence anti-oxidant activity . it would be interesting to determine (a) how this occurs in terms of insect substrate utilisation by the fungus with a view to optimising yields of bioactive fungal components, (b) when the preparation is at the correct stage for use as a medicinal treatment, and (c) if these data could be extrapolated to in vitro culture. cho et al. (2003) and wang et al. (2005) also reported radical scavenging activity with wang et al. reporting activity against colorectal tumour cells. the influence of cs on the immunoactivity of macrophages was determined to probe the mechanism of its alleged tonic effect. the phagocytosis of macrophages were enhanced significantly (jia and lau, 1997) and ''maybe" the tonic effect of cs is accomplished by an enhancing effect on the immune system. some chemical fractions had insulin like and insulin release promoting activity and ''could be developed" as an anti-diabetic agent (young et al., 2001) . cordyceps possessed a strong anti-oxidation activity in all assays tested by li et al. (2001a) . the cultured cordyceps mycelia had equally strong anti-oxidation activity compared to in vivo cordyceps. further, the anti-oxidation activities were increased â10-30 in the partially purified polysaccharide fractions. in an intriguing report, liu et al. (2006) mentions that identification of an effective non-toxic biological radioactivity protector is a ''matter of some urgency". orally administered cs protected mice from bone marrow and intestinal injuries after total-body irradiation. the levels of free radical species within cells are suggested to be a likely mechanism for the purported effects. the biochemical mechanisms of anti-proliferative effects of c. militaris in human leukemia cells were investigated in a convincing study involving cancer treatment . it was found that they inhibited cell growth in a dose-dependent manner, which was associated with morphological change and apoptotic cell death such as formation of apoptotic bodies and dna fragmentation. furthermore, the treatment caused a dose-dependent inhibition of cyclooxygenase-2 (see paterson, 2008) and prostaglandin e2 accumulation. taken together, these results indicated that the anti-proliferative effects were associated with the induction of apoptotic cell death through regulation of several major growth regulatory gene products. the extracts ''may have therapeutic potential" in human leukemia treatment. in addition, corticosterone output by cultured rat adrenocortical cells was increased without increasing the intracellular camp level. the steroidogenic effect was abolished by the protein kinase c inhibitor calphostin c, indicating that its action may involve stimulation of protein kinase c (wang et al., 1998) . c. militaris reduced the fasting serum glucose level and enhances glucose utilisation in skeletal muscles in rats . the fungus demonstrated cytotoxic activities on the three kinds of human cancer cell lines, stomachic adenocarcinoma, colorectal adenocarcinoma, and hepatocellular carcinoma (lim et al., 2004) . cytotoxic activity-guided isolation and identification of active fractions afforded the well-known, cordycepin as an active component (see above). koh et al. (2003b) reported that cs mycelia prolonged swimming endurance capacity and produced an anti-fatigue action in mice. cs reduced the hepatic content of malondialdehyde and the serum concentrations of transaminases and alkaline phosphatase in rats with hepatic fibrosis. treatment with the extracellular biopolymers resulted in a reduction in hepatic hydroxyproline content and normalization of morphological characteristics of the liver, indicating an anti-fibrotic action (nan et al., 2001) . finally, crystals of the fungus stimulated proliferation of erythroid progenitor cells in mouse bone marrow . in a very interesting report, the insect-body part (of the tcm) inhibited proliferation of enhanced human mononuclear cells (hmnc). any differences between the fungus and insect components are well worth further investigation. the production of interleukin-2 and interferon was stimulated by the aqueous methanolic extracts and inhibited by the methanolic extracts (weng et al., 2002) . treatment of patients with condyloma acuminata brought about an increase in interleukin-2 and a decrease in interleukin-10, indicating a recovery in the balance of th1/th2 cytokines. recurrence was also diminished (gao et al., 2000) . interestingly, the ergosterol esters concentrations were much higher in the (dead) caterpillar than the fruiting bodies (yuan et al., 2007) although ergosterol was similar. although why these compounds are of particular interest is ''mystifying" as they are universal in fungi. in a surprising paper, the following may be an example of the mystical nature of some of the reports (see paterson, 2006) . it represents a bizarre rational for undertaking the work and it is surprising that it was published from a scientific perspective. the rational for the work is that cs is a popular chinese tonifying herb, and was/is revered for being, what is referred to as, 'yin-nourishing' and 'yanginvigorating' in chinese medicine (siu et al., 2004) . in order to establish the pharmacological basis for the 'yinnourishing' and 'yang-invigorating' action of cordyceps, the effects of wild and cultured cordyceps on concanavalin a stimulated splenocytes, an in vitro bioassay for 'yinnourishment', and myocardial atp generation capacity, an ex vivo bioassay for 'yang-invigoration', were investigated in mice. the results indicated that wild and cultured cordyceps enhanced the con a-stimulated splenocyte proliferation in vitro and myocardial mitochondrial atp generation ex vivo in mice, with no significant difference in potency of action between the two types of cordyceps. while the immunopotentiating effect was associated with the increase in interleukin-2 production, the stimulation of myocardial atp generation was paralleled by an enhancement in mitochondrial electron transport. when compared with typical 'yin' and 'yang' tonifying chinese herbs, cordyceps was found to possess both 'yin-nourishing' and 'yang-invigorating' activities, with a lower potency in both modes of action. it is impossible to take reports such as these seriously from a scientific standpoint and is given considerable space here to indicate a general problem which may have motivated some of the published reports reviewed herein. this is without attempting to detract from the philosophical aspects of the concepts of yin and yang in terms of two mutually correlated opposites in a general sense. a comprehensive definition of the corresponding philosophy of science is inappropriate: it is enough to state that it is vitally important for science that the information about the surrounding world and the objects of study be as accurate and as reliable as possible. to continue, cs fruiting bodies inhibited various tumour cell lines (kuo et al., 1994) : two fractions were particularly potent. growth inhibitors other than cordycepin and polysaccharides may have been involved; two fractions significantly inhibited (a) the blastogenesis response, (b) nk cell activity and (c) il-2 production (kuo et al., 1996) . neither fraction was cytotoxic, and immunosuppressive ingredients were found to be intracellular. fruiting bodies inhibited human mesangial cells (hmc) activation by il-1 plus il-6 and liver toxicity or mutagenicity were not observed. the fraction was purified to obtain purified compound h1-a (see above). the authors claim a novel treatment for human berger's disease ''in the future". a fraction (a) dose dependently suppressed bronchoalveolar lavage fluids (balf) cells proliferation, (b) reduced interleukin production in lps activated balf cell cultures and (c) affected interleukin mrnas in various significant manners (kuo et al., 2001) . the purported therapeutic activity may be related to modulation of cells functions in bronchial airways. furthermore, the molecular mechanism of cordyceps pruinosa pharmacological and biochemical actions of macrophages in inflammation has not been clearly elucidated . the authors suggest that an extract suppresses inflammation through suppression of nf-jb-dependent inflammatory gene expression, and hence may be beneficial for treatment of endotoxin shock or sepsis. shim et al. (2000) wrote that they attempted to develop ''a new type cordyceps". to obtain this, they investigated the effects of the fruiting bodies of the cultivated fungus of p. japonica grown on silkworm larvae on hyperglycemia in rats and mice and on immunological functions in mice. as mentioned previously, it is not at all clear whether paecilomyces (even) contains anamorphs of cordyceps. therefore, this report is a cause of some concern. immunostimulating activity and a significant anti-fatigue effect in mice were observed. kuo et al. (1994) reported unidentified substances which inhibited tumour cells, but which were not cordycepin or polysaccharides, in the methanolic extract of cs -this report requires further investigation. c. cicadae ascocarps enhanced hmnc proliferation (weng et al., 2002) . in contrast, the insect-body portion suppressed hmnc proliferation. this is a most interesting result in the current author's opinion because of the different effects of the two components. the action mechanisms of the fractions may involve the regulation of interleukin and interferon production in hmnc. overall, the results demonstrated that c. cicadae contained growth modulators for hmnc. unfortunately, the compounds responsible were not characterised. koh et al. (2002) demonstrated that a hot-water extract modulated interleukin-6 production by activation of macrophages and augmented the secretion of haematopoietic growth factors. whereas aqueous methanolic extracts of the ascocarp stimulated proliferation of phytohaemagglutinin-induced proliferation of hmnc. of course, such differences indicate that different compounds are involved or the same compounds are at different concentrations. c. ophioglossoides mycelia prevented cell death in neuronal cells and memory deficits in rats (jin et al., 2004) . two fractions from fruiting bodies inhibited (a) the blastogenesis response, (b) natural killer cell activity, (c) interleukin-2 production and (d) tumour necrosis factor production in phytohaemagglutinin-stimulated human mononuclear cells (kuo et al., 1996) . the levels of interferon, interleukin-1 and tumour necrosis factor produced by cultured rat kupffer cells were increased by the fungus (liu et al., 1996a) . proliferation of cells in balf was inhibited which also reduced tumour necrosis factor (kuo et al., 2001) . in an effort to evaluate the pharmacological effects, including the anti-aging, of the fruiting bodies of the cultivated p. japonica fungus, a new type of cordyceps sp. was investigated (shin et al., 2001) . this statement by the authors is incomprehensible (see above). types of fungi are the typical specimens often held in culture collections. it is not proposed to discuss the described effects herein. hot-water extracts of cordyceps scarabaecola stromata exhibited potent intestinal immune system-modulating activity, while the methanol-soluble fraction manifested intermediate activity (yu et al., 2003) . xu et al. (1992) detected inhibition in melanoma colony formation in murine lungs by cs. the fruiting bodies of ''p. japonica" reduced tumour weight and volume and lengthened the life span of mice inoculated with sarcoma 180 cells (shin et al., 2003) but what this fungus represents in unclear. water and ethanol extracts of cs possessed a potent anti-oxidant activity (yamaguchi et al., 2000b) . anti-lipid peroxidation activities also were detected and accumulation of cholesteryl ester in macrophages was inhibited via suppression of ldl oxidation. hot-water extracts were particularly effective. ''p. japonica" exhibited immunostimulating activity. its ethanolic extract stimulated phagocyteosis and macrophage acid phosphatase activity (shin et al., 2001 (shin et al., , 2003 . c. militaris demonstrated general anti-inflammatory activity (yu et al., 2004a) in mice. the fact that cultured fruiting bodies were employed is interesting rather than extraction from those from the wild and most papers seen for this review either use fruiting bodies from the wild and/ or in vitro biomass. however, it is disappointing that details of the cultivation of the fruiting bodies are not provided as this is required. nitric oxide production and inos gene expression in lps-stimulated raw 264.7 cells are suppressed by ethanolic preparations (won and park, 2005) . a unique insight into how the cultured fruiting bodies were produced in this report and should be referred to: this detail is required in future reports. cs (as supplied by the ''xinhui xinhan artificial cordyceps factory" (sic)) inhibited mda generation via hydroxyl radicals induced by the peroxynitrite generator sin-1 and macrophage accumulation of esterified cholesterol (yamaguchi et al., 2000a,b) . the authors concluded that the cultured cs has anti-oxidant and anti-lipid peroxidation properties and inhibits accumulation of cholesteryl ester in macrophages via suppression of ldl oxidation. the authors conclude correctly that this cultured chinese medicine appears to merit further investigation as an anti-atherosclerotic. in the unusual use of this solvent to create an extract from cs mycelia, apoptosis in human pre-myelocytic leukaemia hl60 cells was induced. in addition, cell proliferation was inhibited . obviously, ethyl acetate may extract different compounds from the fungus compared to the more common water or methanol extracts and the constituents need to be determined. an alcoholic extract of cs inhibited abdominal aortic thrombus formation in rabbits by preventing platelet aggregation (zhao, 1991) . cs was extracted in pbs and dialyzed (chiou et al., 2000) the resulting macromolecule fraction was assayed in anesthetized rats for hypotensive effects and in isolated aorta for vasorelaxant effects. a constituent(s) in cs relaxed vascular beds directly. the in vivo and in vitro effects and its extracted fractions on the secretion of testosterone in mice were studied (hsu et al., 2003a) . cs, watersoluble protein, and poorly water-soluble polysaccharide and protein significantly stimulated in vitro testosterone production in purified mouse leydig cells. the authors concluded that it is ''possible" that cs ''might" contribute to an alternative medicine for the treatment of some reproductive problems caused by insufficient testosterone levels in human males, which is a large leap in conclusions. increase antigen expression was found in hepatoma cells and ''will" provide more effective host immune surveillance against tumour cells (chiu, 1998 ) from a cordyceps extract. in an interesting study, the beneficial effects of the ''traditional chinese medicine cs", on mice with hypoferric anaemia were evaluated by nmr spectroscopy (manabe et al., 2000) . the extract increased hepatic energy metabolism in anaemic mice and was concluded to be due to increased hepatic blood flow. zhang et al. (2006) concluded that ''their" extract ''is" effective in resisting the oxidative damage on liver mitochondria of diabetic mice. qiao and jian (2007) attempted to identify the signaling pathways for the induction of hl-60 cell apoptosis by cs mycelium extract (csme). csme induced nuclear fragmentation and dna degradation, two hallmark events of apoptosis, in the hl-60 cells within 12-24 h of treatment. concomitantly, several major events in the mitochondrial signal pathway occurred, including (a) the loss of mtp, (b) cytochrome c release into the cytoplasm, (c) the decrease in bcl-2 protein level, (d) the translocation of bax protein from cytoplasm into mitochondria, and (e) the activation of caspase-2, -3, and -9. however, caspase-8, the initiator caspase in the death receptor pathway, was not activated. these results suggest that csme induces apoptosis in hl-60 cell through the mitochondrial pathway rather than the death receptor pathway. treatment of d-galactose-induced-aged-mice with an unspecific cs extract resulted in (a) an improved learning ability and memory, (b) an increase in superoxide dismutase activity in erythrocytes, liver and brain, (c) an increase in catalase and glutathione peroxidase activity in blood, (d) reductions in malondialdehyde levels in brain and liver and (e) a reduction in monoamine oxidase activity in the brain . extracts enhanced the antibody response, restored the phagocytic activity of macrophages in tumour-bearing mice, and lengthened the survival period of the mice (yamaguchi et al., 1990 ). an extract down-regulated apoptotic genes in the rat kidney following ischaemia/reperfusion (shahed et al., 2001) . manabe et al. (1996 manabe et al. ( , 2000 found that a mycelial extract increased hepatic energy metabolism, as demonstrated by liver atp:pi value, in diet-induced hypoferric anaemic mice by increasing hepatic blood flow. the following section considers the use of the fungus as whole mycelium and/or fruit-bodies, although the prepara-tions may have to be prepared in water or ethanol in practise. cs down-regulated inflammation-related genes in the rat kidney following ischaemia/reperfusion (shahed et al., 2001) . a similar treatment improved lung function in guinea-pigs and airway inflammation in rats, suggesting a possible asthma treatment . c. pruinosa inhibited (a) gene expression of an interleukin tumour necrosis factor, (b) inducible nitric oxide synthase (inos) and cyclooxygenase-2, and (c) nuclear transcription factor nf-jb activation in a lipopolysaccharide (lps)-stimulated mouse macrophage cell line: this indicated a role in the treatment of endotoxin shock or sepsis . anti-ds-dna production was inhibited and improved survival in mice indicated that cs may be beneficial to patients with systemic lupus erythematosus, an autoimmune disease with involvement of multiple organ systems . the fungus inhibited lymphadenectasis, reduced proteinuria and plasma anti-ds-dna antibody and improved renal function in mrl 1pr/1pr mice (fu and lin, 2001 ). an oral dose of 2-4 g daily for 3 years prevented the recurrence of lupus nephritis and protected renal function in lupus nephritis patients (lu, 2002) . carcinogenesis in the murine forestomach was suppressed by cordyceps (lin, 1984) . results from liu et al. (1996) indicated that the levels of il-1 and inf, produced by cultured rat kupffer cells were increased from rats fed on cs. studies have demonstrated that polysaccharides extracted from these natural products have anti-hyperglycemic effects (lo et al., 2001) . these authors investigated the effects of intragastrically administered cordyceps sp. for alleviating fasting hyperglycemia in diabetic rats. animals had significantly increased serum levels of triglyceride, cholesterol and blood urea nitrogen, and significantly decreased body weight, serum albumin levels and weights of the thymus, lungs and gastrocnemius muscle compared to animals in the control group. in addition, blood glucose was significantly increased compared to the control group; these results suggest that enterally administered cordyceps sp. has potential anti-hyperglycemic ability. these findings reveal that the fungus ''may be used as a nutraceutical to alleviate hyperglycemia in diabetes". oral administration of cordyceps alleviates fasting hyperglycemia . recent evidence has shown that an extract has immunoregulatory activity. the objective was to investigate whether cordyceps has biological activity in regulating the lymphocyte subsets in diabetes. after 2 weeks, body weight, thymus weight, thymocyte number, and the percentages of total t and t helper cells in the thymus were significantly lower in the treatment groups than in the controls. results demonstrate that stz-induced diabetic rats had significantly decreased numbers and subsets of t cells in the thymus. however, oral administration of cordyceps did not improve these changes. the results suggested that oral administration had no significant effect on lymphocyte subsets in stz-induced diabetic rats. hsu et al. (2003b) demonstrated in a convincing study, that cs mycelium regulates mouse cell testosterone production and may suppress stimulated testosterone production via p450 scc enzyme activity. hsu et al. (2003a) demonstrated that the fungus and fractions from it were capable of stimulating testosterone production. the steroidogenic activity was observed in vivo in male mice after 7 days of treatment (huang et al., 2004b) . chen et al. (2005) found that protein kinase a and protein kinase c pathways are acted upon to stimulate steroidogenesis in ma-10 mouse leydig tumour cells. inhibitors of protein kinase a, protein kinase c and phospholipase c and calmodulin antagonists (see paterson, 2008) reduce leydig cell steroidogenesis induced by the fungus. c. militaris inhibited (a) the growth and metastasis of lewis lung cancer cells, and (b) the growth of sarcoma s180 cells implanted in mice. in addition, the survival period of the mice was increased (liu et al., 1997) . liu et al. (1991) showed that p. sinensis inhibited lipid peroxidation but increases the amount of glutathione peroxidase and superoxide dismutase in mouse liver. again the name of the fungus raises similar questions as to those raised for p. japonica and consequently as to what material is being used and whether the experiments could be repeated. finally, cordyceps is included in a list of anti-aging tcm . cs stimulated mitochondrial electron transport and atp production (siu et al., 2004) . the effect of the fungus on hepatic fibrogenesis induced in rats was studied by liu and shen (2003) . it was found that it delayed cirrhotic development and improves liver function by inhibiting expression of transforming growth factor-and plateletderived growth factor and deposition of procollagen i and iii. zhou et al. (1990) presented evidence for the beneficial effects of cs on chronic hepatitis b. the fungus increased dna synthesis in primary cultured rat tubular epithelial cells (tian et al., 1991) . proximal tubular cells were protected from the toxic effects of gentamicin. the possible mechanisms include protection of sodium pump activity, reduction of lipid peroxidation and attenuation of lysosomal over-activity in tubular cells due to phagocytosis of gentamicin (zhen et al., 1992; li et al., 1996) . also, rat kidneys were protected from cyclosporin-induced nephrotoxicity and ameliorated glomerular and interstitial damage (zhao and li, 1993) . bao et al. (1994) reported that ''old" patients were protected from amikacin sulphate toxicity as demonstrated by decreases in urinary nephroaminoglycosidase and microglobulin. also, inhibition by c. militaris of ldl-induced proliferation of cultured human glomerular mesangial cells, which are involved in the development of glomerulosclerosis was observed (zhao-long et al., 2000) . treatment of mice with c. militaris lengthened the swimming time to exhaustion (jung et al., 2004 ). an unspecified cordyceps is one of the components of fuzheng huayu recipe, which is used to control the development of post-hepatic cirrhosis or to prevent complications from the disease (liu et al., 1996b) . the macrophage-stimulating activity of natural fungus and cultured mycelia has been described by zhang (1985) . zhang and xia (1990) demonstrated immunosuppressant effects in the heterotropic heart allograft model in rats and determined that prolonged survival periods were possible. also, zhu and yu (1990) found prolonged mouse skin allograft survival time. the number of t helper cells was increased, as were lyt-1/lyt-2 (t helper cells to t suppressor cells) in peripheral blood and spleen . a mitogenic action was demonstrated on splenic lymphocytes and interleukin-2 from spleen cells of rats with chronic renal failure was augmented (cheng, 1992) . in addition, natural killer cell activity was enhanced (xu et al., 1992) . treatment of patients with post-hepatic cirrhosis resulted in (a) enhancement of natural killer cell function, (b) increased number and improved ratio of cd4þ and cd8þ cells, and (c) reduction in iga and igg levels (zhu and liu, 1992) . treatment of chronic hepatitis b resulted in increased cd4/cd8 ratios, and reductions in hyaluronic acid and procollagen type iii. the data indicate the usefulness of the fungus in adjusting the level of t lymphocyte subsets and treating hepatic fibrosis (gong et al., 2000) . liu et al. (1992) demonstrated increased peripheral natural killer cell activity from healthy subjects and leukaemia patients. improved renal function and augmented cellular immune function in chronic renal failure has also been observed (guan et al., 1992) . the fruiting body portion, but not the carcass portion, of cordyceps reduced weight loss, polydipsia and hyperglycaemia in diabetic rats (lo et al., 2004) . some other somewhat obscure papers are available on the effect of whole fungi (i.e. peizhong, 1984; chen, 1985; zhang, 1985; shao, 1985; liu and xu, 1985; zhang, 1987; chen, 1987; du, 1986; sun, 1985; li et al., 1993) . feng et al. (1987) reported the vasodilating effect of cultured mycelia of cs in an investigation of the cardiovascular system of dogs. thirty three cases of chronic hepatitis b patients treated with cultured cs mycelia have shown that the drug (a) improves liver function, (b) promotes negative transfer hbsag, (c) markedly helps to raise plasma albumin, (d) helps patients resist high gamma globulin and (e) adjusts body immunocompetence (zhou et al., 1990) . it is suggested that the fungus may be a medicine for chronic hepatitis b patients in adjusting protein metabolism and correcting inversion of albumin and globulin. since inflammation has been reported to be associated with chronic diseases inhibitory dietary factors such as the fungus may be beneficial in alleviating disease (hong and lin, 2004) . 17b-estradiol may directly influence the quality of maturing oocytes and thus the outcome of assisted reproduction treatment. cs mycelium is ''believed" to enhance libido and fertility in both sexes. however, the mechanism of its effect in women has not been determined. this is surely a rather thin basis on which to undertake research. huang et al. (2004a) concluded that treatment of granulosa-lutein cells with cs results in increased 17b-estradiol production due, in part, to increased star and aromatase expression. if these data are confirmed, cs may help in the development of treatment regimens to improve the success rate of in vitro fertilization, they state. zhu and liu (1992) found that cultivated cordyceps mycelia inhibited humoral immune hyperfunction and increase the serum complement level in patients with post-hepatic cirrhosis, and improved liver function. whole body insulin sensitivity in rats was increased (balon et al., 2002) . the fungus increased the basal plasma insulin level (zhang et al., 2003) and inhibited hepatic fibrogenesis in rats with ccl 4 -induced liver fibrosis. previous studies by lo et al. (2006) demonstrated that the fruiting bodies of cs attenuated diabetes-induced weight loss, polydipsia, and hyperglycemia in rats. rats were orally administered, fruiting bodies, fermented mycelia, spent broth, or mycelia plus spent broth of the fungus. the results revealed that the mycelia and spent broth had anti-hyperglycemic activities similar to those of the fruiting bodies. the authors , bold claim that the fermented products could be developed as potential anti-diabetic agents or functional foods for persons with a high risk of diabetes mellitus needs further confirmation. yang et al. (2006) mention that mycelium can inhibit tumour growth and induce tumour cell apoptosis. however, the antitumour mechanisms are not fully understood. so, the molecular mechanism was determined. the authors conclude that cell apoptosis is induced by activating caspase-8-dependent and caspase-9-independent pathways and downregulating nf-jb protein expression. mycelia induced human granulosa-lutein cells to produce 17b-estradiol by upregulating expression of steroidogenic acute regulatory protein (star) and aromatase (huang et al., 2004a) . also, steroidogenesis in mouse leydig tumour cells (huang et al., 2001a) was stimulated without involvement of star (huang et al., 2000) . testosterone production was inhibited by human chorionic gonadotropin or dibutyryl cyclic amp. thus, its effect on the signal-transduction pathway for steroidogenesis may be after the production of cyclic amp. it is revealing to read the web sites of some of the commercial products: these are often written in unscientific terms. the best of them at least contain warnings that, ''these statements have not been evaluated by the (us) food and drug administration. this product is not intended to diagnose, treat, cure or prevent any disease". colson et al. (2005) undertook a revealing experiment to determine the effect on male cyclists' performance using a combination of cs and rhodiola rosea ''herbs" -a tradi-tional herbal medicine. importantly, and unusually, the study followed a double blind, randomized, placebo-treatment, pre-post test design. essentially no effect was observed. this is an example of why scientists need to circumspect about making unsubstantiated claims about the powers of these preparations even if spin does help project funding. ''in this regard, the maintenance of a balance of yin and yang -two opposing components involved in life activities as exemplified by the antagonistic action of the sympathetic and parasympathetic nervous systems-is essential in achieving a healthy condition" (leung et al., 2005) . statements such as these leaves the current reviewer bewildered. why these terms are used in a scientific publication does not appear to merit comment. previous studies have shown that long-term treatment with a ''yang-invigorating" chinese herbal formula (vi-28) could increase red cell cuznsuperoxide dismutase (sod) activity in male human subjects. yet the authors conclude, the beneficial effect of vi-28 treatment on mitochondrial functional ability and antioxidant capacity may have clinical implications in the prevention of age-related diseases. ka wai lee et al. (2006) investigated a commercial preparation of a cultivated strain of cs. they state that the immunomodulatory activities have been renowned for centuries. the report describes positively the immunomodulatory features: in vitro results demonstrated that the fungus induced the production of interleukin (il)-1, il-6, il-10 and tumour necrosis factor alpha, augmented surface expression of cd25 on lymphocytes, and elevated macrophage phagocytosis and monocyte production of h 2 o 2 . the authors state that, ''our results possibly provide the biochemical basis for future clinical trials". the current author emphasises that such over extrapolation of data needs to be discouraged. dai et al. (2001) found that cordymax cs-4 (a mycelial fermentation product of cs) ''improved the bioenergy status" in the mouse liver. these findings may explain why cordymax cs-4 is claimed to alleviate fatigue and improve physical endurance especially in aged subjects. reports of athletes' performance being improved may also be supported from these types of reports. cordymax cs-4 lowered fasting plasma levels of glucose and insulin, improved oral glucose tolerance and increased the glucose-insulin index, which measures insulin sensitivity, in rats (zhao et al., 2002) . an unspecified cordyceps is reported to be a component of fuzheng huayu recipe, which is used to control the development of post-hepatic cirrhosis or to prevent its complications (liu et al., 1996b) . as part of the eternal search to find an excelsior of youth, many are interested in anti-aging activity but it is difficult to define what his means scientifically. are the authors stating that the aging process is slowed for example? do people live longer? in any case, this was published in the journal, chinese journal of integrated traditional and western medicine which is an admirable sentiment but difficult to do in practice. a prep-aration of cs referred to as jinshuibao capsule, increased the depressed superoxide dismutase activity and reduced elevated malondialdehyde (mda) level caused by aging when tested in senile patients. in addition, they enhanced the repair of damaged non human animal dna (zhang et al., 1997) . quite extraordinarily beneficial effects on senile patients are claimed and, of course, the constituents of the capsule may be difficult to verify. zhou and lin (1995) used ''jinshuibao", to restore cellular immune function and ''improve the quality of life" of patients with advanced cancer without affecting humoral immune function. obviously, quality of life is a subjective notion and is difficult to define. remarkably, a dried powder preparation of mycelia called bailing capsule (a) prevented rejection of renal transplants, (b) protected renal and hepatic function, (c) stimulated haematopoietic function, (d) improved hypoproteinaemia and hyperlipidaemia and (e) reduced the incidence of infections (sun et al., 2004) . however, such claims must surely carry considerable elements of doubt. in another case of a combined treatment with as many as six other components in addition to cs, the treatment was more effective at preventing acute renal failure than chronic in rats. obviously, it is difficult or impossible to assess the efficacy of the individual components (ngai et al., 2005) . inhibition of apoptosis is a novel area of clinical investigation with great promise and so merits a separate section in this review and will be of particular interest to pharmacologists. in one of the more critical papers, buenz et al. (2005) mention that there is a wide range of uses of cs in the literature, and those claiming altered apoptotic homeostasis are of the most intriguing. however, they emphasize problems created by the (a) difficulty of identifying the species of cordyceps and (b) many conflicting reports of pharmacological function. in response, the authors (a) outline what is known about the ability of cs to alter apoptotic homeostasis, (b) attempt to reconcile differences in function, and (c) identify the challenges and how to progress cs research. many disorders (e.g. stroke, myocardial infarction and hiv) incorporate apoptosis in their aetiology and pathogenesis. the ability to inhibit apoptosis has emerged as an important potential therapy (e.g. cancer). there are reports of cs extracts inhibiting and inducing apoptosis (shahed et al., 2001) ; this is not contradictory but allows a foundation to determine the molecular mechanism of activity. indeed, cordyceps may contain compounds that inhibit apoptosis; however, conflicting evidence has been obtained. the fungus can scavenge reactive oxygen species by inhibiting malondialdehyde formation by sin-1, the peroxynitrite generator, which has been confirmed by xanthine oxidase, hemolysis, and lipid peroxidation assays. furthermore, an isolated extract of cs, h1-a (this is reported as a pure compound (see above), inhibited induced apoptosis, by permeabilizing the cell membrane and upregulating nitric oxide synthase (trubiani et al., 2003) . on the other hand, extracts of cs did not inhibit hydrogen peroxide-induced apoptosis (buenz et al., 2004) , in a reactive oxygen species model (fauconneau et al., 2002) . alternatively, cs down-regulated apoptotic genes and modulated apoptosis in a rat kidney ischemia reperfusion model. reported anti-apoptotic effects of cs include in (a) the mouse (anti-cytotoxic activity, anti-oxidant activity, cell proliferation inhibition), (b) cell culture (anti-proliferation activity, cell proliferation inhibition, hemolysis inhibitory activity, lipid peroxide formation inhibition, radical scavenging effect), (c) human cells (proliferation inhibition, natural killer cell inhibition, tumour necrosis factor inhibition) and (d) the rat (gene expression inhibition). whereas the reported apoptotic effects of the fungus are in: (a) the mouse (anti-tumour activity, metastasis inhibition) and (b) cell culture (proliferation stimulation, cytotoxic activity). in reality these opposite effects are not incompatible. there are three prominent factors that may contribute to the apparent discrepancies (the first and third are fairly obvious). first, certain fungi contain different biologically active compounds. second, extracts may contain a prodrug; a metabolism step may be required to generate the biologically active form. third, different constituents may be assayed as there are multiple methods of extraction utilized in the literature. furthermore, decreases in fas, fas ligand and tumour necrosis factor expression and decreased caspase-3 activity have been demonstrated (shahed et al., 2001) . cs inhibited tnf-a expression (kuo et al., 1996) . however, when apoptosis was initiated via a fas agonist antibody (ch-11) (alderson et al., 1994) , aqueous and alcohol extracts of cs did not rescue cells induced by fas receptor ligation (buenz et al., 2004) . furthermore, cell cycle arrest and/or inhibition of proliferation yield cells resistant to apoptosis. papers concerning proliferation of leukemic u937 cells and glomerular mesangial cells inhibition (zhao-long et al., 2000; lin et al., 1999) may be explained by conferring a apoptotic resistance to cells: the alteration may involve p53 (fridman and lowe, 2003) or nf-jb (karin et al., 2004) . overall, aqueous, and organic extracts of cs have the ability to inhibit apoptosis. cells pre-incubated with cs extracts were equally sensitive to hydrogen peroxide and fas-mediated apoptosis. thus, the putative antioxidant and anti-apoptotic properties of cs were insufficient to rescue cells from apoptosis in vitro (buenz et al., 2004) . furthermore, cancer chemotherapeutics have involved the ability to induce apoptosis. hence the polysaccharide fraction (h1-a) induced apoptosis by inhibiting (a) phosphorylation of bcl-2 and bcl-xl and (b) apoptosis induced by dimethyl sulfoxide (yang et al., 2003) . these data require to be confirmed by further work (buenz et al., 2005) . finally, direct cytotoxic activity may be a factor (nakamura et al., 1999a,b; kuo et al., 1994; sato, 1989; buenz et al., 2005) . a factor which is not often considered is whether the activities of extracts and pure compounds are from the cordyceps of interest or from other contaminating fungi. the issues of anamorph/teleomorph associations are relevant here. for example, epicoccins a-d were isolated from cultures of a cordyceps-colonizing isolate of epicoccum nigrum (zhang et al., 2007b) . gliocladinins a and b are of an isolate of gliocladium sp. that colonized cs (guo et al., 2007) . it is essential that such activity is differentiated from that obtained from the traditional medicine or cordyceps per se. in a series of papers, (a) paecilomyces militaris is shown to possess militarinones a, b, c, d and (b) farinosomes and a deoxymilitarinone substance were detected from paecilomyces farinosus (schmidt et al., 2002 (schmidt et al., , 2003 cheng et al., 2004 cheng et al., , 2006 . the authors do not make statements as to the holomophic connections to cordyceps. hamburger (2007) does make this link to c. militaris (teleomorph) from p. militaris (anamorph) apparently on the basis of the same pigment production. however, it is has been suggested that paecilomyces does not contain anamophic species of cordyceps . hence, comment on these reports is avoided by the current author because the relationships between paecilomyces and cordyceps remain ill-defined. another complicating facet is that the medicine may contain a proportion of the insect host and so what does this bring to the activity? this is an area of investigation which simply is not reported. indeed does the healthy insect have interesting activities, and/or at what stage does the activity occur in the infected insect? could the activity be greater at these stages? the accumulation of bioactive plant metabolites by insects is well documented (brown and trigo, 1994) and insects are used as medicines . these aspects are almost totally ignored in the case of the medicinal cordyceps. it appears as if entomologists have simply not been involved in the field. does the insect have to be dead before the system works or are more active components produced by the fungus as it is in the process of killing the insect? research into these factors could be fruitful. hence, it is worth reporting what is known about the differences between the insect and fungus parts: interestingly, galactomannans isolated from the insect portion of c. cicadae demonstrate potent hypoglycaemic activity in mice (kiho et al., 1990) . the fruiting body portion, but not the carcass portion, of cordyceps reduced weight loss, polydipsia and hyperglycaemia in diabetic rats (lo et al., 2004) . aqueous methanol extracts of c. cicadae ascocarps enhanced human mononuclear cells (hmnc) proliferation (weng et al., 2002) . in contrast, the methanol (100%) extracts of the c. cicadae insect-body portion suppressed hmnc proliferation. interestingly, the ergosterol esters concentrations were much higher in the (dead) caterpillar than the fruiting bodies (yuan et al., 2007) although ergosterol was similar. finally, the fruiting body and the caterpillar parts of cs are claimed to be similar in chemical composition and hence anti-oxidant activity because the fungus had presumable replaced the insect constituents with fungal . little scientific evidence exists to support the numerous herbs used to improve diabetes-related metabolic disorders (lo et al., 2004) . the dual organism medicine (i.e. fruiting body and carcass) has been proposed to have multiple medicinal activities. in one investigation, the effects of the fruiting body and carcass of the preparation on hyperglycemia were investigated. diabetic rats had significantly lower weight gain and higher blood glucose response in oral glucose tolerance test than the control rats; and these changes were significantly reduced by administrating the fruiting body of cordyceps. the results revealed that the fruiting body (not the carcass) of cordyceps attenuated the diabetes-induced weight loss, polydipsia and hyperglycemia, and these improvements suggest that fruiting body has a potential to be a functional food for diabetes. the water extracts from the fruiting body and ''worm" of natural cordyceps were analyzed for their content of nucleosides and polysaccharides; the results showed that the worm had a chemical composition similar to the fruiting body . in addition, both the fruiting body and worm of cordyceps showed similar potency in their anti-oxidation activities in the xanthine oxidase assay, the induction of hemolysis assay and the lipid peroxidation assay. these results suggest that the function of the worm is to provide a growth medium for the fruiting body, and that eventually, the worm is totally invaded by mycelia. aqueous methanol extracts of c. cicadae ascocarps enhanced human mononuclear cells hmnc proliferation (weng et al., 2002) . in contrast, the methanol (100%) extracts of the c. cicadae insect-body portion suppressed hmnc proliferation. this is a most interesting result in the current author's opinion. the following are references concerning the chemical constituents as determined by analytical profiles (guo, 1985; xiao, 1983; . yu et al. (2007b) developed a method involving ''biospecific" extraction and hplc for potential immunological components in cs. the two active compounds were identified as guanosine and adenosine. li et al. (2001b,c) found that cultured cs mycelia have a much higher content of nucleosides than natural cs. guo et al. (1998) described an hplc method for quantitative determination of adenosine and deoxyadenosine. li et al. (1999) determined adenosine in fermented products of cordyceps by reversed-phase hplc. ergosterol in cs can be determined by hplc li et al., 2004) , and, of course, ergosterol is present in all fungi. when there are many questions as to what are the active components, a section on optimisation may seem premature. however, kim and yun (2005) investigated the optimal culture conditions for the production of exopolysaccharides (eps) and cordycepin during submerged mycelial culture of c. militaris and cs. this was not done in the paper hamburger (2007) comments upon. fermentations were performed in flasks and in 5-l stirredtank bioreactors. the concentrations of mycelial biomass, eps and cordycepin achieved in submerged culture of c. militaris were higher than those of cs. as the authors claim, comparative studies between the two fungi are not available and the paper was the first report on the optimum medium composition for submerged culture of cs. cordyceps nutans pat. is another entomopathogenitic ascomycete belonging to the family clavicipitaceae which is parasitic on hemipteran insects (sasaki et al., 2005) . very few investigations have been made with this fungus. in this research, optimum temperature and ph for mycelial growth was determined. however, it appeared that growth remained low and commercial exploitation perhaps limited. however, it would be interesting to include this species in any future taxonomic treatments of the genus. optimisation of culture conditions for mycelial growth and production of polysaccharides and cordycepin were described by park et al. (2001b park et al. ( , 2002 , xu et al. (2002) , kim et al. (2003b,c) , xiao et al. (2004) , mao and zhong (2004) and hsieh et al. (2005) , although cordycepin is usually produced synthetically at present. two cases of lead poisoning were reported (wu et al., 1996) . these two patients took cordyceps herbal medicine for treatment of underlying diseases. loss of appetite and anemic signs of lead poisoning were manifested in one patient with a high blood lead level, while the other patient was asymptomatic. the lead content in the cordyceps powder was found to be as high as 20,000 ppm. after cessation of intake in the asymptomatic patient, and cessation of intake and treatment with chelating agents in the symptomatic patient, the blood lead levels returned to normal range. this report raises concerns about lead poisoning from unusual herbal medicine in general. this present review is not intended to be a taxonomic paper, but is essentially a review of the papers that employ the name cordyceps more or less loosely, to describe the fungus used in medicinally related experiments. however, in a most impressive paper, sung et al. (2007) state that cordyceps comprise over 400 species in their modern phylogenetic classification of cordyceps and the clavicipitaceous fungi. cordyceps fr. host range is broad, ranging from 10 orders of arthropods to the truffle-like genus elaphomyces, although most species are restricted to a single host species or closely related host species. the main objectives of the study was to reassess the (a) morphological traits used currently, (b) taxonomic utility of the anamorphic forms and (3) classification in relation to phylogenetic relationships. it may be worth mentioning that pcrs may be subjected to inhibition, and nucleic acids may be affected by the medium in which the fungus was grown (see paterson, , 2008 . unfortunately, sung et al. (2007) do not provide details of how the fungi were grown for analysis and so it is difficult to conjecture. obviously, as discussed in this review, the fungus produces numerous bioactive compounds which may be inhibitors or mutagens and the effect of metabolite production on the dna preparations need to be determined or misleading results may be obtained. however, to continue, it is worth mentioning that c. militaris maintains its name in the study while c. sinensis is now classified as ophiocordyceps sinensis. the taxon was historically classified in the clavicipitaceae, based on cylindrical asci, thickened ascus apices and filiform ascospores, which often disarticulate into part-spores. the fungus was characterized by having a pathological ecology on elaphomyces and arthropods, with infrageneric classifications emphasizing ascospore morphology, host affiliation and arrangement of perithecia. the production of welldeveloped often stipitate stromata was typical. sung et al. re-classified on the basis of phylogenetic relationships between 162 taxa by employing five to seven genetic loci. three clavicipitaceous clades were determined which rejected the monophyly of cordyceps and clavicipitaceae and most diagnostic characters used in cordyceps were not supported as being phylogenetically informative. however, the most consistent characters with the phylogeny were pigmentation, morphology and morphology of stromata. cordycipitaceae was validated based on c. militaris, the type of cordyceps, which included most cordyceps species that possess bright, fleshy stromata. the new family ophiocordycipitaceae was proposed. the majority of species here produce stromata that often possess aperithecial apices and are darkly pigmented, tough to pliant. elaphocordyceps was proposed for a subclade of the ophiocordycipitaceae, which includes species of cordyceps that parasitize (a) the fungal genus elaphomyces and (b) arthropods. the family clavicipitaceae included the core clade of grass symbionts, and the entomopathogenic genus hypoc-rella and relatives. the new genus metacordyceps is proposed for cordyceps species that are closely related to the grass symbionts in the clavicipitaceae s. s. metacordyceps includes teleomorphs linked to metarhizium and other closely related anamorphs. lists of accepted names for species in cordyceps, elaphocordyceps, metacordyceps and ophiocordyceps are provided. obviously, this work needs to be consulted in future work on the fungus for medicinal properties as does stadler et al. (2003) . too often authors have used highly conditional statements such as; the preparation ''may" have ''possible" activity against, for example, cancer, which are meaningless. it is claimed that modern studies are demonstrating anti-oxidant, vascular, immune, and anti-inflammatory effects (meletis and barker, 2005) and the mechanisms by which these mushrooms work are being elucidated. however, the journal in which the paper is published is dedicated to complimentary and alternative medicines. this implies it is not mainstream scientific and so scientists may not give it as much weight in comparison to, for example, phytochemistry or the journal of natural products. nevertheless, the former reports could be considered as providing leads for more scientific research. in general, problems include too many chemically uncharacterised crude extracts, inadequate taxonomic vigour, and over extrapolation of in vitro data to imply therapeutic value. this needs to be avoided as it falsely raises hopes for cures for serious diseases. furthermore, there are no biochemical data on how the insect are converted into fungal components, or if the insect host per se has pharmacological properties. poor (i.e. inadequate or obsolete) biochemical procedures and assays can also because problems (see hamburger, 2007) . the biological material being used often is not well characterised and there are few indications of specimens being available for other workers to repeat the described work for example (i.e. no voucher specimens are available), with some notable exceptions. a rather limited range of solvents have been employed to extract the components and, for example, chloroform/methanol is particularly efficacious for fungal compounds (e.g. paterson and bridge, 1994) . there is very little on the use of non-polar solvents. paterson et al. (2004) , paterson (2006) and paterson (2008) have advocated a method which may have utility in standardising bioactive fungi. in this scheme, a ''common, readily identifiable" morphological character is determined and then the fungus is analyzed for particular metabolites. in this case the steps may be: 1. produces stroma on lepidopteron insects. 2. produces detectable concentrations of, for example, cordycepin. the analysis for other compounds would be desirable and some potential marker compounds are provided in table 3 . however, the phylogenic approach of sung et al. (2007) will set the standards for decades to come and will profoundly influence future publications in all fields relating to cordyceps. table 3 summary of markers currently used for quality control of cordyceps and associated activities (after li et al., 2006a) compound type pharmacological activities comments nucleosides anti-tumour activities; ca 2+ antagonist; the release of various neurotransmitters presynaptically and anticonvulsant activity; stimulate axon growth in vitro and in the adult central nerve system nucleosides, especially adenosine, are usually used as markers, and the profiles can be applied for authentication of cordyceps polysaccharides anti-oxidation, immunopotentiation, anti-tumour, and hypoglycemic activity; anti-inflammatory activity and suppress the humoral immunity in mice represents the most biological properties of cordyceps, and less used as marker for quality control. thus, it should be developed ergosterol and its analogs cytotoxic activity, anti-viral activity, and anti-arrhythmia effect; suppress the activated human mesangial cells and alleviate immunoglobulin a nephropathy (berger's disease) ergosterol can be used as marker for quality control mannitol diuretic, anti-tussive and anti-free radical activities it sometimes is used as marker for quality control peptides anti-tumour and immunopotentiation activities a potential marker for quality control cordycepin: selective growth inhibitor derived from liquid culture of cordyceps militaris against clostridium spp regulation of apoptosis and t cell activation by fas-specific mab a fermentation product of cordyceps sinensis increases whole-body insulin sensitivity in rats amelioration of aminoglycoside nephrotoxicity by cordyceps sinensis in old patients antitumor sterols from the mycelia of cordyceps sinensis comparison of balanol from verticillium balanoides and ophiocordin from cordyceps ophioglossoides multi-level complexity in the use of plant allelochemicals by aposematic insects selected herbals human exercise performance the traditional chinese medicine cordyceps sinensis and its effects on apoptotic homeostasis cordyceps sinensis extracts do not prevent fas-receptor and hydrogen peroxide-induced t-cell apoptosis fungal populations and species cordyceps sinensis animal, vegetable or both? cordyceps sinesis (berkeley) saccardo: structure of cordycepic acid platelet hemopoiesis and ultrastructure observations in mice treated with natural cordyceps sinensis and its cultured mycelia the effect of natural cordyceps sinensis and its cultured mycelia on murine immuno-organs and function of the mononuclear macrophage system effects of cordyceps sinensis on murine t lymphocyte subsets the effects of chinese herbs on improving survival and inhibiting anti-ds dna antibody production in lupus mice morphological and genetic characterization of a cultivated cordyceps sinensis fungus and its polysaccharide component possessing antioxidant property in h22 tumor-bearing mice recent advances in studies on traditional chinese anti-aging material medica nmr and ir studies on the characterization of cordycepin and 2 0 -deoxyadenosine. zhongguo kang sheng su za shi (chin cordyceps sinensis mycelium activates pka and pkc signal pathways to stimulate steroidogenesis in ma-10 mouse leydig tumor cells effect of cordyceps sinensis on the proliferation and differentiation of human leukemic u937 cells genetic diversity and taxonomic implication of cordyceps sinensis as revealed by rapd markers determination of the anamorph of cordyceps sinensis inferred from the analysis of the ribosomal dna internal transcribed spacers and 5.8s rdna effect of cordyceps sinensis on cellular immunity in rats with chronic renal insufficiency farinosones a-c, neurotrophic alkaloidal metabolites from the entomogenous deuteromycete paecilomyces farinosus novel tetramic acids and pyridone alkaloids, militarinones b, c, and d, from the insect pathogenic fungus paecilomyces militaris protein constituent contributes to the hypotensive and vasorelaxant activities of cordyceps sinensis cordyceps sinensis increases the expression of major histocompatibility complex class ii antigens on human hepatoma cell line ha22t/vgh cells cordycepin (3 0 -deoxyadenosine) inhibits human platelet aggregation in a cyclic ampand cyclic gmp-dependent manner antioxidant and memory enhancing effects of purple sweet potato anthocyanin and cordyceps mushroom extract improvement of insulin resistance and insulin secretion by water extracts of cordyceps militaris, phellinus linteus, and paecilomyces tenuipes in 90% pancreatectomized rats cordyceps sinensis-and rhodiola roseabased supplementation in male cyclists and its effect on muscle tissue oxygen saturation asian herbals: opportunities for marketing traditional chinese medicines in the west cordycepin, a metabolic product isolated from cultures of cordyceps militaris (linn.) link cordymax cs-4 improves steady-state bioenergy status in mouse liver mushrooms in medicine and culture in vitro evaluation of antioxidant activities of aqueous extracts from natural and cultured mycelia of cordyceps sinensis antitumor activity of cordyceps sinensis and cultured cordyceps mycelia rebuttal on comparison of protective effects between cultured cordyceps militaris and natural cordyceps sinensis against oxidative damage induction of heat shock proteins (hsps) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death vasodilating effect of cultured cordyceps sinensis (berk) sacc. mycelia in anesthetized dogs control of apoptosis by p53 effect of cordyceps sinensis on inhibiting systemic lupus erythematosus in mrl 1pr/1pr mice a novel immunosuppressant, isp-i, of isaria sinclairii effect of cordyceps sinensis on the th1/ th2 cytokines in patients with condyloma acuminatum effects of cordyceps sinensis on t lymphocyte subsets and hepatofibrosis in patients with chronic hepatitis b effect of cordyceps sinensis on tlymphocyte subsets in chronic renal failure isolation and identification of 3 0 -amino-3 0 -deoxyadenosine from cordyceps militaris determination of adenosine and 3 0 -deoxyadenosine in cordyceps militaris (l.) link. by hplc bioactive pterphenyl derivatives from a cordyceps-colonizing isolate of gliocladium sp preliminary study of cordyceps barnesii -comparison of the chemical constituents of cordyceps barnesii and cordyceps sinensis comment on comparison of protective effects between cultured cordyceps militaris and natural cordyceps sinensis against oxidative damage evaluation of the anti-inflammation screening model of macrophages cell line by the proinflammatory mediators secretions medium optimization for polysaccharide production of cordyceps sinensis in vivo and in vitro stimulatory effects of cordyceps sinensis on testosterone production in mouse leydig cells regulatory mechanism of cordyceps sinensis mycelium on mouse leydig cell steroidogenesis effects of extracted cordyceps sinensis on steroidogenesis in ma-10 mouse leydig tumor cells upregulation of steroidogenic enzymes and ovarian 17b-estradiol in human granulosa-lutein cells by cordyceps sinensis mycelium effects of cordyceps sinensis on testosterone production in normal mouse leydig cells cordyceps sinensis and its fractions stimulate ma-10 mouse leydig tumor cell steroidogenesis in vivo stimulatory effect of cordyceps sinensis mycelium and its fractions on reproductive functions in male mouse comparison of protective effects between cultured cordyceps militaris and natural cordyceps sinensis against oxidative damage co-n reaction-a new serological activity index-on wegener's granulomatosis world university rankings. the times higher education supplement a xanthocillin-like alkaloid from the insect pathogenic fungus cordyceps brunnearubra bcc 1395 bioxanthracenes from the insect pathogenic fungus cordyceps pseudomilitaris bcc 1620. ii. structure elucidation es-242 derivatives and cycloheptapeptides from cordycepssp. strains bcc 16173 and bcc 16176 structures of cordypyridones a-d, antimalarial n-hydroxy-and nmethoxy-2-pyridones from the insect pathogenic fungus cordyceps nipponica bioxanthracenes from the insect pathogenic fungus cordyceps pseudomilitaris bcc 1620. i. taxonomy, fermentation, isolation and antimalarial activity the immuno-enhancing effect of chinese herbal medicine cordyceps sinensis on macrophage j774 mycelial extract of cordyceps ophioglossoides prevents neuronal cell death and ameliorates beta-amyloid peptide-induced memory deficits in rats a mushroom lectin from ascomycete cordyceps militaris effect of medicinal plant extracts on forced swimming capacity in mice immunomodulatory activities of herbsnsenses tm cordyceps -in vitro and in vivo studies identification of cordycepin, a metabolite of cordyceps militaris, as 3 0 -deoxyadenosine the ikk nf-kappa b system: a treasure trove for drug development occurrence of gal beta (1-3) galnac-ser/thr in the linkage region of polygalactosamine containing fungal glycoprotein from cordyceps ophioglossoides polysaccharides in fungi. xxxii. hypoglycemic activity and chemical properties of a polysaccharide from the cultural mycelium of cordyceps sinensis polysaccharides in fungi. xxv. biological activities of two galactomannans from the insect-body portion of chan hua (fungus: cordyceps cicadae) structural features and hypoglycemic activity of a polysaccharide (cs-f10) from the cultured mycelium of cordyceps sinensis polysaccharides in fungi. xxxvi. hypoglycemic activity of polysaccharide (cs-f30) from the cultural mycelium of cordyceps sinensis and its effect on glucose metabolism in mouse liver a comparative study on the production of exopolysaccharides between two entomopathogenic fungi cordyceps militaris and cordyceps sinensis in submerged mycelial cultures larvicidal activity against plutella xylostella of cordycepin from the fruiting body of cordyceps militaris methanol extract of cordyceps pruinosa inhibits in vitro and in vivo inflammatory mediators by suppressing nf-jb activation optimization of submerged culture process for the production of mycelial biomass and exo-polysaccharides by cordyceps militaris c738 production and characterization of exopolysaccharides from an enthomopathogenic fungus cordyceps militaris ng3 ophiocordin, an antifungal antibiotic of cordyceps ophioglossoides hypocholesterolemic effect of hot-water extract from mycelia of cordyceps sinensis antifatigue and antistress effect of the hot-water fraction from mycelia of cordyceps sinensis activation of macrophages and the intestinal immune system by an orally administered decoction from cultured mycelia of cordyceps sinensis reinventing taxonomy: a curmudgeon's view of 250 years of fungal taxonomy, the crises in biodiversity, and the pitfalls of the phylogenetic age cicadapeptins i and ii: new aib-containing peptides from the entomopathogenic fungus cordyceps heteropoda homocitrullylaminoadenosine, a nucleoside isolated from cordyceps militaris inhibition of nucleic acid methylation by cordycepin. in vivo synthesis of s-3-deoxyadenosylmethionine by wil2 human lymphoblasts abrogation of streptococcal pyrogenic exotoxin b-mediated suppression of phagocytosis in u937 cells by cordyceps sinensis mycelium via production of cytokines cordyceps sinensis mycelium protects mice from group a streptococcal infection differentiation of cordyceps sinensis by a pcr-single-stranded conformation polymorphism-based method and characterization of the fermented products in taiwan growth inhibitors against tumor cells in cordyceps sinensis other than corydcepin and polysaccharides cordyceps sinensis as an immunomodulatory agent regulation of bronchoalveolar lavage fluids cell function by the immunomodulatory agents from cordyceps sinensis activation and proliferation signals in primary human t lymphocytes inhibited by ergosterol peroxide isolated from cordyceps cicadae medicinal and nutraceutical genetic resources of mushrooms a yanginvigorating chinese herbal formula enhances mitochondrial functional ability and antioxidant capacity in various tissues of male and female rats experimental study on effect of cordyceps sinensis in ameliorating aminoglycoside induced nephrotoxicity determination of nucleosides in natural cordyceps sinensis and cultured cordyceps mycelia by capillary electrophoresis anti-oxidation activity of different types of natural cordyceps sinensis and cultured cordyceps mycelia the contents and their change of nucleosides from natural cordyceps sinensis and cultured cordyceps mycelia simultaneous determination of ergosterol, nucleosides and their bases from natural and cultured cordyceps by pressurised liquid extraction and high-performance liquid chromatography the fruiting body and its caterpillar host of cordyceps sinensis show close resemblance in main constituents and anti-oxidation activity quality control of cordyceps sinensis, a valued traditional chinese medicine hypoglycemic activity of polysaccharide, with antioxidation, isolated from cultured cordyceps mycelia a polysaccharide isolated from cordyceps sinensis, a traditional chinese medicine, protects pc12 cells against hydrogen peroxide-induced injury rp-hplc determination of adenosine in fermented cordyceps effect of cordyceps sinensis on erythropoiesis in mouse bone marrow determination of ergosterol in cordyceps sinensis and cordyceps black-bone chicken capsules by hplc antitumor activity of cordyceps militaris on human cancer cell line inhibition of activated human mesangial cell proliferation by the natural product of cordyceps sinensis (h1-1): an implication for treatment of iga mesangial nephropathy inhibitory effect of cordyceps on carcinogenesis of the forestomach in mice oral administration of cordyceps does not affect lymphocyte subsets in stz-induced diabetic rats effects of fermented cordyceps powder on pulmonary function in sensitized guinea pigs and airway inflammation in sensitized rats effects of cordyceps sinensis (cs) on in vitro natural killer cells immuno-pharmacologic activity of cordyceps sinensis (berk) sacc anticarcinogenic effect and hormonal effect of cordyceps militaris link chemical constituents of cordyceps militaris (l.) link effect of fuzheng huayu recipe in treating posthepatitic cirrhosis influence of cordyceps sinensis (berk.) sacc. and rat serum containing same medicine on il-1, ifn and tnf produced by rat kupffer cells protection against radiation-induced bone marrow and intestinal injuries by cordyceps sinensis, a chinese herbal medicine inhibitive effect of cordyceps sinensis on experimental hepatic fibrosis and its possible mechanism anti-oxidation of paecilomyces sinensis (s. pnov.) intragastrically administered chinese herbal medicine cordyceps alleviates fasting hyperglycemia in diabetic rats anti-hyperglycemic activity of natural and fermented cordyceps sinensis in rats with diabetes induced by nicotinamide and streptozotocin the anti-hyperglycemic activity of the fruiting body of cordyceps in diabetic rats induced by nicotinamide and streptozotocin study on effect of cordyceps sinensis and artemisinin in preventing recurrence of lupus nephritis effects of the mycelial extract of cultured cordyceps sinensis on in vivo hepatic energy metabolism and blood flow in dietary hypoferric anaemic mice effects of the mycelial extract of cultured cordyceps sinensis on in vivo hepatic energy metabolism in the mouse hyperproduction of cordycepin by twostage dissolved oxygen control in submerged cultivation of medicinal mushroom cordyceps militaris in bioreactors antiarrhythmic effects of cordyceps sinensis (berk.) sacc medicinal mushrooms: a selective overview combined effects of cordyceps sinensis and methotrexate on hematogenic lung metastasis in mice inhibitory effect of cordyceps sinensis on spontaneous liver metastasis of lewis lung carcinoma and b16 melanoma cells in syngeneic mice activation of in vivo kupffer cell function by oral administration of cordyceps sinensis in rats antifibrotic effect of extracellular biopolymer from submerged mycelial cultures of cordyceps militaris on liver fibrosis induced by bile duct ligation and scission in rats pharmacological actions of cordyceps, a prized folk medicine the nephroprotective effects of the herbal medicine preparation, wh30+, on the chemicalinduced acute and chronic renal failure in rats isolation of galactosaminoglycan moiety (co-n) from protein-bound polysaccharide of cordyceps ophioglossoides and its effects against murine tumors the correlation between molecular weight and antitumor activity of galactosaminoglycan (co-n) from cordyceps ophioglossoides antitumor activity of protein-bound polysaccharide from cordyceps ophioglossoides in mice problems in the use of herbal and natural substances, with a specific example concerning the cardiovascular system growth inhibition of u937 leukemia cells by aqueous extract of cordyceps militaris through induction of apoptosis optimization of submerged culture conditions for the mycelial growth and exobiopolymer production by cordyceps militaris effect of agitation intensity on the exobiopolymer production and mycelial morphology in cordyceps militaris the coronamycin producer: a case of mistaken identity? ganoderma -a therapeutic fungal biofactory ganoderma disease of oil palm -a white rot perspective necessary for integrated control internal amplification controls have not been employed in diagnostic fungal pcr hence potential false negative results fungal enzyme inhibitors as pharmaceuticals, toxins, and scourge of pcr biochemical techniques for filamentous fungi solutions to penicillium taxonomy crucial to mycotoxin research and health inhibitory effect of cordyceps on carcinogenesis of the forestomach in mice cordyceps sinensis mycelium extract induces human premyelocytic leukemia cell apoptosis through mitochondrion pathway a cyclopeptide from the insect pathogenic fungus cordycepssp. bcc 1788 10-membered macrolides from the insect pathogenic fungus cordyceps militaris bcc 2816 optimum temperature and ph for mycelial growth of cordyceps nutans pat. (ascomycetes) studies on anti-tumor activity of crude drugs. i. the effects of aqueous extracts of some crude drugs in shortterm screening test militarinone a, a neurotrophic pyridone alkaloid from paecilomyces militaris (+)-n-deoxymilitarinone a, a neuritogenic pyridone alkaloid from the insect pathogenic fungus paecilomyces farinosus down-regulation of apoptotic and inflammatory genes by cordyceps sinensis extract in rat kidney following ischemia/reperfusion treatment of hyperlipidemia with cultivated cordyceps -a double-blind, randomized placebo control trial trade of cordyceps sinensis from high altitudes of the indian himalaya: conservation and biotechnological priorities effect of cordyceps militaris on the damage of rats induced by n-hexane profiles of nucleosides and nitrogen bases in chinese medicinal fungus cordyceps sinensis and related species pharmacological activities of paecilomyces japonica, a new type cordyceps sp anti-tumour and immuno-stimulating activities of the fruiting bodies of paecilomyces japonica, a new type of cordyceps spp antioxidant and immunostimulating activities of the fruiting bodies of paecilomyces japonica, a new type of cordyceps sp pharmacological basis of 'yin-nourishing' and 'yang-invigorating' actions of cordyceps, a chinese tonifying herb chemotaxonomy of pochonia and other conidial fungi with verticillium like anamorphs clinical study on application of bailing capsule after renal transplantation cordyceps sinensis and cultured mycelia phylogenetic classification of cordyceps and the clavicipitaceous fungi effects of cordyceps sinensis, rhubarb and serum renotropin on tubular epithelial cell growth dmso modifies structural and functional properties of rpmi-8402 cells by promoting programmed cell death rapid and specific detection of hydroxyl radical using an ultraweak chemiluminescence analyzer and a low-level chemiluminescence emitter: application to hydroxyl radicalscavenging ability of aqueous extracts of food constituents free radical scavenging and apoptotic effects of cordyceps sinensis fractionated by supercritical carbon dioxide effects of a watersoluble extract of cordyceps sinensis on steroidogenesis and capsular morphology of lipid droplets in cultured rat adrenocortical cells pharmacological functions of chinese medicinal fungus cordyceps sinensis and related species an experimental study on anti-aging action of cordyceps extract entomogenous fungi that produce 2,6-pyridine dicarboxylic acid (dipicolinic acid) immunomodulatory functions of extracts from the chinese medicinal fungus cordyceps cicadae anti-inflammatory and related pharmacological activities of cultured mycelia and fruiting bodies of cordyceps militaris lead poisoning caused by contaminated cordyceps, a chinese herbal medicine: two case reports structural analysis of a neutral (1 ? 3),(1 ? 4)-b-d-glucan from the mycelia of cordyceps sinensis medicinal herbal extracts -renal friend or foe? part two: herbal extracts with potential renal benefits optimization of submerged culture requirements for the production of mycelial growth and exopolysaccharide by cordyceps jiangxiensis jxpj 0109 studies on chemical constituents of cordyceps sinensis i application of statistically based experimental designs for the optimization of exopolysaccharide production by cordyceps militaris ng3 effects of cordyceps sinensis on natural killer activity and colony formation of b16 melanoma structure and antitumor activity of an alkalisoluble polysaccharide from cordyceps ophioglossoides augmentation of various immune reactivities of tumor-bearing hosts with an extract of cordyceps sinensis inhibitory effects of water extracts from fruiting bodies of cultured cordyceps sinensis on raised serum lipid peroxide levels and aortic cholesterol deposition in atherosclerotic mice antioxidant activity of the extracts from fruiting bodies of cultured cordyceps sinensis cordyceps sinensis mycelium induces ma-10 mouse leydig tumor cell apoptosis by activating the caspase-8 pathway and suppressing the nf-jb pathway effects of exopolysaccharide fraction (epsf) from a cultivated cordyceps sinensis fungus on c-myc, c-fos, and vegf expression in b16 melanoma-bearing mice efficacy of a pure compound h1-a extracted from cordyceps sinensis on autoimmune disease of mrl lpr/lpr mice h1-a extracted from cordyceps sinensis suppresses the proliferation of human mesangial cells and promotes apoptosis, probably by inhibiting the tyrosine phosphorylation of bcl-2 and bcl-xl effects of cordyceps militaris extract on angiogenesis and tumor growth antitumor activity of an extract of cordyceps sinensis (berk.) sacc. against murine tumor cell lines antitumour activity of cordycepin in mice hypoglycemic effect of cordyceps militaris pharmacological activities of stromata of cordyceps scarabaecola isolation and biological properties of polysaccharide cps-1 from cultured cordyceps militaris isolation, purification and identification of polysaccharides from cultured cordyceps militaris structural characterization and antioxidant activity of a polysaccharide from the fruiting bodies of cultured cordyceps militaris. carbohydr macrophage biospecific extraction and high performance liquid chromatography for hypothesis of immunological active components in cordyceps sinensis simultaneous determination of free ergosterol and ergosteryl esters in cordyceps sinensis by hplc anti-diabetic effects of ccca, cmess, and cordycepin from cordyceps militaris and the immune responses in streptozotocin-induced diabetic mice prosecutable function of cordyceps sinensis extracts for hepatic mitochondrial oxidative injuries in diabetic mice induction of hl-60 apoptosis by ethyl acetate extract of cordyceps sinensis fungal mycelium activation of murine peritoneal macrophages by natural cordyceps sinensis and its cultured mycelia lewis lung cancer of mice treated with cordyceps sinensis and its artificial cultured mycelia effects of the exopolysaccharide fraction (epsf) from a cultivated cordyceps sinensis on immunocytes of h22 tumor bearing mice immunomodulatory and antitumour effects of an exopolysaccharide fraction from cultivated cordyceps sinensis (chinese caterpillar fungus) on tumourbearing mice dynamical influence of cordyceps sinensis on the activity of hepatic insulinase of experimental liver cirrhosis influence of cordyceps sinensis on pancreatic islet beta cells in rats with experimental liver fibrogenesis epicoccins a-d, pipolythiodioxopiperazines from a cordyceps-colonizing isolate of epicoccum nigrum clinical and experimental studies on elimination of oxygen free radical of jinshuibao capsule in treating senile deficiency syndrome and its deoxyribonucleic acid damage repairing effects cordyceps sinensis -i as an immunosuppressant in heterotopic heart allograft model in rats cordymax cs-4 improves glucose metabolism and increases insulin sensitivity in normal rats inhibitory effect of cordyceps sinensis and cordyceps militaris on human glomerular mesangial cell proliferation induced by native ldl investigation on distribution and habitat of blaps rynchopetera fairmaire (coleoptera: tenebrionidae) in yunnan cordyceps sinensis in protection of the kidney from cyclosporine a nephrotoxicity inhibitory effects of alcoholic extract of cordyceps sinensis on abdominal aortic thrombus formation in rabbits mechanisms and therapeutic effect of cordyceps sinensis (cs) on aminoglycoside induced acute renal failure (arf) in rats effect of jinshuibao capsule on the immunological function of 36 patients with advanced cancer short-term curative effect of cultured cordyceps sinensis mycelia in chronic hepatitis b modulating effects of extractum semen persicae and cultivated cordyceps hyphae on immuno-dysfunction of inpatients with posthepatitic cirrhosis the scientific rediscovery of a precious ancient chinese herbal regimen: cordyceps sinensis part ii the scientific rediscovery of an ancient chinese herbal medicine: cordyceps sinensis part i immunosuppressive effect of cultured cordyceps sinensis on cellular immune response acknowledgements r.r.m. paterson is funded by grant sfrh/bpd/ 34879/2007 from fundac ßão para a ciência e a tecnologia, portugal. professor nelson lima, universidade do minho is gratefully appreciated for his unstinting support, as are other colleagues therein. l.e. gilbert, university of texas, austin was generous for allowing the use of his images of infected insects (fig. 1c-f ). marc stadler, university of bayreuth, germany is thanked for discussions. key: cord-315591-5ttn8beu authors: xie, yaofei; ma, mengdi; wu, wenwen; zhang, yupeng; zhang, yuting; tan, xiaodong title: dose–response relationship between intergenerational contact frequency and depressive symptoms amongst elderly chinese parents: a cross-sectional study date: 2020-09-15 journal: bmc geriatr doi: 10.1186/s12877-020-01751-0 sha: doc_id: 315591 cord_uid: 5ttn8beu background: given the high prevalence of depressive symptoms amongst the elderly chinese population and the significance of intergenerational contact in this demographic group, the purpose of this study was to examine the association and dose–response relationship between the frequency of intergenerational contact and depressive symptoms. methods: data were obtained from the third wave of the china health and retirement longitudinal study. a total of 5791 participants at age 60 or older were included in this study. depressive symptoms were defined by the 10-item version of the centre for epidemiologic studies depression scale. intergenerational contact included in-person meeting and remote connecting, and they were analysed separately. intergenerational contact frequency was classified into ten categories and then treated as a continuous variable for analysis. we performed univariate and multivariate logistic regressions to identify risk covariables. restrictive cubic spline analysis was used to examine the dose–response relationship between intergenerational contact frequency and the outcome of depressive symptoms. results: both the frequency of meeting and the frequency of connecting with children were independently associated with depressive symptoms in the elderly, and the odds ratios for depressive symptoms increased with decreasing frequencies (p < 0.01). there was a negative dose–response relationship between intergenerational contact frequency and depressive symptoms. the odds of depressive symptoms steadily decreased with increasing frequency of meeting with their children. following an initial increase, the odds rapidly decreased as the frequency of connecting with children increased with an inflection point at once a monthly. both associations were nonlinear (p < 0.001). conclusions: our findings revealed a negative dose–response relationship between intergenerational contact frequency and depressive symptoms in the elderly chinese population. thus, future health interventions should consider cultural norms in shaping the mental well-being of chinese elderly persons. depressive disorders amongst the elderly population is a worldwide public health problem [1] . the global health estimates reported by the world health organization (who) indicate that the prevalence of depressive disorders has peaked amongst the elderly [2] . in contrast to depressive disorders in younger populations, late life depression (major depressive disorders) is a risk factor for many chronic medical conditions [3, 4] . in addition, depression can result in significantly lower quality of life and increase mortality in the elderly population [5] [6] [7] . depressive symptoms are the major manifestations of depressive disorders. the prevalence of depressive symptoms varies between regions and populations. a study of elderly latinos in the united states reported a 25.5% prevalence of depressive symptoms [8] . another study reported a 14.0% prevalence in elderly americans of chinese descent [9] . two population-based studies conducted in germany [10] and greece [11] reported 28.7 and 32.3% prevalence of depressive symptoms amongst elderly, respectively. about 19 .0% of elderly koreans had depressive symptoms [12] . the 2008 chinese elderly mental health survey revealed that over 39% of the elderly participants self-reported depressive symptoms [13] . the 2011 china health and retirement longitudinal study (charls) also reported that approximately 40% of older adults had depressive symptoms [14] . china is facing a rapidly aging society; the proportion of elderly has grown from 13.3% [15] to 17.9% [16] of the population between 2010 and 2018. thus, there is a corresponding growth in the number of older people displaying depressive symptoms. previous studies have found that contact frequency with offspring is inversely associated with depressive symptoms amongst older parents [17] [18] [19] . one explanation is that older parents expect support from their children, and when their adult children do not meet expectations, depressive symptoms may arise [20] . it has been suggested that intergenerational contact is a critical aspect of social support for the elderly [21] , and the lack of which has been implicated in an increased risk of depressive symptoms [22] . indeed, intergenerational contact provides an opportunity for companionship, sharing of interests and opinions, and for expression of emotions. for the elderly, these opportunities foster a sense of belonging to the family, and they also enable family members to offer help and care [23] . children may provide a sense of meaning and order to life, and they may even be a source of self-esteem and prestige for the elderly [24] . intergenerational contact is important for elderly chinese people. chinese confucian cultures emphasises family and filial piety, and the practice of intergenerational contact is a part of filial piety. the absence of filial piety in the lives of chinese elderly is connected with depressive symptoms [25] [26] [27] . one study in elderly chinese-american also reported that those experiencing greater than expected filial piety had a lower risk of depressive symptoms [28] . more than ever, elderly chinese people experience less contact with their adult children. according to the china health and retirement report published by the charls team in 2019, the number of elderly people not living in the same city as any of their children rose from 8 to 11% between 2011 and 2015. in the same period, there was also an increase from 19 to 24% in adult children living in different cities from their parents, and increasing distance between children and parents was associated with less intergenerational contact [29] . in addition, the proportion of 'empty nesters' (i.e., parents who do not live with their adult children) have increased remarkably and now includes nearly half of the elderly population in the country [30] . it is estimated that the proportion of empty-nester households could reach 90% by 2030 [31] . several studies reported a high prevalence of depressive symptoms amongst empty nesters [32] [33] [34] . however, to our knowledge, no study has investigated the direct association between intergenerational contact frequency and depressive symptoms in the elderly chinese population. to address this gap in knowledge, the present study in elderly chinese participants aims to: (a) examine the association between intergenerational contact frequency and depressive symptoms, and (b) explore its dose-response relationship. data were obtained from the 2015 third wave survey data from the charls study. charls is an ongoing longitudinal study that collects demographic, social and economic data as well as the health status of nationally representative samples of middle-aged and elderly chinese residents. charls uses a four-stage sampling method. at the county and village levels, a probabilityproportional-to-size sampling method was used, and a total of 450 villages or communities were included. at the household and individual levels, the charls researchers designed a software package named char ls-geographic information system (charls-gis) to determine each sampling frame on the map. furthermore, a sample of 80 households was randomly selected from a list of all households in each sampling frame. in every household sample, a family member over 45 years old was randomly selected as the main interviewee. face-to-face interviews were then conducted by trained investigators to collect study data. the response rate was over 85% [35] . all the survey data are publicly available online. a total of 5791 participants were retained in the present study after removing the participants younger than 60 years and the participants with missing values on any of the main variables. the sample size was considered sufficient. depressive symptoms were determined using the 10item version of the centre for epidemiologic studies depression scale (ces-d-10) [36] . the cronbach's alpha of the chinese version of this scale was 0.813 [37] . the ces-d-10 contains three items addressing depressive affect, five addressing somatic symptoms, and two specifying positive affect. each item has four options: option 1, "rarely or none of the time (< 1 day)", option 2, "some or a little of the time (1 − 2 days)", option 3, "occasionally or a moderate amount of the time (3 − 4 days)", option 4, "most or all of the time (5 − 7 days)". participants are asked to recall the frequency of specific feelings and behaviours during the past week and to choose the most appropriate response. each item was rated from 0 to 3, corresponding to the first through fourth options. exception include 'item 5' and 'item 8', which are reverse-scored from 3 to 0. the total score of the ces-d-10 scale ranged from 0 to 30, and participants who scored ≥10 points were considered to have significant depressive symptoms [38] . two intergenerational contact types were analysed: inperson "meetings" and remote "connections" made either by phone, text message, postal mail or email. the frequency was categorised into ten numbered items, 1 = almost never, 2 = less than once a year, 3 = once a year, 4 = once every 6 months, 5 = once every 3 months, 6 = once a month, 7 = every 2 weeks, 8 = once a week, 9 = 2-3 times a week and 10 = almost every day. the participants were allowed to select the number closest to the actual frequency. the contact frequency of all adult children was recorded and co-resident children were included under the category of "almost every day". we collected basic demographic characteristics including gender, age, marital status, education level, and residence that have been reported to be associated with depressive symptoms amongst the elderly chinese population as control variables [39] [40] [41] . previous studies reported that the presence of chronic disease was significantly related to depressive symptoms in the elderly [42, 43] . conversely, old parents in poor physical health may stimulate increased contact with their children. so we used the variable of "number of chronic diseases suffered" to reduce the possibility of reverse causation. we analysed the intergenerational contact frequencies of all children in a family using the variable of "number of children" as a covariate to control for the effect of having multiple children. we first conducted a descriptive analysis of all the study variables. pearson chi-square tests and variance analyses were performed to assess differences in ces-d-10 scores and the prevalence of depressive symptoms in the subgroups. next, univariate and multivariate logistic regression models were used to calculate the unadjusted and adjusted odds ratios (ors) of the covariates to identify risk factors for depressive symptoms. finally, we used restrictive cubic splines with four knots at the 25th, 50th, 75th, and 95th centiles to explore the dose-response relationship between intergenerational contact frequency and depressive symptoms. in the restrictive cubic spline analysis, the significant risk factors identified earlier were adjusted in the model. the frequency of "meetings" and the frequency of "connections" were mutually adjusted. a likelihood ratio was used to test for non-linearity [44, 45] . missing values were accounted by using regression interpolation. statistical significance was set to p < 0.05, and all p-values were two-sided. table 1 displays the demographic characteristics, ces-d-10 scores, and the prevalence of depressive symptoms. among the 5791 participants, males accounted for about 56%, the average age was 69 years old, and over 60% were from 60 to 69 years old. nearly two-thirds of the participants were living with their spouse, and more than 70% lived in villages. uneducated participants accounted for about 30% of the sample, and nearly half of them completed education no further than elementary-level. nearly 60% of their household consumption expenditures per capita fell within 0-2000 rmb. more than 80% of participants reported that they were diagnosed with at least one type of chronic disease. over 90% of participants had more than one child. in terms of intergeneration contact frequency, participants that met with their children either at least once a week or 1-2 times a month accounted for approximately 30% of the sample each. over a quarter of participants met with their children 1-2 times every 6 months, and about 12% reported a frequency of ≤1 time per year. the participants who connected with their children either ≥2 times or 1 time a week accounted for approximately one-third of the sample each. about 15% of participants connected with their children 1-2 times a month, while others reported the frequency at ≤1 time every 3 months. the mean ces-d-10 score of all the participants was 8.83 ± 6.68. using ≥10 as the cut-off score, depressive symptoms were identified in 37.52% of the participants. the variance analysis and chi-square test results revealed that gender, marital status, residence, education level, number of chronic diseases, number of children, frequency of meeting with children, and frequency of connecting with children were each associated with differences in ces-d-10 scores and in the prevalence of depressive symptoms (p < 0.001). table 2 presents the results of the logistic regression models for the associated factors of depressive symptoms. the unadjusted ors for significant variables were calculated. we tested for collinearity on all independent variables using tolerance and variance inflation factors (vifs) before multivariate analyses. all values for tolerance were over 0.1 and all vifs were less than 10.0, therefore, there was no collinearity among independent variables. adjusted regression analysis showed that depressive symptoms were more likely to be identified in women (or: 1.69, 95% ci: 1.49-1.92); those who were divorced, widowed, never married, or cohabitated (or: 1.29, 95% ci: 1.13-1.47); those who lived in villages (or: 1.78, 95% ci: 1.47-2.14); those with a low education level; those who met up with their children less than once weekly; and those who connected with their children less than twice weekly. the odds of depressive symptoms increased with an increasing number of chronic diseases: 44, 74, and 234% for one, two, and three or more conditions, respectively. there was no significant association between the number of children and depressive symptoms. multiple logistic regression results demonstrated that intergenerational contacts were independently associated with depressive symptoms amongst the elderly chinese population. figure 1 illustrates the changes in ces-d-10 scores and prevalence of depressive symptoms in conjunction with (a) meeting with children in-person and (b) connecting with children remotely through different methods. overall, it shows that lower ces-d-10 scores and fewer depressive symptoms tend to trend with increasing frequency of intergenerational contact. figure 2 shows the dose-response relationship between depressive symptoms and intergenerational contact frequency resulting from restricted cubic splines analyses. the analyses were adjusted for the factors associated with depressive symptoms in multivariable logistic regression. both models were nonlinear (p < 0.001 for the non-linearity test). figure 2 (a )illustrates the steadily decreasing ors for depressive symptoms with an increasing frequency of meeting with children. remarkably, the odds of depressive symptoms show a significant inverse association with contact frequency when it falls below once monthly (frequency of meeting with children = 6). meanwhile, fig. 2(b) shows the ors for depressive symptoms increased slightly followed by a sharp decrease as the frequency of connecting with children increases. the inflection point for the changes in ors occurs at oncemonthly connections. (frequency of connecting with children = 6). the increasing social-structural constraints on resources and time have reduced intergenerational contact between the elderly chinese population and their adult children. considering china's traditional family culture and the special importance of intergenerational contact for this group, the present study investigated the relationship between intergenerational contact and depressive symptoms. we found overall prevalence of depressive symptoms in the participants was 37.5% as defined by a ces-d-10 score of ≥10, which is higher than the prevalence reported in the elderly japanese population of 11.5%. that study defined depressive symptoms using the geriatric depression scale (gds) with a cut-off score of ≥6 [46] . our result is also higher than the prevalence of 31.5% reported in elderly europeans; the results there were measured using the euro-d scale with a cut-off score of ≥4 [47] . by contrast, the prevalence for institutionalised elderly persons in brazil was 45.8% [48] and it was 60.6% in elderly nepalese [49] . depressive symptoms in these studies were also defined by the gds with a cutoff score of ≥6. the differences in these findings may be attributed to the economic and cultural differences amongst different regions. depressive symptoms amongst the elderly chinese are associated with low levels of education, unmarried status, and location setting of residence, which are consistent with several previous studies [39, 40, 50] . amongst the elderly chinese, intergenerational contact frequency is independently and inversely associated with depressive symptoms; it exhibits a negative dose-response relationship with the odds of depressive symptoms. for in-person interactions, the ors for depressive symptoms did not increase significantly with a decrease of frequency of interaction until they reached a frequency of ≤1 time monthly compared with those who have almost daily contact. the results suggest that children should meet up with their older parents at least once a month to possibly prevent them from developing depressive symptoms. this result is similar to a study in the u.s. that reported that the frequency of in-person interactions with children was inversely associated with the development of depressive symptoms in older parents [51] . for contact by telephone, postal mail, or email, relative to connecting almost everyday, the ors for depressive symptoms rapidly increased with a decrease in the frequency of connection. they reached an inflection point where connections were made once a month, whereby the ors decreased slightly with a decrease in contact frequency. we suggest that other forms of contact are more easily accessible, therefore parents expect a greater frequency of interaction with their children, and they develop depressive feelings more easily when there is a minor decrease in contact frequency. but when the frequency drops to once monthly, their depressive feelings reach a stable level but do not get worse. during the coronavirus disease 2019 (covid19) pandemic, quarantines were implemented to prevent disease transmission, but concurrently, they had a fig. 1 changes in ces-d-10 scores and in the prevalence of depressive symptoms relative to intergenerational contact frequency. frequency: 1 = almost never, 2 = less than once a year, 3 = once a year, 4 = once every 6 months, 5 = once every 3 months, 6 = once a month, 7 = every 2 weeks, 8 = once a week, 9 = 2-3 times a week and 10 = almost every day negative psychological impact [52] [53] [54] . our findings suggest that children should keep close connections with their older parents during periods of quarantine, which may help reduce the risk of depressive symptoms. the associations of depressive symptoms and intergenerational contact frequency might be related to three aspects. first, infrequent intergenerational contact leads to loneliness in older adults, thereby resulting in increased depressive symptoms. loneliness is a subjective and negative feeling that occurs when individuals experience diminished social relationships [55] . on the one hand, infrequent contact with family can heighten the risk for loneliness [56] , because loneliness is usually conceptualized as perceived social isolation [57] , and infrequent social contact is an objective measure of perceived social isolation [58] . moreover, chinese family culture attaches great importance to the happiness of a family union. thus, the elderly chinese are prone to loneliness when they are unable to receive sufficient companionship from their adult children. on the other hand, depressive symptoms were regarded as a logical consequence of loneliness [59] . previous studies have shown that loneliness is consistently and strongly associated with depressive symptoms [60] [61] [62] . therefore, loneliness may be an intermediate step between reduced intergenerational contact and depressive symptoms. second, infrequent intergenerational contact limits the availability of family support for the elderly. social support for many elderly adults comes from family members. specifically, intergenerational support is a primary component that may improve the psychological wellbeing of elderly parents [63] . poulin et al. [64] argued fig. 2 dose-response association between intergenerational contact frequency and the odds for depressive symptoms. frequency: 1 = almost never, 2 = less than once a year, 3 = once a year, 4 = once every 6 months, 5 = once every 3 months, 6 = once a month, 7 = every 2 weeks, 8 = once a week, 9 = 2-3 times a week and 10 = almost every day. or: odd raio; lb.: lower limit; ub: upper limit that family support from adult children can prevent depressive symptoms in elderly chinese people. conversely, loss of support from children is a key reason for the high prevalence of depressive symptoms in this population [13] . furthermore, part of intergenerational contact is the provision of home care, and it has been reported that the chinese elderly who worry about the lack of caregivers tend to have higher levels of depressive symptoms [65] . hence, decreased intergenerational contact may be related to reduced caregiving, thereby leading to increased depressive symptoms. third, infrequent intergenerational contact is not conducive to maintaining a good parent-child relationship. poor relationships are associated with depressive symptoms in the elderly. intergenerational contact is considered a critical indicator of the strength of the parent-child relationship [19] . frequent contact provides opportunities for companionship and socialising, thus promoting the parent-child relationship. li et al. [66] reported that parent-child relationships may directly affect depressive symptoms amongst the elderly chinese population. in addition, a study in elderly people living in the rural areas of the u.s. similarly concluded that parent-child relationships were inversely associated with depressive symptoms [67] . several limitations of this study should be addressed. we attempted to consider all children of survey participants who had multiple children. however, having infrequent contact with one child may matter less if other children maintain relatively more frequent contact. also the effects of contact frequency on depressive symptoms may be different between each child. thus, our use of the average frequency of intergenerational contact for parents with multiple children may produce bias. investigating these potential effects is beyond the scope of our study, but it is important for future studies to investigate each parent-child relationship or factors that contribute to differences between each child. next, we did not have study variables that described qualities stemming from intergenerational contact, such as loneliness, social support and parent-child relationships. therefore, comprehensive and structural relationships for these variables were not obtained. finally, the data were cross-sectional, which allowed us to analyse associations between variables, but a causal relationship between intergenerational contact and depressive symptoms could not be determined. to address these issues, future longitudinal analyses that feature additional variables should be conducted to enhance our understanding of the relationship between intergenerational contact and depressive symptoms. the present study demonstrates that lower intergenerational contact frequency with children is independently associated with greater depressive symptoms amongst the elderly chinese population. the ors for depressive symptoms show an increasing trend with decreasing frequency of contact with children of the participants. our results suggest that provision of depression prevention services should be considered for older chinese people. a number of demographic characteristics are related to depressive symptoms and should be taken into account during screening. scholars and policy makers should pay attention to family cultural norms when health interventions are considered in the elderly chinese population. depression in late life: review and commentary world health organization. depression and other common mental disorders: global health estimates. geneva: world health organization body mass index moderates the relationship between c-reactive protein and depressive symptoms: evidence from the china health and retirement longitudinal study changes in depression among older adults in china: a latent transition analysis depression among older adults: a 20-year update on five common myths and misconceptions family relationships and depressive symptoms among chinese older 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and relationship quality on depression among older rural adults publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the research team of charls are acknowledged for their work. authors' contributions yx conducted data analysis and is a major contributor in writing the manuscript. mm contributed in raw data processing, software application, and writing the manuscript. ww performed part of raw data processing, revised the manuscript. ypz and ytz revised the manuscript. xt designed and was responsible for the study. all authors read and approved the final manuscript. none. the datasets analysed during the current study are available in the charls repository: http://charls.pku.edu.cn/index/en.html. the authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the helsinki declaration of 1975, as revised in 2008. not applicable. the authors declare that they have no competing interests. key: cord-325380-uo1tdi1z authors: hu, caiyun; liang, mingming; gong, fengfeng; he, bin; zhao, dongdong; zhang, guoliang title: efficacy of lianhua qingwen compared with conventional drugs in the treatment of common pneumonia and covid-19 pneumonia: a meta-analysis date: 2020-09-17 journal: evid based complement alternat med doi: 10.1155/2020/5157089 sha: doc_id: 325380 cord_uid: uo1tdi1z methods: seven english and chinese databases were used to search for qualified experimental studies as of july 27, 2020. all data were extracted directly from the included studies, and no special conversion formula was used. the weighted mean difference (wmd), 95% confidence interval (ci), and odds ratio (or) were used for evaluation. results: forty-two studies involving 3793 subjects met the qualification criteria. for common pneumonia, a short duration of flu-like symptoms (wmd = −1.81, 95% ci = −2.12 to −1.50, p < 0.001), sputum (wmd = −1.10, 95% ci = −1.50 to −0.70, p < 0.001), pulmonary rale (wmd = −2.03, 95% ci = −2.74 to −1.31, p < 0.001), pulmonary imaging improvement (wmd = −1.88, 95% ci = −2.28 to −1.47, p < 0.001), curative effect (or = 3.65, 95% ci = 2.81 to 4.76, p < 0.001), and healing period (wmd = −1.68, 95% ci = −2.62 to −0.74, p < 0.001) were associated with the lianhua qingwen group; subgroup analysis based on flu-like symptoms showed statistically significant improvements in fever and cough. for covid-19 pneumonia, improvements in flu-like symptoms (or = 3.18, 95% ci = 2.36 to 4.29, p < 0.001), shortness of breath (or = 10.62, 95% ci = 3.71 to 30.40, p < 0.001), curative effect (or = 2.49, 95% ci = 1.76 to 3.53, p < 0.001), healing period (wmd = −2.06, 95% ci = −3.36 to −0.75, p = 0.002), and conversion of severe cases (or = 0.46, 95% ci = 0.27 to 0.77, p = 0.003) were associated with the lianhua qingwen group; subgroup analysis indicated statistically significant improvements of fever, cough, fatigue, and muscle pain in the lianhua qingwen group compared to the conventional drug group. regarding adverse reactions, no significant difference was detected for common pneumonia (or = 0.75, 95% ci = 0.54 to 1.05, p = 0.097). conclusions: lianhua qingwen combined with conventional drugs may be a promising therapy for treating common pneumonia and covid-19 pneumonia. traditional chinese medicine, with a thousand years of history in china, has been used to treat various diseases [1] [2] [3] [4] [5] . lianhua qingwen (连花清瘟), which is obtained by the reduction and addition of combined maxing shigan decoction and yin qiao powder, has been widely accepted as a broad-spectrum antiviral agent in the clinic [6] . it consists of 13 herbs: lian qiao (fructus forsythiae, weeping forsythia capsule, 连翘), 255 g; ma huang (herba ephedrae, ephedra, 麻黄), 85 g; jin yin hua (flos lonicerae, honeysuckle flower, 金银花), 255 g; ban lan gen (radix isatidis, criteria. an electronic search of pubmed, embase, the cochrane library, foreign medical literature retrieval service (frms), wanfang (a chinese database), vip (a chinese database), and cnki (a chinese database) was performed from the date of inception until july 27, 2020. for the english databases, the following terms were searched in the title, keywords, or abstract: ("lianhuaqinwen" or "lianhua qingwen") and ("pneumonia" or "lung inflammation" or "pulmonary inflammation" or "covid-19" or "coronavirus disease" or "novel coronavirus"). for the chinese databases, the search terms were "lianhuaqingwen" and ("feiyan" or "feibuyanzheng" or "covid-19" or "guanzhuangbindu"). studies were selected based on the following criteria: (1) experimental studies; (2) pneumonia was diagnosed according to clinical symptoms, laboratory tests, chest x-ray results, or relevant diagnostic criteria; (3) the lianhua qingwen group was treated with lianhua qingwen or lianhua qingwen combined with conventional drugs (the conventional drug group was given conventional antibiotics, antiviral drugs, or symptomatic treatment); and (4) relevant data of the efficacy index (i.e., flu-like symptoms (fever, cough, sore throat, nausea, diarrhoea, loss of appetite, fatigue, muscle pain, and headache); sputum; pulmonary rales; shortness of breath; breathlessness; chest tightness; pulmonary imaging improvement; curative effect; healing period; conversion of severe cases; and adverse reactions) were provided. e following types of studies were excluded: letters, case reports, those with duplicate or incomplete data (including those in which the efficacy index did not meet the inclusion criteria), reviews or commentaries, animal-based studies, irrelevant studies, and those with a non-western medicine control. e following information was collected: the first author's name, year of publication, age, sex, sample size, efficacy index, and adverse reactions. all data were extracted directly from the included studies, and no special conversion formula was used. continuous variables included the total number of patients with symptoms (reported as the mean and standard deviation), and categorical variables included the number of patients with symptoms and the number of patients without symptoms. disagreements were resolved by a panel discussion with other reviewers. e quality of the eligible studies was evaluated by the consort statement [13] and the jadad scale [14] , which considered sample size determination, randomization, blinding, and loss to follow-up/ withdrawal; scores of 0-2, 3-4, and 5-7 were rated as low, moderate, and high quality, respectively. e cochrane collaboration risk of bias tool [15] , which consists of seven items, was used to classify each item as low risk of bias, high risk of bias, and unclear risk of bias. statistical analysis was performed using stata 14 (stata corporation, college station, tx, usa). continuous variables are expressed as the weighted mean difference (wmd) and 95% confidence interval (ci), and categorical variables are expressed as the odds ratio (or) and 95% ci. heterogeneity was evaluated with the i 2 statistic: when i 2 > 50%, indicating obvious heterogeneity, a random-effects model was used; otherwise, a fixed-effects model was used [16, 17] . subgroup, sensitivity, and regression analyses were used to explore possible sources of heterogeneity. subgroup analysis was performed based on the pneumonia type or flu-like symptoms. sensitivity analysis was performed to assess the influence of each study on a pooled estimate by excluding studies individually and rerunning the meta-analysis. publication bias was assessed by begg's test and egger's test, and visual estimation (via a funnel plot) was also considered; if bias existed, the "trim and fill" method was used to assess publication bias [18] . a p value <0.05 was considered statistically significant. e detailed flowchart of article selection is presented in figure 1 . a total of 314 citations were identified, and of these, 148 duplicate citations were removed; 59 citations were excluded for irrelevant or animal studies by screening the title and abstract. after full-text screening of the remaining 107 citations, an additional 65 citations were excluded due to the reasons given in figure 1 . ultimately, 42 experimental chinese studies involving 3793 subjects were subjected to the meta-analysis. e publication year ranged from 2012 to 2020 . of these studies, 35 researched common pneumonia (including viral pneumonia, mycoplasma pneumonia, community-acquired pneumonia, bronchial pneumonia, bacterial pneumonia, or pneumonia), and the remaining 7 studies researched covid-19 pneumonia (diagnosed according to the national health commission of the people's republic of china published guidelines for the diagnosis and treatment of covid-19 pneumonia: trial version from the fourth/fifth edition). e control groups were given conventional antibiotics, antiviral drugs, or symptomatic treatment. e main characteristics and quality scores of the eligible studies on common pneumonia and covid-19 pneumonia are shown in table 1 . regarding the risk of bias assessment, 33 studies reported randomization (of which 12 studies clearly described the randomized methods), and the remaining 9 studies were grouped according to interventions or the hospitalization order. only one study reported allocation concealment and blinding method, since the symptom indicators needed to be measured by instruments or humans. erefore, most studies with blinded participants and personnel and a blinded outcome assessment were classified as "unclear risk of bias." concerning incomplete outcome data and selective reporting, since most studies reported complete data on all symptom indicators, there was a low risk of attrition bias and reporting bias. e percentage of risk of bias is shown in figure 2 . irty-one studies compared the duration of flu-like symptoms between the lianhua qingwen and conventional drug groups. among these studies, 29 reported the symptom remission time for fever, and 26 reported the symptom remission time for cough. a short duration of flu-like symptoms was observed in the lianhua qingwen group (wmd � −1.81, 95% ci � −2.12 to −1.50, p < 0.001). subgroup analysis showed significant differences in the durations of fever (wmd � −1.58, 95% ci � −1.99 to −1.17, p < 0.001) and cough (wmd � −2.07, 95% ci � −2.57 to −1.57, p < 0.001) between the lianhua qingwen and conventional drug groups. figure 3 shows a forest plot of flulike symptoms for common pneumonia. sputum. four studies reported the effects of lianhua qingwen and those of conventional drugs on the duration of sputum. e duration of sputum was shorter in the lianhua qingwen group than in the conventional drug group (wmd � −1.10, 95% ci � −1.50 to −0.70, p < 0.001). pulmonary rale. eighteen studies reported an effect on the duration of pulmonary rale. e duration of fever was shorter in the lianhua qingwen group than in the conventional drug group (wmd � −2.03, 95% ci � −2.74 to −1.31, p < 0.001). pulmonary imaging improvement. seven studies reported the duration of pulmonary imaging improvement. e difference between the lianhua qingwen group and the conventional drug group was statistically significant (wmd � −1.88, 95% ci � −2.28 to −1.47, irty studies reported the curative effect of lianhua qingwen and that of conventional drugs. e difference between the lianhua qingwen group and the conventional drug group was statistically significant (or � 3.65, 95% ci � 2.81 to 4.76, p < 0.001). healing period. twelve studies reported the healing period of the lianhua qingwen and conventional drug groups. e lianhua qingwen group had a shorter healing period than the conventional drug group (wmd � −1.68, 95% ci � −2.62 to −0.74, p < 0.001). results from the quantitative analysis of common pneumonia are shown in table 2 . forest plots of other symptoms related to common pneumonia are shown in figure s1 . four studies compared improving flu-like symptoms (fever, cough, sore throat, nausea, diarrhoea, loss of appetite, fatigue, muscle pain, and headache) between the lianhua qingwen and conventional drug groups. e difference in improving flu-like symptoms between the lianhua qingwen and conventional drug groups was statistically significant (or � 3. 18 figure 3 shows a forest plot of flu-like symptoms for covid-19 pneumonia. sputum. ree studies reported the improvement in sputum. e difference in sputum improvement was statistically significant between the lianhua qingwen and conventional drug groups (or � 4.30, 95% ci � 1.01 to 18.22, p � 0.048). shortness of breath. ree studies compared the effect of lianhua qingwen with that of conventional drugs on the shortness of breath, and lianhua qingwen was associated with a better effect than conventional drugs (or � 10.62, 95% ci � 3.71 to 30.40, p < 0.001). breathlessness. ree studies reported improvement in breathlessness in the lianhua qingwen and conventional drug groups. however, it failed to identify a statistically significant difference between the two groups (or � 4.81, 95% ci � 0.97 to 23.86, p � 0.055). ree studies reported the curative effect of chest tightness. a statistically significant difference was identified between the lianhua qingwen group and the conventional drug group (or � 3.02, 95% ci � 1.23 to 7.42, p � 0.016). pulmonary imaging improvement. five studies reported improvement in pulmonary imaging. a statistically significant difference was identified between the lianhua qingwen group and the conventional drug group (or � 1.77, 95% ci � 1.29 to 2.42, p < 0.001). curative effect. five studies compared the curative effect of lianhua qingwen with that of conventional drugs. a statistically significant difference was identified between the two groups (or � 2.49, 95% ci � 1.76 to 3.53, p < 0.001). healing period. two studies reported the healing period of the lianhua qingwen and conventional drug groups. e lianhua qingwen group was associated with a shorter healing period than the conventional drug group (wmd � −2.06, 95% ci � −3.36 to −0.75, p � 0.002). four studies reported the conversion of severe cases in both groups. a statistically significant difference was detected between the two groups (or � 0.46, 95% ci � 0.27 to 0.77, p � 0.003). results from the quantitative analysis of covid-19 pneumonia are shown in table 2 . forest plots of other symptoms for covid-19 pneumonia are shown in figure s2 . lv (2018) sun (2019) wang (2014) chen (2020) study id zhang (2018) lin (2019) xia (2019) tu (2015) wang (2015) gao (2014) wang (2013) dong (2014) zhang (2018) zhang (2018) chen (2018) hu (2018) yang (2016) liu (2017) han (2017) sun (2019) wang (2013) chen (2013) hu (2018) zou (2014) li (2014) liu (2014) meng (2015) tu (2015) zhou (2014) xu (2015) xia (2019) li (2014) wang (2015) zou (2014) lin (2019) wang (2014) jiang (2014) lv (2018) chen (2020) wang (2014) zhu (2015) chen (2013) xu (2012) zhu (2015) jiang (2014) yang (2016) han (2017) liu (2014) liu (2017) chen (2018) gao (2014) chen ( table 2 . figure 3 shows a forest plot of adverse reactions. table 3 . for common pneumonia, high heterogeneity was found in the following indexes: flu-like symptoms (i 2 � 98.0), sputum (i 2 � 62.2), pulmonary rales (i 2 � 97.1), pulmonary imaging improvement (i 2 � 56.5), and healing period (i 2 � 97.0). however, subgroup analysis did not indicate heterogeneity, and no source of heterogeneity was found in the sensitivity analysis. erefore, a meta-regression was performed to explore the likely source of heterogeneity, such as publication year, sample size, and quality score. e results indicated that these covariates could not explain all the heterogeneity and that the heterogeneity might be related to the inconsistency of conventional drugs used in each study and the individual absorption of drugs. for common pneumonia, high heterogeneity was found in the sputum index. since there are limited studies on covid-19 pneumonia, meta-regression was not performed. e results of the meta-regression are summarized in table 4 . e index involving the largest number of qualified studies was used to assess publication bias. for common pneumonia, 30 studies that reported curative effects were used to assess publication bias, and neither begg's test nor egger's test found any visible evidence for publication bias (p begg � 0.153, p egger � 0.577). since antibiotics are a traditional choice used to treat treating pneumonia; however, the inappropriate use of antibiotics leads to increasing problems such as antimicrobial resistance and is related to multiple adverse effects [61, 62] . according to recent research, the death toll will reach 10 million by 2050, due to infections caused by resistant bacteria [63] . a simple infection may be fatal in the future, and it is of crucial importance to identify and find an effective and safe alternative for treating pneumonia. traditional chinese medicine has been extensively used, as it offers unique advantages in regulating homeostasis and improving immunity, prevention, and control. lianhua qingwen is a traditional chinese medicine that can relieve fever, act as an antitussive expectorant, dispel a cold, eliminate inflammation, provide endogenous heat, act as an antiviral agent, and improve immunity [64] [65] [66] . some studies have reported that lianhua qingwen is effective against viral or bacterial infections in pneumonia [40, 46, 48, 67] ; however, its principle of treatment remains inconclusive. animal experiments have shown that lianhua qingwen plays a protective role in lung tissue damage by inhibiting inflammatory cell infiltration and improving protein expression in alveolar epithelial and pulmonary vascular endothelial cells [68] . pharmacological experiments have indicated that a high dosage of lianhua qingwen alters the effectiveness of cyclooxygenase-2 in the arachidonic acid metabolic pathway and decreases decrease virus replication, producing significant improvements in lung inflammation [69] . it was recently reported that lianhua qingwen plays a significant role in the treatment of pneumonia by significantly reducing pathological changes, which might be correlated with the levels of enzymes regulated by lianhua qingwen, such as glutathione peroxidase, lactate dehydrogenase, superoxide dismutase, and malonaldehyde [65] . previous studies reviewed historical records and prevention measures against sars, h1n1 influenza, and middle east respiratory syndrome (mers) and reported that traditional chinese medicine might be an alternative for the prevention and treatment of covid-19 pneumonia [70] [71] [72] [73] . lu et al. [74] reported that lianhua qingwen plays an active role in controlling covid-19 pneumonia, especially mild symptoms. our meta-analysis was performed to compare the effect of lianhua qingwen and conventional drugs on pneumonia symptoms. for common pneumonia, this study observed that the lianhua qingwen group was associated with shorter durations of flu-like symptoms, sputum, pulmonary rale, pulmonary imaging improvement, and healing period than conventional drugs; a statistically significant curative effect was also identified. e subgroup analysis based on flu-like symptoms showed statistically significant differences in fever and cough; sensitivity analysis showed that the pooled results related to common pneumonia were stable. a metaanalysis by zhou et al. [75] revealed that lianhua qingwen combined with another treatment for patients with community-acquired pneumonia could improve the effective rate and pulmonary imaging and shorten durations of fever and cough, consistent with our meta-analysis. however, our meta-analysis was more comprehensive, as more new studies were included, and other important indicators of pneumonia, such as pulmonary rale, sputum, and healing period, were also taken into account. for covid-19 pneumonia, we found that lianhua qingwen was more useful for improving flu-like symptoms, sputum, shortness of breath, chest tightness, pulmonary imaging improvement, curative effect, healing period, and conversion of severe cases than conventional drugs. subgroup analysis indicated statistically significant improvements in fever, cough, fatigue, and muscle pain; however, sensitivity analysis revealed unstable results related to sputum, chest tightness, and pulmonary imaging improvement. is inconsistency might be due to the limited number of eligible studies. only three qualified studies that reported curative effects of typical clinical symptoms were identified, and a further stratified analysis was unavailable for the meta-analysis. several recent studies support our conclusion that lianhua qingwen has a positive effect on the recovery of common pneumonia and covid-19 pneumonia. runfeng however, no other analysis was performed to detect possible sources of heterogeneity and assess the stability of the results. even though the efficacy and outcome indicators were not as complete as ours, the results support our results to a certain extent. our study found a statistically significant difference in adverse reactions between the lianhua qingwen group and the conventional drug group. although sensitivity analysis revealed changes in adverse reactions, subgroup analysis showed no significant difference concerning common pneumonia. yiling pharmaceutical, which is responsible for research on the production of lianhua qingwen, has reported no genotoxicity or nephrotoxicity of lianhua qingwen according to systemic toxicology studies [77] . a meta-analysis focused solely on the safety of lianhua qingwen that involved 40 rcts reported that the incidence of adverse reactions in the lianhua qingwen group was significantly lower than that in the control group (rr � 0.562, 95% ci � 0.412-0.767, p value not reported). subgroup analysis showed that the incidence of digestive system adverse reactions in the lianhua qingwen group was also lower than that in the control group (rr � 0.70, 95% ci � 0.50 to 0.97, p value not reported), suggesting the safety of lianhua qingwen [78] . previous studies have also shown that lianhua qingwen has therapeutic effects on influenza. ree meta-analyses explored the efficacy/safety of lianhua qingwen and conventional drugs for treating influenza. among them, wang et al. [79] showed that lianhua qingwen has a superior curative effect on the treatment of viral influenza, but the incidence of adverse reactions was higher than that of conventional drugs; therefore, clinicians should pay should pay close attention to the safety of lianhua qingwen. niu et al. [80] reported that lianhua qingwen was highly safe and had a better curative effect on evidence-based complementary and alternative medicine the treatment of influenza than oseltamivir, ribavirin, ammonia yellow capsules, and even huaqing pesti capsules. zhao et al. [81] concluded that lianhua qingwen was better than oseltamivir in improving the symptoms of influenza a virus infection, and no significant drug-related adverse reactions were observed in any of the included studies. us, these findings suggest that lianhua qingwen exerts better therapeutic effects by improving disease symptoms than conventional drugs, but the safety of lianhua qingwen cannot be ignored. additional studies with a focus on the safety and association of lianhua qingwen with diseases should be performed. several limitations to our meta-analysis should be noted. first, the quality of the included studies was generally moderate, and only seven studies on covid-19 pneumonia were included; thus, more high-quality research is needed. second, the results of some indicators of covid-19 pneumonia and adverse reactions were unstable. since the number of studies on covid-19 pneumonia were limited, publication bias and meta-regression analysis have not been performed. finally, although english and chinese articles were retrieved, only chinese studies were qualified; therefore, language bias might not be excluded. some advantages should be mentioned. first, to our knowledge, this is the most comprehensive meta-analysis of the efficacy of lianhua qingwen for the treatment of common pneumonia and covid-19 pneumonia. second, to our knowledge, this is the first meta-analysis of the use of lianhua qingwen for the treatment of pneumonia based on several indicators (i.e., sputum, curative effect, and healing period for common pneumonia; flu-like symptoms, shortness of breath, breathlessness, chest tightness, pulmonary imaging improvement, healing period, and conversion of severe cases for covid-19 pneumonia). finally, we determined that lianhua qingwen combined with conventional drugs can better promote the recovery of certain clinical symptoms related to common pneumonia and covid-19 pneumonia than conventional drugs. lianhua qingwen combined with conventional drugs may be a promising therapy for treating pneumonia, including common pneumonia and covid-19 pneumonia, but more high-quality studies are needed to explore the efficacy and mechanism of lianhua qingwen in treating pneumonia. e data used to support the findings of this study are available from the corresponding author upon request. e authors declare that they have no conflicts of interest. e lesson of supplementary treatment with chinese medicine on severe laboratory-confirmed sars patients e use of an herbal formula by hospital care workers during the severe acute respiratory syndrome epidemic in hong kong to prevent severe acute respiratory syndrome transmission, relieve influenza-related symptoms, and improve quality of life: a prospective cohort study a case of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome treated with chinese herbs utilization and practice of traditional/complementary/alternative medicine (tm/cam) in south africa protective essential oil 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mycoplasma pneumonia clinical observation of lianhua qingwen capsule in elderly community acquired pneumonia with fever clinical observation of lianhua qingwen granule in adjuvant treatment of community acquired pneumonia with heat toxicity analysis of the effect of lianhua qingwen granule in treating uremic complicated pneumonia comparison of lianhua qingwen capsule combined with western medicine and simple western medicine in the treatment of pulmonary infection observation on the therapeutic effect of lianhua qingwen capsule combined with azithromycin on community-acquired pneumonia clinical observation on treatment of 49 cases of viral pneumonia with lianhua qingwen capsule erapeutic effect of lianhua qingwen granules on community acquired pneumonia clinical observation of lianhua qingwen capsule in treating community acquired pneumonia observation on the efficacy and safety of lianhua qingwen granule in adjuvant treatment of pneumonia clinical effect of lianhua qingwen granules combined with moxifloxacin tablets in the treatment of acquired pneumonia in the elderly community observation of curative effect of lianhua qingwen granules combined ceftriaxone sodium for injection on the treatment of senile bacterial pneumonia observation on the therapeutic effect of lianhua qingwen granule on non-severe community-acquired pneumonia erapeutic effect observation of lianhua qingwen particles in treating patients with bronchopneumonia clinical evaluation of lianhua qingwen particle on treatment of pneumonia e observation of curative effect of lianhua qingwen capsule for 100 patients with upper respiratory tract infection and pneumonia observation observation on 38 cases of community acquired pneumonia treated by lianhua qingwen capsule efficacy of lianhua qingwen granule combined with moxifloxacin tablets in the treatment of elderly community-acquired pneumonia observed e rearch on clinical efficacy of facilitating the flow of lung-qi and ciear lung-heat observation on the therapeutic effect of lianhua qingwen capsule on community-acquired pneumonia clinical effectiveness and case analysis in 54 ncp patients treated with lianhua qingwen granules clinical observation on 63 suspected cases of new coronavirus pneumonia treated by lianhua qingwen granule combined with western medicine conventional therapy retrospective clinical analysis on treatment of novel coronavirus-infected pneumonia with traditional chinese medicine lianhua qingwen effects of lianhua qingwen granules combined with azithromycin on children with mycoplasma pneumoniae pneumonia lianhua qingwen granules for mycoplasma pneumoniae in children efficacy and safety of lianhua qingwen capsules, a repurposed chinese herb, in patients with coronavirus disease 2019: a multicenter, prospective, randomized controlled trial efficacy of lianhua qingwen combined with arbidol in the treatment of mild covid-19 pneumonia a clinical study on 34 cases of covid-19 pneumonia treated with combination of traditional chinese and western medicines clinical observation on 49 cases of non-critical covid-19 in shanghai treated by integrated traditional chinese and western medicine antibiotic use in children hospitalised with pneumonia in central vietnam short-course vs long-course antibiotic treatment for community-acquired pneumonia: a literature review tackling drug-resistant infections globally: report and recommendations e progress of lianhua qingwen capsule on respiratory system disease efficacy of lianhua qingwen granules in the management of chronic rhinosinusitis without nasal polyps effect of lianhua qingwen on immunity of mice infected with flu virus lianhua qingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (sars-cov-2) effect of lianhua qingwen capsules on inflammatory cytokines and junction protein expression in mice with acute lung injury induced by lipopolysaccharides identification of a pharmacological biomarker for the bioassay-based quality control of a thirteen-component tcm formula (lianhua qingwen) used in treating influenza a virus (h1n1) infection chinese herbal medicine for severe acute respiratory syndrome: a systematic review and meta-analysis traditional chinese herbal medicine as a source of molecules with antiviral activity traditional chinese medicine in the treatment of patients infected with 2019-new coronavirus (sars-cov-2): a review and perspective outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle a meta-analysis of the effect and safety of lianhua qingwen capsules in the treatment of community acquired pneumonia efficacy and safety of integrated traditional chinese and western medicine for corona virus disease 2019 (covid-19): a systematic review and meta-analysis announcement of shijiazhuang yiling pharmaceutical co., ltd. on media reports clinical drug safety of lianhua qingwen preparation: a systematic evaluation systematic review of efficacy and safety of lianhua qingwen capsules in treatment of viral influenza efficacy and safety of lianhua qingwen capsule for influenza: a systematic review efficacy of lianhua qingwen capsule compared with oseltamivir for influenza a virus infection: a meta-analysis of randomized, controlled trials research on clinical efficacy of facilitating the flow of lung-qi and clear lung-heart of community-acquired pneumonia (lung-heart syndrome) figure s1 : forest plot of the comparison between the lianhua qingwen group and the conventional drug group on other symptoms related to common pneumonia. figure s2 : forest plot of the comparison between the lianhua qingwen group and the conventional drug group on other symptoms related to covid-19 pneumonia. (supplementary materials) key: cord-353427-m7xwsqdk authors: cheng, peng; xu, li-zhi; zheng, wan-hong; ng, roger m.k.; zhang, li; li, ling-jiang; li, wei-hui title: psychometric property study of the posttraumatic stress disorder checklist for dsm-5 (pcl-5) in chinese healthcare workers during the outbreak of corona virus disease 2019 date: 2020-08-23 journal: j affect disord doi: 10.1016/j.jad.2020.08.038 sha: doc_id: 353427 cord_uid: m7xwsqdk background: previous studies about the reliability and validity of the updated pcl version for the fifth edition of the diagnostic and statistical manual for mental disorders (pcl-5) have only been evaluated in certain samples of the population, which lacks in the sample of healthcare workers. our study focused on the factor structure, reliability and validity of the pcl-5 among chinese healthcare workers during the outbreak of corona virus disease 2019. methods: we conducted an online survey of frontline healthcare workers using the pcl-5 for ptsd. total of 212 frontline healthcare providers were included in this study. results: the findings showed that pcl-5 is a reliable instrument in our sample. the total and subscale scores showed good internal consistency. the convergent and discriminant validity of the pcl-5 were also well demonstrated. our result showed a better fit with the seven-factor hybrid model compared with other models and supported that the pcl-5 chinese version can be used as a reliable screening tool to conduct psychological screening for chinese healthcare workers. limitation: we could not examine other aspects of reliability and validity like test-retest reliability or criterion validity. we didn't use the gold-standard structured interview for ptsd in our study. besides, most of our samples were young people who had access to the internet. not all professional levels and seniorities were presented because our sample had a lower mean income and educational level. conclusion: our study shows that the chinese pcl-5 has good validity and reliability in frontline healthcare workers during the outbreak. post-traumatic stress disorder (ptsd) is a mental health condition that occurs when an individual experienced or witnessed a terrifying and traumatic event that exceeds the limit of personal psychological endurance. ptsd can cause significant psychological distress, cognitive dysfunction, and impairment in social and occupational functionality. the serious negative effects can extend to other individuals, families, and even society (horesh & brown, 2018) . the four core symptoms of ptsd are repeated recurrence of traumatic experience, continuous avoidance of stimuli related to the traumatic event, negative cognitive and mood changes, and sustained increased alertness (american psychiatric association, 2013). ptsd is a commonly studied psychopathology in the aftermath of disasters because of its high incidence and burden among people who were exposed to disasters (north et al. 1999 ; galea et al. 2005) . while the rate of ptsd in the general population is between 5% and 10%, the incidence of ptsd can be as high as 45.9% among direct victims of disasters and ranges between 10% and 20% among rescue workers (neria et al. 2008 , luo et al. 2008 . a global meta-analysis of a total of which included 76,101 earthquake survivors shows demonstrated that shows nearly a quarter of earthquake survivors were diagnosed with ptsd (dai et al., 2016) . in addition, a survey of the survivors after following the 2008 wenchuan earthquake in china showed an incidence of ptsd as high as 45.9% (luo et al. 2008 ). also, results from a one-year follow-up study of severe acute respiratory syndrome (sars) patients documented a ptsd diagnosis rate of 38.8% (gao, hui, & lan, 2006) . with covid-19 patients were 52.0% more likely to have symptoms of depression, 57.0% more likely to have symptoms of anxiety (lai et al. 2020 ). the escalating ptsd among healthcare workers in this large public disaster call for a reliable assessment tool that can be used to evaluate this treatable condition. while there are many other instruments studied and being used in different settings, this article focuses on the posttraumatic stress disorder checklist for dsm-5 (pcl-5), a 20-item self-report measure that assesses the presence and severity of ptsd symptoms (weathers fw et al., 2013 number of core symptoms, it appears to be effective and reliable, and performs as well yields similar results as longer and more complex measurements (brewin, 2005) . with the release of the fifth edition of the diagnostic and statistical manual of mental disorders (dsm-5), the pcl has been updated to meet the new diagnostic criteria for ptsd (weathers fw et al., 2013) . the dsm-5 revised the diagnostic structure of ptsd from a three-factor-model with 17 symptoms to a four-factor-model comprising 20 symptoms. this change required a re-examination of reliability and validity of both the total and subscale of pcl-5. for the purpose of introduction of our current research, we briefly summarized the relevant studies on the psychometric properties of pcl-5: the reliability and validity of pcl-5 have been well studied in different populations. the internal consistency of the total score has been reported as 0.90-0.96 (for for the four subscales respectively, intrusions: α = 0.77 -0.92; avoidance: α = 0. although the dsm-5 proposed a four-factor model of ptsd that was based on a large collection of research evidence, many studies applying confirmatory factor analytic (cfa) have shown poor fit of dsm-5 model with the studied population. : a seven-factor model that was integrated from several six-factor models. it recently caught the most attention because it has been closely studied in different populations and proven to be the best fit for chinese earthquake survivors, trauma-exposed college students, veterans receiving care at a medical center and military service members seeking ptsd treatment while the rampant 2019-ncov outbreak in china calls close mental health attention, especially to those front-line healthcare workers. close contacts with those infected make them highly vulnerable, not only medically to infection but also psychologically to mental health illnesses. in order to better evaluate their mental health condition, and also to predict ptsd during and after this public health emergency, we developed a chinese version of pcl-5 and tested its reliability, convergent and divergent validity. as the factor model of the pcl-5 was inconclusive from previous studies, given that the seven-factor model has been proven to fit well in different studies, this study aims to test the structural validity of this pcl-5 chinese version and compare the seven-factor hybrid model with other models suggested in the literature. convenience sampling was used in this study. participants were recruited from a hospital in the second xiangya hospital, affiliated with central south university. which was one of the designated hospitals for suspected fever patients 2019-ncov the hospital is located in changsha city, hunan province, china. we conductedthis study within was conducted between two months of the outbreak from february 1 st and to february 25 th , 2020, within two months of the coronavirus outbreak. during which time, the peak number of confirmed cases during the study period was 58,097 in china. the study hospital is a general hospital with a capacity of 3500 beds. it is one of the designated hospitals by the chinese government to admit febrile patients to rule out 2019-ncov infection .to take care of all patients with fever and suspected 2019-ncov infection. the participants were were all actively involved in the direct care of these patients. all participants in this study were frontline medical residents or clinical lab specialists at a high risk of infection and psychological stress. we chose an online questionnaire to survey because: (1) face-to-face survey was impractical given the requirement of quarantine and risk of viral transmission from close personal interaction. (2) the online survey is was fast, easy and convenient for efficient data collection and analysis. participants were selected from those hospital departments of the hospital that are involved either direct contact care to suspected or confirmed 2019-ncov cases or direct handling of biospecimen. this includes included the emergency department, outpatient clinic, clinical lab, radiology, infectious disease, pulmonology, and intensive care unit. the policy of central south university required every radiology resident to conduct direct patient interview and be involved in performing image scanning with the radiology technologist. the studied clinical lab specialists are medical doctor equivalent trainees who graduated from medical school with a preventive medicine degree. one selection criterion is was that the current working environment is at high risk of infection, i.e, reported close contact with 2019-ncov patients or pathgen. a total of 212 subjects were successfully recruited in this study. the sample (n = 212) was diverse in terms of demographic characteristics (table 2 ). since this survey was a web-based self-report, in order to ensure the accuracy, only the individuals aged from 18 to 45 were included. the exclusion criteria included inability to consent, cognitive deficit, severe depression, schizophrenia, bipolar disorder or other mental disorders. the inclusion and exclusion criteria questions were asked by the study personnel to assess the participant's eligibility at the beginning of the survey. this cross-sectional study was approved by the ethics committee of the second xiangya hospital, central south university. the pcl-5 is a self-report measure that consists consisting of 20 items that correspond to the dsm-5 criteria for ptsd. the pcl-5 has 4 subscales, corresponding to each of the symptom clusters in the dsm-5. participants rate how much a problem described in the item statement bothered them over the past month on a 5-point scale from 0 (not at all) to 4 (extremely). item scores are summed to yield a total score ranging from 0 to 80. a chinese version of pcl-5 was developed and used in a previous study on the earthquake-related ptsd symptomatology (wang et al., 2015) . we revised this previously studied pcl-5 chinese version by using translating-callback method (f, c, & d, 1993). after the original version was translated into chinese by two chinese native speaker researchers, the translation was then back-translated into english by two medical english specialists. the back-translation was compared with the original english version. then a psychiatrist and two clinical psychologists reviewed and verified the accuracy of the translation. minor edits were subsequently made until the chinese version of the pcl-5 was adequate. descriptive analysis was used to characterize the study sample in terms of demographic information. for reliability test, the internal consistency of pcl-5 was accessed using cronbach's alpha coefficient, where 0.70 was considered satisfactory (santos, 1999) . analyses were performed using the spss 25.0 and amos 17.0. we summarized the participants' characteristics in table 2 . a total of 212 healthcare providers were included in this study. more than 50% of the participants were recruited from the emergency room, the infectious disease and the pulmonolgy department. together with the intensive care unit, they represented the mainstream medical staff responsible for the diagnosis and treatment of all suspected and confirmed 2019-ncov patients. the monthly income of the majority of subjects was less than 3,000 cny, only 5.2% reported a monthly income greater than 3,000 cny. the income level of subjects was relatively low, due to them still being in the rotation training phase. participants reported an average sum score of 38.81 (sd =12.40) on the pcl-5. means, standard deviations, minimum and maximum values for pcl-5 are presented in table 3 . participants reported an average sum score of 38.8 (sd = 12.4) on the pcl-5. because the cut score is 33 for provisional ptsd diagnosis, 59% of the sample met the criteria of provisional ptsd diagnosis. cronbach's alphas were calculated for the internal consistency of pcl-5. the cronbach's coefficients of subscale scores in terms of the seven-factor model and dsm-5 four-factor model were summarized in table 3 . the cronbach's alpha coefficient of the total score was 0.91, which exceeds the 0.70 level and indicates the high reliability of the pcl-5 chinese version. internal consistency reliability for each subscale is also satisfactory(0.74-0.90). first, we performed an efa with the sample data to explore the underlying structure of pcl-5. the efa showed that the data were appropriate for factoring as shown in table 5 , the factor load of each item on all corresponding subscales was greater than 0.7 in the seven-factor model. average variance extracted (ave) was greater than 0.5, and composite reliability (cr) was greater than 0.8. these results supported a good convergent and discriminant validity of the chinese version of pcl-5 we developed. table 6 , there is an obvious correlation between all subscales, and the correlation coefficient was less than 0.5 and the corresponding square root of ave. this indicates indicated that there was a certain correlation between the factors but also a certain degree of discrimination, indicating demonstrating a good discrimination validity. the current study was designed to test the reliability and validity of a chinese version of pcl-5 in 2019-ncov epidemic direct care healthcare workers. the study focused primarily on 2019-ncov related trauma. we showed that the pcl-5 chinese version has satisfactory internal consistency and validity. besides additionally, we tested the underlying latent structure of the questionnaire. our results indicated that the seven-factor structure of pcl-5 is a reasonable screening instrument among chinese this study also demonstrated proved that the chinese version of pcl-5 has good convergent validity and discriminant validity of the chinese version of pcl-5. the load of each item in its corresponding dimension was greater than 0.7, which confirmed that the high representativeness of the items it contains. we can interpret that the chinese version of pcl-5 has this translated to a good convergent validity, and t the fact that those items have better correlation between items and its with their corresponding subscale or summary score was higher than that between item and with the non-corresponding subscales or summary score, indicates indicated a good divergent validity of the instrument. another outcome of this study is was that a high percentage of subjects (59%) reported ptsd symptoms (average sum score of 38.8) and met the criteria of provisional ptsd diagnosis. this is wasconsistent with the findings from another recently published chinese study in the covid-19 crisis (lai et al., 2020) that reported among nearly 1,300 chinese frontline healthcare workers, 71.5% reported feelings of distress, although a lower percentage (44.6%) had symptoms of anxiety. in this article, the authors used the 22-item impact of event scale-revised (ies-r) and the 7-item generalized anxiety disorder (gad-7) scale to assess the severity of symptoms of distress and anxiety. the ies-r is a 22-item self-report measure of ptsd symptom severity with broader coverage than pcl-5. the majority of participants (60.5%) were medical staff in wuhan -the most affected city in china. another difference is that they used the gad-7 to assess generalized anxiety in the past two weeks. as pcl-5 also evaluates other ptsd symptoms than anxiety, those people who scored high in our study may not be detected from gad-7. despite the important findings of this study, tthere are limitations with this studywhich warrant disclosure. first, due to the limited number of test scales, we could not examine other aspects of reliability and validity such as test-retest reliability or criterion validity. and we did not use other scales to evaluate ptsd symptoms and other psychological characteristics to assess convergent and divergent validities of the pcl-5. further research is needed to compare the pcl-5 results with the diagnosis and symptoms determined using the gold-standard structured interview for ptsd, such as the clinician administered ptsd scale for dsm-5 (caps-5). it is also necessary to test the relevance of pcl-5 to other scales to assess convergent and divergent validity. second, the participants were limited to frontline healthcare workers in a designated treatment hospital for 2019-ncov. the traumatic event was relatively simplistic, only limited to the risk of infection of one kind of disease. to generalize the results, we need further studies to test the psychometric properties of pcl-5 in different populations and various traumatic events. third, due to contagious property of the new coronavirus, our study was conducted online with an intention to minimize the risk of virus transmission. the findings may not apply to paper-and-pencil based assessments. however, the psychometric information we obtained can offer some insights into similar research conducted remotely. forth, the samples of our study were from the departments with a relatively high risk of exposure to 2019-ncov, medical staff in other departments with lower exposure risks may have different symptomology therefore deserves future study. however, the psychometric information we obtained can offer some insights into similar research conducted remotely. finally, our participants did not represent all age groups because only those with access to the online questionnaire, mostly young, were able to complete the survey. not all professional levels and seniorities were presented because our sample had a lower mean income and educational level in comparison with the general population of healthcare providers in china. to our knowledge, this study is the first to test the reliability and validity of the chinese version of pcl-5 using a representative sample of frontline healthcare workers during the 2019-ncov outbreak. we have shown that the pcl-5 chinese version is a feasible, reliable, and structurally valid instrument for screening ptsd in frontline healthcare workers. our result demonstrated a better fit with the seven-factor hybrid model compared with other models and supported that the pcl-5 chinese version can be used as a reliable screening tool to conduct psychological screening for chinese healthcare workers during the outbreak of 2019-ncov. we also found that almost 60% of healthcare workers met the criteria of provisional ptsd diagnosis. this helps establish and improve the warning mechanism of ptsd crisis for early intervention of potential ptsd patients during and after covid 19 2019-ncov disaster. limitations of this study include the small sample size and health disaster focus. for better generalizability, future studies on a larger population and other occupational samples are needed. the authors declared that they have no conflicts of interest to this work. we declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. peng cheng: data collection, literature review, translation and manuscript drafting. of the funding source: this study was supported by the national key r&d program of china hunan provincial natural science foundation of china jennifer marton and dr. ahmed aboraya for the help of english language proofreading and editing. thanks also to dr diagnostic and statistical manual of mental disorders structural equation modeling in practice: a review and recommended two-step approach a systematic literature review of ptsd's latent structure in the diagnostic and statistical manual of mental disorders: dsm-iv to dsm-5 dimensional structure of dsm-5 posttraumatic stress symptoms: 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treatment-seeking military service members key: cord-316853-vaea6siv authors: xie, nanzhen; qin, yan; wang, taiwu; zeng, ying; deng, xia; guan, li title: prevalence of depressive symptoms among nurses in china: a systematic review and meta-analysis date: 2020-07-07 journal: plos one doi: 10.1371/journal.pone.0235448 sha: doc_id: 316853 cord_uid: vaea6siv background: depression is one of the most common mental disorders, profoundly impacting an individual’s performance and quality of life. due to their unique working conditions, nursing is counted among the occupational groups at high risk for developing depression. because of the shortage of nursing resources in china, chinese nurses suffer from heavy daily workloads more than those in many other countries. therefore, this study aimed to evaluate the overall prevalence of depressive symptoms and analyse the potential risk factors of depressive symptoms in chinese nurses. methods: a systematic literature search in pubmed, embase, web of science, the chinese biomedical literature database (cbm), the china national knowledge infrastructure (cnki), and the weipu and wanfang databases up to dec 31st, 2019 was performed regarding the prevalence of depressive symptoms in chinese nurses. eligibility assessment and data extraction were performed independently by 2 researchers, and meta-analysis was used to synthesize the data. heterogeneity was evaluated using cochran’s q test and quantified using the i(2) statistic. to explore the potential source of heterogeneity, subgroup analyses were also performed. in addition, both funnel plot and egger’s tests were adopted to assess publication bias. results: a total of 102 studies published from 1996 to 2019 covering 22 provinces were included for further analysis. the total number of participants was 52,592, with a range of 46 to 7205 per study. the overall prevalence of depressive symptoms in chinese nurses was 43.83% (95%ci: 40.26%-47.42%), and 31.12% (95%ci: 27.30%-35.07%) were classified as mild degrees of depressive symptoms. the prevalence of depressive symptoms may be significantly affected by region, province or municipality and department marital status. moreover, an increasing trend in the prevalence of depressive symptoms was observed in recent years. conclusion: the results presented a high prevalence of depressive symptoms among chinese nurses, which suggests interventional programmes by health decision-makers to improving the mental state of nurses is needed urgently, especially in nurses with high risk factors for depressive symptoms. furthermore, the nationwide investigation of depressive symptoms prevalence should be performed with a standard diagnostic tool, which may be more useful for policy makers and planners. a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 the results presented a high prevalence of depressive symptoms among chinese nurses, which suggests interventional programmes by health decision-makers to improving the mental state of nurses is needed urgently, especially in nurses with high risk factors for depressive symptoms. furthermore, the nationwide investigation of depressive symptoms prevalence should be performed with a standard diagnostic tool, which may be more useful for policy makers and planners. depression is one of the most commonly diagnosed mental disorders or statuses, sometimes resulting in serious damage to the patient's work ability [1, 2] , performance [3, 4] , interpersonal communications, physical health [5, 6] , and quality of life [7] ; some cases of depression may even result in the patient committing suicide [8] . according to the world health organization (who), approximately 300 million people of all ages suffer from depression worldwide, with an increase of more than 18% between 2005 and 2015. the global point, one-year and lifetime prevalence of depression are 12.9%, 7.2% and 10.8% respectively [9] . depression is one of the biggest sources of disability and imposes a considerable economic burden on society [10] . in addition, more women are affected by depression than men [11] . it has been reported that doctors and nurses are one of the highest risk groups for developing depression [12] . special working conditions, such as burnout [13, 14] , high tension, overloaded clinical work, and occupational stress, seriously threaten the mental health of nurses. in addition, nurses often have to witness many different life events, such as disease, trauma, and even death, which imposes further physical and psychological effects on them. because of the shortage of resources for nurses in china, chinese nurses suffer from heavy daily workload more than those in any other country. the psychological status of nurses not only directly affects their own health but also affects the quality of medical care provided for their patients in a hospital setting [15] . some studies have shown that the most common psychological problems experienced by nurses are anxiety and depression [16] , and the incidence of depression in nurses has been showing an increasing trend [17, 18] . at present, relevant studies at home and abroad have found that there is a very high prevalence of depression in the nurse population [19, 20] . for example, studies from usa, taiwan, and south korea found the depressive symptoms prevalence in nurses population ranged from 18% to 61.7% [21] [22] [23] [24] [25] . furthermore, a total of 46 cases of nurse suicide were reported or published from 2007 to 2016 [26] . although various studies have been published in different regions in chinese mainland, there has been no systematic comprehensive study about the prevalence of depressive symptoms. therefore, the primary aim of this study is to quantitatively assess the prevalence of depressive symptoms in nurses from chinese mainland and its primary related influencing factors by systematic review and meta-analysis. all potential articles from pubmed, embase, web of science, the chinese biomedical literature database (cbm), the china national knowledge infrastructure (cnki), and the weipu and wanfang databases were obtained by electronic search. the last search for all databases was performed on dec 31st, 2019. the keywords used for relevant studies were ("prevalence" or "frequency" or "epidemiology") and ("depression" or "mental health disorder" or "major depression disorder" or "mood disorder" or "affective disorder") and ("nurses" or "nurse") and ("china" or "chinese"). each keyword was searched individually or in combination to avoid missing relevant articles and maximize outputs. manuscripts that fulfilled all the following criteria were included for further analysis: (1) crosssectional study, or cohort studies that reported the prevalence of depressive symptoms; (2) targeted objects were nurses in chinese mainland; (3) data available for depressive symptoms prevalence and corresponding depression scale; (4) the depression measuring scales adopted for depression assessment were well recognized internationally, for example, zung's self-rating depression scale (sds) [28] . studies that met the following criteria were excluded: (1) not an original study, such as a review or editorial; (2) non-peer-reviewed local or government report or conference abstract; (3) studies from regions of china other than chinese mainland (including hong kong, macao, and taiwan); (4) duplicate published studies; (5) nurses that were in specific training stages: students, standardized training or rotation; (6) nurses with specific characteristics, including pregnancy, perimenopause, and nurses suffering from trauma following an earthquake; (7) studies with small sample sizes (n<45). to evaluate the selected articles, the 'ahrq cross-sectional/prevalence study quality checklist' [29, 30] was used as a research instrument. which is the most widely accepted quality assessment tool for a cross-sectional study [31] . this instrument is available at http://www. ncbi.nlm.nih.gov/books/nbk35156/ and also can be found in the s1 table. the instrument includes 11 items, which are answered with "yes", "no" and "unclear" respectively. 1 point will be given if one item is satisfied, and 0 point will be given for items not involved or unclear in the study. article quality was assessed as follows: low quality = 0-3; moderate quality = 4-7; high quality = 8-11. the evaluation was conducted independently by two authors, and possible disagreements were settled through discussions with a third author. the following information was extracted from all included studies: title, year of publication, province, sample size, number of positive cases, diagnostic methods and other potential factors that may affect the prevalence of depressive symptoms in nurses and that was provided in the studies. some of studies did not contain all the above-mentioned variables. point estimates and 95% confidence intervals (95%cis) for the prevalence rate of depressive symptoms in nurses were calculated for each study. to avoid having a confidence interval (ci) outside of the 0-1 range as well as studies with large weightings when the prevalence proportion becomes too small or too large, we calculated prevalence estimates with the variance-stabilizing double arcsine transformation [32] . statistical heterogeneity was evaluated by cochran's chi-squared test (with p < 0.10 indicating statistically significant heterogeneity) and the statistic i 2 [33] . heterogeneity with an i 2 of 0 to 40% was treated as not important, while an i 2 of 30 to 60% was treated as moderate heterogeneity, i 2 of 50 to 90% was treated as substantial heterogeneity and i 2 of 75 to 100% was treated as considerable heterogeneity [34] . if obvious heterogeneity existed (with p < 0.10), a random effects model was adopted for pooled results; otherwise, a fixed effects model was adopted. fixed-effect models assume that the population effect sizes are the same for all studies [35] . in contrast, random-effects model attempted to generalize findings beyond the included studies by assuming that the selected studies are random samples from a larger population [36] . furthermore, to identify potential influential studies, sensitivity analysis was performed by sequentially removing individual studies and evaluating the effect on the overall estimate. in addition, subgroup analysis was performed based on other potential sources of heterogeneity, such as province, regions (northwest, southwest, northeast, south, central, east and north china), severity of depressive symptoms, department, gender, age, job title, marriage, education background, shift work and hospital grade (if available). furthermore, meta-regression was also performed to identify the causes of heterogeneity or examine the impact of moderator variables on study effect size of the prevalence. publication bias was examined by funnel plots, and statistical significance was assessed by egger's test. in addition, for the meta-analysis, we assumed that the included studies were a random sample from each study population. meta-analysis was carried out with the "meta" package version 4.11-0 [37] and graphical representation with ggplot2 package version 3.3.0 [38] of r language version 3.6.3 [39] . through the initial search, a total of 3142 potentially relevant citations were identified. a total of 264 duplicate papers were removed first, and 2734 papers were excluded after scanning their titles and abstracts. after screening the full texts of the included articles, 42 studies were excluded for the following reasons: prevalence unreported(n = 28); intervention study of small samples(n = 5); no mention of psychological scale(n = 4); duplicates (n = 3); wrong data (n = 1); after psychological intervention(n = 1). finally, a total of 102 studies meeting the inclusion and exclusion criteria were included for further analysis (fig 1) , of which 3 were published in english-language journals, and the others were published in chinese-language journals. the basic characteristics of the final included studies are shown in s1 table. these studies were published ranging from 1996 to 2019, covering 22 provinces, autonomous regions and municipalities. the scales used for depression assessment were listed as follows: zung's self-rating depression scale (sds) [28] , centre for epidemiologic studies-depression scale (ces-d) [40] , beck depression inventory (beck) [41] , beck depression inventory (2nd ed) (bdi-ii) [42] , hospital anxiety and depression scale (hads) [43] , hamilton depression rating scale (hamd) [44] , and patient health questionnaire (phq-9) [45] . the total number of participants was 52,592, with a range of 46 to 7205 per study. the ahrq cross-sectional/ prevalence study quality checklist was applied to evaluate the study quality (s1 and s2 tables). among the selection items, the evaluation results ranged from 2 to 8, with the median score was 4. overall, 65 of 102 studies have moderate or high quality, indicating a medium quality of the studies included. a total of 28,382 cases among the 52,592 nurses in the studies were found to have different degrees of depressive symptoms; the overall prevalence of depressive symptoms in nurses was 43.83% with 95%cis of 40.26%-47.42%, with significant heterogeneity (i 2 = 98.50%, p < 0.01). a total of 37 studies reported different degrees of depressive symptoms. after we pooled the results based on the severity of the depressive symptoms, the pooled prevalence and 95%cis were 31 geographic analysis based on provinces and regions was performed. we found that the highest prevalence of depressive symptoms was in nurses from the northeast (54.69%, 95%ci: 50.51%-58.84%) and the lowest was in south china (37.59%, 95%ci: 32.75%-42.56%) ( table 1 ). the prevalence of depressive symptoms in nurses among different provinces is shown in table 1 . the highest and lowest prevalence of depressive symptoms were found in hubei province (58.62%, 95%ci: 49.55%-67.41%) and in inner mongolia (22.41%, 95%ci: 5.39%-46.20%), respectively. overall, the geographic location could significantly affect the prevalence, regardless of whether it was broken down by region or province. we also performed subgroup analysis by year. as shown in fig 3, the lowest and highest prevalence were 26.64% (95%ci: 21.27%-32.38%) in 1999 and 62.99% (95%ci: 53.22%-72.26%) in 2017, respectively. concerning the results of subgroup differences for prevalence in different years, a significant difference in terms of the prevalence trends was also found (p < 0.01). other factors that may affect the prevalence of depressive symptoms in nurses were also analysed. the pooled estimates by potential risk factors associated with depressive symptoms in nurses are presented in tables 2 and 3 . of all factors analysed in our study, the prevalence of depressive symptoms was significantly affected by department (table 2) ; the lowest prevalence in addition, we also found that marriage, educational background, age, job title, hospital grade, and shift work did not significantly affect the prevalence of depressive symptoms in nurses (table 3) . publication bias was examined by funnel plot and egger's test. a funnel plot shows that publication bias may exist (fig 4) , which was also confirmed by the result of egger's test (t = -6.20, p < 0.01). a sensitivity analysis for the pooled results was conducted by sequentially removing individual studies, and no significant differences before and after pooling were found, indicating stability in the pooled results. along with the rapid development of the economy in china, psychological problems have become increasingly more common. nurses, as an important role in hospitals, have been increasingly demonstrating depressive symptoms. although many articles have been published to assess the prevalence of depressive symptoms in chinese nurses, a comprehensive study on this population is still absent. in our study, a total of 102 studies with 52,592 participants were obtained to assess the prevalence of depressive symptoms in mainland chinese nurses. to our knowledge, this is the most comprehensive report to date to estimate that estimates this statistic, which may provide useful and valuable information for health decision-makers, helping them to properly implement interventional programmes and prevention activities. in our study, the overall prevalence of depressive symptoms in mainland chinese nurses was 43.83%, with 95%ci of 40.26%-47.42%, and obvious heterogeneity was demonstrated. we also found that the prevalence may be affected by regions/provinces, hospital department, and time, and may not be affected by educational background, age, job title, marriage, hospital grade, or shift work. because of the high prevalence of depressive symptoms in chinese nurses, which may result in large problems for society overall, we suggest that decision-makers should take actions to aid nurses in safeguarding their psychological wellbeing. in a previous meta-analysis [46] , the prevalence of depression in nursing students worldwide was 34.0% and was affected by age and geographical regions, with asian nursing students experiencing a higher prevalence (43.0%). we may see that both student and professional nurses, especially in asia, have a very high prevalence of depression; this prevalence is higher than even that of older patients with diseases such as stroke, hypertension, diabetes and coronary heart disease [47] , and is similar to that of empty-nest elderly individuals [48] . in addition, the prevalence of depression among chinese nurses is higher than that of nurses in iran [49] and chinese hong kong [50, 51] , australian midwives [52] , and hungarian [53] and australian [54] nurses. however, to our surprise, only 13.2% of nurses in vietnam have depression [55] , as well as 24.9% of iranian nurses working in military hospitals [56] . in addition, the chinese nurses even seem to have higher prevalence of depression than some special populations, such as people living with hiv with 38% [57] , outpatients with 27.0% [58] , and indian elderly population with 34.4% [59] . therefore, we may conclude that chinese nurses were at a particularly high risk of having depressive symptoms. moreover, based on the time trend shown in fig 3, the prevalence of depressive symptoms among chinese nurses may have increased in recent years, especially in large hospitals with a low ratio of doctors to nurses and of nurses to patients. we also found that the prevalence of depressive symptoms was significantly different based on geographic distribution and hospital department. in total, we could see that nurses from the hubei province and the northeast region had the highest prevalence of depressive symptoms. this may be because of the occupational environment and policies in each region. from table 2 , we can see that the departments with the highest prevalence of depressive symptoms for nurses are infectious diseases, paediatrics, haemodialysis, icu, and oncology. this may be due to the heavy workload and time pressures inherent in working in these departments. in addition, we also found that, in terms of marital status, despite no significant difference was found, divorce/widowhood/separation had higher prevalence than the others, which may be due to the sample size. to our surprise, we found that the prevalence of depressive symptoms in department of psychiatry wasn't that high as we expect, which may be due to as follows [60] : 1) more professional education about mental health was obtained, 2) the workload and difficulty of nurses in department of psychiatry were easier than others, 3) as closed-off plos one management was adopted in most department of psychiatry, they didn't face the trouble from family members of patients, 4) psychopaths often didn't have physical disease, 5) more medical disputes existed in general hospitals than psychiatric hospitals. in china, there is a large shortage of resources for nurses, the ratio of the nurse population to the total population is 1:1750, which is much lower than that of some developed countries (1:140-1:320) [61] . nurses are faced with heavy workloads, especially in the grade 3a hospitals in the city. however, the present situation cannot be changed in a short period of time. due to the recent covid-19 pandemic, the impact on mental health on healthcare workers is tremendous and more nurses suffer from depression [62, 63] . it is suggested that hospital managers should pay attention to the physical and mental state of their nurses, establish mechanism for the prevention and control of negative emotions such as depressive symptoms, formulate feasible measures to reasonably reduce the workloads of nurses, improve the working environment and the sense of occupational identity, improve and maintain the quality of life while ensuring the quality of medical service, and ensure the physical and mental health of the nurses. these steps may play a role in saving resources and improving nurses' quality of life and work efficiency [64] . the strengths of this review include a comprehensive analysis of the literature to identify all potential articles related to the topic, a robust methodology in conducting the systematic review, and combining estimates generated from the meta-analyses. the meta-analysis results also have some limitations that should be acknowledged: 1) all studies used a cross-sectional observational study design; 2) most of the literature included in this study was published in chinese-language journals, with very few in english-language journals, the overall quality of included studies; 3) the criteria and cut-off for diagnosis varied with studies, which may have led to the heterogeneity observed; 4) only 22 provinces in chinese mainland have been covered with regards to the prevalence of depressive symptoms in their nurses, which may have led to deficiencies or inaccuracies in estimating the overall prevalence; 5) some potential confounding factors were analysed to try and understand the high heterogeneity, but the main reason is still unknown; 6) as the limitation of sample size in some groups, such as department of infectious diseases, anhui and jilin provinces, some results still need further confirmations; and 7) publication bias could not be avoided. despite the considerably high heterogeneity and existence of publication bias in the study, the prevalence of depressive symptoms among nurses in chinese mainland is higher than that in many other countries. as the worldwide prevalence of depression is expected to increase over the next few decades [65] , these results could provide useful and valuable information for health decision-makers. furthermore, the nationwide investigation of depression prevalence should be performed with a standard diagnostic tool, which may be more useful for policy makers and planners. depressive 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multinational, multicentre study on the psychological outcomes and associated physical symptoms amongst healthcare workers during covid-19 outbreak. brain, behavior, and immunity psychological impact of the covid-19 pandemic on health care workers in singapore. annals of internal medicine cost-of-illness studies of depression: a systematic review depression and other common mental disorders-global health estimates key: cord-286531-3syf6upw authors: dong, chuanmei; cao, simin; li, hui title: young children’s online learning during covid-19 pandemic: chinese parents’ beliefs and attitudes date: 2020-09-08 journal: child youth serv rev doi: 10.1016/j.childyouth.2020.105440 sha: doc_id: 286531 cord_uid: 3syf6upw online learning has been widely promoted to replace traditional face-to-face learning during the covid-19 pandemic to maintain young children’s learning and play at home. this study surveyed 3275 chinese parents’ beliefs and attitudes around young children’s online learning during the lockdown of the covid-19 pandemic. most parents (92.7%) in the study reported that their children had online learning experiences during the pandemic, and many (84.6%) spent less than a half-hour each time. the parents generally had negative beliefs about the values and benefits of online learning and preferred traditional learning in early childhood settings. they tended to resist and even reject online learning for three key reasons: the shortcomings of online learning, young children’s inadequate self-regulation, and their lack of time and professional knowledge in supporting children’s online learning. also, the hardship caused by the covid-19 pandemic has made them suffering, thus more resistant to online learning at home. the results suggested that the implementation of online learning during the pandemic has been problematic and challenging for families. the chinese parents were neither trained nor ready to embrace online learning. the paper concluded with implications for policymakers and teacher education. learning, opportunities, and learning experiences children receive at home (erdogan, johnson, dong, & qiu, 2019) . to fill this research gap, this study endeavors to understand how chinese parents perceive their young children's online learning during the covid-19 lockdown through a large-scale online survey. online learning refers to "the learning experienced through the internet" either in the synchronous or asynchronous environment where students engage with instructors and other students at their convenient time and place (singh & thurman, 2019, p. 302) . online learning has seen a fast growth during the past decade because it has greater flexibility in terms of time, place and pace of the study, easier and more effective access to a wider variety and greater quantity of information, and lower financial cost (chen, 2010; khurana, 2016) . in a globalized digital age, government agencies, educational institutions, corporations worldwide are increasingly promoting online learning, resulting in a shift from traditional face-to-face classes to distance and online learning (aldhafeeri & khan, 2016) . with the advancement of new communication technologies, online learning can provide a rich, authentic learning ecology that can facilitate collaboration and interdependence between learners (aldhafeeri & khan, 2016) . however, researchers (chen, 2010; o'doherty, dromey, lougheed, hannigan, last, & mcgrath, 2018) have expressed their concerns about the quality of online learning and highlighted the main difficulties in creating an online learning community with a high degree of social presence and engagement. in addition, some scholars are also concerned about the major problems of online learning, such as social isolation, lack of interactivity and participation, delayed or insubstantial amount of feedback (khurana, 2016) . similarly, young children's digital learning has also been debated and criticized. some scholars (jiang & monk, 2015; radesky, eisenberg, kistin, gross, block, zuckerman, & silverstein, 2016) highlighted their concerns about online risks and dangers, addiction to videos, social isolation, and physical health issues. others suggested that parents play the mediating role to prevent harm and regulate children's online activities, such as setting up technology use rules for and monitoring their children's media use (nouwen & zaman, 2018) . all these concerns, however, could not prevent online learning from rapidly expanding in the past decade and extensively reaching millions of young learners at an unprecedented speed (franklin, burdette, east, & mellard, 2015; silverman, 2020; zalaznick, 2019) . more and more online programs have been developed and delivered to support young children with disabilities and/or living in remote or disadvantaged situations to provide learning flexibility (smith, burdette, cheatham, & harvey, 2016; zalaznick, 2019) . in addition, online technologies have become the social, cultural, and personal artifacts that inhabit the contemporary child's 'multimodal lifeworld' (arnott & yelland, 2020) . it thus should be promoted to build a multimodal learning ecology for contemporary children, parents, and teachers. while online learning appears to be more prevalent in the future (franklin et al., 2015) , a lack of research has addressed online learning in the early years, specifically. this study will fill this gap by surveying chinese parents who have engaged in their young children's online learning during the covid-19 pandemic. parents' beliefs and attitudes around early digital and online learning have been found polarized in the past decade. on the one hand, parents have started to appreciate the value of digital devices and tended to feel comfortable with young children's use at home (livingstone, mascheroni, & dreier, 2015; mikelic preradovic, lesin, & sagud, 2016; sharkins, newton, albaiz, & ernest, 2016) . they also supported the appropriate use of digital devices in early years settings (isikoglu erdogan, johnson, dong, & qiu, 2019; kumpulainen & gillen, 2019) . in particular, parents even held positive attitudes towards young children's computer use and believed that children should gain valuable technical skills and should be educated on how to use computers to enhance their academic development and future opportunities, such as employment (hatzigianni & margetts, 2014 , perradvoci et al. 2016 ). in the increasingly diverse digital landscape, parents believed that a range of digital and online technologies could offer young children new knowledge and learning. and those parents with a higher education level tended to believe that digital and online learning can develop children's learning competencies, language, self-expression, and social competencies (lepicnik-vodopivec & samec, 2013) . on the other hand, parents were concerned about the dangerous content on the internet and the risks of unrestricted digital use. they were worried about the impact of digital use on children's social and health development (plowman et al., 2012; lepinic & samec, 2013; jiang & monk, 2016) . more recently, due to the rapid growth of screen technologies (e.g., ipads, smartphones), parents have expressed their uncertainty about whether mobile devices could be beneficial or harmful to their children and how to adopt these mobile screen technologies (radesky et al., 2016 , livingstone et al. 2015 , erogan et al., 2019 . the eu kids online project (livingstone, 2015) , for instance, revealed that parents with higher income and education had employed a wide range of practices and strategies to manage restrictions for digital device use and had spent efforts to promote offline activities for children while limiting digital activities at home. some parents set rules and limits on the frequency and duration of using digital devices but did not recognize the importance of their role and involvement in supporting young children's technological engagements (plowman 2012 , hatzigianni & margartts, 2014 . the studies, as mentioned above, have explored parents' perspectives and practices on children's digital use in general, leaving their beliefs and attitudes about online learning unstudied. in particular, during the covid-19 pandemic, the sudden shift to online learning has presented new opportunities and unexpected challenges to the affected young children and their parents. under such unique circumstances, there is a need to examine parental beliefs and attitudes concerning online learning and readiness and acceptance to make this drastic shift. furthermore, most of the existing studies are western-centric and may not represent views from the eastern countries, where the culture and educational philosophies might differ. indeed, parental beliefs about digital technologies and media are not formed in a vacuum; instead, they are shaped by cultural norms (mansour, 2008) . thus, it is of great theoretical importance to understand chinese parental beliefs and attitudes around young children's online learning during the lockdown as a unique study in terms of time and place. the outbreak of covid-19 in wuhan started spreading in china in december 2019, and then was declared as the public health emergency of international concern by the world health organization (who) on 30 january 2020. the national authorities worldwide have responded to this crisis by implementing travel bans, lockdowns, workplace hazard controls, and facility closures. preschools, schools, and universities have been closed either on a nationwide or local basis in 172 countries, affecting approximately 98.5 % of the world's student population (unesco, 2020) . china is no exception. as an urgent response to the covid-19 pandemic, in early february 2020, the ministry of education of china (2020a) mandated that all schools and universities stop face-to-face teaching and use internet platforms to deliver online learning. school children were required to attend online classes to continue their education. although preschools were not required to deliver online learning and had no mandatory online educational programs, ece stakeholders including educators from public sectors and private curriculum developers were proactively engaged in designing digital curriculum resources and introducing educational apps and platforms to guide parents to support their children's learning and play at home (ministry of education, 2020b). under such circumstances, many chinese parents followed the suggestions from teachers and educational authorities to provide online learning to their children during the lockdown. such influences on parents in adopting online learning are not difficult to understand in chinese sociocultural contexts. chinese early childhood education is shaped by its social culture and educational tradition. confucian culture has strongly influenced the relationships between teachers and children in chinese society (llasera, 1987) , which has laid great emphasis on adoring authority and respecting teachers (hargreaves, 2000) . tobin et al., (1989, p. 209 ) found that the role played by chinese preschools and teachers in the relationship with families is "explicitly political and ideological." preschools are viewed as social representatives, so they have the "right and responsibility" to correct the deficiencies of indulgent parents. preschool teachers, "as government employees with a governmental mandate," carry authority into their interactions with parents and see their roles as supporting and correcting parents (tobin et al., 1989) . accordingly, the controversial digital and online learning for young children has been conducted under this unique and special circumstance in china. without training and preparation for online teaching, chinese parents and teachers have been engaged in this brand new experiment of digital and online learning for young children. naturally and expectedly, these parents and teachers might have encountered many difficulties, problems, obstacles in this unexpected experiment. thus, this unique scenario has provided an ideal arena for us to understand chinese parents' beliefs and attitudes around young children's online learning at home. accordingly, this study aims to address the following research questions through an online survey: 3. what were chinese parents' attitudes towards online learning for their young children? this survey study was conducted in an inland city of henan province, which is located in the central area of china. altogether 3275 parents whose children were enrolled in local early childhood education programs voluntarily completed the online survey. the majority of them were aged between 30-39 years (68.3%), and between 20-29 years (19.8%), few were aged between 40-49 years (11.0%), very few were 50 years or above (0.9%), and none was under 20 years. their educational levels were very diversified: junior secondary school, high school, associate degree, bachelor, and postgraduate degree. and their occupation also varied greatly: government/public organizations, state-owned enterprise, private enterprise, personal owned business, freelancer, and unemployed. most of the parents have one or two children; very few of them have three or four plus. half parents (50.5%) reported their children were 3-4 years old, and some (34.5%) were 4-5 years old. the background information of the sample is presented in table 2 below. the questionnaire consists of three parts and includes 41 closed questions and two openpart iii: parents' beliefs and attitudes around online learning. this section adopted a five-point likert scale (ranging from "strongly disagree" to "strongly agree") to ask for parents' perspectives about online learning. the 27 questions could be classified into three subscales. the 27 questions could be classified into three subscales. subscale one is about the pros and cons of online learning (9 items): parents were asked to compare online learning with the traditional face to face approach. to generate an initial pool of question items for measuring parents' beliefs and attitudes, previous studies on online learning (aldhafeeri & khan, 2016 , o'doherty, dromey, lougheed, hannigan, last, & mcgrath, 2018 , singh & thurman, 2019 were identified and reviewed. in particular, the two doctoral theses on the role and the effects of online learning were used to guide the design of the questionnaire items (chen, 2010 , khurana, 2016 . in their doctoral work, they compared both traditional and online education and examined the pros (e.g. convenience) and cons of online learning (e.g. lack of social presence) for learners. the main advantages and shortcomings identified in their study were 're-examined' in this study. specifically, the questions were centered on the efficiency, content, cost, effect, learning atmosphere, outcomes of online learning for young children and families. subscale two is focused on the value of online learning for young children (10 items): parents were asked to evaluate the value of online learning based on the five learning and developmental areas ( wellbeing, language, society, science, and arts) outlined by the educational authorities (ministry of education, 2012). as indicated earlier in the literature, specific research studying online learning in the early years is limited, this study aimed to fill this research gap by studying parents' beliefs about and attitudes towards the value of online learning for young children. as a result, the frequent topics and heated debates (e.g. brady & hill, 1984; elkind, 2007; house, 2012 , plowman, mcpake, & stephen, 2012 parents were asked to evaluate the impact of online learning on parenting and family education suggested by the educational authorities (ministry of education, 2020). since this study was conducted during the pandemic, online learning was provided as an alternative approach to supporting children's learning and family education at home. the questions were also used to examine the impact of online learning on parenting and family education (see the questionnaire in an appendix). the internal consistency of part iii was measured, and the reliability for its three subscales was 0.80, 0.89, and 0.78, respectively, indicating satisfactory reliability. the survey was administrated in middle march 2020 after parents and children had been quarantined at home for two months since china imposed national lockdown in late january. all the parents and young children had gained substantial experiences with online learning. the participants were invited by their children's preschools to complete this online survey conducted on wenjuanxing (www.wjx.cn), the leading online survey platform in china that provides functions equivalent to amazon mechanical turk. the participants were clearly informed throughout the study that participation in this research was completely voluntary, and they could withdraw their participation at any time without any reason. both quantitative and qualitative approaches were adopted in analyzing the data in this study. first, the quantitative data were analyzed using ibm spss 26.0 software. first, data cleaning was conducted, and the very few missing values (<0.5%) were replaced with the mean of the concerned variable. second, descriptive statistical analysis was performed to calculate the frequency, mean, and sd of parents' characteristics and children's online learning activities during the outbreak of covid-19. finally, for analysis, the responses were given a score for each item from one to five: 1=strongly disagree; 2=disagree; 3=neutral; 4 =agree; 5=strongly agree. items that were phrased negatively were subsequently re-coded to make the scales read in the 'positive' direction, lower scores, therefore, reflecting negative or less positive beliefs. the mean scores were calculated for each scale, which provides an overall picture of the parental responses. second, the qualitative data collected from the two open-ended questions were analyzed using nvivo 12 software. the two questions are: (1) what areas would you allow your child/ren to continue to learn online after the pandemic? 2) what are your comments or opinions on young children's online learning? the research team collaboratively conducted data coding and analysis. the process of coding the data was cyclical and iterative, involving numerous conversations among the two coders to eliminate inconsistencies in interpreting the data due to who was coding. throughout the coding process, coders worked from the same codebook, as exemplified in table 1 , which allows each coder in the research team to consistently and reliably analyze the data. the qualitative data were parents' brief comments to the open-ended questions, and they were mainly 1-3 short sentences. generally, the qualitative data collected were straightforward for generating categories. the two coders also met to discuss any disagreements of coding and used strategies (e.g. redefining the codes) to reach agreement on coding. thematic analysis (braun & clarke, 2008) was employed to identify, analyze, and report patterns generated from the data. the qualitative data analysis followed their step-by-step guide in six phases. (1) familiarising ourselves with the data; (2) generating initial codes, such as opposing online learning; (3) searching for themes; (4) refining and reviewing themes; (5) defining and naming themes; and (6) writing qualitative results. for instance, parents' comments were first coded into two broad categories: supporting online learning and opposing online learning. the initial categories were then reorganized and sorted into themes around reasons for and against online learning. among all the reasons identified, the three themes emerged: shortcomings of online learning, young children's inadequate selfregulation, and parental lack of time and professional knowledge. overall, most parents (92.7%) reported that their children had online learning experiences during the pandemic, and many (84.6%) spent less than a half-hour each time. specifically, these parents indicated that their children learned online once (43.1%) or multiple times (18.4%) per day, whereas some had only once or twice or three times per week. in addition, about one-third of the children had less than 15 minutes of online activities per time, and some had an average between 15-20 minutes. the majority of the parents used free online learning resources with no or meager cost. and the children's online learning was mainly delivered and guided by preschool teachers or other staff; some were guided by online apps, webs, and others, as shown in table 3 . table 4 presents the analysis results about the young children's online learning activities during covid-19. first, many young children watched the recorded lessons online once, or multiple times per day, some children watched only once or twice or three times per week, only a small percentage of them never did so. the children's online learning content was varied, including literacy, brain exercises, and science, as well as arts. a small number of parents commented in the open question that their children were learning physical exercise and language online. second, many young children attended the live class online once, or multiple times per day, some children attended only once or twice or three times per week, about of them never did so. third, many young children used wechat once, or multiple times per day, some children used it only once or twice or three times per week, and many of them never did so. fourth, many young children used the learning apps once, or multiple times per day, some children did it only once or twice or three times per week, but half of them (50.7%) never did so. fifth, majority of the children attended online with parent presence once (38.5%) or multiple times (31.3%) per day, some children did it only once (2.8%) or twice or three times (22.0%) per week, very few of them (5.3%) never did so. sixth, many children interacted with the instructor online once or multiple times per day, some children did this only once or twice or three times per week, many of them (16.3%) never did so. last, many parents interacted with the instructor online once (20.6%), or multiple times per day, half of them interacted only once or twice or three times (48.8%) per week, whereas many of them (17.3%) never did so. the quantitative data showed that the parents had relatively less positive beliefs about the value of online learning. the subscale one measured parental beliefs about the pros and cons of online education compared to traditional learning in educational settings. the mean for this scale was 2.54, with a medium standard deviation of 0.61. only a small percentage of participants believed that online learning has better learning content (18.4%), better learning outcomes (11.0 %), and is more efficient (12.6%) than the traditional approach. about half parents neither agreed nor disagreed on the statements about the pros and cons of online learning, indicating a neutral position on the value of online education. there were very few parents (1.7%) among those who provided the comments, indicating that under the special pandemic situation, online education can be used to support children's learning. furthermore, the qualitative data indicated that the parents believed that traditional learning in educational settings was better than online learning in creating a learning atmosphere with better learning outcomes. some parents even commented that "online learning at home does not have a learning atmosphere" (parent 7), "the efficiency of online learning is not high " (parent 30), and "online learning atmosphere is not good " (parent 14). these parents also explained their negative beliefs on online learning: lacking social interactions with peers, children did not treat online learning as a formal class; therefore were unable to focus on the learning. in addition, parents found it difficult to manage children's online learning at home as they did not have teachers' authority, as shown in the following quotes from their responses to the two open questions. the quantitative analysis indicated that the parents were less positive about the benefits of online learning. the subscale two had a mean of 2.80 and a medium standard deviation of 0.66. a small percentage of parents believed that online learning could enhance young children's language development (21.2%), literacy (25.2%), social skills (24.8%), independent skills (17.8%), arts (21.1%) and physical health (10.9%). in general, more parents perceived that online learning could help children gain more science knowledge (37.6%). approximately half of the participants had a neutral attitude towards the role of online learning for supporting children's development in language, literacy, independence, social skills, science knowledge, and arts. the qualitative analysis found that some parents commented that "during the special [pandemic] situation, children can learn online" (parent 1). in contrast, others argued that "although children can learn via online approaches, the learning quality is not good" (parent 20), and "the learning effect of online learning is bad" (parent 2). some parents further explained that young children had weak self-regulation and a short attention span thus could not engage in online learning. for instance, they commented " children are too young, and their mind can't concentrate" (parent 17) and "online learning efficiency is low, and children's self-regulation is poor, " (parent 10) and "their initiative is not high, although they were learning the content as they were in school." in addition, the parents indicated their strong resistance and opposition towards online education caused by their concerns about the negative effects on children's development. as shown in the following quotes from their responses to the two open questions, the parents believed that online learning had more harm to young children than its benefits. among all the concerns, the most critical one is about the negative effect on young children's eye vision. some parents emphasized the potential harm to young children's social development and physical health, especially eye vision. there was a dilemma for parents to adopt online learning for their children, as revealed by a parent: children can learn some knowledge via online approaches, but they would develop an interest in watching smartphones and tv, which is not good for their eyes. in general, many parents stated harm and challenges caused by online learning without mentioning any benefits, as shown in the following quotes. the quantitative data from subscale three measured parents' beliefs and attitudes about the impact of online learning on parenting and family education, with a mean of 3.21 and a standard deviation of 0.57. approximately half parents believed that online learning kept their children from doing nothing at home during the outbreak of covid-19 (60.5%) and improved parent-child relationship (47.6%) and inspired their educational ideas (47.8%), and allowed them to see that children can participate in many forms of activities (45.9%). overall, the parents had slightly more positive perceptions of the impact of online learning on their family education. in contrast, the qualitative data found that some parents perceived children's online learning as inconvenient, challenging, and time-consuming. about 1.6% of the parents expressed that "[online learning] wastes too much adults' working time (parent 16) and adds burden to parents (parent 26) and affects parents' work significantly (parent 31). this is because children do not have adequate self-control abilities (parent 34), and children's online learning needs parents to stop their job to accompany them at home (parent 17) and cost time and efforts (parent 30). in addition, these parents mentioned various barriers for them to implement home online learning, including time constraints and professional knowledge in teaching children. notably, the parents who had more than one child identified more barriers to their younger children's online learning and juggled between their carer and worker responsibilities. in total, about 8.7% of the parents commented that they would not recommend online learning in the early years, and they hoped online learning to be ceased as soon as possible after the pandemic. for instance, one parent wrote "disapprove online learning after the kindergarten reopens," while another commented, "hope to start kindergarten soon to implement traditional education." among these parents, some questioned the 'appropriateness' of online learning and similarly stated, "children are too young with weak self-regulation, and online learning is not appropriate," and ' online learning is not suitable for young children" (parent 19). such finding is also supported by the quantitative findings that only a few parents (8.9%) were willing to pay for online learning after the pandemic, and more than half of parents indicated that they would not allow their children to learn online once the covid-19 lockdown is over. as the first exploration of chinese parents' beliefs and attitudes around online learning during the covid-19 pandemic, this study has found that many young children had online learning experiences that were delivered by their kindergarten teachers or online learning apps at no or low cost. their parents, however, had different views about this online learning experience. this section will discuss these findings and their implications for future studies and practical improvements. firstly, this study found that the parents held a belief that online learning is less effective than traditional learning in early childhood educational environments. they believed that online education lacked a learning atmosphere and social interactions to engage young children, resulting in poor learning outcomes. these generally negative beliefs about online learning could be related to the two major causes. the first one is that the lockdown of covid-19 has caused a sudden shift to online learning. thus, it has challenged the traditional parental understanding of childhoods and expectations about early childhood educational practices, which should include free play and outdoor activities (stephen & edwards, 2018) . as noted by arnott and yelland (2020, p.126) , "challenges remain in our understanding of childhoods in the 21 st century and in integrating new technologies into children's learning cultures." the dominant ideas and popular discussion about childhoods in a digital age are either passive/at-risk or empowered (craft, 2012; dong, 2018; mertala, 2019b; stephen & edwards, 2018) . such polarised debates have led parents and educators to believe that young children's use of digital technology is inappropriate and often caused dilemma and confusion for those seeking to incorporate digital technologies into young children's learning (dong & mertala, 2020; house, 2012; isikoglu erdogan et al., 2019) . to support educators, parents, and children to use new technologies better, researchers advocated a reconceptualization of 'childhoods' and 'play' in the digital age so digital artifacts can be embraced as unique and distinct resources to provide them with new opportunities for learning and play (arnott & yelland, 2020; edwards, 2016) . therefore, these chinese parents need to update their knowledge and develop a new understanding of 'childhoods,' 'learning,' and 'play' through parental education or family-school partnership programs. the second cause might be the major shortcomings of online learning, as noted by the critics (khurana, 2016; chen, 2020; doherty et al., 2018) : social isolation and lack of interactivity, which have repeatedly been reported by the parents during this unexpected experiment. vlachopoulos and hatzigianni (2016) have emphasized the need to address critical issues around students' online learning experiences and course outcomes. this study, however, found that all these critical issues had not been solved, even though many advancements had been made in digital and online technologies. therefore, chinese parents tended to have negative perceptions of digital and online learning. secondly, this study found that most chinese parents had a major concern about vision problems caused by online and digital learning. such concern has been shared by many parents and early childhood educators internationally (hatzigianni & kalaitzidis, 2018; mertala, 2019a; sharkins et al., 2016; wartella & jennings, 2000) . in china, the prevalence of myopia appears to have rapidly increased in recent years, and more and more young children are reported to be short-sighted (ku, steptoe, lai, hu, chu, yen, & chen, 2019) . this problem has been attributed to the increased screen-time by the public (guarino, 2018) . therefore, the ministry of education and the seven other national authorities jointly issued (ministry of education, 2018) to regulate children's technology use by limiting the screen time. therefore, this concern reported by the chinese parents in this study is sensible and should be carefully addressed by the developers and designers of digital and online learning programs. thirdly, this study found that the parents were also worried about the lacking of physical activity as well as the addiction to screens such as tv and smartphones caused by digital and online learning. this concern is also reasonable and understandable, given that all the young children were quarantined at home during the covid-19 pandemic, and digital and online learning became their only channel to interact with teachers and peers. this finding is consistent with the existing ones that have suggested that parents and educators were concerned about the negative effect of screen time on young children's health development (edwards et al., 2012; livingstone et al., 2015; radesky et al., 2016; rhodes, 2017) . the chinese parents in this study reported using different strategies to restrict digital device use and making many efforts to promote offline activities for children while limiting digital activities at home. and some chinese parents have even planned to stop children's access to online learning once the pandemic is over. all these findings jointly indicated that chinese parents tended to view digital and online learning negatively. though this study was conducted in a different context (china) at a unique time , the findings of chinese parents' negative beliefs and attitudes around online learning are consistent with some western studies conducted in eu countries (livingstone, 2015 et al.,) and australia(australian government, 2019), which found that parents have been concerned about online risks and too much online time. specifically, the recent national survey of 3520 parents of children aged 2-17 that parents believed that their children spent too much time playing games, using social media, and streaming tv shows. however, the chinese parents tended to be more worried about children's eye vision deterioration caused by watching screens, which may be due to their younger age of their children in this study. first, this study found that chinese parents tended to reject online learning because their children had no or low self-regulation. this finding provides empirical evidence to support the claim that self-regulation is a prerequisite for successful online engagement and learning (vlachopoulos & chatzigianni, 2017) . furthermore, the chinese parents highly valued the linkage of self-regulation to the confucianism heritage that children should be self-restraint and self-regulate to follow the social rules and norms. this is more than the definition of self-regulation: "self-generated thoughts, feelings, and behaviors oriented to attaining goals" (zimmerman, 2002, p. 65) . however, this finding indicates that chinese parents might expect their children to learn and show self-control and self-regulation at a young age (luo, tamis-lemonda, & song, 2013) . second, this study found that chinese parents tended to reject online learning because their children were uninterested, inactive, and unfocused during online learning. this finding suggests that the young chinese children could not be regarded as self-regulated learners, who should be "metacognitively, motivational and behaviourally actively participants in their learning" (zimmerman, 1990, p. 4) . this finding, however, contradicts with the existing ones that young children were strongly interested in media and technology (sharkins et al., 2016) and that chinese children were curious and excited about digital programs (dong, 2016; dong & mertala, 2019; jiang & monk, 2015) . this discrepancy might be caused by the difference in the quality of digital and online learning, as one parent said that "the content of online learning is not very attractive to children" (parent 3). therefore, it might be the poor quality and boring content of online learning that has caused the resistance and even rejection of chinese children and parents. the media of digital and online learning itself might not be the cause. this is why vlachopoulos and hatzigianni (2017) suggested that the design of online learning played an important role in shaping learners' perceptions of online learning. third, this study found that many parents, especially those with more than one child, tended to reject online learning because they had no time to support children's online learning at home. this finding is consistent with that study by (li, shi, wu, & li, 2020) , who found chinese parents of only-child tended to have more opportunities and educational resources than those of non-only children. the parents of only-child would invest more time and energy to help their child to excel in academic performance. besides, the chinese parents in this study generally perceived online learning as time-consuming and burdensome. similarly, smith et al. (2016) found that online learning required parents' significant time commitment. but the american parents in their study still wanted to be engaged in their children's online learning, even though they were shocked by the time required to support their child's online learning. the chinese parents in this study, however, did not realize the importance of their involvement and tended to reject to support their children's online learning. last but not least, this study found that the parents were negative about online learning because the covid-19 lockdown had made them suffering from the hardships and the unexpected demand from online learning. they felt unable to educate young children as their conventional role was not the teacher of a child, and they were not trained to do so. chinese parents and grandparents were often blamed by teachers for spoiling their children (tobin, hsueh, & karasawa, 2009) and allowing too much screen time (dong & mertala, 2019 . therefore, they tended to feel unconfident to teach their children at home and believed that their "children listen more to their teachers and have a better learning atmosphere at school" (parent 13). accordingly, they were so eager to send their children back to preschools. digital and online learning is gaining popularity due to its advantages, such as greater flexibility, wider access, and low cost (khurana, 2016; chen, 2010) . however, this study found that the implementation of online learning during the covid-19 pandemic has been problematic and challenging for chinese families. chinese parents generally had negative beliefs and attitudes about the values and benefits of online learning and preferred traditional learning in early childhood educational environments. this is because they were neither trained nor ready to embrace online learning. the hardship caused by the covid-19 pandemic has made them suffer, thus more resistant to online learning at home. and these chinese parents were more concerned about the shortcomings of online learning, their children's inadequate self-regulation, and their lack of time and professional knowledge in supporting online learning. this study, however, has certain limitations. first, a large-scale quantitative study can provide representative and diversified evidence about the target topic. still, it has no way to gain an in-depth understanding of individualized situations and problems. interview or mixed-methods studies should be conducted to thoroughly explore chinese parents' authentic views, concerns, and difficulties. second, this online study simply collected self-report data, which might have a socially desirable bias. further studies with triangulation of methods (i.e., teacher-, self-, and peer-report) are needed to cross-check the results. nevertheless, for the first time, this study has investigated chinese parents' beliefs and attitudes concerning digital and online learning during the outbreak of covid-19. the national lockdown has unavoidably affected many children's physical attendance at educational settings and made online learning an emergent alternative to maintain the continuity of learning and play at home (early childhood australia, 2020; silverman, 2020). even though online learning has been widely promoted in china to replace traditional education during the pandemic, the findings of this study indicate that the chinese parents were neither trained nor ready for doing so. this implies that the educational authorities need to do more to get chinese parents ready for online learning and to consider more about young children's age and learning interests. the findings from this study have implications for policymakers and educators globally who are promoting online learning as an alternative to young children and their families during the pandemic. the promotion and implementation of online learning to replace traditional early childhood education during emergent situations like covid-19 need to be carefully considered and well planned to support families, rather than adding extra burdens to them. this means that the promoters should consider the complexity and diversity of families (e.g. more than one child learning online and parents' working full time at home) when suggesting an online class to young children, and provide parents with flexibility and convenience. in addition, the provider of online learning should improve the design of online programs (e.g. easy login) to make parents effortless in using the program. elkind, d. 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(equity). district administration self-regulated learning and academic achievement: an overview becoming a self-regulated learner: an overview. theory into practice: becoming a self-regulated learner ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☒the authors declare the following financial interests/personal relationships which may be considered as potential competing interests:there is no research fund fo the project and the research has followed ethical procedure throughout the study. there is no conflict of interest. key: cord-353866-0r1b44id authors: sun, hongpeng; zhang, qiuju; luo, xiao; quan, hude; zhang, feng; liu, chang; liu, meina title: changes of adult population health status in china from 2003 to 2008 date: 2011-12-02 journal: plos one doi: 10.1371/journal.pone.0028411 sha: doc_id: 353866 cord_uid: 0r1b44id objectives: the purpose of this study was to examine the change in health status of china's adult population between the years of 2003 and 2008 due to rapid economic growth and medical system improvement. methods: data from the third and fourth chinese national health services surveys covering 141,927 residents in 2003 and 136,371 residents in 2008 who were aged >18 years were analyzed. results: chinese respondents in 2008 were more likely to report disease than in 2003. smoking slightly decreased among men and women, and regular exercise showed much improvement. stratified analyses revealed significant subpopulation disparities in rate ratios for 2008/2003 in the presence of chronic disease, with greater increases among women, elderly, the han nationality, unmarried and widow, illiterate, rural, and regions east of china than other groups. conclusions: chinese adults in 2008 had worse health status than in 2003 in terms of presence of chronic disease. china's reform of health care will face more complex challenges in coming years from the deteriorating health status in chinese adults. in recent years, the healthcare system in china has significantly improved [1, 2, 3, 4] . in 2001, beijing succeeded in the bid to host the 2008 olympic games. subsequently, chinese government and civil organizations launched extensive fitness programs for the general public to raise the level of physical activity and health. as a result, more sports facilities were built with free access in the community, there was increased parkland, and news media also participated in this campaign [5] . china suffered greatly in the 2003 when the worldwide prevalence of severe acute respiratory syndrome (sars) took a sharp rise. since that lesson, there is evidence that chinese people have improved their general and personal hygiene and diet, undertaken more intensive physical exercise, and increased the overall frequency of hand washing [6] . over the next 5 years, following 2003, chinese healthcare systems have made significant reforms, and reflected on the vulnerability of public health [7, 8] . available health resources in china have been continuously increasing along with china's dramatic economic development [9, 10, 11] . from 2003 to 2009, the medical insurance system in china underwent rapid development and the government input among total health expenditure increased by 17%. a new type of rural cooperative medical care system, a form of community-based health insurance for the rural population, was piloted in some counties in 2003; coverage rate reached 72.6% by december 2004, and would gradually cover all rural residents by 2010 [12, 13] . at the same time, urban resident health insurance scheme included 80% of cities by the end of 2007. urban employee basic health insurance scheme in china has covered all cities since 2008 [13, 14, 15] . with healthcare reform deepening, these systems made the proportion of out-of-pocket payments drop to 30% and will be further reduced in future [13] . during the last decade, the health status of china's population has been changing. chinese life expectancy increased from 71.4 years in 2000 to 73 years in 2005; infant mortality decreased from 25.5/1000 live births in 2003 to 15.3/1000 live births in 2007 while maternal mortality declined from 51.3/100,000 to 36.3/ 100,000 live births at the same time [16] . although infectious disease, malnutrition, child, and maternal mortality rates have decreased, chronic and noncommunicable disease mortality has gradually increased [17] . for example, cancer and stroke are the major causes of death, accounting for 44.8% of all deaths in 2008, followed by respiratory disease and heart disease; chronic and noncommunicable disease mortality increased from 76.5% of allcause death in 2003 to 82.5% in 2008 [18] . on the other hand, such indicators are insensitive to nonfatal conditions that contribute indirectly to death. whether chinese overall health status changed during the period from 2003 to 2008 remains unresolved. hence it is imperative to assess population health using indicators that reflect contemporary health issues. this study aimed to describe the male and female adult chinese population health status in multiple dimensions, including overall morbidity, presence of illness in the last 2 weeks and chronic disease in the last 6 months, and healthy behavior as regards smoking, alcohol consumption, and physical activity, using data from the most recent national health services surveys by the chinese government in 2003 and 2008. the main objective of these surveys was to measure performance of health systems and forecast health demand and long-term health problems. our study provided important information for furthering research questions for future studies. the china national survey employed a multistage cluster sampling to select the sample randomly. the mainland of china was clustered according to the government administrative geographic system [19] . both surveys were conducted in the same sampling areas, whereas all households were randomly selected again. first, 94 counties and cities were randomly selected from rural and urban areas (95 areas were selected in 2003). second, 5 towns were selected from each county and 5 communities from each city respectively, resulting in 470 towns or communities. third, 2 villages in each town and 2 neighborhoods in each community were randomly selected. fourth, 60 households were randomly selected in each village or neighborhood, resulting in about 56,400 households in 2008 (57,000 households in 2003). during the survey, candidate households that could not be contacted by interviewers on three calls on different days were replaced. survey completion rate was maintained at .95%. interviewers, who were trained, explained the purposes and confidentiality of the survey then invited family members to participate. residents could choose not to participate and their participation in the survey was accepted as oral consent. adult residents were themselves required to answer questions; if they were not at home at the time of the survey then their nearest relative could serve as proxy. as a result, the survey response rate for adults was 83% in 2008 (77.8% in 2003). completeness of questionnaires was checked by a district survey manager at the end of each day. if there was missing information and errors on the survey, probands could be re-surveyed the next day. a 5% sample of households was randomly selected and resurveyed to examine survey quality by telephone or visit again; the agreement was 95%. the quality of survey data and consistency check demonstrated a myer's index of 3.48; there was no age preference in the survey. the results of goodness-of-fit showed that the sample was not significantly different with the general population in age distribution. similarity coefficient and gini concentration ratio indicated that family size in the survey was consistent with the established national picture. demographic variables included sex, age, ethnicity, marital status, education level, rural/urban residency, and geographic region. ethnicity was grouped into han or minority. educational level was categorized into five categories such as illiterate, elementary school, junior high school, senior high school, and college or university or higher. china was geographically grouped into urban (city) or rural areas (town or village) after the governmental administration system, as well as eastern china, mid-china, and western china based on economic development status; eastern china is considered the most developed region, mid-china less developed, and western china the least. information about smoking, alcohol consumption, and physical exercise were collected. presence of illness in the previous 2 weeks and physician-diagnosed chronic diseases in the last 6 months was recorded. the same survey method was used in both the 2003 and 2008 surveys. definitions of variables have been described in detail elsewhere [20, 21] . all analyses were conducted separately for women and men, urban and rural, and total. descriptive statistics were used to test the statistical differences in sociodemographic characteristics, smoking, alcohol consumption, physical exercise, presence of illness (in the previous 2 weeks) and chronic disease between the two surveys. because of the large sample size and multiple categories in sociodemographic characteristics variables, p-values for differences between the two surveys were not reported. finally, multiple binomial regressions with a log link were used to generate adjusted p-values to examine whether chinese residents of 2008 had better health status compared with in 2003. clustering of individuals within family was adjusted for using generalized estimating equations in sas 9.1 proc genmod [22, 23] . stratified analyses by sociodemographic variables were conducted for chronic disease to determine whether adjusted rate ratio (rr) and 95% confidence interval (95%ci) for 2008/2003 differed across strata. demographic characteristics for residents are presented in table 1 . there was a difference in composition of some age groups between the two surveys: 18 presence of illness in the previous 2 weeks was 19 (table 3) . however, the proportion of drank alcohol frequently was similar between 2008 and 2003. chinese residents in 2008 were significantly more likely to perform regular exercise than in 2003 (14.6% vs. 11.3%). compared with men, women were less likely to smoke and frequently drink alcohol in 2003 and 2008, and had more likelihood to perform regular exercise. rural residents did less regular exercise than urban residents, and smoked more. after adjusting for independent variables listed in table 1 our review of data for the china third and fourth national health services surveys suggests conclusions in three broad areas. first, we found that chinese population in 2008 was more likely to report illness compared with 2003, but less likely to smoke and more likely to do regular exercise. second, chronic diseases in 2008 were more highly prevalent than in 2003, particularly hypertension, diabetes, heart disease, and stroke. third, the disparity in the prevalence chronic disease of the two surveys was distinctly evident in different subpopulations. in the current study, we found that prevalence rates of chronic diseases in the last 6 months before the surveys increased from 2003 to 2008. for example, the prevalence of hypertension and diabetes in 2008 approximately doubled since 2003, and that of stroke increased by 1.4 times. however, the prevalence of infectious disease did not change. there are several possible explanations for the above findings. first, china's population has been in very rapid transition from a youthful to an aging population as life expectancy has increased [24, 25, 26] . birth rates have fallen, and china's one-child family policy has been a strong driver of population aging [27] . the rapid decrease in china's birth rate, combined with stable or improving life expectancy, has led to an increasing proportion of elderly people. in 1982, only 7.6% of the population was aged .60 years; this proportion grew to 10.5% by 2000. in our study this proportion was 13.6% in 2003 and 15.4% in 2008. the un predicts that .453 million chinese will be aged .60 years by 2050 [28] . this so-called graying of china's population has increased the incidence rates of diseases associated with elderly populations, and will become more problematic in future [29] . second, many of the known risk factors for chronic diseases have dramatically increased as societal change progresses. these behavioral elements include changing diets, levels of physical activity, and alcohol and tobacco consumption and have accelerated shift at a historically unprecedented pace and scale in china. dietary grains intake decreased substantially, whereas that of meat, fat, and edible oil increased [30, 31, 32] . consequently, obesity in chinese people has increased as well as hypercholesterolemia [33, 34] . obesity is a major public health problem since it contributes to development and exacerbation of major chronic diseases [35, 36, 37] including heart disease, type 2 diabetes, and some cancers. in addition, the increase in overweight people and obesity can be attributed to physical inactivity [38] . physical activity helps a person maintain better posture and balance, stronger muscles and bones, more vitality, reduced stress, and continued independent living in later life [39] . although the present research revealed that chinese adults were more physically active in 2008 compared with 2003, only 14.6% of adult residents reported exercising $3 times per week. this may be due to improved access to physical activities or enhanced awareness of health. however, overall chinese adult population health status has not been improved due to short time and small proportion of residents performing frequent exercise; hence it seems that the prevalence and burden of chronic diseases will continue to grow. the third possible explanation is that the prevalence of hypertension in china has been rising rapidly during the period from 2003 to 2008. our results indicate that the prevalence of hypertension in the last 6 months before the survey has doubled from 3.6% in 2003 to 7.1% in 2008; and 17.5% of chinese people had been diagnosed with hypertension by medical doctors. however, the true prevalence of hypertension should be higher than reported because of respondents' unawareness of their condition. previous national studies suggest that the prevalence of hypertension in the chinese adult population has increased from 5.1% in 1959, to 7.7% in 1980, to 13.6% in 1991, and to 18.8% in 2002 [40, 41, 42] . nevertheless they should be compared cautiously owing to methodological differences in sampling and to differences in the criteria used to define hypertension. in addition, control of hypertension in china is far from optimum. according to the national nutrition survey of 2002, 18.8% of chinese adults had hypertension, and of the 24% affected individuals who were aware of their condition, 78% were treated and 19% adequately controlled [40, 42] . at the same time, 27.2% of diabetes patients took medication and 9.7% achieved controlled diabetes [43] . therefore a national education program that can eliminate the huge gaps among presence, awareness, treatment, and ability to control of hypertension and diabetes should be given to the public, clinicians, and healthcare decision makers. fourth, insurance coverage that has been increasing in china, leading to higher health services utilization [13] . previous national health services surveys revealed that the 2-week consultation rates were 11.8% of urban residents and 13.9% rural residents in 2003 [20] . the percentages increased to 12.7% of urban and 15.2% rural in 2008. therefore chinese adults in 2008 seemed more likely to detect disease. the increasing range in the prevalence of chronic disease was more significant in women, han chinese, elderly, widowed, illiterate, rural, and eastern china than other subpopulations. the presence of chronic disease is rapidly increasing among more affluent people. for example rural residents, who have benefited from china's economic development similarly to urban populations, have experienced dramatic lifestyle changes in the past two decades. they are doing less physical work owing to mechanization and eating more high-protein or -fat food; and are therefore more likely to be aware of the presence of chronic disease and insurance coverage, especially the new rural cooperative medical care scheme, more health service utilization, and better transport have enabled rural residents to visit physicians [12, 13] . as a result, they are more likely to report illness. social determinants of health have become important factors associated with the decline of health status. our findings suggest that to promote health status we should focus on elderly and widowed people and promote higher national educational level. prevention strategies such as reduction of tobacco use, exposure to second-hand smoke, less dietary intake of salt and fat, and promotion of increased physical activity should also be prioritized. there are four major limitations to this study. a major limitation is that data were collected through two cross-sectional surveys, whereas the two questionnaires did not have precisely the same structure. also, the cross-sectional nature allows for errors in recall. a second limitation is that the present study was based on observational data; therefore we cannot be completely sure of the association between demographic characteristics and health status, even after controlling for potential confounders. a third limitation is that we only analyzed seven major risk factors but were unable to assess other important risk factors of diet and obesity. the fourth major limitation is that the prevalence of chronic disease was likely underestimated because only physician-diagnosed chronic disease in the last 6 months was recorded. however, this study mainly explored relative change for presence of chronic disease from 2003 to 2008. some bias in both cross-sectional surveys could be offset to some extent. despite these limitations, our findings make a significant contribution to address the health characteristics of chinese adult population. additional research is needed to explore the reasons for the patterns we found, including how the outcomes examined in our study might differ for rural residents compared with urban residents. future studies also might explore how types of health insurance might be related to health status. in conclusion, our analysis demonstrates that chinese adults in 2008 had worse health status than 2003 in terms of presence of various chronic diseases. especially, prevalence of hypertension and diabetes in 2008 was twice that in 2003. however, smoking showed slight decrease among men and women, and regular exercise suggested much improvement. our results also indicate that prevalence of chronic illnesses increased more among women, elderly, han chinese, unmarried and widowed, illiterate, rural, and those in eastern china. public health policy should pay explicit attention to these issues. as economic development and environmental degradation continue, systems of disease prevention and health promotion in china will face ever-bigger difficulties and challenges. adjusted p value ,0.001 for 2008 versus 2003 after adjustment for age, minority, marital status, education, gender (or residence area) and geographic region prevalence of smoking, alcohol intake, and physical activity in respondents aged .18 years in china. men women urban rural total adjusted p value ,0.001 for 2008 versus 2003 after adjustment for age, minority, marital status, education, gender (or residence area) 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in china the nutritional status and dietary pattern of chinese adolescents a new stage of the nutrition trends of obesity and underweight in older children and adolescents in the united states obesity: preventing and managing the global epidemic is china facing an obesity epidemic and the consequences? the trends in obesity and chronic disease in china human body composition and the epidemiology of chronic disease who reassesses appropriate body-mass index for asian populations overweight and obesity in china prevalence, awareness, treatment, and control of hypertension in china: data from the china national nutrition and health survey hypertension prevalence and status of awareness, treatment and control in china a description on the chinese national nutrition and health survey in 2002 the authors thank the china ministry of health for providing the data for the analysis. conceived and designed the experiments: ml hs hq. analyzed the data: hs qz. wrote the paper: hs xl fz cl. key: cord-323307-nu9ib62h authors: dong, dong; lei, ming; hua, panyu; pan, yi-hsuan; mu, shuo; zheng, guantao; pang, erli; lin, kui; zhang, shuyi title: the genomes of two bat species with long constant frequency echolocation calls date: 2016-10-26 journal: mol biol evol doi: 10.1093/molbev/msw231 sha: doc_id: 323307 cord_uid: nu9ib62h bats can perceive the world by using a wide range of sensory systems, and some of the systems have become highly specialized, such as auditory sensory perception. among bat species, the old world leaf-nosed bats and horseshoe bats (rhinolophoid bats) possess the most sophisticated echolocation systems. here, we reported the whole-genome sequencing and de novo assembles of two rhinolophoid bats – the great leaf-nosed bat (hipposideros armiger) and the chinese rufous horseshoe bat (rhinolophus sinicus). comparative genomic analyses revealed the adaptation of auditory sensory perception in the rhinolophoid bat lineages, probably resulting from the extreme selectivity used in the auditory processing by these bats. pseudogenization of some vision-related genes in rhinolophoid bats was observed, suggesting that these genes have undergone relaxed natural selection. an extensive contraction of olfactory receptor gene repertoires was observed in the lineage leading to the common ancestor of bats. further extensive gene contractions can be observed in the branch leading to the rhinolophoid bats. such concordance suggested that molecular changes at one sensory gene might have direct consequences for genes controlling for other sensory modalities. to characterize the population genetic structure and patterns of evolution, we re-sequenced the genome of 20 great leaf-nosed bats from four different geographical locations of china. the result showed similar sequence diversity values and little differentiation among populations. moreover, evidence of genetic adaptations to high altitudes in the great leaf-nosed bats was observed. taken together, our work provided a useful resource for future research on the evolution of bats. bats (order chiroptera) are one of the largest monophyletic clades in mammals (order chiroptera), and constitute nearly 20% of living mammalian species. they can perceive their surroundings using a wide range of sensory systems, and have long been regarded as the most unusual and specialized species of all mammals. most bats are sophisticated echolocators and rely on their echolocation systems for navigation. however, old world fruit bats have no laryngeal echolocating ability, and navigate largely by vision. based on overwhelming molecular genetic evidence, it has been proposed that echolocating bats are paraphyletic (teeling, et al. 2005) . old world fruit bats and some laryngeal echolocators (including rhinolophidae, hipposideridae, craseonycteridae, megadermatidae, and rhinopomatidae families) are a natural group -the suborder yinpterochiroptera, and the remaining laryngeal echolocating bats are grouped to another suborder yangochiroptera . two distinct navigation approaches can be employed by echolocating bats: low duty cycle (ldc) echolocation and high duty cycle (hdc) echolocation (teeling 2009 ). ldc echolocators can separate pulse and echo in time to avoid forward masking, whereas some species of hdc echolocators separate pulse and echo in frequency. it has been documented that rhinolophoid bats might possess the most sophisticated echolocation systems (jones and teeling 2006) . recently, results from some hearing-related genes suggested sequence convergence in laryngeal echolocating bats (li, et al. 2008; davies, et al. 2012) . we attempted to investigate whether similar patterns can be detectable in other hearing-related genes. furthermore, a sensory trade-off between investment in vision and echolocation has been identified (dechmann and safi 2009) . loss-of-function in short-wave sensitive opsin (sws1 gene) occurred in rhinolophoid bats, which use hdc echolocation and can emit long constant frequency calls (zhao, et al. 2009 ). although several bat genomes have been sequenced (zhang, et al. 2013) , the evolutionary mechanisms of the rhinolophoid bats remains unclear. comparative genomics will provide us opportunities to investigate whether similar patterns can be detectable in other sensory genes. the great leaf-nosed bat (hipposideros armiger) and the chinese rufous horseshoe bat (rhinolophus sinicus) are two important species of rhinolophoid bats. first, these are model organisms with remarkable hdc echolocation ability and can emit continuous ultrasonic calls of long constant frequency with remarkable acoustic features (doppler-shift compensation) (schnitzler, et al. 2003) . we can comprehensively explore how rhinolophoid bats evolved a specialized form of echolocation. second, they are important reservoir hosts of emerging viruses, and the chinese rufous horseshoe bat has been suggested to carry the direct ancestor of severe acute respiratory syndrome (sars) coronavirus (ge, et al. 2013) . in this work, we presented the genomes of the great leaf-nosed bat and the chinese rufous horseshoe bat using the next generation sequencing platform (illumina hiseq 2500). the result revealed the adaptation of auditory sensory perception in hdc echolocators, and showed an extensive contraction of olfactory receptor gene repertoires as well as pseudogenization of some vision-related genes. furthermore, we performed genome re-sequencing to analyze the population genetic structure of the great leaf-nosed bats. the genomic data provide genetic evidence of adaptive evolution in rhinolophoid bats. a female great leaf-nosed bat (hipposideros armiger) and a female chinese rufous horseshoe bat (rhinolophus sinicus) were captured from a cave (n 30°20.497′ genomic dna was extracted from bat muscle using the qiagen dneasy blood and tissue kit. six paired-end libraries with insert size of 170 bp, 500 bp, 800 bp, 3k bp, 8k bp and 20k bp were constructed and sequenced for the great leaf-nosed bat and the chinese rufous horseshoe bat, respectively. the libraries were sequenced using illumina hiseq2500 platform, which has a read length of 101 bp. low quality sequencing reads were filtered out and potential sequencing errors were removed. the following filtering criteria were carried out: 1) filter reads with >5% unidentified nucleotides; 2) filter reads with >10 nucleotides aligned to the adapter sequence, allowing <3 mismatches; 3) remove putative pcr duplicates generated by pcr amplification in the library construction process. finally, we generated 476.5 gb and 288.5 gb of sequences for the great leaf-nosed bat and the chinese rufous horseshoe bat, respectively. the genome sequences were assembled using allpaths software (butler, et al. 2008 ). briefly, contigs were generated by constructing a de bruijin graph with the sequencing reads from short-insert library data. the graph was simplified to generate the contigs by removing tips, merging bubbles and solving repeats. the sequencing reads were mapped to the assembled contigs, and the scaffolds were constructed by weighting the rates of consistent and conflicting paired-end relationships. at last, we retrieved the read pairs with one end that uniquely mapped to the contigs and the other end located in the gap region, a local assembly for these collected reads was performed to fill the gaps. a more detailed genome assembly method is provided in supplementary methods. total rnas of the two bats were extracted from brain, cerebellum, heart, liver, stomach, kidney, lung and muscle tissues for the generation of transcriptome data. paired-end libraries for rna sequencing were constructed using the illumina mrna-seq prep kit. the quality and integrity of the rna samples were determined using the agilent2100 bioanalyzer. poly(a) mrnas were isolated using oligo(dt) beads, fragmented, and converted to cdnas followed by end repair, adaptor ligation, and pcr amplification. the libraries thus generated were sequenced using the illumina hiseq2500 platform as described above. we searched for tandem repeats across the genomes using tandem repeats finder. transposable elements were predicted in the genomes by homology search against the known transposable elements (te) in repbase (jurka, et al. 2005 ) (version 20110920) using repeatmasker version 3.3.0 (tarailo-graovac and chen 2009). the protein-coding genes of the bat genomes were annotated by combining homology-based, ab initio and rna-seq gene prediction methods. at first, rna-seq data were assembled using the trinity package (trapnell, et al. 2013) . pasa (version r2012-06-25) (haas, et al. 2003) was then used to map the assembled transcripts. based on the set of gene models, a training set was constructed for de novo predictors by selecting the genes with complete structures and at least 100% mapping rate for uniprot vertebrate proteins. for the ab initio prediction, augustus (stanke and waack genes with the training set generated by pasa. for homology-based gene prediction, the protein sequences of human, mouse, dog, cow, little brown bat and large flying fox were downloaded from ensembl release 72 and mapped onto the repeat-masked genome using genblasta (she, et al. 2009 ). rna-seq data were mapped to the genome using tophat (trapnell, et al. 2009 ), and the transcription-based gene structure were generated by cufflinks (trapnell, et al. 2013) . the final gene set was generated by merging all genes predicted using glean software (http://sourceforge.net/projects/glean-gene/). to infer gene function, it was based on the best match of the alignment to the swissprot and translated embl nucleotide sequence data library databases using blastp. interproscan (mulder and apweiler 2007 ) was used to determine motifs and domains in the final gene set. to evaluate completeness of the genomes and annotations, cegma method (parra, et al. 2007) was employed. we used the treefam methodology (li, et al. 2006) to define gene families in 14 mammalian genomes (human, macaque, mouse, rat, dog, cat, horse, rhinoceros, cow, pig, little brown bat, large flying fox, great leaf-nosed bat and chinese rufous horseshoe bat). the protein sequences of other 12 mammalian species were obtained from ensembl database (release 72). gene family expansion and contraction analysis was performed by café software (de bie, et al. 2006) . a random birth and death model was proposed to study gene gain and loss in the gene families across a user-specified phylogenetic tree. a global parameter λ (lambda), which described both gene birth (λ) and death (μ = -λ) rates across all branches of all gene families was estimated using the maximum likelihood method. a conditional p-value was calculated for each gene family, and families with conditional p-values less than 0.05 were considered to have a significantly accelerated rate of expansion and contraction. protein sequences of the aforementioned 14 mammals were aligned using muscle software (edgar 2004) . all orthologous genes were concatenated to one super gene for each species. raxml (stamatakis 2014 ) was applied to build phylogenetic trees. we partitioned the data by coding genes, and evaluated the model parameter independently for each partition. in all partitioned analyses, the empirical base frequencies and the evolutionary rates were estimated independently for every partition. bootstrap support was obtained by repeating the original partitioned ml raxml analysis on 100 bootstrap replicates for each dataset using different random number seeds in each repetition. next, we inferred the species tree using coalescent method: maximum pseudo-likelihood estimation of species tree (mp-est) (liu, yu, et al. 2010) . individual gene tree for each gene was estimated using the maximum-likelihood method and rooted by an outgroup (human). species trees were estimated from the rooted gene trees in the program mp-est with 100 bootstrap replicates. the results supported that bats are member of scrotifera (chiroptera + carnivores + perissodactyla + cetartiodactyla) with bat lineage diverging from fereuungulata (carnivores + perissodactyla + cetartiodactyla). the values of ka, ks, the ka/ks ratio were estimated for each gene using the codeml programs nested in the paml package (yang 2007) . in order to detect positively selected genes, optimized branch-site likelihood model (zhang, et al. 2005) was used. we separately explored the positively selected genes in the great leaf-nosed bat and the chinese rufous horseshoe bat. for each analysis, only one bat species was selected as foreground branches, and all other species were regarded as the background branches. the revised branch-site model a was employed, which attempts to identify positive selection acting on some sites on the "foreground branches". using an likelihood ratio test (lrt), the alternative hypothesis that positive selection occurs on the foreground branches (ka/ks > 1) is compared with the null hypothesis (ka/ks=1). bayesian empirical bayes values were used to identify sites under positive selection. then, branch two-ratio model was applied to detect accelerated evolved genes in specific lineage. the one-ratio model assumed an equal ka/ks ratio for all lineages in the phylogeny, and the two-ratio model assumed two ka/ks ratios: one branch for the background, one for the foreground branch leading to the specific species. then, clade model c was employed to test for positive selection along the rhinolophoid bats. the two clades were assumed to share sites under purifying selection and neutral evolution, but to differ at a third site partitions under divergent selection. the null model used for the clade model c was m2a_rel (weadick and chang 2012) , whose lrt has a relatively lower false-positive rate. go annotations were downloaded from ensembl databases and were assigned to these orthologous genes. the binomial test was used to identify go categories with more than 20 gene that had an excess of non-synonymous changes in bat lineages. next, we used the program mapp (multivariate analysis of protein polymorphism) (stone and sidow 2005) to evaluate the physicochemical impact of these convergent amino acid substitutions on bats. physicochemical variations can be used to predict how these particular convergent amino acid substitutions might affect protein function. in this work, we performed a probabilistic analyses of the sequence convergence in echolocating bats. a maximum likelihood approach, implemented in the software package codeml ancestral, was used. we compared the pair-wise branches of two echolocating bat in the phylogeny, and posterior probabilities of all possible amino acid substitutions were calculated. the probabilities of divergent and convergent substitutions were calculated as the sum of joint probabilities of substitutions between the two branches of echolocating bats. convergence and divergence estimates were based on posterior distributions of ancestral states and substitutions. the same state (same amino acid) represents convergent substitutions, and the different state represents divergent substitutions. finally, to further validate that the convergence between two branch pairs of echolocating bats was significant, we performed the simulation analysis to compare the observed probabilities against that of the null hypothesis. simulated sequences were generated using evolver, another package from paml package (yang 2007) . the branch-wise convergence probabilities were calculated with 1,000 replicates. we used the similar in silico method as previously reported in dong et al. (dong, et al. 2009 ). at first, we used previously published or genes in vertebrates as query sequences (niimura and nei 2007) and conducted a tblastn search against the genome sequences with a cutoff e value of 1e-10 to identify the or gene repertoires. here, we totally identified or gene repertories from eight mammalian genomes (the site (http://genome.ucsc.edu). then, the non-redundant blast-hits were extended to the 5' and 3' directions along the genome sequences, and the potential coding regions were extracted from these sequences. the chemosensory receptor genes in mammals have high sequence similarity. here, we re-performed a tblastn against the genome sequences using or coding genes identified from each species, and the non-redundant blast-hits were used to identify the or pseudogenes containing interrupting stop codons or frameshifts. to identify partial or genes from these sequences, we extracted the sequences that did not have any nonsense or frameshift mutations. we then constructed a multiple alignment of these sequences together with functional or genes by the program e-ins-i in mafft version 5.8 (katoh, et al. 2002) . from those alignments, we extracted partial or sequences that meet the following criteria. when the c-terminal region of an or gene is missing from the genome sequence, the n-terminal region should contain an initiation codon at a proper position and should not contain any nonsense mutations, frameshifts, or long gaps. when the n-terminal region is missing, the c-terminal portion should have a stop codon at a proper position and should not contain any nonsense mutations, frameshifts, or long gaps. we also identified 6 and 10 sequences with nonsense stop codon in the great leaf-nosed bat and chinese rufous horseshoe bats, which miss both a start and stop codons. however, these sequences were removed because they have relatively short sequence length (~400 bp) and have strong sequence similarity with bitter taste receptor genes. to assign identified or genes into distinct or gene families, a collection of protein sequences from horde database version 42 (safran, et al. 2003 ) was used. to detect the extensive gain and lose of or gene repertories, we employed the reconciled tree method (nam and nei 2005) , in which the topology of a gene tree is reconciled with that of a species tree. an in-house program was applied. briefly, based on the phylogenetic tree of or genes, we compared the condensed gene tree and the species tree under the parsimony principle. the number of ancestral genes can be estimated, and the information of the past occurrence of gene expansion and contraction. here, we used a 70% condensed tree of or genes for analyses. a list of vision-related genes were obtained from go category of visual perception (go:0007601). we subjected human vision-related proteins to tblastn against the genomes with cutoff threshold of e-value 1e-5. we found that best-hits for each human protein by using the criteria that more than 30% of the aligned sequences showed an identity above 30%. genewise algorithm was employed to identify potential pseudogenes with parameters -genesf -for -quiet. those genes with frame shifts or pre-mature stop codons were considered as candidates. we then filtered them as follows: 1) we aligned all human proteins to their corresponding genomic loci, and those genes with frameshifts or premature stop codons in human-to-human alignments were removed; 2) as for the human-to-human alignments, those genes with obvious splicing errors near their frameshifts or premature stop codons were removed; 3) candidate pseudogenes with a low number of sequencing reads covering their frameshift or premature stop codon sites were regarded assembly error. those genes with a number of reads containing genotype variations at these sites were considered as heterozygous and were also removed. we used a method based on ka/ks to identify go categories that significantly above average in the great leaf-nosed bat genome and chinese horseshoe bat genome. at first, the ka and ks rates are calculated by paml package from all aligned bases with quality score larger than 20 in orthologs, using the f3x4 codon frequency model and the rev substitution matrix. in order to examine the evolution function catalog, we downloaded the go annotation of human gene from the ensembl biomart database (release-71). we estimated the average ka and ks values for those genes which have annotated go as following equations (s1, s2). where t is the number of annotated genes within go categories, i a and i a are the numbers of non-synonymous substitutions and sites, i s and i s are the numbers of synonymous substitutions and sites in gene i, as estimated by paml, respectively. the expected proportion of non-synonymous substitutions a p in a go category was then calculated (s3). for a given go category c, the probability c p of observing an equal or higher number of non-synonymous substitutions and synonymous substitutions was calculated assuming a binominal distribution (s4). where c a and c s are the total number of non-synonymous and synonymous substitutions in go category c, respectively. we applied an approach to the binomial test described above to identify go categories that have an excess of non-synonymous changes on one lineage. for lineages x and y, the average proportion of non-synonymous substitutions were calculated by the following formula (s5). x is the total number of non-synonymous substitutions in the x lineage, y is the total number of non-synonymous substitutions in the y lineage, and the divergence of the proportion of non-synonymous substitution numbers in different lineages between the observed and expected obeys binomial distribution, the formula is as in the following equation (s6). as described for the absolute rate tests, we then computed this statistic for every go category, as well as for every category in 10,000 randomly permuted data sets. we sampled a total of 20 great leaf-nosed bats distributed in four different locations. genomic dna was extracted from wing membranes of each individual. paired-end sequencing library with an insert size of 500 bp was constructed for each sample, and sequenced on the illumina hiseq 2500 platform with 2×101 bp mode. duplicate sequencing reads were filtered out according to the following criteria: 1) any reads with >10% unidentified nucleotides; 2) reads with >10 nt aligned to the adapter sequence, allowing <10% mismatches; 3) reads with 50% bases having phred quality <5. the filtered reads were mapped to the genome using bwa, and samtools were used to call snps. then, we filtered snps using vcftools and gatk under the following criteria: 1) coverage depth >4 and <10000; 2) root mean square mapping quality >10; 3) the distance of adjacent snps >10 bp; 4) the distance to a gap > 10; 5) read quality value >30. to estimate phylogenetic relationships, the genetic distances were calculated among all samples to generate a neighbor-joining (nj) tree using phylip. we performed a principal component analysis using the package gcta. the population structure was inferred using frappe (v1.1) with a maximum likelihood method (tang, et al. 2005) . sliding-window approach (10 kb window sliding in 10 kb step) was employed to quantify polymorphism levels (θ π , pairwise nucleotide variation as a measure of diversity) and genetic differentiation (fst) between the high altitude region (dq) and low altitude regions (tw, jx and gz). to detect significant signatures of selective sweep, z-transformed fst values was calculated. next-generation genome sequencing was carried out, generating 476.5 gb and 288.5 gb of sequences for the great leaf-nosed bat and the chinese rufous horseshoe bat (supplementary table s1 ), respectively. the genome size was estimated to be 2.18 gb and 2.07 gb for the great leaf-nosed bat and the chinese rufous horseshoe bat ( supplementary fig.1 supplementary fig.3 ). known transposon-derived repeats account for 25.8% and 28.5% of the genomes in the great leaf-nosed bat and the chinese rufous horseshoe bat, respectively, which are lower than other non-bat mammalian species (supplementary table s5 ). to facilitate the genome annotation, we generated a high-depth transcriptome data from these two rhinolophoid bats. with repeats masked, the genome was annotated by integrating the homologous prediction, ab initio prediction and transcription-based prediction methods. as a result, a non-redundant reference gene set of 22,009 and 23,152 protein-coding genes were generated for the great leaf-nosed bat and the chinese rufous horseshoe bat ( supplementary fig.4) , respectively. we employed cegma method to evaluate the completeness of genome annotation. the result showed that the vast majority of the core genes were present in our predicted gene sets (97.08% for the great leaf-nosed bat and 96.14% for the chinese rufous horseshoe bat), indicating the completeness of gene sets identification. next, we aligned the transcriptome sequencing reads to the predicted genes, and the result showed that approximately 96% of exons are accurately covered (96.8% for the great leaf-nosed bat and 97.1% for the chinese rufous horseshoe bat). comparative analysis showed a high gene sequence similarity between them (91%, supplementary fig.5 ). we next examined the level of homology between our predicted genes and sequences in the uniprot database. the result showed that >92% of the genes were functionally annotated (94% for the great leaf-nosed bat and 92.2% for the chinese rufous horseshoe bat). compared with the gene families in other three mammalian species -the little brown bat, large flying fox and human, we identified 8,792 homologous gene families shared by five species. a total of 975 gene families were specific to the rhinolophoid bats ( fig. 1) . further functional annotation indicated that the rhinolophoid bats specific gene families were significantly over-represented in two major functional categories: atp binding (43 genes, f.d.r.= 0.0002) and immunity and host defense (25 genes, f.d.r.= 0.0051; supplementary table s6) . until now, the relationship of bats to other members of superorder laurasiatheria has proven difficult to resolve. some studies insisted that bats belong to the clade of pegasoferae which comprises chiroptera, carnivores and odd-toed ungulates (lindblad-toh, et al. 2011; meredith, et al. 2011; mccormack, et al. 2012) , whereas others proposed that bats are a sister group to the clade comprising carnivores and euungulata (pumo, et al. 1998; murphy, et al. 2001; murphy, et al. 2007; song, et al. 2012; zhang, et al. 2013) . to determine the phylogenetic position of bats within the superorder laurasiatheria, a total of 4,569 single-copy 1:1 orthologous genes were fig.6 ). the result based on nucleotide data was in line with previous analysis that bats are a sister group to odd-toed ungulates, whereas the result based on amino acid data supported that bat bats are sister group to the fereuungulata (carnivores + perissodactyla + cetartiodactyla). to account for the tree discordance among loci, coalescent method was applied. coalescent trees were highly consistent with the result inferred from amino acid data using partitioned method ( supplementary fig.7) . to dissect the phylogenetic signal, previously published eight different phylogenetic hypotheses ( supplementary fig.8) were proposed (waddell, et al. 1999; murphy, et al. 2001; nishihara, et al. 2006; prasad, et al. 2008; lindblad-toh, et al. 2011; meredith, et al. 2011; mccormack, et al. 2012 table s7 , supplementary fig.9 ). the result is consistent after incorporating the data from eulipotyphyla group ( supplementary fig.10) . we subsequently estimated the divergence time among these 14 mammalian species. the bat lineage seems to be diverged from fereuungulata around 81 million years ago, and the rhinolophoid bats seem to be diverged from the old world fruit bats around 68 million years ago. comparative genome analyses were carried out to assess the evolution and innovation within the rhinolophoid bats. we next determined the expansion and contraction of gene orthologous clusters during evolution. the result identified 48 significantly expanded and 65 significantly contracted gene families in the great leaf-nosed bat, 46 significantly expanded and 54 significantly contracted gene families in the chinese rufous horseshoe bat (fig. 2) . functional annotation showed that gene family contraction mainly included many olfactory receptor gene families in both rhinolophoid bat lineages (supplementary table s8 ), which is consistent with the result that the olfactory system is aberrant in some echolocating bats. many of the expanded gene families in both rhinolophoid bats are significantly enriched in immune-related functional categories (supplementary table s9 ). moreover, we identified 577, 453 and 182 positively selected genes in the great leaf-nosed bat, the chinese rufous horseshoe bat and the large flying fox, (supplementary tables s10, 11, 12), respectively. olfaction is of great importance in the lives of bats. many bats can use olfaction for mother-pup recognition, find food and avoid danger. in old world fruit bats, olfaction appears to be of particular importance, and fruit bats can find food from scent cues. animals that rely heavily on the sense of smell tend to have large numbers of or genes, while species that always use other senses have fewer functional or genes (niimura and nei 2007) . it has been suggested that bats displayed a diverse olfaction abilities. in order to describe the diversity of bat or gene repertoires, we identified the entire set of or genes of four bat species (supplementary methods, supplementary table s13 ). in line with previous work (hayden, et al. 2014) , we observed that echolocating bats have less fraction of or pseudogenes (18% for the great leaf-nosed bat, 16% for the chinese rufous horseshoe bat and 14% for the little brown bat) than non-echolocating bats (26% for the large flying fox). however, further analysis showed that the large flying fox and little brown bat have more than 400 intact or genes while these two rhinolophoid bats only have <300 intact or genes. this finding is consistent with the result that rhinolophoid bats have a relatively small olfactory epithelium than the frugivorous pteropodidae (neuweiler 2000) . next, we reconstructed a protein neighbor-joining tree of all newly identified intact or genes in bats (fig. 3a) . it is obvious that or genes can be classified into two distinct classes based on sequence similarity: class i, postulated to bind to water-borne molecules, and class ii, hypothesized to bind to airborne molecules. the exact number of or genes in each class/or family are shown (supplementary table s14 , table s15 ). it seems that four bat species contain similar number of or genes in class i, while or gene contraction occurred in two rhinolophoid bats in class ii . previous works have documented that the number of or genes varies extensively among mammalian species, and extensive gains and losses of or genes have been observed (niimura and nei 2007) . to further understand the evolutionary changes of or gene repertoires, we estimated the gains and losses of the or genes in a diverse range of mammals (supplementary methods). evolutionary changes in the number of or genes in mammals have been shown in fig. 3b . we can clearly identify an extensive or gene contraction events occurred to the branch leading to the common ancestor of bats. further extensive gene contractions can be observed in the branch leading to the rhinolophoid bats. this finding also suggests massive "birth-and-death" of or genes in the bat species. table s18 ). since high omega may be due to stochastic effect caused by extremely small sample size, we removed these genes with omega value of 999. the result is also stable that more positively selected genes were detected in the branches leading to echolocating bats (12 genes, great leaf-nosed bat, p = 9.1e-5; 10 genes, chinese rufous horseshoe bat, p = 8.8e-3; 10 genes, little brown bat, p = 0.011). next, branch model (two-ratio model) was carried out with the attempt to detect genes with accelerated evolution in the bat species. the result further indicated that more hearing-related genes have higher ɷ values on the branches leading to echolocating bats than all other lineages (supplementary table s19) . clade model c implemented in paml was employed (weadick and chang 2012) , and the result also persisted that more positively selected genes were detected in the branches leading to echolocating bats (supplementary table s20 ). moreover, a significant association between the average number of non-synonymous substitutions for all the hearing-related genes leading to each mammalian species and the estimated frequency of best hearing sensitivity for that species (r = 0.84, p = 0.00032, fig. 4 ) was observed. no significant correlation between such hearing frequencies and number of synonymous changes was observed (p = 0.132). a significant association between the number of non-synonymous changes between sister taxa was observed (r = 0.67, p = 0.006). it is obvious that echolocating bats have typically undergone many more non-synonymous changes in the hearing-related genes than non-echolocating mammals. these results indicated the evolution of ultrasonic hearing in the rhinolophoid bats has involved in adaptive amino acid replacements in the hearing-related genes, which provided evidence conferring greater auditory sensitivity to ultrasonic frequency. previous works have documented that seven hearing-related genes underwent convergent evolution in echolocators (li, et al. 2008; liu, cotton, et al. 2010; davies, et al. 2012; shen, et al. 2012 ). here, genome-wide signatures of convergent evolution were examined in laryngeal echolocating bats. except for the previously reported seven hearing-related genes, we totally identified 10 genes examined in the sound of perception category containing potential sequence convergent loci (site-wise convergence posterior probabilities > 0.5). to confirm our result, we amplified and sequenced these 10 hearing-related genes from another two echolocating bats (eptesicus fuscus and miniopterus natalensis). the result also showed that these 10 genes have higher convergence probabilities occurred in echolocating bats from a wider range of taxa, and the convergence probabilities between branches were significant based on simulations (supplementary table s21 ). however, maximum likelihood trees recovered the topology that all laryngeal echolocating bats formed a monophyletic clade for only four genes (col1a1, icam1, bsnd and strc, supplementary fig.11 ). further analyses showed that echolocating bats are paraphyletic based on synonymous substitutions, whereas the non-synonymous trees revealed monophyly of laryngeal echolocators for only one hearing-related genes (strc gene, supplementary fig.12 ). next, multivariate analyses of protein polymorphism (mapp) was employed to detect the physicochemical impact of convergent substitutions in echolocating bats. mapp scores were estimated for the amino acid variants nested in the strc gene, and the result showed that these replacements had important functional effects (mapp score = 18.61, p = 1.44e-4 for h28q; mapp score = 10.33, p = 3.98e-3 for a39t; mapp score = 7.37, p = 2.27e-2 for v169i). we further measured the number of sites with convergent amino acid substitutions along the branches as a direct measurement of sequence convergence, and found that the number of convergent sites in the branch pairs is proportional to the number of divergent sites ( supplementary fig.13 ). the number of convergent sites in the laryngeal echolocating bats does not significantly exceed that between the branch pair of the little brown bat and large flying fox, given their numbers of divergent sites (supplementary table s22 ). no significant differences was observed in the total number of sites that have experienced convergent substitutions from hearing-related genes. this result indicated that there is no exceptional genomic signature indicative of adaptive convergence between laryngeal echolocating bats, and genes with adaptive convergent substitutions might confine to few specific genes. bats are nocturnal mammals. the eyes of most echolocating bats are relatively small and poorly developed, whereas old world fruit bats often have excellent eyesight . rhinolophoid bats have the most sophisticated echolocation ability, and have been proposed that some genes involved in visual perception may have undergone relaxed selection (zhao, et al. 2009 ). we next examined the molecular basis for the poor visual perception in the echolocating bats. of bats have long been regarded as important reservoir hosts of emerging viruses (calisher, et al. 2006) . to examine population dynamics and understand evolutionary processes, we sampled 20 great leaf-nosed bats from 4 major distributed locations in china, including one group from high-altitude region (fig. 6a, table s28) are located at the intergenic regions. in order to resolve their phylogenetic relationships, we constructed a neighbor-joining (nj) tree based on pairwise genetic distances (fig. 6b) . this result showed that the great leaf-nosed bats formed separate groups according to the different locations. principal component analysis clearly divided these samples into four groups (dq, gz, jx and tw, fig. 6c) . these results suggested that there were significant population structures among the great leaf-nosed bat populations. furthermore, we performed population structure analysis. when k=4, all these four populations were clearly separated (fig. 6d) . next, we measured the genetic diversity values (θ π ) of four populations, and found similar sequence diversity values (dq: 0.0012, gz:0.0009, jx:0.0009 and tw:0.0011, supplementary fig. s14 ). we further observed that the population differentiation statistic (fst) between populations, and the result showed little differentiation among populations (fst ranging from 0.013 between jx and tw to 0.057 between tw and dq, supplementary table s29) , which suggests universal inter-region gene flows. since the method of population differentiation has been widely used to detect selective sweeps (akey, et al. 2010; axelsson, et al. 2013; gou, et al. 2014 table s31 ). the result showed that genes related to catabolic process are likely to have been targets of recent positive selection. interestingly, we found that five genes (epas1, plxnd1, gja1, sell and chdh) belong to hypoxia response related go categories (pugh and ratcliffe 2003; storz and moriyama 2008) , including 'angiogenesis', 'blood coagulation', 'blood vessel morphogenesis' and 'oxidoreductase activity'. epas1 can respond to the changes in available oxygen in the cellular environment under the high-altitude conditions. our work suggested that epas1 is involved in a selective sweep during the move of bats from low to high altitude. although hypoxia go categories are not over-represented, these highlighted hypoxia-related genes gave us a clue that genetic adaptations might be associated with high altitude. using deep sequencing and de novo assembly, we generated two genomes of rhinolophoid bats. rhinolophoid bats can perceive the world by using a wide range of sensory mechanisms, some of which have become highly specialized. these genome data provided useful resources to decipher the molecular adaptations of phenotypic traits. rhinolophoid bats arguably possess the most sophisticated echolocation systems, and can emit relatively long calls adapted to detect and classify the wing beats of insects. they are heavily reliant on hearing for a variety of ecologically important roles. previous works have documented that hearing-related genes are predominantly evolutionarily conserved in mammals (kirwan, et al. 2013) . here, we found evidence that some hearing-related genes have undergone darwinian selection associated with the evolution of specialized constant frequency echolocation. positive selection acting on hearing-related genes in rhinolophoid bats might result from the extreme selectivity used in auditory processing by these bats. many previous works have reported the sequence convergence of some hearing-related genes reuniting echolocating bats (li, et al. 2008; liu, et al. 2011; davies, et al. 2012; . we found no genome-wide sequence convergence for echolocation, indicating erroneous phylogenetic grouping are still rare it has been suggested that the enlargement of one area of brain might be associated with the reduction in size of other brain area (harvey and krebs 1990) . the auditory cortex and the inferior colliculus are extremely enlarged in the volume in laryngeal echolocating bats (especially in rhinolophoid bats), while visual brain areas are relatively enlarged in old world fruit bats (dechmann and safi 2009 ). the trade-off has been proposed in investment in brain tissues because of the extreme energetic demands imposed by neural processing. our result showed more visual perception genes have become pseudogenes in rhinolophoid bats, and it is reasonable to speculate that some visual perception gene may have undergone relaxed natural selection in echolocating bats. meanwhile, positive selection acting on some hearing-related genes was identified. such concordance suggests that some genes are impacted by natural selection, which raised the possibility that changes at the sensory genes will have direct consequences for those genes controlling for other sensory modalities, perhaps via trade-offs. this finding supports the longstanding but weakly supported assumption that bats are experiencing trade-off between vision and audition . olfaction is of great importance in the lives of bat species. previous works have identified olfactory receptor (or) gene repertoire in the little brown bat and the large flying fox using the profile hidden markov model (hayden, et al. 2010; hayden, et al. 2014 in specific gene family. a possible explanation is that the little brown bat has no well-developed olfaction ability, but tends to recognize specific odorants after recent or gene duplication. these comparative analyses have provided great insights into adaptation to their specialized sensory mechanisms. in this work, we re-sequenced the genome of 20 great leaf-nosed bats from four distributed locations. the genome re-sequencing analysis has been performed based generally on the following considerations: 1) to characterize the genetic diversity and patterns of evolution; 2) to understand the genetic bases of adaptation to high altitude in the great leaf-nosed bats. efforts for the conservation measures will benefit from the knowledge of population genetic structure of the great leaf-nosed bats. here, we found very little differentiation among populations, which suggests universal inter-region gene flows or incomplete lineage sorting. a broader geographical scale analysis is needed in the future. furthermore, we provided evidence of genetic adaptation in the great leaf-nosed bat that are associated with high altitude. selective sweep mapping was conducted for populations from different altitudes, and identified several hypoxia-related genes with a high extent of differentiation on the genome scale. epas1 is transcription factor that respond to the changes in the available oxygen in the cellular environment under high-altitude conditions, and mutations at epas1 are tightly associated with hematologic phenotypes (van patot and gassmann 2011). previous works have documented that epas1 polymorphisms are associated with tibetan people with lower hemoglobin concentrations (beall, et al. 2010) . a loss-of-function role of epas1 might exist in high-altitude adaptation. so, our result indicated potential high-altitude hypoxia adaptation mechanisms of the great leaf-nosed bat. our work is based on a limited genome re-sequencing resource, and data from more samples are necessary for future work. however, false positives notwithstanding, the results provided valuable staring points for experimental follow-up, and suggested an initial evolutionary scenario of bats in adaptation to high-altitude hypoxia. to the best of our knowledge, it is the first time to report the de novo assembled genome and genome re-sequencing of bats with long constant frequency echolocation calls. these data are essential for us to understand the evolution of bats. tracking footprints of artificial selection in the dog genome the genomic signature of dog domestication reveals adaptation to a starch-rich diet natural selection on epas1 (hif2alpha) associated with low hemoglobin concentration in tibetan highlanders prediction of complete gene structures in human genomic dna allpaths: de novo assembly of whole-genome shotgun microreads bats: important reservoir hosts of emerging viruses parallel signatures of sequence evolution among hearing genes in echolocating mammals: an emerging model of genetic convergence cafe: a computational tool for the study of gene family evolution comparative studies of brain evolution: a critical insight from the chiroptera evolution of olfactory receptor genes in primates dominated by birth-and-death process muscle: multiple sequence alignment with high accuracy and high throughput isolation and characterization of a bat sars-like coronavirus that uses the ace2 receptor whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia improving the arabidopsis genome annotation using maximal transcript alignment assemblies comparing brains ecological adaptation determines functional mammalian olfactory subgenomes a cluster of olfactory receptor genes linked to frugivory in bats the evolution of echolocation in bats repbase update, a database of eukaryotic repetitive elements mafft: a novel method for rapid multiple sequence alignment based on fast fourier transform a phylomedicine approach to understanding the evolution of auditory sensory perception and disease in mammals the hearing gene prestin reunites echolocating bats treefam: a curated database of phylogenetic trees of animal gene families the hearing gene prestin unites echolocating bats and whales a high-resolution map of human evolutionary constraint using 29 mammals a maximum pseudo-likelihood approach for estimating species trees under the coalescent model convergent sequence evolution between echolocating bats and dolphins the voltage-gated potassium channel subfamily kqt member 4 (kcnq4) displays parallel evolution in echolocating bats parallel evolution of kcnq4 in echolocating bats parallel adaptive radiations in two major clades of placental mammals ultraconserved elements are novel phylogenomic markers that resolve placental mammal phylogeny when combined with species-tree analysis impacts of the cretaceous terrestrial revolution and kpg extinction on mammal diversification interpro and interproscan: tools for protein sequence classification and comparison resolution of the early placental mammal radiation using bayesian phylogenetics using genomic data to unravel the root of the placental mammal phylogeny evolutionary change of the numbers of homeobox genes in bilateral animals the biology of bats extensive gains and losses of olfactory receptor genes in mammalian evolution pegasoferae, an unexpected mammalian clade revealed by tracking ancient retroposon insertions cegma: a pipeline to accurately annotate core genes in eukaryotic genomes confirming the phylogeny of mammals by use of large comparative sequence data sets regulation of angiogenesis by hypoxia: role of the hif system complete mitochondrial genome of a neotropical fruit bat, artibeus jamaicensis, and a new hypothesis of the relationships of bats to other eutherian mammals human gene-centric databases at the weizmann institute of science: genecards, udb, crow 21 and horde from spatial orientation to food acquisition in echolocating bats genblasta: enabling blast to identify homologous gene sequences parallel evolution of auditory genes for echolocation in bats and toothed whales parallel and convergent evolution of the dim-light vision gene rh1 in bats (order: chiroptera) consel: for assessing the confidence of phylogenetic tree selection resolving conflict in eutherian mammal phylogeny using phylogenomics and the multispecies coalescent model raxml version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies gene prediction with a hidden markov model and a new intron submodel physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity mechanisms of hemoglobin adaptation to high altitude hypoxia estimation of individual admixture: analytical and study design considerations using repeatmasker to identify repetitive elements in genomic sequences hear, hear: the convergent evolution of echolocation in bats? a molecular phylogeny for bats illuminates biogeography and the fossil record differential analysis of gene regulation at transcript resolution with rna-seq tophat: discovering splice junctions with rna-seq hypoxia: adapting to high altitude by mutating epas-1, the gene encoding hif-2alpha towards resolving the interordinal relationships of placental mammals an improved likelihood ratio test for detecting site-specific functional divergence among clades of protein-coding genes paml 4: phylogenetic analysis by maximum likelihood comparative analysis of bat genomes provides insight into the evolution of flight and immunity evaluation of an improved branch-site likelihood method for detecting positive selection at the molecular level the evolution of color vision in nocturnal mammals this project is supported by key construction program of the national '985' project of east china normal university to dong dong (79633006), and the national natural science foundation of china (no. 31570382) to shuyi zhang. we thanks shanghai majorbio bio-pharm biotechnology co., ltd. for genome sequencing and dr.chao-hung lee for providing valuable advices.. dd designed the study, and dd, ml, ph, yp, sm, gz, ep, kl and sz carried out the data analysis. dd wrote the manuscript. all authors read and approved the final manuscript. the authors declare no competing financial interests. key: cord-340119-af8i359n authors: wang, shi-xin; wang, yan; lu, yu-bao; li, jie-yun; song, yu-jun; nyamgerelt, munkhtuya; wang, xue-xi title: diagnosis and treatment of novel coronavirus pneumonia based on the theory of traditional chinese medicine date: 2020-04-15 journal: j integr med doi: 10.1016/j.joim.2020.04.001 sha: doc_id: 340119 cord_uid: af8i359n since the outbreak of novel coronavirus pneumonia (coronavirus disease 2019, covid-19) in december 2019, it has rapidly spread to 187 countries, causing serious harm to the health of people and a huge social burden. however, currently, drugs specifically approved for clinical use are not available, except for vaccines against covid-19 that are being evaluated. traditional chinese medicine (tcm) is capable of performing syndrome differentiation and treatment according to the clinical manifestations of patients, and has a better ability of epidemic prevention and control. the authors comprehensively analyzed the etiology and pathogenesis of covid-19 based on the theory of tcm, and discussed its syndrome differentiation, treatment and prevention measures so as to provide strategies and reference for the prevention and treatment with tcm. since december 2019, the novel coronavirus pneumonia (coronavirus disease 2019, outbreak in wuhan, hubei province, china has rapidly spread across the world and has now infected a total of 348678 people in 187 countries (march 21, 2020) [1] . china has listed covid-19 as a class b infectious disease and has undertaken preventive and control measures according to class a infectious diseases [2] . with the spread of the epidemic, presently, patients infected with the novel coronavirus, as well as those with asymptomatic infection, are the main sources of infection; thus, covid-19 is an infectious disease with a medium to slightly high contagious capacity [3] . the incubation period of the disease is generally 7 days, and the longest is 14 days; however, some cases have reported an incubation period of 24 days as well [4] . common clinical manifestations include fever, dry cough and fatigue. computerized tomography of the chest can show multiple ground glass shadows of the pulmonary lobes, indicative of conditions such as respiratory distress syndrome, shock and sepsis, which can even lead to death [5] . thus far, although china has announced six trials and strategies for the diagnosis and treatment of the disease, the focus remains mainly on symptomatic treatment, new drugs specifically approved for the infection are not available. clinical trials for new drugs such as remdesivir and coolidge are underway; however, the clinical promotion and short-term use of these drugs is unlikely. therefore, given the particularities of this disease, it is of critical clinical value to formulate a set of treatment plans using integrated traditional chinese medicine (tcm) and western medicine, based on the concept of prevention and treatment. to utilize the advantages of integrated traditional chinese and western medicine in the prevention and treatment of covid-19, this paper discussed the etiology and pathogenesis of covid-19 from the viewpoint of integrated tcm and western medicine, the treatment measures for different susceptible groups, and the effect along with matters needing attention, so as to provide a reference for the prevention and treatment of covid-19. coronavirus is a type of a ribonucleic acid virus with an envelope structure, characterized by rod-like protuberances on the surface and can infect multiple host species, causing a variety of diseases [6] . the covid-19 pathogen is a novel coronavirus (2019-ncov), which can infect humans and is significantly clustered with the bat-like severe acute respiratory syndrome coronavirus (sars-cov) sequence isolated in 2015, with a nucleotide similarity of 88%. based on these results, it can be concluded that 2019-ncov is similar to sars-cov and middle east respiratory syndrome coronavirus (mers-cov) [7] . it is a zoonotic pathogen that can cause severe respiratory diseases in humans and can be transmitted from person to person [8] . therefore, the international committee on taxonomy of viruses announced that the official classification of the novel coronavirus is sars-cov-2. there is no virus theory in tcm, and according to the clinical characteristics of covid-19, the disease belongs to the category of "plague" [9] . as the general treatise on the etiology and symptomology says [10] , "if a person feels grumpy and gets sick, he will be easily infected by evil qi, which may even exterminate the family, and extend to outsiders." the common symptoms in the early stage of covid-19 in mildly infected patients include fever, fatigue and dry cough, which could be easily confused with other common exogenous diseases. however, according to wu you-ke's the treatise on epidemic febrile diseases [11] , which mentions "the febrile disease is non-wind, non-cold, non-heat and non-damp; it is a different feeling between heaven and earth," the cause of this disease is very clear, differing from the other six exotic evils, and presenting characteristics of a strong and contagious epidemic virus. wuhan, the center of the outbreak pathogen, is located in the east of jianghan plain of china. the vertical and horizontal water areas of the city's rivers account for one-fourth of the total city area, demonstrating the natural environmental basis of "damp evil" [12] . at the initial stage of this epidemic, most patients presented symptoms of fever; however, there were also patients with no fever or low fever, and some patients presented gastrointestinal symptoms, such as indigestion and loose stool, as well as chest tightness and fatigue, coinciding with the characteristics of "damp evil" in tcm. hence, this disease is an epidemic, with the primary nature of "damp" and "toxic," and thus can be termed "damp toxin disease." furthermore, in 2019, wuhan experienced a warm winter climate, with incoming heat instead of cold. from the perspective of tcm, this kind of climate change is prone to generate damp-heat in the human body, which persists and is difficult to eliminate from sanjiao (one of the six fu-organs in tcm theory). some patients have a recurrent fever, bitter mouth, insomnia, upset, chest tightness and shortness of breath, fatigue, yellow or greasy tongue coating, and slippery pulse, which are manifestations of the evil underlying shaoyang meridian according to the six-meridian syndrome differentiation theory [13] . notably, the most severe cases developed dyspnea one week later, which even progressed to acute respiratory distress syndrome, septic shock, intractable metabolic acidosis, and coagulation dysfunction, leading to death [14] . according to tcm, the toxins from these patients not only hurt the qi but also injure the nutrient blood and result in blood stasis; the pericardium transmission channel is also reversed, resulting in mental changes. dampness stagnates for a prolonged period and turns into heat; heat toxin accumulates for a long time, resulting in stasis; stasis and heat combine mutually and then generate syncope, which consumes qi and yin and leads to a deficiency. according to the principle of "three factors and measures," there exist various etiological characteristics in different regions, as well as climatic factors. fan et al. [15] observed and analyzed the tcm pathological characteristics of "dryness" in hunan cases, and concluded that dryness and dampness are mainly due to "child disease to mother" in the course of the disease. in the theory of tcm, dryness evil can easily injure the lung. lung and spleen belong to "gold" and "soil" in the five-element theory of tcm. dryness turns into dampness. dampness easily traps spleen. wet soil is the mother of dryness "gold." furthermore, excessive lung dryness injures the spleen "soil"; hence, both lung dryness and spleen dampness are significant. in contrast, yu et al. [16] summed up the data and concluded that the diseases in guangdong province and gansu province were caused by warm-heat toxin or epidemic toxin, which was closely related to their regional environment. guangdong province is hot and humid all year round, and the epidemic qi can easily mix with evils of damp and heat to attack the lung; however, the overall 2019 winter temperature in gansu province was higher than that experienced in previous years. additionally, gansu is located in the northwest region of china, which is mostly dry and warm, and susceptible to the evil of dryness that can cause lung disease. tcm runs through the whole idea of disease differentiation all the time, and the unified relationship between man and nature has been called "correspondence between man and nature" in ancient books, which presents considerable advantage in the treatment of covid-19 in different populations and regions. compared with other diseases, the evil qi of the "damp toxin epidemic" is relatively fixed, and hence, the etiology and pathogenesis are relatively fixed, with obvious stages of disease progression in clinical settings. understanding the consistency of the stages also allows for clinical diagnosis and evidence-based treatment. after careful assessment of the four pieces of diagnostic evidence available regarding the confirmed cases, it was observed that this epidemic is mainly caused by a dampness pathogen, with the disease location of mainly sangjiao, and the core pathogenesis is "dampness, heat, poison, blood stasis and deficiency," which runs through the whole process of dampness and intoxication and closure of the lung. the treatise on epidemic febrile diseases [11] ascertains that typhoid fever does not infect people, but epidemic diseases can infect people. the evil of typhoid fever enters from the orifices, while the evil of epidemic disease enters only from the mouth and nose; it has been observed that during an epidemic, the evil comes from the mouth and nose, remains in the membrane, and unconsciously lurks in the human body [17] . covid-19 is located in the lung, where evil qi first invades the body from the mouth and nose, repressing the lung qi. in turn, the lung fails to disperse and descend, with symptoms of dry cough. the "damp evil" is heavy and viscous, blocking the qi mechanism and causing chest tightness, body heat, and muscle soreness. "damp evil" traps the spleen, easily injuring yang qi. the spleen dominates and transports water and food through the body. when the qi fails to rise, the spleen cannot be nourished, and symptoms begin to appear, including fatigue, gastric congestion and loose stool. the spleen and stomach act as the exterior and interior of each other; hence, the spleen's dysfunction affects the stomach's absorption. the dampness accompanying the epidemic toxin into heat is manifested as high fever, occasional yellow phlegm, obvious asthma due to the dampness toxin, and sticky stool due to the stagnation of dampness. wang qingren stated in correcting mistakes in medicine that "the plague toxin burns its blood inside, and if the blood is burned and refined, the blood will coagulate [18] ." during this period, the heat toxin burns the body fluid, and dampness suppresses the qi mechanism, resulting in the stasis of blood, manifested in the form of increased dyspnea and additional mental problems occurring during the reverse transmission of the pericardium. in the later stage, the body is damaged by fluid consumption, and is deficient in both qi and yin. during this period of treatment, attention should be paid to whether there is any residual evil in the body. given the differences in etiology and pathogenesis attributed to climatic factors in different regions, fan et al. [19] observed and stated that owing to climatic factors, dryness has been present in the lung for a prolonged period. on encountering the epidemic toxin, dampness and cold will collide with each other, and obstruct the lung and chest, injuring vital qi, leading to the stagnation of the qi mechanism and abnormal rise and fall of evil qi, finally leading to a deficiency of vital energy. although there exist differing opinions, combined with the clinical manifestations of the published and confirmed cases, the main etiology and pathogenesis can be attributed to "dampness, heat, toxin, blood stasis and deficiency." furthermore, the pathogenesis may differ among individuals. in the case of adults without underlying diseases, because of being in the prime of life, the presence of vital qi, as well as the balance and coordination of movement and transformation of qi, blood, yin and yang, is sufficient to resist external evil, demonstrating no susceptibility or mild susceptibility, with a short disease course and a good prognosis. in children, for the viscera are not well developed, presenting delicate viscera, unfilled shape and qi, and immature yin and yang, they fall sick easily and quickly [20] . however, in the overall growing phase, they are made up of "pure yang", are robust, and will recover easily. patients with underlying diseases, such as diabetes, hypertension, heart disease, chronic tracheitis, tumors, or other diseases, usually suffer from a deficiency of vital qi; if they experience the external evil, the disease is often characterized by severe illness, rapid progression, and rapid transmission, resulting in critical illness and even death. pregnant women have a special physiological state, with a relative deficiency of yin-blood and relative hyperactivity of yang qi. the growth of the fetus blocks the rise and fall mechanism of the qi in pregnant women, which may lead to poor operation of qi and blood. therefore, the elderly, the infirm, children and pregnant women require close monitoring. currently, there are no drugs specifically approved for covid-19. in the treatment plan announced by the national health commission of the people's republic of china [21] , western medicine offers mainly symptomatic treatment support, including early oxygen therapy and the use of corticosteroids. the treatment plan comprises antiviral therapies, including interferon-α, lopinavir, ritonavir and ribavirin; however, the curative effect remains unsatisfactory. chinese medicine is now fully involved in the treatment of covid-19 patients [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] , utilizing the advantages of tcm syndrome differentiation and treatment, improving the cure rate, and reducing mortality (table 1) . fever is the main symptom of the disease, with most hiding fever not accompanied by a cold. other symptoms include sleepiness and discomfort, dry cough and less phlegm, thirst without the desire to drink, chest tightness and palpitation, occasional muscle aches, nasal congestion and runny nose, and loose stools. no sweat, no sthenic heat or irritable heat sensation, and no sore throat. the tongue is dark red, or its edge is red, the moss is thin and white, and the pulse has no fixed point. currently, according to published data, covid-19 clinically manifests as different stages of disease progression. tcm treatment requires syndrome differentiation and treatment based on the stages, which are defined as initial stage (mild), progressive stage (severe), extreme stage (extremely severe) and recovery stage (convalescent stage). the medicines' sources, medicines' names in latin and english are presented in table 2 . the damp toxin in the shangjiao membrane should be treated for "damp-heat clearance to cure the lung," including separating and dissipating the damp-heat, paying critical attention to the smooth release of lung qi. furthermore, it is crucial to closely monitor the potential of the toxin to enter the blood in order to resolve the dampness, eliminate the filth, promote the qi mechanism, resolve blood stasis, and relieve the blood vessel networks, thereby following the principles of the huopu xialing decoction and sanren decoction [14] . the combination prescription includes guanghuoxiang, peilan, banxia and doukou for aromatizing, drying and regulating qi; xingren for promoting lung qi; fuling, zexie, huashi, tongcao, danzhuye and yiyiren for relieving and removing dampness or allowing the removal of dampness; and mudanpi and chishao for resolving blood stasis. the combination of these herbs can smoothen the sanjiao qi mechanism, dissipate and dissolve the dampness, resolve blood stasis, and dredge collaterals. toxins causing dampness can increase the heat in the body; this dampness and heat can lead to infection of the lung and negatively affect the functioning of the lung. during the progressive stage, if the disease is not properly treated, the heat and dampness cause the lung to close, with the possibility of internal closure and external prolapse appearing. it is necessary to discuss treatment from the point of qi this period is dominated by asthenia, with many changes necessitating individual syndrome differentiation and treatment. some studies have emphasized that xue's wuye lugen decoction can be used as reference to clear the residual evil and promote lung circulation, activate the spleen, and strengthen healthy qi [14] . the five leaves in the formula float and bring the evil to the surface. among them, huoxiang leaf, bohe, fresh lotus leaf and peilan leaf are all fragrant and good at invigorating the spleen. lugen and dongguazi can be used for infiltration. the formula is light and nimble and can be used for dispersing, purging, and infiltration. additionally, it is necessary to pay attention to the following points. (1) focus on removing dampness. the process of dampness removal is considered during diagnosis and treatment of the disease. although the epidemic toxin is mainly characterized by toxic heat, dampness and turbidity, it is difficult to separate the heat and dampness characteristics from the initial stages of the infection to the end. it is also difficult to only get rid of heat without removal of dampness as well. dampness is yin evil, and it is unsuitable to use cold and cool drugs during the early stage; warm and tonic herbs in the later stage should also be used cautiously. furthermore, it is permissible to use a combination of drugs to resolve dampness, dry dampness, and drain dampness during different stages. (2) promoting blood circulation and resolving blood stasis. the patients should be treated with drugs for promoting blood circulation and resolving blood stasis immediately after the appearance of lung shadow. during covid-19, the patients present high fever, sputum mixed with blood, dark purple-colored tongue, and consolidation or ground glass shadows in early lung images. pathological reports indicated diffuse alveolar damage, hyperemia, hemorrhage, edema, and pulmonary interstitial inflammation, which are all manifestations of blood stasis. therefore, during the different stages of treatment, it is necessary to combine products promoting blood circulation and eliminating blood stasis, dredging blood vessels, removing blood stasis, reducing alveolar damage, preventing pulmonary interstitial fibrosis, and reducing sequelae, which is conducive to the comprehensive rehabilitation of patients. additionally, there are no specific chinese medicine prescriptions for the elderly, pregnant women, children, and patients with underlying diseases. hence, it is essential to study the signs and symptoms of covid-19 cases to provide effective treatment. tcm focuses on the idea of "prevention of disease," advocating prevention before the disease occurs and prevention of change after disease. therefore, those who have a history of exposure or have been in close contact with epidemic areas should be prioritized with the treatment principles, including stabilizing qi and strengthening the exterior, removing heat, and detoxifying the body according to the composition of the prescription and climatic factors in different regions, to practice prevention before disease occurrence. in the cases of patients with chronic illness or those susceptible to infection, emphasis should be given to strengthening the vital energy, improving immunity, and using yupingfeng powder to invigorate qi and solidify the exterior [26] . individuals with underlying diseases can be treated regionally according to their diseases. according to tcm, after conception, the whole body's yin-blood is gathered in chong meridian, ren meridian, and the uterus, placing the pregnant women in a special physiological state of a relative deficiency of yin-blood and relative hyperactivity of yang qi. the growing fetus will block the rise and fall of qi and blood, resulting in poor operation of qi and blood. "it should be cool before pregnancy and warm after birth" is the general principle of regulation and stabilization in tcm before and after pregnancy. this can be adjusted and treated in advance to prevent the occurrence of disease, and the method of nourishing yin and clearing heat, regulating the qi mechanism, and calming the fetus is adopted. young children are not full of qi; their yin and yang are immature, and their viscera are delicate, especially, the lung, spleen and kidney [26] . hence, it is recommended to protect the qi of the spleen and stomach in advance to nourish other organs, strengthen their physique, and resist the evil of epidemic disease, utilizing sijunzi decoction or yupingfeng powder to invigorate the qi for consolidating superficies [26] . according to tcm, different people have different physical characteristics, and hence, different treatment principles and medication plans should be generated based on their physical characteristics (table 3) . based on the existing treatment schemes, the prescription composition and dosage recommended for prevention and treatment of covid-19 during different stages are introduced in table 4 . renshen 9 g, baizhu 9 g, fuling 9 g, gancao 6 g shengmai drink renshen 9 g, maidong 9 g, wuweizi 6 g, danshen 6 g guizhi decoction guizhi 9 g, shengjiang 9 g, dazao 9 g, honey-fried gancao 6 g shenzhu powder cangzhu 1000 g, chenpi 1000 g, houpo 1000 g, honey-fried gancao 360 g, guanghuoxiang 250 g, sharen 120 g huangqi guizhi wuwu decoction huangqi 15 g, guizhi 12 g, baishao 12 g, shengjiang 25 g, dazao 4 g huopu xialing decoction and sanren decoction guanghuoxiang 6 g, peilan 6 g, banxia 9 g, doukou 6g, xingren 9g, fuling 9 g, zexie 6 g, huashi 18 g, tongcao 6 g, danzhuye 6 g, yiyiren 12 g, mudanpi 6 g, chishao 6 g progressive stage lei's aromatic turbid-resolving method guanghuoxiang 3 g, peilan 3 g, chenpi 6 g, banxia 6 g, dafupi 3 g, houpo 3 g, heye 9 g jiedu huoxue decoction combined with shengjiang powder lianqiao 6 g, gegen 6 g, chaihu 9g, danggui 6g, shengdihuang 15g, chishao 9g, taoren 24g, honghua 15 g, zhiqiao 3 g, gancao 6 g, jiangcan (wine fried) 6 g, chantui 3 g, jianghuang 9 g, dahuang (raw) 12 g extreme stage shenfu sini decoction honey-fried gancao 12 g, fuzi 10 g, ganjiang 6 g, renshen shigao 1500 g, hanshuishi 1500 g, huashi 1500g, shuiniujiao 500 g, lingyangjiao crumbs 500 g, muxiang 500 g, chenxiang 500 g, xuanshen 500 g, shengma 500 g, gancao 240 g, mangxiao 5000 g, xiaoshi 930 g, shexiang 38 g, zhusha 90 g, jinbo 3000 g, dingxiang 30 g suhe xiang pill suhexiang 60 g, baizhu 60 g, muxiang 60 g, shuiniujiao 60 g, xiangfu 60 g, zhusha 60 g, hezi 60 g, tanxiang 60 g, anxixiang 60 g, chenxiang 60 g, shexiang 60 g, dingxiang 60 g, bibo 60 g, longnao 60 g, ruxiang 60 g recovery stage xue's wuye lugen decoction huoxiang leaf 6 g, bohe leaf 1.8 g, fresh lotus leaf 3 g, pipaye 15 g, peilan leaf 4.5 g, lugen 30 g, dongguazi 15 g according to the description of discharge criteria in the diagnosis and treatment protocol for covid-19 (trial version 7) [40] , the evaluation of covid-19 should be based on body temperature (more than 3 days after returning to normal), obvious improvement of respiratory symptoms, and pulmonary imaging (obvious alleviation of inflammation). if the above symptoms and signs are relieved and the respiratory pathogen nucleic acid test is negative for two consecutive times (the sampling interval is at least 24 hours), patient can be considered to be cured. however, we believe that the quantification of lung imaging related to the above efficacy evaluation index is insufficient. hence, we suggest that the lung imaging of patients with covid-19 should be comprehensively evaluated, based on the definition of the lung segment and the density criteria of high, medium and low grades, to better evaluate the treatment efficacy. the use of tcm adopts the holistic concept, combined with symptoms, signs and other corresponding manifestations, to examine the syndromes and seek the causes, to support the selection of drugs based on syndrome differentiation. syndrome differentiation and treatment, as one of the characteristics and advantages of tcm, is very important in diagnosis and treatment. for example, in the treatment of covid-19, the syndrome types differ among individuals in different regions, under different climatic conditions, and for relatively different physiques. syndrome differentiation should be clearly defined in combination with different factors and clinical syndrome characteristics. prescriptions are mainly used to improve immunity, balance human qi, blood, yin and yang, and recover organ function. according to the study of covid-19 treatment herbs [41, 42] , chinese herbal medicines with a higher probability to directly inhibit sars-cov-2 have been selected, including lianqiao, gancao, sangbaipi, jinyinhua, sangye, pipaye, and other herbs, commonly used to treat viral pneumonia. drugs should be selected and utilized according to the corresponding syndrome types. furthermore, with disease development, the drugs should be given the flexibility to deal with different syndrome types, and the whole process should be adjusted according to the principle of "three factors and measures," undertaking multi-target treatment. tcm also plays a leading role during the recovery period and post-discharge convalescence. currently, although some patients present a negative nucleic acid test accompanied by alleviated pneumonia and recovered body temperature, they may still demonstrate symptoms, including fatigue, shortness of breath, loss of appetite, and anxiety. some patients may present pulmonary fibrosis due to poor absorption of pulmonary inflammation, which may affect the quality of life; additionally, some patients may suffer adverse reactions during drug therapy. it is crucial to resolve such related issues when tcm is involved. however, we do not advocate taking medicine without incident, and the preventive prescription is only a corresponding choice for people with an imbalance of qi, blood, and yin and yang. when selecting the prescription, attention should be paid to the syndrome and symptoms, especially in special groups, such as children, pregnant women, and the elderly. moreover, any special physique should be closely monitored when using medicine of china on screening effective prescriptions for the prevention and treatment of the novel coronavirus pneumonia [43] . as of february 5, four pilot provinces have used the qingfei paidu decoction to treat 214 confirmed cases, with a treatment course of 3 days, demonstrating a total efficacy rate exceeding 90%, among which over 60% of the patients showed significant improvement in symptoms and imaging manifestations, and 30% patients demonstrated stabilized symptoms without aggravation. concurrently, lianhua qingwen granule [44] is used in clinical treatment based on the principle of clearing away epidemic toxin, dispersing the lung, and expelling heat. reportedly, it has been confirmed to significantly improve fever, cough, expectoration, and shortness of breath in confirmed cases of covid-19. according to the feedback of clinical data, the efficacy of tcm in the clinical treatment of covid-19 is great, and it still needs to be adjusted and improved with the clinical accumulation. in brief, the combination of chinese and western medicine can complement each other's advantages, which can improve the comprehension of the core of the disease, and cooperate actively and effectively in clinical settings to enhance overall efficacy. the study was not supported by any funding. wsx and lyb wrote the article; wy revised part of the article and made grammatical corrections; wxx provided research ideas; ljy reviewed the article and provided guidance; nm and syj collated the data. the authors declare that they have no conflict of interest. tracking coronavirus: map, data and timeline pharmaceutical work guidance and 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by novel coronavirus comprehensive analysis of the diagnosis and treatment plan of traditional chinese medicine for the prevention and treatment of pneumonia infected by novel coronavirus general office of the national health commission of the people's republic of china. diagnosis and treatment protocol for covid-19 (trial version 7) in silico screening of chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus traditional chinese medicine is a resource for drug discovery against 2019 novel coronavirus (sars-cov-2) clinical observation of qingfeipaidu decoction in the treatment of novel coronavirus pneumonia retrospective clinical analysis on treatment of coronavirus disease 2019 with traditional chinese medicine lianhua qingwen. zhongguo shi yan fang ji xue za zhi 2020; epub ahead of print key: cord-348486-3ji6nwer authors: turcios-casco, manfredo a.; cazzolla gatti, roberto title: do not blame bats and pangolins! global consequences for wildlife conservation after the sars-cov-2 pandemic date: 2020-09-19 journal: biodivers conserv doi: 10.1007/s10531-020-02053-y sha: doc_id: 348486 cord_uid: 3ji6nwer this pandemic situation requests a correct understanding of our impacts on wildlife conservation, which would also provide benefits for our species. in this commentary we revised and discussed some of the repercussions that sars-cov-2 pandemic may have to wildlife. we propose four actions that should be taken into account to protect and conserve wildlife in this pandemic era: wildlife “wet” markets must close; human interference with wildlife must be reduced; bats and pangolins must be conserved and not blamed; and chinese traditional medicine must be more controlled. while the sars-cov-2 outbreak was expanding in a pandemic, many research groups tried to rapidly identify its likely origin and initially pointed to bats (chiroptera). some studies suggested that bats, because of their unique behavior (fan et al. 2019) , are the most probable natural host of the new coronavirus and, via an unknown intermediate, they infected humans (guo et al. 2020) . although some authors have suggested that the origin of this new coronavirus could be a chinese lab (xiao and xiao 2020) , new evidence has focused on the recombination of sars-cov-2 by a potential spillover from bats to sunda pangolins (manis javanica), that have a weak immune system and can be easily attacked by new pathogens (cazzolla gatti 2020a). in fact, although some scientific evidence is still needed to support this hypothesis, it is likely for pangolin coronavirus to have originated (andersen et al. 2020; lau et al. 2020) . however, the animal species that is at the origin of sars-cov-19 has yet to be identified (cyranoski 2020) . nonetheless, this is not a new situation. other viruses, such as the sars-cov, the mers-cov and the indian nipah virus (hu et al. 2015) , are responsible for zoonoses and epidemics transmitted by infected reservoir animals to human beings. animals host pathogens that in normal conditions are rarely transmitted to our species. however, the abuses perpetrated on the environment at a global scale (i.e. wildlife poaching and trade, deforestation, wildfires, climate change, overfishing, etc.) increase the likelihood of interspecies transmission (cazzolla gatti 2020b). the identification of the possible origin and hosts of this new coronavirus has seemingly fostered ancestral fear towards bats from the public opinion and even their worldwide mass culling or eradication was claimed (zhao 2020) . while scientists try to track back the evolutionary road of the new coronavirus, threats to bats have increased. for example, in china people have started requesting that hibernating bats in or near their houses be expelled and, in some cases, bats were captured and released into the wild in unsuitable habitats (zhao 2020) . this is why, since this pandemic started, we have been concerned about the repercussions that misconceptions on these species could have on wildlife and, particularly, on bat and pangolin conservation efforts. when we see what happens in the streets where the market takes place in wuhan, where customers walk through animal waste and blood, it is not hard to understand how deadly viruses can easily pass from one species to another. there is ample occasion for spillover due to the mixture of dogs, cats, snakes, raccoons, genets, chickens, pigs, bats, pangolins, fish of all types and sizes. indifferent, but not oblivious, buyers stroll in front of piles of tiny cages where animals wait for hours, often for days, for their death sentence. this is the fate, for instance, of the malayan pangolin (manis javanica), a critically endangered species according to the international union for conservation of nature (iucn) (challender et al. 2019) . the malayan pangolin is illegally trapped in malaysia and indonesia, in those forests where trees are logged to produce tropical timber, paper and palm oil (cazzolla gatti et al. 2019; cazzolla gatti and velichevskaya 2020) . then, pangolins are sold in chinese wet markets like the one in wuhan because, with thousands of other critically endangered animals and plants, they are thought to be essential elements of traditional chinese medicine (cazzolla gatti 2020a). the scales of this mysterious and rare animal are extracted through boiling the bodies that are then dried, which is considered helpful for breastfeeding, preventing infections and treating epidermal problems. considering the absence of any scientific basis for these practices, it seems even more regrettable to justify the extermination of any species on earth. similarly, rhinolophus species, a bat genus supposedly responsible for previous epidemic viruses, are captured in china and sold in wet markets because their dried body parts are added to wines or to powders to detoxicate the body (wassenaar and zou 2020). moreover, in some regions of asia, many people continue to eat bat's flesh because it is considered a delicacy, and in china it is believed to have medicinal qualities (humane society international 2019). bats are affected by climate change (the extreme temperatures, in particular) and deforestations for intensive agriculture. for instance, forest logging may force bats to feed on insects whose life cycle is disrupted by climate change and by the use of pesticides (stechert et al. 2014) . moreover, the increased proximity of farms to caves, once surrounded by natural forests, increases the chances for bats to interact with livestock (calisher et al. 2006 ). here we propose four urgent actions that should be taken into account in order to reduce the risk of future pandemics and, at the same time, protect wildlife: 1. wildlife ''wet'' markets must close. the unhygienic, mixed-species markets that sell alive and dead animals, often captured illegally from their natural habitats, and that are linked to most of the recent zoonotic epidemics (humane society international 2020) must close after the enactment of international agreements. 2. human interference with wildlife must be reduced. any impact that our species has on wildlife (e.g. deforestation, overfishing, habitat degradation, pollution, etc.) must be halted. the interactions between researchers (particularly in biogenetics labs), biologists, and conservationists must also be based only on ethical and professional principles and must avoid interference with natural processes and wildlife. 3. bats and pangolins must be conserved and not blamed. there are more than 1,400 bat species in all continents excluding antarctica and most of them participate in diverse ecological processes and ecosystem services from pollination to seed dispersal, from pest control to ocean and land fertilization at many ecological levels (kunz et al. 2011; bat conservational international 2020) . moreover, as the second most diverse extant mammal group, bats have faced many human-related problems that influence their populational trends (e.g. extermination with fire set into their caves, demonization related to witchcraft and superstitions, and more important nowadays, consideration as harmful mammals due to their relations with diseases). similarly, pangolins are an endangered group of only 8 species that live in asia and sub-saharan africa. they are nocturnal and solitary animals in nature, they meet conspecifics only to mate and live in hollow trees or ground borrows (maurice et al. 2019 ). therefore, their chances to get in contact with bats and become an intermediate host of pathogens is unlikely in nature. however, pangolins are captured and forced to survive in small cages in wet markets, surrounded by alive and dead bats. under such conditions, due to the weak immune system of pangolins, an infection becomes very likely (cazzolla gatti 2020a). moreover, pangolins have very few offspring during their life and are the most smuggled mammal and one of the most endangered animal in the world (challender et al. 2014; challender and waterman 2017) . due to their unique eco-physiological characteristics, both bats and pangolins are very sensitive to temperature variations, and climate change can increase the pressures on their populations (cazzolla gatti 2020a). therefore, we must stop threatening their survival by halting poaching and taking serious action to reduce deforestation, forest degradation, and climatic changes. 4. chinese traditional medicine must be controlled. although chinese traditional medicine dates back to more than 5000 years, there is an urgency to regulate it beyond any cultural preconception or discrimination. many animal products are included in recommended treatments and the use of wildlife in these medications has had a huge impact on their conservation status (mainka and mills 1995) . although the demand for wildlife in the chinese traditional medicine has occurred for thousands of years, the recent human population growth (there are currently 1.400 billion people in china) and the higher average income have had a catastrophic effect on nature. moreover, for almost all species employed in the chinese traditional medicine, the areas from which they are taken to supply these practices belong to underdeveloped or developing countries where environmental regulations and controls are scarce. we acknowledge that a sudden shift (for instance towards the use of cultivated plants as substitutes) of traditional medicine practices and the radical abandon of animal use for millions of people would be unlikely and unrealistic. however, in this pandemic era, international agencies must increase the protection of species in their habitats, enforce legislation and control of local and international wildlife trade. sanctions, including political and economic strong actions (which are needed to protect the planet and not only the interests of developed countries), should be started if chinese authorities will not effectively patrol and punish the exploitation of wildlife and endangered species. the implementation of new, more stringent international laws and the increase of public environmental awareness will be to the benefit of these species and will reduce future risks of zoonotic diseases. alternative sources of income for the areas where wildlife is threatened such as the transfer of sustainable know-how from developed countries for the development of ecotourism and conservation activities, can also reduce environmental pressures at its source. protecting wildlife will also mean protecting ourselves. the proximal origin of sars-cov-2 bat conservational international (2020) bci's faq on bats and covid-19 bats: important reservoir hosts of emerging viruses the pangolin's revenge: sars-cov-2 did not emerge from a lab but from wildlife exploitation coronavirus outbreak is a symptom of gaia's sickness certified ''sustainable'' palm oil took the place of endangered bornean and sumatran large mammals habitat and tropical forests in the last 30 years sustainable palm oil may not be so sustainable implementation of cites decisions 17.239 b) and 17.240 on pangolins (manis spp.) mystery deepens over animal source of coronavirus. pangolins are a prime suspect, but a slew of genetic analyses has yet to find conclusive proof bat coronaviruses in china the origin, transmission and clinical therapies on coronavirus disease 2019 (covid-19) outbreak: an update on the status bat origin of human coronaviruses wildlife-markets-and-covid-19-white-paper-final-6 ecosystem services provided by bats possible bat origin of severe acute respiratory syndrome coronavirus 2. emerg infec dis wildlife and traditional chinese medicine: supply and demand for wildlife species the ecological impact on the distribution of pangolins in deng-deng national park, eastern region cameroon insecticide residues in bats along a land usegradient dominated by cotton cultivation in northern benin, west africa /sars-cov-2: rapid classification of betacoronaviruses and identification of traditional chinese medicine as potential origin of zoonotic coronaviruses the possible origins of 2019-ncov coronavirus covid-19 drives new threat to bats in china publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgements we are grateful to esther carmen (department of environment and geography, university of york, uk and konrad lorenz institute for evolution and cognition research, klosterneuburg, austria) for her help and suggestions in revising our manuscript. conflict of interest the authors declare no conflict of interest. key: cord-340995-t1zu7uqa authors: jiang, sida; cui, qiuji; ni, bingwei; chen, yingying; tan, ying; chen, weiping; chen, yu zong title: databases for facilitating mechanistic investigations of traditional chinese medicines against covid-19 date: 2020-06-02 journal: pharmacol res doi: 10.1016/j.phrs.2020.104989 sha: doc_id: 340995 cord_uid: t1zu7uqa nan questions require a more comprehensive mechanistic understanding and clinical evaluation of these traditional medicines. as part of the efforts for probing these questions, the possible mechanisms of these traditional chinese medicines have been studied based on the experimental and predicted targets of the chemical ingredients, which have been derived from the liquid chromatograph-mass spectrometry [4] and obtained from literature surveys [5, 6] . these studies have shown that the knowledge of the chemical ingredients of the traditional chinese medicines are highly useful for covid-19 investigations. in particular, the knowledge and clinical profiling of the activities of the chemical ingredients enables the multi-omics studies for finding the clinically-relevant targets [3] , and the molecular structures of the chemical ingredients are needed for molecular docking and target binding studies in target assessment [5] . additionally, the knowledge of the chemical ingredients facilitates the molecular and disease network analysis with respect to the experimental and predicted targets for understanding the network pharmacology [4] , and the statistical frequency of appearance analysis of the literature-reported chemical ingredients and mechanisms for focusing on the high confidence mechanisms [6] . the mechanisms of the traditional chinese medicines are multifaceted in general and for the treatment of covid-19 in particular [1, 2, 5, 6] . therefore, more comprehensive investigations are needed for understanding the mechanisms of these traditional chinese medicines, and for unveiling their benefits and adverse effects. a key step towards such investigations is to obtain the chemical ingredients of these traditional chinese medicines, particularly the molecular structures and activities. in addition to the literature surveys [5, 6] , it is of interest to explore the these databases also provide a variety of the activity-related information useful for mechanistic investigations ( table 1) weiping chen designed this work and wrote the manuscript. the authors state no conflict of interest and have received no payment in preparation of this manuscript. traditional chinese medicine for covid-19 treatment the use of traditional chinese medicines to treat sars-cov-2 may cause more harm than good the pros and cons of traditional chinese medicines in the treatment of covid-19 chemical composition and pharmacological mechanism of qingfei paidu decoction and ma xing shi gan decoction against coronavirus disease 2019 (covid-19): in silico and experimental study a review of therapeutic agents and chinese herbal medicines against sars-cov-2 (covid-19) review on the potential action mechanisms of chinese medicines in treating coronavirus disease 2019 (covid-19) we acknowledge the support from the national key r&d program of china key: cord-019106-vpc76p2c authors: yates, j. frank; de oliveira, stephanie title: culture and decision making date: 2016-09-14 journal: organ behav hum decis process doi: 10.1016/j.obhdp.2016.05.003 sha: doc_id: 19106 cord_uid: vpc76p2c the study of culture and decision making addresses variations in how and why people from different cultures sometimes tend to decide differently. this review is organized around what is intended to be a comprehensive analysis of the distinct fundamental questions that people must answer in the process of making virtually all real-life decisions. our emphasis was on recent developments as well as identifying important yet neglected topics (e.g., how decision episodes get started—or not, and why some decisions are never implemented). early as well as current efforts have focused mainly on east asian and north american caucasian cultures, with little treatment of other populations. in such studies, individualism and collectivism have been the dominant explanatory factors although related but distinct concepts such as “tightness” and “looseness” have been welcome additions to recent discussions. throughout, the review emphasizes practical concerns, such as the challenges of intercultural learning and collaboration. ''they were a rather unusual couple, weren't they? i wonder how they chose each other -their opinions and personalities are so different." ''i have the same impression. do you think it has anything to do with the fact that they are from ____, where many marriages are arranged, even if no longer officially?" a conversation like this illustrates the topic of this review-the roles of culture in people's decision-making behavior. the commenting couple observes the outcome of what, in their own culture, would seem to be a surprising marriage decision by another couple. they speculate, perhaps naively, that arranged marriage traditions, common in some cultures but not others, had a significant impact on how the other couple chose each other. this scenario illustrates just one of many questions that a specialist in culture and decision making, or even a layperson, is likely to encounter. one purpose of this review is to describe and interpret major themes in evolving scholarship on culture and decision making. another is to argue for greater research attention to key unsettled or unaddressed questions. ''culture" can mean many things. by ''culture" we refer to the myriad ways of living exhibited by a particular group of people, ways that are transmitted from one generation to the next and which distinguish that group from others (cf. smith, 1997) . researchers frequently use nationality as a proxy for culture, but other factors such as religion and social class can divide people into distinctly identifiable ''cultures" as well (cohen, 2009 ). people who rely on different modes of subsistence can give rise to distinct cultures, too (talhelm et al., 2014; uskul, kitayama, & nisbett, 2008) , as can people who carved out their migratory path on a frontier as opposed to settling in a pre-developed area (kitayama, conway, pietromonaco, park, & plaut, 2010) . while we embrace this broad definition of culture, much of existing work on culture and decision making has focused on north american and east asian populations to the neglect of others. as for the term ''decision," we will refer to a commitment to a course of action that is intended to serve the interests and values of particular people (yates & potorowski, 2012) . in our experience, it is rare for people's everyday characterizations of decisions to conflict with the definition used here, although people of different cultures may disagree on whether a given specific event constitutes a decision (savani, markus, naidu, kumar, & berlia, 2010) . because our topic is so broad, it is impossible to be exhaustive in answering every question related to it. instead, we cover how key phases in the decision making process are handled in various cultures. the ''cardinal issue perspective" (cip) describes ten challenges, or ''cardinal issues," that are addressed deliberately or unconsciously in nearly every decision (yates & potorowski, 2012) . ten issues is a lot, but the benefit of starting with the cip is that it provides a detailed and comprehensive anatomy of a decision. the list begins with what happens before decision deliberations begin: does a decision need to be made, or not? who will make the decision, and how will they go about their work? will the decider invest many or few resources into the decision-making process? the deciding party then addresses issues that comprise the core of the decision process: what options are available or could be created? what important possible outcomes are associated with each option? what is the likelihood of each outcome occurring? how good or bad would each outcome be for the decision maker (and/ or other parties)? how should one manage tradeoffs between options? finally, the decision maker deals with issues in the aftermath: what do other parties think of the decision? what can the decision maker do to assure that the decision is implemented? fig. 1 displays the names attached to the cardinal issues roughly in the order they tend to present themselves in many real-life decision episodes. an advantage of using this framework for the present review is that we not only attend to what is ''out there" in the literature, but we also consider important aspects of decision making that somehow escaped researchers' attention. for example, while issues related to judgment and value have been well researched across cultures, other key issues, such as whether a decision needs to be made, have been relatively under studied. the cip directs attention to such gaps. our readers may be interested in a broad variety of questions, most of which we expect are covered by one of the ten cardinal issues. in each issue's discussion we focus on describing what decision-making differences have been observed between cultures. in sum, we organize the bulk of this paper according to the cip issues for clarity and for comprehensiveness. not every phase of the decision-making process has received substantial attention in cross-cultural research. therefore we highlighted topics that have received little attention or may be fruitful for further research. to facilitate interpretation of the findings, we have written a preface describing major constructs that have been used to explain cultural differences. finally, we avoided repeating discussions of work that has already been expertly reviewed previously, particularly work on risk and judgment (e.g., by choi, choi, & norenzayan, 2004; savani, cho, baik, & morris, 2015; weber & hsee, 2000; weber & morris, 2010) . broad social and cognitive differences have been proposed as drivers of more specific cultural differences discussed in this review. one dimension of culture that has received substantial attention is individualism-collectivism (or, similarly, independenceinterdependence, hofstede, 1980; markus & kitayama, 1991; oyserman, coon, & kemmelmeier, 2002; triandis, 2004) . these dimensions are associated with different conceptualizations of the ''self." individualistic cultures bestow greater autonomy on the ''self"; each person is understood to be a discrete entity, independent of others, with relatively immutable characteristics and with free agency. individualistic cultures tend to value personal goal pursuit as opposed to accommodation to others' goals. uniqueness and self-expression are also generally valued in such cultures. collectivistic cultures, by contrast, view the ''self" as part of a whole. each person is expected to work with his or her ingroup toward goals, to vary one's personal behavior according to social context, and to generally ''fit in" and pursue group harmony. as reviewed below, these differences have been proposed to underlie much cross-cultural variation in decision-making, such as the decision modes people use, their preferences, negotiation styles, creativity, and more. a related construct that has received relatively less attention is cultural norm strength. ''tight" cultures have many norms that are strictly enforced socially, whereas loose cultures have fewer norms which may be violated to some degree without penalty (gelfand, nishii, & raver, 2006; gelfand et al., 2011) . while most cultural differences have been interpreted in light of the individualism/ collectivism framework, many differences could be explained by differences in tightness/looseness instead. the two constructs are somewhat correlated, with collectivistic cultures being tighter than individualistic cultures. this may explain why, in decision-making, collectivists often weigh input from others more than individualists; they may be concerned with adhering to norms. cognitive style has also been a popular framework with which to study cultural decision-making differences (choi et al., 2004) . holistic thinking is a cognitive style frequently associated with east asian cultures. it is characterized by attention to context, an emphasis on relationships between entities, belief that the world is in constant flux, and tolerance for apparent contradiction (nisbett, peng, choi, & norenzayan, 2001; peng & nisbett, 1999) . analytic thinking is frequently associated with western cultures, and it is characterized by a focus on the main object, a category (vs. relationship-based) view of objects, belief that the world is stable and predictable, and adherence to rules of formal logic such as non-contradiction. cognitive style has been theoretically linked to social orientation, such that individualists are relatively analytic, and collectivists are relatively holistic . cognitive style has been used to explain various aspects of decision-making, such as what type of information people attend to and how people think about the future. it is worth noting that while the above frameworks are often invoked as plausible explanations of cultural differences, many studies do not empirically test such links across a broad range of cultures. (we return to similar issues in ''future directions.") it is also worth noting that while simple cross-cultural comparisons enlightened by these frameworks are abundant, culture has increasingly been understood as a non-fixed, dynamic, and context-dependent phenomenon (briley, wyer, & li, 2014) . social context activates particular mindsets -say, an independent mindset -and this mindset in turn can influence one's judgments and decisions temporarily (oyserman, sorensen, reber, & chen, 2009 ). in another situation, an opposing mindset may be adopted such that the same person's judgments and decisions take on an altogether different pattern. this is not to say that culture has no stable component -societies reinforce relatively constant patterns of living and people internalize those ways of living to some degree. moreover, psychological tendencies associated with different cultures may be due to powerful and relatively stable ecological forces such as climate, population density, disease burden, history of migration, and modes of subsistence (gelfand et al., 2011; kitayama, varnum, & sevincer, 2014; talhelm et al., 2014; uskul et al., 2008) . evidence from neuroscience also supports the constancy of cultural mindsets to some degree; repeated ways of thinking leave physical effects on the brain (kitayama & uskul, 2011) . while it is beyond the scope of this paper to explore the antecedents of every cultural difference in decision making, we propose that cultural differences are both stable and contextdependent. we anticipate that exploration of the origins and nature of cultural differences will continue. 3.1. -need: ''does a decision need to be made?" good decision making depends, in part, on the decision maker's ability to recognize whether and when a decision needs to be made. for example, entrepreneurs must be particularly good at spotting opportunities before others see them, and pilots must be able to detect threats before disaster befalls their aircraft. decision makers must also avoid acting upon perceived opportunities and threats that are in fact non-existent. ultimately, perceptions of one's environment determine whether the individual makes a decision at all, for better or for worse. little work has been done explicitly on this issue in both the general and the cross-cultural judgment and decision making literatures. we review cultural differences in processes that contribute to how people address the ''need" issue, especially focusing on how people perceive their environments. we are not aware of work that explicitly links these perceptions to decision initiation. thus this question is ripe for further research: do cultural differences in environment perception lead to differences in when and how decisions are initiated? before the decision-making process even begins, people from different cultures are attending to their environments in different ways. for example, focusing on positive versus negative information can reflect whether someone is oriented to approach opportunities or avoid threats (higgins, 1997) . hamamura, meijer, heine, kamaya, and hori (2009) found that canadians and americans recalled more positive information than negative information after reading about hypothetical life events (study 1) or product reviews (studies 2, 3). americans rated negative reviews to be less helpful (study 3). japanese participants showed either the reverse tendency (study 1) or equal memory for approach and avoidance information (studies 2 and 3). in related work, the reported personal goals of korean nationals, asian americans, and russians were more likely to be focused on avoiding threats than those of european americans (elliot, chirkov, kim, & sheldon, 2001) . eye-tracking data across different tasks suggests that various east asian groups look more at photograph backgrounds than do north americans (chua, boland, & nisbett, 2005; masuda, wang, ishii, & ito, 2012) , and they preferentially attend to different parts of the face when judging emotions (jack, blais, scheepers, schyns, & caldara, 2009 ). these visual attention findings have been linked to judgment and memory differences in other areas of psychological research (masuda & nisbett, 2001; masuda et al., 2008) , but we consider attention differences relevant to the ''need" issue; as people attend to different aspects of the world around them, they will feel the need (or not) to make decisions to address different opportunities and threats. even when attending to the same information, cultures vary in how they interpret it -is it a threat, an opportunity, or neither? consider the severe acute respiratory syndrome (sars) epidemic of the early 2000s. when reflecting upon the same outbreak, chinese people were more likely than canadians to identify several positive features of the situation (e.g., having time for rest, appreciating relationships more, ji, zhang, usborne, & guan, 2004) . in a hypothetical stock trading task, canadians were more likely than chinese to purchase rising stocks (ji, zhang, & guo, 2008) , indicating that canadians were more likely to see a rising trend as an opportunity. chinese participants were more likely than canadians to purchase falling stocks; thus chinese were more likely to see falling trends as opportunities. as for selling, canadians were more willing than chinese to sell falling stocks, but chinese were more willing than canadians to sell rising stocks. these findings have been attributed to cognitive style differences. recall that one feature of holistic thinking is the expectation of future change. east asians' holistic tendencies may lead them to expect that trends are susceptible to change. cultures that value personal agency and independence -such as those of north americans generally and the u.s. american middle class in particular -appear to view the very act of decisionmaking as desirable (kitayama, snibbe, markus, & suzuki, 2004; snibbe & markus, 2005) . they presumably like making decisions because it is a means of expressing individualism. relative to cultures where individual agency is not so prized, people in individualistic cultures may either address the ''need" issue by engaging in lots of decision making or, relatedly, simply construing more of their actions as decisions. americans, as compared to indians, are more likely to label mundane actions like opening a refrigerator as decisions (savani et al., 2010) . working class americans report having fewer choices at work than people from the upper middle class, and they are also more likely to perceive individual decisionmaking as undesirable (stephens, fryberg, & markus, 2011) . in sum, the above cultural differences plausibly may lead people to approach decision-making differently from the very beginning. cultures vary in whether they focus on opportunities or threats, and they also vary in their interpretations of the same information as a threat, an opportunity, or neither. finally, people vary in how much they feel the need to engage in decision-making (or to call particular actions ''decisions"). the expression ''decision mode" refers to who (or what) is involved in making a given decision and how that decision is made (alattar et al., 2016) . we focus our discussion on cultural variations in the ''who" part of the challenge first, and then on ''how" decisions are made. notably, work on this cardinal issue encompasses various cultural groups and appeals to varied explanations for cultural differences. some cultures endorse individual decision making while other groups encourage the involvement of multiple people, in some form or another. research on this difference has conceptualized culture nationally (e.g., indian, russian) as well as by social class. some work suggests that middle class americans would rather make decisions individually, whereas working-class americans prefer the involvement of others. in one set of studies, americans of working-class backgrounds were more likely than americans from middle class backgrounds to experience negative affect when making a decision by themselves (stephens et al., 2011) . unlike higher-ses americans, they preferred that others make decisions on their behalf and were less likely to devalue an item that was chosen for them by somebody else (snibbe & markus, 2005) . in studies of cross-national differences, americans were less likely than russians to offer unsolicited advice (chentsova-dutton & vaughn, 2012), potentially reflecting a preference for independent, individual decision-making. in the same set of studies, russians were more likely to ask for advice than americans, and they were also more likely to offer advice, even when it was not requested. in another cross-national study, indian participants were more likely than americans to comply with advice (savani, morris, naidu, kumar, & berlia, 2011) , suggesting that they, like russians, might customarily include other people in their decision making. moreover, indians were more likely than americans to experience positive outcomes (e.g., closer relationships) when they included others' considerations into their decision processes (studies 1, 2, and 3). variations in how decisions are made tend to coincide with variations in who makes the decision. western researchers have largely assumed that people make decisions by following their own preferences and values, but people in many cultures discount personal preference and instead seek advice, at times deferring to others' preferences, especially when the perceived norm is to discount one's own desires (savani, markus, & conner, 2008; savani, wadhwa, uchida, ding, & naidu, 2015) . we return to this distinction in the ''value" section. cultures also vary in whether they prize more deliberative decision making or more rapid, intuitive decision making. in one study, koreans favored ''intuitive" decision making modes over ''logical" modes, whereas canadians favored both equally (buchtel & norenzayan, 2008) . the finding that koreans particularly value intuition is consistent with evidence suggesting that chinese prefer simpler decision modes than do americans (e.g., lexicographic modes, chu & spires, 2008 ; recognition-based decision making, weber, ames, & blais, 2004) . altogether, it seems that among east asians, japanese prefer thorough, slower decision modes whereas koreans and chinese prefer faster intuitive or rule-based modes. some proposed explanations for differences in decision mode use appeal to cultural norms associated with individualism or collectivism. in independent cultural contexts, there is social approval for meeting goals that promote independent values such as selfexpression, uniqueness, and autonomy or self-reliance (snibbe & markus, 2005) . making decisions individually represents a means of self-expression and exercising independence. in more interdependent contexts, by contrast, there is social approval for including others in the decision process. interdependent goals promote social harmony and accommodating to others' expectations. by including other people in the decision-making process, an interdependent person can anticipate any disapproval that would result from various options, ultimately arriving at a decision that is informed by others' preferences and therefore likely to be socially accepted. alternative explanations for mode differences merit attention, too. regarding the russian/american difference in advice giving, chentsova-dutton and vaughn (2012) argue that russians value advice because they are accustomed to living in a society where official means of information exchange and social aid are unreliable. thus, in their case, collaboration is not driven by a collectivistic desire to please others but rather by a desire to disseminate helpful information. in contrast to the russian case, savani et al. (2011) do not attribute advice giving and accommodation in india to the lack of a reliable informational infrastructure. rather, they propose that high population density and limited social mobility lead to strong reputational concerns for individuals. these concerns, the authors contend, lead people to strive to be known as supportive and selfless in their advice giving so that they are trusted and embraced in their social networks. 3.3. investment: ''what will it cost to make this decision?" the ''investment" issue concerns how much of a resourcemental energy, time, money -someone will devote to the decision process. a decision made intuitively requires little investment. a decision that is pondered at length reflects a greater investment on the part of the decision maker. research on indecisiveness reveals interesting cultural differences in how the ''investment" issue is handled. a person who customarily takes an inordinately long time to decide is said to be ''indecisive," although indecisiveness is measured in a variety of ways (e.g., using a scale, measuring extremity of preferences, and time required to make the decision). many between-and withinregion comparisons have been made, and some results are inconsistent. regarding east/west contrasts, researchers found most east asian groups -including participants from japan, hong kong, and taiwan -to be more indecisive than westerners of european heritage (li, masuda, & russell, 2014; mann et al., 1998; yates et al., 2010) . results for mainland chinese comparisons have been mixed, although leaning toward the side of higher chinese decisiveness; tse, lee, vertinsky, and wehrung (1988) found mainland chinese to be more decisive than hong kongers and canadians, but patalano and wengrovitz (2006) found no difference between mainland chinese and americans. in malaysia, ethnic chinese were found to be more decisive than ethnic malays (swami et al., 2008) . a more recent study compared east asians, south asians, and european canadians (ng & hynie, 2014) . the investigators found that their east asian participants (of unspecified national heritage) were significantly more indecisive than their participants of south asian and european heritages. how have researchers proposed to explain cross-cultural variations in decision making investment? tse et al. (1988) found strong decisiveness among their chinese participants, and they speculated that that was a reflection of chinese traditions of classifying the world into sharply defined categories-''black or white" (p. 89). mann et al. (1998) interpreted high indecisiveness for other (non-chinese) asian groups as resulting from more collaborative decision-making practices in collectivistic societies. thus, when confronted with an unpleasant or difficult personal decision problem, east asian individuals would be accustomed to calling on others for assistance rather than confronting the challenges alone. this, in turn, can require more time and social energy to navigate the decision. indecisiveness in east asian culture (besides that of mainland china) has been attributed to naïve dialecticism (ng & hynie, 2014; peng & nisbett, 1999) and need for cognition (nfc; cacioppo & petty, 1982) . these factors, in ng and hynie's data, mediated the link between culture and indecisiveness. naïve dialecticism involves embracing conflicting beliefs about the world, such as affirming both the positive and negative side of an issue. this cognitive approach may require more energy and reflection to reach a decision, given its complexity. high need for cognition, by definition, would also promote more cognitive investment in the decision-making process. yates et al. (2010) proposed that relevant norms common in china and japan might differ despite their shared collectivism; japanese might be especially indecisive because they value indecisiveness, perhaps under a more flattering label such as ''thoroughness." the japanese participants of yates et al. (2010) reported being more indecisive than chinese and americans, and they were more likely than chinese and americans to admire indecisive people, too. moreover, in a ''think aloud" reasoning task, the japanese participants chose to spend far more time on their deliberations than did their chinese and american counterparts, indicating a preference for thoroughness. li et al. (2014) documented a moderating role for decision importance in indecisiveness. they suggest that important decisions universally require the use of similar, high-investment strategies, diluting cultural differences. in their study of european canadians and hong kong chinese, both groups demonstrated equally high indecisiveness for important decision problems (e.g., choosing a career). cultural differences were only observed for unimportant decisions (e.g., choosing what to have for dinner). note that this is another example in which cultural differences depend on context -not all decision problems reveal the same pattern of differences. earlier reviews of culture and decision making did not elaborate on the ''options" issue specifically (weber & hsee, 2000; weber & morris, 2010) , but research related to this topic has burgeoned recently. here we focus on creativity, which is important for decision makers because it helps them effectively produce good choice sets that, ideally, contain the best possible option. a poor choice set does not allow the decider to even contemplate the best possible option because it is not contained in the set for consideration. creativity is also critical in contexts such as negotiations because meeting the needs and desires of all parties often requires reworking existing options imaginatively. creativity and culture have been studied together from several different angles. a few studies have focused on whether (and why) some cultures are more creative than others. westerners have at times been perceived as more creative than east asians (e.g., niu & sternberg, 2001) , and more recently both research and developmental programs have aimed to study and improve creativity in east asia (wu & albanese, 2010) . the evidence for western dominance in creativity is debatable (morris & leung, 2010) as such cultural comparisons depend on the social era in which creativity was measured and what measure of creativity was used. other research has investigated the degrees to which novelty and usefulness are central to different cultures' definitions of creativity. in a comparison among china, japan, and the u.s., the influence of perceived novelty on creativity ratings of products did not vary by country, and usefulness was more related to creativity for americans and japanese than for chinese subjects (paletz & peng, 2008) . few other studies have examined novelty and usefulness separately, but this distinction will be important for future work in order to determine more precisely how cultures define and evaluate creativity (erez & nouri, 2010) . a more well-supported contributor to cultural variation in creativity is variation in social orientation. researchers have suggested that individualistic cultures promote deviance, uniqueness, and divergent thinking, whereas collectivistic cultures promote conformity in thinking (erez & nouri, 2010) . goncalo and staw (2006) found that, when instructed to be creative, subjects experimentally primed with individualism (vs. collectivism) generated more creative solutions to a problem. they also found that whether groups were asked to list the most creative or the most practical idea from their idea sets, ideas listed by individualistic groups were judged to be more creative than those of collectivist groups -regardless of whether they were instructed to be creative or practical (study 3). the authors suggest that individualistic groups both generated and chose more creative ideas because of their inclination toward divergent thinking and, in a group context, their desire to be unique and to stand out in discussions for idea selection. collectivistic groups, by contrast, were hesitant to share deviant ideas and to suggest unique options for selection. these study results support the idea that cultural differences in creativity may be due, at least in part, to how creative processes are shaped by social orientation. they also demonstrate that creativity is malleable via priming of social orientation. newer research has investigated when and how cross-cultural experience -either introduced in the lab or measured via individual histories -affects creativity for individuals. first, exposure to other cultures influences creativity when the exposure is ''deep" and promotes a challenge to one's customary ways of thinking and behaving. maddux and galinsky (2009) found that the extent to which individuals adapt to-not merely live in -a foreign culture predicts creativity. notably, some evidence suggests that cross-cultural exposure should be broad and deep in ''moderation." cross-cultural experience of fashion house directors has been found to be beneficial for the perceived creativity of the house's products (godart, maddux, shipilov, & galinsky, 2015) , but only when the breadth and depth of the experience was not too extreme. the authors argued that too much depth of cross-cultural adaptation could lead people to lose sight of what is interesting and unique in the culture and they may become cognitively entrenched. too much breadth in crosscultural experience (e.g., living in too many places) could lead people to become cognitively overwhelmed by information and therefore unable to use it well. second, exposure to other cultures enhances creativity when the exposure allows for mental juxtaposition of two or more cultures. leung and chiu (2010) found that measured (study 2) and experimentally-induced (study 1) multicultural experience predicted creativity, but only when cultures were presented in tandem, either juxtaposed (e.g., a slide set on chinese culture and american culture) or blended (e.g., a slide set on east/west cultural fusion). leung and chiu (2010) suggest that these effects occur because people with multicultural experience can sample ideas from non-overlapping cultures during the creative process, and joint presentation (vs. only presenting a single culture) also facilitates broader sampling. this in turn should lead to generating creative ideas. tadmor, galinsky, and maddux (2012) argue that mere access to more cultural information does not lead to creativity, however. they instead suggest that the manner in which the information is processed is key. specifically, integrative complexity -being able to understand and combine multiple perspectivesyields high creativity. tadmor et al.'s findings support this mechanism. they found that only people who adopted an ''integration" acculturation strategy -identifying with both their host and heritage cultures -were more creative (cheng, sanchez-burks, & lee, 2008, found similar results) . those who identified with neither culture or with only one culture were less creative despite also having had multicultural experience. integrative complexity mediated the effect of acculturation strategy on creativity, suggesting that integration acculturation boosted people's ability to simultaneously access and combine disparate information from different cultures. decisions often yield both intended outcomes and side effects. although side effects are unrelated to the decision maker's original aims, they matter to decision quality because they affect the people the decision was intended to serve, for better or for worse. exploring potential consequences of each option is usually in the best interests of the decision maker. despite its obvious afterthe-fact importance for how well or poorly decisions can turn out, there is no literature on how people address the ''possibilities" issue per se. nevertheless, two related findings from prior crosscultural studies suggest a couple of compelling topics for future investigation. the first, mentioned earlier in this article, is the observation of variations in the degree of individualism (vs. collectivism) across cultures. there are vertical and horizontal varieties of these tendencies. vertical forms of interpersonal relationships entail acceptance of hierarchies of responsibilities, privileges, and rights (singelis, triandis, bhawuk, & gelfand, 1995) . in contrast, horizontal forms emphasize equality among peers. it seems plausible to anticipate that especially large numbers of people would normally participate in decision making in horizontal collectivistic societies. to the extent that these arrangements are managed well, we should expect that the resulting broader perspectives would also imply good recognition of possibilities. the second relevant finding is that some cultures emphasize broad, holistic thinking rather than narrowly focused analytic thinking (masuda & nisbett, 2001) . evidence suggests that koreans make use of more information than americans in judgment tasks, and that the relationship between holistic thinking and preference for large information sets is positive at the individual level within each culture (choi, dalal, kim-prieto, & park, 2003) . holistic thinking might promote more thoroughness in detecting potential consequences of any option under consideration. 3.6. judgment: ''what would happen if that action were pursued?" judgments are different from decisions. whereas decisions are commitments to particular courses of action, judgments are opinions as to what was, is, or will be some decision-relevant state of the world (yates & potorowski, 2012) . decisions rest at least partly on judgments, and highly accurate judgments support good decision making. because people engage in judgment at several points in the decision process, much of the work on culture and judgment is covered in other sections of this paper. here, we review cultural differences in overconfidence and attribution. phillips and wright (1977) sparked great interest in cultural variations in judgments nearly 40 years ago. english and chinese participants answered trivia questions and indicated how confident they were in each of their answers. the chinese judgments were much more overconfident than english judgments. consider the items for which the participants said that they were 80% sure that their chosen answers were correct. the english students were, in fact, correct on about 67% of those occasions. the corresponding statistic for the chinese students was only 52%. the basic finding of high chinese overconfidence was extended to some other east asian groups in studies comparing participants from britain, hong kong, malaysia, and indonesia (e.g., wright & wisudha, 1982; wright et al., 1978) . other studies found similar patterns of overconfidence in mainland china, taiwan, and india (e.g., lee et al., 1995; yates et al., 1989) . japanese people seem to be a notable exception in asia, having displayed confidence more similar to that of americans (yates, lee, shinotsuka, patalano, & sieck, 1998) and at times even exhibiting under-confidence (yates et al., 2010) . apart from east asia, a high degree of overconfidence has been found among mexicans relative to americans (lechuga & wiebe, 2011) . more broadly, stankov and lee (2014) examined overconfidence in 33 countries. overconfidence was widespread but differed in degree according to region. the authors attributed overconfidence differences to variations in ability rather than confidence judgments per se, since confidence differed little from one country to the next while ability varied substantially. why are the judgments of many asian cultures-but notably, not japanese culture-so often highly overconfident? asian overconfidence is all the more surprising given that the need to selfenhance appears to be absent or attenuated in east asian cultures (heine & hamamura, 2007) . in the chinese case, research suggests that they think less probabilistically than the english do. when asked in an open-ended manner whether a certain event is going to occur, chinese participants were more likely than english participants to reply with words that do not acknowledge degrees of uncertainty at all (e.g., ''yes" or no") or with only a limited range of different probability phrases (e.g., ''probably") (lau & ranyard, 2005) . cultural differences in holistic thinking have also been proposed to explain overconfidence differences. one feature of holistic thought is the belief that everything in the world is somehow connected to everything else. this presumption has been suggested as a contributor to the relatively strong tendency for koreans to exhibit the hindsight bias (choi & nisbett, 2000) . in this view, events that are observed to have occurred can easily be rationalized as having been inevitable because of the chain of connections revealed after the fact. this, in turn, could lead to overconfidence for groups that think holistically (vs. analytically). lechuga and wiebe (2011) suggested that similar reasoning might be extended as an account for extreme overconfidence, too. so far, however, data have not supported this notion, and this account does not explain why japanese people are not overconfident. another plausible contributor to high overconfidence in some asian cultures is that those cultures do not have traditions that encourage individuals to seek out arguments that might contradict the wisdom of their first impressions as to the possible outcomes of an uncertain event (yates et al., 2010) . japanese people may be an exception to this rule given that they are especially thorough and deliberate in their reasoning and this practice tends to reduce overconfidence generally (sieck & yates, 2001) . when people observe interesting events -say, a man kicks a dog on the street -they tend to make causal judgments in an attempt to make sense of the situation. the man might kick his dog because he is a cruel man (dispositional attribution) or he might kick the dog because the street is known to be dangerous and the dog startles him (situational attribution). research with westerners has documented many routine ''errors" in causal attribution; for example, they have been found to overestimate the causal influence of people and underestimate the influence of contextual factors in the situation (ross, 1977) . soon after the initial observations of attribution errors, however, cross-cultural work with indians and americans found that although children in the two cultures explain events similarly, differences emerge with age; american adults make more reference to dispositional (vs. situational) factors when explaining someone's behavior, whereas indian adults make more reference to situational (vs. dispositional) factors (miller, 1984) . research with several east asian groups and north americans has found that the former group is more prone to attributing causality to contextual factors. these judgment differences have been observed consistently in cultural artifacts such as newspapers, as well as in survey and experimental culture-priming studies (lee, hallahan, & herzog, 1996; morris & peng, 1994; peng & knowles, 2003) . this is not to say that east asians do not assign causality to people; they are more likely to do so, however, for collectives rather than individuals (menon, morris, chiu, & hong, 1999, referring to hong kong and japanese asians vs. americans). when they do assign causality to an individual leader, it has been found to be based on the actions of the leader's group; thus individuals are held responsible according to their group's behavior (zemba, young, & morris, 2006) . these differences have been explained by appeals to cognitive style. holistic thinking, which is valued in east asian contexts, involves attending to context and the relationships among objects . western thinking tends to be more analytic, which involves focusing on objects independently and viewing them as discrete. these tendencies may lead east asians to attribute causality to context and westerners to attribute it more to internal dispositions. a western exception may be latin americans. work with mexicans has found them to be more holistic than u.s. americans in some aspects. however, results have been inconsistent (lechuga, santos, garza-caballero, & villarreal, 2011; lechuga & wiebe, 2011) . 3.7. value: ''what will particular people like and dislike, and how much?" the ''value" issue pertains to the fact that people make different decisions in part because they value or like different things. addressing this issue in decision making involves predicting to what extent the beneficiary of a decision will like or dislike attributes or outcomes of the decision. because cultures differ in what they value, they will differ in their appraisals of how good or bad particular options are. for example, residents of former frontier regions in the united states are more likely to choose unique names for their babies, possibly because frontier environments fostered an ethos of independence which in turn may have led people to value uniqueness (varnum & kitayama, 2011) . u.s. residents in regions with higher pathogen prevalence tend to vote less for third-party candidates, possibly because higher pathogen prevalence seems to encourage value for conformity (varnum, 2013) . in this section we elaborate on several cultural value differences as well as how cultures adjust their valuation of options over time. cultures differ with respect to the influence of personal values on decisions. there is evidence that indians make choices that are less closely linked to their personal preferences than do u.s. students (savani et al., 2008) . as previously discussed, in indian and several other collectivist cultures, people often use decision modes that involve and take other people into account. therefore, the values and expectations of others -not just one's ownbecome an important consideration in decision-making. from this perspective, it makes sense that the decision maker's own values would have relatively less impact than in an individualistic culture, where fewer concerns must be considered. people in collectivist cultures can even find positive value in choosing options that adhere to norms rather than following personal preference. in one study, both brazilians and americans indicated that they were likely to follow norms when deciding on behavior. further, the brazilians were far more likely than the americans to also indicate that they would be happy about following those norms (bontempo, lobel, & triandis, 1990) . similarly, indians have not reported feeling constricted or burdened when accommodating others in their decision making (savani et al., 2011) . thus, although personal value matters enormously in westerners' decision-making, they appear to be less important in other cultures due to their collectivism and tightness. a conceptually related principle focuses on the significance of the self for the decision maker. when reporting what courses they would be interested in taking, for example, european canadians' choices were more strongly associated with their ratings of expected enjoyment than were east asians' choices (falk, dunn, & norenzayan, 2010) . in addition to expected enjoyment, evidence suggests that north americans highly value options that are associated with the self. consider the ''endowment effect," whereby prospective sellers value objects more than do prospective buyers. this phenomenon was found to be stronger among canadians and americans than among asians of various backgrounds (maddux et al., 2010) . the effect was even stronger for canadians when subjects' cognitive association between self and object was experimentally strengthened. ''spreading of alternatives" is a value-related phenomenon that can occur after making a choice. imagine having to choose only one of two items that you find equally appealing -say, you only have enough money for one suit despite finding two that you really want. after choosing one item in this type of situation, decision makers often feel badly because they must forego the rejected item which they nevertheless liked as much as the chosen item. researchers have found that after such a choice, people tend to change their values such that they rate the chosen item more highly than the rejected item despite initially liking the two equally. this presumably helps people feel better about their decisions since their values become aligned with them, ''justifying" those decisions. heine and lehman (1997) found this ''spreading of alternatives" effect in canadians, particularly for situations in which decisionrelevant negative arousal was induced, but japanese participants did not exhibit spreading of alternatives in any of their conditions. another study found again that in a typical dissonance experimental paradigm, japanese did not exhibit spreading of alternatives (kitayama et al., 2004 , but see izuma et al., 2010) . when primed to think about others, however, japanese participants did exhibit the effect. the authors suggested that the interdependent values of their japanese subjects meant that imagining the presence of others activated anxiety about social approval, and thus it became important to exhibit values consistent with their decisions. research comparing working versus middle-class americans also suggests that middle-class americans, for whom choice may be an important aspect of the ''self," exhibit this dissonance effect in a standard paradigm whereas working class americans do not (snibbe & markus, 2005) . thus, the change in value that follows tradeoffs in decisions is not uniform across cultures and depends on culture-specific activation of negative arousal. imagine gamble g: if a fair coin is tossed and it comes up heads, the player loses $5, and if the coin comes up tails, the player is awarded $x. suppose jill and luke are each asked to indicate the smallest amount $x would have to be in order for them to be willing to play. jill responds, ''$8," and luke responds, ''$10." who appears to hate losing money more? most of us would say, ''luke," because it takes $2 more in order to persuade luke to risk losing the same amount of money ($5). in the standard language of decision scholarship, we would say that luke is more ''loss averse" and the difference of $2 indexes his additional, relative loss aversion. as this fictional example suggests, how a person feels about losses is an important element of how that person decides. that is why loss aversion has become a more popular focus of research, including across cultures, often using methods similar in logic to the procedure illustrated. wang, rieger, and hens (2016) studied people from 53 countries around the globe to shed light on potential cross-cultural variations in loss aversion. eastern european groups represented in their study had especially high loss aversion while african groups on average had the lowest loss aversion. the authors measured various cultural variables in search of explanations of country-and individual-level differences. country-level individualism was positively correlated with loss aversion. this relationship was also found at the individual level while controlling for country-level effects, such that a person's deviation from her country's mean individualism level was correlated with her loss aversion levels. this finding is consistent with weber and hsee's (2000) ''cushion hypothesis." they proposed that collectivist cultures support risk taking because one's close social network members can offer financial support in the event of setbacks. thus, there is less reason to fear losses; they often can be alleviated. also of note is that other country-level factors such as religious composition were related to loss aversion, although potential explanations remain to be explored. a key feature of kahneman and tversky's (1979) prospect theory is that how a person feels about a given decision outcome is not fixed. instead, it depends on the decision maker's ''reference point," which varies from one moment to another. if, at a given moment, kevin has eaten zero cookies, the prospect of eating one freshly-baked chocolate chip cookie sounds fabulous to him. if, at another given moment, kevin just finished eating two cookies, then the prospect of eating one more cookie may sound nice but is likely not proportional to the excitement generated by eating the first cookie. if he waits for three hours and ''re-sets" his reference point back to zero, eating that third cookie will be just as pleasurable as eating the first cookie. arkes, hirshleifer, jiang, and lim (2008) found that people ''re-set" their reference points more after gains than after losses, reflecting behavior that maximizes hedonic pleasure. (this asymmetry makes subsequent gains especially satisfying and subsequent losses less aversive.) the same authors (arkes, hirshleifer, jiang, & lim, 2010) replicated this effect with both americans and asians (chinese and korean nationals), suggesting that this ''hedonic engineering" may be a general human strategy. however, the asian subjects adjusted their reference points more than american subjects. this tendency may reflect lower loss aversion in asians. the authors also hypothesized that it may be related to east asians' preference for accommodation to circumstances rather than altering circumstances to fit one's own preferences (hsu, 1981) . consider the following grossly simplified apartment search situation: apt 1: condition: ⁄⁄⁄ distance: ⁄⁄ apt 2: condition: ⁄⁄ distance: ⁄⁄⁄ in this display, the stars represent degrees of goodness of a given apartment with respect to the considerations described-the condition of the apartment and its distance from the decision maker's workplace. more stars indicate greater goodness, in the decision maker's eyes. observe that the situation illustrates ''feature conflict." one feature dimension favors apt 1 while the other favors apt 2; neither alternative would be described as ''dominating" the other. such a situation is sometimes described as a challenging ''tradeoff dilemma." apt 1 is better by one star on condition whereas the opposite is true for distance. if the searcher chooses apt 1, it might be because she feels that, in picking apt 1 over apt 2, she has traded a one-star advantage on distance for a one-star advantage on condition, and that that is consistent with what her actual experiences would be if she were to live in each apartment. the ''tradeoffs" issue concerns how people should and do, in fact, resolve tradeoff dilemmas. this is important because almost all decision situations eventually are reduced to such dilemmas, in some form or another. our primary concern here is whether and how cultures differ in how they resolve tradeoff dilemmas. there has been very little research on the matter. however, efforts by p.c. chu and eric spires have been informative about cultural variations involving the people's republic of china, taiwan, japan, and the u.s. (chu & spires, 2008; chu, spires, farn, & sueyoshi, 2005; chu, spires, & sueyoshi, 1999) . one key finding has been that japanese decision makers are significantly more attracted to noncompensatory schemes for addressing dilemmas and that americans are among the most strongly inclined toward compensatory schemes. a ''compensatory" approach is one such that weakness on one feature dimension can be offset or ''compensated for" by strength on another. this was implied in our apartment example, where the decision maker chose apt 1 because she felt that gaining an extra star's worth of condition more than made up for the sacrifice of suffering an extra star's burden in commuting each day. a ''noncompensatory" scheme is one for which a deficiency on one feature dimension cannot be offset by strength on another. suppose that in our apartment case, the searcher's scheme is such that an apartment simply must have three stars or more with respect to condition. thus, no matter how good apt 2 was on distance, it would never be chosen. this is just one form of noncompensation we see. why would japanese decision makers be attracted to noncompensatory schemes? the data necessary to answer this question have not been reported. however, chu et al. have suggested three contributors. the first is japanese aversion to confrontation. another is the relative comfort of chinese culture (in the prc and taiwan) with compromise as implicit in the chinese ''doctrine of the mean." a third is tied to the fact that noncompensatory schemes are comparatively easy to apply. this is just one among several research directions for the future in this domain. 3.9. acceptability: ''how can we get others to agree with our decision?" how other people feel about our decisions can spell the difference between decision success and failure. some years ago, a major insurance company announced its decision to deny insurance policies to women involved in relationships with men who abused them. in response, many in the public and the government were outraged and threatened boycotts. the company reversed its decision. the ''acceptability" issue is about how to avoid situations in which other parties undermine one's decision because of their opposition to the decision or to how it was reached. there is good evidence that cultures often differ substantially in how they address the acceptability issue. we focus in particular on decisions in negotiations. 3.9.1. strategy differences in intra-cultural negotiations several cultural differences in negotiation practices have been observed. in some studies, relative to their counterparts of another culture, americans have been found to prefer direct communication (adair, brett, & okumura, 2001) and take a more competitive approach (pearson & stephan, 1998) . in contrast to americans, japanese negotiators have been seen as more likely to use indirect communication and influence (e.g., sympathy, reference to status) while brazilians more strongly favor collaboration, accommodation, and avoidance, especially for negotiations with in-group members. other work has examined cultural effects in a more nuanced way. gelfand et al. (2013) studied negotiating groups vs. individuals in japanese and american cultures. they expected that groups would show greater cultural differences because social monitoring, which occurs in groups but not individual settings, would amplify concerns for adhering to social norms. thus, a group (vs. solo) negotiation would strengthen already-present norms of competitiveness for americans, whereas group negotiation would strengthen already-present norms for harmony with their taiwanese participants. the researchers also expected that groups would outperform individuals in u.s. contexts, because people in groups would be more competitive than individuals. in the east asian context, groups would perform worse than individuals, because people in groups would be more concerned with harmony, which is detrimental to achieving optimal negotiation outcomes. the study found partial support for this idea; american teams did not outperform solo negotiators, but taiwanese groups performed worse than solo negotiators. taiwanese groups also performed more poorly than american groups. the latter effect was mediated by harmony differences; taiwanese groups performed more poorly due to their concerns with maintaining harmony. are any particular strategies for negotiation universally beneficial for joint outcomes? examined negotiating dyads from france, russia, japan, hong kong, brazil, and the united states engaged in intra-cultural negotiation. japanese and american dyads had the highest joint gains, followed by ones from brazil and france. hong kong and russian dyads had the lowest outcomes. the authors found that cultural characteristics such as individualism and hierarchy did not seem related to joint outcomes. instead, other factors were more important for achieving good joint outcomes, including values for information sharing, the ability to deal with several issues simultaneously, and motivation to continually improve on current options. graham, mintu, and rodgers (1994) studied the ''problemsolving approach" (psa) to negotiation across 11 cultures. this approach emphasizes the use of information exchange to understand the other party's needs and concerns, ultimately with the goal of achieving mutually beneficial outcomes. the authors did not test the effect of its use on joint outcomes, but found it to be beneficial to the opposing party's profit in 5 cultures. it was detrimental to the user's profit in only one culture -mexican -and the use of psa was likely to be reciprocated in 8 of the cultures. they did find that bargainers from more individualistic cultures had lower psa scores (that is, they bargained with more individualistic strategies) and achieved higher profits. future work should further test whether and how negotiation practices can be successfully transplanted from one cultural context to another. negotiating cross-culturally (vs. intra-culturally) has been associated with certain negative outcomes which may be partly due to variation in how cultures negotiate. there is evidence that negotiation results in higher joint gains the more that parties use tactics that are typical of their own cultures (adair et al., 2001) . specifically, single-culture dyads (american and american, japanese and japanese) had higher joint profit outcomes than inter-cultural dyads (american and japanese). american (vs. intercultural) dyads were more likely to use direct communication, whereas japanese (vs. intercultural) dyads were more likely to use indirect communication and influence tactics. adair and colleagues' findings also suggest that one culture adapting negotiation styles to match the other culture's style is not enough to increase joint profit. in their study, japanese, but not american, negotiators adjusted their styles during intercultural negotiations. despite this adjustment, intercultural dyad outcomes were inferior to intra-cultural dyad outcomes. while that study did not find one party's adaptation of specific strategies to be sufficient, other research has suggested that ''cultural intelligence" (cq) plays an instrumental role in achieving mutually beneficial outcomes. cq is the ability to effectively adapt to culturally diverse situations (earley & ang, 2003) . it includes preparing for, adapting to, and learning from cross-cultural interactions as well as engaging in perspective-taking (mor, morris, & joh, 2013) . in one study, negotiating dyads that had higher overall cq were shown to be more likely than lower cq dyads to employ mutually-beneficial bargaining strategies (integrative information behavior), which led to more joint profit (imai & gelfand, 2010, study 2) . importantly, the dyads were only as effective as their lowest-cq members. other factors such as international experience, emotional intelligence, and extraversion failed to predict integrative information behaviors (imai & gelfand, 2010) . cq has also been found to be positively related to cultural perspective taking which, in turn, boosts intercultural cooperation (mor et al., 2013) . a cultural perspective-taking intervention designed by mor et al. successfully increased negotiators' cooperation, particularly for negotiators who were low in cq. thus, there is good reason to expect that cq can be manipulated and improved. during negotiations, values can clash, sometimes intractably. in ordinary decisions, the negative aspects of an option can be compensated for by adding something appealing, like money (recall ''compensatory strategies" for making tradeoffs). however, ''sacred values," sometimes referred to as ''protected values," appear to be immune to material tradeoffs (jassin, sheikh, obeid, argo, & ginges, 2013) . for example, someone who does not ''sacredly" value gun ownership might support legislation that offers cash for handing in firearms in an attempt to reduce gun violence. if gun ownership is a sacred value for that person, however, virtually any option involving handing in his or her weapons would be unacceptable. moreover, attempts to ''sweeten" options that violate sacred values with money can actually backfire -such options become even less appealing because they evoke moral outrage (ginges & atran, 2014) . research suggests that better ways of handling sacred values in cross-cultural decisions include adding a culturally meaningful, symbolic gesture (such as an apology) to increase the value of an option (atran & axelrod, 2008) . it seems that nearly everyone has made new year's resolutions that were forgotten within a few weeks. such instances illustrate the ''implementation" issue, which concerns the actions people take in their attempts to assure that their decisions do not suffer the fate of so many resolutions. it is easy to appreciate the significance of the ''implementation" issue in personal and organizational life. nevertheless, the decision implementation literature is recent and remains small but can be expected to grow rapidly. representative papers include those by gollwitzer (1999) , dholakia and bagozzi (2002) , and nickerson and rogers (2010) . the line of work represented by these articles is specifically about the benefits of using ''implementation intentions" -concrete, actionable plans to carry out a decision. the strategies people employ to ensure that their decisions ''stick" might vary between cultures, and the effectiveness of such strategies may vary as well. we imagine that adhering to precise plans might make someone a stick-in-themud in some cultures, but an admirable colleague in others. this review reveals several areas of progress in the study of cross-cultural decision making. since initial reviews of this discipline, which focused on probability judgments, risk, and decision making modes (weber & hsee, 2000) , many other topics have received attention. overall, the following cardinal decision issues have enjoyed the most attention: ''mode," ''investment" (indecisiveness), ''options," ''judgment", ''value," and ''acceptability." certain features of the ''need" issue -such as attention -have been studied, but it would be illuminating for scholars to directly study how cultures vary (or not) in the way they begin the decision making process itself. the ''possibilities," ''tradeoffs," and ''implementation" issues appear to have received relatively little attention, but they are clearly relevant to the quality of the decision outcome and the effectiveness of the decision being acted upon, respectively. therefore we recommend that scholars give attention to and ask questions regarding these less studied issues. what have studies in cross-cultural decision making contributed besides describing differences in decision making in particular cultures? such studies have yielded evidence that many presumed ''basic" processes are not universal (henrich, heine, & norenzayan, 2010) . such work has also attempted to explain cultural differences, attributing them to psychological forces such as individualism or to more distal forces that shape human psychology (e.g., modes of subsistence or migration history). many important and generative lines of research have examined only two or three cultural groups, often of east asian and western origin. while that body of work has been richly informative, we note three resulting limitations. one, obviously, is that the generalizability of those findings to other cultural groups might be limited. someone who hopes to learn about mexican decision making would be ill-advised to only read the literature largely about east asians and conclude, ''since mexicans are fairly collectivistic, like east asians, their decision making practices must be similar." thus we propose that investigators focus their efforts on a more diverse set of national cultures as well as differences within regional boundaries. a second, related limitation is that individualism and collectivism are frequently used to explain cultural differences to the neglect of other factors. when considering only a single east asian and western cultural group, this construct may very well account for differences. however, other collectivistic cultures likely make decisions very differently than, say, japanese people, so other factors will need to be developed and examined as explanations of those differences. a third limitation is that early cultural work in psychology seldom differentiated between individual and group-level effects. that differentiation is crucial to properly understanding the relationships between variables of cultural interest. hypothetically, a researcher might find a positive relationship between individualism and preference for unique products across 30 cultures at the group level. however, if the investigator were to look at individuals within a given culture, the relationship might be virtually null, reversed, or variable between groups (na et al., 2010) . some researchers have indeed demonstrated this type of effect (leung & cohen, 2011) . in closing, we raise a final question for scholars to explore: how can this research help people make better decisions? can individuals from one culture import another culture's decision making strategies in order to improve decision making effectiveness? effectiveness is subjective; it depends on the extent to which the intended outcome is achieved for the decision's beneficiary. nevertheless, decision making practices of one culture may have inherent benefits or pitfalls affecting any culture that uses them. for example, toyota's american offices seem to have imported very thorough japanese decision making strategies (liker, 2004) . thoroughness might almost universally reduce people's likelihood of being blindsided by unexpected consequences, but it may also render decision making slow and cumbersome. researchers may also explore what factors lead to successful (vs. disastrous) transfer of decision making practices. must features of a particular strategy ''match" the culture in order 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china, japan, and the united states blaming leaders for organizational accidents: proxy logic in collective-versus individual-agency cultures key: cord-333479-d0mgma42 authors: duan, li; shao, xiaojun; wang, yuan; huang, yinglin; miao, junxiao; yang, xueping; zhu, gang title: an investigation of mental health status of children and adolescents in china during the outbreak of covid-19 date: 2020-07-02 journal: j affect disord doi: 10.1016/j.jad.2020.06.029 sha: doc_id: 333479 cord_uid: d0mgma42 objective: : the sudden outbreak of coronavirus disease 2019 (covid-19) has had a dramatic effect on the mental health of the public. in the present study, we demonstrated the psychological effects on children and adolescents associated with the epidemic . methods: : by using convenience sampling method, questionnaires, such as spence child anxiety scale, child depression inventory and coping style scale, were distributed to participating 359 children and 3254 adolescents online. results: : the anxiety levels of children and adolescents were (23.87±15.79) and (29.27±19.79), respectively. 22.28% respondents were suffering from depressive symptoms. seven significant factors associated with increased levels of anxiety, including female, resident in urban regions, emotion-focused coping style. nine factors associated with increased levels of depression, such as smartphone addiction (or 1.411, 95% ci 1.099–1.180), internet addiction (or 1.844, 95% ci 1.209–2.811), and resident in hubei province (or 3.107, 95% ci 1.252–7.708). two additional factors associated with decreased levels of depressive symptoms: hours spend on internet per day before the epidemic (or 0.652, 95% ci 0.609–0.697) and tendency to apply problem-focused coping style (or 0.937, 95% ci 0.923–0.951). conclusion: : our findings indicate that the covid-19 outbreak has had a significant psychosocial impact on children and adolescents. findings of current levels of anxiety and depression not only highlight the need to address emotional distress for children and adolescents during the epidemic but also provide researchers with scientific fundamentals to formulate targeted interventions based on the significant influencing factors. since the outbreak of the covid-19 at the end of 2019, a series of effective epidemic preventive and control strategies have been developed and conducted by the chinese government to curb the spread of the virus. the general public, especially the high-risk group (e.g., elderly people with chronic underlying diseases, children, and others with lower immunologic function), are suggested to stay indoors in quarantine at home, which is recognized as the best way to eliminate chances of being infected. however, due to the long period of separation from the outside world, the impact of multi-channel negative information, excessive fears of being infected, and even the shame and guilt for the infection, many people across china, particularly residents at the epicenter of the outbreak in wuhan, are experiencing fear, loneliness, panic, anxiety and depression amid the coronavirus outbreak (duan and zhu, 2020; xiang et al., 2020) . these negative physical and psychological costs have also been reported in previous studies, such as suicide, substantial anger and sleep disorders (barbisch et al., 2015; rubin and wessely, 2020; wang et al., 2019) . for children and adolescents, due to the lower incidence of infection and mortality than adults, professionals were less focusing on the unique clinical features of covid-19 and mental health status in children (ma et al., 2020) . furthermore, evidence has shown that children and adolescents who experienced disasters might suffer from greater stress and trauma because of the lack of development of proper emotional reactions and coping techniques (lazarus pj, 2003; roussos et al., 2005) . when emotional support and spiritual guidance from family members, teachers, as well as other significant peers and adults in their lives could not be met due to home confinement, deferred back-to-school and lifestyle changes, it adversely affected the mental health of children and adolescents (sprang and silman, 2013) . additionally, according to the latest data from the china's national health of commission, the overall situation in the chinese mainland is somewhat coming to a plateau ( national health commission of china, 2020) . the number of new confirmed cases has dropped dramatically, but authorities are warning that strict prevention measures should stay in place to prepare for a potential comeback of the virus. therefore, in order to effectively cooperate with the government's epidemic prevention work, more than 220 million children and adolescents were confined at home and informed to postpone the start of the spring semester until further notice (wang et al., 2020) . meanwhile, online studying courses which was delivered by tv broadcasts and the internet have been opened gradually to students to guarantee their needs of learning, according to a guideline released by the china's ministry of education (ministry of education of china, 2020) . however, due to lack of monitoring and evaluation of students participating in online courses, the inefficiency of the experience of these courses, unstable network signals, and often no networks in remote rural areas, many parents, students, and teachers have complained of the poor effectiveness of online learning. these effects can be compacted by adverse consequences of reduced vision, as well as unconscious smartphone/internet addiction, and may further contribute to mental distress in children and adolescents. here, we assessed the current status of mental health issues among children and adolescents affected by the epidemic and analyzed its influencing factors to provide scientific guidance to psychological professionals and the government in formulating targeted policies. this study was designed as a cross-sectional online questionnaire survey that was administered during the spread of covid-19 in china. we developed the online questionnaires on the official website of "questionnaire star," which is recognized as a professional online questionnaire survey, evaluation, and voting platform. a set of self-rating questionnaires were distributed to children and adolescents who ranged from grade one in primary school to grade three in high school (aged from 7 to 18 years) in mainland china by employing convenient sampling method. with the help of directors in education bureau, we distribute e-questionnaires to teachers and told them the purpose, significance and announcements of this survey in details. then, they assigned it to school-students and their guardians. before completing questionnaires, all participants and their guardians were debriefed on the study purpose and contents. once consented, participants began filling out the set of questionnaires online. we also included our email addresses and phone number to the first page of questionnaires so that participants could consult and interact with us at any time. the set of questionnaires involved in this study were mainly composed of seven sections. -sociodemographic characteristics were self-designed and included questions regarding sex, age, place of residence, number of siblings, region, family status, education level, and number of electronics owned. -covid-related questions were developed by our research team and assessed the current situation of the respondents' family members involved in anti-epidemic work, the degree of concerns about the epidemic, the implementation of the precaution and control measures, the impact of the epidemic on their course of study and graduation, as well as the electronic products/internet use patterns before and during the epidemic. -the chinese version of spence child anxiety scale (scas) is a 44-item self-report likert's scale that measures anxiety in children and adolescents (zhao et al., 2012) . spence (spence, 1997) first developed it by using community samples, and it has since been used widely in other countries (essau et al., 2011) . this study evaluated the anxiety status of participants affected by the epidemic on a 6-factor scale, including items such as separation anxiety, physical injury fear, social phobia, panic disorder, obsessive disorder, and generalized anxiety. -the child depression inventory (cdi) is a 27-item self-report measure designed to evaluate the severity of depressive symptoms in children and adolescents (kovacs & beck, 1977) and has demonstrated satisfactory levels of reliability and validity in the chinese population (wang et al., 2015) . in general, the total score of cdi is 19 or higher can be identified as possessing clinical depressive symptoms, while scores of 12-18 indicate subclinical depression, and scores of 12 or lower are considered normal (stewart and sun, 2007) . in this study, we classified respondents with clinical depressive symptoms with scores 19 or higher. -the short version of smartphone addiction scale (sv-sas) is a 10-item self-rated developed by kwon et al. 2013 (kwon et al., 2013 and is recognized as a valid screening tool for the prevalence of smartphone addiction. it uses cut-off points by sex, where 31 and 33 classify "excessive smartphone uses in male and female users," respectively. -the internet addiction scale (ias) consists of 20 items derived from the dsm-iv-tr (cooper, 2001) [diagnostic and statistical manual of mental disorders (4th edition, text revised)] in order to identify diagnostic criteria of pathological gambling and the degree of preoccupation and compulsiveness to go online. according to young (young, 1998) , three types of internet-user groups were identified as internet addicts (scores of 70 or higher), possible internet addicts (scores 40-69), and non-addict (39 or lower). in this study, we defined participants with internet addiction with scores 70 or higher. -the coping style scale (css) was developed by chen et al. in 2000 based on the theory of social interaction and self-regulation and measures middle school students' competence in coping with stress (chen sl et al., 2000; folkman et al., 1986 ). this 36-item self-rate scale can be divided into two subscales of problem-focused coping and emotion-focused coping. the former consists of three dimensions, including solving problems, seeking social support, and positive rationalizations, while the later contains four dimensions, including endurance, avoidance, expressing emotions, and fantasy/denial. all data were analyzed using spss (version 18.0, spss inc., chicago). apart from descriptive statistics and frequency analysis of demographic characteristics and covid-related information, t test and analysis of variance (anova) were used to analyze the difference in levels of respondents' anxiety. moreover, multiple linear regression and bivariate logistic regression analyses were used to assess the association between outcome variables (the reported level of anxiety and clinical depressive symptom) and potential predictors (e.g. concerns related to the epidemic, smartphone/internet addiction, and coping style) while adjusting for other identified explanatory variables. in the process of running models, the forward stepwise selection algorithm was used, and variables in the model were screened based on significance levels of the wald inclusion test statistic being less than 0.05. moreover, pearson's correlation analysis was performed to analyze the associations among scas, cdi, smartphone/internet addiction, and coping style, and the statistical significance level was set at 0.05. the sample size of our survey recruited online included 3,613 chinese students. as table 1 shows, the study participants comprised 1,812 males (50.15%) and 1,801 females (49.85%) collected from 20 provinces in mainland china. however, considering that hubei is the hardest-hit place of this epidemic, we classified the sample sources by residential areas, namely 27 (0.75%) in hubei province and 3,586 (99.25%) from other regions. respondents were mainly from nuclear families (68.56%), extended families (24.08%), and single-parent families (5.45%). the sample comprised children aged 7-12 years (9.94%) and adolescents aged 13-18 years (90.06%) and who were in primary school (6.03%), secondary school (55.43%), or high school (38.54%). among them, 54 (1.49%) and 18 (0.51%) who failed the high school/college entrance examination and had to return to secondary/high school again for resuming their study, respectively. additionally, there were 128 (4.01%) respondents who already had electronics before 7-year-old. furthermore, an in-depth analysis of 3,183 respondents who possessed electronic devices showed that the average age at which they started owning electronic devices was 12.14±2.66 years, and the highest rate of smartphone penetration was 90.76% (2889/3183), followed by computer 30.19% (961/3,183) and tablets 26.99% (859/3,183). after analyzing the information related to the epidemic (table 2) , 173 (4.71%) respondents reported that their family members were involved in the anti-epidemic work, and 49 (28.32%) of them were health care professionals (e.g., frontline doctors and nurses). a total of 20 (0.55%) of the participants stated that their family members, friends, or other acquaintances had been infected with coronavirus. in all, 91.06% of respondents clearly reported concerns about this epidemic, and almost the same proportion (93.86%) reported that they have strictly implemented protective measures (e.g., wear mask, wash hands, or avoid public places and crowds). moreover, 1,976 (54.69%) and 1,288 (35.65%) participants reported that the epidemic has affected their learning and graduation, respectively. average time per day spent on internet during the epidemic was also much longer than before, whereas study, as the main reason for internet use, became more significant during the epidemic. after conducting surveys on the willingness to engage in medicine in the future, we found that more people (18.74%) were determined to work in healthcare than those (7.67%) who were a little uncertain after the outbreak. among all respondents, 805 (22.28%) and 218 (6.03%) of them had scores above the threshold for clinical depressive symptoms (19 or higher) and internet addiction (70 or higher). as for sas, due to the gender differences in cutoff values for smartphone addiction, it was found that the prevalence rates of smartphone addiction in male and female respondents were 10.30% and 13.06%, respectively (table 2) . additionally, as shown in table 4 , we analyzed the current situation of the respondents' anxiety level and coping style by variables of gender and age, and the results showed that the anxiety levels of adolescents were significantly higher than those of children (f=62.07, p<0.01), and the total scores of scas for females were significantly higher than those of males (f=10.59, p<0.01). the anxiety levels of males and females in each group of children and adolescents are listed in table 3 . in table 4 , results of anova and t test analyses showed that there were 18 variables had significant difference in scas scores (levels of anxiety) (p<0.05). additionally, in order to further analyze the significant factors associated with the level of respondent' anxiety, we conducted multiple linear regression analysis and obtained the following factors to construct a multiple linear regression model of anxiety: clinical depression levels, implementation of the precaution and control measures, sex, family member or friend was infected with coronavirus, occupation of the mother involved in the epidemic, region (e.g., rural, urban), and emotion-focused coping style, which accounted for 31.0% of the total variance ( table 5) . (table 7) . anxiety symptoms are the most common clinical diagnoses in children and adolescents and can act as a significant risk factor for contributing to other psychiatric disorders in adulthood. moreover, it may worsen by facing the increasingly complex social milieu, and being a cause of impairments in various life domains and can increase societal costs for families (bodden et al., 2008; essau et al., 2008) . similarly, clinical depressive symptoms in children and adolescents are common and recurrent diseases associated with memory impairments (günther et al., 2004) , poor interpersonal relationships (lam et al., 2003) , and even high-risk suicidal behaviors (yorbik et al., 2015) . with the sudden outbreak and rapid spread of covid-19 at the end of 2019, the mental health of children and adolescents in china has been put at risk. according to the results of our investigation, we found that levels of anxiety in children and adolescents during the epidemic were much higher than before (zhao et al., 2012) . as shown in table 3 , the overall scores of five dimensions (including separation anxiety, physical injury fear, social phobia, panic disorder, and generalized anxiety) were higher than before the outbreak, especially the fears of physical injury in children and social phobia in adolescents. this finding may be due to the fact that at the initial stage of the outbreak, protective and therapeutic responses were not yet in place, and the surge in the number of confirmed cases and deaths led children to become excessively concerned about physical damage to themselves and their family caused by exposure to coronavirus. in addition, dong et al. (dong et al., 1994) reported that chinese adolescents demonstrated higher levels of social-evaluative fears than adolescents in western countries. moreover, negative reports on domestic and foreign social media regarding covid-related discrimination and unfair treatment of chinese people, as well as rumors and misinformation around origins of the infectious disease may be an important reason for worsening their social phobia and other mental disorders (calisher et al., 2020) .. the findings were in line with previous research indicating that anxiety, depression, and feelings of helplessness can be worsened by sars-related social discrimination in public places (zheng et al., 2005) . having a family member or friend infected with coronavirus was also significantly associated with increases in anxiety levels. this may be due to the fact that respondents are concerned about the health of the infected and simultaneously afraid of being a suspected or confirmed case, given their level of direct contact. we suggest that the increased awareness of infection control in respondents is consistent with their psychological state of anxiety, thereby reducing the risk of infection. in traditional chinese culture, fathers often assume the role of breadwinners, while mothers tend to perform the bulk of housework and childcare and have more emotional interaction with their children (lee, 2002) . this appeared to be an important factor affecting the anxiety level of the respondents, who believed that if their mother was not medical staff, this exposed them to insufficient and non-standardized protections, as well as a weaker social support network within their mothers' work environment. given that the outbreak originated in a highly dense urban area, and there have been subsequently many more deaths in this area, it could be the case that anxiety levels of urban residents are higher than those of rural areas. significant sex differences in anxiety levels have been reported in many studies (essau et al., 2008; li et al., 2008) , potentially resulting in women being more sensitive to the stressful events of covid-19 and correspondingly expressing stronger concerns and fears. this study also revealed that the prevalence of clinical depression symptoms in children and adolescents was 22.28% during the covid-19 outbreak, which was much higher than the generally estimated 13.2% (stewart and sun, 2007) in china and 2%-6% (phillips et al., 1999) in western countries. results of regression analysis (table 6 ) and pearson's correlation analysis (table 7) showed that levels of clinical depression symptoms were significantly associated with anxiety. evidence has shown that anxiety disorders and depression demonstrate higher overlap in symptomatology, clinical instability, and treatment (lonigan et al., 1994) . it has been estimated that roughly 25%-50% of depressed youth display comorbid anxiety disorders and about 10%-15% of anxious youth have depression (axelson & birmaher, 2001) . this suggests that attention should be paid to the proper medication and psychological interventions. due to the significant number of confirmed patients, as well as the relative shortage of medical resources and first-line medical staff, the rate of mortality in hubei province is higher (4.9%) than the national mortality rate (2.1%) (national health commission of china, 2020). moreover, a series of effective prevention and control measures (e.g., cities on lockdown, traffic controls, postponed semesters) in wuhan (the capital of hubei province) were implemented more strictly and lasted longer than other regions, leading to the interviewed children and adolescents experiencing greater isolation and for a longer period of time. these factors may explain why living in residential areas was a significant factor affecting depression levels of the respondents. moreover, we also found that students' graduation being affected by the epidemic was significantly associated with increases in depression. chinese students may be particularly academically motivated, particularly in successfully completing entrance examinations (essau et al., 2008 ) that will determine the quality of higher education and job prospects. given the current state of the epidemic however, students are taking classes online at home, which may have controversial results due to poor efficiency in managing online courses, visual impairment in students, and instability in internet signals. during the epidemic, 29.58% respondents reported that they spent more than five hours per day online, which could be a potential risk factor for addiction to the internet or smartphones. studies have shown that smartphone/internet overuse may lead to mental or behavioral problems, causing poor performance in study, decreased real-life social interaction, neglecting personal life, relationship disorders, and mood dysfunction (kahraman and demirci, 2018; soni et al., 2017) . psychopathological screening studies on internet addicts have shown that anxiety disorders are the most common diagnoses in this group (liu et al., 2011) , and adverse consequences in sleep disturbances/decreased sleep quality caused by electronic media use at night have been shown to be significantly associated with depressive symptoms (lemola et al., 2015) . in contrast, we observed that respondents spend much less time online pre-outbreak than they did during the outbreak (table 2) , which can also explain the significant correlation between the average time per day spend on internet before the epidemic was significantly associated with the decrease of levels of depressive symptoms. review of the literature has revealed that stress-coping theory posits a broad framework of problem-focused and emotion-focused coping strategies (herman and tetrick, 2009 ). problem-focused strategies tend to concentrate efforts towards fixing a stressful problem, while emotion-focused strategies concentrate on minimizing the emotional outcomes of the problem using strategies such as endurance, avoidance, or venting to someone else. it has been reported that greater degrees of ruminative coping instead of actively seeking for solutions were related to high levels of depressive symptoms, while problem-focused and distractive coping style was negatively associated with depression (li et al., 2006) . we also observed that a problem-focused coping style was closely related to decrease in clinical depression, while an emotion-focused coping style was negatively associated with the increase in depression. this study investigated the mental health status of children and adolescents in mainland china during the epidemic of covid-19. specifically, we examined anxiety and depression and investigated the related influencing factors. the findings of this study not only remind researchers and government officials should be more concerned about the mental health of children and adolescents who are often neglected in the wake of the outbreak due to their comparatively lower mortality than elderly adults, but also provide a scientific basis for the formulation of targeted psychological interventions. this study also has several limitations. first, data collection was completed by distributing questionnaires to children and adolescents online. the results and conclusions may be influenced by the degree of understanding and cooperation of the respondents, especially the younger children who need help of their guardians. second, the stylized answer forms of those questionnaires are convenience for statistics, but it limits the response of subjects and let them fail to express their subjective views on relevant issues. third, due to the fact that the epidemic situation in hubei was not fully controlled during the investigation period, it was difficult to collect data and the sample size was relatively small in this region, which limited the applicability and generalization of the results. therefore, in follow-up studies, we plan to increase the sample size (especially in hubei and other hard-hit regions), employ face-to-face surveys, qualitative interview methods, follow-up studies, and collect responses from primary guardians so as to further improve the study design and the scientific nature of the results. the authors have no conflicts of interest to disclose. no conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. i would like to declare on behalf of my co-authors that the work described was original research that has not been published previously. 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outbreak on chinese students living in japan key: cord-291279-8rfx9qde authors: li, zhuman; han, chuangchuang; huang, huihong; guo, zhijun; xu, feng title: novel coronavirus pneumonia treatment with traditional chinese medicine: response philosophy in another culture date: 2020-07-10 journal: front public health doi: 10.3389/fpubh.2020.00385 sha: doc_id: 291279 cord_uid: 8rfx9qde nan in late 2019, novel coronavirus (sars-cov-2) caused pneumonia in wuhan was spread to the whole country and was identified by world health organization (who) as "public health emergencies of international concern" (1-4). on the morning of march 12, 2020 beijing time, who officially identified it as a pandemic 1 . up to june 15, 2020, the novel coronavirus disease (covid-19) has swept over 200 countries and territories, resulting in more than 7.6 million confirmed cases and over 0.42 million confirmed deaths 2 . the novel coronavirus-caused pneumonia has a powerful infectious force for some population groups, and up to now no specific drugs could cure it (5, 6) . since the novel pneumonia outbreak, china national health committee issued seven editions of diagnosis and medical treatment plan 3 . more than 40,000 medical staffs including traditional chinese medicine (tcm) doctors from all over the country were called up to wuhan, and other cities in hubei provinces to treat patients 4 . the epidemic situation displays a good trend after severe prevention and control in china 5 . in the 7th edition of diagnosis and medical treatment plan issued by national health commission (nhc) of china, many tcm remedies are recommended for covid-19 patients in medical observation period. huo xiang zheng qi capsule is recommended for patients when there is clinical manifestation of "fatigue accompanied by gastrointestinal discomfort"; and jin hua qing gan granule, lian hua qing wen capsule, and shu feng jie du capsule are recommended for patients when fatigue with fever occur. according to a news release from the national administration of tcm, the integration of traditional chinese and western medical treatment can achieve satisfactory results for resolution of symptoms of covid-19 6 . in the medicine field of china, there is always a dispute between the modern medicine and the traditional medicine for a long time. the pros and cons of debate have its own perspective and opinion. we are pleased to see that in the face of severe epidemic situation, there are mixed teams of modern medicine doctors and tcm doctors. the majority of covid-19 patients in china have been treated with integrated chinese and modern medicine. hundreds of herbal remedies have been used throughout the country (7). the chinese government and academic experts in herbal medicine have recommended incorporating tcm into conventional treatment methods so as to generate synergistic effect by the combinational therapy of chinese and western medicine (7) . unfortunately, the experience of tcm in the treatment of epidemic situation has not been widely recognized and used for reference in the western occident developed countries. the lack of high-quality scientific evidence may be one of important reason that would lead to reject. another fundamental reason is that the whole theory system of tcm is not acknowledged by western-trained audience. it might be due to different culture, more specifically, different treatment philosophy. tcm has its strong material base from single monomeric compounds to chinese herb extracts in covid-19 treatment. psychosocial pharmacological effect probably plays an important role in the traditional medicine (8) . so what is the exactly treatment philosophy in tcm culture to the novel coronavirus disease? chinese public in general are always long taught that tcm is a national quintessence with an ancient historical origin. in addition to tcm, peking opera, martial arts, and calligraphy are well-known as the "four quintessence of china" both at home and abroad. national quintessence itself is more related with culture and social custom than with natural science. tcm has been played an indispensable role in the prevention and treatment of epidemic diseases in history. during the sars epidemic in 2003, the intervention of tcm has also achieved therapeutic effect (9, 10) . in the broad and profound tcm theory system, the present covid-19 is just one of common epidemics. even covid-19 is brand new emerging severe infectious disease caused by a brand new coronavirus and no specific drug is used to cure in modern medicine, tcm still has confidence to fight the epidemic. in tcm culture perspective, covid-19 is an epidemic disease caused by an epidemic evil with dampness and heat, which is called li-qi in chinese (11) . after li-qi invades the human body, it enters the lung first to make the lung-qi (vital essence of lung, which is in charge of breath function) stagnate, then lead abnormal breath movement, phlegm-heat accumulation and block, and finally bring out the dead yin and the dead yang (12) . according to tcm treatment philosophy, dampness should be eliminated first, and then heat be cleared away. after heat and phlegm are cleared away, the body is restored to normal function at last (13) . there seems to be something in common between virus and li-qi. both think that there is an external cause of disease. modern medicine refer it virus, they usually hope to find specific drug to cure the disease. however, tcm does not know microbiology and could not capture the virus entity, they could only focus on li-qi-induced symptom with herbal remedies. the aim of tcm treatment is simple, so long as tcm remedies provide effective way to regulate functional disorders of the human body. therefore, tcm remedies are used to detoxify poisonous dampness and heat, to strengthen body to resist pathogenic factor, to adjust the harmony of the internal relationship of the human body. that is to say, when tcm doctors treat this kind of disease, they do not have to make the cause clear to start. it is of importance to solve the symptoms for most patients. a small, non-randomized, single center retrospective observational study reported a shorter average duration of viral shedding and faster resolution of radiological pneumonia in hospitalized covid-19 patients prescribed jin hua qing gan granules for more than 2 days as compared with those receiving conventional care (14) . the potential efficacy of this herbal medicine for covid-19 treatment should be further investigated in adequately powered randomized controlled trials. the understanding and description of tcm is based on the ancient macro understanding of nature and the use of speculative philosophy such as yin-yang. in the course of history, since tcm started and developed without synchronizing with modern chemistry, biology and physics, it had to takes the road of philosophical thinking. however, by the aid of advanced science, modern medicine embarks another road of development. it can be said that tcm and modern medicine are two trees growing up in the soil of two different cultures. although high-quality clinical trial evidence is lacking at present, the efficacy of tcm remedy on symptom improvement cannot be ignored. to treat covid-19, tcm and modern medicine should complement each other and cooperate with each other since tcm can contribute as an alternative measure. zl, ch, hh, zg, and fx were responsible for the design of this work and interpretation of finding and drafting the work. fx approved the final version to be published and is accountable for all aspects of the work to ensure its accuracy and integrity. all authors contributed to the article and approved the submitted version. a novel coronavirus outbreak of global health concern clinical features of patients infected with 2019 novel coronavirus in wuhan a novel coronavirus from patients with pneumonia in china a familiar cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster discovering drugs to treat coronavirus disease 2019 (covid-19) clinical medication response under new major infectious disease: off-label use and compassionate use traditional chinese medicine contributes to the treatment of covid-19 patients psychological, social, and behavioral factors that influence drug efficacy: a noteworthy research subject in clinical pharmacology is traditional chinese medicine useful in the treatment of sars? effect of glucocorticoid with traditional chinese medicine in severe acute respiratory syndrome (sars) consideration of traditional chinese medicine in treatment of highly pathogenic human coronaviruses sars-cov-2 and sars-cov. chin trad herb drugs analysis and thinking on traditional chinese medicine in preventing and treating severe cases of novel coronavirus pneumonia traditional chinese medicine theory and clinical study on novel coronavirus pneumonia (ncp) infection effect of jinhua qinggan granules on novel coronavirus pneumonia in patients the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 li, han, huang, guo and xu. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-343163-khnyx9qu authors: zhao, rui; hynes, stephen; shun he, guang title: defining and quantifying china's ocean economy date: 2013-06-21 journal: mar policy doi: 10.1016/j.marpol.2013.05.008 sha: doc_id: 343163 cord_uid: khnyx9qu in recent years, the chinese government has been increasingly supportive of the development of the ocean economy, implementing several national ocean-related strategies. for the first time, china's 12th five-year plan for national and social development (2011—2015) includes “developing the ocean economy” as a key national development strategy for the country. because of this, the demand for ocean economic statistics and indicators is growing rapidly. the aim of this paper is to define and quantify the value of the major ocean industries in china and to examine the growth in the major chinese ocean industries in the period 2001 to 2010. the paper also outlines a methodology that provides a robust quantification of the marine sector over time. it finds that in 2010 the major ocean industries in china contributed $239.09 billion to the national economy and employed over 9 million individuals. a nation's economy has been described as a mechanical engine comprised of interconnected, moving parts [1] . in china, the ocean economy is now seen as a critical component of that engine. following the reform of economic trade policy, especially in the period 2001-2010, china's ocean economy has been growing rapidly, in line with national gdp. also, as the second largest economy in the world, china is paying more attention to the sustainable development of its ocean economy. one important reason for this is that since joining the world trade organization (wto), chinese trade with other nations has steadily expanded as a proportion of national economic activity, to the point where it affects approximately 70% of china's economy [2] . china also has access to a significant marine resource base with a coastline of more than 32,000 km [3] and more than 7300 islands [4] in its territorial waters. coupled with this, china has sovereign jurisdiction over a vast area of continental shelves and exclusive economic zones (eezs) (as defined by the un convention on the law of the sea) equal to approximately 3 million km 2 of offshore waters. china also has marine oil reserves of an estimated 24 billion tons and natural gas reserves of over 1.6 billion cubic meters [5] . seaborne commerce is one of the most essential elements of international trade in china. according to cheng [6] , "without trade, china could not sustain its economy, let alone maintain the growth rates necessary to maintain high employment figures". ocean commerce in 2008 alone represented approximately 10% of china's gross domestic product (gdp), with a value of approximately $456 billion. moreover, some 85% of its international trade moves by the sea lanes [2] . china's increasing reliance on oil imports to sustain its rapid economic expansion is a key element of this marine commerce. china imported over half of the oil it consumed in 2009, the majority of which was transported by tankers [7] . since the productive land resources in china, as well as other countries around the world, are increasingly reaching the limits of economic and ecological exploitation, the value of the oceans as a resource for economic development has become increasingly more prominent. a number of coastal countries have launched programs explicitly aimed at strategic initiatives for the development of their ocean resources [2] . for example, in 2002 the canadian department of fisheries and oceans launched canada's oceans strategy which provides an overall strategic approach to oceans management in that country [8] . in july 2010, u.s. president obama signed executive order #13547 establishing a national policy for the stewardship of the ocean, coasts, and the great lakes which aims to significantly improve the management of the u.s.'s marine resources [9] . elsewhere, in 2011, the irish prime minister launched ireland's first national integrated marine plan entitled "harvesting our ocean wealth-an integrated marine plan for ireland" [10] . the plan sets out actions and an implementation model which includes a number of integrated government delivery mechanisms aimed at supporting an integrated system of policy and program planning for irish marine affairs. similar to these other nations, china has also been planning for the strategic development of the oceans as a resource for economic development. in 1996 the chinese government unveiled the china ocean agenda 21 which put forward a sustainable development strategy for china's marine resources. the main aims of this strategy were to effectively safeguard the state's marine rights and interests internationally, provide protection for delicate marine ecosystems and realize the sustainable development of china's ocean economy [11] . with the aim of furnishing marine policy makers in china with marine activity statistics, the ocean economy accounting system (oeas) of china was established in 2006 [12] . the purpose of the system was to develop the required range and quality of ocean economy data at regional and national level. this paper provides a critique of this system and also uses it to define and quantify the ocean economy in china. while song et al. [13] have previously examined the developments in the chinese marine economic statistical system over the past 20 years this paper add to the literature by examining how the industries within the chinese marine economy has changed in both value and in terms of the numbers employed over the period 2001 to 2010. this paper also compares the chinese oeas to the marine economic accounting system used in the us and examines how closely the chinese ocean economy follows the general movement in chinese gdp. in what follows, this paper first reviews chinese marine policy that resulted in the increased need for reliable and standardized ocean economy statistics. the development of the oeas is then described along with the accounts that the system is comprised of. the definition and value of the ocean industries in china and their relevant importance to the overall chinese economy are then compared to the definition for ocean economy industries in the us and europe. availability and easy access to a wide range of natural and economic data on a country's oceans and coastal regions is the basis for strategic decision-making on coastal and maritime policy [14] . in march 2011, china's 12th 5-year plan for national and social development (2011-2015) was released by central government and is currently being implemented. this is the first time that china has adopted a "five-year-plan" for economic development where "developing the ocean economy" has been identified as a key national development strategy. according to the 12th five-year plan (2011-2015), china's major objective in developing the ocean economy during the 2011-2015 period is to optimize the structure of the marine sector through the development of marine industries using scientific planning. the plan also has the aim of ensuring that marine resources are sustainably and reasonably utilized, that mechanisms of integrated marine management should be improved; that marine environmental protection and land-based pollution control should be coordinated; that the trend of excessive development of offshore resources will be controlled; that the management of any marine reclamation activities will be strengthened and that the protection and restoration of marine ecosystems should be promoted. the first measure above related to the optimization of the structure of the marine sector is of particular relevance to the research presented in this paper as the availability of a wide range of accessible data on ocean economic activities is necessary for achieving the efficient management of the marine economy. sustainable ocean and coastal management in china requires information on ocean industrial activities and socio-economic trends and on the environmental and coastal impacts of policies and financial instruments directed towards marine industries. the first real indication of china's interest in focusing on the ocean and coast, rather than on its hinterland, for potential economic growth, occurred in 2003 when the first guideline document for the development of its national marine economy was published by the state council. this document entitled "an outline of the planning of national marine economy development" targeted a gross value added figure for the chinese ocean economy of 4% of gdp in 2005 and approximately 5% in 2010. in the decade since this guidance document was published, and as can be seen in the results section of this paper, china's marine economy has been steadily approaching these targets. indeed, according to one of the few papers that profiled china's marine economy, the value of marine activity in 2008 was estimated at 9.87% of gdp [15] ,1 . at the coastal provincial level, five ocean economic zone development pilot plans have also been approved by china's central government for guangdong, shandong, zhejiang, fujian and tianjin [16] . the purpose of these pilot zones is to establish a new sustainable development pattern for china's coastal regions that are heavily involved in marine economic activities [17] . compared with the commercial development of land, there is a relative lack of experience in relation to ocean development in china. there are many aspects of this ocean zonal approach that needs to be explored, not least the need to balance increasing the economic opportunities from china's vast marine resources with the need to protect the marine environment. given this need, the chinese state department decided to choose some provinces as pilot marine economic development test sites. now within the top strategic plan for the country, the development plans for 11 ocean economic development zones have become national strategies in china [18] . in order to promote the development of what is seen as two strategically important marine industries; two national plans have also been released to boost the emerging ocean industries of seawater desalination and marine bio-medicine. in december 2012, the national development and reform commission issued the 12th five-year plan for seawater desalination; this is the first specific ocean industry five-year plan, which targets china's desalination where output is forecast to reach more than 2.2 million cubic meters/day by 2015. in order to accelerate the development of the 'bio-industry', at the very beginning of 2013, the chinese state council issued the 12th five-year plan for bioindustrial development, in which marine bio-medicine was identified as one of the key development areas. the most important part of these plans is that the central government will make available more opening financial, investment policies on ocean economy development. it can be predicted that with these five year plans in place these industries, and indeed all industries in the chinese ocean economy, will be given appropriate policy support that has not been available to the same degree up to this point. the policy makers in these industries and in the pilot marine economic zones will obviously require better quality baseline information related to the ocean economy than has been available previously. given the series of national strategies related to the development of the ocean economy reviewed above, it becomes very important to provide all marine policy makers, planners and decision makers with accessible and reliable information regarding the role of the ocean industries in local and 1 this is a larger estimate of the value of the ocean economy than presented in this paper for 2008 as this paper has examined only the data on the 12 major ocean industries in china whereas the figure of 9.87 includes ocean related industries (those enterprises that form a technical and economic link with the major marine industries) as well. national economies which ultimately should allow for better management and conservation of china' abundant marine resources. the methodology followed by the chinese national marine data and information service to quantify the size and composition of the ocean economy is very similar to the methodology employed by the us national oceans economic program (noep) as well as methodologies followed by other coastal countries that have analyzed their respective ocean economies, such as canada, australia and ireland [19] [20] [21] [22] . the chinese methodology is reviewed here but for a more in-depth discussion in relation to the developments in the chinese marine economic statistical system over the past 20 years the interested reader should see song et al. [13] . in that paper the authors argue that marine economic data gathering has gone from dispersed efforts to a concentrated approach, increasing from partial coverage of industry categories to comprehensive statistics and transitioning to more institutionalized management of marine economic statistics. they suggest that the practical significance of these developments is an improved national data set for the marine economy and policy makers that will continue to develop in the future. similar to the issues faced by the other countries that prepare ocean economy statistics, estimates of the value of the ocean industries in china are limited due to the definitional and data limitations. nevertheless, with the growing realization of the importance of marine economic activity to the wider chinese economy, china's oeas was established exclusively for ocean economy data collection in 2006 to meet the practical needs of ocean economic management. the system was developed and is operated by the chinese national marine data and information service within china's state oceanic administration. the oeas includes four basic parts, which are the principal account, the elementary account, the natural capital account and the green ocean account. the principal account, which is also called the gross ocean product (gop) account, is the most highly developed component within the system and is concerned with the identification and quantification of ocean economic activity. the elementary account is concerned with the development of an input-output matrix that disaggregates the major ocean industries from the standard industry classifications in the national input-output tables. this account also analyses the quantity and value of exports and imports through chinese sea ports and estimates the value of marine related capital. the third major account within the system is concerned with the assessment of the non-market values associated with china's marine resources. the green ocean account combines the market and non-market analysis from the principal and the natural capital accounts in order to provide policymakers with a holistic view of the overall value of china's ocean economy. the elementary account, the natural capital account and the green ocean account are still at an early stage of development. fig. 1 presents the framework of china's oeas. based on the oeas, this paper focuses on the principal account where the major ocean industries in china are defined and quantified. the basic goal of defining and quantifying major ocean industries within the elementary account of the oeas is to permit consistent measurement of the contribution of the ocean to the china economy across time and regions. similar to many other ocean economy reporting exercises [19] [20] [21] [22] , five basic steps are followed to quantify the chinese ocean economy: 1. source the data. in this step, the ocean economy activities are identified via government collected data within national accounts. these sources in china's case are outlined in section 4. this involves estimating the proportion of total economic activity within a particular sector that is ocean-related. for example, within the pharmaceutical sector a number of companies produce marine based bio-products. distinguishing between marine and non-marine businesses within such a sector requires a more disaggregated look at the profile of the companies within this sector. this involves recording the levels of value-added, employment and new measures for each industry that is identified within the marine sector. 4. identify gaps. certain ocean sectors are clearly identifiable within national account (for example marine transport and fishing) but for some other industries, in particular emerging ocean industries, accounting system it is more difficult to quantify the size and composition of the sectors. these industries and the data deficiencies need to be highlighted. estimate the value of the ocean economy relative to total economic activity in the wider economy. these five steps were applied to estimate china's ocean industries. as previously noted, identifying the marine activity in national accounts can be difficult and often requires additional national accounts manipulation [23] . examples of difficulties that can occur when trying to complete marine economic accounts include incomplete data on marine sectors, marine activities being part of statistical classes which also include non-marine businesses, indicators of marine activity being available at country level but not at local level and the issues surrounding the confidentiality of certain marine activities either for reasons of national security (in the case of defense) or for various other reasons, such as commercially sensitive activities or in cases where one business makes up too high a percentage of the total turnover of a given statistical class and can thus be too easily identified. these issues aside, colgan [24] proposes four principles for developing a robust profile of ocean industries: for example, the definition of a unit of employment should be the same across all locations and industries. industry data should be observed and measured in a consistent manner over successive time periods in order to allow for trend analysis. the data should reflect standard economic theory describing the measurement of economic activity. 4. replicability. the data should be replicable over time and form the basis of a future data series. in addition to the above, where possible the sectors identified and the method of quantification should be defined in such a manner so as to allow the data to be compared internationally. also the release of information on the state of the ocean economy should be timely. that is to say, the length of time between the marine economic activity or event taking place and the availability of statistical outputs related to that activity should be as short as possible to be of the most relevance to policymakers. this later principle is often not in the control of those attempting to assemble ocean economy accounts but depends on the time lags involved between the collection and dissemination of national accounts by central statistical agencies. as outlined above, defining the ocean industries in the chinese ocean economy is the first step towards quantifying the value of the ocean economy. in order to standardize the ocean economy data collected across the whole country, china's state oceanic administration released a document in 2006 defining the statistical standard for industrial classification for ocean industries and their related activities (gb/t 20794-2006). this document sought to establish a statistical standard for ocean economy data collecting across all regions in china. the ocean industrial classifications within this document divided the marine sector into two parts; ocean industries and ocean related industries. − ocean industries refers to industries involved in the production or supply of service for developing, utilizing and/or protecting the ocean. this part of the ocean economy includes 12 major marine industries such as offshore oil and gas, marine mining, marine salt manufacturing, the marine chemical industry, marine biomedicine, marine electric power generation, seawater utilization, marine shipbuilding, marine engineering and construction, marine communications and transportation, coastal tourism, marine scientific research, and education. − ocean-related industries refer to the enterprises that form a technical and economic link with the major marine industries. these industries are defined as suppliers and customers of the ocean industries; they produce inputs for the latter or use outputs from the latter in the production process. some of these activities are not necessarily performed at sea or even in the coastal zones. these industries include agriculture and mangrove forestry (that for example provide feed for marine use and that in turn use sea water to irrigate certain species of plants cultivated on chinese wetlands), marine equipment manufacturing, ocean-related building and installation, marine wholesale and retail services, etc. the ocean economy therefore, as defined by china's state oceanic administration's industrial classification for ocean industries and their related activities, is the summation of both ocean and ocean related industrial activities that are aimed at developing, utilizing and protecting the ocean. fig. 2 provides the relationship between the different layers that make up the chinese ocean economy in china. china's ocean economy includes three layers of content. the core layer represents 12 major ocean industries which are outlined in table 1 . they are the major ocean activities that use ocean resources as key inputs or which provide goods and services that are directly used in the marine environment. the support layer represents the scientific, research, education and ocean management service sectors that provide key information to the core layer industries. the activities of the support layer provide the platform for the sustainable development of the major ocean industries. the outer layer represents the ocean-related enterprises which have a technical and economic link with the major marine industries (the indirect and induced economic impacts of the core layer). in china's case, all relevant ocean industries cannot be directly identified within national statistical databases. measuring total ocean economic activity is therefore a complicated issue, especially when it is difficult to obtain sufficient base data for all possible ocean industries as is the case in china. this paper therefore focuses on the major ocean industries in china for which data is available. while some small and emerging sectors are excluded from the analysis presented in this paper, the industries analyzed still represent a high proportion of the total value of the market based ocean economy in china. the major ocean industries classified are marine fishery, offshore oil and gas, ocean mining, marine salt, shipbuilding, the marine chemical industry, marine biomedicine, marine engineering, marine electric power, the seawater utilization industry, marine communications and transportation and coastal tourism. the definitions of these industries in china are presented in table 1 ,2 . once the chinese ocean industries are defined, the data collection and quantifying phase begins. generally, the major ocean sectors and industries in china were defined based on the statistical classification of ccsnei (classification and code standard of national economy industry), which is quite similar to the naics (north american industrial classification system). the us national ocean economic program (noep) which compiles marine economic data in the us extracts their ocean economy data based on the naics. similarly, in europe, the relevant institutes in france, britain and ireland collect ocean economic statistics based on the nace (classification of economic activities of the european communities) coding system 3 . all government statistics programs in china are compiled on the basis of ccsnei. table 2 provides a comparison of definitions and codes for each of the ocean sectors reported in china and america (in the later case reported by the noep). in china's case, 12 industries are defined based on the 4-digit codes of ccsnei, while six ocean industries are defined by the us noep based on the 6-digit codes of naics. seven of china's defined ocean industries have corresponding classification in the usa ocean economy accounting system. however the corresponding classification in the us system is often at a higher level of aggregation. for example while the chinese system has separate categories for offshore oil and gas and offshore mining, in the us system these industries are grouped together under the heading of "minerals-offshore". the types of activities under the headings of offshore mining, shipbuilding and marine construction is also much broader in the chinese classification compared to the us one. as table 2 demonstrates, certain ocean industries are clearly identifiable within the chinese national accounts. indeed many of the major ocean industries have their own 4-digit ccsnei code (see for example marine fishing, seawater salt industry and submarine pipeline transportation). however, as mentioned in section 3, data on some ocean based activities is very difficult to obtain; for example, one cannot isolate marine chemical industries data from general chemical industry classification employed by the national bureau of statistics of china (nbsc). therefore, certain sub-sectors especially table 1 classification and definition of major ocean industries. marine fishery includes mariculture, marine fishing, marine fishery service industry and marine aquatic processing, etc. offshore oil and gas industry refers to production activities of exploring, exploiting, transporting and processing raw oil and natural gas in the ocean ocean mining industry includes the activities of extracting and dressing beach placers, beach soil chloride and sand, submarine geothermal energy, and coal mining and deep-sea mining, etc. refers to the activity of producing salt products with the sodium chloride as the main component by utilizing seawater, including salt extracting and processing shipbuilding industry refers to the activity of building ocean vessels, offshore fixed and floating equipment with metals or non-metals as main materials as well as repairing and dismantling ocean vessels marine chemical industry includes the production activities of chemical products of sea salt, seawater, sea algal and marine petroleum chemical industries marine biomedicine refers to the production, processing and manufacturing activities of marine based medicines and marine health care products by using organisms as raw materials (or by extracting these organism's useful components) marine engineering and building industry refers to the architectural projects construction and its preparations in the sea, at the sea bottom and seacoast for such uses as marine production, transportation, recreation, protection, etc., including constructions of seaports, coastal power stations, coastal dykes, marine tunnels and bridges, land terminals of offshore oil and gas fields as well as building of processing facilities, and installation of submarine pipelines and equipment, but not the projects of house building and renovation marine electric power refers to the activities of generating electric power in the coastal region by making use of ocean energies and ocean wind energy. it does not include the thermal and nuclear power generation in the coastal area seawater utilization refers to the activities of the direct use of sea water and the seawater desalination, including those of carrying out the production of desalination and applying the seawater as water for industrial cooling, urban domestic water, water for fire fighting etc., but not the activity of the multipurpose use of seawater chemical resources marine communications and transportation refers to the activities of carrying out and serving the sea transportations with vessels as main vehicles, including ocean-going passenger transportation, auxiliary activities of water transportation, pipeline transportation, loading, unloading and transport as well as other transportation and service activities coastal tourism refers to the tourist related activities that take place in the coastal zone, on sea islands as well as recreational activities that use the ocean; including water based sports, marine mammal and bird watching, etc. 3 in what follows the data extracted from these censuses and national accounts to quantify the size and composition of china's ocean economy is reported. in 2010 the major ocean industries had a combined value (in terms of gross value added (gva) 4 ) of us$239.09 billion 5 ; accounting for 4.03% of china's overall gdp. china's major ocean industries employed approximately 9.25 million individuals. table 3 presents the value added and employment for each major ocean industry within the china's ocean economy. in terms of gva, coastal tourism is the largest contributor to the overall value of the ocean economy with us$78.33 billion of value added. the marine communications and transportation industry is the next largest category producing us$55.92 billion. when it comes to employment, the marine fishery industry is the biggest contributor, employing 5.53 million individuals, followed by coastal tourism at 1.24 million and the marine communications and transportation industry at 0.81 million. in china's case, the coastal tourism, the marine communications and transportation industry and the marine fisheries industry dominate the ocean economy. these are categories that have also been found to dominate other ocean economies internationally [19] [20] [21] [22] . it would appear however that the high numbers employed in the fisheries sector relative to the other two dominant sectors is somewhat unique to china's ocean economy. since the data sources employed to quantify the ocean economy are also a historical record of the economic activities it is possible to analyze the growth (or otherwise) of the major ocean industries over time. the reduced growth rates in these two years reflect the fact that the major ocean industries are vulnerable to unexpected shocks to the economy. in 2003, the sars (severe acute respiratory syndrome) virus broke out in china. sars was the first severe and readily transmissible new disease to emerge in the 21st century [25] . this hit the chinese economy heavily, especially the industries involved in international trade. due to their export-oriented characteristics, the ocean industries were greatly affected. the fall in the growth rate of the ocean economy in 2009 was due to the financial crisis of 2007/2008, which is considered by many economists to be the worst financial crisis since the great depression of the 1930s [26] . a massive stimulus package from the chinese government saw the economy through the worst of the financial crisis but still the growth rates of national gdp went down significantly, especially for the ocean related industries. it would therefore appear that the major ocean industries are more vulnerable to the impact of unexpected events (e.g. the sars outbreak in 2003 and global recession in 2007) than the general economy. also any events impacting on international trade have a higher impact on the ocean economy. this is not surprising given, as mentioned in section 1, that seaborne commerce is an essential part of chinese trade; alone represented 10% of china's gross domestic product in 2008 [2] . [27] . the tourism sector bounced back strongly in 2004 due in part to a rescue package from the government that included tax rebates, employment and training measures and financial aid. also domestic and pan-asian tourism boards put in place action plans to revitalize the stricken sector. as mentioned above, when it came to the global financial crisis, the major chinese ocean industries also suffered severely in 2009, resulting in the decline of two important major ocean industries; the marine communication and transportation industry and the offshore oil and gas industry. the value of these sectors decreased by 8.51% and 39%, respectively, in 2009. the marine communication and transportation industry has long been the dominant support of china's international trade and continues to integrate markets between china and other countries. in the decade of 2001-2010, the marine communication and transportation industry had been growing rapidly due to the fast development of china's international trade. the only year that saw a decrease in the rate of growth of this sector was 2009. the offshore oil and gas industry is also a very important component of the ocean economy in china. in 2010, marine oil and gas output exceeded 50 million tons of oil equivalent, which makes china one of the world's major marine oil and gas producers. china's offshore exploration platforms are distributed both on coastal waters and in its deepwater territorial seas which increases the risk of ocean environmental pollution of the coastal area. the sharp drop in the value of the offshore oil and gas industry in 2009 was in line with global trends and was mainly due to the decline in international oil prices caused by the financial crisis. table 4 provides a comparison of the chinese ocean economy value (as a percentage of gdp) and employment figures to other ocean economies internationally. such comparisons, while interesting, can be misleading as the "marine/ocean" sector does not formally exist in most national accounts and as pointed out by semru [28] figures made available by national marine agencies are often based on different underlying definitions of the sector and different methods of collection of data and classification of activities into different categories. indeed, it is worth noting that all of the marine economic reports reviewed in table 4 recognize the limitations of official statistics-gathering procedures in capturing the importance of marine activities in their national economies. in general, the value added by ocean based activity to a country's national income is less than 5% of gdp. in france, ireland, the us and canada it is less than 2% of gdp. it should also be noted that the figures for france, the uk and canada include public sector marine related output such as defense, education and research. france has the longest running track record for publishing national marine economic accounts. ifremer publishes the marine economics assessment every two years for france. the 2011 version reported on in table 4 includes separate categories for the private and public sectors of the economy and estimates a total value for its ocean economy of $28.19 billion, representing 1.2% of gdp. the only country with a marginally higher share of marine activity in national gdp than china is britain at 4.2%. the one major difference between the marine economies in both countries driving this statistic is the relative importance of offshore oil and gas. in britain, offshore extraction of oil and gas is a substantial industry that makes a very important contribution to the uk economy. pugh [29] reports a gross value added (at current basic prices) for the offshore oil and gas sector in britain of £19,845 million. this figure represents 43% of the entire value of the ocean economy in britain whereas in china the offshore oil and gas sector represents only 8% of the total value of the ocean economy although activity in this particular field in china is likely to increase with a number of new exploratory offshore licenses being issued in recent years and proven substantial marine oil and gas reserves [5] . the comparison of china's ocean economy and the us ocean economy is worthy of further examination, given the comparative economic value and influence these two countries share. in 2010, the value added by ocean based sectors in these two countries are almost at the same level. in the usa it was reported as $266.72 billion while in china it was $239.09 billion. however, the share of the ocean based income in overall gdp is quite different, in china it is 4.03% (and this includes only the 12 major ocean industries classified in table 1 ) while in the us it is only 1.82% (based on the fact that the national gdp of the usa is almost twice that of china). it would also appear that the indicative employment in china's ocean economy is much larger than that of america. the discrepancy between the shares of employment in the sector and the share of ocean based activity in the countries respective gdp would appear to indicate that labor productivity might be relatively lower in the chinese ocean economy compared to the us ocean economy. however the real explanation is more likely to be reflected in the fact that in china 553,000 individuals are employed in the labor intensives primary production activity that is the marine fishery industry. in comparison, more persons are employed in higher value added industries in the us ocean economy. while shifting up this value added chain is an important objective for the chinese ocean economy sector (as can be seen in the government's support for emerging industries such as marine energy, marine bio-medicine and marine technology and the fact that industries using marine high technologies have been growing rapidly at an average annual rate of more than 20% in the last decade), the importance of the primary fisheries jobs to rural china in particular should not be underestimated. this paper builds on the work carried out by oeas in china, which established the framework of ocean economy accounting in china. it also demonstrates how it is possible to compile ocean economy data, from the existing government databases in china. the chinese ocean economy was divided into two separate parts for the purpose of the analysis presented; the ocean industry and ocean-related industry. data was collected for 12 major ocean industries. using a similar methodology to that developed in previous international studies, it was found that the major ocean industries produced us$239.09 billion in value added output in 2010 and accounted for 4.03% of china's national gdp. the major ocean industries were found to employ 9,253,000 individuals. this analysis also found that coastal tourism, marine communication and transportation industry and the marine fishing industry dominate in china's ocean economy. a time series analysis for the period 2001 to 2010 found that the chinese ocean economy follows a very similar growth path to that of the national economy. it would appear from the analysis however that given the international nature of the activities in the ocean economy, the major ocean industries demonstrate a higher level of vulnerability in terms of the impact of unexpected shocks to the economy. while this paper has undertaken an analysis of the chinese ocean economy, defining and quantifying the coastal economy in china is an area worthy of further research. in this case the chinese coastal economy could be defined as all activity which takes place in a predefined coastal area and would include all economic activity in the coastal region; however those areas and regions are defined. 6 this task is all the more relevant given the five ocean economic zones that have already been established in a number of china's coastal provinces, with more in the development pipeline. along with the ocean economy information described in this paper such coastal economy statistics would allow policy makers, planners and government to make more informed coastal planning and marine environment management decisions. due to the rapid development of marine science and technology in recent years, all kinds of new marine industries are emerging and thereby expanding the scope of the marine economy. therefore, further research is required in order to establish an appropriate methodology for the classification and collection of economic data for these emerging ocean industries-data that is very difficult to extract from national economic accounts. as colgan [24] points out "knowledge of the marine economy is very imprecise because little has been invested in developing the needed data, especially in comparison with the investment in the understanding of other natural resources". the adoption of the "developing the ocean economy" strategy and the establishment of five ocean economy pilot test sites by the chinese government were in recognition of the importance of marine activity to the economy in china. this increased focus on the ocean economy means policy-makers require accessible and reliable information regarding the role of the ocean industries in the wider economy [2] . with the implementation of the ocean-related plans, the goal of "developing the ocean economy" is occurring at a rapid pace. this rapid development however requires detailed information on the marine activities that policy makers can use to ensure that the development is sustainable and does not jeopardize other marine policy goals especially in relation to the marine environment and the conservation of marine species. in the past china's traditional model of development was characterised by the extensive exploitation of marine resources and spaces particularly in regards to the extraction of marine life for human consumption. intense competition among coastal provinces in relation to the developing of traditional marine industries such as fishing, aquaculture and port activity was another feature of chinese marine development in the past. indeed it could be argued that the establishment of container terminals in all provinces has not been an efficient use of valuable coastal resources in china. the new model of marine development in china places a higher value on the management and conservation of marine resources and ecosystem functions and recognises the importance of these resources to the new emerging marine industries and to coastal tourism in particular. the collection, compilation and management of socio-economic data for the various marine sectors is an important element of the information system required for promoting this more sustainable approach to marine policy. work has also been done internationally in establishing the value of the non-market ecosystem services from marine resources (and/or ecosystem functions) so that they may be accounted for in marine policy decision making. this however has not generally been the case in china. if the country truly wishes to underpin the value of the marine economic activity and the many biotechnology and other opportunities associated with it, with the quality of the country's marine environment then significant investment will be required in research aimed at establishing the non-market or public good element of the total economic value of marine resources in china. noaa report on the ocean and great lakes economy of the united states ocean development strategy research study group. china's ocean development report state oceanic administration state oceanic administration of china. national island protection plan. beijing: state oceanic administration publication state oceanic administration of china. national marine function zoning plan (2011-2020). beijing: state oceanic administration publication outline of the planning of national marine economy development. beijing: state oceanic administration publication sea power and the chinese state: china's maritime ambitions oil imports hit alarming level in china: study. chinese daily canada's oceans strategy. fisheries and oceans canada publication joint ocean commission initiative. america's ocean future. joint ocean commission initiative publication harnessing our ocean wealth-an integrated marine plan for ireland state oceanic administration of china. china ocean agenda 21 studies on marine economic accounting system and methodology from behind the great wall: the development of statistics on the marine economy in china defining standard statistical coastal regions for ireland an analysis on the contribution of ocean economy to the national economic development of china state oceanic administration of china. national oceanic development 12th five-year plan. beijing: state oceanic administration publication a detailed explanation of national marine economic development pilot projects ocean development strategy research study group. china's ocean development report state oceanic administration state of the us ocean and coastal economies 2009 s ocean industries: contribution to the economy 1988-2000. prepared for the economic and policy analysis division, department of fisheries and oceans by the economic contribution of australia's marine industries quantifying the value of multi-sectoral marine commercial activity in ireland the importance of estimating the contribution of the oceans to national economies measurement of the ocean and coastal economy: theory and methods. usa: national ocean economics project world health organization communicable disease surveillance and response. severe acute respiratory syndrome (sars): status of the outbreak and lessons for the immediate future. world health organization publication sovereign credit risk in the eurozone the effects of sars on the chinese tourism industry socio-economic indicators of marine-related activities in the uk economy. london: the crown estate marine economics department, ifremer new zealand's marine economy 1997 to 2002. an experimental series report by statistics this research was supported through the chinese ocean economy accounting system project which was started by the chinese national marine data & information service in 2006. rui zhao and stephen hynes were based at the center of the blue economy in the monterey institute of international studies in monterey, california during the writing up of this paper. dr. hynes was on placement at the center as a fulbright scholar. the authors would also like to thank judy kildow and jason scorse for their assistance. key: cord-322982-c4xhg567 authors: patou, m.‐l.; chen, j.; cosson, l.; andersen, d. h.; cruaud, c.; couloux, a.; randi, e.; zhang, s.; veron, g. title: low genetic diversity in the masked palm civet paguma larvata (viverridae) date: 2009-04-17 journal: j zool (1987) doi: 10.1111/j.1469-7998.2009.00570.x sha: doc_id: 322982 cord_uid: c4xhg567 the masked palm civet is distributed through south‐east asia, china and the himalayas. because of its potential role in the severe acute respiratory syndrome (sars) epidemic, it has become important to gather information on this species, and notably to provide a tool to determine the origin of farm and market animals. for this purpose, we studied the genetic variability and the phylogeographic pattern of the masked palm civet paguma larvata. first, two portions of mitochondrial genes, cytochrome b and the control region, were sequenced for a total of 76 individuals sampled from china, the indochinese region and the sundaic region. results indicated a low genetic variability and suggested a lack of a phylogeographic structure in this species, which do not allow inferring the geographic origin of samples of unknown origin, although it is possible to distinguish individuals from china and the sundaic region. this low variation is in contrast to the well‐marked morphological differentiation between the populations in the sundaic and chinese–indochinese regions. we also used five microsatellite loci to genotype 149 samples from two wild and four farmed populations in china, where the masked palm civet is farmed and where the sars coronavirus was isolated. these analyses also showed a reduced variability in chinese civets and showed that farmed populations did not exhibit a lower genetic diversity than wild populations, suggesting frequent introductions of wild individuals into farms. the masked palm civet paguma larvata (mammalia, carnivora, viverridae) is distributed in tropical and subtropical zones across the himalayas, china, indochina, the malay peninsula, sumatra and borneo (jennings & veron, 2009; fig. 1) . in china, it is mainly distributed in the southern regions, but it can also be found in hubei, shaanxi, shanxi, sichuan and xizang provinces (gao, 1987; wang, 2003; smith & xie, 2008) . the species has been introduced to japan (corbet & hill, 1992) . there is no recent taxonomic revision of this species and no consensus on the validity of subspecies. based mainly on facial pattern and body colour, up to 15 subspecies of masked palm civet have been recognized (wozencraft, 2005) , and up to nine in china (jiang, li & zeng, 2003) . although quite common in the original habitat, the masked palm civet may face a serious threat of local extinction due to habitat destruction and hunting (sodhi et al., 2004; steinmetz, chutipong & seuaturien, 2006) . in robertson & hunter, 2004) , it is vital to develop a tool to identify their geographic origin. although the sars-like cov has now been discovered in horseshoe bats as well (li et al., 2005a,b) , song et al. (2005) have described the role played by masked palm civets as intermediate hosts during the 2003/2004 outbreak in guangdong. however, the origin of this virus is still debated (see li et al., 2005a,b; janies et al., 2008) . the purpose of the present study was to evaluate the genetic diversity in the masked palm civet and to provide a phylogeographic pattern in order to determine the geographic origin of farm and market civets. this may allow for future comparisons of the species' population structure with the occurrence of the virus in its population. for this purpose, we sequenced a portion of two mitochondrial genes, the cytochrome b (cytb) and the control region (cr), both shown to be suitable markers for carnivore species phylogeography (e.g. li et al., 2005a,b; marmi et al., 2006; cosson et al., 2007; veron et al., 2007) , and analysed five polymorphic microsatellite markers in chinese wild and farmed populations. for the mitochondrial study, 76 hair and tissue samples (see table 1 ) were obtained from different parts of the range of the masked palm civet, from various sources (see acknowledgments) or collected by the authors. two individuals of common palm civet paradoxurus hermaphroditus were used as an outgroup according to patou et al. (2008) . for the microsatellite study, the sampling was expanded to 149 individuals from china only. they were sampled from two wild and four farm populations, as follows: one wild population from the south-east of sichuan province north-west of the liangshan mountain range (from xihua university museum) (n = 17); one wild population from houhe national nature reserve in hubei (n = 49); four farm populations: nibin farm in sichuan province (n = 20); wufeng farm in hubei province (n = 23); quwo farm in shanxi province (n= 12); rongxian farm in guangxi province (n = 28). natural distribution of the masked palm civet paguma larvata, in grey. molecular sampling is denoted on this map by the circles (whose size is proportional to the sampling's size). the colour of circles indicates the different genetic groups retrieved. the extraction and pcr procedures are the same as those described in cosson et al. (2007) . the 3 0 end of cytb (c. 150 bp) and the cr from the 5 0 end down to the second variable domain (c. 850 bp) were amplified using the following primers for amplification and sequencing: l126: 5 0 -cga agcataatattccgac-3 0 , h526: 5 0 -acatactggg caagcacag-3 0 (this study), lcr1 and hcr2 (cosson et al., 2007) ; l400: 5 0 -taatcgctagtccccatgaa-3 0 , h810: 5 0 -ctgcgtcgagacctttacg-3 0 , lcr2: 5 0 -gt acctcttctcgctccggg-3 0 , hsc2: 5 0 -ttgtttgtg gggtttggcaaga-3 0 , l840: 5 0 -catgtagctggact tattct-3 0 and h1340: 5 0 -gttcatatttcaccatggg gttaac-3 0 (this study). the fragments amplified using these primers pairs overlap for about 100 bp, allowing for appropriate assembling of the cr sequence. pcr products were visualized in a 1.5% agarose gel to check for expected size of fragments and specific amplification. positive pcr products were purified using the 'qiaquick pcr purification kit' (qiagen, holden, germany). both strands (light and heavy) were sequenced in all cases using an automated dna sequencer (abi3100, applied biosystems, foster city, ca, usa). sequences were treated using sequencher 4.14 (gene codes corporation, ann harbor, mi, usa) and then the blastn 2.2.14 program (altschul et al., 1997) to check for contamination. sequences were aligned in bioedit (hall, 1999) . five polymorphic microsatellite markers were isolated and characterized (see chen et al., 2008) , and were used for screening the two wild populations and four farm populations in china. for genotyping of the samples, pcr products were electrophoresed using an abi 3100 dna sequencer. the fragment length of the pcr products was determined with genescan (version 2.1, applied biosystems), and marker genotypes were assigned to the animals using genotyper (version 2.5, applied biosystems). phylogenetic analyses were performed using bayesian inference (bi). parameters were set according to mrmodeltest 2.0 (nylander, 2004) . bi analyses were performed with mrbayes version 3.1 (ronquist & huelsenbeck, 2003) using 5 000 000 generations and five metropolis-coupled markov chains monte carlo (mcmcmc) with nodal support assessed by bayesian posterior probabilities (bpp). the burn-in period was chosen after having explored output parameters with tracer v 1.3 (rambaut & drummond, 2004) . analyses were run twice to ensure convergence of the results. we used the arlequin 2.0 software (excoffier, laval & schneider, 2005) to carry out several analyses: (1) analysis of molecular variance (amova, excoffier, smouse & quattro, 1992) to test for genetic differentiation between putative geographical regions and (2) computation of haplotypic as well as nucleotidic diversity (p) for each of the groups. in the absence of clear partitions retrieved by the phylogenetic analyses, amova were performed for different putative geographical partitions to see which could better describe our data that is find the partition that minimizes the intra-population variability and maximizes the inter-population variability. several geographical partitions were tested: (1) group 1: 'china' versus group 2: 'indochinese region and allies'+'sundaic region'; (2) group 1: 'china'+ 'sundaic region' versus group 2: 'indochinese region and allies'; (3) group 1: 'china'+'indochinese region and allies' versus group 2: 'sundaic region'. as two chinese haplogroups were suggested, partitions were also attempted with these two distinct groups but this did not improve the description of our data significantly. specimens from japan (c-399; ml-372; ml-373; ml-374), hong kong (ml-375) and taiwan (l-46; l-47; l-48) were included in the same group as vietnamese samples (c-317; l-51; c-292; l-59) as they share their haplotype. a mismatch distribution of the pairwise differences among haplotypes was produced to test for the hypothesis of a sudden population expansion. genetic distances among samples were computed using mega v 3.1 (kumar, tamura & nei, 2004) under the kimura two parameters (k2p) model. the software tcs (clement, posada & crandall, 2000) was used to reconstruct a haplotype network using the statistical parsimony method with a 95% confidence interval and gaps were treated as missing data. some ambiguities (loops) were observed in the network. they were resolved using an empirical criterion derived from the coalescent theory that is the frequency, topological and geographical criteria identified by pfenninger & posada (2002) . allele frequencies, the mean number of alleles per locus, observed heterozygosity (h o ) and expected heterozygosity (h e ) were computed using the genetix software package (belkhir et al., 1996) . comparison of alleles' number between different sample sizes and measurement of the allelic richness (i.e. number of alleles independent of sample size) were performed using the program fstat v 2.9.3 (goudet, 2001) . a hardy-weinberg (hw) test for each locus in each population and global tests for all populations were performed with genepop (raymond & rousset, 1995) . the program fstat was also used to test for linkage disequilibrium (ld) between the polymorphic loci within each species and calculate two different measures of the genetic differentiation over subpopulations (f st , kimura & crow, 1964 ; r st , kimura & ohta, 1978) as well as inbreeding coefficients (f is ). the sequential bonferroni correction was applied to derive significance levels for the analysis involving multiple comparisons (rice & gaines, 1989) . the genetic divergence between each pair of six palm civet populations based on allele frequencies was calculated according to nei's d a genetic distance (nei, tajima & tateno, 1983) using population v 1.2.28 (http://www.cnrs-gif.fr). genetic distances; trees were also constructed from these genetic distances values using the neighbour-joining clustering (saitou & nei, 1987) . bootstrap re-sampling (n = 1000) was performed to assess the robustness of dendrogram topologies. we also used a clustering method that does not use a spatial prior, as implemented in structure 2.0 (pritchard, stephens & donnelly, 2000) , to detect the maximum number of populations (k), five independent runs of k= 1-6 were performed with 1 â 10 6 mcmc repeats and a burn-in of 1 â 10 6 . k was identified using the maximal values of ln p (d) (the posterior probability of the data for a given k). moreover, the program bottleneck v1.2.02 was used to test for heterozygosity excess and to determine whether allele distributions within populations had been affected by recent changes in the size of the two wild populations (cornuet & luikart, 1996; luikart & cornuet, 1998) . we gathered portions of cytb and cr sequences for 76 specimens of pag. larvata (genbank accession numbers eu910377-eu910531; table 1 ). for a few samples, we were unable to obtain the complete sequence owing to the dna's quality. the 3 0 end of the cr was composed of highly repeated dinucleotidic motifs (ca), whose number differed for each individual and was excluded from the analyses. we thus used a composite fragment located at and positions (plus a short fragment between these two boundaries) of the javan mongoose complete mitochondrial genome (herpestes javanicus ay873843, penny & mclenachan, 2005) corresponding to the 3 0 end region of the cytb (c. 150 bp), the first hyper-variable region (hvr1) and the central conserved domain of the cr. these parts of the cr did not give any alignment problems and were thus aligned by eye. the dataset included 811 characters and 26 parsimonyinformative sites. the consensus tree provided in bi (model: hky+i+g including two substitutions' categories and a burn-in period fixed at 3000 generations) yielded a polytomy with few supported clades (fig. 2) . the monophyly of pag. larvata was strongly supported (bpp = 1.00), and a few clades were well supported: (1) among the three partitions tested for amovas, partition (1) (china vs. the remaining regions) was the one that maximized the percentage of variation (c. 19.6%), explained by differences among groups while within-population variations still explained c. 70% of the total variation. these results suggested that the chinese group was the most differentiated group among the three. this was also reflected by the pairwise f st (f st china/sundaic = 0.035; f st china/ indochina = 0.025; f st sundaic/indochina = 0.014). each of the three groups exhibited almost the same genetic characteristics (table 2) . genetic distances ranged from 0 to 2.5% within the species, with a mean pairwise genetic distance of 0.57%. the mismatch distribution, including all specimens (fig. 3) , yielded a unimodal distribution corresponding to the expected distribution in case of a rapid population expansion. the 76 individuals corresponded to 50 haplotypes differing from 1 to 15 mutations (see fig. 1 for the geographical distribution of these haplotypes). the haplotype network (fig. 4) was rooted by haplotype l-97 (sichuan province). individuals from the sundaic region were all connected to this haplotype, exhibiting a star-like structure. one of the sundaic individuals (l-50, singapore) was connected by a higher number of mutations (n = 5) to the root haplotype. indochinese region and allies' (japan, hong kong and taiwan) individuals were nested within the network and were poorly differentiated from the chinese individuals. we noticed one distinct indochinese individual (l-16) from northern laos, differing from the root haplotype by four mutations. for the chinese group, no geographical structure (either between the different chinese provinces or 0.01 l71hunf between the different farms) was retrieved. an important result was the fact that individuals from the sundaic region were not directly connected to the chinese haplogroups, while individuals from the indochinese region and allies were connected to both chinese and sundaic individuals. the five loci were highly polymorphic in pag. larvata with 43 alleles observed and the allele number for each locus ranging from 3 (pc119) to 14 (pc58) ( table 3) . allele frequency distributions showed 9 rare (o5%) of a total of 43 alleles summed over loci, for a mean of 20.9%. the overall f is values per locus ranged from à0.028 (pc119) to 0.204 (pc14), showing an overall f is of 0.111 (table 3) . pairwise f st values for different civet populations ranged from à0.001 to 0.132, and no pairwise f st value differed significantly from zero. the guangxi and hubei farms and hubei wild populations showed a high degree of genetic diversity (table 4 ). in contrast, the lowest genetic diversity was observed in the shanxi farm population and the sichuan wild population in all measures of genetic diversity. the results of the hw equilibrium test (table 5) , computed at each locus showed that 26 of 30 locus-population combinations deviated from the hw equilibrium (po0.05) after correction for multiple tests across populations and loci. almost all the deviated cases are related to the positive f is , indicating an hw equilibrium deviation in the direction of the heterozygote deficit. significant ld was only found between loci pc14 and pc58 in the wild hubei population. the genetic distances ranged from 0.042 (hubei wild and farm populations) to 0.238 (sichuan and shanxi farm populations) ( table 6 ). the pairwise f st ranged from à0.001 (hubei wild and farm populations) to 0.132 (shanxi and sichuan farm populations) ( table 6) . a genetic distance tree of the six civet populations (fig. 5 ) was reconstructed and yielded three highly supported distinct lineages (bootstrap values of 100): (1) hubei wild and farm populations were grouped together; (2) the sichuan wild population and the shanxi farm population clustered with the guangxi farm population; (3) the sichuan farm population was separate from these two branches. however, no structure was identified in the bayesian clustering analysis (the maximal values of ln p (d) =à2034.9 for a given k= 1) implemented in structure. according to the wilcoxon sign-rank test, under the infinite allele model, stepwise mutation model and two-phase model, for the two wild populations neither of the p-values approached significance of heterozygote excess at the 5% level. the two wild populations exhibited a normal allele frequency distribution shape. genetic tests for a population bottleneck performed on each of the two wild populations provided no significant genetic signature of populations' decline. the genetic divergence among the studied pag. larvata populations was quite low (mean pairwise genetic distance c. 0.6%) and did not express any clear phylogeographic signal. the sequenced markers (cytb and cr) are usually variable in other carnivores (see studies by davison et al., 2001; cosson et al., 2007; tchaicka et al., 2007 ; but see pe´rez-haro et al., 2005) . comparatively, for a similar cr fragment (hvri, 346 bp), the variability was lower in the masked palm civet than in closely related species: the binturong arctictis binturong (cosson et al., 2007) and the common palm civet par. hermaphroditus (patou et al., unpubl. data) . the genetic variability in masked palm civets was also explored in a nuclear gene (nuclear intron 7 of the b-fibrinogen; m.-l. patou, unpubl. data) , which also showed low variability (mean pairwise genetic distance c. 0.3%). comparable results were obtained for the complete cytb gene by j. chen (unpubl. data) and masuda et al. (2008) . moreover, the microsatellite analyses did not contradict these findings. these molecular results were in contrast with the marked morphological differences observed among the masked palm civet populations (pocock, 1934a,b; g. veron, pers. obs.) , suggesting unlinked evolutionary mechanisms at the molecular and morphological levels in this species. in fact, the relationships between morphological and molecular evolution have long been debated (e.g. omland, 1997; bromham et al., 2002) . an empirical study on rodents (renaud, chevret & michaux, 2007) concluded that correlations between morphological and molecular evolution can be lost when organisms had to answer to an ecological change. in this case, morphological changes may occur rapidly (as observed in specialized taxa; e.g. semi-aquatic genet genetta piscivora, which exhibits very distinctive morphological features but small genetic distance values to other genets, gaubert et al., 2004) . in the masked palm civet, two main morphotypes can be distinguished and their distribution limit appears to be located in southern thailand by the study of a high number of museum specimens (n = 225; from amnh, new york; bmnh, london; mcz, cambridge; mnhn, paris; usnm, washington; institute of zoology, beijing; and observation of wild and captive individuals, g. veron, pers. obs.). specimens from malaysia and indonesia do not have the black and white head pattern, but have a yellowish face, and their body colour is dark brown. specimens from the other parts of the range display the typical black and white head pattern with a conspicuous white longitudinal band on the nose, and the body colour is lighter, varying from beige, yellowish and grey to light brown. the northern morphotype seems to display much more variability in the colour and head pattern than the southern one. the head and body length of the northern and southern morphotypes does overlap, while hainan and taiwan specimens are smaller (head and body length not exceeding 540 and 600 cm, respectively) than specimens from other populations (head and body length up to 790 cm). however, despite the low variability and lack of structure, in our molecular results, none of the sundaic individuals was found in the china-indochina clade, suggesting a putative population subdivision. three haplogroups of masked palm civets were suggested through our analyses: (1) sundaland, (2) the indochinese region, japan, hong kong and taiwan, poorly differentiated from (3) china. the indochinese region and allies haplogroup was connected to the other two. in general, haplotypes were not highly differentiated from each other, with few missing intermediates inferred. the sundaic haplogroup exhibited a high number of haplotypes relative to the low number of samples. besides, one haplotype (l-50 from singapore) appeared to be quite divergent. this suggested a putative variability in this region. diverging haplotypes were also found in vietnam and northern laos (l-16). individuals from taiwan, hong kong and japan shared haplotypes with vietnamese samples. taiwan and hong kong individuals were closely related to those from vietnam, rather than to chinese civets, as could have been expected. however, taiwan and hong kong masked palm civets were not believed to have been introduced. the subspecies from taiwan, whose most striking morphological difference is the smaller size, cannot be validated from our results. in japan, although several authors suggest that the masked palm civet may be native (sasaki, 1991; masuda et al., 2008) , there are clear mentions of introductions (e.g. kuroda, 1955; dobson, 1994) . they took place in the 1940s, but the exact date is unclear (kuroda, 1955; nawa, 1965) . civets were believed to come from taiwan or south china and brought as cage animals (kuroda, 1955) . in our study, except for one individual (c-399), which was only connected to the root haplotype, other samples from japan shared haplotypes with vietnam and taiwan individuals or were closely linked to them. this result could support an indochinese origin for the japanese civets. our results did not support a sundaic or a chinese origin. the poor variability exhibited by the chinese individuals as well as the shape of the mismatch distribution suggested a recent population expansion. on the other hand, wilcoxon's test did not suggest the occurrence of a bottleneck. the expansion could be a natural northern expansion during pleistocene as suggested by tong (2006) , or a more recent expansion due to human activity and notably by moving these animals for the farming and consumption purposes. civet trade is important (bell et al., 2004) and farming in china was conducted on a large scale. we found no museum specimens (n = 225) having localities more northerly than 3019'n. corbet & hill (1992) mapped the distribution up to 3510'n in china; nowadays, the species is recorded as far north as 3919'n (zhang, 1997) . the lack of genetic variability and of structure within the chinese samples does not agree with the division of the chinese populations into nine subspecies as suggested by gao (1987) and jiang et al. (2003) , and, in fact, the morphological evidence does not support this subdivision either. our microsatellite analysis results suggested a reduced population subdivision across the six chinese populations studied. the mean f st value of 0.035 from all loci indicated that 96.5% of the genetic variation was explained by the differences among individuals and 3.5% by the differentiation among populations. the greatest genetic differentiation occurred between shanxi and sichuan farm populations (f st = 0.132), which indicated that perhaps they originated from two distinct populations. the lowest genetic differentiation occurred between hubei wild and farm populations (f st =à0.001), which was consistent with the fact that all individuals in hubei farm were cultured many years ago from the hubei wild population. there was also reduced differentiation between the hubei and the sichuan wild populations (f st = 0.018). we are uncertain whether this value was an accurate measure of the level of genetic differentiation between different civet subspecies. to fully address this issue, however, more rigorous investigation with a greater number of samples from different wild populations will be needed. the results of this study showed that the farm civet populations did not exhibit a lower genetic diversity than the wild populations in china. wild civet populations were an important genetic resource for farm populations. many local farms introduced different wild populations and crossbred these with local populations, which resulted in a genetic exchange between different populations. whether captive breeding was beneficial or harmful for native civet populations is unknown, but this practice may accelerate the crossbreeding and genetic exchange between different populations. the low genetic diversity of mitochondrial dna and the lack of a structure among the masked palm civet populations did not allow inferring the geographic origin of an animal with unknown origin. indeed, we found no molecular evidence supporting the monophyly of any particular clade matching with a peculiar farm, chinese province or geographical region, and our results did not support any subspecies subdivision. however, three main haplogroups were put forward while the individuals from malaysia and indonesia exhibited a putatively higher genetic diversity. the chinese farmed populations did not exhibit a lower genetic diversity than the chinese wild populations, and this probably resulted from bringing in new wild individuals regularly. by these captures, the wild population may be at risk. the discovery of the sars-like cov in masked palm civets in the southern china markets has led to the interdiction of the farming of this species. whether this has not been replaced by increased local trapping and wildlife traffic is unknown, but should be considered. gapped blast and psi-blast: a new generation of protein database search programs genetix4.05. available at animal origin of sars 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disaster cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human. proc. natl. acad. sci collaborating to conserve large mammals in southeast asia conservation and economic importance of the mustelids and viverrids in china phylogeography and population history of the crab-eating fox (cerdocyon thous) mammalian faunal differentiations between north and south china during the quaternary period systematic status and biogeography of the javan and small indian mongooses (herpestidae, carnivora) a complete checklist of mammal species and subspecies in china, a taxonomic and geographic reference order carnivora. in mammal species of the world distribution of mammalian species in china we thank the following people for their contribution and/or for having kindly supplied samples: wang hanzhong (wuhan institute key: cord-322908-e3gok0ot authors: huang, fangfang; li, ying; leung, elaine lai-han; liu, xiaohua; liu, kaifeng; wang, qu; lan, yongqi; li, xiaoling; yu, haibing; cu, liao; luo, hui; luo, lianxiang title: a review of therapeutic agents and chinese herbal medicines against sars-cov-2 (covid-19) date: 2020-05-20 journal: pharmacol res doi: 10.1016/j.phrs.2020.104929 sha: doc_id: 322908 cord_uid: e3gok0ot the epidemic of pneumonia (covid-19) caused by novel coronavirus (sars-cov-2) infection has been listed as a public health emergency of international concern by the world health organization (who), and its harm degree is defined as a global “pandemic”. at present, the efforts of various countries focus on the rapid diagnosis and isolation of patients, as well as to find a treatment that can combat the most serious impact of the disease. the number of reported covid-19 virus infections is still increasing. unfortunately, no drugs or vaccines have been approved for the treatment of human coronaviruses, but there is an urgent need for in-depth research on emerging human infectious coronaviruses. clarification transmission routes and pathogenic mechanisms, and identification of potential drug treatment targets will promote the development of effective prevention and treatment measures. in the absence of confirmed effective treatments, due to public health emergencies, it is essential to study the possible effects of existing approved antivirals drugs or chinese herbal medicines for sars-cov-2. this review summarizes the epidemiological characteristics, pathogenesis, virus structure and targeting strategies of covid-19. meanwhile, this review also focus on the re-purposing of clinically approved drugs and chinese herbal medicines that may be used to treat covid-19 and provide new ideas for the discovery of small molecular compounds with potential therapeutic effects on novel covid-19. broad-spectrum antiviral drug in the prevention and treatment of malaria [34] . cq/hcq block viral from entering into cells by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification, as well as regulate immunity through attenuation of cytokine production, inhibition of autophagy and lysosomal activity in host cells [35, 36] . cq can inhibit sars-cov-2 infection at a low-micro molar concentration and hcq is more potent than cq [37, 38] . a multicenter clinical trial involving more than a dozen hospitals in china showed that cq can improve radiologic findings, enhance viral clearance and reduce disease progression in the treatment of patients with covid-19, so china has included cq in the recommendations regarding the prevention and treatment of covid-19 [37, 39, 40] . at the same time, another clinical trial showed that hcq can significantly shorten the clinical recovery time and promote the absorption of pneumonia among patients with covid-19 [41] . notably, azithromycin reinforced the effect of cq/hcq in covid-19 patients, but the publishing journal's society subsequently declared that the trial did "not meet the society's expected standard" [42, 43] . conversely, the higher cq dosage should not be recommended for critically ill patients with covid-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir [44, 45] . in summary, although cq/hcq have shown anti-sars-cov-2 efficacy both in vivo and in vitro trials as well as relatively well tolerated, some clinical trial designs and outcome data have not been submitted or published to peer review [46] . it is not recommended in the use of cq/hcq for covid-19 outside of the hospital or a clinical trial due to lack of reliable efficacy data and potential toxic effects [47, 48] . remdesivir (gs-5734), a prodrug of gs-441524 developed by the american pharmaceutical company gilead sciences, showed promise at the peak of the ebola virus outbreak due to its low ec50 and host polymerase selectivity against the ebola virus [49, 50] . subsequently, research about it also showed significant anti-sars-cov and mers-cov activity [51, 52] . as a nucleoside analog with exonuclease resistance, remdesivir is metabolized to active nucleoside triphosphates that effectively prevents the elongation of the rna chain by inhibiting rna polymerase, but will not be digested with a viral exonuclease (nsp14) with proofreading activity [53] . compared with ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and favipiravir (t-705), remdesivir j o u r n a l p r e -p r o o f has the best efficacy and the lowest toxic side effects on anti-sars-cov-2 in vero e6 cells [32] . the united states first reported the clinical case of remdesivir in the treatment of sars-cov-2 associated pneumonia [54] . currently, a number of clinical trials are ongoing, aiming to verify the safety and antiviral activity of remdesivir in the treatment of covid-19. clinical findings of the team of professor cao bin of the china-japan friendship hospital suggested that the remdesivir is adequately tolerated but do not provide significant clinical or antiviral effects in severe patients with covid-19 [55] . however, the results of the global clinical trial are believed that remdesivir can relieve symptoms and reduce mortality, especially for patients in intensive care who require mechanical ventilation [56] . meanwhile, the clinical trials in chicago have suggested that early covid-19 patients benefit more due to the reduction of lung damage [57] . in conclusion, remdesivir is still in the consideration of one of the most promising drugs for treatment covid-19 currently [58] . lopinavir/ritonavir (lpv/r), also known as kaletra, is an oral combination agent for treating hiv approved by the fda, which has shown anti-coronavirus efficacy in studies of sars and mers [59] [60] [61] [62] . as a new protease inhibitor, lpv/r interrupts viral nucleic acid replication via inhibition of 3clpro [63] . xushun guo's team at sun yat-sen university school of medicine derived a homology modeling to confirm that lpv/r significantly inhibited the function of cep_c30 to prevent the sars-cov-2 reproduction cycle [64] . in addition, two groups in china and korea have reported lpv/r can improve the clinical symptoms of patients with covid-19 [65, 66] . besides, lpv/r can achieve better antiviral effects when used with interferon or ninavir than alone [67] . however, the latest evidence suggests that it may cause liver damage and prolong hospital stay in the covid-19 infected patients [68] . furthermore, no benefit was observed with lpv/r treatment beyond standard care in hospitalized adult patients with severe covid-19 [69] . therefore, whether lpv/r can become an important adjuvant drug in anti-sars-cov-2 therapy and improve the clinical outcome of patients remains to be determined. j o u r n a l p r e -p r o o f previously, we summarized small molecules currently used/planned to treat covid-19, which may be an important short-term strategy for the treatment of covid-19, but their efficacy and safety in covid-19 need to be further confirmed by clinical trials. drug development against covid-19 appears to be crucial in the context of a rapidly evolving epidemic, however, the conventional development of new drugs is time-consuming with safety concern. therefore, it seems unrealistic to synthesize new drugs and perform safety and toxicity tests over a short period of time. antiviral therapy with chinese herbal medicines have been recorded for a long time in chinese history, and previous studies have shown that chinese herbal medicines have great potential for preventing sars transmission [105] . given the low toxicity and availability of chinese herbal medicines, screening active compounds targeting viral or host targets from chinese herbal medicines may be a potential strategy for treating covid-19. in this review, we summarized potential chinese herbal medicines ( table 2 ) that may treat covid-19 by targeting proteins such as spike protein, ace2, 3clpro, plpro and rdrp. we also predicted the binding affinities between these compounds and covid-19 related targets by molecular docking, with a focus on six compounds: quercetin, andrographolide, glycyrrhizic acid, baicalin, patchouli alcohol, and luteolin. and the binding patterns of these six compounds to the key targets of sars-cov-2 are shown in figure 2 . quercetin, a flavonoid compound, is widespread in fruit and vegetables. as a dietary source compound, quercetin exerts diverse biological activities including anti-inflammatory, anti-oxidant, anti-viral, anti-allergic, anti-cancer, mood-improving as well as vasoprotective [106] [107] [108] . studies have found that quercetin exhibits antiviral properties against a variety of viruses, including influenza a virus (iav) [108] , hepatitis c virus (hcv) [109] , enterovirus 71 (ev71) [110] , and sars-cov, etc [111, 112] . it has been confirmed that quercetin showed a good inhibitory effect on sars-cov 3clpro expressed in pichia pastoris, with an inhibition rate of 82% [111] . in addition, enzyme inhibition assays in vitro also showed that quercetin had inhibitory activity against sars-cov 3clpro [112] . since the 3clpro sequence of sars-cov-2 is highly similar to that of sars-cov [10, 25] , we speculated that quercetin may also exhibit antiviral effects on sars-cov-2. however, it has not been documented whether quercetin inhibits sars-cov-2, so we docked quercetin to 3clpro as well as other key targets, and the docking results showed that quercetin bound well to each target, with a binding energy of -5.6 kcal/mol to 3clpro. surprisingly, we found that quercetin bounds better to spike protein, ace2, rdrp and plpro indicating good potential against sars-cov-2. in addition, it has a wide range of sources with relatively low cost, so it is worth testing its efficacy against sars-cov-2 infection. andrographolide, the main active component isolated from the extract of the herb andrographis paniculata, has a wide range of biological activities including immunity regulation, anti-virus, anti-bacteria, anti-parasite, anti-tumor, and anti-hyperglycemia [113, 114] . previous studies have shown that andrographolide has a broad spectrum of antiviral properties, which inhibits various virus infections including influenza a virus (iav) [115] , human immunodeficiency virus (hiv) [116] , chikungunya virus (chikv) [117] , dengue virus (denv) [118, 119] , and enterovirus d68 (ev-d68) [120] . atchara paemanee et al. suggested that andrographolide may exert j o u r n a l p r e -p r o o f broad-spectrum antiviral activity by interfering a variety of cellular pathways (including autophagy, unfolded protein response (upr) pathway and oxidative stress, etc.). they further found the anti-dengue virus activity by acting on grp78, a key regulator of unfolded protein response [119] . in addition, andrographolide exerts antiviral activity against h1n1 by inhibiting the activation of rlrs signaling pathways and thereby improving h1n1 virus-induced cell death [121] . to test the anti-viral activity against sars-cov-2, we docked andrographolide with key targets, and the results also showed that andrographolide bound well to the key targets including spike protein, ace2, 3clpro, rdrp and plpro, which indicated that andrographolide has potential efficacy against sars-cov-2. moreover, enmozhi, s. k. et al. proved andrographolide as a potential inhibitor of sars-cov-2 3clpro through in silico studies [122] . overall, as a plant-derived compound, andrographolide is widely distributed with low cytotoxicity, but its potent antiviral activity against a variety of viruses calls for further investigation. glycyrrhizic acid is a plant product isolated from the traditional chinese medicine licorice rdrp and spike is -6.9 kcal/mol, -7.3 kcal/mol, -7.2 kcal/mol, -6.5 kcal/mol, respectively. it can be seen that glycyrrhizic acid also has strong binding affinity to other targets. given the antiviral effect of glycyrrhizic acid on sars-cov, and its potential interaction with ace2, we speculated that glycyrrhizic acid may have potential to treat sars-cov-2. moreover, glycyrrhizic acid plays an important role in inhibiting immune hyperactivation and cytokine storm factor development [129] , therefore, we believe it is worth testing its efficacy against sars-cov-2 infection. baicalin and specific binding to proteases by itc map, native electrospray ionization mass spectrometry (esi-ms) and its chemical structure [28] . at the same time, we used molecular docking to study the docking of baicalin to other key targets of sars-cov-2, in which the binding energy of baicalin to the target plpro was -8.5 kcal/mol. the results of docking showed that baicalin bounds strongly to other targets of sars-cov-2 (table 2) . therefore, it can be reasonably speculated that baicalin is one of the potential drugs for covid-19 treatment. in view of the low toxic effect of baicalin, its effect against sars-cov-2 warrants further study. patchouli alcohol (pa), a tricyclic sesquiterpene compound extracted from the traditional chinese medicine patchouli, has a wide range of pharmacological and biological effects including antiviral, immunomodulatory, anti-inflammatory, antioxidative, and antitumor [134] . pa has been found to have anti-influenza a (iav) effect in vitro, while h1n1 virus is the most sensitive to pa [135] . in addition, yunjia yu et al. found that intracellular pi3k/akt and erk/mapk signaling pathways may be involved in the anti-iav effect of pa and pa significantly inhibits the in vitro proliferation of different iav, suggesting that pa may block iav infection by directly killing viral particles and interfering with some early stages after viral adsorption [136] . another study showed that pa also has an effect against influenza virus (ifv) in vivo and enhances protection against ifv infection in mice by enhancing host immune responses and attenuating systemic and pulmonary inflammatory responses [137] . to investigate the anti-sars-cov-2 activity of pa, we investigated the possibility of pa binding to sars-cov-2 related targets using molecular docking ( table 2 ). the docking results showed that the binding effect of pa and rdrp was satisfactory, which provided some support for the antiviral effect of pa. the above study results showed that patchouli alcohol had antiviral effect and also modulated the levels of inflammatory cytokines, suggesting that pa may be a novel and effective antiviral and anti-inflammatory drug for covid-19. luteolin, a natural flavonoid extracted from chinese herbal medicine, displays multiple biological activities, including anti-inflammatory, anti-cancer, antioxidant, antiviral, and heart protective [138] . it was reported that luteolin can interfere with the virus in early virus life cycle, to a certain extent, block the absorption and internalization of influenza virus, thereby inhibited the replication of iav [139] . the above experiments suggested that luteolin is a potential antiviral drug that inhibits viral replication by regulating host proteins. in addition, minhua peng et al. confirmed luteolin inhibited the dengue virus ns2b/ns3 protease activity by analyzing the nucleotide sequence of the luteolin-resistant escape mutant [140] . it also has been documented luteolin has an anti-epstein-barr virus (ebv) effect, and in immunoblot analysis, 20 μg/ml of luteolin showed a significant inhibitory effect on ebv lytic cycle [141] . another study showed that luteolin extracted from torreya nucifera is an effective sars-cov 3clpro inhibitor [112] . to interrogate the anti-sars-cov-2 effect of luteolin, we performed molecular docking of luteolin to j o u r n a l p r e -p r o o f key targets of sars-cov-2. the docking results showed that luteolin bound well to the key target of sars-cov-2. among them, the binding energy of luteolin to ace2 was -7.1 kcal/mol ( table 2 ). taken together, luteolin has a good antiviral effect, which suggests that luteolin may be a potential drug for the treatment of covid-19. the results of molecular docking are shown in table 2 . from the target point of view, the binding effect of ace2 and plpro with these natural compounds was more prominent; while from the natural compounds, the lowest binding energy was -9.0 kcal/mol for cryptotanshinone and plpro, while the highest was -4.3 kcal/mol for lignan and 3clpro, that is to say, the range of binding energy was from -9.0 kcal/mol to -4.3 kcal/mol, which indicated that the natural compounds had a good binding effect with the target. our aim of docking was to select natural compounds with high potential efficacy against sars-cov-2, but it should be pointed out that these compounds cannot be considered to treat covid-19 only by such a screen which is aimed to provide priority to focus. furthermore, the 3d structure of the targets we used were based on the reported gene sequences. if the virus mutates during transmission, new screening is recommended. in conclusion, our review summarizes more than a dozen of natural compounds classified as antiviral/pneumonic protectors, which may directly inhibit sars-cov-2. however, their actual effect in the treatment of covid-19 needs to be verified by further studies. covid-19 poses a great threat to global health and safety. it is an urgent task for us to control the spread of the epidemic and reduce the mortality rate as soon as possible. but so far, the specific mechanism of the virus is still unclear, and no specific drug has been developed for the virus. at treatment. this review also has limitations. the large and rapidly published literature on covid-19's treatment means that the findings and recommendations are constantly evolving as new evidence arises. it is not uncommon that drugs that proved effective at an early stage based on small-scale clinical trials later turned out to be ineffective. we look forward to the cooperation of all scientists around the world to develop effective drugs to treat current and future potential 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traditional chinese medicine for treatment of coronavirus disease 2019: a review covid-19: an update on the epidemiological, clinical, preventive and therapeutic evidence and guidelines of integrative chinese-western medicine for the management of 2019 novel coronavirus disease multidrug treatment with nelfinavir and cepharanthine against covid-19 key: cord-333595-9erjf8rk authors: maurushat, alana title: the benevolent health worm: comparing western human rights-based ethics and confucian duty-based moral philosophy date: 2008-02-14 journal: ethics inf technol doi: 10.1007/s10676-008-9150-1 sha: doc_id: 333595 cord_uid: 9erjf8rk censorship in the area of public health has become increasingly important in many parts of the world for a number of reasons. groups with vested interest in public health policy are motivated to censor material. as governments, corporations, and organizations champion competing visions of public health issues, the more incentive there may be to censor. this is true in a number of circumstances: curtailing access to information regarding the health and welfare of soldiers in the kuwait and iraq wars, poor health conditions in aboriginal communities, downplaying epidemics to bolster economies, and so forth. this paper will look at the use of a computer worm (the benevolent health worm) to disseminate vital information in␣situations where public health is threatened by government censorship and where there is great risk for those who ‹speak out’. the discussion of the benevolent health worm is focused on the peoples’ republic of china (china) drawing on three public health crises: hiv/aids, sars and avian influenza. ethical issues are examined first in a general fashion and then in a specific manner which uses the duty-based moral philosophy of confucianism and a western human rights-based analysis. technical, political and legal issues will also be examined to the extent that they better inform the ethical debate. censorship in the area of public health has become increasingly important in many parts of the world for a number of reasons. groups with a vested interest in public health policy are motivated to censor material. this may include governments, corporations, professions, and organizations. the censorship may be direct (legal sanctions) or indirect (corporate and individual self-censorship). as experts in the field, ngos and other citizen movements champion competing visions of public health issues, the more incentive there may be to censor. this is true in a number of circumstances. for example, curtailing access to information regarding the health and welfare of soldiers in the kuwait and iraq wars, poor health conditions in aboriginal communities, downplaying epidemics to bolster economies, and so forth. this paper will look at the use of a computer worm (the benevolent health worm) to disseminate vital information in situations where public health is threatened by government censorship and where there is great risk for those who 'speak out'. while there are many examples along the spectrum of public health censorship, this paper's discussion of the benevolent health worm will be limited to that of the peoples' republic of china (china) drawing on three public health crises: hiv/aids, sars and avian influenza. in each of these situations, chinese citizens faced a public health epidemic (which then spread to the international community). in each of these situations the chinese government heavily censored information, allowing the disease to unnecessarily spread faster in an uncontained manner. and in each of these situations individuals who vocalized or published unauthorized news articles on the epidemic (many prominent experts, doctors and activists) were detained without reason serving time in prison. some were threatened or charged with divulging a state secret. the author uses china by way of example due to the extremity of the example, as well as her experience and familiarity with politics, censorship strategy and legal developments in the region. 1 the use of a controversial technology such as a computer worm to disseminate uncensored, sanctioned public health information in china presents contentious ethical issues worth examining. when is the use of an illegal technology ethical? does the dual use of a computer worm for malicious or benevolent reasons play a part in the analysis? if so, at what point? is motivation the determining factor? intended use? actual consequences? is there a moral duty to write and disseminate public health information which differs from authorized accounts? is the duty a general duty or is it specific to certain members of society? does the mode of information delivery play a part in an ethical analysis? are anonymous modes of dissemination less ethical than methods which provide accountability? to what extent does the source of the information factor into the equation? what role does risk of criminal sanction play in ethics? does the risk of criminal sanction depend on the actual use or potential consequences of the technology? does the violation of human rights justify the illegal activity? if so, is the chinese context justifiable? is the use of a benevolent worm compatible with western ethical traditions? chinese ethical traditions? the above questions are raised to illustrate the abundance of ethical queries triggered by the topic, and are not meant to be fully covered in this paper. for the purpose of this paper, an account will be given of the censorship environment in china both in general and in the specific context of public health. this will be followed by an account of technical aspects of the benevolent health worm inasmuch as it will inform and frame the debate on ethical issues. a further account will be given examining the use of an illegal technology such as a computer worm to disseminate non-authorized public health information. the core of the paper will examine ethical issues in a general fashion, and then in a specific manner drawing on the moral philosophy of confucianism and western notions of civil liberties/human rights. confucianism is often thought to be incompatible with western rights-based theories (democracy, civil liberties, human rights and other autonomous rights based theories). the point is not to justify the benevolent health worm through either a 'western' or 'eastern' lens. the point, rather, will be to examine many of the ethical issues from multiple perspectives. in particular, the perspective of chinese moral philosophy -confucianism -which is rooted within the framework of values and duties -will be used along side a western human rights-based analysis. 2 the use of western rights-based theories (human rights) alongside the eastern duty-based theory of confucian moral philosophy provides an interesting platform for an ethical analysis of the benevolent health worm. the author will suggest how human rights and confucian moral philosophy may be used to better understand the ethical issues presented with the use of the benevolent health worm. the paper does not aim to justify the use of the benevolent worm. instead, there is the modest aim to initiate ethical debate on the subject. the application of the analysis could extend to a broader examination of benevolent payloads, and, further along the spectrum, the ethical use of illegal technologies. governments in china have traditionally utilized censorship as a means for control. using censorship as a control mechanism has historically been pitted against the chinese promotion of intellectual growth. 3 the rise of the chinese communist party (ccp) brought with it the continued ideal of control over the dissemination of works and ideas. china continues to censor books, newspapers, and basically, most forms of publications that threaten the governing regime or criticize china's attitude towards human rights. 4 included in this overall censorship strategy is tight control of the media and the internet. all news agencies, including news websites and chatrooms, must be accredited. and sale of foreign news in china may only be purchased and published from the state-run government news agency, xinhua. review and enforcement of laws and regulations is performed by two agencies (one for press, radio, film and television, and the other for written publications including the internet), both of which are run by the communist party's central propaganda department (cpd). against the backdrop of what could best be described as a labyrinth of laws and regulations, the cpd issues weekly informal directives to news agencies and internet service providers (e.g. google and microsoft) on news items requiring restrictive coverage. virtually all statutes and regulations concerned with communications (news or otherwise) contain vague language allowing authorities sufficient flexibility in determining which publications are in breach of the law. 5 navigating through the ever-changing and complex media and internet regulations is a seemingly never-ending process. while the regulations are ever-changing, there is a standard set of vaguely written provisions which appear in all such regulations: divulging state secrets; harming the honour or interests of the nation; spreading rumours which may disturb social order; and inciting illegal assemblies which could disturb social order -all punishable as a criminal offence. state secrets provisions are the most problematic as their wording and interpretation in practice has proven malleable to political will. it is difficult for writers (whether they be journalists or mere bloggers) to determine in advance whether their message would contravene the law. where writers publish illegal content they are subject to a number of punishments such as dismissal from employment, demotion, libel, fines, closure of business, and imprisonment. imprisonment for illegal new stories extends to employees of foreign news agencies. for example, hong kong based journalist ching cheong (singapore's straits times) and zhoa yan (new york times) were arrested and detained for reporting articles about communist party leaders. 6 news around sensitive topics such as a public health crisis is heavily censored and monitored. historically, individuals who reported and disseminated sanctioned public health news were often detained without reason and, in some cases, these individuals were charged with divulging a 'state secret'. many academics and experts have written on the scope of 'state secret' in china. the notion of 'state secret' has traditionally been broad and deliberately ambiguous, while its scope of application is ever-changing. 7 it remains impossible to ascertain whether a person's actions would fall within a 'state secret'. people have been charged with this serious offence for the dissemination of banned information related to human rights, revealing draft laws (white papers), publishing unauthorised news reports, and publishing information critical of governing authorities. the act of circumventing the ''great firewall'' for illicit purpose, and mere research on internet censorship, could conceivably fall within the parameters of 'state secret'. the ccp's unpredictable use of broad, ambiguous laws to deter freedom of expression is heavily criticized in the international arena. while 'state secret' laws remain a potent threat, the ccp has a number of criminal provisions which it regularly uses to curtail the dissemination of sanctioned information. to paraphrase a prominent malaysian journalist steve gan, ''we have the right of freedom of expression. the problem is that we have no rights once such words are freely expressed.'' 8 the same could be said of china. access to information may involve more than freedom of expression; timely information may have repercussions for the health and welfare of individuals. indeed, there are three specific areas where censorship and a lack of accurate information distributed in a timely manner have had unrefuted consequences in china in recent history: aids, sars and avian influenza (often referred to as bird flu). the chinese government has suppressed and continues to suppress information on the spread of 5 c. zissis.''mediacensorshipinchina''councilonforeign relations, 2006 hiv/aids. by 1987 the government had reported only 4 known cases claiming that aids was a foreigners' disease. 9 the lack of reporting and ineffective preventative measures led a number of people to become aids activists. these activists reported significant rates of people infected hiv and campaigned for the government to take proactive measures to reduce the spread of this debilitating disease. many aids activists, including the famous activist wan yanhai, have been detained and charged with divulging a state secret. 10 infected blood supplies appear to have initially been the main source of the problem. infected blood supplies, however, still taint china with many people in poorer areas donating blood for money while drug use, prostitution and a lack of educative measures continue to exacerbate the situation. the reality today is that china has one of the highest hiv/ aids rates in the world outside of africa. while we will never know the effect that accurate and timely information would have had in this epidemic, it is certainly plausible that access to such important information could have reduced the rate of infection. similar to the hiv/aids crisis, the chinese government withheld critical health information on severe acute respiratory syndrome in 2002. china has a longstanding tradition of curtailing news deemed harmful to society and to china's image. in the case of sars, it was thought that exercising tight media control would reduce public fear and lessen economic damage in the region. 11 the lack of reliable dissemination of information and the underreporting of infected sars patients to the world health organization allowed the disease to spread more readily from guangdong province to other provinces in china, to hong kong and to other countries in the world. 12 the sars health crisis can be partially attributable to nondisclosure of pertinent information. avian influenza (also referred to as bird flu) while avian influenza a has not yet reached the level of crises of hiv/aids or sars in china, historical events give clear signs that any information provided by chinese officials should be perceived with caution. 13 it is believed that quiao songju, a chinese farmer, was arrested and detained for reporting a potentially infectious bird in the anhui province. 14 prominent hong kong virologist, guan yi, was invited by the chinese government to study abf. his account of the disease was vastly different from the official version reported by the chinese government. guan's publications are censored in china while it has been made known to the prominent virologist that he should not return to china. it is rumoured that guan has been threatened with detainment and there is further speculation that he may be in violation of having disclosed a 'state secret'. china's newly drafted censorship rules compound the situation. the newly drafted law states that it is a criminal act to publish any information on 'sudden events' without prior authorization from the chinese government. 'sudden events' are defined as 'industrial accidents, natural disasters, health and public security issues'. 15 the government claims that the law is aimed at irresponsible journalists who report untruths potentially causing panic among the public. critics have claimed that the draft law is aimed at preventing future disclosures of embarrassing news. 16 public health epidemics would fall under the category of sudden events. the internet and wireless technologies have been heralded as vehicles of free expression. it has generally been thought that no government could control information on the internet, hence the expression ''the internet routes around censorship. '' in china, 9 this is increasingly no longer true. the chinese government erected, through its golden shield project, what has become known as the 'great firewall of china'. access, control and censorship of internet content in china is most often attributed to the 'great firewall of china'. this is, however, something of a misnomer; the firewall is merely one path in a maze of controlling technologies and non-technological means in an overall internet censorship strategy. this censorship strategy is comprehensive, incorporating sophisticated technologies, numerous regulatory measures, market influences, and aggressive policing and surveillance of internet activity, resulting in an atmosphere of self-censorship. laws regulating free speech and the internet are implemented out of concern for the potential harm posed by unfettered access to sites that contain political, ideological, social, or moral content that the ccp perceives as harmful. china has adopted a comprehensive internet censorship strategy utilizing a range of control mechanisms. mechanisms of control include laws and regulations pertaining to physical restrictions, regulations of use, ownership and operation of internet service providers (isps), internet access providers (iaps), and internet content providers (icps). 17 similar to media regulations, a series of ever-changing internet regulations are also relevant to the dissemination of information. authorized access entails individuals having to obtain licenses for internet access. in order to obtain a license, individuals are required to register with the local police and provide their names, the names of their service provider, their e-mail addresses, and list any newsgroups in which they participate. this, of course, does not mean that anonymity and pseudonymity cannot be achieved for chinese cybersurfers. users have flocked to cybercafe´s and universities to access the web. the ccp has responded by shutting down many cyber-cafe´s, then later by requiring all cybercafe´s and universities to obtain user identification, and to keep detailed logs of user activities (the regulations are complex and comprehensive). the extent to which such entities have fully complied with the law in practice has not been explored, but the threat of surveillance continues to lead to an environment of self-censorship. the ability to access banned documents and to communicate anonymously is challenged. information flows from the internet subscriber (home, cybercafe´) to the internet service providers (isps) to four gateways controlled by the ministry of posts and telecommunications. 18 isps are regulated through a myriad of laws which are, again, ambiguous and complex. it is difficult for any party to know if they are in compliance with the law. the regulations require isps to restrict and control access to harmful/banned websites, allow surveillance software on their systems, and keep logs of user activity. 19 email is neither private nor anonymous when using an isp regardless of whether a domestic or foreign service is used. isps must and do comply with requests to reveal personal information of the true identity of users as well as information about email content. for example, both yahoo!china and yahoo!hk have disclosed confidential user information of prominent journalists by releasing internet protocol addresses to chinese authorities. many journalists deliberately have email accounts in jurisdictions such as hong kong with a strong rule of law tradition in order to shield their identities from chinese authorities. yahoo!hk handed over the internet protocol address (not the user's name) of journalist shi tao to chinese authorities based merely on an informal request. as such, yahoo!hk circumvented formal judicial requirements of a court order compelling the disclosure of confidential information. yahoo!hk claims that they disclosed the information in compliance with a criminal investigation in mainland china. the dispute has become one of many disputes over the scope of chinese jurisdiction in hong kong. disclosure of an internet protocol address is not classified as personal information under hong kong law making it safe for isps to circumvent their otherwise legal obligation to keep personal information confidential under the privacy ordinance. the securing of shi tao's internet protocol address led the chinese authorities directly to a specific computer port number, and directly to shi tao's computer. the information was classified in china as state secret. shi tao was arrested and sentenced to 10 years in jail. 20 recent popular methods for dissemination of taboo/illegal documents include spam, weblogs and chatrooms -all delivery methods involving the internet which allow for some degree of anonymity or . 18 the precise number of gateways has not been established. some report 3, others 4, and others 5. the author has taken the middle figure as an average only. this ambiguity illustrates the cloud that shrouds accurate information pertaining to the 'great firewall'. 19 liang, footnote 17. 20 for a short article on the privacy commissioner's ruling see, http://www.reuters.com/article/worldnews/ idussha24136320070315. pseudonymity. chinese officials have recently begun to crack down on weblog and chatroom use, introducing a host of new regulations directly targeted at information deemed harmful to chinese society. china's filtering/anti-spam technology has likewise greatly evolved so that spam has become a less effective means of communicating information. those who continue to engage in the exchange of banned communications, whether it be via spam, weblogs, text message or other fora, potentially face criminal charges. as the regulations are written in the traditional fashion of ambiguously overbroad provisions, the reality is that merely opening a spam message known to contain harmful material, or forwarding the message could be a contravention of the law. is it possible to route around censorship in china? circumventing the 'great chinese firewall' is achievable using a number of different methods which range from the use of web proxies (tor, anonymizer, dynapass, psiphon) to accessing the internet in peak times (state surveillance requires a large amount of bandwidth), to the use of encryption services. proxies such as tor may still be blocked at the node level (although currently they are not). while state surveillance requires large amounts of bandwidth, the threat of legal and economic sanction plus self-censorship -isps restricting access to potentially contentious sites, cybercafe´s and universities discouraging banned websurfing, individuals refraining from accessing even potentially illegal material -effectively fills the gap left by technological constraints. the use of encryption is able to circumvent filtering and keyword sniffing technology at the router level, but this does not provide a safety net for those wishing to disseminate contraband information. as stated previously, isps must and do comply with requests to disclose personal information. many isps have also built censorship functions into their encryption technology. activists using the encrypted skype technology, for example, have been cautioned against its use due to built-in censorship functions. 21 encrypted messages may arouse further suspicion which may lead from monitoring of general data traffic over the internet to the surveillance of specific individuals and groups. regardless of the method employed, the threat of criminal sanction is always a possibility. the ability to use the internet to publish sanctioned information is a risky proposition. assuming that there are strong ethical arguments in favour of disseminating sanctioned information in times of public health crises, a new mechanism will be required for large-scale information delivery. the benevolent health worm provides one possible solution. a benevolent computer worm is a form of malware. malware typically includes the following types of computers programs: virus, worm, trojan horse, spyware, adware, spam, bot/agent, zombie, exploit, bug, keylogging and so forth. malware refers to computer software which either acts maliciously or whose effects are malicious -the two are not necessarily synonymous. in a wider context, malicious would extend to any type of computer code installed without consent regardless if any damage occurs to the computer. the theory is that the malicious component encompasses the use of bandwidth and again, that there is no consent. the idea of a benevolent virus or worm is not novel. early research and debate focused on the use of a worm to patch existing security flaws in software. 22 expressed more precisely by leading it expert bruce schneier, ''patching other people's machines without annoying them is good; patching other people's machines without their consent is not … viral propagation mechanisms are inherently bad, and giving them beneficial payloads doesn't make things better.'' 23 under this definition, no malware could be construed as benevolent. the weakness of this argument is that its discussion has been limited to patching and similar e-commerce activities, where consent is desirable from a corporate ethics perspective and is necessary in order to conclude a binding legal contract. missing from this discussion is the application of a benevolent worm outside of the e-commerce realm, along with the discussion of the difference between consent and informed consent, the latter being the legal requirement in most jurisdictions. the subject of informed consent in the digital age is contentious. it has been argued that consent is given in most internet applications through checking the ''i agree'' button of end-user license agreements and privacy policy statements. this is not representative of informed consent. most users do not read end-user-license agreements (eula). when they do, such licenses contain onerous obligations unilaterally imposed on them expressed in complex, aggressive legal rhetoric -most of these types of terms remain untested in law and run against the basic tenants of the law of contracts, namely consideration, meeting of the minds, and adequate notice of change of terms. this is perhaps best illustrated by way of example. many corporations, such as sony, release products with an end-user license term authorizing them to utilize rootkits, backdoors and digital rights management systems for a variety of unspecified purposes, all of which may be subject to change without notification to the user. the rootkits, in turn, render computers vulnerable to intruders to install malicious applications onto their computers. digital rights management systems allow monitoring devices which track the use of a work (for example, a music c.d.), which could theoretically be used as evidence to bring legal suits against those who make illegal use of the copyrighted work. the author uses the example of consent to illustrate the discrepancy between tangential concepts of theory and practice. the author agrees that informed consent is a desirable feature in software distribution mechanisms. concluding that consent is required in all contexts is to prematurely rule on an issue which has, so far, only been discussed in the limited context of electronic commerce. if consent is gained, do benevolent payloads become ethical? if there is no consent, are benevolent worms precluded from becoming ethical? it appears as though the debate on consent and malware has inherited the intellectual baggage of assumptions surrounding consent. nowhere is this better articulated than in the famous essay by robin west, ''authority, autonomy, and choice: the role of consent in the moral and political visions of franz kafka and richard posner.'' 24 west exposes the fallacy in posner's theory that choice and consent in a legal system allow for an increase both in morality and autonomy. within the confines of benevolent payloads, there is an assumption that lack of consent is inherently bad or unethical contrasted with acts where a vague notion of consent is obtained, thereby magically summoning the requisites of legal and ethical action. the presence of consent should be regarded as one component in an analysis of all factors contributing to an ethical framework. an effects analysis would look to whether any tangible damage, other than use of bandwidth, has been done to the computer, webserver or user, or in the event that other types of damage are sustained, whether there are compelling reasons to derogate from the principles of user consent and avoiding damaging third party property. more importantly, an effects analysis would address the issues of when it is permissible to utilise bandwidth and install software on a user's computer without their consent. when, if ever, does a benevolent payload become permissible or mandatory as a moral duty? in a larger sense, the issue is one of normative ethics drawing on effects-based analysis in consequentialism with that of moral duty in deontology. while a robust examination of types of malware is not required to understand the benevolent health worm, a basic understanding of the differences between a virus and worm is essential, as the underlying technology of a worm alleviates some of the ethical and legal issues for its intended benevolent use. a virus is a ''block of code that inserts copies of itself into other programs''. viruses generally require a positive act by the user to activate the virus. such a positive act would include opening an email or attachment containing the virus. viruses often delay or hinder the performance of functions on a computer, and may infect other software programs. they do not, however, propagate copies of themselves over networks. again, a positive act is required for both infection and propagation. a worm is a program that propagates copies of itself over networks. it does not infect other programs nor does it require a positive act by the user to activate the worm. in this sense, it is selfreplicating. irrespective of the characterization nearly all computer viruses and worms infect either software or hard-drives without the authorization of the computer owner. similarly, all computer viruses and worms utilize bandwidth imposing a strain on traffic and resource demands. all computer viruses and worms may inadvertently cause unexpected damage to a computer system and may contain bugs. the benevolent health worm is no exception. there are ways to minimize damaging effects of the worm through technical design. such elements include: (1) slow-spreading, (2) utilize geo-location technology to limit its propagation within a region (''.cn'' and its equivalent for the internationalized domain name in chinese characters), (3) installation of short and reasonable shut-down mechanisms to avoid perpetual replication, (4) low-demand bandwidth, and (5) undergo professional debugging standards. 25 the benevolent health worm would be an information delivery method with worm-like characteristics. a computer worm is a self-replicating computer program containing a tailor-designed payload. the payload would be programmed to spread from computer to computer in china with the specific function of displaying the information in a pop-up window, or override a user's default web page with one displaying information. in the case of the benevolent health worm, the message would contain vital information relating to a public health crisis otherwise unavailable through traditional media sources. the information would ideally come from a trusted source containing accurate and truthful information (see discussion in following sections). the payload would be carefully programmed to prevent any deliberate or positive technical action by the recipient. the recipient would, therefore, have no knowledge or control of the worm. the latter points require elaboration. the selfreplication method of worms is ideal in this situation as it is only the infected computer which takes part in the dissemination of sanctioned information; the person whose computer is infected is technically prohibited from any deliberate or accidental positive acts, and has no control or knowledge of the worm. in order to achieve this, the pop-up message generated by the worm must have the following features: • must not be a virus in that it must be self-replicating, • not contain links to additional sources of information, • the user would not be able to save the information to his or her computer, • the user could not forward the message to others, and • the information would disappear from the system altogether after a specified amount of time. in the case of the latter, the pop-up would appear for a specified time (e.g. 10 min) and re-appear each time a person turned on their computer for a programmed length of time (e.g. 2 weeks). at the end of a short period of time (e.g. 2 weeks) the worm would completely disappear from the user's computer systemall technically feasible through the programming of the payload. these features greatly reduce if not eliminate any risk to the recipients of the information. all elements necessary to prove a criminal act are removed: positive act, knowledge or foreseeable knowledge, mens rea, and motive. a chief criticism of the use of viruses and worm for benevolent purposes is that there are safer alternative means of achieving the same goal. 26 the same cannot be true with the benevolent worm. alternative means of health distribution would include: illegal news reporting; illegal dissemination of news domestically through a blog, chatroom or spam; spam techniques from a foreign jurisdiction; and access to materials outside of china through anonymizing technologies such as web proxies. a common flaw of these methods is the necessity of a positive act by both the sender and recipient of information. this is especially so for the first two means. a positive act, whether it is through technical (e.g. virus) or manual (e.g. forward spam message) would allow for the possibility of dual criminal charges. meanwhile there are further challenges with the latter two distribution means of foreign spam and web proxies. as pre-eminent human rights activist sharon om has noted, human rights spamming lists are potentially illegal under the united states can spam act. 27 the use of anonymizing technologies such as web proxies is by no means fool proof. such technologies are capable of being blocked (policy choice not a technical feat), even trust-enabled web proxies such as psiphon. 28 in the case of the benevolent health worm, only the sender of the information would perform a positive act. these acts would still be illicit on many fronts but the sender would bear a greater risk than the recipient. the programmer of the human rights worm will be in violation of computer misuse law. in the event that the computer programmer is not necessarily the person or group who distributes the worm, those individuals responsible for ''letting the worm loose'' could face criminal and civil charges. finally, the authors of the actual information appearing in the pop-up screen may be charged with a number of criminal acts including state secret and possibly the new law on disclosure of non-authorized news on 'sudden events.' positive acts are performed by those actors along the sender chain while recipients of information remain removed from the process short of reading the content displayed in the window. stated another way, the benevolent worm potentially offers a way to restore an individual's right to 25 physical and mental well-being through a method that reduces the risk of persecution for those who disseminate un-authorized information and reduces and possibly removes the risk for those who receive the information. the above scenarios, however, envision the propagation of the worm and information writing to be performed by individuals within china. such risks could be greatly reduced by creating the worm outside of china. while it is true that computer misuse is illegal in most jurisdictions, the threat of sanction depends greatly on political will. with open american support of projects which address human rights and democracy in suppressed regions, congressional hearings on internet censorship in china and, more specifically, us corporate compliance and aid in censorship; and the passing of the global internet freedom act, it is hard to believe that, at least in the united states, that there would be political will to prevent the benevolent worm. if anything, there may be available funding. there is a strong psychological and political element to the creator (and disseminator) of the worm. a worm created inside china would have the distinct advantage of appearing to be change from within; a worm created outside china raises issues of external meddling, sovereignty, imperialism, or worse yet, information warfare. these issues will be more fully integrated into the ethical discussion below. the ethical dimensions of the benevolent worm encompass several layers. a more sophisticated approach would be to treat the layers as information branches in the total infosphere. 29 for the purpose of this paper i will adopt a simpler approach referring to the author/producer, sender/distributor, recipient, content, delivery method and medium of communication. one great concern in the propagation of public health information through a computer worm is that of trusted source. trusted sources may be divided into two groups. the first involves the content of the information. the second relates to the information producers -authors and distributor. the 'who' in 'who says what' may be more important than the 'what'. in this sense, a worm released by a national state could be construed as interference with sovereignty and may not carry the same weight as a worm released by a trusted ngo working in the region. the reality, however, is that there is no full-proof method between distinguishing between a trusted and deceptive source. all electronic commerce applications suffer from the same ambiguity of trusted and deceptive sources. the following analysis, therefore, assumes that it is possible to utilize trusted sources. indeed it may be a great leap of faith. the analysis further assumes that the issue of public health endemics is sufficiently grave to warrant deviation from traditional paths of information dissemination (as discussed in the previous sections). western-based rights treatises, in particular human rights frameworks, may provide some justification of a benevolent health worm. human rights or civil liberties frameworks operate on two theoretical models. the first is one related to public international law where states bind themselves to legal obligations contained in treaties. the second involves the universality principle of human rights based on moral rights as opposed to legal rights. a similar dichotomy is to distinguish between what is legal and what is legitimate. the law -that is, what is legal -is premised on the notion that there, ''is a system of enforceable rules governing social relations and legislated by a political system.'' 30 breach of a rule results in an activity being classified as illegal. legitimacy in this context is used in its broadest sense to reflect what is moral which need not be legal. discussions of morality are naturally dependent on the framework of the analysis. the notion of morality as seen through the lens of natural law (e.g. aquinas, aristotle, religion), would likely differ from morality as seen through the lens of normative jurisprudence (e.g. virtue ethics, utilitarianism, deontology). the moral or ethical framework shapes the debate. this section of the paper does not use a specific ethical framework such as deontology to discuss issues of human rights. to the extent that any differentiation is made, there is some delineation between what is legal versus legitimate. the debate will mostly inter-mingle notions of legality with those of legitimacy, as well as notions of binding public international law with the universal principle of human rights. the aim is to initiate ethical debate on the subject, not to fully justify the use of a benevolent worm. 29 l. floridi. information ethics, its nature and scope. in j. van under a legal rights based theory, specific rights and obligations are only provided to the extent of treaty provisions in international law. such rights may or may not be entrenched in domestic/national law. where rights are protected under international law, they may contradict and clash with domestic law. the nexus between national and international law has been discussed using the theories of dualism and monism. as the honorable justice kirby writes: ''for the monist, international law is simply part of the law of the land, together with the more familiar areas of national law. dualists, on the other hand, assert that there are two essentially different legal systems. they exist ''side by side within different spheres of action -the international plane and the domestic plane. '' 31 the clash between national and international law is influenced by whether a court adopts a monist or dualist position. the chinese government and courts use a dualist theory where human rights are viewed as a matter of 'foreign affairs.' as one human rights expert writes, ''the chinese government essentially views these obligations as a matter of foreign affairs, and seeks to insulate the domestic arena from the reach of international human rights law, both in symbolic and practical terms. '' 32 international tribunals and courts also adopt a dualist approach. national law is treated as a fact. an obligation in international law cannot be avoided or excused due to a clash with domestic/national law. other governments and courts adopt a monist approach. this can be seen in the erosion of the dualist approach in many countries such as australia and canada. there have been many court decisions which integrate international law principles into the national landscape. the second level relates to the universality of human rights. universality is not a legal proposition but a moral one; that human rights are naturally acquired at birth regardless of the area of the world where you reside. human rights subsist regardless of international and domestic legal obligations. regardless of the interpretation of human rights, the benevolent health worm represents undisputed legal and moral rights which may be stated in a simple form: everyone has the right of freedom of expression, and the right to the enjoyment of the highest attainable standard of physical and mental health. these rights are legally protected in a number of international, regional, and united nations treaties to which china is party, and, according to the model of human rights one adheres to, are inherently entrenched regardless of the law. 33 the constitution for the people's republic of china (prc) recognizes ''freedom of speech'', however, the concept of free speech is viewed differently in china than in western democracies. reed, an expert on freedom of expression in china, notes: ''the prc believes that rights are only instruments for realizing state objectives. individual rights are merely residual freedoms found within the confines of the law. if necessary, all rights must be sacrificed for the good of the common collective. as a result, china traditionally keeps the dissemination of information and freedom of expression to a minimum. the ccp controls all facets of government, including the freedom of expression granted in the constitution.'' 34 several distinct questions surface as a result of the above passage. is china within its legitimate sovereign right to censor free speech on public health issues on the grounds that such discourse falls under the exemption of ''national security''? is civil disobedience justified in the context of disobeying the law for a higher purpose whether it be construed as a moral obligation or interpreted as for the greater good of the community (emphasis here on worm created within china)? would a worm created outside of china be a deliberate act of interference with a nation's sovereignty? under what circumstances might the benevolent worm be construed as part of information warfare? public health as 'national security' threat according to one view, national security always trumps individual rights because security, on a hobbesian-type view, is necessary for a peaceful society in which persons can enjoy their liberty and rights. this view appears to be gaining adherents at least among legislators. on the moderate viewpoint, free speech rights are defeasible, but only when appropriate justification for 31 m. kirby censorship is available. in order to protect free speech rights, legislative limitations on censorship powers are necessary. in a rights-respecting society, balancing involves prioritizing different rights in the case of conflicts between prima facie rights (e.g. freedom of expression may conflict with freedom of religion). in the case of liberal democracies, there should be strong limitations on violations of freedom of expression and liberty. on the other hand, as we have seen in the quotation from reed, above, from the perspective of the prc, rights are merely instrumental to the common good, and balancing rights can be done by determining what maximizes the common good. rights can be overridden whenever the common good requires. 35 under public international law, governments are allowed to restrict the free flow of information to protect interests such as national security or public morals. national security ideology has, however, been used by authorities to justify human rights infringement. for this reason, international documents and principles were developed to keep rights exemptions confined to narrow determinations. for example, the johannesburg principles on national security, freedom of expression and access to information 36 adopt a standard whereby freedom of expression and access to information may only be restricted where a number of conditions are met: prescribed by law, protects a legitimate national security interest, and is necessary in a democratic society. for example, a legitimate national security interest is incitement to violent overthrow of a government. national security restrictions are not justifiable in the case, for example, of ''embarrassment or exposure of wrongdoing, or to conceal information about he functioning of its public institutions …'' (principle 2(b)). china's restrictions on free speech and access to information clearly do not adhere to the johannesburg principles or other international standards for protecting the right to information. as human rights watch notes, ''prior censorship in particular is severely disfavoured in international law, and not permitted in many constitutional systems. a decision to block access to online material should be subject to the highest level of scrutiny, with a burden on the government to demonstrate that censorship would effectively avert a threat of irreparable, imminent, and weighty harms, and that less extreme measures are unavailable as alternatives to protect the state interest at issue. at present, it seems apparent that china engages in no such scrutiny … '' 37 moreover, the decision to punish certain speakers merely for exercising their right to speak frankly online (or off) is arbitrary and unpredictable with no opportunity for an individual or group to know in advance whether their actions comport with the law. the inability to comply with the law based on a lack of transparency severely undermines any attempt to posit a law as moral. morality here is used in a procedural sense along the line of natural law theorist, lon fuller's essential principle that the law should be written and promulgated in a fashion which guides behaviour. conscientious objection and civil disobedience i will refer to two general types of civil disobedience. the first is better known as 'conscientious objection' where the moral agent performs or abstains from performing an act to preserve the agent's own moral integrity. there is only the duty to obey a just law. fashioned in a similar vein, there may in fact be a moral obligation to disobey an unjust law. 38 in the case of the benevolent worm, a number of parties including the author/producer, and sender/distributor may feel morally compelled to send what they believe is vital, accurate health information otherwise not available within china. conjecturing on the moral agent's dilemma, the agent is motivated to break the law in order to achieve a number of possible goals such as informing the populace of important news related to the epidemic and to encourage behaviour associated with containing the disease in question. 39 35 g. hagen and a. maurushat, surveillance, technology, and national security: issues in civil liberties, course materials. asia-america institute in transnational law, 2005. 36 available at http://hei.unige.ch/humanrts/instree/ johannesburg.html. 37 human rights watch, footnote 21. 38 martin luther king junior, for example, writes: ''how can you advocate breaking some laws and obeying others?'' the answer is found in the fact that there are two types of laws: there are just and there are unjust laws. i would agree with saint augustine that ''an unjust law is no law at all.'' ''… one who breaks an unjust law must do it openly, lovingly … and with a willingness to accept the penalty. i submit that an individual who breaks a law that conscience tells him is unjust, and willingly accepts the penalty by staying in jail to arouse the conscience of the community over its injustice, is in reality expressing the very highest respect for law.' ' (1963) the other type of disobedience, on the other hand, is known as 'civil disobedience' in the sense that it, ''is conscientious disobedience of the law directed primarily … at bringing about a change in a law, policy, institution that is morally unjust or otherwise morally unacceptable ... or a law which may be acceptable in itself but which is disobeyed in order to protest against the offending law.'' 40 the moral agent, in this instance, is motivated to affect change in the law. in the case of the benevolent worm, however, this would likely be a possible ancillary effect rather than a primary goal. conscientious objection and civil disobedience have been justified on a number of grounds. 41 one thought is that disobedience of the law may be justified where there is no disrespect or harm to others. another ground speaks to a utilitarian approach of bringing about useful reconsideration of public policy, respect for human rights, interests of minorities and disadvantages groups, and actual reform of the law. it has been shown that other methods such as news reporting and spam potentially create harm not only for the sender but also for the recipient of sanctioned health information. the benevolent worm has the goal of safely minimizing harm to the sender and attempts to eliminate harm to the recipient (realizing, of course, that unintended consequences are not always foreseeable). many philosophers have specified that justifiable civil disobedience ought to be non-violent with the agent ready and willing to accept punishment as a consequence for breaking the law. this view seeks to disassociate civil disobedience from revolutionary disobedience. the author suggests that this dichotomy is more useful in a democratic state with rule of law whose political leaders and citizens first have respect for their constitutions and second for human rights in general. the dichotomy, therefore, seems less appropriate for autocratic states with documented histories of human rights abuse. would a worm created outside of china be a deliberate act of interference with a nation's sovereignty? the answer to this question may lie in the meaning of sovereignty. in modern international law the notion of sovereignty is ''people's sovereignty rather than the sovereign's sovereignty … [whereby] no serious scholar still supports the contention that internal human rights are ''essentially within the domestic jurisdiction of any state'' and hence insulated from international law.'' 42 the notion of sovereignty in human rights is, therefore, predominantly premised on democracy and rule of law. china is not a democratic nation adherent to the rule of law. it does not, however, follow that china is not entitled to sovereignty but rather, that issues of sovereignty are burdened with additional questions. yet sovereignty has generally been understood as one nation interfering with another nation's legitimate right to runs its affairs. one thinks of the invasion of iraq and not generally of information on public health endemics. sovereignty issues may be affected by the 'who' in 'who says what'. a worm released by the canadian government, for example, could conceivably be construed as intentional sovereign interference. a worm released by a ngo, on the other hand, would be less likely to be perceived as sovereign interference; this would be further buttressed by a trusted ngo with strong links to china. in an extreme circumstance the benevolent worm might be construed as part of information warfare (iw). defined simplistically, information warfare refers to, ''actions taken to affect an adversary's information and information systems while defending one's own information and information systems. '' 43 there are six broad components to iw: physical attack/destruction, electronic warfare, computer network attack, military deception, psychological operations, and operations security. it is difficult to conceive how the benevolent worm in its described application in this paper would fit into any one of these categories. one cannot, however, rule out the possibility of a worm with false and potentially harmful information concerning an epidemic to be released as part of an overall iw strategy. a strategy of disinformation, however, is applicable in a number of contexts including conventional means of information dissemination such as false news reporting, spam, and so forth. careful attention to trusted sources could reduce the risk of the worm being perceived as iw. 40 at its most base conception, 'asian values' emphasize the community as opposed to the individual or self. it has been argued that human rights are incompatible with 'asian values'. expressed more poignantly by samuel huntington: the traditionally prevailing values in east asia have differed fundamentally from those in the west and, by western standards, they are not favourable to democratic development. confucian culture and its variants emphasize the supremacy of the group over the individual, authority over liberty and responsibility over rights. 44 expressed somewhat differently, western human rights-based rhetoric focus on rights of an individual whereas eastern confucian moral philosophy focuses on the duties of an individual to the community. the following analysis places ethical debate on the benevolent worm in the confucian moral philosophy tradition. confucian moral philosophy is often referred to as a duty-based philosophy. confucian ethical teachings are grounded in five moral values: li (ritual), hsia (filial piety, duty to family), yi (righteousness), xin (honesty and trustworthiness), ren/jen (benevolence, social virtue, humaneness towards others), and chung (loyalty to the state). confucius' view of duty was not traditionally extended to all people but was limited to five relationships: ruler to subject, father to son, eldest brother to younger siblings, husband to wife, and friend to friend. there has never been a duty from human to human in traditional confucian thought. two contentious issues are raised in applying confucius' teachings to the benevolent health worm. first, the values of ren, benevolence towards others, may compete with that of chung, loyalty to the state. second, there is no general duty between humans outside of the five relationships. the value of chung requires a person to be loyal to the state but not at any cost. confucius writes, ''if a ruler's words be good, is it not also good that no one oppose them? but if they are not good, and no one opposes them, may there not be expected from this one sentence the ruin of his country?'' [confucius, the analects, book 13 translated by legge]. the most important value as espoused by confucius was ren. a major component of ren involved individual self-cultivation in virtuous action. it has further been suggested that li -norms of social ritual and interaction -is a critical component in analysing ren. li is learned by socializing and interacting with persons who embody ren. 45 as lai writes: the paradigmatic man is a creator of standards rather than a follower … and he possesses a keen sense of moral discrimination. moral achievement reaches its culmination in those who have attained the capacity to assess events and who, being attuned to li, embody a sense of rightness. 46 good governance and social order were derived from a hierarchical chain of individual virtuous action thus it is written that, ''their hearts being rectified, their persons were cultivated. their persons being cultivated, their families were regulated. their families being regulated, their states were rightly governed. their states being rightly governed, the whole kingdom was made tranquil and happy'' [confucius, great learning, translated by legge] . what of the case where ren is not personally cultivated leading to poor governance? loyalty to the state is loyalty to a righteous government who has fulfilled its duties to its citizens in the spirit of ren; loyalty to the state has never been an absolute. by no means does the author suggest that the overall governance of china has been poor under the current administration. china has had to face many problems that other nations, and in particular wealthy democratic nations, have never had to address: starvation, extreme poverty, territory occupation, a devastated economy, and population explosion to name but a few. while china has overcome many hurdles to better provide for its people, its record on factors contributing to human dignity is poor (freedom of expression, protection of minorities, access to important and timely information, and so forth). it is within this limited latter context of human dignity that it is conceivable to characterize governance as poor. the manner in which public epidemics such as hiv/aids, sars and bird flu has been handled is evidence that the government has not fulfilled its duties to the extent required under the spirit of ren. this resembles the notion of obeying just laws, and being further obliged to disobey unjust laws. the formation of a person's character through virtuous action is strongly tied to a sense of community and to one's role in a community. for this 44 similarly, extension of duties beyond the classic five relationships has also been newly interpreted. it could be said that certain members of society may have the duty to disclose information on epidemics which could save lives, reduce the spread of the infectious disease, and perhaps altogether avoid a disease reaching the level of epidemic. certain societal members may include scholars, doctors, journalist, experts, ngos, and other international organizations. this bears a resemblance to justifications of the moral agent in conscientious disobedience. the dissemination of vital information is potentially a virtuous act whether it is through direct means of an internet website, news publications, or whether it is less direct through a benevolent health worm. of course, the opposite could be argued for those who adhere to a traditional view of confucian moral philosophy. it becomes more difficult to justify the benevolent worm in the absence of one of the five relationships giving rise to duties. the most relevant relationship to the benevolent worm is that of ruler and subject. the ruler-subject relationship is predicated on the subject's respect for the ruler. this is similar to chung, loyalty to the state. again, there is the assumption that the ruler will have ren, and will act as an example to his subjects. in the absence of ren, the subject duty to obey the ruler is lessened. regardless of the framework adopted, the use of a benevolent worm does not seem to represent any clear abdication from confucian moral philosophy. water holds up the boat; water may also sink the boat. emperor taizong (600-649, tang dynasty) in much the same way, benevolent payloads have the potential to be destructive. they also have the potential to be beneficial. benevolent payloads have in the past been analysed in the context of patches and e-commerce. conclusion has been reached in the wider technological community that benevolent payloads are simply a 'bad idea' because there is no consent, and there are safer methods available. there has been no analysis of benevolent payloads outside of the electronic commerce context. the benevolent health worm provides an interesting case study which undermines and challenges many of the ethical issues of benevolent payloads. this article has attempted to untangle many of the complex ethical issues surrounding the benevolent health 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cost of content regulation on internet commerce reporters without borders. government turns deaf ear to call for ching cheong's release liberalism and the limits of justice benevolent worms, crypto-gram newsletter aids in china: an annotated chronology confucian ethics: a comparative study of self, autonomy and community virtue ethics, the analects, and the problem of commensurability law and ideology the bioethical principles and confucius' moral philosophy learning, and politics: essays on the confucian intellectual. suny is china hiding avian influenza? human rights as ''foreign affairs'': china's reporting under human rights treaties world health organization. who urges member states to be prepared for a pandemic chinese information warfare: a phantom menace or emerging threat? the strategic studies institute media censorship in china'' council on foreign relations key: cord-337546-60xq8dpg authors: chang, chia-chien; yang, alan h. title: weaponized interdependence: china's economic statecraft and social penetration against taiwan date: 2020-12-31 journal: orbis doi: 10.1016/j.orbis.2020.02.002 sha: doc_id: 337546 cord_uid: 60xq8dpg nan how do great powers utilize economic and social instruments to coerce the other countries? in this section, we elaborate the theories of economic statecraft and social penetration. economic statecraft and asymmetrical interdependence. china is not the first great power to resort to economic statecraft and societal penetration in pursuing national ambition. at the end of world war ii, the political economist albert o. hirschman published national power and the structure of foreign trade, analyzing how foreign trade could be used as an instrument of national power. the theme of hirshman's book is nazi germany's strategy to expand its trade and political influence during the 1930s. hirschman pointed out that the gain from "seemingly harmless" trade relations can result in the dependence of the country that receives the traded goods. prior to world war ii, nazi germany had already launched "bloodless invasions," using economic carrots to penetrate the political systems and societies of hungary, bulgaria, romania, and others. nazi germany's economic practices, including the export of capital, personnel, and enterprises, had created a dense network of interests and customers with the result of rendering eastern and southeastern europe subservient to nazi germany. 5 although hirschman was writing against the backdrop of nazi germany's economic aggression, his work has a broader implication for international relations today. hirschman elucidated that trade relations, or economic interdependence broadly defined, could be used as a means of political pressure and leverage because economic interdependence is usually asymmetrical, suggesting that in such an economic relationship one state is more dependent on the other. and political power and dominion arises out of the asymmetry. in international relations, power is the crucial "currency" of great power politics, and states compete for it among themselves. 6 therefore, great powers constantly pursue asymmetrical economic relationships in order to create dependence and political dominance. david baldwin, senior political scientist in the woodrow wilson school at princeton, refers to such pursuit of power through economic means as economic statecraft, defined as influence attempts relying on resources which have a reasonable semblance of a market price in terms of money. economic statecraft, baldwin contends, has been practiced for centuries. and the utility of economic statecraft has been systematically underestimated. 7 today, it is all too common for great powers to resort to economic statecraft and social penetration to further their national interests. nuclear program. 8 the russian federation launched cyber warfare to destabilize ukraine's democratic order. moreover, russia misinformed and polarized u.s. voters by extensive propaganda and penetration of social media platforms. 9 as a rising power, aiming at building its own order and sphere of influence, china has been engaging extensively in economic and social penetration of other countries. for instance, china banned rare earth metals exports to japan and curtailed the import of japanese autos due to the territory disputes regarding the senkaku/diaoyu island in the east china sea. china, as noted, also banned banana imports from the philippines to coerce the philippines to concede in the south china sea dispute. 10 more important, economic globalization, the development of supply chains, and breakthroughs of network technology have jointly transformed and updated china's coercive capabilities. some liberal scholars argue that global networks create mutual dependence that decrease states' incentives to engage in conflict or coercion. however, as political scientists henry farrell at george washington university and abraham l. newman at georgetown university show, global connectivity actually creates new opportunities for great powers to coerce, manipulate, and penetrate. like hirschman's emphasis on power asymmetry in economic interdependence, farrell and newman also find that modern globalization results in asymmetrical networks, in which some states are far more connected than others. those states become the "hubs" of the global networks and have the capabilities to exploit "weaponized interdependence." specifically, those great powers can utilize their hub positions to gather information or cut off financial and information flows, discover and exploit vulnerabilities, compel policy change, and deter unwanted actions. 11 sharp power and social penetration. financial power, hub positions in the global exchange networks, and information supply chains also enable authoritarian regimes to engage in comprehensive social penetration and manipulation of other societies. christopher walker and jessica ludwig of the national endowment for democracy analyze such phenomena through a lens of "sharp power," defined as authoritarian influence efforts to "pierce, penetrate, or perforate the information environments and societies in the targeted countries." to delegitimize democracies and other universal human-rights regimes, authoritarian regimes seek to incite and amplify existing divisions in democratic societies by manipulating or faking the information that reaches them. they also use financial incentives to induce media or civil societies in democracies to censor opinions that may be critical of those authoritarian regimes. finally, they employ new digital technologies to spread false and divisive discourse. authoritarian regimes usually exercise their sharp power through four types of social exchanges: cultural exchange programs, academic/think tank cooperation, media, and publishing. for example, china established a global network of confucius institutes all over the world to host cultural, educational, and academic exchange programs. each year, china also hosts several all-expenses-paid media and think tank conferences and exchanges with journalists and scholars worldwide. those programs and conferences, no matter how diversified they are, share one thing in common: censorship. program staff usually seek to block discussions on sensitive topics, such as taiwan, tibet, uyghurs, or other human rights issues in china. criticisms are discouraged, especially those that challenge the legitimacy of the chinese communist party (ccp). participants are expected to promote a positive image of china, as well as to praise china's social, economic, and cultural model and its achievements. 12 of course, liberal hegemons or other democratic great powers also regularly promote their culture and political values worldwide. joseph nye uses "soft power" to describe liberal powers' pursuit of and competition for international attractiveness, legitimacy, and credibility. 13 however, there are two qualitatively different characteristics between soft power and sharp power. first, as nye indicates, soft power rests in the ability of persuasion and voluntarism: you persuade your target to voluntarily follow your request with legitimate values or reasons. sharp power, in contrast, fundamentally rejects voluntarism. sharp power relies on the deceptive use of information and covert operations to mislead the target. in other words, sharp power is actually a type of coercive power because it eliminates the target's voluntary choices by manipulating ideas, political perceptions, electoral processes, and so on. 14 second, openness is the prerequisite for developing soft power, while sharp power is based on opacity, censorship, and barriers to free flows of information. ultimately, soft power hinges on legitimacy, and no one can sustain legitimacy without transparency. a country is likely to lose its international legitimacy, as well as soft power, if it continues to rely on covert operations or secret diplomacy, or if its actions are opaque or have a hidden agenda. in contrast, opacity facilitates manipulation through disinformation and is thus conducive to sharp power. liberal democracies historically countered sharp power by promoting open information and transparency of state behaviors. however, information and communication technologies have created the opportunities for authoritarian regimes to exploit the openness and interdependence of global networks. today, authoritarian regimes like russia and china regularly spread fake news worldwide to sabotage democratic societies while raising barriers to fact-checking. they use international propaganda machines and cyber techniques to dump disinformation externally so as to crowd out the global information markets and drive out other news providers or media companies. at the same time, they further tighten domestic censorship. china, for instance, has launched several censorship programs, like the "great firewall" and "great cannon" among others, which guarantee that the chinese state-own news media can monopolize its domestic marketplace of information (ideas, news, knowledge, etc.). one central goal behind the use of sharp power is to delegitimize democracies, as well as to decrease democratic soft power. dictatorships manipulate the information and destabilize democratic societies in order to show that democratic institutions and values, such as freedom and universal human rights, are no better than authoritarian ones in solving domestic disputes. furthermore, they combine sharp power with economic statecraft to propagate the argument that authoritarianism (dictators often calling it "strong nation") could be an alternative model, perhaps a better one, for development. of course, authoritarian regimes may face international backlash once their sharp power operations are disclosed. however, dictators can still benefit from sharp power because it could help consolidate authoritarian grips on domestic affairs. because dictatorships impose censorship, they can block external information and shape domestic opinions about international responses. dictators may even take advantage of international pushback to stimulate domestic resentment and patriotism. in essence, the priority is to strengthen authoritarian stability by using sharp power to penetrate other societies. china has exploited global networks in a number of ways. first, as hirschman reminded us, great powers regularly seek to convert their economic might into political leverage around the world. china is no exception. with the development of global and regional connectivity, china has used its financial muscles to gain control over major natural resources and strategic locations and to influence other states' stances in disputes. china has provided a substantial amount of aid to african countries to harden its grasp on natural resources. beijing has also launched comprehensive programs of financial statecraft, known as belt and road initiatives (bri), to establish its sphere of influence in the indo-pacific region and even the whole of eurasia. china's financial prowess successfully has swayed some states' stances in many regional disputes. philippine president rodrigo duterte's recent concession on the south china sea dispute is one notable example. another salient case is china's successful effort to induce the solomon islands to end its diplomatic relationship with taiwan. 15 second, the fundamental goal for the chinese leadership is to create a world that is safe for china's authoritarian regime. such an objective could be achieved if there are more non-democratic regimes around the world, or more countries adopting the "china model." therefore, china does not only seek to develop its repressive capacities, but also it tries to export its censorship regime-encouraging other authoritarian regimes to censor and silence domestic dissidents with the technologies and programs it supplies. china's strategy is twofold: first, it has exploited global supply chains and cross-border networks to upgrade its infrastructural power for censorship and monitoring domestic citizens. for example, china has engaged in intellectual property theft worldwide and cyber espionage to increase its information and communication technologies. 16 it has also provided various governmental supports to develop huawei, china's largest telecommunications company and chinese "national champion" of the 5g industry. huawei's success and control over 5g network technologies have enabled the chinese government to collect and store the data of almost every chinese citizen. the government also used similar industrial policies to develop hikvision digital technology and dahua technology, chinese manufacturers and the world's two largest suppliers of video surveillance products. the monitoring capacity provided by chinese surveillance camera companies, together with huawei's big data technology, strengthen china's policing capacity and the communist party's censorship. 17 the second fold of china's strategy is to export its censorship regime to other countries as well as surveillance hardware and data-analytics tools. china has engaged in social penetration into other societies and wielded its sharp power globally to justify the china model. for example, beijing is cultivating media elites and government ministers around the world to create a network of countries that will follow its lead on internet policy. chinese officials have held many all-expensespaid trainings, workshops, seminars, and conferences with representatives from other countries. during those events, china regularly propagates that the chinese model of censorship is helpful in combating terrorism and fake news, monitoring public opinion, china/diplomacy/article/3027827/us-cancels-solomon-islands-meeting-after-disappointmentit. 16 and ensuring cyber security. several countries introduced cyber-security laws that closely mimic china's own version after their official participated in those events. 18 finally, and much more concerning, the chinese state apparatus has been developing its "information troops" to silence or deter dissidents as well as to enforce pro-china views at home and abroad. the great majority of these troops-called by some as the "50-cent army"-may not actually be part of the security apparatus, but independent operators including student volunteers at universities, communist youth league members, and government bureaucrats. 19 according to political scientists gary king at harvard, jennifer pan at stanford, and margaret e. roberts at university of california san diego, the chinese state apparatus is involved in faking several hundred million social media accounts and posts. 20 the chinese information troops often use social media to launch campaigns against voices or opinions that criticize the chinese government or challenge the legitimacy of the ccp. the troops constantly use fake news or specious arguments to manipulate public opinion. with help from chinese government censorship, they can easily silence dissents and "manufacture" some public consensus. then, backed by this manufactured consensus, the chinese government is able to resort to coercion against the dissenters. in january 2016, chou tzu-yu, a taiwanese singer in the korean pop band twice, performed while holding a taiwanese national flag on a korean tv show. the chinese government and information troops directed a campaign that led to a ban on chou's presence on almost every tv show in china. and beijing demanded that chou's korean management company, jyp, refund the loss of those shows. eventually, chow was forced to bow deeply and tearfully read a scripted apology that accepted "one china" in the media. 21 in august 2019, china ordered the hong kongbased airline cathay pacific to suspend any staff that supports pro-democracy protests in hong kong. perhaps even more telling was china's ban on the broadcasts of the preseason games of the u.s. national basketball association (nba) due to a tweet by houston rockets general manager daryl morey that appeared to support the hong kong pro-democracy movements. although morey was soon forced to delete the tweet, the chinese government still demanded that the company remove morey from his post. when nba commissioner adam silver insisted that freedom of expression s i 2020| 9 is a principle not to be compromised, the chinese government and information troops launched a series of boycott campaigns against the nba. 22 in sum, economic statecraft and social penetration have become china's common practices to further its national goal. taiwan, which is highly dependent on china for its economy, is on the frontline of china's weaponized interdependence. as indicated earlier, the reunification of taiwan is china's self-defined core interest. hence, china has been engaging in economic and social penetration into taiwanese society. china's aim toward taiwan is threefold: increasing taiwan's dependence to cultivate pro-china factions in taiwanese society, constraining taiwan's pursuit of independence and democratic values, and forcing taiwan to gradually accept china's preferred version of "one-country, two-systems." china has been taiwan's largest trading partner. in 2018, china accounted for 24.2 percent of taiwan's foreign trade (while taiwan only accounted for about 5 percent of china's foreign trade). china continues to be the largest destination of taiwanese foreign direct investment (37.3 percent in 2018) and the top destination for taiwanese heading overseas to work. in 2018, 404,000 taiwanese worked in china, (including hong kong and macao), accounting for 54.9 percent of all taiwanese nationals working overseas. china is the largest single source of visitors to taiwan. in 2019 (january-october), 26 percent of total tourists visiting taiwan were chinese citizens. 23 these statistics indicate that the economic and social network interdependence between china and taiwan is highly asymmetrical. decades ago, hirschman depicted how nazi germany used industrial policies, market size, and technology to shape eastern and southeastern european neighbors' foreign trade relations, making them substantially dependent on the german market. those efforts contributed to the rise of germany's power over them before and during wwii. today, china is poised to establish its own sphere of influence over taiwan. just as great powers did in history, china has been engaging in the "5m" approach of economic statecraft and social penetration against taiwan: money, manpower exchange, misinformation, mooching (cultivating compradors), and magnifying (propagating the "chinese dream"). roman philosopher marcus tullius cicero (106 bc-43 bc) argued: "the sinews of war are infinite money." even during peacetime, money is one of the most crucial foundations for national power and statecraft. regarding china's economic and social statecraft, money could be broadly understood as any forms of positive inducements-providing quid pro quos to anyone for their loyalty and behaviors consistent with china's national interest. those quid pro quos include, but are not limited to, economic and societal benefits, such as granting market/profit shares, licensing, subsidies, protections, and various forms of privileges. in general, china utilizes its monetary power in three ways: positive quid pro quos, negative sanctions (or threaten to launch negative sanctions), and penetration of taiwanese companies for future collusion. positive quid pro quos. there are various examples of china using quid pro quos to gain leverage in taiwan. one of the most significant examples was the economic cooperation framework agreement (ecfa), a preferential trade agreement signed in 2010 between china and taiwan. through ecfa, china unilaterally lowered tariffs on many taiwanese agriculture goods and others. here, we find a historical parallel. in the 1930s, as hirschman pointed out, germany supported the agricultural economies of southeastern europe by not only paying them higher prices, but also by promising them stability in both price and volume of their exports. therefore, germany cultivated vested interests in those countries, and tied the interests of existing powerful groups in their societies to relations with germany. 24 likewise, china's quid pro quos have created powerful vested interests in taiwanese society and misperceptions about taiwan's economy and governance. for example, although the data shows that in recent years taiwan's economic situation has been relatively stable, compared with most of the countries in the region, as well as globally, still a substantial portion of taiwanese population think that the ruling party democratic progressive party (ddp) and incumbent president tsai ing-wen did not handle the economy or cross-strait relations well. 25 although ecfa created powerful vested interests in supporting china's influence, it also provoked taiwanese societal discontent with the hollowing-out effect on taiwan provide for "national treatment" to induce taiwanese youth, enterprises, startup entrepreneurs, and blue-and white-collar workers in many sectors. taiwan-funded companies may be qualified to take part in china's key industries, such as major technological equipment, 5g networks, and civil aviation. in addition, the measures allow taiwanese athletes to be treated as chinese nationals when joining professional sport leagues in china. 26 china's economic statecraft has gained success in a number of cases. in december 2018, days after the dpp's landslide defeat in the local elections, wu paochun, an international award-winning taiwanese baker, announced that he was going to open branches of his bakery in china. however, in order to appease chinese netizens, wu issued a statement saying that he was born in "taiwan, china" and is "proud to be chinese." wu insisted that "two sides of the strait are one family" and is willing to promote economic exchanges and trade across the taiwan strait. wu also hoped that he could participate in the "measures to promote cross-strait economic and cultural ties" released by china's taiwan affairs office of the state council. 27 china's tactics are especially effective in the entertainment industry. several taiwanese celebrities currently working in china have made supportive statements consistent with china' interests, even including the sovereignty issue. in 2016, after the permanent court of arbitration negated china's "nine-dash line" claims to the south china sea, many chinese celebrities started to post a map of the territory that china officially claims, including the nine-dash line. the image also bears a slogan: "china: we cannot lose a single inch [of territory]" and "china's territorial sovereignty doesn't need others to arbitrate." 28 in 2018, then, after a taiwanese director made an independence-leaning, pro-democracy award speech at the golden horse film festival and awards (the chinese-speaking world's version of "oscars"), beijing immediately censored the broadcast of the award ceremony. this time, many taiwanese celebrities working in china immediately posted or re-tweeted that image and the slogan: "china: we cannot lose a single inch" even though taiwan has different claims on its own sovereign territory and the south china sea dispute. 29 negative sanctions or threatening. negative sanctions are common in china's toolbox of economic statecraft. once china successfully cultivates asymmetrical networks with other states, or private actors, and makes them highly dependent on china, beijing becomes more capable of coercing them by cutting (or threatening to cut) the money flows. for example, the chinese recently suspended a program that allowed individual tourists from 47 chinese cities to travel to taiwan, citing the current state of relations between the two sides. the scheme had been in place since 2011 under the more china-friendly administration of former president ma ying-jeou. the suspension is commonly interpreted as china's effort to dampen local support for the dpp by cooling the tourism industry in taiwan. 30 another salient example was the "yifang fruit tea event." yifang fruit tea ( , yä« fä�ng shuç� shuç� guç� chã¡) is one of the famous taiwanese tea brands that has opened many shops around asia. in august 2019, when the pro-democracy protests in hong kong escalated, one of yifang fruit tea shops in hong kong closed for a day and put up a sign that read in chinese: "stand together with hong kongers." chinese netizens were furious because it seemed like yifang fruit tea was backing pro-democracy protests in hong kong. they called for a boycott on yifang, which soon spread to other taiwanese bubble tea brands, including gong cha, heytea, coco, and a little tea. days after the boycott, yifang fruit tea issued a statement on social media in china, saying that yifang firmly supports "one country, two systems" and opposes protests and strikes in hong kong. 31 china also constantly enacts negative sanctions in the entertainment industry. in august 2019, china's film regulator announced that it was prohibiting the chinese movie industry from participating in taiwan's golden horse awards. 32 in addition, a popular taiwanese youtuber lost his business in china after a video of him interviewing taiwan's president went viral. in the video, potter king, a taiwanese internet celebrity with a significant following on both sides of the taiwan strait, addressed taiwan's leader, tsai ing-wen, as "president." king's chinese distributor immediately demanded that he to take down the interview from taiwanese social media. his chinese social media accounts were also seized by the chinese distributor, who removed the video from chinese social media. later, the chinese distributor released a statement indicating that potter king's contract had been terminated. it described king's language and actions as "inappropriate," and "it strongly rebukes any actions which undermines china's dignity and sovereignty. it firmly insists 'one china' principle." 33 china also seeks to use licensing or customs inspection to coerce taiwanese companies to accept the "one-china principle." for example, taiwanese companies need to label their goods as made in "taiwan area, china," instead of "made in taiwan" or "made in taiwan, r.o.c." when they export to china. if they do not comply, then they may face extra duties or longer inspection time. in some cases, customs agencies in china destroyed imported taiwanese products that did not have the newly required "taiwan area, china" label. 34 illegal buyout and forced collusion. lastly, china is also launching two sophisticated monetary statecrafts to penetrate individual taiwanese companies as well as the whole industries. chinese state-owned or state-backed enterprises constantly use their enormous financial resources to lure taiwanese companies, especially those with crucial know-how, to cooperate and jointly develop business. for example, in 2015, tsinghua unigroup ltd, a chinese state-owned technology conglomerate, planned to spend billions to acquire stakes in three taiwanese semiconductor companies. the three targets, silicon precision industries co. (spic), powertech technology inc., and chipmos technologies inc., are all leading chip packing and testing companies in the global arena. 35 the case was controversial because tsinghua unigroup's parent company, tsinghua holding, is considered deeply connected with the chinese communist party. tsinghua holding's former communist party secretary, hu haifeng, is the son of hu jintao, the predecessor of xi jinping. tsinghua unigroup used to have strong government support; in fact, its acquisitions were far beyond its yearly revenue. 36 because the acquisition of tsinghua unigroup raised concerns about market monopoly and national security, the taiwanese regulatory agency reviewed it carefully. in the end, the three investment plans of tsinghua unigroup failed. however, there are many cases where chinese state capital tried to enter taiwan through a third location (either hong kong or singapore) in order to circumvent taiwanese regulations. more concerning still is china's collusion strategy. once chinese state-owned enterprises (soes) acquire controlling shares of a taiwanese company, these enterprises not only want to grab the crucial know-how/technologies of that company, but they also try to leverage the newly acquired company as part of broader economic statecraft. one notable example was a case of china's economic espionage, in which a taiwanese company was charged with helping a chinese soe steal a u.s. company's intellectual property. according to the u.s. department of justice's indictment, prior to the intellectual property theft, fujian jinhua integrated circuit, co., ltd. ("fujian jinhua"), a chinese soe, did not possess dram technology. then, fujian jinhua sought help from a taiwanese individual, chen zhengkun, who previously worked for micron (the u.s. company) and became the president of a micron subsidiary in taiwan responsible for manufacturing micron's dram chips. chen resigned from micron in july 2015 and immediately began working at united microelectronics corporation ("umc"), a taiwan semiconductor foundry. while at umc, chen arranged a cooperation agreement between umc and fujian jinhua; with funding from fujian jinhua and the chinese government, umc would transfer dram technology to fujian jinhua. chen later became the president of fujian jinhua and was responsible for its dram production facility. while at umc, chen recruited taiwanese employees from micron to join him at umc. those taiwanese employees stole and brought to umc several micron trade secrets related to the design and manufacture of dram. 37 manpower exchange is another part of china's economic and social statecraft. china is not the first great power to use its networks of manpower to cultivate external influences. in hirschman's study, anecdotal evidence shows the export of german trained and skilled labor contributed to germany's penetration into foreign countries. china is practicing similar tactics. what makes china's manpower strategy so special is its size, and how comprehensive and sophisticated china's manpower networks have become. the flows of manpower as well as other types of social exchanges create opportunities for china to not only develop the united front in the taiwanese society, but also to breed taiwanese affinity with the ccp. the chinese state apparatus has been using multiple manpower channels to make direct contacts with local people and grant benefits to them. china's statecraft used to focus on the "three middles and the youth"-the youth, small and medium enterprises, middle-and low-income classes, and the population in the middle and southern taiwan, who are traditionally considered more pro-independent. in 2017, yu zhengsheng, the chairman of the chinese people's political consultative conference (cppcc) and member of the politburo standing committee, further unveiled that china's economic and social statecraft is going to target "one generation and on stratum" in taiwan-the younger generation and the grassroots. 38 china has launched its social penetration operations through those channels, and two are most influential: religious networks established by local temples and quasiillegal organizations, and various "cross-strait exchange groups." traditionally, china used to manipulate these two channels to penetrate the whole taiwanese society, including both the younger generation and the grassroots. in recent years, religious networks have become china's main instrument toward the grassroots because of the political-societal role local temples play in the communities. as for the younger generation, china has become more inclined to rely on cross-strait exchange groups to tempt the taiwanese youth with travel, studying, and job opportunities. religious networks, local temples, and quasi-illegal organizations. in taiwan, temples play an important role in local lives and communities. because of their huge cash flows and unsupervised finances, temples are the foundation of taiwan's underground economy. temples also serve as a place for regular gathering and information sharing within the communities. finally, temples usually function as local charities in taiwan and may provide emergency support in natural disasters (though their roles in this regard are limited). therefore, temples tend to have important political influence over local communities and a capacity for political mobilization. because a large number of people on both sides of the taiwan strait share similar religions, the chinese state apparatus has noticed the potential to use temples and religious exchanges to win local people's heart. accordingly, the chinese state apparatus has been actively seeking local agents' help to develop cross-strait religious networks with temples in taiwan. one famous agent is the chinese unification promotion party, also known as the unionist party. the unionist party was founded in 2005 by the "white wolf" chang an-lo, formerly a key member of the bamboo union, a gang accused of engaging in organized crime. the unionist party is controversial not only because of its strong pro-unification stance, but also due to its aggressive tactics. for example, it provoked violence and attacked pro-independence demonstrators in the 2017 "sing! china" event at national taiwan university. in addition, its members were constantly seen holding chinese flags outside the taipei 101 skyscraper to confront falun gong ( , fç� lun gå�ng) members. 39 moreover, in 2019, during a rally in taiwan supporting pro-democracy movements in hong kong, the unionist party members threw red paint at the participants. 40 furthermore, the unionist party held several conferences and activities in taiwan to promote the idea of unification by any means, including brute force. the unionist party also uses its networks to help chinese people more easily enter taiwan to conduct political propaganda. for example, the unionist party invited li yi, a chinese scholar, who once argued for the necessity of using force for unification, to deliver a political speech in a pro-unification conference although li's visa was only for tourism. in addition, chang wei, son of chang an-lo, runs the huaxia dadi travel service co, a shadow travel agency for chinese tourists. huaxia dadi and other shadow travel agencies have used "fake exchange proposals" to secretly and illegally help more than 5,000 chinese people enter taiwan, including chinese civil servants. according to one report in commonwealth magazine, there are three pillars of the unionist party: gangs (or former gangs), temples, and overseas taiwanese businesses. the unionist party and temples have a close cooperative relationship, and some have secured important positions in temple groups. a notable example is lin kuo-ching, a former gang member, who is now a member of the unionist party's central committee. lin serves as the honorary chairman of several temples, and has excellent relations with the taiwan mazu fellowship run by yen ching-piao. moreover, because smaller temples usually find it hard to establish channels for interaction with temples in china, they turn to the unionist party for help. in exchange, they give party members lucrative contracts for the temple's processions and rituals. now, several small and medium private temples around taiwan are said to have links with the unionist party. 42 in sum, the unionist party, other pro-unification organizations, and taiwanese local temples jointly have created a powerful network of local political mobilization. such a network has become a major channel for the chinese state apparatus to target the grass roots in taiwan and cultivate local communities' affinity with china and the ccp. cross-strait exchange groups. the cross-strait exchange groups are another crucial element of china's social penetration efforts. for many years, the chinese government has used semi-official or puppet organizations to increase and deepen economic, social, and cultural ties between taiwan and china. the aim of those groups has been to cultivate a shared "pan-chinese" identity and to create vested interests in unification. a common strategy for those exchange groups is free tours to specific places in china. such "tours" are planned by the exchange groups, and travel expenses and accommodation are fully covered. during each tour, taiwanese participants are exposed to political propaganda. on occasion, ccp officials deliver keynote speeches. taiwanese participants are also likely to receive some benefits (or promise of benefits). last, personal networks between taiwanese and chinese are established during the interactions. those tours could increase the likelihood that participants rejoin similar tours in the future. with increased participation, powerful bonds are likely to develop between the taiwanese participants and china. those bonds may become useful tools for the chinese government to shape the identity and interest of the taiwanese participants, making them more willing to accept china's influence. previously, those exchange groups mostly focused on taiwanese adults or the elderly. recently, they have shifted their target to taiwanese youth. according to the data, every summer, more than 3,000 taiwanese students participate in such china tours. there are usually five kinds of tours. 43 the first is theme workshops or forums. the themes include: leadership, entrepreneurship, development, technology, and chinese history and culture. such tours tend to be organized by top chinese universities and usually contain political propaganda. the second kind of tour is corporate internships. participants have the opportunity for internships in different chinese companies. their travel expenses and accommodation are covered, and they can earn stipends. participants can develop their personal networks. following the internships, participants also have chances to become full-time employees. this kind of tour can cultivate participants' material interest in china and has the potential to function as positive quid pro quos. the third kind of tours is natural and historic sites, and business parks. this kind of tour is usually the presentation of china's soft power. the fourth type of tour is academic conferences and expert workshops. because there are many high-ranking chinese universities, and those universities have more resources to hire renowned professors, this kind of tours can attract taiwanese students seeking more educational opportunities and future employment. finally, there are "art and sport exchange tours." to some extent, this kind of tour functions as the "ping pong diplomacy" between the united states and china from the 1970s. however, such tours have powerful potential as economic and social statecraft because they target even younger generations, such as teenagers, or the athletes, who face an insecure job market in taiwan. china also resorts to sharp power to misinform the taiwanese public, manipulate the society, and sabotage taiwan democracy. china's manipulation in taiwan's politics has been carried out through different channels over years. with the development of cyber technologies, china has also been making greater effort in nurturing pro-communist media and strengthening its capability to manipulate social media in taiwan. in january 2016, when tsai ing-wen won the presidential election, members of "diba," a forum with more than 20 million followers on china's largest search engine baidu, called upon chinese web-users to flood prominent taiwan-related facebook pages with anti-taiwan independence comments. within 12 hours, there were 40,000 negative comments on tsai's facebook page. "diba expedition"-an abbreviated description of the campaign-became a top trending search on china's social media weibo. 44 another example was the rise of han kuo-yu, the kuomintang (kmt) party's presidential candidate in 2020 and mayor of kaohsiung city. han was a largely unknown name until late summer 2018, barely four months before the 2018 mayoral election. however, han started his meteoric rise through the polls. he eventually won a landslide victory in the critical election. many people attributed han's ascendancy to his personal charisma and popularity on social media. for example, han kuo-yu's official facebook account had half a million followers at the end of the campaign. however, a careful analysis shows that china's information manipulation may have contributed to han's victory. as paul huang points out, many of han's facebook supporting groups were created, managed, and nurtured by what looks very much like a professional cyber group from china. those groups helped mobilize the support for han through many means, including using fake news to manipulate the public attitude. 45 china's manipulation tactics and espionage are also common in taiwanese academia. an anonymous scholar from national sun yat-sen university pointed out that since 2016, unidentified hackers have silently accessed and checked the email of more than 10 professors of political science and international relations through several fake accounts posing as senior school administrators. the intruders' ip address has been traced back to china, hong kong, and the united states. this year, the hackers' ip addresses were highly concentrated in hong kong and were suspected of being a domain address generated by using a virtual private network (vpn). 46 this suspicion indicates that china may have extended its cyber espionage network into the taiwanese academia and universities to increase political control by monitoring the behavior of teachers and students. another method for china to penetrate taiwan's society and politics is "mooching." the purpose of mooching is to cultivate local political agents loyal to the ccp, 47 and to use them to undercut the capacity and authority of taiwanese government. to some extent, the strategy is similar to colonial authorities' policy toward local compradors. the mooching approach resembles the manpower exchange approach. for example, both approaches include approaching/inviting taiwan's opinion leaders, 48 local politicians, community leaders, 49 and key figures, such as retired ministers, 50 exmilitary generals, religious leaders, school principals, and teachers, as well as young students to take part in cross-strait forums and various exchange programs organized by china's public and private sectors. nevertheless, these two approaches are different. first, they rely on different ways to govern cross-strait ties. the manpower exchange approach focuses on building institutionalized channels to conduct routine cross-strait interactions, while the mooching approach emphasizes developing informal networks to deal with ad hoc tasks. second, each approach has a distinct strategic goal. the manpower exchange approach seeks to shape taiwanese general public opinion toward china and the ccp, and to foster a group of constituents that can influence taiwanese politics in china's favor. in contrast, the mooching approach aims for cultivating specific pro-china agents to conduct ad hoc cross-strait affairs. a salient example is the recent taiwanese evacuation from wuhan due to the coronavirus. after the 2019 outbreak of the novel coronavirus (also commonly known as the wuhan coronavirus) in china, taiwan's government kept requesting that beijing permit the evacuation of taiwanese citizens from wuhan. however, the chinese government did not respond to taiwan's request because china stopped official communications with the incumbent government led by president tsai ing-wen since 2016. china also continues to block taiwan's attendance at the world health organization, constricting the taiwanese government's ability to receive timely information about the coronavirus situation. beijing eventually allowed an evacuation flight due to the worsening situation. however, media reported that the chinese officials only collaborated with pro-china taiwanese businesspersons and elites when drafting flight manifests, rather than allowing taiwan's government to directly handle the evacuation. 51 the mooching method is also widely adopted by china's local governments, enterprises, and associations when they approach young taiwanese. for example, china's universities provide young taiwanese doctorates with assistant 49 the author interviewed a community leader in yilan county on his opinion regarding cross-strait local community interaction. he argued, "china is developing democracy at the grassroots level. wealthy and strong community organizations are important to improve their quality of life. therefore, community representatives came to taiwan to learn about the development and reinvigoration of local community and are aimed at establishing close ties between grassroots communities in china and taiwan. from their perspective, it is to facilitate natural social integration of both sides. nevertheless, with our successful experience, they shall and will thank taiwan and maintain good relationship with us." interview with a local community leader in yilan county, dec. 19, 2019. 50 huang tzu-ti, "x-defense minister of taiwan says beijing approached him," taiwan news, dec. 2, 2019, https://www.taiwannews.com.tw/en/news/3828785. 51 "coronavirus: beijing allows taipei to evacuate taiwanese in wuhan," the straits times, feb 05, 2020, https://www.straitstimes.com/asia/east-asia/beijing-allows-taipei-to-evacuatetaiwanese-in-wuhan; and nick aspinwall, "taiwan's coronavirus response hits obstacles set by chinese government?," the diplomat, feb. 7, 2020, https://thediplomat.com/2020/02/taiwans-coronavirus-response-hits-obstacles-set-bychinese-government/. professorships. 52 local governments offer young entrepreneurs with funding for startups, working spaces, law services (ex. company registration service), and other business incentives. 53 some professional associations even provide young taiwanese professionals with certificates related to their future careers. for example, young tea farmers in central taiwan are encouraged to take china's version of certification in tea art. it is easier for those with china's professional qualification certificates to seek jobs in china and to promote taiwanese tea products in chinese market. 54 china's final approach to penetrate taiwanese society is "magnifying." similar to the misinformation approach, magnifying is also a strategy of using media to create disinformation to manipulate taiwanese public opinion, a case of china's sharp power. however, the two approaches have different missions and tactics. the goal of the misinformation approach is to delegitimize taiwan's democratic institutions and values. hence, misinformation regularly relies on fake news to amplify existing divisions, instigate social conflicts, trigger political instability, and sabotage public trust and confidence in the taiwanese government. in contrast, magnifying is designed to propagate the china model, glorify the "chinese dream," and preach the necessity of reunification of taiwan and china. therefore, the magnifying approach adopts media propaganda that exalts the success of china's development, highlights china's cultural significance, praises china's contribution to the world, and advocates the benefit and the inevitability of joining china's sphere of influence. in recent years, the chinese state apparatus and pro-china forces have targeted the southern localities of taiwan by using various media channels, such as traditional radio stations and new social media. the local radio stations in the central and southern part of taiwan traditionally were the primary local sources of everyday information in support of the pro-taiwan independence sentiments, and the audience is regarded as deep-green supporters and anti-china hot-liners. in taiwan, the key member of chinese unification promotion party hosts radio programs in the southern cities in conjunction with new social media, such as live streaming facebook fans page, to convey the pro-china ideology and disinformation to local people. the brainwashing information includes praising china's political economic development and industrial policy under the leadership of xi jinping, promoting the success of the bri globally, and advocating the cross-strait social and economic integration. 55 some programs even argued that the people's liberation army, china's warships, missiles, and fighters circumnavigating taiwan were to defend taiwan against terrorism or other countries, including the united states and japan. 56 these programs are to formulate a new pro-china social echo chamber in the deep-green localities of taiwan. cross-strait relations between china and taiwan used to maintain a fragile balance. however, since the global financial crisis of 2007-08, china has become more assertive in challenging international norms, pursuing national rejuvenation, and wielding its power globally. china's threatening behaviors have pushed the relationship between taipei and beijing toward the brink of crisis. in order to counter china's threat, taiwan needs to be vigilant and take necessary measures. first, taiwan must pay attention to china's economic and social penetration and cultivate the general will and commitment to defending its democracy and sovereignty. as hirschman underscored, when facing great power's threat of domination, if a small country pays greater attention to the asymmetrical relationship, and maintains a stronger commitment to defending its autonomy, the "disparity of commitment" could generate room for the smaller country to maneuver to achieve greater autonomy. 57 taiwan's democracy is the best antibody against china's penetration. the taiwanese government as well as taiwanese people must be vigilant against china's statecraft. taiwan must be deeply committed to its democratic development and institutions. recently, taiwan passed a new cybersecurity law and enacted new penalties on fake news. the government and civil society also cooperate to form fact-checking mechanisms to curb fake news and disinformation. taiwan is initiating an "antiinfiltration law" to counter external interference in domestic affairs, such as elections and legislations. those measures are essential to assure taiwan's democratic resilience against china's threat and malicious penetration. in addition, taiwan must continue seeking, building, and strengthening relationships with democratic, like-minded allies. china's economic and social leverage arise from its hub position in global networks, in which many other countries are asymmetrically dependent on china. of course, chinese markets, resources, and civil societies are valuable assets for world development, and there are always opportunities for cooperation with china. while, it is unnecessary to cut off economic interactions with china, taiwan should pursue a diversification strategy. taiwan has sought to contribute to one cluster among the contending regional approaches in the indo-pacific region, including the u.s.-led free and open indo-pacific (foip) strategy, the ira, social media and political polarization in the united states china's unilateral sanctions weaponized interdependence: how global economic networks shape state coercion what is 'sharp power'? how sharp power threatens soft power: the right and wrong ways to respond to authoritarian influence the rise of digital authoritarianism fake news: national security in the post-truth era how the chinese government fabricates social media posts for strategic distraction, not engaged argument a 16-year-old pop star was forced to apologize to china for waving taiwan's flag taiwan rebukes beijing's new 26 measures for cross-strait exchanges taipei times the social media 'war' over the south china sea you can speak whatever you want in the golden horse film festival:' from 'taiwan as an independent country' to 'china: we cannot lose a single inch china bans citizens from traveling to taiwan as individual tourists storm in a bubble teacup over taiwan firm's support for hong kong protesters absence of china a 'loss' at chinese-language 'oscars' in taiwan taiwan youtuber loses china business over tsai interview goods manufactured in taiwan and exported to china are required to be labeled 'made in taiwan, china,' source tells china's tsinghua unigroup to invest $12 billion via world's biggest private placement chinese cyber-operatives boosted taiwan's insurgent candidate hackers accessed to and monitored the email accounts of political science professors of national sun yat-sen university for three years most of the participants were strongly encouraged to show their support for chinese nationalism, recognize the traditional cultural roots as the basis for the unification of the two sides of the taiwan straits the opinion leaders, including scholars, experts, and retired military officers, were invited to participate in china's state-run tv programs and expressed their support for the chinese government or the unification of the two sides of the taiwan straits, which led the chinese people to mistakenly believe that this was the mainstream opinion of taiwanese society. see, chung li-hua interview with a young tea farmer who was encouraged to take the qualification exam of tea artist in china chang mong-tsung's facebook page china provides no solution for taiwan japan's indo-pacific vision, and india's act east policy to reinforce its relationships with the like-minded countries and other democracies in the region taiwan's nsp not only seeks to build trade and investment linkages, but also pursues mutually beneficial social bonds through people-to-people centered networks since xi jinping consolidated his grip on power, the risk of china abusing its power has increased dramatically. today, the chinese government is imposing stringent rules on domestic citizens, including detention camps in xinjiang and the social credit/surveillance system for all citizens. it also has become much more aggressive in challenging democratic values and universal human rights globally. china has been using its financial and technological power to export censorship and promote authoritarianism to other countries. it has leveraged its position in global networks to penetrate other democratic societies to undermine universal values including the freedom of expression. beijing's social penetration and economic coercion pose severe challenges for democracies unpacking taiwan's presence in southeast asia: the international socialization of the new southbound policy a taiwanese vision for a free and open indo -pacific region key: cord-336753-4212ftlc authors: luo, lu; jiang, jingwen; wang, cheng; fitzgerald, martin; hu, weifeng; zhou, yumei; zhang, hui; chen, shilin title: analysis on herbal medicines utilized for treatment of covid-19 date: 2020-05-27 journal: acta pharm sin b doi: 10.1016/j.apsb.2020.05.007 sha: doc_id: 336753 cord_uid: 4212ftlc as coronavirus disease 2019 (covid-19) pandemic poses a substantial global public health threat, traditional chinese medicine (tcm) was used in 91.50% of the covid-19 cases in china, showing encouraging results in improving symptom management and reducing the deterioration, mortality, and recurrence rates. a total of 166 modified herbal formulae consisting of 179 single herbal medicines were collected for treating covid-19 in china. glycyrrhizae radix et rhizome, scutellariae radix, and armeniacae semen amarum are the most frequently utilized in clinics, most of which are antipyretic (47, 26.26%), expectorant and cough-suppressing (22, 12.29%), and dampness-resolving (21, 11.73%) from traditional descriptions. a total of 1212 chemical components containing β-sitosterol, stigmasterol, and quercetin were primarily selected. additionally, using complex system entropy and unsupervised hierarchical clustering, 8 core herbal combinations and 10 new formulae emerged as potentially useful candidates for covid-19. finally, following scaffold analysis, self-organizing mapping (som) and cluster analysis, 12 clusters of molecules yielded 8 pharmacophore families of structures that were further screened as pharmacological targets in human metabolic pathways for inhibiting coronavirus. this article aims to make more easily accessible and share historical herbal knowledge used in contemporary treatments in a modern manner to assist researchers contain the global spread of covid-19. while covid-19 is now being effectively controlled within china, it is increasingly affecting other countries worldwide, most notably the u.s., iran, and italy since feb 25, 2020 1 3 with a long history of combating epidemic diseases with relatively low mortality, tcm has accumulated a rich antiviral herb knowledgebase from clinical observation and pharmacological selection. this is historically based on a phenomenological approach and relies on complex mixtures of herbal medicines, as well as nonpharmacological holistic interventions, such as acupuncture and health lifestyle guidance 5 . with pandemic diseases, tcm has shown the agility to be administered more quickly and more efficiently than conventional medicine 4 . it asserts that health is a state of harmony between an individual's internal physiological network of factors and that of an external environmental 6 . diagnosis is through syndrome differentiation called "bian zheng", a holistic analysis of clinically observed information that guides personalized treatment options 4 , which may be adaptably changed dynamically during disease progression 7 . from point of tcm, epidemic disease is considered caused by an external pathogenic attack (traditionally named pestilent qi or evil qi) due to climatic or environmental changes. in the battle between healthy qi (immunity) and pathogenic qi (pathogen), a weakened immune system results in disease, while exhaustion of healthy qi leads to death 7 . consequently, different syndromes can manifest as disease progresses. from tcm perspective, the fundamental pathogenic factor of covid-19 would be termed as "dampness accumulation in the lung", which invades from the exterior to the interior attacking other organs as disease develops from the early stage to mild, moderate, severe, critical, and recovery stages. according to the syndrome differentiations, the pathogenesis in the mild and moderate stages of covid-19 is damp accumulation in the lung. during the severe and critical stages, dampness develops to "damp-heat toxin and congests in the lung". while heat toxin "burns" or rapidly depletes qi and yin, this subsequently would appear as what is termed "dual vacuity of qi and yin of lung and spleen in the recovery stage" 3 . it could be otherwise expressed somewhat as exhaustion of the lung system, its moisture, membranes and resource to recover, along with its fundamental immune supporting system. herbal formulations are then frequently modified as signs and symptoms change along with the diagnosis and corresponding syndrome differentiations. appropriate herbal formulae are administered, containing herbs composed in a hierarchy called "jun chen zuo shi", relating to their primary, secondary, tertiary and quaternary functional class order, respectively 8 . through design, herbal formulae guide a combination of different herbal medicines based on the individual synergistic properties of each herb. the jun 4 (monarch) component is the principal phyto-complex targeting the major symptom of the disease. it synergizes with the chen (minister) herbs to support its therapeutic effects. the zuo (assistant) medicinal reduces or eliminates possible adverse or toxic effects. lastly, the shi (courier) herbs facilitate the delivery of the principal components to desired sites (e.g., target organ), or facilitate the overall action of the other components. the whole formulae thus strive for a synergistic effect that targets active phytochemicals to their designated sites of action 8 . furthermore, herbs can be administered through a diverse number of routes including oral intake, nasal inhalation, moxibustion, and herbal plasters (fig. 1 24, 25 . the rich experience and herbal knowledgebase in fighting pandemics, are now explored here as a foundation 5 to further explore potential effective components and combinations in herbal medicines using more recent advances in data analysis. the components were converted to murcko scaffolds, dissecting molecules into ring systems, linkers, side chain atoms, and frameworks, by scaffold analysis 32 . som arranges the position of these structures in two-dimensional space, after which the dataset contains inherently similar structures and is suitable for inclusion and further cluster analysis 33 . finally, the cluster map of the complete dataset was computer generated followed by visually assessing the largest common groupings of clusters, 6 by reducing the cluster numbers manually until all the disparate clusters without neighbors were included, but the main clusters remained 34 . (2018-007-02, "feather spray"©2018), the r function for statistic computing platform: x86_64-pc-linux-gnu (64-bit)] 35 and pajek visualization 36 . armeniacae semen amarum (ku xing ren) has been used for the treatment of pain and inflammatory diseases such as asthma, bronchitis, emphysema, constipation, nausea, leprosy and leukoderma 77 . the herb has been used to reduce fever, relieve cough and quench thirst. amygdalin is the major compound, which has been reported to have anti-inflammatory and analgesic effects in the inhibition of the cox-2 9 pathway 77 . ephedrae herba (ma huang) has traditionally been used in china for bronchial asthma, coughs, colds, flu, fever, edema, and arthralgias. the aerial parts of different ephedra species contain from 0.02% to 3.4% of six optically active alkaloids. ephedrine is the major isomer comprising 30%-90% of the total alkaloids 78 . it enhances the release of norepinephrine from sympathetic neurons. the vasoconstrictor and bronchodilator effects explain the traditional use of ephedra as a nasal decongestant and anti-asthmatic 78 . it was reported that the growth of h1n1 virus was inhibited when the cells were treated with its extract immediately after infection. its inhibitory effect was completely or partially reversed by fecl 3 , a tannin-reactive agent, suggesting that tannin is one of the active components in the extract 78 . citri reticulatae pericarpium (chen pi) promotes the circulation of qi and is widely taken for coughing by drying dampness and expectorating phlegm 79 we have explored 8 groups of core combinations by hierarchical clustering with 98 individual herbs whose modified mutual information is over 0.03, drawn from the 166 the sixth group focuses on expelling the pathogen and strengthening the spleen. the seventh group aims at tonifying qi and nourishing yin. the last one regulates qi, 11 warms the interior, and relieves pain ( fig. 4a and supporting information table s6 .1). the core combinations found here correspond with the traditional rules of herbal medicine composition and compatibility to reinforce particular functions in the treatment of covid-19. for core combinations of chemical components, only herbs appeared twice or above and with modified mutual information over 0.1 were included, at last 12 core combinations were obtained. some chemical components share the same category of traditional therapeutic effect (fig. 2d) , which may signify potential synergistic effects. there are mutual groupings within these core combinations of herbal pairs and chemical components, thus supporting that the herbs and formulae containing these properties may act as potential candidates for covid-19 treatment ( fig. 4b and table s6 .2). 1164 murcko scaffolds and 40 aliphatic straight chain fragments were removed from the data and not considered further as they produced useless ring structures (fig. 5a ). som resulted in distinctly dispersed map of structural similarly components. therefore, the dataset is diverse yet contains inherently similar structures suitable for inclusion and further cluster analysis. the clusters were self-organized (som) based on the ring system (fig. 5b ). analysis mapping of the nearest neighbours visually exhibited both diverse clusters and clearly associated families of structures (fig. 5c) . finally, 12 significant clusters with distinctly different structures were discovered, from which one representing each family were screened in silico for coronavirus activity, against approximately two million molecules using chembl online database 82 (12%), 229e (16%) and nl63 (72%). herbs containing the same pharmacophore clusters above, due to their chemical scaffold similarity and nearest neighbours, are more likely to behave pharmacologically similar. therapeutically they may possess synergistic properties when used in combinations due to possessing chemical similarities, yet different when act on similar metabolic targets in slightly a different manner. this is the inverse analog of "shotgun chemistry" where similar compounds are applied en masse, often indiscriminately in either chemical, biological, dna analysis or in drug discovery 83 . further pharmacophore synergy investigations are encouraged and could be thought of "selective shotgun" chemistry based on these findings. table s7 ). tcm asserts that pandemic diseases occur naturally and periodically as the climate or geographic situations change. tcm also emphasizes the enhancement of immune function to encourage the body to expel external pathogens. this is also done through the use of herbal formulations derived from careful analysis of syndromes likely to arise in a given year or season. this preventative strategy has also been useful in the treatment of covid-19. in addition to assisting in the relief of symptoms for most patients in all stages, this approach is especially appealing due to the strong emphasis on both prevention and participation in the recovery of various disorders 79 . the prevention strategy appears in three parts: preventing occurrence, deterioration, and reoccurrence. tcm seems to have shown encouraging results in reducing the rate of mild illness, deterioration to severe stage and overall mortality as well as shortening total disease duration. when combined with modern biomedicine, herbal medicines could relieve hypoxemia and chronic obstructive pulmonary disease (copd) 84 this study relies on computational analysis, which has the inherent weakness of not possessing aspects of qualitative judgment and "common sense", that human conducted analysis possesses. to offset this as much as practically possible, this 16 study's scope only focused on herbal medicines which have been developed, selected and proficiently used in practice over thousands of years. additionally, it included herbs only which have been well studied, possessing "drug like" bioavailability, further bringing a "real-world", pharmacological information to the initial dataset. the application of relatively novel computational, pattern recognition and in silico methodologies to a preselected knowledge base of herbal formulae most frequently used, in-part attempts to overcome the shortcomings of the network analysis and computational analysis approach. the 8 resulting pharmacophores and core combinations were based on firstly traditional use, secondly "drug like" characteristics and thirdly reported in silico bioactive pharmacophore structure. therefore, we propose they present the most likely candidates, taking the constraints of this study into account, to be included, in few multiples or in combination to support the composition of completely novel covid-19 herbal formulae. the strengths of computational methods far outweigh their weaknesses. they bestow the ability to recognize and extrapolate useful patterns from herbal datasets which would otherwise take many years, if at all possible for human researchers to explore and uncover. the combination of this blended approach, as presented here, utilizes the combined advantages of both, to enable new useful knowledge obtained from a meaningful practical foundation. the pharmacologically active ingredients of a phyto-complex are not always the original molecules in its natural state, but maybe their host-specific metabolites or molecular complexes formed following co-administration with other herbs. the multicomponent nature of traditional medicines leads to multiple potential molecular interactions, multiple targets, and a myriad of metabolic byproducts, which requires a more network-oriented and holistic approach 94 . the approach could be further refined by the application of omics technologies to optimize the synergistic effect of herbal remedies. with clinicians and basic researchers creating a database of personal therapeutic responses, continual improvements to the evolution and creation of herbal formulations would become possible 5 . integration of western and chinese medical conceptual perspectives has enormous potential for constructing modern technological and social innovations. they are poised to merge within the arena of personalized medicine systems, wherein patients can take a greater role in managing their health and wellness 95 . in a time of increased international awareness of the environment, health and personal responsibility for mankind, an integration of east 17 and west should most likely be mutually beneficial 91 . as the global spread of covid-19 continues to worsen, it is necessary to disseminate the many advantages of traditional medicines for the prevention and treatment of covid-19. bridging the gap between traditional and conventional medicine during this global covid-19 spread is both timely and crucial. we sincerely hope that this study will serve as a reference to the global covid-19 research community. herbal formulae were collected from 26 protocols for treating covid-19. using complex system entropy and 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immunomodulatory effects of licochalcone a on experimental autoimmune encephalomyelitis 18β-glycyrrhetinic acid delivered orally induces isolated lymphoid follicle maturation at the intestinal mucosa and attenuates rotavirus shedding antiviral and immune stimulant activities of glycyrrhizin against duck hepatitis virus effect of a combination of glutamyl-tryptophan and glycyrrhizic acid on the course of acute infection caused by influenza (h3h2) virus in mice pharmacological effects and pharmacokinetics properties of radix scutellariae and its bioactive flavones anti-inflammatory effects of scutellaria baicalensis water extract on lps-activated raw 264.7 macrophages effects of scutellariae radix on gene expression in hek 293 cells using cdna microarray flavones from scutellaria baicalensis georgi attenuate apoptosis and protein oxidation in neuronal cell lines scutellariae radix extracts suppress ethanol-induced caspase-11 expression and cell death in n 2 a cells antioxidant activity of anti-inflammatory plant extracts the extract of compound radix scutellariae on mrna replication and ifn expression of influenza virus in mice the flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines differential inhibitory effects of baicalein and baicalin on lps-induced cyclooxygenase-2 expression through inhibition of c/ebpβ dna-binding activity binding aspects of baicalein to hiv-1 integrase baicalin, an inhibitor of hiv-1 production in vitro human 24 cytomegalovirus-inhibitory flavonoids: studies on antiviral activity and mechanism of action extract from scutellaria baicalensis georgi attenuates oxidant stress in cardiomyocytes effects of armeniacae semen and amygdalin on the lipopolysaccaride-induced prostaglandin e 2 synthesis and nitric oxide production in mouse bv 2 microglial cells ephedra in perspective-a current review citri reticulatae pericarpium (chen pi): botany, ethnopharmacology, phytochemistry, and pharmacology of a frequently used traditional chinese medicine anti-inflammatory property of the urinary metabolites of nobiletin in mouse anti-inflammatory and antioxidant mechanism of tangeretin in activated microglia the chembl database in 2017 meta-sourcetracker: application of bayesian source tracking to shotgun metagenomics exploration of potential clinical application value and mechanism of chinese materia medica for tonifying qi and activating blood in covid-19 with hypoxemia. chin tradit herbal drugs 2020 application of integrative medicine protocols on treatment of coronavirus disease 2019 characteristic analysis on international clinical trial registry of covid-19 analysis report of evidence-based registered clinical trials of tcm treatment for covid-19 clinical study on 34 covid-19 cases treated with integrated medicine covid-19 suspected cases treated with lianhua qingwen decoction: a clinical observation of 63 cases chapter 1: medicine east and west: two ways of seeing, two ways of thinking. chicago: contemporary a global scientific challenge: learning the right lessons from ancient healing practices can chinese medicine be used for prevention of coronavirus disease 2019 (covid-19)? a review of historical classics, research evidence and current prevention programs oseltamivir compared with the chinese traditional therapy maxingshigan-yinqiaosan in the treatment of h1n1 influenza: a randomized trial deciphering ancient combinatorial formulae: the shexiang baoxin pill east is east and west is west and never the twain shall meet: work engagement and workaholism across eastern across eastern and western cultures the authors thank dr. zheng yu all authors declare no conflict of interests. key: cord-314205-6d5yloxp authors: tambo, ernest; ugwu, chidiebere e.; guan, yayi; wei, ding; xiao-ning,; xiao-nong, zhou title: china-africa health development initiatives: benefits and implications for shaping innovative and evidence-informed national health policies and programs in sub-saharan african countries date: 2016 journal: int j mch aids doi: nan sha: doc_id: 314205 cord_uid: 6d5yloxp background and introduction: this review paper examines the growing implications of china’s engagement in shaping innovative national initiatives against infectious diseases and poverty control and elimination in african countries. it seeks to understand the factors and enhancers that can promote mutual and innovative health development initiatives, and those that are necessary in generating reliable and quality data for evidence-based contextual policy, priorities and programs. methods: we examined the china-africa health cooperation in supporting global health agenda on infectious diseases such as malaria, schistosomiasis, ebola, tb, hiv/aids, neglected tropical diseases (ntds) prevention, control and elimination spanning a period of 10 years. we reviewed referenced publications, global support data, and extensive sources related to and other emerging epidemics and infectious diseases of poverty, programs and interventions, health systems development issues, challenges, opportunities and investments. published literature in pubmed, scopus, google scholar, books and web-based peer-reviewed journal articles, government annual reports were assessed from the first forum on china-africa cooperation (focac) in november 2006 to december 2015 third ministerial conferences. results: our findings highlight current shared public health challenges and emphasize the need to nurture, develop and establish effective, functional and sustainable health systems capacity to detect and respond to all public health threats and epidemic burdens, evidence-based programs and quality care outcomes. china’s significant health diplomacy emphasizes the importance of health financing in establishing health development commitment and investment in improving the gains and opportunities, importantly efficiency and value health priorities and planning. conclusions and global health implications: strengthening china-africa health development agenda towards collective commitment and investment in quality care delivery, effective programs coverage and efficiency, preparedness and emergency response is needed in transforming african health information systems, and local health governance structures and management in emerging epidemics. furthermore, innovative evidence of operational joint solutions and strategies are critical in advancing healthcare delivery, and further enhancing universal health care, and sustainable development goals to attain global health improvements and economic prosperity. in a rapidly globalizing world with increasing health and epidemiologic transitions, the international community and multilateralism have become highly active, coordinated and robust. the effectiveness of these initiatives depends on the effectiveness of regional and international cooperation on health challenges and issues. [1] there are, however, little substantive information and knowledge gaps on how international cooperation and activities can best be used as tools for the management of global health and attainment of sustainable development goals (sdgs). [1, 2] china-africa heath development initiatives is timely to address public health and health research gaps, south-south health development platforms and cooperation in shaping innovative national health evidence policies, priorities, programs and benefits in developing countries. international bilateral or multilateral cooperation on health development has been evolving rapidly since the late twentieth century to meet the increasing needs of vulnerable populations, moving forward effective universal health coverage (uhc) and sdgs. [2, 3] in addition, to face the challenges of health and epidemiologic transitions, ageing and globalization challenges, collaborative diplomacy on health security have become more vital than ever in not only saving lives and improving public health but also in improving and providing long lasting benefits to both world's poorest and developed countries. at the same time, however, the rising concern on response and funding from international health actors (who, world bank, un/undp, etc.) remains challenging and requires more efforts and collaboration in harmonizing multilateral efforts and timely actions in emergencies situations. [4, 5] while the news have often reported on the growth of chinese involvement in africa, there has been very little literature on its effects on public health. there is a need for deeper analysis on china's cooperation and efforts at improving public health large-scale development in africa. there are no statistics showing declines in mortality or disease burden. furthermore, it's still unclear exactly how the chinese approach differs from the western approach, as the difference between the "horizontal" and "vertical" approaches are never described practically or operationally. [3, 4, 6] moreover, there is an urgent need to understand factors that can promote mutual and beneficial health development initiatives. [2, 3] the growing trend and quest for chinese multilateral cooperation is increasingly paramount and imperative in tackling the persistent global financial crisis, reducing mass unemployment, and revamping the public burden of infectious diseases of poverty. [4, 5] strategic and timely china-africa health development cooperation is much needed in training and capacity development, exchanges, technical assistance and technology transfer. also, strengthening health systems in scaling up health and medical skills transfer to achieve universal coverage, health equity and overall long-term benefits of improved quality healthcare delivery towards sustainable national development and growth. [2, 3, 6] reciprocally, to support china in meeting up with the growing demand on natural resources and citizenry needs, international laws and declarations are critical areas for international cooperation. the current political environment and commitment to address health problems has created unprecedented opportunities for bilateral health cooperation. [4, 5] furthermore, as china has become an increasingly important part of global health over the past decades, interest in china's international health cooperation has increased among public health professionals internationally and in china. [3, 5, 6] thus, this systematic analysis of china-africa cooperation is timely in leveraging on infectious diseases and poverty alleviation health experiences and lessons learned in reshaping strategic health diplomacy formulation and enhancing successful approaches in health programs and networks in africa. [5, 7] the importance of international, multilateral cooperation for health and disease prevention and control has been recognized as a vital approach and instrument in global health agenda. however, there is a dearth of literature on the potential impact of china strategic diplomacy and policy approaches on the global health inter-dependence, focusing mainly on aspects of existing and emerging threats from disease prevention and control to elimination programs and strategies. [6, 8] few scholarly publications have paid attention to the behavior and politics of global actors. primarily, how china-africa health development will shape the global health priorities cooperation and collaboration requires further investigation. [4] [5] [6] [7] in china, there exists a few articles regarding international cooperation on health concerns aspects of social science. [2, 6, 7] to address the operational and translation research to health policy and practice gaps, challenges and opportunities, more systematic analyses might be required in further understanding the importance of strategic and comprehensive engagement. [4, 7, 8] jointly and mutually beneficial africa-china heath development initiatives could be the turning point for collaborative support and research projects, resource sharing and analysis for new public health policy dimensions and strategic impact. programmatic and robust partnerships are paramount in fostering context health and sustainable public health innovations for health information for all generations. it will, in turn, impact on communities and populations, fostering efficient and effective global health initiatives towards enhanced economic trade, growth and stability, promoting the course of human rights and equity, reinforcement of environmental and wildlife protection and regulations, access and use of health services and medical commodities in achieving uhc and mainstreaming of the sdgs. [8, 9] this review paper examines the implications of china engagement in global health initiatives in africa particularly as it relates to the benefits in health systems strengthening and innovations, emerging epidemics and infectious diseases of poverty initiatives prevention, control and elimination. it seeks an understanding of the drivers and operational enhancers that can promote innovative health development initiatives necessary for reliable and quality data for evidencebased contextual policy, priorities and programs of global health impact. a systematic literature review examined chinese international health cooperation and global health agenda on infectious diseases prevention, control and elimination. in particular, challenges and opportunities related to ebola and other emerging epidemics as well as health systems development issues, global health investment and support were reviewed. referenced publications and extensive sources of data include books, pubmed, scopus, and google scholar and webbased peers reviewed journal articles, government annual reports and conference proceedings, policy reports and conference papers. the books reviewed were related to health, public policy and international cooperation. the journal articles concern all of this paper's research areas since the first forum on china-africa cooperation (focac) and the third ministerial conference from november, 2006 to december, 2015. government documents came from the china-africa partnership members, related countries' government agencies (e.g. ministry of health) and other international agencies and organizations, such as global fund, world health organization (who), the world bank and the united nations (un). [10, 11] all review materials were published, and experts 'reports were assessed. published papers on chinese foreign diplomacy and policy reports and previous chinese literature in relation to infectious diseases prevention and control and elimination programs, research and funding were reviewed to trace international health cooperation actions, information communication and strategies including forum on china-africa cooperation (focac) declarations on health development in 2013 and 2015 in beijing and cape town respectively. [12, 13] furthermore, screened abstracts of the citations were identified for potentially relevant studies and full text documents were obtained for relevant publications. the articles were scrutinized to ensure that multiple publications from the same study related to trade and commerce, socio-economic, science and technology transfer were excluded. this systematic literature search which identified 334 unique records were reviewed and 277 records were excluded based on review of the title and abstract. overall, 57 full publications and 13 reports met the inclusion criteria and were analyzed ( figure 1 ). www.mchandaids.org | © 2016 global health and education projects, inc. china-africa engagement represents a comprehensive view of the relationship at maintaining the momentum of high-level exchanges, mutual trust and practical cooperation in acknowledging the efforts and contributions made by china to support africa's peaceful and stable development. the year 2015 undoubtedly marked a milestone in sino-african relations, maintaining china's tradition in diplomacy by promoting special consultation in support of the south-south cooperation, sino-african trade and commerce bloc and intergovernmental authority on development (igad). the paradigm shift in the chinese global health is one of the most important geopolitical cooperation of our time. china's initiative at promoting peace and social justice enhanced the pace of chinese participation in helping african countries resolve conflicts. hence, the chinese government continues to work and support the international partnership and collaboration with african union in safeguarding peace and stability in africa, promoting the development of africa, and advancing the integration process of africa. the forum on china-africa cooperation (focac), continues to deepen the new type of china-africa strategic partnership by advancing economic and trade cooperation, and actively exploring a common path that reflects both china's and africa's realities in reducing the major causes of emerging threats and diseases in these countries. our findings showed that in the last two decades (2006-2016), the focac has been targeted at promoting win-win mutual aid under the multilateral framework, thus strengthening cooperation in health, agriculture and food security. focac has also improved the level of investment and finance cooperation, by supporting africa's infrastructure construction needs and capacity building in attaining uhc, from millennium development goals (mdgs) to attaining sdgs through china-africa "one health" strategy. for example, the west africa's ebola outbreak that affected sierra leone, liberia and guinea witnessed the importance of china partnership in fighting ebola, and the needs for economic and social reconstruction in the post-ebola period. the chinese government worked with international community, humanitarian agencies and frontline non-governmental organizations including african countries to contain and control ebola epidemics in west africa. compared to other developed countries, china provided a robust technical and non-technical assistance to 13 countries in and around the affected west africa sub-region valued at about $120 million (usd), and pledged an extra $5 million (usd) to the un response multi-partner trust fund to support recovery and rehabilitation process of the affected countries. in addition, china also provided logistics in major affected provinces, including the supply and free distribution of ebola protection kits, mobile laboratory testing vehicles and building new national ebola research laboratories. also skills development of over 13,000 health workers and health professional were improved through training and capacity development. there was also post-ebola recovery and reconstruction plans and assistance in social and economic development projects in the most affected countries namely guinea, liberia and sierra leone. the china-africa relations has grown into a new development era with major pillars such as political equality and mutual trust, promoting win-win collaboration, mutually enriching cultural exchanges, mutual joint health projects, public safety and security, coordinated china-africa wider range solidarity for economic partnership, cooperative and interestingly, the second ministerial forum of china-africa health development was held in cape town, south africa in october 2015. its theme was promoting the availability of healthcare service in africa in improving china-africa's cooperation in public health in post-ebola era. there were more than 200 participants, including the health ministers of china and over 40 african countries, as well as representatives from the au and international organizations such as the world health organization and unaids. the meeting adopted the cape town declaration and its implementation framework to promote china-africa collaboration in public health. it developed a roadmap for china and african countries to work together to address the key health problems affecting the african continent. the latter johannesburg summit was the second summit since the inception of focac 20 years ago and the first held in africa. the timely conference resulted in upgrading new type of china-africa relationship into a comprehensive strategic and cooperative partnership. as a marked indication of this collaboration, china pledged to provide $60 billion (usd) funding support for 10 major china-africa cooperation plans to be implemented in health-related challenges and issues. these ranged from addressing poor access and availability of quality and essential medicines and medical devices, weak health systems and capacity development, lack of entrepreneurship and technology transfer, unreliable and inexistent monitoring and evaluation (m&e) programs/projects. noteworthy, weak regional approach and national sustained health policy reforms, inadequacies in skills and knowledge capabilities to tackle emerging epidemics and infectious diseases with limited resources were documented and should be addressed. the new plans also cover industrialization, agricultural modernization, infrastructure, financial cooperation, green development, trade and investment facilitation, poverty reduction, public health, cultural and people-to-people exchanges, upholding regional peace and security. ten (10) cooperation plans were based on the blueprints to guide the african union (au) agenda 2063 on africa's development in the coming 50 years towards meeting africa's needs and citizenry benefits. their aim will be to address the three bottlenecks holding back africa's development that is: inadequate infrastructure, lack of professional and skilled personnel, and funding shortage. each plan will have chinese financial, technical or material support and will provide a strong development impetus to future china-africa cooperation including africa-china young leaders' forum. strengthening china-africa cooperation in agricultural modernization, agricultural technology transfer and management requires investment in capacity building development at improving complete africa's agricultural production, to food auto-sufficiency value chain and productivity. building up capability is an important way to contribute to food security in africa, and should be given priority in the context of china-africa cooperation projects. the cooperation will enhance agricultural transformation upgrading, increase agricultural production and processing and safeguard food security in africa bearing in mind the prevailing malnutrition and food shortages that directly impact population health. strengthening weak capacity development and health systems is a major priority to tackle the bottlenecks hindering independent and sustainable development of africa. proactive china-africa concrete priorities and measures should be encouraged for chinese and african entrepreneurs, businesses and financial institutions to expand investment through various means, such as public-private partnership (ppp) and build-operate-transfer (bot), to support african flagship projects in african countries. these include, the programme for infrastructure development and the chinese presidential infrastructure championing initiatives in africa, in addition to building railroad, highway, regional aviation, ports, electricity, water supply, information and communication and other infrastructure projects. supporting african countries in establishing transportation facilitating infrastructure connectivity and economic integration in africa. furthermore, china plans to build transnational and trans-regional infrastructure www.mchandaids.org | © 2016 global health and education projects, inc. projects to achieve sub-regional connectivity and integration. both parties can combine the national development needs and demand in fostering economically-beneficial projects and drive africa's infrastructure construction in a balanced and orderly manner. adequate planning and coordination of health development initiatives, construction and renovation, and research collaborative networks in particular promoting construction of transnational highway networks has commenced. there is an urgent need to establish joint china-africa bureau for health development initiatives that will enhance coordination and evaluation of projects. likewise, establishing comprehensive human and infrastructure capacity building and transfer of technology is core. furthermore, china-africa businesses investment, construction and operation in africa should be explored. expansion in vaccine production and medical devices, agriculture and water resources, solar, wind and renewable energy, biomass power generation in power transmission and transformation and maintenance should be nurtured. while advancing its own development, china tries to offer what assistance it can to africa without setting any political conditions, and to benefit african people through developmental advances. in recent years, china has implemented measures adopted at the focac ministerial conferences. china has actively developed cooperation with africa in areas relating to public amenities, medical and health care, climate change and environmental protection, humanitarian aid, and other fields. china has also strengthened cultural and educational exchanges and scientific and technological cooperation in an effort to improve africa's ability to develop independently. china has offered assistance to africa in digging wells for water supplies, and in building affordable housing, broadcasting and telecommunications facilities, and cultural and educational sites in an effort to improve the productive and living conditions of local people. since 2009, china has carried out dozens of welldigging projects in the sudan, malawi, zimbabwe, djibouti, guinea and togo, playing a positive role in easing water problems for local people. it has also provided support for the building of portable dwellings in south sudan, schools in benin, and rural schools in malawi, and in doing so, improved local living conditions and educational facilities. china's largest aid project in the central african republic is the construction of the boali no. 3 hydropower station, which, after it was completed 2010, greatly relieved electricity shortages in bangui and surrounding areas with potential usefulness in improving data access and information sharing for public health benefits. supporting cultural and educational exchanges make up an important part of the new type of strategic partnership between china and africa. by supporting young africans studying in china, sending young chinese volunteers to africa and developing joint research initiatives, china tries to promote mutual understanding between china and african countries and strengthening the social foundation of their friendship. holding human resource training programs and courses are important components of capacity building. from 2010 to 2012, china held various training courses for 54 countries and regions in africa; the courses involved a total of 27,318 officials and technicians, and covered topics relating to economics, foreign affairs, energy, industry, agriculture, forestry, animal husbandry and fishing, medicine and health care, inspection and quarantine, climate change, security, and some other fields. in addition, chinese medical teams, agricultural experts and enterprises located in africa have also trained local people in an effort to enhance local technological capabilities and upgrading china-africa cooperation in science and technology. from 2010 to 2012, in advancing cooperation in medical and health care, china helped build 27 hospitals in ghana, zimbabwe and other african countries. china has also sent 43 medical teams to 42 african countries and regions, treating over 5.57 million patients. in recent years, in addition to building hospitals, donating drugs and organizing medical training programs, china has also launched an initiative called "brightness or "evidence" action," to treat cataract patients and provided mobile hospitals. china also built bilaterally-run eye centers, and helped build demonstration and training centers for diagnosis and treatment technologies, thereby effectively advancing sino-african cooperation in medical and health care. china also gave 66 african researchers the chance to do post-doctoral research in china and donated 150,000 yuan ($24,000) worth of research equipment to each of the 24 researchers who had returned to their home countries to work upon completing their joint research projects in china. chinese aid and investment in africa health development have made substantial contributions to the continent's development over the last 15 years. china-africa health development builds on the existing focac platform to coordinate health research program that aims to advance capacity and technology transfer to cutting-edge research. in advancing access, uptake and utilization of health commodities in tackling china and africa health needs and issues. filling these important gaps and challenges requires collection and production of real-time evidence care development trajectory. investing in priorities health needs, economic and political, scientific and technological development and empowerment inequalities should be addressed through this win-win mutual partnership with institutions and other international stakeholders in line with global health engagement in infectious and emerging diseases and epidemics especially in africa and china. further, this is necessary in strengthening international health commitment and investment towards new model of health bilateral development that is based on equality, accountability, mutual respect that is more balanced, stable, human rights, inclusive and harmonious society. industrialization, diversification of trade, infrastructure development, and regional economic integration are all the right ingredients for africa's sound economic future. however, in the near term, in light of china's own economic slowdown, questions do exist about the implications of china's economic ties with africa and the sustainability. china has implemented "african talents program" to train 30,000 african personnel in various sectors, offered 18,000 government scholarships, and build cultural and vocational skills training facilities in african countries. china and africa will deepen their cooperation in the health sector, step up high-level exchanges in health-related fields and hold a china-africa high-level health development programs and activities. china will continue to send medical workers to africa, while continuing to run the "brightness action" campaign in africa to provide free treatment for cataract patients. it will also help african countries enhance their capacity building in meteorological infrastructure and forest protection and management of potential threats and disasters. the research capacity of local partners in china-africa relations has reached a new historic level. africa, a continent full of hope and thirst for development, has become one of the world's fastest growing regions, while china, the world's largest developing country, and has maintained forward momentum in its development. with increasing common interests and mutual needs, the two sides have great opportunities to accelerate their economic and trade cooperation. currently, the chinese people are working hard to realize the chinese dream of national revival, while african people are committed to the african dream of gaining strength through unity and achieving development and renewal. with a spirit of mutual respect and win-win cooperation, china will continue to take concrete measures to build a sino-african community of shared destinies featuring all-round, diversified and deep cooperation. it will work to advance china-africa economic and www.mchandaids.org | © 2016 global health and education projects, inc. trade cooperation to help both sides make their respective dreams come true. china is also willing to enhance its cooperation with the rest of the world to promote africa's prosperity and development. china and africa should work together to promote the development of the "china-africa joint research centre" project and cooperate in biodiversity protection, prevention and treatment of desertification, sustainable forest management and modern agriculture demonstration. the chinese side will support africa in implementing 100 clean energy and wild life protection projects, environment friendly agricultural projects and smart city construction projects. strengthening china-africa "one health" strategy cooperation through wildlife and environment protection will help african countries to improve their protection and conservation capabilities. there should be more efforts in building environmental capacities in african countries with training opportunities on environmental and ecological conservation. the possibility of cooperating on joint wildlife protection projects against the illegal trade of fauna and flora products, especially by addressing endangered species poaching, deforestation and environment, degradation and climate change impact on the african continent, should be explored. in its first 10-years of china-africa partnership implementation plans, china and africa share the view that the current development strategies of china-africa partnerships are highly compatible in fostering china centenary goals and africa union (au) 2063 agenda. the two sides shall make full use of their comparative advantages to transform and upgrade mutually beneficial cooperation focusing on better quality and higher efficiency to ensure the common prosperity of their peoples. [14, 15] joint health research establishment is needed for a comprehensive strategic and cooperative partnership for china-africa mutual trust, win-win results and sustained economic growth. [2, 7, 9, [16] [17] [18] health and medical technology capacity building and transfer, exchanges and mutual learning is needed in enhancing chinese and african citizenry, mutual assistance in public health security and safety. promoting healthcare solidarity and cooperation can be very supportive in enhancing national health planning and interventions implementation between china and african countries in international affairs. [6, 7, 19, 20] moreover, improving and encouraging care delivery strategic mechanisms such as bilateral joint and strategic dialogues, foreign ministries' political consultations, and joint/mixed commissions on economic and trade cooperation is imperative; through exchanges and cooperation between the national people's congress of china and african national parliaments, regional parliaments, the pan-african parliament and the african parliamentary union, to consolidate the traditional medicines integration in china-africa friendship and promoting mutually beneficial cooperation. [3, 6, 8, 11, 14, 21] our findings documented that china's commitment to continuously support africa in many areas include agriculture and health sector, trade and commerce, science and technology projects implementation. these included construction of regional and community hospitals and treatment centers, infrastructures and facilities to fight infectious diseases, support by chinese medical care delivery teams and improve capacities to respond to public health and sanitary crises throughout africa including dr congo, cameroon, togo, ivory coast, angola, namibia, mozambique, sudan, algeria, south africa, zambia, egypt, nigeria, ghana, liberia, guinea and sierra leone. these equipped ultramodern infrastructure and facilities investment include emergency, resuscitation, pediatrics, surgery, obstetric and gynecology, medical imaging, and related technical units worth billions of us dollars (figure 1 ). these joint efforts are positive milestones to strengthen intercontinental cooperation in view of attaining a sustainable impact in achieving universal health coverage and access to basic medicine. in particular, accelerating the fight against hiv/aids, tb, malaria, schistosomiasis, maternal-child health, reproductive health and improving universal immunization coverage against vaccine preventable diseases across africa. [21] [22] [23] [24] chinese comprehensive and pragmatic efforts was once again documented when the chinese government immediately offered emergency relief to the three west african countries most affected by ebola and to their 10 neighboring countries of ghana, mali, togo, benin, drc, the republic of congo, nigeria, cote d'ivoire, senegal and guinea-bissau. with the situation turning more serious and based on the needs of epidemic regions, china later announced three consecutive rounds of assistance. china has also promised that in so far as ebola persists in africa, her assistance will not stop. [7, 8, 10, 11, 15] china stood shoulder-to-shoulder with the african people in fighting ebola to the final victory of global disease free generations. west africa ebola epidemics 2014-2016 led to net losses of $6.2 billion us dollars in the three most affected countries (liberia, sierra leone, guinea) in terms of gross domestic products (gdp). as these countries embark on recovery and reconstruction, china has promised assistance in health systems strengthening, capacity building, health infrastructures and equipment support, amongst others. [5, 8, 13, 23] the urgent need for data and information sharing, material and technical transfer cannot be over emphasized in improving public health and medical resources access through mutual commitments and support. promoting health data and information sharing, educational exchanges and capacity development to support the establishment of robust infectious diseases surveillance-response systems in african countries and all remote provinces/cities is imperative in institutionalization of china-africa forum on cooperation between provinces or local governments. [3, 17, 19, 22, 25] the china-africa development fund "cad-fund" is one of new methods for china-african new strategic partnership, which was fully controlled by the chinese government. cad fund is one of the eight measures which was announced by chinese government at the beijing summit of the focac in november 4 th , 2006 aimed to support chinese companies to develop the cooperation with africa and enter the african market. [1, 3, 5] distinctive characteristics in the capital nature, the business area, and operation mode is continually following the investment philosophy: to build up "bridge linking" and "connection" of the economic and trade cooperation between china and africa; to enhance self-develop capability of africa; to strictly fulfill the investment environment and social responsibility; to promote mutually beneficial and win-win between china and africa by market-oriented operation. [5, 7, 21] cad-fund is a pioneering move in the process of mutual and beneficial china-africa cooperation. it remedied the gap under the traditional model of free aid and loans. with the increasing african countries double public health burden (chronic illnesses and infectious diseases), new investment models and market-oriented economic development and operation should be examined in achieving sustained and healthy dual or self-development. [9, 11, 18] the direct investment is essential. improving people's livelihood for african regions by additional large scale (e.g.: network project) investment to african countries could be beneficial in long terms. [14, 20] for instance, the chinese government officially approved the establishment of the cad-fund, with first-phase funding, usd 1 billion, provided by china development bank. cad-fund operated independently based on market economy principles under a standardized corporate governance structure. china development bank (cdb), the shareholder, has a great wealth of experience in project review and management and is backed up with sound expert resources. having invested in five funds and three specialized fund management companies, the bank has developed sophisticated fund management and risk control systems. cdb has accumulated profound experience vis-à-vis investing in africa through its "going global" initiative. [19] [20] [21] cdb, by virtue of its overall resources and advantages, will provide a high level of professional support. again, on the investment side, the ministry of commerce revealed that china's direct investment in africa stood at $1.19 billion (usd) in the first half of 2014, falling over 40 percent year on year. the downturn is attributed to the sluggish global economic recovery, international commodity fluctuations, and the ebola outbreaks. [8, 17, 21] globalization and global health initiatives on infectious diseases of poverty associated consequences have shown the world is closely linked as emerging threats and epidemics of infectious diseases can strike anywhere at any time irrespective of race, religion and financial capacity of the country. these have precipitated growing opportunities in internationalization of south-south and south-north health cooperation in changing outcomes. [8, 9] the advances in technological development and increases in global interconnections are increasingly being utilized inexpensive and prompt health information communication diffusion broadly and interdependence between different people, regions and continent benefits. [8, 9] improvements in communication and information technologies has enabled international responses to health threats and disaster crisis more rapidly and in a coordinated fashion, [7] bringing about greater sharing of information and increasing international interactions and collaboration. [10] globalization requires increasing cooperation among countries to ensure the stability and security of the global system, a reason why implementation of international agreements and joint declarations has become important. [10, 21] for instance, industrial demand and globalization coupled with intense urbanization have been generating new ecological, climate and environmental threats and associated consequences beyond local, regional boundaries and worldwide. these consequences and issues have raised the need for international cooperation and foreign assistance agreements either as direct delivery of services, capacity transfer or implementation of health interventions such as the global fund to fight aids, tuberculosis and malaria. [5, 8, 10, 22] in today's more interdependent world, international cooperation, which involves the interaction of countries, international organizations and non-government actors, shapes values, policies and rules. as globalization continues to widen the gaps, development and implementation of comprehensive health models between developing and developed nations, the interest in global health partnership and foreign assistance effectiveness has grown in importance at improving funding on health systems priorities including scaling up access to essential medicines and service delivery, universal health coverage and building new primary healthcare facilities. [11, 18, 20, 21] international mutual cooperation and aid is one of the most effective weapons in reshaping and transforming regional and national health capabilities which benefits through provision of global public goods, infectious disease control and alleviation of poverty. [12, 23] the widespread influence of globalization has increased the need for international cooperation to address emerging opportunities for and threats to global health in improving the health status of populations in developing nations. [7, 9] as of november 2015, the majority of african exports to china remains in natural resources. according to the statistics by chinese customs, crude oil, iron ore, diamonds, and agricultural products together accounted for 56.5 percent of chinese imports from africa during the first three quarters of 2015. and this number is on the low end because china's demand for raw materials has been suppressed by its economic slowdown this year. in this sense, china's intention of downplaying the importance of natural resources in sino-africa trade in its policy manifestation is clear, given the mutually understandable winwin image associated with sino-africa economic relations aspirations. china's international health development cooperation initiatives since the 1980s, health privatization and reforms expectations and outcomes from international coalitions were formed to address the heavy global challenges, including national burden of infectious diseases, poverty and inequality. with the global funds support from early 2000, the vertical approach to funding and aid has been gradually shifting to a horizontal approach and from mere bilateral efforts to multilateral organizations, local and international ngos, aimed at reshaping major funding, cooperation, new alliances and networks. [10, 13] furthermore, boosting provision of aid or humanitarian assistance paradigm shift from a small-scale task plan to large multiple programs financial support projects and programs. multifaceted nature and complexity of health and the multi-sectorial interactions that influence it have induced an increasing number of organizations to become active in the health field. [2, 14] broad-ranging partnerships are increasingly being set up to target specific health problems. [6, 15] for example, to achieve roll back malaria or polio eradication a global partnership was formed with, among others, ministries of health in polio-endemic countries, rotary international, united nations children's fund (unicef), the governments of australia, canada, denmark, japan, the united kingdom and the united states. reciprocally, from 1994 to 2001, the eu contributed €4.5 million to hiv/aids prevention in china, setting up six provincial level regional training centers to provide technical assistance to medical personnel in hiv/aids prevention. [14, 15] this collaborative support is advantageous for capacity building, educational exchanges between institutions of all levels and dual technology transfer. such efforts have been reported between china and the united kingdom (uk), the us, and australia in research and development and helpful in solving health issues and developmental challenges including climate changes and globalization of trade and travel. [8, 11, 16] previously, the establishment of cooperation between china and other countries has been done through the signing of agreements and regular corporate communication. contemporary advances in implementation mechanisms are performed by joint engagement and participation in mutual win-win partnership and joint health programs funding or investment seeking based on local and national priorities and real time field interventions. [17, 19] furthermore, china has dispatched more than 50 medical teams and more than 1,000 medical personnel to 39 african countries. chinese governments highly valued and appraised local people and the team's devotion, willingly and generosity in providing medical services, training and technical assistance, in strengthening health systems development through focac partnership. [3, 6, 9] in contrast to previous international vertical health approach, chinese horizontal approach and process (people-people approach and relations) has been appraised in responding to the need of the populations. there is an urgent need for reliable and effective evidence in strengthening health systems development including constructing health care facilities, providing medicines and medical equipment, improving more targeted care access and utilization require contextual and scalable community-based programs and activities beneficial to both chinese and african citizenry. [1, 3, 7, 14, 15] china's importance in sustainable development and global health goals, is aimed not only in fighting poverty and health inequality among the world's people, but in enhancing opportunities to live a free, healthy and fulfilled life. [1, 2, 18] achieving health for all remains an important component of sdg targets and requires reducing national public health burden of infectious diseases of poverty. addressing knowledge gaps between the developing and developed countries require innovative international and multilateral cooperation with priorities on significant infectious diseases, emerging epidemics, the rise of obesity related cardiometabolic and other www.mchandaids.org | © 2016 global health and education projects, inc. chronic diseases. the mdgs, adopted and supported after the millennium summit of the united nations in september 2000, provided a substantial progress in the reduction of poverty and marked improvements in infectious diseases and some neglected tropical diseases in most endemic countries through the global funds. it also offered other bilateral aid to the poorest and vulnerable populations worldwide by improving maternal health, reducing child mortality, while combating hiv/aids, malaria and other diseases. [5, 8, 12, [21] [22] [23] attaining the sdgs and health for all by 2050 depends primarily on national efforts supported by domestic and regional public-private partnerships and global strategy of increasing access of the world's poor to essential health services. it also depends on support from international multilateral cooperation and collaboration within countries. [15, 17, 20] further efforts should be devoted at reducing inequality and poverty in health aimed at accelerating progress towards the sdgs and should be a pubic priority. it is worth mentioning that there is still disproportionate health disparity between developing and developed countries. [19, 21] for example children life expectancy chances are dramatically different depending on where they are born. in china life expectancy is longer than in african countries due to premature mortality ratio associated with malaria, tuberculosis and hiv/aids as well as chronic infections, mainly maternal-child and elderly healthcare delivery. [13, 23, 27, 28] china's global solidarity and partnership support from national income and resources could be a role model on how to assist and work a win-win bilateral collaborative network, technical assistance during threats and epidemics disaster crisis for the safe of humanity, environment and ecosystem. china health expenditure increased more than 30fold and accounted for 5.1% of the gross domestic product (gdp) in 2011. [17, 20, 22] who supported by other governments continues to provide necessary technical and financial support to china through renewed strategic cooperation agenda on transfer of know-how and skills to africa in tackling infectious diseases control towards elimination. [1, 9, 20, 29] chinese cooperation is aimed at achieving global health responsibility, which entails strengthening health systems, improving universal health coverage and reducing morbidity and mortality from major infectious diseases of poverty. such recent efforts in the field of public health include multiple partnerships between the national institute for parasitic diseases (nipd), shanghai with several african institutions and universities in the areas of capacity development and training, technology transfer and exchanges coordination and leadership. [19, 23, 30] most importantly, is the implementation of malaria and schistosomiasis elimination networks across africa (e.g., tanzania, zanzibar, sudan). [17, 33] lessons learned and technical assistance from chinese researchers, ongoing consultation on strategic partnership could be very important in strengthening joint malaria and schistosomiasis projects network with sudan, cameroon, zimbabwe, south africa and mali are substantial opportunities. in addition, provision of technical support and colossal solidarity supply of personal protective equipment (ppe) in sierra leone, liberia and guinea were of tremendous assistance both to humanitarian frontline organizations as well as chinese teams and local community health benefits in west africa ebola containments and community rehabilitation. for example, china provides funding and technology, while who guides technical support and coordination. [18, 19, 31] furthermore, in 2013, the chinese government assisted in 2013, to develop and implement strategic plans on snail control and elimination of schistosomiasis. it should be recalled that chinese experts have provide technical assistance to pakistan, nepal, lao, myanmar, vietnam, nigeria, tanzania, angola and namibia to assist in global polio eradication and global fund for malaria and hiv/aids and tuberculosis (gfmat) efforts. [14, 18, 19] china is also reducing inequalities in health and contributing to strengthening global health through supporting collaboration in the global health arena. china is strengthening national and regional priorities in line with international health regulations (ihr) (2005), strengthening the asia pacific strategy for emerging diseases (apsed) network, global schistosomiasis alliance (gsa) to arboviralnet. [2, [29] [30] [31] [32] this will enhance capacity in health security and diplomatic power to create maneuver space for international multi-polar geopolitics and financial systems. china has become a giant economic power and vital component of the international commodity chain, allowing for more effective broad-based consultation and participation on global health issues and international finance via different channels by active support of multilateral diplomacy and politics. [23, 25, 30, 31] the first world bank trust fund to end poverty was established in promoting growing china's interest and role in global health development, and china's health reforms leadership in reducing poverty and strengthening both health systems resource and infrastructure investment. [24] this is essential in embracing and upholding performance-based to outcome-based financing in partners countries. some good examples of chinese initiatives in global health need further assessment including the use the new partnership in optimizing institutional governance, organizational structure, social and environmental benefits towards social cohesion, healthy life and living, wellbeing of all citizens and sustainable development at all levels. [9, 14, 18, 21, 24, 29, 33] integration of china multilateral policies in projects and programs will be a tremendous boost with the increasingly geographic expansion and spread of emerging epidemics and climate changes impacts on global health concern. proactive china-africa leadership commitment and investment is needed in addressing in tie-bound manner evolving local or global threats and emergency situations in endangering collective health initiatives in upholding international health regulations (ihr). [23] [24] [25] the sudden emergence in 2003 of severe acute respiratory syndrome (sars) in china was a vivid example of how international health cooperation in the future depends on a better appreciation of the meaning of modernization, as interpreted by each country, and recognition that modernization itself is a complexity of many factors. [24, 25] future multilateral cooperation will be influenced by strategic innovative multi-sectoral partnerships, health programming and resource mobilization, bilateral to multilateral governance systems, creation of enabling institutional space, effectiveness and outcomes impact. new and advanced health diplomacy, and foreign health policy in public health systems is an important point of entry and worth pursuing by the joint china and africa interests and values. [23, 26, 30, 31] health as an instrument of foreign diplomacy and policy presents several mutual gains both for community and its populations' protection. safety and security are health priorities that can be improved through further public health development cooperation. international multilateralism in health development under china-africa partnership holds great promise in increasing opportunities and businesses and diminishing traditional unilateralism over time. [27] [28] [29] nurturing sustainable joint institutional projects that promote community-based programs could be vital for active engagement in policy discourse, participation and community empowerment. the un's sustainable development policy functions and goals coordination will be overtaken by global partnerships or other agencies to develop new international health norms and standards. [27, 28, 30, 31, 34, 35] ultimately, the quality and effectiveness of china-africa health development initiatives and programs, when channeled through government and institutions partnerships, have the potential strengths in improving good governance and accountability in global health security. [29, [32] [33] [34] [35] china's economic importance in improving china-africa health development initiatives in strengthening contextual health priorities and programs is imperative. fostering china-africa innovative evidence-based national health policies and health operational joint solutions and strategies is critical in advancing healthcare delivery access to, availability and effective implementation. moreover, in shaping programs and interventions benefits in further improving uhc, sdgs in attaining global health and economic prosperity in africa. ethical considerations: this paper was based on the review of existing and publicly-available information. conflict of interest: the authors advances in addressing technical challenges of point-of-care diagnostics in resourcelimited settings. expert review of molecular diagnostics china's engagement in global health governance: a critical analysis of china's assistance to the health sector of africa the dragons' gift: the real story of 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diseases of poverty surveillanceresponse systems: the key to elimination of tropical diseases scaling up impact of malaria control programmes: a tale of events in sub-saharan africa and people's republic of china technology innovation for infectious diseases in the developing world global health diplomacy: a global health sciences working paper brazil"s ascendance: the soft power role of global health diplomacy strengthening health systems: "new continent" in china-africa health collaborations. paper presented at the 2013 china health forum china"s soft power in africa: from the "beijing consensus" to health diplomacy key players in global health: how brazil, russia, india, china and south africa are influencing the game china-africa development cooperation: identity transformation and system reconstruction global health governance and mechanism for china and africa's participation. paper presented at the 2013 china health forum global health 2035: a world converging within a generation historical evolution and chinese definition of global health considerations when disseminating american-developed, evidence-based health promotion programs in china china engages global health governance: processes and dilemmas an appeal to the global health community for a tripartite innovation: an «essential diagnostics list china's engagement in global health governance: a critical analysis of china's assistance to the health sector of africa the political origins of health inequity: the perspective of the youth commission on global governance for health china's distinctive engagement in global health ground-truthing" chinese development finance in africa china's provincial diplomacy to africa: applications to health cooperation key: cord-350057-2rac6nql authors: yao, xuebiao; li, dangsheng; pei, gang title: in focus: molecular and cell biology research in china date: 2013-08-07 journal: nat rev mol cell biol doi: 10.1038/nrm3638 sha: doc_id: 350057 cord_uid: 2rac6nql an interactive, intellectual environment with good funding opportunities is essential for the development and success of basic research. the fast-growing economy and investment in science, together with a visionary plan, have attracted foreign scholars to work in china, motivated world-class chinese scientists to return and strengthened the country's international collaborations. as a result, molecular and cell biology research in china has evolved rapidly over the past decade. supplementary information: the online version of this article (doi:10.1038/nrm3638) contains supplementary material, which is available to authorized users. the study of cell biology and embryology in china stemmed from the generation of the eminent biologist shizhang bei, who returned to china from germany in 1929. bei and his colleagues helped to build the chinese academy of sciences (cas) in the 1950s (fig.1 (timeline) ), and he later became the first director of the institute of biophysics (ibp) in 1958. landmark achievements of chinese cell biologists in the 1960s and 1970s include the first demonstration of asexual reproduction in amphibian s by xi zhu (shanghai institute of cell biology (sicb), cas) 1 , and the establishment of the first human liver cancer cell line by ruiming chen at the same institute 2 . the development of molecular and cell biology (mcb) in the subsequent two decades was compromised by the agenda and resources available in the country, as the nation spent its limited resources on areas tied to the nation's economy and interests. the political movements also set all scientific research curricula back during this period, until china opened its door to the west in the 1980s. in the next two decades, a large population of chinese students and scholars went abroad to study modern sciences, including mcb. although these scholars made great discoveries overseas, the development of mcb research in china remained slow-paced due to the lack of expertise, resources and financial support. during the past decade, many mcbbased research centres and programmes in china have made ground-breaking progress, which has attracted international collaborators and prompted the return of thousands of chinese scientists from overseas. the chinese society for cell biology (cscb) was founded in 1980, and it currently has 7000 active members, which represents 20% of mcb researchers in china. the cscb has played an increasingly important part in advancing mcb research in china by organizing biennial national meetings, sponsoring special conferences and workshops on selective topic s and advocating the need for initiating specific research and funding programmes for emerging scientific areas. this essay highlights the current organization of mcb research programmes in china, funding opportunities and application procedures, career development initiatives for chinese scientists returning from abroad and for foreign scholars, as well as the opportunities for scientific collaborations. key mcb discoveries in china mcb has been appreciated by scientists in china since it emerged as the foundation of modern biological sciences, and the deficiency of mcb research in the 1960-1980s in this country was due to political movements. the fast-growing economy over the past decade was the powerhouse for the rapid development of innovative mcb research, both basic and translational, in china. over the past decade, on average there has been a more than 10% annual increase in research funding support from two major chinese research fundin g agencies, the national natural science foundation (nsfc) and the ministry of science and technology (most). as a result, scientists in china have made a number of major contributions to the field of mcb during this time. examples include the delineation of the molecular mechanisms underlying β-arrestin signalling [3] [4] [5] , bacteri a-host and virus-host cell inter actions 6-9 , necroptosi s 10,11 , dna hydroxylation and demethylation 12, 13 , autophagy plasticity and its regulation by protein acetylation [14] [15] [16] , the role of acetylation in cellular metabolism 17, 18 and the induction of pluripotency 19, 20 . the creatio n of androgenetic haploid embryonic stem (ag-haes) cells and their application in the generation of genetically modified mice 21, 22 , as well as the functional delineation of cellular plasticity and homeostasis regulators based on structural insights, has also been achieved by mcb researchers in china [23] [24] [25] . these examples, which are discussed in more detail in box 1, are just snapshots of the exciting and successful research currently being carried out by talented scientist s in china. abstract | an interactive, intellectual environment with good funding opportunities is essential for the development and success of basic research. the fast-growing economy and investment in science, together with a visionary plan, have attracted foreign scholars to work in china, motivated world-class chinese scientists to return and strengthened the country's international collaborations. as a result, molecular and cell biology research in china has evolved rapidly over the past decade. research in diverse areas of modern biological sciences. in general, under this scheme a principal investigator is granted a 5-year term with an internationally competitive scale of salary and funding, and renewal is contingent on the performance of the researcher. today, the nibs model has been adopted in other research units to help promote the career development of young scientists. an interactive, intellectual environment and funding programmes that provide an incentive to scientists are key to ensuring scientific advances and breakthroughs in mcb research in china. there are several independent funding programmes in china (table 1) . for both basic and translational mcb research, the nsfc, a leading fundin g organization that was founded in 1986, is the major channel of financial support. funded projects cover almost all disciplines of mcb, and the recent funding invested by the government exhibits a typical annual growth of 20%. this has resulted in seminal findings and high-impact publications in recent years, which has argued convincingly for continue d support for mcb research. recently, the nsfc joined the national institutes of health (nih) in the united states to fund bilateral collaboration grants to promote scientific exchange and colla boration between the two nations (see below) (table 1) . the second avenue for funding basic and translational research in mcb is the most. one of the renowned programme grants sponsored by most is the '973' projec t, which supports synergistic efforts by multiple research teams. this programme, which was initiated in march 1997 by the chinese government, aimed to develop basic research, innovations and technologies that were aligned with national priorities in economic and social development. in 2006, the initial 973 programme had expanded into several specialized disciplines, and it became known as the national key basic research programme. the new programme now includes several specific research areas such as protein sciences, stem cell research, reproductive biology and developmental biology. one of the major differences between nsfc and most grants is the application format. the nsfc grant is primarily designed for individual principal investigators, similar to the nih ro1 type of research grant (but not to the same scale of funding) in the united states. by contrast, the 973 programme grants are very much like the p50 grants awarded by the nih, in which multiple principal investigators work together as a consortium to take on a scientifically challenging theme that is deemed impossible or too hard for any individual research group to tackle. the third avenue of mcb funding is from the ministry of health (moh) of china. moh grants fund translational biology-based projects (such as the development of new drugs) that focus on the most prevalent diseases in china. these grants primarily fund consortium efforts in which a large number of cross-disciplinary teams tackle problems associated with hiv infection and viral hepatitis, two major epidemic health threats in china. this newly developed funding scheme is less organized and has recently been criticised. in particular the depth of evaluation systems was subject to criticism, as the moh has an underdeveloped peer-review system and is less experienced in grant administration. with a new central government and its strategic creation of a big and interactive moh (this is combined with a family planning policy), this funding channel is expected to be overhaule d and optimized. typically, applications for funding from the nsfc and most are due once a year in march compared with three cycles per year for nih funding. the annual success rate at the nsfc is about 20%, although this varies slightly depending on the discipline. one deadline per year may present challenges for young scientists who have just arrived in the country and set up their laboratory in the middle of a year. in addition, the depth of peer-review varies among different funding agencies and among different disciplines in the same agency. given the relatively short history of research funding administration in china and its fast pace of growth, optimizing the procedures involved will accelerate research and development in mcb in china. in addition, there is an internal funding pipeline within the cas to support mcb research. however, there are no regular deadlines, and the programmes are orchestrated by specific requests for application. it is worth noting that the funding agencies in china are taking increasingly strict measures with regard to scientific ethics to minimize the issue of scientific misconduct that has occurred in china and could setback the fast-growing phase of scientific research and development. the hundred talent initiative was started by the cas in 1994 to recruit distinguished chinese scholars under the age of 45 from overseas to fill the intellectual gap in cas research institutes, as well as at the university of science and technology of china (ustc). the hundred talent scientists are generally provided with ample laboratory space, a solid start-up package and the position of principal investigator. so far, more than 1000 scholars have been recruited under this initiative. most hundred talent scientists received additional funding, for example from the 973 project, and also recognitio n as nsfc outstanding young scientist awardees. today, many hundred talent recruits remain active in research and education in academic settings in cas institutes and universities beyond this. the hundred talent project also has a partnership with the max planck society (mps) in germany, and gang pei returned from the usa as a cas-mps junior group leader in 1995. in 1998, li ka shing, the president of cheung kong holdings (a company that develops residential, office, retail, industrial and hotel properties in hong kong), worked with the moe to build the 'cheung kong scholars' programme for recruitin g research scholars and professors from overseas, regardless of their nationalities, to universities nationwide to work for the moe. like the hundred talent initiative, the cheung kong scholars programme has been very successful and remains open for recruiting overseas talents not only in mcb but also other disciplines such as mathematics, physics and chemistry. however, cheung kong scholarships primarily supplement salary, and scholars will thus need to negotiate with their home institute a start-up package and laboratory space. eminent haematologist and leukaemi a cell biologist zhu chen was one of the first cheung kong scholars. today, many cheung kong scholars are actively engaged in research, education and scientific administratio n nationwide. given the success of the aforementioned talent-recruiting strategies, the rapid development of the country's economy and the urgent need to recruit additional talents to encourage economic transformation, the central government initiated an ambitious thousand talent project in 2008. this project aims to attract primarily scientists in china have made major contributions to the field of molecular and cell biology (mcb) over the past decade. due to space limitations, only selected examples are described. gang pei and colleagues identified a unique five-transmembrane g protein-coupled receptor (gpcr) implicated in cytokine signalling 3 . using gpcrs as a model system, they revealed the spatial dynamics of β-arrestin and its role in epigenetic reprogramming 4 and delineated how β-arrestin orchestrates cellular energy homeostasis 5 . using crystal structure-aided delineation, zihe rao and colleagues (at the institute of biophysics (ibp)) and tsinghua university) illustrated the mechanism of action underlying a key protease of the severe acute respiratory syndrome (sars) virus and its interaction with an inhibitor 6 . jijie chai (national institute of biological sciences (nibs)) established how the bacterial effector protein avrpto activates plant immunity 7 . furthermore, nieng yan and yigong shi (both are at tsinghua university) defined the structural basis of transcription activator-like (tal) effector-dna interactions; tal effectors are secreted by phytopathogenic bacteria and recognize host dna through a central domain of tandem repeats 8 . finally, feng shao (nibs) delineated the host cell response to bacterial virulence, suggesting that bacterial virulence factors rewire the host cell signalling circuitry 9 . two independent teams led by jiahuai han (xiamen university) and xiaodong wang and xiaoguang lei (nibs) delineated the mechanism underlying necroptosis and discovered chemical inhibitors of this process 10, 11 . the paternal dna in a zygote undergoes active demethylation before the first mitosis, and guo-liang xu's group from the institute of biochemistry and cell biology at the shanghai institutes for biological sciences (ibcb-sibs; he was also a chinese academy of sciences-max planck society (cas-mps) junior group leader at that time) revealed the mechanisms underlying this. they showed that the dioxygenase ten-eleven translocation 3 (tet3) catalyses the oxidation of 5methylcytosine in the paternal genome in mouse zygotes, which results in the generation of 5hydroxymethylcytosine 12 . they also discovered that the oxidized cytosine can be removed by thymine dna glycosylase 13 , thus providing insights into the mechanism of dna methylation. using caenorhabditis elegans, hong zhang (who was at the nibs) identified several unique regulators of autophagy 14 . li yu and sheng-cai lin, who are at tsinghua university and xiamen university, respectively, independently unravelled how acetylatransferases orchestrate autophagy dynamics through the acetylation of effector proteins on lys residues 15, 16 . using a proteomics-based approach, guoping zhao, shimin zhao and their colleagues (fudan university) identified an acetylome underlying the regulation of liver cell metabolism and illustrated the potential signalling cascades involved in liver cell homeostasis 17, 18 . the groups of jinsong li (ibcb-sibs) and qi zhou (institute of zoology in beijing, cas) generated transgenic mice using androgenetic haploid embryonic stem (ag-haes) cells 21, 22 . haploid cells are versatile and are easy to genetically manipulate. independently, both research groups established mouse ag-haes cells by transferring sperm into an enucleated oocyte. they also used ag-haes cells to produce live animals via injection into oocytes. duanqing pei (guangzhou institutes of biomedicine and health) showed that mesenchymal-to-epithelial transition is required for reprogramming fibroblasts into induced pluripotent stem cells 19 . the reprogramming factors for inducing pluripotency were primarily identified from es cell-enriched, pluripotency-associated factors. however, recent developments from the laboratories of hongkui deng and chao tang (peking university) show that mesendodermal lineage specification factors could cooperate with ectodermal specification factors to reprogramme mouse somatic cells to the pluripotent state in the absence of exogenous oct4 (also known as pouf51 and oct3) and sox2 (ref. 20 ). the group of jia-wei wu recently carried out a structure-function analyses to elucidate amp-activated protein kinase (ampk) activation 23 , and yigong shi's group used a structural biology-based approach to identify a membrane transporter 24 . both of these groups are at tsinghua university. in addition, structure-based studies, carried out by mingjie zhang (fudan university and hong kong university of science and technology research consortium), showed that a lipid-induced conformational switch controls the activity of the snare ykt6 (ref. 25 ). xiamen university nature reviews | molecular cell biology tenured full professors from major research universities from developed countries. the chinese professors already employed by chinese institutions are not eligible to apply. similarly to the hundred talent initiative, successful thousand talent candidates are provided with ample laboratory space, a generous start-up package and full professorship. in addition, they are offered a salary scale comparable to their earnings overseas. distinguished programmed cell death researcher xiaodong wang was one of the first thousand talent investigators, and he relocated to china from the united states. so far, the number of scholars who have qualified for the thousand talent candidacy has reached about 1000. however, the overall full-time employment rate is far below the number of candidates who have been awarded one of these grants, as many successful candidates remain at the stage of negotiation and planning for their research projects in china. the central government subsequently initiated the young thousand talent recruitment programme (introduced above). both young chinese scientists working abroad and foreign scientists from oversea s can apply for such a grant. in general, young thousand talent investigators with full-time commitment receive similar packages to hundred talent investigators. so far, four groups of scientists have been selected under this project, which brought a total of 400 scholars to china, the majority of which are chinese, while the fifth group is being reviewed. finally, there are programmes similar to the thousand talent programme aiming to recruit tenured faculty members of foreign nationalities. the programme is called 'thousand talent for foreign scientists' (also known as 'wai zhuan qian ren'). collectively, all these programmes are designated for chinese scientists who return from overseas or foreign scientists who want to work in china. by contrast, funding programmes for chinese scientists who would like to perform research abroad are scarce, except for scholarships for graduate students and postdoctoral fellows to visit foreign institutions. all career development plan applications begin with the human resources department of the perspective institutes and/or universities. there is a dramatic increase in academic job advertisements from chinese institutes in major scientific journals, such as science and nature, and on the institutes' websites. often all interested candidates are invited to apply, regardless of their nationalities. as for collaborative efforts, the nsfc provides a number of funding opportunities (table 1) . recently, the nih has jointly awarded grants with the nsfc for collaborative projects related to cancer, allergies, immunology and infectious diseases, using supplemental mechanisms that provide additional funding for joint studie s (see nih funding opportunities and notices). in addition, grants are available for international collaborations; such applications should be initiated and submitted by chinese investigators and the proposed project projects should be based on hypothesis-driven research with potential synergism from overseas partners. in general, there are specific milestone requirements for these collaboration grants. the timely and joint publication in high impact journals is essential for renewals. typically, this is a 5-year grant with an annual budget of 100,000 us dollars to support expenses related to scientific exchange and technology transfer. in addition, bilateral collaboration grants are available that are awarded through a request for applications procedure. for this type of grant, both the chinese investigator and the foreign collaborator should write and submit their applications to the nsfc and the respective co-sponsoring agency in the country of the collaborator. in general, the nsfc provides funding support to the chinese applicants and finances travel in both directions between the awardees and their foreign collaborators, while funding from the collaborators' country supports their research and travel expenses for scientific exchanges. the criteria for funding this type of joint venture are based on the merit of the collaboration, which is assessed individually on both sides by the respective funding agencies. following peer-review, the nsfc and the partner funding agencies will finalize the awardees for bilateral co llaborations. the typical 5-year programme requires annual exchange visits, one scientific workshop or conference per funding cycle to train young scholars and joint peer-reviewed publications on the proposed project. this type of joint grant can be renewed upon its successful completion. typically, guidelines for the aforementioned grant applications are published on the nsfc website in late december, with a due date for applications in mid-march of the following year. publishing and exchanging mcb there is a long list of scientific journals in china that publish mcb-related studies. however, many of them are not well-known in the academic community around the world. partly because of this, more than 90% of mcb researchers from laboratories in china publish their work in international journals, as milestone achievements in grant applications are often defined by this. in recent years, the initiative of developing china's own brand-name international journals has received increasing support from multiple parties, including governmental agencies, local institutions and the broad community of scientists. as a result, premium international journals are starting to emerge from china, a prominent example of which is cell research. this journal has an impact factor that is competitive with key international journals and it is co-sponsored by the institute of biochemistry and cell biology (ibcb), shanghai institutes for biological sciences (sibs), cas and cscb. there is no doubt that as scientific research continues to flourish in china, more goodquality journals will emerge from chinese biological societies. scientific communication and conferences in china have also benefited from the rapid economic growth, as well as from intellectual input from scientists who return to china from overseas. traditionally, there have been few high-quality scientific conferences in china; one of these, the xiangshan science conference (which covers select subjects) is sponsored by the cas and nsfc. in general, most of the attendees of this conference are invited scientists from domestic institutes. however, a number of high-quality international conferences have taken place in china since 2008. the first international conference on cellular dynamics and chemical biology, which was held in hefei, china (12-15 september 2008) , focused on how specific molecules and their inter actions could be visualized in real space and time by bringing the disciplines of photonics, chemistry and biology together 26 . this conference was held in conjunction with the fiftieth anniversary of the ustc, and around 100 international scholars attended. it has now developed into a biennial event that attracts worldrenowned cell biologists from abroad (fig. 3) . from personal experience, students and postdoctoral fellows were offered ample opportunities to interact with speakers in the auditorium, during coffee breaks and the subsequent tour to the yellow mountain, a spectacular landmar k and sightseeing venue. the cold spring harbour laboratory (cshl) asia scientific advisory board held its first meeting in suzhou (4-5 october 2008 ) and decided to hold the first cshl asia conferences in suzhou starting in 2010 for a period of 10 years. these conferences aim to bring together top level scientists in order to promote communication and co llaboration within the field of life sciences. so far, cshl asia conferences are deemed to be very successful, aside from the high fees. in addition to international conferences, the cscb holds its biennial 'mountain meeting' series to present exciting unpublished advances on select topics. moreover, the cscb also holds a biennial meeting that aims to be similar in scope to the american society for cell biology (ascb) meeting. the most recent meeting was held 19-21 april 2013 and featured distinguished plenary speakers from abroad. the conference had eight concurrent mini-symposia, and more than 1000 scholars attended this exciting event. in general, the visa application process to attend conferences in china is rather quick and easy at chinese consulates and embassies overseas. in turn, chinese students and postdoctoral fellows are very much interested in attending international conferences and workshops. it is also encouraging to see that the visa application procedures for chinese scholars attending overseas symposiums, such as the ascb annual meeting and gordon research conferences, has been simplified over recent years. although mcb research in china has evolved rapidly over the past decade, there is certainly room for improvement in the scientific environment and in scientific output. so, what can be done better to catalyse scientific discoveries? the engine of scientific discovery is powered by motivated and talented scientific teams working together. specifically, the molecular delineation of the general principles that govern cellular plasticity and dynamics often requires synergism among chemistry, photonics, these centres provide scholarships for visiting researchers, which cover the costs of the conducted experiments and lodging for the visitin g scholars. administratively, mcb research could be further promoted by implementing new strategies such as merit-based competitiv e grant renewals for the most successful projects. this would avoid a 1-year gap in funding for such researchers and also the time spent on the application process; funding sources such as the 973, 863 and nsfc key projects require a second level of peer-review which consists of giving an oral presentation in front of a scientific panel. if merit-based competitive grant renewals were in place, principle investigators could file competitive renewals 1 year ahead of the completion of the project. in addition, it would be costeffective and productive if a 1-year extension that does not require the award of any new funding could be granted to researchers so that they don't have to rush to spend the remaining funds towards the end of a 5-year grant. it is also important to mentor young scientists at the early stages of their careers, as the scientific community needs 'new blood' to ensure that great scientific discoveries are made in the future. it is interesting to note that the tenure-track system has begun to be launched at universities and institutes in china, such as tsinghua university and the nibs, to promote the career development of early stage and mid-stage scientists. given the differences in research culture between the west and china, it will be very helpful for young principal investigators who have just started their own independent laboratories in china to be mentored by established early career scientists returning from abroad. along the line of career development, fair merit-based evaluation will certainly strengthen scientific advances. to promote scientific exchange, the cscb has initiated collaborations with partner societies, such as the ascb and the asia pacific organization of cell biology, to co-sponsor conferences and workshops. the cscb will continue to improve research and training environments by organizing joint conferences with partner societies on specialized topics and providing low-fee access to graduate student s and postdoctoral fellows. cells are a basic unit of life; all molecules play their parts on the cellular stage in order to participate in the spectacular complexity and diversity seen in a living organism. like all other basic scientific disciplines, mcb research demands not only quantitative, combinatory and systematic scientific approaches with experimental and conceptual novelty, but also the overhaul of infrastructures, funding mechanisms and, even more crucially, the culture, so that these parameters are comparable between countries. cultural changes pose a more challenging task than changes in infrastructure or funding strategies, especially in a country with a history of several 1000 years like china. the scientific advances durin g the past two decades in china seem to provide good reason for optimism and confidence that the trend will continue for another 20 years, as long as it relies more on the power and creativity of each 'cell' , the individual scientist. we hope that scientific and administrative processes will orchestrate the hypothesis-driven 'bottom-up' approach with the strategic 'top-down' design to allow great landmark scientific achievements to be made in china. spawning of the first fatherless toad in the world establishment and characterization of liver cancer cell line bel-7402 in vitro five-transmembrane domains appear sufficient for a g protein-coupled receptor: functional five-transmembrane domain chemokine receptors a nuclear function of β-arrestin-1 in gpcr signaling: regulation of histone acetylation and gene transcription deficiency in b-arrestin-2 signaling complex contributes to insulin resistance the crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor the structural basis for activation of plant immunity by bacterial effector protein avrpto structural basis for sequence-specific recognition of dna by tal effectors structurally distinct bacterial tbc-like gaps link arf gtpase to rab1 inactivation to counteract host defenses rip3, an energy metabolism regulator that switches tnf-induced cell death from apoptosis to necrosis mixed lineage kinase domain-like protein mediates necrosis signaling downstream of rip3 kinase the role of tet3 dna dioxygenase in epigenetic reprogramming by oocytes tet-mediated formation of 5-carboxylcytosine and its excision by tdg in mammalian dna c. elegans screen identifies autophagy genes specific to multicellular organisms function and molecular mechanism of acetylation in autophagy regulation gsk3-tip60-ulk1 signaling pathway links growth factor deprivation to autophagy regulation of cellular metabolism by protein lysine acetylation acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux a mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts induction of pluripotency in mouse somatic cells with lineage specifiers generation of genetically modified mice by oocyte injection of androgenetic haploid embryonic stem cells androgenetic haploid embryonic stem cells produce live transgenic mice structural insight into the autoinhibition mechanism of amp-activated protein kinase common folds and transport mechanisms of secondary active transporters lipid-induced conformational switch controls fusion activity of longin domain snare ykt6 visualization and orchestration of the dynamic molecular society in cells the authors thank q. lin (shanghai institutes for biological sciences (sibs)), y. shi (university of science and technology of china (ustc)), l. li (sibs), s. du (national natural science foundation (nsfc)), x. zhang (ministry of science and technology (most)) and x.-f. wang (duke) for critical reading of the manuscript and the chinese society for cell biology (cscb) for support. the authors apologize to those colleagues whose work could not be fully discussed due to space limitation s. this work was supported, in part, by 973 projects 2010cb912103 and 2011cb910202; nsfc projec t 90913016. the authors declare no competing financial interests. key: cord-355120-fg8iqhxq authors: gong, linna; zou, wei; zheng, keyang; shi, birui; liu, menghua title: the herba patriniae (caprifoliaceae): a review on traditional uses, phytochemistry, pharmacology and quality control date: 2020-08-23 journal: j ethnopharmacol doi: 10.1016/j.jep.2020.113264 sha: doc_id: 355120 cord_uid: fg8iqhxq ethnopharmacological relevance: herba patriniae has been used for thousands of years in china as a traditional chinese medicine with heat-clearing and detoxicating effects. it is applied widly for the treatment of rheumatoid arthritis, diarrhea, acute hepatitis, pelvic inflammatory disease and ulcerative colitis in clinic. two species, namely patrinia scabiosaefolia fisch. (ps) and patrinia villosa juss. (pv) from the caprifoliaceae family, are considered as herba patriniae in the pharmaceutical industry. aim of the review: this paper aims to comprehensively outline the traditional uses, botanical description, phytochemistry, pharmacology, toxicology, quality control, pharmacokinetics and patents of herba patriniae, and elaborate the same/different characteristics between ps and pv. materials and methods: detailed information of herba patriniae was collected from various online databases (pubmed, web of science, google schola, china national knowledge infrastructure database, national intellectual property administration, prc national medical products administration), and those published resources (m.sc. thesis and books). results: a total of 233 compounds have been identified in herba patriniae, including triterpenoid saponins, flavonoids, organic acids, iridoids, and volatiles. a very distinct difference was observed, that ps is rich in triterpenoid saponins and volatiles, while pv contains more flavonoids. two source species of herba patriniae gave similar pharmacological effects on anti-cancer, anti-inflammatory, antioxidant, antimicrobial, sedative and hypnotic effects. but there were no reports were on antipruritic, proangiogenic and anti-diarrheal effects for ps, and no studies on anti-diabetic effects for pv. generally, herba patriniae showed non-toxic in the clinical dose, but mild side effects, such as temporary leukopenia, dizziness and nausea, could be found when large and excessive dosage is used. a variety of compounds have been quantified for the quality control of ps and pv. the variety, growth environment, growth time, and harvest time not only affected the contents but also the pharmacological activities of the bioactive compounds. in the past year, patents for compositions containing pv and ps have been filed, mainly involving human health, hygiene, agriculture, and animal husbandry. unfortunately, the research on pharmacokinetics is insufficient. only the prototype components and metabolites were repored after intragastric administration of total flavonoids extract from pv in rats. conclusion: herba patriniae has displayed a significant medicinal value in clinic, but the differences in phytochemistry, pharmacological effects and the content of compounds have been found between two official recorded species. about side effects and pharmacokinetic characteristics, the differeces between two species have not been well studied. for a better clinical use of herba patriniae, it is urgent to establish systematic pharmacology, quality control, pharmacokinetics, and clinical researches on the same/different characteristics between ps and pv. 3-o-α-l-rhamnopyranosyl-(1→2)-β-d-xylopyranosyl-12β, 30-dihydroxy-olean-28, 13β-olide c 41 kaempferol-3-o-arabinoside c 20 h 18 kaempferol-3-o-β-d-trirhamninoside c 33 compounds are in pv, and only 3 compounds are in both ps and pv. according to the 300 aglycone, all of them were divided into oleanane type (1-57) and ursane type (58-66). further, the oleanane type is divided into 5 different types, including oleanolic acid 302 type (1-29), 13, 28-epoxy-oleanolic acid type (30-34), 11, 12 epoxy-13, flavonoids is a class of famous natural products with widely biological activities, their chemical structures are prescribed in figure 3 . j o u r n a l p r e -p r o o f isolated from ps. only 1 compound (131) was a common constituent of the two plants. 366 their chemical structures were prescribed in figure 5 . "heat" is a conception in traditional chinese medicine, which is the synonym of "fire" (table 4) . total saponin extract (pv was crushed and immersed in 1000 ml 70% ethanol for 12 h, refluxed and extracted at 40 °c, and concentrated under reduced pressure to remove ethanol and purified to obtain the total saponin extract.); 1/16, 1/32, 1/64 and 1/128 ml/ml for 48 h the total saponin of pv significantly inhibited tgf-β-induced emt, and up-regulated the expression of e-cadherin and down-regulated the expression of n-cadherin and nf-κbp65 in crc sw480 cell. the ethanol extract from ps treatment increased apoptosis and the ratio of pro-apoptotic bax/bcl-2 in ht-29 cells and crc tumor tissues. it also induced a decrease in mitochondrial membrane potential in ht-29 cells and activated caspase-9 and -3. yellow essential oil of 0.2 mg/g (w/w) was obtained.); 50-200 μg/ml for 24 h a498, a549, bel-7402, ht-29, mcf-7, k562 and sgc-7901 cell lines six flavonoids isolated from pv (a 75% aqueous ethanol crude extract (400 mg) of the leaves of pv was separated in one single isolation procedure to obtain 44.9 mg of (2s)-5, 7, 2′, 6′-tetrahydroxy-6, 8-di (γ, γ-dimethylallyl) flavanone with 99.1% purity, 35.5 mg of (2s)-5, 7, 2′, 6′-tetrahydroxy-6-lavandulylated flavanone with 98.8% purity, 79.8 mg of (2s)-5, 7, 2′, 6′-tetrahydroxy-4′-lavandulylated flavanone with 99.3% purity, and 45.8 mg of (2s)-5, 2′, 6′-trihydroxy-2′′, 2′′-dimethylpyrano [5′′, 6′′: 6, 7] flavanone with purity 98.8%, 39.8 mg of (2s, 3′′s)-5, 2′, 6′-trihydroxy-3′′-γ, γ-dimethylallyl-2′′, 2′′-dimethyl-3′′, 4′′-dihydropyrano [5′′,6′′: 6, 7] flavanone with 98.6% purity, 9.6 mg of licoagrochalcone b with 97.5% purity.); administration 3 day (2s)-5, 7, 2′, 6′-tetrahydroxy-6, 8-di (γ, γ-dimethylallyl) flavanone, (2s)-5, 7, 2′, 6′-tetrahydroxy-6-lavandulylated flavanone and (2s)-5, 7, 2′, 6′-tetrahydroxy-4′-lavandulylated flavanone exhibited high anticancer activities (ic 50 < 7 μg/ml) in a dose-dependent manner, and when the concentration of these compounds exceeded 15 μg/ml, the proliferation of cancer cells were completely inhibited, especially for k562 cancer cells (ic 50 < 3.1 μg/ml). j o u r n a l p r e -p r o o f species reference a stock concentration of 250 mg/ml.); mouse: intragastric administration, 1.93 g/kg/day, 5 days a week for 3 weeks; cells: 0.5-2 mg/ml for 24 h anti-inflammatory effect female icr mice, female sd rats, pid rat model (negative control: saline; positive control: dexamethasone) ethanol extract (30g pv was extracted with 300 ml 70% ethanol under reflux for 1h, extracted twice, filtered and concentrated to 1 g/ml concentration, and then dried.); female icr mice: intragastric administration, 0.08 g/kg for 0, 0.25, 0.5, 1 and 2 h to measure the ear edema thickness, or continuously observe and record the number of writhes in the 15min; sd rats: intragastric administration, 0.55 g/kg for 1 h to measure the paw volume or 0.08 g/kg for 7 days to measure the cotton pellet weight; pid rats: intragastric administration, 0.55 g/kg for 28 days the 70% ethanol extract of pv (0.08 g/kg) was significantly reduced the ear edema thickness induced by arachidonic acid and the writhing response induced by acetic acid in icr mice (80% and 48%, respectively), and (0.55 g/kg and 0.08 g/kg) inhibited the carrageenin-induced paw edema and the granuloma formation induced by a cotton pellet in sd rats (23% and 44%, respectively), as well as markedly (0.55 g/kg) suppressed the serum levels of il-8, tnf-α, and il-6 protein in pid rats. pv (zheng et al., 2012) ap rat model (negative control: saline) water extract (decocting ps with boiling distilled water for 3 h); intragastric administration, 100 mg/kg/day for 5 days the water extract of ps (100 mg/kg) reduced the ratio of pancreatic weight/body weight, the levels of serum lipase and amylase, and suppressed the secretion of il-1β, il-6, and tnf-α in ap rats, as well as increasing the levels of hsp60 and hsp72 in pancreas. ethyl acetate extract (15 kg ps was extracted with hot ethanol under reflux for 4h, extracted for four times, and 220 g total extract was obtained by vacuum evaporation. this extract was then dissolved in distilled water, extracted and separated with ethyl acetate, and evaporated in vacuo to yield 5.9 g.); cells: 10-100 μg/ml for 24 h; mice: intragastric administration, 300 mg/kg for 24 h the ethyl acetate extract of ps treatment on raw 264.7 cells, inhibited the production of no and il-6 induced by lps and the expression of inos and cox-2 at the protein and mrna levels in a concentration-dependent manner (10-100 μg/ml), in which the inhibition was operated by suppressed the level of nf-κb activity. in addition, the ethyl acetate extract of ps inhibited the production of tnf-α and il-6 in splenocytes of balb/c mice stimulated by lps. 200 μg/ml for 24 h therefore, the essential oil extract of ps has a significant anti-neuroinflammatory activity. rat models of focal cerebral ischemia-reperfusion (negative control: saline; positive control: nimodipine and naoluotong) total flavonoids (the content of total flavonoids in herba patriniae is 51.76%.); intragastric administration, 50, 100, 200 mg/kg/day for 7 days the total flavonoids (50, 100, 200 mg/kg) significantly reduced the levels of il-1β, icam-1, il-6, caspase-3, bax and enhanced the levels of bcl-2 and ngf in the brain tissue of rats. moreover, the total flavonoids (100, 200 mg/kg) significantly suppressed the percentage of cerebral infarction area, the production of nf-κb p65 and tnf-α, which showed significant neuroprotective effect. with 400 ml petroleum ether for 5 h, then dissolved with 400 ml 60% ethanol, refluxed and extracted for 2 h at 70 °c, extracted twice. the extract was centrifuged at 4000 r/min for 10 min, collected the supernatant and dried to obtain crude extract.); intragastric administration, 60, 120, 240 mg/kg/day for 10 days activity in mice with acute liver injury by decreasing the activities of alt and ast in serum, reducing the content of mda and activity of ldh in liver, and enhancing the activities of t-sod, t-aoc and gsh in liver. the water extract exhibited a stronger clearance rate for scavenging dpph and oh than ethanol extract both in ps and pv. moreover, the contents of chlorogenic acid and total flavonoids in the extracts are positively correlated with free radical scavenging ability. hela cells (negative control: culture solution; positive control: ribavirin) polysaccharide mixture (ap3) (1 kg of herba patriniae was immersed in 7000 ml distilled water at room temperature for 12 h, filtered, the drug residue was repeatedly extracted with 5000 ml of distilled water, the two extracted filtrates were combined, concentrated under reduced pressure to 1000 ml, and ap3 was obtained after purification.); 0.02-2 mg/ml for 0, 2, 4, 6, 8 h 70% ethanol extract (200 g of pv was immersed in 70% ethanol at 60 °c for 2.5 h, repeatedly extracted twice, and the two ethanol extracts were combined, filtered and concentrated to 200 ml by rotary evaporation, and obtained ethanol extract with a crude drug concentration of 1 g/ml.); 125-250 mg/ml the minimum inhibitory concentration of the extract was between 125-250 mg/ml. when the temperature was 23-160 °c, and the uv irradiation time was 10-50 min, the extract maintains high antimicrobial activity. (dai and lin, 2011) pseudomonas aeruginosa (negative control: deionized water) water extract (herba patriniae was crushed and immersed in deionized water for 2 h, then boiled for 2 h (w/v was 1/5), filtered and evaporated in vacuum, and then freeze-dried to obtain solid extract.); 1.6 mg/ml for 24 h the water extract of herba patriniae dramatically suppressed the expression of biofilm-associated key genes (alga, algu, bdla, pela, ppyr and pslm), thus decreased the biofilm formation and changed the structure of the biofilm of pseudomonas aeruginosa.it also reduced exopolysaccharide production and increased swarming motility. ethanol and water extract (the crude drug content in ethanol and water extract are both 1 g/ml.); intraperitoneal injection, 0.5 g/ml/10 g the ethanol extract of ps (0.5 g/ml/10 g) had an obvious sedative effect on mice, its sedative time was longer than water extract and its intensity was similar to that of pentobarbital, while without hypnotic effect. j o u r n a l p r e -p r o o f model experimental subject and administration results species reference petroleum ether, chloroform, ethyl acetate and n-butanol extract from 95% ethanol extract: intragastric administration, 0.12 g/kg, 5 h after administration, the number of mouse activity in 10 minutes was recorded; 95% ethanol extract: intragastric administration, 0.45 g/kg, 5 h after administration, the number of mouse activity in 10 minutes was recorded mice (negative control: saline), patients 60% ethanol extract, volatile oil and dried ethanol extract (60% ethanol extract: the root of ps was crushed and immersed in 60% ethanol, then distilled under reduced pressure until 20% extract contains 10-15% ethanol.); 60% ethanol extract: (mice: intragastric administration, 30 g/kg); volatile oil (mice: intragastric administration, 0.2 g/kg; patients: 20 mg/capsule, 1-2 capsules/day, 1 times/day, 10-14 days); dried ethanol extract (mice: intragastric administration, 7.5 g/kg; patients: 1 g/tablet, 2-4 tablets/day, 2-3 times/day, 10-14 days) the 60% ethanol, volatile oil, and dried ethanol extracts from ps possessed sedative and hypnotic effect on mice induced by pentobarbital sodium and patients suffered from neurasthenia or neurasthenic syndromes with insomnia. 60% ethanol, dichloromethane layer, ethyl acetate layer, n-butanol layer and water layer extract (the 60% ethanol extract: 50 g pv was crushed and refluxed with 500 ml 60% ethanol at 85 °c for 2 h, extracted twice, filtered and concentrated by rotary evaporation under reduced pressure to obtain a solid powder 4.75 g; extracts of different polar parts: 500 g pv was crushed and refluxed with 5000 ml 60% ethanol at 85 °c for 2 h, extracted twice, filtered and concentrated by rotary evaporation under reduced pressure to no alcohol taste, and then diluted with 2000 ml water and extracted with dichloromethane, ethyl acetate and n-butanol, extracted twice. after vacuum drying, the extract was 1.77, 2.28 and 10.61 g, respectively, the water layer extract was 23.34 g.); isolated intestine cramps model: 0.02-1.28 mg/ml; in vivo: intragastric administration, 100, 200, 400 mg/kg/day, 7 days all the five extracts of pv exhibited an anti-diarrheal effect in a dose-dependent manner (100-400 mg/kg), in which the effect of dichloromethane layer is stronger than that of other polar extracts. these results provide ideas for further research on its traditional medicine. patriniae is quite safe for animals and people at a reasonable dosage. the water boiled extraction method: 2.5 g pv powder was boiled in 50 ml water for three times, 2 h, 1.5 h, 1 h, respectively, the extract was filtered and water was added to 250 ml for constant volume. the ethanol refluent extraction method: 2.5 g pv powder was refluxed and extracted with 50 ml methanol for three times, 2 h, 1.5 h, 1 h, respectively, the extract was filtered and water was added to 250 ml for constant volume. the suoshi extraction method: 2.5 g pv powder was extracted in a cable extractor with 50 ml methanol for 4 h with 50 ml methanol, the extract was filtered and water was added to 250 ml for constant volume. the supersonic extraction method: 2.5 g pv powder was subjected to ultrasonic extracted with 50 ml methanol for 45 min, three times, the extract was filtered and water was added to 250 ml for constant volume. j o u r n a l p r e -p r o o f repeatedly boiled with 1 l of water, the two extracted filtrates were combined, the 50 ml extract was concentrated in a water bath to a thick paste. quercetin kaempferol 1 g ps or pv powder was extracted with 20 ml of hydrochloric acid-methanol (1:20, v/v) mixed solution under reflux for 1 h, filtered and methanol was added to 25 ml for constant volume. in pv, twelve batches have been determined with the contents of 0.061-1.046 mg/g for quercetin and 0.082-0.701 mg/g for kaempferol. in ps, fourteen batches have been determined with the contents of 0.062-0.938 mg/g for quercetin and 0.045-0.542 mg/g for kaempferol, indicating that the quercetin and kaempferol content in the samples from different sources were significantly different. ursolic acid oleanolic acid 1 g herba patriniae powder was subjected to ultrasonic extracted with 30 ml methanol for 45 min, after the weight loss is made up, filtered and the extract of 1 ml was extracted and fixed volume to 10 ml with methanol. the contents of ursolic acid and oleanolic acid for 6 batches were 0.218%-0.498% and 0.158%-0.473%, respectively. pv (chen, 2008) hederagenin oleanolic acid ursolic acid 2 g herba patriniae powder was subjected to ultrasonic extracted with 50 ml methanol for 60 min, filtered, the drug residue was washed with proper amount of methanol, combined the filtrate and the washing solution, evaporated, and dissolved in 10 ml water, then extracted with 20 ml water-saturated n-butanol, extracted three times, combined the extracts and evaporated to dryness. the residue was heated and hydrolyzed with 20 ml methanol and 4 ml hydrochloric acid for 4 h, then added with 10 ml water and shaken and extracted with 20 ml chloroform, extracted twice, combined the extracts and evaporated to dryness. the residue was dissolved and fixed volume to 10 ml with methanol. the contents of hederagenin, oleanolic acid and ursolic acid have been determined in ten batches. the result was that the contents of the compounds were significantly different among the different samples. the concentration ranges were 0.002%-0.556%, 0.019%-0.592% and 0.022%-0.630% for hederagenin, oleanolic acid and ursolic acid. in ps, the contents of palmic acid, hexanoic acid and cis-anethol were 9.54-12.14%, 8.27-10.23%, 6.68-8.34%, respectively. in pv, the contents of camphogen, β-ionone and β-damascenone were 9.55-11.89%, 5.98-6.54%, 5.94-7.56%, respectively. table 7 . most of the patents are human health products (88), 678 13 patents for animal husbandry, 6 patents for agriculture and 1 patent for fisheries. j o u r n a l p r e -p r o o f yellow essential oil of 0.2 mg/g (w/w) was obtained.); 50-200 μg/ml for 24 h a498, a549, bel-7402, ht-29, mcf-7, k562 and sgc-7901 cell lines six flavonoids isolated from pv (a 75% aqueous ethanol crude extract (400 mg) of the leaves of pv was separated in one single isolation procedure to obtain 44.9 mg of (2s)-5, 7, 2′, 6′-tetrahydroxy-6, 8-di (γ, γ-dimethylallyl) flavanone with 99.1% purity, 35.5 mg of (2s)-5, 7, 2′, 6′-tetrahydroxy-6-lavandulylated flavanone with 98.8% purity, 79.8 mg of (2s)-5, 7, 2′, 6′-tetrahydroxy-4′-lavandulylated flavanone with 99.3% purity, and 45.8 mg of (2s)-5, 2′, 6′-trihydroxy-2′′, 2′′-dimethylpyrano [5′′, 6′′: 6, 7] flavanone with purity 98.8%, 39.8 mg of (2s, 3′′s)-5, 2′, 6′-trihydroxy-3′′-γ, γ-dimethylallyl-2′′, 2′′-dimethyl-3′′, 4′′-dihydropyrano [5′′,6′′: 6, 7] flavanone with 98.6% purity, 9.6 mg of licoagrochalcone b with 97.5% purity.); administration 3 day (2s)-5, 7, 2′, 6′-tetrahydroxy-6, 8-di (γ, γ-dimethylallyl) flavanone, (2s)-5, 7, 2′, 6′-tetrahydroxy-6-lavandulylated flavanone and (2s)-5, 7, 2′, 6′-tetrahydroxy-4′-lavandulylated flavanone exhibited high anticancer activities (ic 50 < 7 μg/ml) in a dose-dependent manner, and when the concentration of these compounds exceeded 15 μg/ml, the proliferation of cancer cells were completely inhibited, especially for k562 cancer cells (ic 50 < 3.1 μg/ml). reference a stock concentration of 250 mg/ml.); mouse: intragastric administration, 1.93 g/kg/day, 5 days a week for 3 weeks; cells: 0.5-2 mg/ml for 24 h anti-inflammatory effect female icr mice, female sd rats, pid rat model (negative control: saline; positive control: dexamethasone) ethanol extract (30g pv was extracted with 300 ml 70% ethanol under reflux for 1h, extracted twice, filtered and concentrated to 1 g/ml concentration, and then dried.); female icr mice: intragastric administration, 0.08 g/kg for 0, 0.25, 0.5, 1 and 2 h to measure the ear edema thickness, or continuously observe and record the number of writhes in the 15min; sd rats: intragastric administration, 0.55 g/kg for 1 h to measure the paw volume or 0.08 g/kg for 7 days to measure the cotton pellet weight; pid rats: intragastric administration, 0.55 g/kg for 28 days the 70% ethanol extract of pv (0.08 g/kg) was significantly reduced the ear edema thickness induced by arachidonic acid and the writhing response induced by acetic acid in icr mice (80% and 48%, respectively), and (0.55 g/kg and 0.08 g/kg) inhibited the carrageenin-induced paw edema and the granuloma formation induced by a cotton pellet in sd rats (23% and 44%, respectively), as well as markedly (0.55 g/kg) suppressed the serum levels of il-8, tnf-α, and il-6 protein in pid rats. pv (zheng et al., 2012) ap rat model (negative control: saline) water extract (decocting ps with boiling distilled water for 3 h); intragastric administration, 100 mg/kg/day for 5 days the water extract of ps (100 mg/kg) reduced the ratio of pancreatic weight/body weight, the levels of serum lipase and amylase, and suppressed the secretion of il-1β, il-6, and tnf-α in ap rats, as well as increasing the levels of hsp60 and hsp72 in pancreas. ethyl acetate extract (15 kg ps was extracted with hot ethanol under reflux for 4h, extracted for four times, and 220 g total extract was obtained by vacuum evaporation. this extract was then dissolved in distilled water, extracted and separated with ethyl acetate, and evaporated in vacuo to yield 5.9 g.); cells: 10-100 μg/ml for 24 h; mice: intragastric administration, 300 mg/kg for 24 h the ethyl acetate extract of ps treatment on raw 264.7 cells, inhibited the production of no and il-6 induced by lps and the expression of inos and cox-2 at the protein and mrna levels in a concentration-dependent manner (10-100 μg/ml), in which the inhibition was operated by suppressed the level of nf-κb activity. in addition, the ethyl acetate extract of ps inhibited the production of tnf-α and il-6 in splenocytes of balb/c mice stimulated by lps. 200 μg/ml for 24 h therefore, the essential oil extract of ps has a significant anti-neuroinflammatory activity. rat models of focal cerebral ischemia-reperfusion (negative control: saline; positive control: nimodipine and naoluotong) total flavonoids (the content of total flavonoids in herba patriniae is 51.76%.); intragastric administration, 50, 100, 200 mg/kg/day for 7 days the total flavonoids (50, 100, 200 mg/kg) significantly reduced the levels of il-1β, icam-1, il-6, caspase-3, bax and enhanced the levels of bcl-2 and ngf in the brain tissue of rats. moreover, the total flavonoids (100, 200 mg/kg) significantly suppressed the percentage of cerebral infarction area, the production of nf-κb p65 and tnf-α, which showed significant neuroprotective effect. dpph essential oil extract (the dried whole plant of ps (500 g) was distilled with double distilled water of 5000 ml for 4 h, and the yellow essential oil of 0.2 mg/g (w/w) was obtained.); 0.5-2 mg/ml the volatiles extract of ps has a dose-dependent scavenging effect on dpph radical, with ic 50 of 1.455 mg/ml. with 400 ml petroleum ether for 5 h, then dissolved with 400 ml 60% ethanol, refluxed and extracted for 2 h at 70 °c, extracted twice. the extract was centrifuged at 4000 r/min for 10 min, collected the supernatant and dried to obtain crude extract.); intragastric administration, 60, 120, 240 mg/kg/day for 10 days activity in mice with acute liver injury by decreasing the activities of alt and ast in serum, reducing the content of mda and activity of ldh in liver, and enhancing the activities of t-sod, t-aoc and gsh in liver. oh, dpph and o 2ethanol and water extract (the ethanol extract: 100 g ps or pv was immersed in 1.5 l 70% ethanol for 30 min, refluxed and extracted for 2 h, filtered, repeated 3 times, combined filtrate, concentrated and freeze-dried. the contents of chlorogenic acid, caffeic acid and total flavonoids in the ethanol extract of pv were 64.37 ± 2.43, 21.19 ± 1.24, and 293.00 ± 2.65 mg/g, respectively, and in the ethanol extract of ps were 83.80 ± 1.15, 1.12 ± 0.09, and 318.00 ± 2.65 mg/g, respectively. the water extract: 100 g ps or pv was immersed in 1.5 l distilled water for 30 min, refluxed and extracted for 2 h, filtered, repeated 3 times, combined filtrate, concentrated and freeze-dried. the contents of chlorogenic acid, caffeic acid and total flavonoids in the water extract of pv were 94.18 ± 1.94, 19.05 ± 0.75, and 334.00 ± 5.20 mg/g, respectively, and in the water extract of ps were 117.29 ± 0.85, 1.52 ± 0.09, and 383.00 ± 3.61 mg/g, respectively.); 5, 10, 15 mg/ml for scavenging oh and dpph; 0.5, 1, 1.5 mg/ml for scavenging o 2the water extract exhibited a stronger clearance rate for scavenging dpph and oh than ethanol extract both in ps and pv. moreover, the contents of chlorogenic acid and total flavonoids in the extracts are positively correlated with free radical scavenging ability. polysaccharide mixture (ap3) (1 kg of herba patriniae was immersed in 7000 ml distilled water at room temperature for 12 h, filtered, the drug residue was repeatedly extracted with 5000 ml of distilled water, the two extracted filtrates were combined, concentrated under reduced pressure to 1000 ml, and ap3 was obtained after purification.); 0.02-2 mg/ml for 0, 2, 4, 6, 8 h the polysaccharide mixture (ap3) exerted an obvious dose-dependent anti-rsv effect with tc 50 and ec 50 values of 11.45 and 0.0986 mg/ml, respectively. moreover, the therapeutic index (ti = tc 50 /ec 50 ) was 116.12. selected data 757 of acute abdomen treated by integrated traditional chinese and western medicine affiliated hospital of guangzhou college of traditional chinese medicine nephroprotective effects of chlorogenic acid against sodium arsenite-induced 761 oxidative stress, inflammation, and apoptosis scutellarin exerts anticancer effects on human 763 leukemia cells via induction of sub-g1 cell cycle arrest, apoptosis and also inhibits 764 migration and invasion by targeting raf/mek/erk signalling pathway a biological herbicide for killing eupatorium adenophorum beijing chinese traditional patent medicine 769 specification. printing office of beijing medicinal materials company surgery of chinese medicine. people's 771 medical publishing house biological products identification institute of the ministry of health structure of scabioside f structure of scabioside g triterpene glycosides of patrinia 779 scabiosofolia. i. chemistry of natural compounds compilation of traditional chinese medicine preparations. people's medical 782 publishing house five key points of improving fertility rate of cows. rural science and technology syrup for preventing and treating 786 endometriosis of qi stagnation and blood stasis type wine for preventing and treating endometriosis of 788 qi stagnation and blood stasis type a composition for preventing skin 790 aging and a skin care product containing the composition selection of medical prescriptions of cixi and guangxu the study on anti-tumor effect and its 794 mechanism on sarcoma u14 mice of cervical cancer by the alcohol extract of patrina 795 villosa patrinia scabiosaefolia 797 inhibits colorectal cancer growth through suppression of tumor angiogenesis modern research progress on patriniae the benefit of interplanting bitter vegetables in newly planted tea garden is 802 good traditional chinese 804 medicine composition for treating colitis and proctitis and application thereof determination of isovitexin and isoorientin from patrinia villosa juss by hplc. 807 china pharmaceuticals inhibitory effect of aqueous extract of patrinia villosa juss on 809 central nerve system ethyl acetate extract of patrinia scabiosaefolia 811 downregulates anti-apoptotic bcl-2/bcl-x(l) expression, and induces apoptosis in human 812 breast carcinoma mcf-7 cells independent of caspase-9 activation anti-inflammatory effects of methanol extract of patrinia scabiosaefolia in mice 816 with ulcerative colitis coumarins and triterpenoid glycosides from the roots of patrinia 818 scabiosaefolia triterpenoid glycosides from the roots of patrinia scabiosaefolia medicine for treating gastritis and preparation method thereof traditional chinese medicine composition for treating 999 gynecological tubal blockage and preparation method thereof studies on anti-inflammation chemical constitutes of 1001 patrinia villosa antihypertensive twin drugs by caffeic acid and ferulic acid with telmisartan preparation method of whitening toner the anti-respiratory syncytial 1007 virus effect of an active compound (ap3) from a chiese medicinal herb-herba patriniae 1008 in vitro a health product for cervicitis health beverage with the function of preventing hepatobiliary 1011 disease and preparation method thereof inhibitory effects of anti-sars traditional chinese medicines on the 1013 uv irradiation of lambda-lysogen studies on the constituents of patrinia 1016 scabiosaefolia fisch isolation and identification of triterpenoid saponins from patrinia 1018 scabiosaefolia fisch a traditional chinese medicine lotion for treating vulvar 1020 inflammation and its application method prevention and treatment of "climbing beedisease" with herba patriniae a preparation method for extracting non-residual insecticides from plants a traditional chinese medicine composition for treating pancreatitis ethanol extract of patrinia scabiosaefolia 1029 induces the death of hum, an renal cell carcinoma 786-o cells via sirt-1 and mtor 1030 signaling-mediated metabolic disruptions standard of chinese herbal medicine in liaoning 1033 liaoning science & technology publishing house chemical composition, anticancer, 1035 anti-neuroinflammatory, and antioxidant activities of the essential oil of patrinia 1036 scabiosaefolia composite pig feed containing rhubarb and 1038 preparation method thereof current situation and laboratory research progress of invasive aspergillus 1040 simultaneous determination of five organic acids in patriniae herba by 1043 dual-wavelength reversed phase high performance liquid chromatography. traditional 1044 chinese drug research and clinical pharmacology simultaneous determination of 1047 protocatechuic acid, chlorogenic acid and caffeic acid in herba patriniae by 1048 dual-wavelength hplc simultaneous determination of quercetin 1050 and kaempferol in herba patriniae by rp-hplc a method for preparing the extract of patrinia scabiosaefolia clinical application progress of patriniae in gynecological diseases. chinese 1055 medicine modern distance education of china giganteaside d induces ros-mediated apoptosis in human 1058 hepatocellular carcinoma cells through the mapk pathway oleanolic acid derivative and 1061 preparation method thereof a triterpenoid 1063 saponin with antitumor effect patrinia scabiosaefolia induces mitochondrial-dependent apoptosis in a mouse model of 1066 colorectal cancer the nursing experience of the treatment of ulcerative colitis with the preserved 1068 enema of herba patriniae decoction a traditional chinese medicine formula for the treatment 1071 of stomach disease chinese traditional and herbal drugs determination of volatile component from patrinia villosa 1075 (thunb.) juss. and patrinia scabiosaefolia fisch by gc-ms a traditional chinese medicine composition for treating non-alcoholic 1079 fatty liver of liver stagnation and spleen deficiency type and its application traditional chinese medicine composition for treating horse 1082 sinus abscess and preparation method thereof traditional chinese medicine composition for treating tail 1084 preparation method thereof a cytotoxic natural product from 1086 patrinia villosa juss chemical constituents from patrinia 1089 villosa juss effects and 1092 mechanisms of iridoid glycosides from patrinia scabiosaefolia on improving insulin 1093 resistance in 3t3-l1 adipocytes medicine for treating leucorrhea abnormality and preparation 1096 method thereof patch for regulating prostate hyperplasia and its conditioning 1098 method oral medicine for treating chronic pelvic inflammatory disease research on materia medica of herba patriniae. lishizhen medicine and materia 1103 medica research ethnomedicinal 1105 toxicology of species from the genus ajuga 1106 l.: a systematic review clinical observation and pharmacological 1109 investigation of the sedative and hypnotic effects of the chinese drug rhizome and root of 1110 medicine combination for treating vaginitis and preparation method 1112 thereof traditional chinese medicine for promoting the rehabilitation of 1114 pelvic inflammation and its preparation method application of traditional chinese medicine in the preparation of drugs for the prevention 1117 and/or treatment of chronic pelvic inflammation simaltanous determination of hederagenina, 1119 oleanolic acid and ursolic acid in herba patriniae by hplc. chinese journal of 1120 experimental traditional medical formulae n-acetylglycoside of oleanolic acid (aridanin) displays promising 1124 cytotoxicity towards human and animal cancer cells, inducing apoptotic, ferroptotic and 1125 necroptotic cell death design, synthesis and biological evaluation of amino acids-oleanolic acid influenza virus inhibitors drug for internal and external application in the treatment of chronic 1131 eczema and preparation method thereof phytochemical studies of 1133 seeds of medicinal plants. iii. ursolic acid and oleanolic acid glycosides from seeds of 1134 patrinia scabiosaefolia fischer gynecological anti-itching tablet and its 1137 preparation method natural acne composition and application thereof anti-oxidant and anti-inflammatory effects of caffeic acid: in vivo evidences in a model 1141 of noise-induced hearing loss luteolin improves 1144 hypercholesterolemia and glucose intolerance through lxrα-dependent pathway in 1145 diet-induced obese mice preparation method 1147 and application method of breath freshening oral care liquid patrinia 1149 scabiosaefolia extract suppresses proliferation and promotes apoptosis by inhibiting the 1150 stat3 pathway in human multiple myeloma cells efficient new method for extraction and 1153 isolation of three flavonoids from patrinia villosa juss. by supercritical fluid extraction 1154 and high-speed counter-current chromatography studies on chemical constituents of patrinia villosa juss supercritical fluid extraction of aurentiamide acetate from 1160 patrinia villosa juss and subsequent isolation by silica gel and high-speed counter-current 1161 chromatography studies on chemical constituents of patrinia villosa isolation and structure identification of chemical 1165 constituents from patrinia villosa preparative isolation of four new and two known 1168 flavonoids from the leaf of patrinia villosa juss. by counter-current chromatography and 1169 evaluation of their anticancer activities in vitro preparative isolation and separation of a novel 1172 two known flavonoids from patrinia villosa juss by high-speed counter-current 1173 chromatography a preparation 1175 method of qingre xuanfei xiaoer reke oral liquid tujia medicine pharmacopoeia committee of the ministry of health of p. r. china, 1978. pharmacopoeia of the 1178 people's medical publishing house efficacy of baijiangcao san on immune function and intestinal 1181 function in children with recurrent upper respiratory tract infection miao medicine volume of chinese materia medica. guizhou science and 1184 technology publishing house herbal health tea clinical and fungal morphological examination of common dermatomycosis facile synthesis of the 1191 naturally cytotoxic triterpenoid saponin patrinia-glycoside b-ii and its conformer a traditional chinese medicine for the treatment of liver disease scientific research cooperation group of herba patriniae in yan'an city for the prevention and 1196 control of keshan disease inhibitory effect of patrinia scabiosaefolia on 1200 acute pancreatitis standard of chinese herbal medicine in 1202 shandong province shanghai college of traditional chinese medicine whitening and dispelling yellow soap and 1205 preparation method thereof list of yunnan ethnic medicine. yunnan institute for drug control herba patriniae decoction enema in the treatment of anal cryptitis: a report of 367 1208 cases experiment of chinese herbal medicine in the treatment of venomous snake bite 1210 of xiangxi yellow cattle. chinese journal of traditional veterinary science sichuan food and drug administration chemical constituents from patrinia villosa treatment of 52 cases of acute hepatitis with artemisiae scopariae herba-herba 1218 pharmacopoeia of the people's republic 1220 of china artificial cultivation technology of edible wild 1223 vegetable herba patriniae. fujian agricultural science and technology. s1, 172 weaning piglet feed additive and 1226 preparation method thereof qian jin yi fang. people's medical publishing house qian jin fang. china traditional chinese medicine press，beijing. 1229 the anti-angiogenic effects of traditional chinese medicine-part i: heat-clearing and 1261 detoxicating tcm 1263 iridoids: research advances in their phytochemistry, biological activities, and 1264 pharmacokinetics medication rules for prescriptions containing herba 1266 patriniae based on data mining manufacturing process and quality control 1269 method of pharmaceutical composition with effect of treating dark circles chinese herbal medicine preparation for treating cancer and 1272 preparation method thereof traditional chinese medicine 1274 composition for treating lung cancer with phlegm and blood stasis syndrome and 1275 preparation method thereof tai ping sheng hui fang. people's medical publishing house a traditional chinese medicine for the treatment of acne study on quality standard of herba patriniae 1280 distributed in henan province pharmacological study and clinical application of patrinia 1282 scabiosaefolia treatment of cutaneous pruritus mainly by herba patriniae livestock feed formula determination of inositol in herba patriniae color atlas of miao medicine in china. guizhou science and technology 1290 publishing house study on development of chemical composition and pharmacological action of 1292 patrinia scabiosaefolia fisch pharmacology and application of traditional chinese 1294 medicine. people's medical publishing house anti-inflammatory effect of three iridoids in 1296 human neutrophils medicine effect compare and extraction 1298 process study on two kinds of patrinia based on inhibition rate of smmc-7721 1299 hepatocarcinoma cells effects of total flavonoids from 1301 patriniae on neuroprotective effect and inflammatory factors of focal cerebral ischemia 1302 reperfusion injured rats loganin attenuates 1305 intestinal injury in severely burned rats by regulating the toll-like receptor 4/nf-κb 1306 signaling pathway study on antifungal activity screening and mechanism of traditional chinese 1308 medicines. shanghai: the second military medical university chemical components of the petroleum 1310 ether extract of patrinia villosa a facial mask to enhance the ability of antioxidation a medicinal wine for preventing breast disease effects of saponins of patrinia villosa against invasion 1316 and metastasis in colorectal cancer cell through nf-kappab signaling pathway and emt studies on chemcial 1319 constituents in patrinia scabiosaefolia new flavonoid from 1321 patrinia villosa clinical application of herba patriniae traditional chinese medicine composition for treating 1325 dysmenorrhea and preparation method thereof a traditional chinese medicine composition for treating 1327 cancer antibacterial and environment-friendly laundry detergent and 1329 preparation method thereof chemical composition and antioxidant activity of volatiles 1331 from patrinia villosa juss obtained by optimized supercritical fluid extraction medicine for treating stomach disease and preparation method 1334 thereof formula for treating aids studies on the constituents of patrinia villosa flavonoids extracting study on different parts of patrinia villosa juss 1339 by four methods the anticancer potential of apigenin via immunoregulation processing technology of tea or 1344 food applied production made of patrinia villosa study on the sedative active parts of herba 1347 gc-ms analysis of 1350 volatile oil from six medicinal plants in changbai mountain clinical observation on the therapeutic effect of herba patriniae 1353 decoction in the treatment of pelvic endometriosis clinical 1356 observation of compound herba patriniae tablets in the treatment of 62 cases of psoriasis 1357 vulgaris traditional chinese medicine formula for treating breast diseases and 1360 preparation method thereof a 1362 new biphenyl neolignan from leaves of patrinia villosa (thunb.) juss. pharmacogn mag. 1363 a kind of botanical insecticide an agricultural insecticide gu jin ming fang isolation and identification of new acetylated 1368 saponin from radix and rhizome of patrinia scabiosaefolia. chinese traditional and 1369 herbal drugs study on the chemical components from patrinia 1371 scabiosaefolia fish. ex link by supercritical fluid extraction isolation and identification of triterpenoide 1374 compound from patrinia scabiosaefolia medicine for treating dysmenorrhea studies on the chemical constituents of patrinia 1378 scabiasaefolia fisch herba patriniae is good at treating neurasthenia chinese herbal medicine compound preparation for preventing and treating pigeon 1383 trichomoniasis and preparation method thereof a new triterpene lactone from the roots of patrinia 1385 scabiosaefolia a traditional chinese medicine granule for treating acute cough 1387 caused by pulmonary tuberculosis a traditional chinese medicine granule for treating cough 1389 caused by pneumonia a traditional chinese medicine granule for treating cough 1391 chronic pharyngitis a 1393 new sesquiterpene lactone glycoside and a new quinic acid methyl ester from patrinia 1394 villosa 1396 preparation method and application of traditional chinese medicine mouthwash a traditional chinese medicine external cleaning agent for treating 1399 infectious wounds caused by multiple drug-resistant bacteria medicine for treating orchitis and preparation method thereof the comparison and analysis of the patrinia villosa tea quality by different processing 1404 technologies. modern food science and technology preparation method for preventing and treating appendicitis bacteriostatic toilet paper and preparation method thereof compound extract of traditional chinese medicine for the treatment of postmenopausal 1412 osteoporosis and its preparation method composite preparation for preventing and treating pigeon diarrhea traditional chinese medicine preparation for controlling swine fever a chinese medicinal composition for treating diabetes medicine for treating appendicitis traditional chinese medicine composition for treating 1421 cervical erosion of women a traditional chinese medicine composition for treating lung pain patrinia scabiosaefolia 1425 inhibits the proliferation of colorectal cancer in vitro and in vivo via g1/s cell cycle arrest compound chinese herbal medicine fertilizer for promoting 1428 growth anti-diarrheal effect of 1430 extracts from patrinia villosa juss antitumor effects of 1433 saponin extract from patrinia villosa (thunb.) juss on mice bearing u14 cervical cancer traditional chinese medicine 1437 preparation for treating chicken infectious bronchitis and anti-fallopian tube injury and 1438 preparation method thereof antiproliferative activity of ursolic acid in 1440 mda-mb-231 human breast cancer cells through nrf2 pathway regulation treatment of 287 cases of pelvic inflammation with self-made smilacis 1443 glabrae rhizoma-herba patriniae decoction a traditional chinese medicine composition for anti-breast 1446 cancer study on hplc fingerprints of patrinia villosa a preparation method of detoxification and moistening intestines 1450 peony scented tea jin gui yao lüe wild grass is a good feed for disease prevention of soft-shelled turtle and fish 1453 (2). fishery guide to be rich sheng ji zong lu. people's medical publishing house the process 1456 optimization of extraction and purification for total flavonoids and comparative study on 1457 the efficacy of anti-liver tumors in vitro before and after purification. lishizhen medicine 1458 and materia medica research traditional chinese medicine for treating cirrhotic ascites and 1460 preparation method thereof a traditional chinese medicine formula for the treatment of bronchitis analysis of chemical constituents of patrinia scabiosaefolia fisch the anti-inflammatory and 1466 anti-nociceptive activities of patrinia villosa and its mechanism on the proinflammatory 1467 cytokines of rats with pelvic inflammation an analysis of nutrient constituents 1470 of wild patrinaia villosa effect of patrinia villosa juss extract on the 1472 sleep function and spontaneous activity of mice. chinese journal of clinical 1473 rehabilitation rapid analysis and identification of the 1475 main constituents in patrinia scabiosaefolia fisch composition for 1478 preventing and treating animal mastitis and preparation method and application thereof determination of oleanolic acid and ursolic acid in herba patriniae from 1481 different habitats application of oleanolic acid and its analogues in combating pathogenic bacteria pronged strategy of β-lactamases and hemolysins pu ji fang (volumes 351). people's medical publishing house application of herba patriniae and traditional chinese medicine 1489 composition for treating pig blue ear disease the ancient and modern use of herba patriniae phytochemical studies on the seeds of medicinal plants (4): flavonoids and 1493 triterpenoids in patrinia villosa. foreign medicine (fascicles of traditional chinese 1494 medicine) traditional chinese medicine 1496 composition and traditional chinese medicine preparation metabolomic study on the preventive effect of patrinia 1499 scabiosaefolia fisch on multipathogen induced pelvic inflammatory disease in rats. evid 1500 based complement alternat med the chemical constitutes from patrinia scabiosaefolia fisch r=xyl(1→3)rha(1→2)ara r=rha(1→2)xyl r=giu(1→3)rha(1→2)ara r=xyl(1→3)rha(1→2)ara r=glu(1→4)xyl(1→3)rha(1→2)xyl-14 r=xyl 15 r=rha(1→2)xyl-16 r=h 17 r=xyl(1→3)rha(1→2)xyl r=giu(1→3)rha(1→2)ara-19 r=h 20 r=xyl(1→3)rha(1→2)xyl r=glu(1→4)xyl(1→3)rha(1→2)xyl r=glu(1→4)xyl(1→3)rha(1→2)ara r=xyl(1→3)rha(1→4)xyl r=glu(1→4)ara(1→3)rha(1→4)xyl r=xyl(1→4)glu(1→3)ara r=rha(1→2)xyl r=xyl(1→3)rha(1→2)xyl r=xyl(1→3)rha(1→2)xyl r=xyl(1→3)rha(1→2)ara r=rha(1→2)ara r=glu(1→3)rha(1→2)ara r=rha(1→2)ara r=xyl(1→3)rha(1→2)ara r=glu(1→3)rha(1→2)ara 4″-dihydroxyphenyl) ethyl 70 r=7″r-(3″,4″-dihydroxyphenyl) ethyl 71 r=7″s-(3″,4″-dihydroxyphenyl) ethyl 72 r=7″s-(3″,4″-dihydroxyphenyl) ethyl r=rha(1→3)-(4‴-ac-rha r=rha(1→3)-(4‴-ac-rha)-(1→6)gal r=rha(1→3)rha(1→6)gal r=rha(1→3)-(4‴-ac-rha)-(1→6)gal r=rha(1→3)rha(1→6) the water extract of ps (0.5 g/ml) has a strong inhibitory effect against staphylococcus aureus, streptococcus and escherichia coli, and it has a weak antibacterial effect on pasteurella and salmonella, while the ethanol extract (0.5 kaempferol-3-o-arabinoside c 20 h 18 kaempferol-3-o-β-d-trirhamninoside c 33 70% ethanol extract (200 g of pv was immersed in 70% ethanol at 60 °c for 2.5 h, repeatedly extracted twice, and the two ethanol extracts were combined, filtered and concentrated to 200 ml by rotary evaporation, and obtained ethanol extract with a crude drug concentration of 1 g/ml.); 125-250 mg/mlthe minimum inhibitory concentration of the extract was between 125-250 mg/ml. when the temperature was 23-160 °c, and the uv irradiation time was 10-50 min, the extract maintains high antimicrobial activity. (dai and lin, 2011)pseudomonas aeruginosa (negative control: deionized water)water extract (herba patriniae was crushed and immersed in deionized water for 2 h, then boiled for 2 h (w/v was 1/5), filtered and evaporated in vacuum, and then freeze-dried to obtain solid extract.); 1.6 mg/ml for 24 hthe water extract of herba patriniae dramatically suppressed the expression of biofilm-associated key genes (alga, algu, bdla, pela, ppyr and pslm), thus decreased the biofilm formation and changed the structure of the biofilm of pseudomonas aeruginosa.it also reduced exopolysaccharide production and increased swarming motility. ethanol and water extract (the crude drug content in ethanol and water extract are both 1 g/ml.); intraperitoneal injection, 0.5 g/ml/10 g the ethanol extract of ps (0.5 g/ml/10 g) had an obvious sedative effect on mice, its sedative time was longer than water extract and its intensity was similar to that of pentobarbital, while without hypnotic effect. j o u r n a l p r e -p r o o f model experimental subject and administration results species reference petroleum ether, chloroform, ethyl acetate and n-butanol extract from 95% ethanol extract: intragastric administration, 0.12 g/kg, 5 h after administration, the number of mouse activity in 10 minutes was recorded; 95% ethanol extract: intragastric administration, 0.45 g/kg, 5 h after administration, the number of mouse activity in 10 minutes was recorded mice (negative control: saline), patients 60% ethanol extract, volatile oil and dried ethanol extract (60% ethanol extract: the root of ps was crushed and immersed in 60% ethanol, then distilled under reduced pressure until 20% extract contains 10-15% ethanol.); 60% ethanol extract: (mice: intragastric administration, 30 g/kg); volatile oil (mice: intragastric administration, 0.2 g/kg; patients: 20 mg/capsule, 1-2 capsules/day, 1 times/day, 10-14 days); dried ethanol extract (mice: intragastric administration, 7.5 g/kg; patients: 1 g/tablet, 2-4 tablets/day, 2-3 times/day, 10-14 days) the 60% ethanol, volatile oil, and dried ethanol extracts from ps possessed sedative and hypnotic effect on mice induced by pentobarbital sodium and patients suffered from neurasthenia or neurasthenic syndromes with insomnia. 60% ethanol, dichloromethane layer, ethyl acetate layer, n-butanol layer and water layer extract (the 60% ethanol extract: 50 g pv was crushed and refluxed with 500 ml 60% ethanol at 85 °c for 2 h, extracted twice, filtered and concentrated by rotary evaporation under reduced pressure to obtain a solid powder 4.75 g; extracts of different polar parts: 500 g pv was crushed and refluxed with 5000 ml 60% ethanol at 85 °c for 2 h, extracted twice, filtered and concentrated by rotary evaporation under reduced pressure to no alcohol taste, and then diluted with 2000 ml water and extracted with dichloromethane, ethyl acetate and n-butanol, extracted twice. after vacuum drying, the extract was 1.77, 2.28 and 10.61 g, respectively, the water layer extract was 23.34 g.); isolated intestine cramps model: 0.02-1.28 mg/ml; in vivo: intragastric administration, 100, 200, 400 mg/kg/day, 7 days all the five extracts of pv exhibited an anti-diarrheal effect in a dose-dependent manner (100-400 mg/kg), in which the effect of dichloromethane layer is stronger than that of other polar extracts. j o u r n a l p r e -p r o o f table 6 . quantitative analysis for the quality control of herba patriniae. the water boiled extraction method: 2.5 g pv powder was boiled in 50 ml water for three times, 2 h, 1.5 h, 1 h, respectively, the extract was filtered and water was added to 250 ml for constant volume. the ethanol refluent extraction method: 2.5 g pv powder was refluxed and extracted with 50 ml methanol for three times, 2 h, 1.5 h, 1 h, respectively, the extract was filtered and water was added to 250 ml for constant volume. the suoshi extraction method: 2.5 g pv powder was extracted in a cable extractor with 50 ml methanol for 4 h with 50 ml methanol, the extract was filtered and water was added to 250 ml for constant volume. the supersonic extraction method: 2.5 g pv powder was subjected to ultrasonic extracted with 50 ml methanol for 45 min, three times, the extract was filtered and water was added to 250 ml for constant volume. j o u r n a l p r e -p r o o f repeatedly boiled with 1 l of water, the two extracted filtrates were combined, the 50 ml extract was concentrated in a water bath to a thick paste. quercetin kaempferol 1 g ps or pv powder was extracted with 20 ml of hydrochloric acid-methanol (1:20, v/v) mixed solution under reflux for 1 h, filtered and methanol was added to 25 ml for constant volume. in pv, twelve batches have been determined with the contents of 0.061-1.046 mg/g for quercetin and 0.082-0.701 mg/g for kaempferol. in ps, fourteen batches have been determined with the contents of 0.062-0.938 mg/g for quercetin and 0.045-0.542 mg/g for kaempferol, indicating that the quercetin and kaempferol content in the samples from different sources were significantly different.ps, pv ursolic acid oleanolic acid 1 g herba patriniae powder was subjected to ultrasonic extracted with 30 ml methanol for 45 min, after the weight loss is made up, filtered and the extract of 1 ml was extracted and fixed volume to 10 ml with methanol. the contents of ursolic acid and oleanolic acid for 6 batches were 0.218%-0.498% and 0.158%-0.473%, respectively. pv (chen, 2008) hederagenin oleanolic acid ursolic acid 2 g herba patriniae powder was subjected to ultrasonic extracted with 50 ml methanol for 60 min, filtered, the drug residue was washed with proper amount of methanol, combined the filtrate and the washing solution, evaporated, and dissolved in 10 ml water, then extracted with 20 ml water-saturated n-butanol, extracted three times, combined the extracts and evaporated to dryness. the residue was heated and hydrolyzed with 20 ml methanol and 4 ml hydrochloric acid for 4 h, then added with 10 ml water and shaken and extracted with 20 ml chloroform, extracted twice, combined the extracts and evaporated to dryness. the residue was dissolved and fixed volume to 10 ml with methanol. the contents of hederagenin, oleanolic acid and ursolic acid have been determined in ten batches. the result was that the contents of the compounds were significantly different among the different samples. the concentration ranges were 0.002%-0.556%, 0.019%-0.592% and 0.022%-0.630% for hederagenin, oleanolic acid and ursolic acid. key: cord-323479-vlgv3nwq authors: speranza, jasmine; miceli, natalizia; taviano, maria fernanda; ragusa, salvatore; kwiecień, inga; szopa, agnieszka; ekiert, halina title: isatis tinctoria l. (woad): a review of its botany, ethnobotanical uses, phytochemistry, biological activities, and biotechnological studies date: 2020-03-01 journal: plants (basel) doi: 10.3390/plants9030298 sha: doc_id: 323479 cord_uid: vlgv3nwq isatis tinctoria l. (brassicaceae), which is commonly known as woad, is a species with an ancient and well-documented history as an indigo dye and medicinal plant. currently, i. tinctoria is utilized more often as medicinal remedy and also as a cosmetic ingredient. in 2011, i. tinctoria root was accepted in the official european phytotherapy by introducing its monograph in the european pharmacopoeia. the biological properties of raw material have been known from traditional chinese medicine (tcm). over recent decades, i. tinctoria has been investigated both from a phytochemical and a biological point of view. the modern in vitro and in vivo scientific studies proved anti-inflammatory, anti-tumour, antimicrobial, antiviral, analgesic, and antioxidant activities. the phytochemical composition of i. tinctoria has been thoroughly investigated and the plant was proven to contain many valuable biologically active compounds, including several alkaloids, among which tryptanthrin, indirubin, indolinone, phenolic compounds, and polysaccharides as well as glucosinolates, carotenoids, volatile constituents, and fatty acids. this article provides a general botanical and ethnobotanical overview that summarizes the up-to-date knowledge on the phytochemistry and biological properties of this valuable plant in order to support its therapeutic potential. moreover, the biotechnological studies on i. tinctoria, which mainly focused on hairy root cultures for the enhanced production of flavonoids and alkaloids as well as on the establishment of shoot cultures and micropropagation protocols, were reviewed. they provide input for future research prospects. the genus isatis l., which belongs to the brassicaceae family, comprises about 80 herbaceous annual to perennial species diffused in the middle east and central asia and extending to the mediterranean region [1] [2] [3] . i. tinctoria has a long and well documented history as a medicinal plant in both eastern and western cultures. its therapeutic properties have been esteemed in europe and in traditional chinese medicine (tcm) for centuries. the first written records in europe about the medicinal uses of this plant were by hippocrates (460 b.c.) who supported its use for treating wounds, ulcers, and haemorrhoids. galen (129-216 b.c.) and pliny (23-79 b .c.) recommended it as well [6, 28] . due to the huge cultivation in europe for the production of indigo dye, from the 12th century until the 17th century, i. tinctoria was also extensively used as a medicinal plant to treat snake bites, wounds, and other inflammatory ailments [6, 29] . these medicinal properties have been widely described in a number of renaissance and baroque herbal texts, which recommended woad for treating haemorrhoids, ulcers, and tumours [6] . various authors have mentioned different medicinal uses for i. tinctoria leaves and roots. the leaves have been utilized in the treatment of typhoid, measles, and the flu [30] . garland [31] reported their use against the tremendous inflammation of the skin due to st. anthony's fire, which is a dreaded illness that was common in the middle ages. other uses such as treating iposideremic the root is cylindrical, slightly tortuous, externally greyish-yellow, or brownish-yellow, wrinkled longitudinally and lenticellate transversally, with rootlets or rootlet scars. root stock slightly expanded, which exhibited dark green or dark brown petiole bases arranged in whorls, and dense tubercles. basal leaves are oblong-lanceolate, entire to toothed, and long-petioled. cauline leaves, which are narrower than basal and gradually reduced upwards, are simple, entire, sagittate, usually amplexicaul, with acute auricles. the flowers are gathered in a racemose inflorescence, with yellow petals, tetradynamous androecium, consisting of six stamens with two filaments shorter than the others. fruits are pendulous siliques, oblong-obovate, or elliptic-obovate hairless or shortly hairy. this species is very variable, particularly in the size, shape, and hairiness of the silique [1, 2, 13, 24] . there are conflicting views on the taxonomy of i. tinctoria (european woad) and i. indigotica (chinese woad). the latter was described for the first time by fortune in 1846, and initially considered plants 2020, 9, 298 4 of 40 as a distinct species. afterward, some taxonomists have classified it as a variety of i. tinctoria [17] . angelini et al. [25] reported that i. indigotica presents morphological, genetic, and physiological differences with respect to the european i. tinctoria, even though it is closely related to this one. the seedlings of both species develop a rosette in the first year of their cycle. the leaves i. indigotica show a glaucous instead of a shiny surface, which is rarely pubescent with a greater thickness and a more upright habit. the high degree of genetic diversity between the two species was confirmed by various studies [26, 27] . despite this, i. indigotica is currently considered a synonym of i. tinctoria, and not a separate species, as confirmed by the consulted taxonomic databases known as the plant list, international plant names index (ipni), and tropicos. on the other hand, the euro+med plantbase does not mention i. indigotica in the list of synonyms. i. tinctoria has a long and well documented history as a medicinal plant in both eastern and western cultures. its therapeutic properties have been esteemed in europe and in traditional chinese medicine (tcm) for centuries. the first written records in europe about the medicinal uses of this plant were by hippocrates (460 b.c.) who supported its use for treating wounds, ulcers, and haemorrhoids. galen (129-216 b.c.) and pliny (23-79 b.c.) recommended it as well [6, 28] . due to the huge cultivation in europe for the production of indigo dye, from the 12th century until the 17th century, i. tinctoria was also extensively used as a medicinal plant to treat snake bites, wounds, and other inflammatory ailments [6, 29] . these medicinal properties have been widely described in a number of renaissance and baroque herbal texts, which recommended woad for treating haemorrhoids, ulcers, and tumours [6] . various authors have mentioned different medicinal uses for i. tinctoria leaves and roots. the leaves have been utilized in the treatment of typhoid, measles, and the flu [30] . garland [31] reported their use against the tremendous inflammation of the skin due to st. anthony's fire, which is a dreaded illness that was common in the middle ages. other uses such as treating iposideremic anaemic diseases (due to iron deficiency), scurvy, and, in general, hypovitaminosis have been correlated to the relevant levels of iron, and of vitamins a and c present in the leaves. moreover, the leaf extracts have been used for their anabolic, astringent, and detergent properties. according to these skills, the extracts were utilized in treating acrodermatitis, haemorrhagic diathesis, eczema from scrofulous, furunculosis, intoxications, hypercholia, jaundice, gastric neurosis, hives, torpid sores, scrofulous, heartburn, and seborrhoea [32] . the bitter and refreshing roots have been utilized to reduce scarlet fever. the root extracts have been used to treat patients with solid tumours and leukaemia, which is a traditional usage that led to purification of indirubin [9] . after i. tinctoria lost its importance as a source of indigo for dying, its curative properties in europe fell into oblivion. it has only just recently emerged into western awareness as having medicinal properties, which is mostly due to its antiviral properties [28] . the european pharmacopoeia currently reports the monograph of i. tinctoria root (isatidis radix) for use in official european phytotherapy [24] . in china, woad has an equally rich history as dye and a medicinal plant. the chinese pharmacopoeia reports three monographs for i. tinctoria: băn lán gēn (isatidis radix), dà qīng yè (isatidis folium), and qing dai (indigo naturalis) [9, 33] . these herbal preparations are considered as somewhat differing medicines. băn lán gēn (isatidis radix) is the dried root of i. tinctoria harvested in some provinces of r.p. china such as hebei, jiangsu, and anhui during the autumn, dried in the sun, and processed into granules (banlangen keli). the product is very popular throughout china and it is most commonly consumed when dissolved in hot water or tea [34] . it reduces the body temperature and soothes the sore throat. it is indicated for eruptive epidemic diseases, pharyngitis, laryngitis, scarlet fever, erysipelas, and carbuncles. it is utilized for treating hepatitis, mumps, the flu, mononucleosis, viral skin plants 2020, 9, 298 5 of 40 diseases such as herpes simplex, herpes zoster, and pityriasis rosea, epidemic cerebrospinal meningitis, and diphtheria [34] [35] [36] [37] . băn lán gēn has been one of the eight major medicines recommended by the chinese government for preventing and controlling the deadly severe acute respiratory syndrome (sars) [38] . dà qīng yè (isatidis folium) consists of i. tinctoria dried leaves [39] collected in the summer and the autumn from different provinces of r.p. china such as hebei, jiangsu, anhui, and henan and dried in the sun. dà qīng yè is used against the virus of b-encephalitis, mumps, and influenza and for treating the leptospirosis [36] . qing dai (indigo naturalis) is a dark blue powder prepared from the leaves of various plants including i. tinctoria, baphicacanthus cusia (nees) bremek., indigofera suffruticosa mill., indigofera tinctoria l., or polygonum tinctorium ait. it is used in tcm as a haemostatic, antipyretic, anti-inflammatory, and in the treatment of bacterial and viral infections [40, 41] . another preparation, called dang gui long hui wan, consisting of 11 herbal medicines including i. tinctoria, has been used in tcm as a remedy for various chronic diseases including chronic myelocytic leukaemia [14] . clinical trials have not assessed the safety of i. tinctoria leaf or root preparations. traditional chinese herbal texts do not list adverse effects, except gastro-intestinal disorders such as nausea and vomiting in some patients [36, 42] . i. tinctoria, like other species belonging to the brassicaceae family, shows an interesting chemical profile characterized by a large variety of compounds. i. tinctoria represents a valuable source of bioactive compounds such as alkaloids, phenolic compounds, polysaccharides, glucosinolates, carotenoids, volatile constituents, and fatty acids (table 1) . i. tinctoria is an important source of two known indolic alkaloids called indigo and indirubin. the first one has a blue colour instead of the second one that has a red colour and both of them are extensively used to dye textiles, cosmetics, foods, and pharmaceutical preparations. the plant is not able to synthetize directly into the indigoid pigments, but it produces several precursors: indican, isatan a, isatan b, and isatan c ( figure 2 ). when the leaves are damaged and exposed to air, precursors are submitted to enzymatic hydrolysis by β-d-glucosidase and β-glucuronidase. after cleavage of the o-glycosidic linkage, the indoxyl is released giving, in turn, indigo (blue indigoid pigments) through the oxidation process, and producing isatin as a side reaction thanks to an oxygen-rich environment. eventually, the condensation of indoxyl with isatin produces indirubin (red indigoid pigment), whereas the condensation with dioxindole, coming from isatan c, produces isoindirubin (red indigoid pigment) [44] . the indigo precursors indicant as well as isatans b and c were detected by maugard et al. [44] in the acetone/acetic acid 1% v/v extracts of i. tinctoria young and old fresh leaves. moreover, the number of indigo precursors in these samples was quantified by the same team, who established that isatan b was the major precursor. the concentration of indigo precursors was higher in the young, fresh leaves than in the oldest ones. a later study of oberthur et al. [53] . about i. tinctoria liophylized or air-dried leaves identified isatan a as the major indoxyl glycoside and gave the correct structure of isatan b, which was previously assigned by epstein et al. [54] . furthermore, the same team showed how the content of indigo precursors strictly depended on the post-harvest treatments. a mix of i. tinctoria young and older rosette leaves were submitted to three different post-harvest treatments: immediate shock freezing with liquid n 2 followed by freeze drying, air drying at room temperature, and drying in a thermostatic oven at 40 • c. the highest concentrations of isatans a and b were found in freeze dried leaf samples whereas the indican had the lowest amount. on the other hand, the other two treatments lead to high concentrations of indican and complete disappearance of isatans a and b. in all samples, the isatan b concentrations were lower than those of isatan a. these data and the enzymatic conversion of indican to isatan b underlined the biosynthetic pathway where isatan b derived from indican is, at the same time, a biogenetic precursor and degradation product of isatan a. eventually, the production and amount of indigo precursors depend on the cultivars and harvest period, which also influenced the indigo dyes' composition [55] . (7z, 10z, 13z)-hexadecatrienoic acid corchorifatty acid b 9-hydroxy-(10e, 12e, 14e)-octadecatrienoic acid 9-oxo-(10e, 12z, 15z)-octadecatrienoic acid polysaccharides root [34] 4.1. alkaloids i. tinctoria is an important source of two known indolic alkaloids called indigo and indirubin. the first one has a blue colour instead of the second one that has a red colour and both of them are extensively used to dye textiles, cosmetics, foods, and pharmaceutical preparations. the plant is not able to synthetize directly into the indigoid pigments, but it produces several precursors: indican, isatan a, isatan b, and isatan c ( figure 2 ). when the leaves are damaged and exposed to air, precursors are submitted to enzymatic hydrolysis by β-d-glucosidase and β-glucuronidase. after cleavage of the o-glycosidic linkage, the indoxyl is released giving, in turn, indigo (blue indigoid pigments) through the oxidation process, and producing isatin as a side reaction thanks to an oxygenrich environment. eventually, the condensation of indoxyl with isatin produces indirubin (red indigoid pigment), whereas the condensation with dioxindole, coming from isatan c, produces isoindirubin (red indigoid pigment) [44] . the indigo precursors indicant as well as isatans b and c were detected by maugard et al. [44] . in the acetone/acetic acid 1% v/v extracts of i. tinctoria young and old fresh leaves. moreover, the number of indigo precursors in these samples was quantified by the same team, who established that isatan b was the major precursor. the concentration of indigo precursors was higher in the young, fresh leaves than in the oldest ones. a later study of oberthur et al. [53] . about i. tinctoria liophylized or air-dried leaves identified isatan a as the major indoxyl glycoside and gave the correct structure of isatan b, which was previously assigned by epstein et al. [54] . furthermore, the same team showed how the content of indigo precursors strictly depended on the post-harvest treatments. a mix of i. tinctoria young and in addition to the indigo precursors, indigoid pigments named trans-indigo (indigotin, blue), trans-indirubin (isoindigotin, red), cis-indirubin (isoindirubin, red), iso-indigo (indigo brown), and cis-indigo were detected by hplc in the acetone/acetic acid 1% v/v extracts of i. tinctoria young and old fresh leaves ( figure 3 ) [44] . it is also important to point out that the indigo dyes indigo and indirubin appear under the fermentative conditions, used in the old natural indigo production, or after a drying process at 40 • c [45] . beyond the study of i. tinctoria fresh leaves, one unique analysis on dried rosette leaf extracts were carried out by mohn et al. [33] . thanks to the extractions performed through two different solvents, known as dichloromethane and methanol, it was possible to obtain a broad-based characterisation of the i. tinctoria profile. the lc-ms analysis of dichloromethane extracts showed various indolic alkaloids such as isatin, isoindigo, indoxyl indigo, and indirubin. instead, in the methanolic extracts, only indican was detected [33] . recently, lc-ms analysis of i. tinctoria frozen and lyophilized and dried leaf extracts were performed and the obtained metabolite profiles were compared. in the lyophilized extracts' analysis, beyond the characterization and quantification of 122 compounds previously described, the following indole derivatives were described for the first time: acetylindican, malonylindican, two dioxindole glucosides, dioxindole malonylglucoside (isatan c), 6-hydroxyindole-3-carboxylic acid 6-o glucoside, and 6-hydroxyindole-3-carboxylic acid glucose ester [45] . several research studies carried out on i. tinctoria dried roots showed two new and five known indole alkaloid glycosides. the structure of the two new indole alkaloid glycosides isatindigoside a and isatindigoside b were determined by extensive spectroscopic data analysis including 1 d, 2 d nmr, ir, and hr-esi-ms data analysis. the known glycosides isatindosulfonicacid a 3-o-b-d-glucopyranoside, indole-3-acetonitrile 6-o-b-d-glucopyranoside, isatindigobisindoloside a, isatindigobisindoloside b, and isatindigobisindoloside f, were identified by comparing spectroscopic and optical rotation data [37] . furthermore, a new indole alkaloid with an unusual carbon skeleton named isatisindigoticanine a were detected by the same team [56] . leaf samples whereas the indican had the lowest amount. on the other hand, the other two treatments lead to high concentrations of indican and complete disappearance of isatans a and b. in all samples, the isatan b concentrations were lower than those of isatan a. these data and the enzymatic conversion of indican to isatan b underlined the biosynthetic pathway where isatan b derived from indican is, at the same time, a biogenetic precursor and degradation product of isatan a. eventually, the production and amount of indigo precursors depend on the cultivars and harvest period, which also influenced the indigo dyes' composition [55] . in addition to the indigo precursors, indigoid pigments named trans-indigo (indigotin, blue), trans-indirubin (isoindigotin, red), cis-indirubin (isoindirubin, red), iso-indigo (indigo brown), and cis-indigo were detected by hplc in the acetone/acetic acid 1% v/v extracts of i. tinctoria young and old fresh leaves ( figure 3 ) [44] . it is also important to point out that the indigo dyes indigo and indirubin appear under the fermentative conditions, used in the old natural indigo production, or after a drying process at 40 °c [45] . beyond the study of i. tinctoria fresh leaves, one unique analysis on dried rosette leaf extracts were carried out by mohn et al. [33] . thanks to the extractions performed through two different solvents, known as dichloromethane and methanol, it was possible to obtain a broad-based characterisation of the i. tinctoria profile. the lc-ms analysis of dichloromethane extracts showed various indolic alkaloids such as isatin, isoindigo, indoxyl indigo, and indirubin. instead, in the methanolic extracts, only indican was detected [33] . recently, lc-ms analysis of i. tinctoria frozen and lyophilized and dried leaf extracts were performed and the obtained metabolite profiles were compared. in the lyophilized extracts' analysis, beyond the characterization and quantification of 122 compounds previously described, the following indole derivatives were described for the first time: acetylindican, malonylindican, two another important compound of this class is tryptanthrin, indolo-[2,1-b]-quinazoline alkaloid ( figure 4 ), which is also responsible for some biological activities of i. tinctoria. honda et al. [43] isolated and identified tryptanthrin from i. tinctoria dried rosette leaf chloroform extracts for the first time. moreover, more than 70 isatis samples of different origin were analysed and the tryptanthrin content in the leaves varied from 0.56 to 16.74 × 10 −3 % [57] . the tryptanthrin synthetic pathway is not known, but it is a product of the post-harvest process. its formation is apparently favoured by the drying process and elevated temperature (40 • c) and, on the contrary, the lyophilization and fermentative conditions decreased its concentration [58] . plants 2020, 9, x for peer review 19 of 43 dioxindole glucosides, dioxindole malonylglucoside (isatan c), 6-hydroxyindole-3-carboxylic acid 6-o glucoside, and 6-hydroxyindole-3-carboxylic acid glucose ester [45] . several research studies carried out on i. tinctoria dried roots showed two new and five known indole alkaloid glycosides. the structure of the two new indole alkaloid glycosides isatindigoside a and isatindigoside b were determined by extensive spectroscopic data analysis including 1 d, 2 d nmr, ir, and hr-esi-ms data analysis. the known glycosides isatindosulfonicacid a 3-o-b-dglucopyranoside, indole-3-acetonitrile 6-o-b-d-glucopyranoside, isatindigobisindoloside a, isatindigobisindoloside b, and isatindigobisindoloside f, were identified by comparing spectroscopic and optical rotation data [37] . furthermore, a new indole alkaloid with an unusual carbon skeleton named isatisindigoticanine a were detected by the same team [56] . another important compound of this class is tryptanthrin, indolo-[2,1-b]-quinazoline alkaloid ( figure 4 ), which is also responsible for some biological activities of i. tinctoria. honda et al. [43] isolated and identified tryptanthrin from i. tinctoria dried rosette leaf chloroform extracts for the first time. moreover, more than 70 isatis samples of different origin were analysed and the tryptanthrin content in the leaves varied from 0.56 to 16.74 × 10 −3 % [57] . the tryptanthrin synthetic pathway is not known, but it is a product of the post-harvest process. its formation is apparently favoured by the drying process and elevated temperature (40 °c) and, on the contrary, the lyophilization and fermentative conditions decreased its concentration [58] . the main class of secondary metabolites in i. tinctoria polar extracts is represented by phenolic compounds [16, 47] . phenolics can be divided into three main categories: flavonoids, phenolic acid, and their conjugates [16] . the identified flavonoids represent the major class of the phenolic the main class of secondary metabolites in i. tinctoria polar extracts is represented by phenolic compounds [16, 47] . phenolics can be divided into three main categories: flavonoids, phenolic acid, and their conjugates [16] . the identified flavonoids represent the major class of the phenolic constituent and are derivatives of flavones and of flavonols [46] . in methanolic extract from dried leaves, the presence of p-hydroxybenzoic, o-methoxybenzoic, p-methoxybenzoic, dihydrocaffeic, and 4-hydroxy-3-methoxyphenylpropanoic acid has been reported [48] . they found methyl esters of several phenolic acids, like ferulic, sinapic, salicylic, vanillic, and 4-hydroxyphenylacetic acids as a result of acidic hydrolysis. the same kind of extract was analysed by mohn et al. [33] . in dried rosette leaves, they found vicenin-2, stellarin-2, isoorientin, isovitexin, isoscoparin, and some of their glucosides ( figure 5 ). simultaneously, the isocoparin, sinapic, and ferulic acids turned out from the analysis of dichloromethane extract from the same plant material. simultaneously, the isocoparin, sinapic, and ferulic acids turned out from the analysis of dichloromethane extract from the same plant material. the drying process may cause changes in the metabolite profile even among phenolic compounds. on this account, lyophilization of freshly harvested plant material was introduced to prevent biochemical decomposition, e.g., deglycosylation. as a result of this procedure, a large group of conjugates between hydroxycinnamic acids and a hexose or dihexose (10 compounds), glycerate (two compounds), malate (one compound), or glucaric acid (45 compounds) was detected in the rosette leaf methanol extract. all of the conjugates showed one or two moieties of p-coumaric, ferulic, or sinapic acid. furthermore, two glucaric acid conjugates containing a higher molecular weight dilignol-like esterified moiety in which coniferyl alcohol was linked to ferulic acid via a typical lignin 8-o-4 linkage were detected. in addition, hydroxycinnamic acids conjugated with flavone glucosides were identified. among benzoic acid derivatives, only two compounds were confirmed, which include hexoside and hexose ester of protocatechuic acid [16] . many flavonoids showed carbohydrate and acid moieties and, according to it, many derivatives of the flavonoid aglycones were detected. nguyen et al. [16] was found in the polar extract from rosette leaves' flavone compounds mono or diglicosylated on the c-6 position with a rare 1→3 glycosidic linkage. flavone compounds with additional glycosylation of the o-7 position and esterification with a hydroxycinnamic acid derivative such as p-coumaric, ferulic, or sinapic acid were identified. moreover, the same authors reported the presence of six flavone glucosides conjugated with hydroxycinnamic acid. they identified isoscoparin with its eight derivatives including: 3"-osinapoyl glucoside, 3"-o-feruloyl glucoside and 3"-o-p-coumaroyl glucosides of isoscoparin, in the same extract, the luteolin-6-c-glucoside-7-o-glucoside was detected for the first time and it has not been described in other plants before. miceli et al. the drying process may cause changes in the metabolite profile even among phenolic compounds. on this account, lyophilization of freshly harvested plant material was introduced to prevent biochemical decomposition, e.g., deglycosylation. as a result of this procedure, a large group of conjugates between hydroxycinnamic acids and a hexose or dihexose (10 compounds), glycerate (two compounds), malate (one compound), or glucaric acid (45 compounds) was detected in the rosette leaf methanol extract. all of the conjugates showed one or two moieties of p-coumaric, ferulic, or sinapic acid. furthermore, two glucaric acid conjugates containing a higher molecular weight dilignol-like esterified moiety in which coniferyl alcohol was linked to ferulic acid via a typical lignin 8-o-4 linkage were detected. in addition, hydroxycinnamic acids conjugated with flavone glucosides were identified. among benzoic acid derivatives, only two compounds were confirmed, which include hexoside and hexose ester of protocatechuic acid [16] . many flavonoids showed carbohydrate and acid moieties and, according to it, many derivatives of the flavonoid aglycones were detected. nguyen et al. [16] was found in the polar extract from rosette leaves' flavone compounds mono or diglicosylated on the c-6 position with a rare 1→3 glycosidic linkage. flavone compounds with additional glycosylation of the o-7 position and esterification with a hydroxycinnamic acid derivative such as p-coumaric, ferulic, or sinapic acid were identified. moreover, the same authors reported the presence of six flavone glucosides conjugated with hydroxycinnamic acid. they identified isoscoparin with its eight derivatives including: 3"-o-sinapoyl glucoside, 3"-o-feruloyl glucoside and 3"-o-p-coumaroyl in the same extract, the luteolin-6-c-glucoside-7-o-glucoside was detected for the first time and it has not been described in other plants before. miceli et al. [46] characterised, for the first time, the phenolic compounds of the hydroalcoholic extract (70% methanol) from i. tinctoria lyophilized cauline leaves. among 13 identified flavonoids, derivatives of flavones and flavonols, which were quantitatively dominant, were vicenin-2, isovitexin, and apigenin glucosides. some of them like kaempferol, buddleoside, and quercetin have not been detected in isatis before. moreover, the authors reported the presence of phenolic acids like neochlorogenic, chlorogenic, caffeic, ferulic, sinapic, p-coumaric, and coumarylquinic acids ( figure 6 ). neochlorogenic and sinapic acids were dominant compounds. the same authors also performed a comparative analysis of hydroalcoholic extracts from rosette leaves, cauline leaves, and flowers of i. tinctoria [47] . according to the results, the phenolic profile of both types of leaves was very similar, but cauline leaves showed more than double the phenolic content than rosette leaves. a lower number of phenolic compounds was detected in the flower extract. nonetheless, they were found to be quantitatively close to those of cauline leaves. the main flavonoids detected in leaves and flowers from i. tinctoria were vicenin-2, stellarin-2, isovitexin, luteolin-glucuronide, and quercetin. among them, vicenin-2 turned out to be the most abundant flavonoid detected in the cauline leaf extract, whereas luteolin-glucuronide and stellarin-2 were the main compounds for rosette leaves and flowers, respectively [47] . i. tinctoria is a notable source of glucosinolates, which are synthesis and storage products of isothiocyanates. when the plant tissue is damaged, glucosinolates are released and converted by myrosinase (β-thioglucosidase). this is an enzyme that coexists with these compounds in plants even though it is physically separated [19] . the enzyme hydrolyzes the glucose moiety into the main skeleton by giving isothiocyanates and, under certain conditions, this reaction may lead to other types of products like thiocyanates, indoles, epithionitriles, and nitriles [59] . these compounds are responsible for the bitter and pungent taste and for most of the biological activities of the glucosinolates such as anticancer, antioxidant, and antibacterial factors. moreover, glucosinolates are known as goitrogens because they prevent the absorption of iodine, which causes swelling of the thyroid. from the same authors also performed a comparative analysis of hydroalcoholic extracts from rosette leaves, cauline leaves, and flowers of i. tinctoria [47] . according to the results, the phenolic profile of both types of leaves was very similar, but cauline leaves showed more than double the phenolic content than rosette leaves. a lower number of phenolic compounds was detected in the flower extract. nonetheless, they were found to be quantitatively close to those of cauline leaves. the main flavonoids detected in leaves and flowers from i. tinctoria were vicenin-2, stellarin-2, isovitexin, luteolin-glucuronide, and quercetin. among them, vicenin-2 turned out to be the most abundant flavonoid detected in the cauline leaf extract, whereas luteolin-glucuronide and stellarin-2 were the main compounds for rosette leaves and flowers, respectively [47] . i. tinctoria is a notable source of glucosinolates, which are synthesis and storage products of isothiocyanates. when the plant tissue is damaged, glucosinolates are released and converted by myrosinase (β-thioglucosidase). this is an enzyme that coexists with these compounds in plants even though it is physically separated [19] . the enzyme hydrolyzes the glucose moiety into the main skeleton by giving isothiocyanates and, under certain conditions, this reaction may lead to other types of products like thiocyanates, indoles, epithionitriles, and nitriles [59] . these compounds are responsible for the bitter and pungent taste and for most of the biological activities of the glucosinolates such as anticancer, antioxidant, and antibacterial factors. moreover, glucosinolates are known as goitrogens because they prevent the absorption of iodine, which causes swelling of the thyroid. from the chemical point of view, glucosinolates are (z)-n-hydroxyminosulfate esters characterized by sulphur-linked β-d-glucopyranose moiety and an amino acid-derived side chain. they are divided into three groups according to their amino acid side chain: aliphatic glucosinolates, aromatic glucosinolates, and indole glucosinolates [60] . in i. tinctoria seeds, aliphatic glucosinolates as gluconapin, progoitrin, and epipogoitrin, which were mainly detected, but indolic glucosinolates like glucoisatisin/epiglucoisatisin (inseparable epimeric mixture present only in seeds), glucobrassicin and neoglucobrassicin were also identified. the glucosinolate pattern of the seeds extract showed differences when compared to the extract obtained from the rosette leaves. in fact, the extracts obtained from i. tinctoria frozen and liophylized rosette leaves, mainly contained indolic glucosinolates including glucobrassicin, neoglucobrassicin, sulfoglucobrassicin, and glucotropaeolin ( figure 7 ) [49, 50] . the analysis carried out by the same authors also showed that the glucosinolate content in the leaf samples was higher than that of the seed samples. taviano et al. [47] showed that a very low amount of glucoiberin, glucobrassicin, and 4-methoxyglucobrassicin are contained in the liophylized leaf (rosette and cauline) and flower of 70% methanol extracts. furthermore, recent studies reported, for the first time, the presence of gluconapoleiferin in the the analysis carried out by the same authors also showed that the glucosinolate content in the leaf samples was higher than that of the seed samples. taviano et al. [47] showed that a very low amount of glucoiberin, glucobrassicin, and 4-methoxyglucobrassicin are contained in the liophylized leaf (rosette and cauline) and flower of 70% methanol extracts. furthermore, recent studies reported, for the first time, the presence of gluconapoleiferin in the frozen and lyophilized rosette leaf methanol extracts [16] . carotenoids are highly lipophilic metabolites and, for this reason, the extraction and separation conditions were optimized for the analysis. on one hand, the dichloromethane extract of i. tinctoria dried rosette leaves showed several known carotenoids like (all-e)-β-carotene and various lutein isomers [33] . on the other hand, in the hexane/acetone extract (1:1 v/v) obtained from the dried rosette leaves, it was possible to detect more and other unknown carotenoids like (all-e)-lutein, (z)-neochrome, (15z)-violaxanthin [33] . moreover, in the same extract, the lipophilic chlorophyll degradation products phaeophytin a, b, and pyrophaeophytin a, b were identified. phenolic derived compounds with higher molecular weight belonging to monolignols and oligolignols were described by nguyen et al. [16] . in methanol extracts of i. tinctoria frozen and lyophilized rosette leaves, monolignols and oligolignols, derived from coniferyl and synapyl alcohol, were characterized by lc-ms for the first time. some of these compounds were previously identified in other plants such as arabidopsis thaliana and linum usitatissimum. furthermore, several compounds containing hexose, guaiacyl, and syringyl units linked by 8-5 and 8-o-4 bonds were detected for the first time and all compounds were found in a hexosylated form. authors underlined that they were accumulated in the vacuole of mesophyll and epidermal cells rather than in the cell walls of the leaf nervature. this finding suggested that oligolignols may play some physiological role in i. tinctoria leaves. the volatile constituents of i. tinctoria were characterized in leaves and roots. the first extraction from fresh leaves was carried out by condurso et al. [19] through solid-phase microextraction and gas chromatography-mass spectrometry (spme/gc-ms). this analysis allowed them to identify several compounds such as acids, alcohols, aldehydes, esters, ethers, furans, hydrocarbons, isothiocyanates, thiocyanates, ketones, nitriles, sulfurated compounds, monoterpenoids, and sesquiterpenoids. a high portion of volatile isothiocyanates was detected in the leaves (40% of the total volatile fraction), especially 3-butenyl isothiocyanate that is the aglicone of gluconapin. the 2-hydroxy-3-butenyl isothiocyanate, that is, the aglicone of progoitrin and epiprogoitrin, was also identified. after the isothiocyanates, aldehydes were the most represented class and both aliphatic and aromatic types were identified, especially the (z)-2-esenal (a typical aldehyde from leaves). among the sulfurated compounds, the 2-ethylthiophene was the most abundant one. moreover, saturated and unsaturated alcohols were identified with tetradecanol as the main component. almost 7% of the volatile fraction was represented by monoterpenoids and sesquiterpenoids. ten monoterpenoids and two sesquiterpenoids were detected and the monocyclic monoterpenoid limonene was the major one. furthermore, the nitriles that derive from isothiocyanates due to the loss of sulphur were detected, which were 4-pentenenitrile, 3-hydroxy-4-pentenenitrile, heptanenitrile, octanenitrile, and 2-phenylacetonitrile as the most abundant ones. verzera et al. [51] carried out the first extraction of i. tinctoria dried root volatile constituents by spme/gc-ms and the same main classes of compounds were identified. the volatile content of roots was also characterized by a high portion of 3-butenyl isothiocyanate that represents 82% of the total plants 2020, 9, 298 20 of 40 volatiles. after isothiocyanates, the alcohols and nitriles were the most abundant classes and they, respectively, constituted 4.9% and 3.6% of the total volatile content. the other classes of compounds are even less represented. different studies have shown that polysaccharides from roots are important bioactive components of i. tinctoria. in a study carried out by han et al. [34] , the conditions that gave the maximum extraction yield of the polysaccharides from i. tinctoria root (11.19% ± 0.04) have been established. the seeds of i. tinctoria, like those of other plants belonging to family brassicaceae, show an interesting fatty acid composition, which is the highest among all isatis spp. (10%). according to kizil et al. [52] , seeds contain erucic acid (26.48% of total fatty acid fraction), oleic, linoleic, linolenic acids as the major components, and other fatty acids like palmitic, stearic, arachidic, and tetracosanoic. moreover, mohn et al. [33] reported the presence of palmitoleic and α-lysolecithin in dichloromethane dried rosette leaf extracts. additionally, the presence of the triterpenoid ursolic acid was confirmed by these authors. the microelement analysis of the i. tinctoria seeds carried out by kizil et al. [52] showed a number of studies have been conducted to evaluate different biological activities of i. tinctoria in both in vitro and in vivo experimental models. biological investigations are mainly based on the ethnopharmacological uses of the plant as an effective anti-inflammatory, anti-tumour, and antiviral herbal remedy. in addition, other biological activities such as analgesic, antimicrobial, and antioxidant have been highlighted (table 2 ). i. tinctoria has been appreciated for centuries in europe and, in tcm, for its anti-inflammatory properties. for this reason, several in vivo and in vitro research studies were carried out in order to assess its anti-inflammatory potential. solvents with different polarity and diverse extraction procedures (maceration, reflux extraction, co 2 supercritical fluid extraction (sfe), and accelerated solvent extraction (ase)) were utilized in order to establish the best condition to extract the bioactive compounds contained in the leaves and roots of i. tinctoria. one of the earliest studies investigated the effects of the treatment with an aqueous extract of i. tinctoria in a model of chronic pseudomonas aeruginosa lung infection mimicking cystic fibrosis in rat. i. tinctoria (400 mg/kg b.w., s.c. once a day for 10 days) was able to decrease the frequency of the lung abscess and the severity of the macroscopic pathological changes in lungs. the i. tinctoria extract was also able to modulate and decrease the inflammatory response in the lungs by enhancing the shift in the inflammatory response from an acute type inflammation dominated by polymorphonuclear leukocytes to a chronic type inflammation dominated by mononuclear leukocytes [61] . the anti-inflammatory activity of lipophilic i. tinctoria leaf extracts was demonstrated. recio et al. [18] showed the efficacy of sfe and dichloromethane (dcm) extracts obtained from dried rosette leaves of i. tinctoria, using two experimental models of acute inflammation including carrageenan-induced mouse paw oedema and 12-o-tetradecanoylphorbol 13-acetate (tpa)-induced mouse ear oedema. the sfe (os, 75-125 mg/kg) and dcm (os, 125-175 mg/kg) extracts showed dose-dependent anti-inflammatory activity in the carrageenan-induced mouse paw oedema. particularly, the potency of the sfe extract was found higher than that of dcm. in the second in vivo model of acute inflammation, the topical application of the dcm and sfe extracts (0.5 mg/ear) significantly inhibited the tpa-induced ear oedema and the topical administration was more effective than the systemic one. in sub-chronic inflammation induced by repeated application of tpa in the mouse ear, both oral (150 mg/kg) and topical (1 mg/kg) administration of dcm extract inhibited oedema formation and reduced the neutrophil infiltration, which decreased the various parameters of the inflammatory response such as the hypertrophy of fibroblasts, papillomatosis, acanthosis, hyperkeratosis, and spongiosis [18] . the anti-inflammatory properties of these extracts have been explained with multi-faceted effects including, among others, a marked cox inhibitory activity, with a preferential inhibition of cox-2, inhibition of 5-lox, inos, histamine and serotonine release, and leukocytic elastase, as previously demonstrated by danz et al. [17, 92] . in a model of delayed-type hypersensitivity (dht) induced by dinitrofluorobenzene (dnfb) in mice, the lipophilic dcm extract, topically administered (1 mg/ear), inhibited the response both during the induction phase and the inflammatory phase. instead, the oral administration had no effect [18] . adjuvant-induced arthritis in rats is an experimental in vivo model mimicking the rheumatoid arthritis and it was utilized with the aim to evaluate the effect of a dcm extract on chronic inflammatory diseases [64] . in this model, the dmc extract (os, 150 mg/ml once/day, on days 17-23 by injection of the adjuvant) led to a significant reduction of paw oedema induced by injection of mycobacterium butyricum. this effect did not result in a dose-dependency. a decreased joint damage, a reduction of tissular and articular inflammatory markers (oedema, cell infiltration, articular damage, pannus, cysts etc.), bone, and cartilage erosion was observed. interestingly, the treatment over two weeks with a high dose of i. tinctoria extract did not determine macroscopic lesions of the rat gastric mucosa. the treatment did not cause a significant difference in tissue levels of cox-1 and cox-2, immunohistochemically determined. these results appear to disagree with those reported by orberthür et al. [29] where a preferential inhibition of cox-2 and a reduced expression of inos was observed. in vitro studies demonstrated that the dcm extract is able to inhibit both tumour necrosis factor-α (tnf-α) and il-β production in raw 264,7 macrophages [64] . thus, the anti-inflammatory and anti-allergic activity of i. tinctoria dcm extract highlighted in the arthritis and dth models was related to the reduction of the production of these cytokines. brattström et al. [65] demonstrated the anti-inflammatory effects of sfe extract from the i. tinctoria leaves in a murine experimental model of allergic airway disease (asthma). the extract, administered intranasally (10-100 µg/mouse) to ovalbumin immunised balb/c mice, determined a dose-dependent inhibition of the allergic reaction, which decreases the methacholine-induced airway hyperresponsiveness (ahr) and eosinophil recruitment, as determined both in the bronchoalveolar lavage (bal) fluid and in the lung homogenates. the observed effect was related to the reduced production of the typical mediators of the th2 immune response il-4, il-5, and rantes (regulated on activation normal t cell expressed and secreted) highlighted after treatment with i. tinctoria extract. the anti-inflammatory activity of i. tinctoria was also evaluated in a clinical pilot study. the efficacy of the topical administration of different lipophilic extracts of i. tinctoria leaves was confirmed on healthy human volunteers using two experimental models, called sodium lauryl sulfate-induced irritant contact dermatitis and uvb-induced erythema. i. tinctoria extracts are effective when administered during the induction phase of dermatitis whereas they did not show any anti-inflammatory activity in the uvb-induced erythema model [63] . various lipophilic constituents belonging to different chemical classes play an important role in the anti-inflammatory activity of i. tinctoria extracts such as the alkaloidis tryptanthrin, indirubin, indolinone, and fatty acids as linolenic acid. tryptanthrin possesses a unique pharmacological profile. it has been shown to be highly selective toward the cox-2 isoenzyme [17, 92] . nonetheless, other studies reported tryptanthrin as a non-selective cox inhibitor [93] . it inhibited 5-lipooxygenase (5-lox) catalysed leukotriene synthesis in vitro and in vivo [18, 92, 94] , and inos catalysed nitric oxide (no) production [93] . in particular, tryptanthrin was found to be a potent natural inhibitor of cellular leukotriene biosynthesis in human whole blood and it is effective in vivo after oral administration in several experimental models such as in a murine model of inflammatory bowel disease (100 mg/kg p.o. for 3 days), in carrageenan-induced paw oedema in mice (50 mg/k p.o.), and in the rat pleurisy model (10 mg/kg p.o.) [18, 94, 95] . on the contrary, this compound, when topically administered, showed no significant anti-inflammatory effect in an animal model (tpa-induced ear oedema) [18] as well as in a clinical pilot study. in this study, carried out on healthy human volunteers, tryptanthrin, topically administered, did not manifest any protective effect both in the uvb-induced erythema model and in sodium lauryl sulfate-induced dermatitis [63] . thus, the pure compound is not effective when administered by topical application. this observation was also confirmed by oberthür et al. [62] through an experimental model of cutaneous micro-dialysis. it has been shown that the tryptanthrin contained in the extracts penetrates to a greater extent than that of pure solutions. this is because, in the first case, the alkaloid remains in molecular dispersion while, in the second case, it tends to crystallize on the surface of the skin. one of the active compounds isolated from i. tinctoria leaves responsible for the anti-allergic properties is the alkaloid indolin-2-one. it has been demonstrated that indolinone inhibits compound 48/80-induced histamine release from rat peritoneal mast cells [96] . moreover, indolinone was found to block ige-mediated degranulation of sensitized mast cells at nm concentrations without directly interfering with signalling upstream of the histamine-containing granules [97] . several studies demonstrated that indirubin is a potent inhibitor of cyclin-dependent kinase 5 (cdk5/p25) and glycogen synthase kinase-3-β (gsk-3-β) [98] as well as interferon-γ and interleukin (il)-6 [99] . in the experimental model of lps-induced pulmonary oedema in mice indirubin was shown to diminish oxidative stress and inflammation by reducing mda production as well as il-1β and tnf-α expression [100] . the analgesic potential of the lipophilic extract of i. tinctoria dried rosette leaves (dcm extract) was shown in vivo by an acetic acid-induced abdominal writhing test. the oral administration of the extract (200 mg/kg), before the intraperitoneal injection of acetic acid, reduced the number of writhing and stretching movements in mice while tryptanthrin (40 mg/kg) had no such effect [18] . i. tinctoria has been used in china to treat patients with solid tumours and leukaemia [9] . phase i/ii clinical trials highlighted very encouraging therapeutic effects of i. tinctoria in treating chronic myelocytic leukaemia [101] . experimental studies with transplantable tumours demonstrated that i. tinctoria significantly prolonged the life span of walker carcinosarcoma 256 bearing rats [101] . the anti-cancer properties of this species have been mainly attributed to the alkaloids' indirubin and tryptanthrin, whose activity has been demonstrated by in vivo and in vitro experimental models. numerous studies showed the potential efficacy of these compounds against a broad range of tumour types and the mechanisms of action underlying their activity have been elucidated. the bisindole indirubin has been described about 40 years ago as being active in treating human chronic myelocytic leukaemia. several trials published in china indicated that indirubin orally administered at the dose of 150-200 mg of per day led to remission in 60% of patients [9] . it was reported to induce complete remission in 26% and partial remission in 33% of 314 patients suffering from chronic myelocytic and chronic granulocytic leukaemia, which exhibited low toxicity and had limited adverse effects [66] . in animal leukaemia and lung carcinoma models, indirubin showed a good inhibitory effect and low toxicity [6] . it was found to inhibit dna synthesis in rats bearing walker-256 sarcoma [102] . a weak binding of indirubin to dna has been demonstrated in vitro by wu et al. [103] using the isotope labelling method, the spectrophotometric method, and thermal denaturation measurements, which shows that the binding between indirubin and dna might be of a hydrogen bond rather than ionic. in an experimental study carried out by zhang and colleagues [75] , the treatment for 25 days with indirubin (10 mg/kg per day) has proven to be effective in inhibiting prostate tumour growth in a xenograft mouse model (balb/c nude mice) by inhibiting tumour angiogenesis, as confirmed through a chick chorioallantois membrane (cam) assay and a mouse corneal model (c57bl/6 mice). western blot analysis highlighted that indirubin suppressed endothelial cell viability by blocking a vascular endothelial growth factor receptor 2-(vegfr2) mediated janus kinase (jak)/stat3 signalling pathway in endothelial cells. in particular, the phosphorylation and activation of jak2 and stat3 was suppressed, and the stat3 downstream genes including bcl-2, bcl-xl, cyclin d1, cyclin a, and survivin were down-regulated. the same authors also showed that indirubin effectively inhibited proliferation and induced apoptosis in human umbilical vein endothelial cells (huvec), while also inhibiting migration and capillary-structure formation. the core proteins involved in apoptosis including caspase-3 and parp were found to be activated. the anti-tumour properties of indirubin and its derivatives appear to correlate with their antimitotic potential and inhibition of cyclin-dependent kinases (cdks) and cell cycle regulatory molecules, which play an essential role in the regulation of cell proliferation, transcription, and apoptosis [70, 104] . it was found that indirubin and its analogues inhibited the proliferation of the human large cell lung carcinoma lxfl529l and human mammary carcinoma mcf-7 cells. the more soluble analogue indirubin-3 -monoxime induced g2/m arrest in mcf-7 cells synchronized in the g2/m phase by a transient exposure to nocodazole and this effect was mediated by the inhibition of cdk1 and cdk1/cyclin b activity. this was suggested as a major mechanism by which indirubin derivatives exert their potent anti-tumour efficacy [70] . indirubins are also efficient inhibitors of cdk2 and cdk5/p35. they act by competing with atp for binding to the catalytic subunit of the kinase [102, 105] . the crystal structure of the complex cdk2/indirubin derivatives showed that indirubin interacts with the kinase's atp-binding site through van der waals interactions and three hydrogen bonds [102] . another study published by damiens et al. [106] reported that, after transient treatment with indirubin-3'-monoxime of human breast epithelial hbl-100 cells synchronized in g2/m by nocodazole, cells underwent an endoreplication. after the compound has been removed, the polyploid cells became aneuploid and, later, died from necrosis. this mechanism of endoreplication followed by cell death may contribute to the anti-tumour properties of indirubins. the indole quinazolinone alkaloid tryptanthrin showed cancer chemo-preventive efficacy in intestinal tumour formation induced by azoxymethane in f344 rats [69] . it was found to be able to inhibit the growth of the murine myeloid leukaemia wehi-3b jcs cells in the tumour-bearing balb/c mice [73] . recently, tryptanthrin has also been shown to be an effective suppressor of non-melanoma skin cancer (nmsc), as demonstrated by using dimethylbenz[a]anthracene/phorbol 12myristate 13acetate (dmba/pma) induced skin carcinogenesis model in swiss albino mice [79] . it was found that the compound disrupted dmba/pma-induced expansion of hair follicle cells by suppressing the activation of β-catenin, which is a major driver of hair follicle cell proliferation. additionally, tryptanthrin suppressed the activation of erk1/2 and p38, in which both promote β-catenin activation and lowers the expression of c-myc and cyclin-d1. these are the transcriptional targets of β-catenin, which are widely implicated in carcinogenesis. increasing evidence demonstrated that tryptanthrin is highly cytotoxic to a variety of a solid tumour and leukaemia cell lines and has a broad range of downstream targets that regulate tumour-associated cell processes including cell growth, cell cycle progression, and survival. tryptanthrin was found to inhibit the growth of human gastric cancer (hgc), lung cancer (hlc), and promyelocytic leukemia hl-60 cells with ic 50 values of 1.5-4.2 µg/ml [67] . it showed significant cytotoxicity against non-small cell lung cancer nci-h460, human glioblastoma sf-268, and human breast cancer mcf-7 cell lines with ic 50 values of 8.5-22.6 µm [78] . tryptanthrin also exhibited a multi-drug resistance reversing effect in doxorubicin-resistant breast cancer mcf-7 cells (mcf-7/adr), which is higher than that of the multi-drug resistance (mdr)-reversing agent verapamil through down-regulation of mdr1 gene expression, and partly by modulating the gstpi-related pathway, which is a non-transporter pathway [71, 72] . liao and leung [76] reported that tryptanthrin is able to inhibit the growth of the n-myc amplified human neuroblastoma la-n-1 cells (ic 50 = 15.8 ± 1.41 µm) as well as two other human neuroblastoma cell lines sh-sy5y and sk-n-dz, which induced cell cycle arrest at the g0/g1 phase. western blot analysis showed a marked down-regulation of cyclin d1, cyclin d3, cdk4, and cdk6, which are known to be associated with the cell-cycle progression from the g1 to the s phase. la-n-1 cells treated with tryptanthrin underwent marked morphologic differentiation, enhancement of acetylcholine esterase activity, and up-regulation of various differentiation markers including growth-associated protein 43 (gap43), microtubule-associated protein tau (mapt), calcitonin gene related peptide (cgrp), and somatostatin, with an effect superimposable to that of 5 µm 9-cis-ra used as a positive control. moreover, tryptanthrin treatment led to a significant reduction of the n-myc proto-oncogene expression. the anti-angiogenic activity has been proposed as an important mechanism underlying the anti-cancer properties of tryptanthrin against various solid tumours. a study published by liao and colleagues [77] demonstrated that tryptanthrin inhibited angiogenesis both in vitro and in vivo. in particular, it inhibited the proliferation of human microvascular endothelial hmec-1 cells and interrupted the migration and capillary-like structure formation. the anti-angiogenic effect was confirmed in vivo by a matrigel plug assay. the underlying molecular mechanisms of action were explained by a reduced expression of pro-angiogenic factors such as ang-1, pdgfb, and mmp2, suppression of the phosphorylation of vegfr2, and blockade of the vegfr2-mediated erk1/2 signalling pathway. molecular docking studies indicated that tryptanthrin could bind to the atp-binding site of vegfr2. concerning the antileukemic activity, at low concentrations (0.5 µg/ml), tryptanthrin was found to be able to enhance the expression of cell differentiation markers in human monocytic u-937 and promyelocytic hl-60 leukaemia cells, which is indicative of their differentiation into monocytes and macrophages. higher concentrations inhibited cell proliferation and induced cell death by apoptosis in the cultures by damaging the mitochondria that induces the apoptotic cascade through a caspase-3/fas antigen pathway [68] . chan et al. [73] reported the potent anti-proliferative efficacy of tryptanthrin against murine myeloid leukaemia wehi-3b jcs cells, with an ic 50 value of 1.5 µm at 48 h of treatment. flow cytometric analysis showed the cell cycle arrest of the cells at the g0/g1 phase in a dose-dependent manner. the expression of the cell cycle-related genes including cyclin d2, d3, cdk 2, 4, 6 was found to be significantly down-regulated at 24 h as measured by real time pcr, which led us to propose the prevention of the cell cycle progression from the g1-phase into the s-phase. this causes cell cycle arrest as one of the mechanisms for leukemic cell growth inhibition. furthermore, it has been suggested that tryptanthrin exerts its anti-tumor effect on wehi-3b jcs cells by triggering cell differentiation, as demonstrated by morphological and functional studies. miao et al. [74] had proved that tryptanthrin significantly inhibited human chronic myeloid leukaemia k562 cell proliferation with an ic 50 value of 8.8 µg/ml after 48 h of treatment. cell cycle distribution analysis showed that it inhibited proliferation by blocking the cell cycle progression at the g0/g1 phase and, subsequently, progressing into apoptosis. the underlying mechanism has been attributed to the damage of mitochondrial membrane and the cyt-c-caspase-3 dependent mechanisms. besides the lipophilic compounds indirubin and tryptanthrin, the polar phenolic constituents have also been shown to contribute to the anti-cancer properties of i. tinctoria. recently, the anti-proliferative properties of polar extracts obtained from i. tinctoria rosette leaves together with those from the cauline leaves and the flowers have been evaluated [47] . to achieve the separation of the polar compounds from the lipophilic ones, frozen and lyophilized plant material was sequentially extracted with dichloromethane and 70% methanol. i. tinctoria polar extracts showed anti-proliferative effects against the human anaplastic thyroid cancer atc cell lines cal-62, 8505c and c-643. particularly, after 48 h of treatment, the basal leaf extract markedly inhibited the growth of cal-62 cells, which caused nearly 85% reduction of viability at the highest tested dose (1 mg/ml). the significant anti-proliferative effects against atc cell lines have been related to the flavonoids and the phenolic acids contained in the extracts, characterized by hplc-pda/esi-ms. another study published by the same authors confirmed that phenolics were mainly responsible for the observed activity. the anti-proliferative properties of the phenolic-rich fraction obtained from i. tinctoria cauline leaf polar extract has been demonstrated, which caused 80% and 65% growth inhibition in cal-62 and 8505c cells, respectively, after 48 h of exposure at the maximum tested dose (0.1 mg/ml). the activity of the phenolic-rich fraction against these cell lines was similar to that of sunitinib used as a positive control, when tested at the dose of 10 µm for 72 h [46] . a few research studies investigated i. tinctoria as a potential source of valuable compounds with anti-microbial efficacy against bacterial and fungal species. more thorough studies have been conducted on components with antiviral activity, which have led to the identification of possible mechanisms of action ( table 2) . the results of a study carried out by dornberger and lich [81] on the anti-microbial activity of a hydroalcoholic (water/ethanol) extract of the fresh whole plant evaluated by an agar diffusion test indicated that, among the 23 tested strains (gram-positive, gram-negative, yeast, and fungi), only the gram-positive tetracycline-resistant bacillus mycoides sg 756 tf, b. subtilis atcc 6633, and micrococcus luteus sg 125 a, and the yeast saccharomyces cerevisiae jh 3 showed weak sensitivity to the extract. by contrast, ullah and colleagues [85] recently reported the good anti-microbial properties of different extracts from i. tinctoria. in particular, the study concerned the evaluation of anti-microbial activity of fractions obtained from different parts of the plant (branches, flowers, leaves, and roots) by extraction with 14 different solvents, which was performed using a micro-titer plate method against seven bacterial and four fungal strains. the obtained results showed that the extracts displayed antibacterial activity, more elevated against gram-positive strains (b. subtilis, m. luteus and staphylococcus aureus). in many cases, it was higher than the antibiotic cefotaxime used as a positive control as well as antifungal activity (except for branches). in general, the leaves were found to be the best plant part and ethyl acetate, n-hexane, chloroform, and acetone as the most efficient solvents for the extraction of antimicrobial compounds. the possible utilization of i. tinctoria in combination therapy with commonly used antibiotics for treating infections caused by meticillin-resistant s. aureus (mrsa), which is a widespread cause of both community-acquired and hospital-acquired infections associated with significant mortality and morbidity, has been suggested. the dried leaf hydroalcoholic (75% ethanol) extract of i. tinctoria was found to be able to potentiate the effects of four antibiotics (penicillin g, gentamicin, ciprofloxacin, and ceftriaxone) against both mrsa (isolated from hospital patients) and standard (atcc25923) s. aureus strains [82] . among the phytochemicals contained in i. tinctoria, the alkaloid tryptanthrin has been proven to have an antimicrobial effect. nonetheless, there are discrepancies between the results of various research studies. one of the earliest published works is that of honda and colleagues, who evaluated the activity of tryptanthrin against a wide variety of microorganisms including bacteria, yeasts, dermatophytes by the agar dilution streak method, and phytopathogens by the paper disc method. the results of these investigations demonstrated that it displays strong activity against bacillus subtilis (mic: 25 µg/ml) and b. polymyxa (mic: 50 µg/ml), and it is a highly specific antimicrobial agent against dermatophytes, which are causative of athlete's foot, namely trichophyton mentagrophytes, t. rubrum ifo 5808, t. tonsurans var. sulfureum ifo 5945, microsporum canis ifo 9182, m. gypseum ifo 8307, and epidermophyton floccosum ifo 9045 (mics: 3.1-6.3 µg/ml) [43, 80] . by contrast, the results of the agar diffusion assay carried out by chiang et al. [83] revealed that tryptanthrin showed no effect on tested fungi including the dermatophytic pathogens e. floccosum atcc 18397, m. gypseum atcc 14683, and t. rubrum atcc 10218. the same authors reported that tryptanthrin significantly (≥12.5 µg/disc) inhibited the growth of s. epidermis atcc 12228 and s. aureus atcc 6538, and only weakly suppressed mrsa atcc 43300 even at 100 µg/disc. this last result is in disagreement with that of a more recent study, which highlighted a promising anti-bacterial activity of tryptanthrin against mrsa, as evaluated by the agar diffusion method (mic 62.5 µg/ml) [84] . the traditional chinese medicine bǎn lán gēn (isatidis radix) is widely employed in the prevention and treatment of a wide range of viral infections including seasonal flu, the deadly severe acute respiratory syndrome (sars), viral pneumonia, mumps, pharyngitis, and hepatitis [87, 107] . different types of compounds effective against influenza viruses have been isolated from i. radix. indirubin has been shown to have powerful activity vs. the influenza virus a/nws/33-and b/lee/40-infected bronchial epithelial cells h292 by reducing both the expression and production of the chemokine rantes [86] . the polysaccharide compounds contained in i. radix also have anti-influenza virus activity, as demonstrated by in vitro investigations. it has been reported that a polysaccharide isolated from i. radix inhibited the attachment of the influenza virus to the red blood cells, which promoted the generation of anti-influenza viral igg antibodies [88] . in a study carried out by li et al. [87] , i. radix polysaccharides showed potent anti-influenza a virus activity against human seasonal influenza viruses (h1n1 and h3n2) and avian influenza viruses (h6n2 and h9n2). they were found to effectively inhibit the expression of pro-inflammatory cytokines (il-6) and chemokines (ip-10, mig, and ccl-5) induced by the human influenza virus pr8/h1n1 and the avian influenza virus h9n2. furthermore, the polysaccharides reduced the expression of the toll-like receptor (tlr)-3 induced by the pr8/h1n1 virus. these results led to hypothesize that the underlying mechanism of action of the polysaccharides is to impair the upregulated expression of pro-inflammatory cytokines/chemokines induced by the influenza virus by inhibiting the expression of host tlr-3. the in vitro antiviral efficacy of the i. radix polysaccharide against type ii herpes simplex virus (hsv-2) has been recently demonstrated [88] . using the 3-(4,5-dimethylthiazole-2-yl)-2,5diphenyltetrazolium bromide (mtt) assay, this effect was shown to occur mainly by inhibiting the viral duplication and adsorption. in the last decade, some research has focused on the study of i. tinctoria as a source of natural antioxidants. the first published articles concerning the antioxidant properties of i. tinctoria extracts were those of fialova et al. and of yang et al. [89, 90] . in the first work carried out on a hydroalcoholic extract of the leaves, good radical scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl (dpph) test was found (sc 50 = 103.9 µg/ml) whereas the second one reported very weak activity in the same test as well as in the trolox equivalent antioxidant capacity (teac) and in reducing power assays for an ethanol extract obtained from dried chinese i. tinctoria. the results of subsequent investigations on i. tinctoria leaves indicated that phytochemicals belonging to different chemical classes act as antioxidants, such as alkaloids and phenolic compounds. in a study carried out by zhao and collegues [91] , the antioxidant properties of the indole alkaloids indigo and indirubin were evaluated by means of different in vitro assays. indigo and indirubin were found to be more effective for superoxide anion scavenging (ec 50 = 0.61 mg/ml and 0.74 mg/ml, respectively). this effect has been attributed to the presence of some electrophilic groups, such as keto or aldehyde, which facilitate the release of hydrogen from the o-h bond and stabilize the superoxide anion. both compounds exhibited scavenging activities on a dpph-free radical, whereas they did not show hydroxyl radical (oh•) scavenging activity and reducing power. it is well known that polyphenols represent the main class of natural antioxidants, which act in different ways such as radical scavengers because phenolic groups are excellent nucleophiles and are also able to inhibit lipid peroxidation, as breakers of the oxidation reaction by binding with free radicals generated through lipid peroxidation, and as chelators of metal ions that induce oxidation [108] . aimed at establishing the involvement of phenolic compounds in the antioxidant properties of i. tinctoria, recently, the polar extract obtained from the rosette leaves and also those from the cauline leaves and the flowers have been investigated by in vitro assays based on different mechanisms [47] . lyophilized plant material was sequentially extracted with dichloromethane and 70% methanol in order to separate the polar compounds from the lipophilic ones. the polar extracts were found to possess good radical scavenging (dpph test) and ferrous ions' chelating activities and moderate reducing power, and those from cauline leaves and flowers displayed better antioxidant efficacy than the rosette leaf extract. the calculated coefficient of determination (r 2 ) indicated that flavonoids were the phenolic compounds mainly involved in the observed antioxidant properties. another study carried out by the same authors on the phenolic-rich fraction obtained from i. tinctoria cauline leaf polar extract confirmed that phenolics were mainly responsible for the good radical scavenging properties [46] . in particular, the activity has been mainly related to the flavonols detected in the fraction, which have all the essential structural elements for potent radical scavenging activity. compared to flavone compounds, the flavonols contain more hydroxyl groups (one to six) among which the oh group at the c-3 position has a very high ability to scavenge the dpph radical, such as quercetin and rutin, which are well-known potent antioxidants. interestingly, these works have highlighted the antioxidant activity not only of the rosette leaves, which are commonly utilized for their medicinal properties, but also of the cauline leaves and the flowers, which indicates a broader range of usage possibilities for this relevant species. even the roots of i. tinctoria are a source of antioxidant compounds. indeed, the polysaccharides contained in the roots were found to possess antioxidant properties in vitro. in particular, in a study conducted by han et al. [34] , the polysaccharides extracted from the dried roots exhibited an appreciable radical scavenging activity in the 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (abts) assay, reaching, at the maximum tested concentration (0.3 mg/ml), a percentage of inhibition (64.3%) close to that of vitamin c used as a reference compound. it has been reported that the phytochemical profile of i. tinctoria field-cultivated is highly affected by various factors including cultivar, geographical regions, climatic fluctuations, and soil conditions [109] . the techniques concerning plant in vitro cultures and the possibilities of increasing the accumulation of secondary metabolites established by plant biotechnology are a known, alternative source of many valuable biologically active secondary metabolites used in medicine as well as in cosmetology and the food industry [110, 111] . the many strategies used in plant biotechnology aimed at increasing the in vitro culture biomass and/or bioactive metabolites' production. the elaboration of micropropagation protocols creates the possibilities of increasing and facilitating the specific, often very demanding, plant multiplication [112] . for increasing the secondary metabolites production in in vitro cultured biomass, different, specific strategies have been introduced [113] . the most important ones are: the selection of high productivity cell lines, elaboration of the optimal culture conditions (e.g., selection of basic formulation of the culture medium, type of plant growth regulators, and their concentrations in the media, types of cultures, and optimal lighting and temperature conditions), establishment of cultures with a high degree of organogenesis (shoot, root cultures), application of biotic or abiotic elicitors, and genetic transformation (e.g., hairy root cultures). increasing the biomass production and the scale-up of cultures' production in the special plant bioreactors are also important aspects of biotechnology studies [111, 114, 115] . the growing interest in the beneficial values of i. tinctoria has been concentrated mainly on the roots of this plant as the best source of demanding metabolites. as apparent from the analysis of the latest scientific literature, the biotechnological studies on i. tinctoria are limited mainly to hairy root cultures. interestingly, within the last four years, the teams of two researchers: gai and jiao from northeast forestry university, harbin in china, have published a series of research publications on i. tinctoria hairy root cultures. the cultures were successfully initiated from in vitro petiole explants co-cultured with agrobacterium rhizogenes with the addition of acetosyringone and arginine. in the obtained hairy root cultures, the high production of alkaloids [116] and flavonoids [117] was confirmed. within the alkaloids epigoitrin, isatin, indole-3-carboxaldehyde, tryptanthrin, indigo, and indirubin were qualitatively and quantitatively determined by lc-ms/ms. the total alkaloid content (521.77 µg/g dw (dry weight)) was 1.12 times higher than in two-year-old roots of field grown plants (464.69 µg/g dw) [116] . under the study on flavonoid composition, eight bioactive constituents were estimated by the lc-ms/ms method: rutoside, neohesperidin, buddleoside, liquiritigenin, quercetin, isorhamnetin, kaempferol, and isoliquiritigenin [117] . under optimal conditions, the total flavonoid content (438.10 µg/g dw) was found to be 1.28 times higher than in two-year-old field grown roots (341.73 µg/g dw) analyzed for comparison. additionally, in vitro antioxidant assays demonstrated that hairy root extracts exhibited higher activities than those from roots of field grown plants [117] . such promising results prompted the chinese team to perform the elicitation experiments on these cultures in order to boost the bioactive metabolites' production. the elicitation experiment with chitosan was proven to increase the flavonoid yield in i. tinctoria hairy root biomass [118] . in comparison with the control (2.31 mg/g dw), a 7.08-fold enhancement of total flavonoids (16.35 mg/g dw) was achieved in 24-day-old hairy root cultures elicited by 150 mg/l chitosan for 36 h [118] . under another study, the i. tinctoria hairy root cultures were exposed to ultraviolet radiation (uv-a, uv-b, and uv-c) in an attempt to promote the production flavonoids. results showed that the maximum flavonoid accumulation (7259.12 µg/g dw) in hairy root cultures treated by 108 kj/m 2 dose of uv-b radiation increased 16.51-fold as compared to the control (439.68 µg/g dw) [119] . moreover, the same teams proved the increase of flavonoid production after i. tinctoria hairy root cultures co-cultivation with two immobilized live gras (generally recognized as safe) fungi: aspergillus niger and aspergillus oryzae. a. niger strains were exhibited as the better biotic elicitor in the plant-fungus co-cultivation system. the highest flavonoid production (3018.31 µg/g dw) was achieved after treatment with spores at the concentration of ca.104 spores/ml, temperature of 30 • c, ph 7.0, and time of 72 h. the total amount of flavonoids increased 6.83 times in comparison to control hairy roots (441.91 µg/g dw) [120] . a recent work on elicitation of i. tinctoria hairy root cultures proved enhanced production of flavonoids as well as alkaloids after abiotic elicitation protocol applied with salicylic acid and methyl jasmonate [121] . as determined by central composite design based on a mathematical model, the maximum accumulation of alkaloids was found in biomass elicited by 142.61 µm salicylic acid for 28.18 h and flavonoids in biomass elicited by 179.54 µm methyl jasmonate for 41.87 h. these amounts increased 5.89-times and 11.21-times, respectively, in comparison with the control. the above described biotechnological studies on i. tinctoria hairy roots are a good example of the importance of optimization culture conditions, aimed at high secondary metabolites' production. authors claim that their research studies are a promising and effective approach for the enhanced production of flavonoids and alkaloids in i. tinctoria in vitro cultures, which allows for the improved applicability of these valuable compounds in pharmaceutical fields, and that their studies pave the way toward the successful commercialization of this culture system in the future. in the available scientific literature, there is only one publication on the development of the micropropagation protocol for i. tinctoria, based on the adventitious shoot regeneration method. under the work of saglam and ciftci [122] , the effective shoot regeneration system was developed using 'isubgol' as a cheap alternative gelling substance. the leaf and hypocotyl explants were cultured on murashige and skoog (ms) [123] medium solidified with 6.5 g/l agar or 15 g/l isubgol containing different concentrations of ba (6-benzyladenine) and naa (1-naphthaleneacetic acid). maximum regeneration of 12.65 and 17.80 shoots per leaf explant was observed on ms medium solidified with agar containing 1 mg/l ba with 0.25 mg/l naa and on ms medium solidified with isubgol containing 0.50 mg/l ba, respectively. maximum regeneration of 19.87 and 20.55 shoots per hypocotyl explant on agar and isubgol gelled media was recorded on ms medium containing 0.50 mg/l ba with 0.25 mg/l naa, and 1 mg/l ba, respectively. the gelling agent isubgol gave better shoot regeneration as compared to agar. in the existing literature, only one study on shoot cultures of i. tinctoria is available. in particular, reference [124] obtained the establishment of i. tinctoria shoot cultures starting from the nodal segments of young plants cultured on ms and gamborg (b5) [125] media supplemented with ba or kin (kinetin) with or without naa. the best multiplication rates were obtained on b5 medium supplemented with 1 mg/l ba (3.4 shoots per explant). the addition of naa to the tested media did not increase multiplication. currently, under the cooperation of our teams, from the department of chemical, biological, pharmaceutical and environmental sciences, university of messina (messina, italy), and the department of pharmaceutical botany, jagiellonian university, collegium medicum (kraków, poland), in vitro shoot cultures of i. tinctoria have been successfully initiated, which aimed to investigate whether they could represent a potential source of bioactive compounds (figure 8 ) [unpublished] . the cultures were successfully initiated from the seeds, and the preliminary media composition optimization was performed. the ms media variants with ba and kin as cytokinins and naa and iba (indole-3-butyric acid) as auxins in different concentrations (range from 0 to 2 mg/l) were tested. the best conditions for agar shoot cultures were proven to be ms medium containing 1 mg/l ba and 1 mg/l naa on which the biomass increment was equal to 3.58-fold (fresh weight). not increase multiplication. currently, under the cooperation of our teams, from the department of chemical, biological, pharmaceutical and environmental sciences, university of messina (messina, italy), and the department of pharmaceutical botany, jagiellonian university, collegium medicum (kraków, poland), in vitro shoot cultures of i. tinctoria have been successfully initiated, which aimed to investigate whether they could represent a potential source of bioactive compounds (figure 8 ) [unpublished] . the cultures were successfully initiated from the seeds, and the preliminary media composition optimization was performed. the ms media variants with ba and kin as cytokinins and naa and iba (indole-3-butyric acid) as auxins in different concentrations (range from 0 to 2 mg/l) were tested. the best conditions for agar shoot cultures were proven to be ms medium containing 1 mg/l ba and 1 mg/l naa on which the biomass increment was equal to 3.58-fold (fresh weight). intensive biotechnological studies on i. tinctoria shoot culture are in progress and are aimed at obtaining high production of secondary metabolites in the biomass (as well as in the growth media) such as phenolic acids or glucosinolates, which were never studied before. i. tinctoria has an ancient and well-documented history as an indigo dye and medicinal plant. it has been long utilized as an ornamental crop and an animal feeding plant, and, currently, its importance increased in cosmetic industry. due to the relevance of this species, a large number of in vitro and in vivo investigations carried out on i. tinctoria mostly in the last 20 years have provided reasonable support for its various traditional uses, which shows that the diverse extracts or compounds isolated from different parts of this species have a broad spectrum of biological activities. as far as we know, there is only one previous review article by hamburger (2002) , which reported studies published from 2000 to 2002 focusing only on the anti-inflammatory activity of i. tinctoria extract and its active component tryptanthrin. this article review provides an up-to-date and comprehensive overview mainly on the phytochemistry and the biological properties demonstrated for this valuable species in order to support its therapeutic potential and to offer input for future research prospects. the article also focuses on all attempts in plant biotechnology studies for the enhanced production of bioactive compounds from i. tinctoria hairy root and shoot cultures as an alternative to intensive biotechnological studies on i. tinctoria shoot culture are in progress and are aimed at obtaining high production of secondary metabolites in the biomass (as well as in the growth media) such as phenolic acids or glucosinolates, which were never studied before. i. tinctoria has an ancient and well-documented history as an indigo dye and medicinal plant. it has been long utilized as an ornamental crop and an animal feeding plant, and, currently, its importance increased in cosmetic industry. due to the relevance of this species, a large number of in vitro and in vivo investigations carried out on i. tinctoria mostly in the last 20 years have provided reasonable support for its various traditional uses, which shows that the diverse extracts or compounds isolated from different parts of this species have a broad spectrum of biological activities. as far as we know, there is only one previous review article by hamburger (2002) , which reported studies published from 2000 to 2002 focusing only on the anti-inflammatory activity of i. tinctoria extract and its active component tryptanthrin. this article review provides an up-to-date and comprehensive overview mainly on the phytochemistry and the biological properties demonstrated for this valuable species in order to support its therapeutic potential and to offer input for future research prospects. the article also focuses on all attempts in plant biotechnology studies for the enhanced production of bioactive compounds from i. tinctoria hairy root and shoot cultures as an alternative to plant raw materials. plant in vitro culture technology has emerged as an attractive alternative for the field cultivation of i. tinctoria. due to the high therapeutic value of i. tinctoria, the biotechnological approach represents a promising way to develop safe and more effective extracts than traditional ones. the large-scale production of biotechnological extracts, enriched in desired metabolites and obtained by different in vitro systems, should become the goal of further scientific studies. flora europaea the european garden flora systematics and phylogeny of the brassicaceae (cruciferae): an overview genetic variation and population structure in a eurasian collection of isatis tinctoria l adaptability and variation in isatis tinctoria l.: a new crop for europe isatis tinctorial-from the rediscovery of an ancient medicinal plant towards a novel anti-inflammatory phytopharmaceutical an ancient dye plant of interest as a multifunctional crop new archaeobotanical finds of isatis tinctoria l. (woad) from iron age gaul and a discussion of the importance of woad in ancient time spectral and photophysical studies of substituted indigo derivatives in their keto forms cultivation and use of isatis tinctoria l. (brassicaceae) in southern italy diversity of the intracellular mechanisms underlying the anti-tumor properties of indirubins geographic population structure in an outcrossing plant invasion after centuries of cultivation and recent founding events phenylpropanoid profiling reveals a class of hydroxycinnamoyl glucaric acid conjugates in isatis tinctoria leaves identification and isolation of the cyclooxygenase-2 inhibitory principle in isatis tinctoria anti-inflammatory and antiallergic activity in vivo of lipophilic isatis tinctoria extracts and tryptanthrin the leaf volatile constituents of isatis tinctoria by solid-phase microextraction and gas chromatography/mass spectrometry european directorate for the quality of medicines cosmetic ingredientdatabase (cosing) sowing date, transplanting, plant density and nitrogen fertilization affect indigo production from isatis species in a mediterranean region of spain nutraceutical value of woad (isatis tinctoria) flower buds of ecotypes from sicily european directorate for the quality of medicines differences in leaf yield and indigo precursors production in woad (isatis tinctoria l.) and chinese woad a high degree of genetic diversity is revealed in isatis spp. (dyer's woad) by amplified fragment length polymorphism (aflp) discussion on the botanical origin of isatidis radix and isatidis folium based on dna barcoding herbal antivirals: natural remedies for emerging, resistant and epidemic viral infections hplc based activity profiling for 5-lipoxygenase inhibitory activity in isatis tinctoria leaf extracts medicinal plants of east and southeast asia: attributed properties and uses a comprehensive metabolite profiling of isatis tinctoria leaf extracts optimisation of extraction conditions for polysaccharides from the roots of isatis tinctoria l. by response surface methodology and their in vitro free radicals scavenging activities and effects on il-4 and ifn-γ mrna expression in chicken lymphocytes medicinal plants of china indole alkaloid glycosides from isatis tinctoria roots antiviral decoction of isatidis radix (bǎn lán gēn) inhibited influenza virus adsorption on mdck cells by cytoprotective activity the pharmacology of chinese herbs in chinese drugs of plant origin assessment of indigo (polygonum tinctorium ait.) water extracts' bioactive compounds, and their antioxidant and antiproliferative activities handbook of chinese herbs and formulas; institute of chinese medicine isolation of an antidermatophytic, tryptanthrin, from indigo plants, polygonum tinctorium and isatis tinctoria identification of an indigo precursor from leaves of isatis tinctoria (woad) metabolic markers for the yield of lipophilic indole alkaloids in dried woad leaves (isatis tinctoria l.) chemical characterization and biological activities of phenolic-rich fraction from cauline leaves of isatis tinctoria l. (brassicaceae) growing in sicily phenolic profile, antioxidant and cytotoxic properties of polar extracts from leaves and flowers of isatis tinctoria l. (brassicaceae) growing in sicily a novel anthranilic acid derivate from isatis tinctoria extraction and analysis of intact glucosinolates-a validated pressurized liquid extraction/liquid chromatography-mass spectrometry protocol for isatis tinctoria, and qualitative analysis of other cruciferous plants glucosinolate pattern in isatis tinctoria and i. indigotica seeds volatile constituents in dried roots of isatis tinctoria l. (brassicaceae) microelement contents and fatty acid compositions of some isatis species seeds the elusive indigo precursors in woad (isatis tinctoria l.)-identification of the major indigo precursor, isatan a and a structure revision of isatan b origin of indigo of woad the content of indigo precursors in isatis tinctoria leaves-a comparative study of selected accessions and post-harvest treatments isatisindigoticanine a, a novel indole alkaloid with an unpresented carbon skeleton from the roots of isatis tinctoria quantitative determination of the dual cox-2/5-lox inhibitor tryptanthrin in isatis tinctoria by esi-lc-ms tryptanthrin content in isatis tinctoria leaves-a comparative study of selected strains and post-harvest treatments thermal degradation of glucosinolates phytochemical characterization and biological activities of a hydroalcoholic extract obtained from the aerial parts of matthiola incana (l.) r. br. subsp. incana (brassicaceae) growing wild in effects of chinese medicinal herbs on a rat model of chronic pseudomonas aeruginosa lung infection a comparative study on the skin penetration of pure tryptanthrin and tryptanthrin in isatis tinctoria extract by dermal microdialysis coupled with isotope dilution esi-lc-ms prevention of experimentally induced irritant contact dermatitis by extracts of isatis tinctoria compared to pure tryptanthrin and its impact on uvb-induced erythema anti-arthritic activity of a lipophilic woad (isatis tinctoria) extract the plant extract isatis tinctoria l. extract (ite) inhibits allergen-induced airway inflammation and hyperreactivity in mice clinical studies of 314 cases of cml treated with indirubin cytotoxic effects of substances in indigo plant (polygonum tinctorium lour.) on maligant tumour cells cell differentiation and apoptosis of monocytic and promyelocytic leukemia cells (u-937 and hl-60) by tryptanthrin, an active ingredient of polygonum tinctorium lour prevention of azoxymethane-induced intestinal tumors by a crude ethyl acetate-extract and tryptanthrin extracted from polygonum tinctorium lour inhibition of cyclin-dependent kinase 1 (cdk1) by indirubin derivatives in human tumour cells tryptanthrin inhibits mdr1 and reverses doxorubicin resistance in breast cancer cells downregulation of gstpi expression by tryptanthrin contributing to sensitization of doxorubicin-resistant mcf-7 cells through c-jun nh2-terminal kinase-mediated apoptosis modulatory effects and action mechanisms of tryptanthrin on murine myeloid leukemia cells proliferation-attenuating and apoptosis-inducing effects of tryptanthrin on human chronic myeloid leukemia k562 cell line in vitro indirubin inhibits tumor growth by antitumor angiogenesis via blocking vegfr2-mediated jak/stat3 signaling in endothelial cell tryptanthrin induces growth inhibition and neuronal differentiation in the human neuroblastoma la-n-1 cells tryptanthrin inhibits angiogenesis by targeting the vegfr2-mediated erk1/2 signalling pathway isolation and cytotoxicity evaluation of the chemical constituents from cephalantheropsis gracilis pre-clinical evidences for the efficacy of tryptanthrin as a potent suppressor of skin cancer the antimicrobial specificity of tryptanthrin screening for antimicrobial and presumed cancerostatic plant metabolites the synergistic activity of antibiotics combined with eight traditional chinese medicines against two different strains of staphylococcus aureus an in vitro study of the antimicrobial effects of indigo naturalis prepared from strobilanthes formosanus moore in vitro anti-mrsa activity of couroupita guianensis extract and its component tryptanthrin antibacterial and antifungal activity of isatis tinctoria l. (brassicaceae) using the micro-plate method inhibition of rantes expression by indirubin in influenza virus-infected human bronchial epithelial cells radix isatidis polysaccharides inhibit influenza a virus and influenza a virus-induced inflammation via suppression of host tlr3 signaling in vitro antiviral activities of radix isatidis polysaccharide against type ii herpes simplex virus in vitro isatis tinctoria l. (dyer's woad) from the standpoint of phenolic compound content and scavenging activity evaluation of antioxidant and antimicrobial activities from 28 chinese herbal medicines optimization of ultrasound-assisted extraction of indigo and indirubin from isatis indigotica fort and their antioxidant capacities inhibitory activity of tryptanthrin on prostaglandin and leukotriene synthesis tryptanthrin inhibits nitric oxide and prostaglandin e2 synthesis by murine macrophages on the inhibition of 5-lipoxygenase product formation by tryptanthrin: mechanistic studies and efficacy in vivo the natural plant product tryptanthrin ameliorates dextran sodium sulfate-induced colitis in mice inhibitory activity of indolin-2-one derivatives on compound 48/80-induced histamine release from mast cells e,z)-3-(3',5'-dimethoxy-4'-hydroxybenzylidene)-2-indolinone blocks mast cell degranulation structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases indirubin inhibits inflammatory reactions in delayed-type hypersensitivity indirubin improves antioxidant and anti-inflammatory functions in lipopolysaccharidechallenged mice indirubin and meisoindigo in the treatment of chronic myelogenous leukemia in china indirubin, the active constituent of a chinese antileukemia medicine, inhibits cyclin-dependent kinases studies on the mechanism of indirubin action in the treatment of chronic granulocytic leukemia. v. binding between indirubin and dna and identification of the type of binding molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional chinese phytomedicine indirubins inhibit glycogen synthase kinase-3β and cdk5/p25, two kinases involved in abnormal tau phosphorylation in alzheimer's disease. a property common to most cdk inhibitors? anti-mitotic properties of indirubin-3 -monoxime, a cdk/gsk-3 inhibitor: induction of endoreplication following prophase arrest anti-sars coronavirus 3c-like protease effects of isatis indigotica root and plant-derived phenolic compounds phenolic profile and biological properties of the leaves of ficus vasta forssk. (moraceae) growing in egypt environmental factors affecting growth and development of banlangen (radix isatidis) in china biotechnology for the production of plant secondary metabolites factors influencing somatic embryogenesis induction and plant regeneration with particular reference to arabidopsis thaliana (l.) heynh. plant growth regul factors affecting the production of secondary metabolites elicitation, an effective strategy for the biotechnological production of bioactive high-added value compounds in plant cell factories schisandra lignans production regulated by different bioreactor type establishment of high-productive isatis tinctoria l. hairy root cultures: a promising approach for efficient production of bioactive alkaloids establishment of hairy root cultures by agrobacterium rhizogenes mediated transformation of isatis tinctoria l. for the efficient production of flavonoids and evaluation of antioxidant activities chitosan elicitation of isatis tinctoria l. hairy root cultures for enhancing flavonoid productivity and gene expression and related antioxidant activity ultraviolet radiation for flavonoid augmentation in isatis tinctoria l. hairy root cultures mediated by oxidative stress and biosynthetic gene expression remarkable enhancement of flavonoid production in a co-cultivation system of isatis tinctoria l. hairy root cultures and immobilized aspergillus niger elicitation of isatis tinctoria l. hairy root cultures by salicylic acid and methyl jasmonate for the enhanced production of pharmacologically active alkaloids and flavonoids effects of agar and ısubgol on adventitous shoot regeneration of woad (isatis tinctoria) a revised medium for rapid growth and bio assays with tobacco tissue cultures acknowledgments: jasmine speranza thanks the foundation "prof. antonio imbesi" for the fellowship. the authors declare no conflict of interest. key: cord-336794-ok6j19kf authors: lu, meiqi; lu, zhen; zhang, ting; wang, wei; xue, ye; cao, zhiqun title: efficacy and safety of chinese patent medicine injection for covid-19: a protocol for systematic review and meta-analysis date: 2020-06-19 journal: medicine (baltimore) doi: 10.1097/md.0000000000020706 sha: doc_id: 336794 cord_uid: ok6j19kf background: corona virus disease 2019 (covid-19) has caused a worldwide epidemic since its discovery. the outbreak of virus infection has aroused great concern of the world health organization (who). covid-19 is highly infectious and has a high infection rate. so far, no specific drug has been found to cure it. china as one of the first countries attacked by epidemic has shown outstanding in fighting against the covid-19. the contribution of traditional chinese medicine can not be ignored. as a kind of representative of traditional chinese medicine, the chinese patent medicine injection has significant effect in reducing the clinical symptoms of patients and preventing the deterioration of the disease. however, there is no systematic review of its efficacy and safety. the purpose of this study is to evaluate the efficacy and safety of chinese patent medicine injection in the treatment of covid-19. methods: all randomized controlled trials of chinese patent medicine injection for covid-19 will be included. the following electronic databases will be searched: pubmed, web of science, the cochrane library, embase, china national knowledge infrastructure, wanfang database, chinese scientific journal database, chinese biomedical literature database and some clinical trial registration websites. two researchers will independently screen titles, abstracts, full texts, and extract data, then assess the bias risk of each study. we will conduct meta-analyses to assess all the available evidence of the efficacy and safety. results: systematic review of current evidence will be provided from the indexes of efficacy and safety. conclusion: evidence regarding the efficacy and safety of chinese patent medicine injection in the treatment of covid-19 will be provided to clinicians. prospero registration number: crd42020182725 corona virus disease 2019 (covid19) is an acute respiratory syndrome caused by novel coronavirus "2019-ncov", which has a large-scale epidemic [1, 2] and has aroused great concern in global public health. [3] the epidemic of covid-19 has been controlled in china, but the virus is still spreading in europe and north america. [4] spain is currently one of the countries most affected by covid-19, with 210,773 confirmed cases as of april 28, 2020. [5] similarly, italys situation is no better. [6] the main clinical manifestations of covid-19 patients were fever, cough and fatigue, and some patients also had nasal congestion, runny nose, and diarrhea. [7] covid-19 can spread from person to person, [8, 9] and is highly infectious, with a variety of transmission modes (droplets, close contact, faecal, etc.). [10, 11] the population is generally susceptible to infection. western medicine mainly adopts antiviral, oxygen therapy, nutritional support and other standard supportive treatment, [12, 13] but there is still a lack of specific drugs. [14] vaccine development is progressing rapidly, but the first wave of the pandemic may not be contained. [15] in traditional chinese medicine, covid-19 is classified as "epidemic disease", which is caused by the feeling of the qi of disease. traditional chinese medicine has a long history in the this work is supported by shandong co-innovation center of classic tcm formula, shandong university of traditional chinese medicine (2019kfy15). ethical approval was not necessary, for this article does not contain any studies with human or animal subjects performed by any of the authors. treatment of epidemic diseases, [16] and has accumulated rich clinical experience. at present, many authoritative experts of traditional chinese medicine believe that covid-19 may be related to dampness, heat, toxin, blood stasis, qi deficiency, turbid toxin and turbid dampness. [17, 18] in the fight against covid-19 epidemic, chinese medicine played a significant role. the specific manifestations are as follows: the combination of traditional chinese medicine and western medicine can reduce the clinical symptoms of common patients, shorten the course of treatment, and promote healing; for severe and critical patients, it can reduce the lung exudation, control the inflammatory overreaction, and prevent the deterioration of the disease; for patients in the recovery period, it can remove the residual pathogens, support the healthy qi, and promote the recovery of the body. [18] as a new and unprecedented infectious disease, covid-19 has become a global concern of the world health organization (who) because of its rapid spread around the world. [19] the early intervention of traditional chinese medicine and the combination of traditional chinese and western medicine are important means to improve the cure rate of the covid-19 and reduce the mortality. [20] therefore, it is necessary for us to evaluate the efficacy and safety of chinese patent medicine injection in the treatment of covid-19 based on the existing evidence. in order to better guide the clinical application of chinese patent medicine injection for covid-19 and provide better treatment options. it is urgently needed to accomplish this review. this work aims to evaluate the current evidence for the efficacy and safety of chinese patent medicine injection in treating covid-19, and provide reliable evidence-based medical evidence for the clinical treatment of covid-19. this protocol has been registered in the international prospective systematic registration review (prospero) and the registration number is crd42020182725. this study has followed the guidelines of preferred reporting items for systematic review and meta-analysis protocols (prisma-p). [21] 3.1. inclusion criteria 3.1.1. types of studies. this study includes all relevant randomized controlled trials (rcts) of chinese patent medicine injection for treating covid-19 published in chinese or english, regardless of allocation hidden or blinded. the population included patients diagnosed with covid-19, regardless of gender, age, race, nationality, and other characteristics. the patients in treatment group must have been treated with a kind of chinese patent medicine injection (including xiyanping injection, xuebijing injection, reduning injection, tanreqing injection, xingnaojing injection, shenfu injection, shengmai injection, shenmai injection), whether combined with other pharmacotherapies or applied separately. the treatment of control group was commonly used symptomatic medication such as antiviral, anti-infective, nutritional support drugs, or no treatment was given. once treated with one of chinese patent medicine injections, the trial will be excluded. 3.1.4. outcomes. the primary outcomes of our interest are as follows: 1. clinical effective rate (rate of positive to negative for nucleic acid test), 2. disappearance rate of main symptoms (including fever, fatigue, cough,etc.), 3. occurrence rate of light or common type to severe form, 4. mortality rate. the secondary outcomes of our interest are as follows: 1. improvement of secondary symptoms (chest pain, difficulty breathing, muscle ache, nausea, vomiting, diarrhea, etc), 2. chest computed tomography (ct) imaging improvement, 3. peripheral blood index detection like c-reactive protein (crp), procalcitonin (pct), white blood cell count (wbc), lymphocyte count (lym), 4. safety index, incidence of adverse events. the exclusion criteria were as follows: 1. non-randomized controlled trial, and self-control, 2. case report, 3. experience summary, 4. animal experiment research, 5. systematic review, and meta-analysis. we will use the computer to search the following electronic bibliographic databases: pubmed, web of science, the cochrane controlled trials central register system (central) cochrane library, embase, china national knowledge infrastructure (cnki), wanfang database, chinese scientific journal database (vip database), and chinese biomedical literature database (cbm). limited the search time from the establishment of databases to may 2020. we will apply a combination of mesh terms and free-text to search and adjust the search strategy according to the characteristics of each database. pubmeds detailed search strategy is shown in table 1 . in addition, the ongoing trials registered in the chinese clinical trial registry website (www.chictr.org.cn), american clinical trials registry website (clinicaltrials.gov), world health organizations international clinical trials registry platform (who ictrp) will also be searched. 3.4. data collection and analysis 3.4.1. identification and selection of studies. firstly, we will use endnotex7 software to find the repeated title information. when the retrieval is complete, repeated references will be deleted. the 2 researchers (ml and zl) then independently screen the titles and abstracts to rule out apparently unrelated studies. subsequently, the literature after preliminary screening will be inspected in full text to determine whether to be included. the details of selection process are shown in figure 1 . in this process of extracting, the data will be filled into the preduring the data extraction, the microsoft excel data extraction form will be used to extract the data from the literature included. we will attempt to extract the following data information from each study: first author, title, country/region, year of publication, study design, sample size, intervention approach, outcome indicators, adverse events. if the required data is missing, we will try to contact the literature authors by e-mail or phone to ensure the accuracy of the relevant information. 3.4.3. measure of treatment effect. two reviewers (ml and zl) will analysis the treatment effect by review manager 5.3. statistics for the analysis of efficacy indicators will use odds ratio (or), continuous variables will use weighted mean difference (wmd), and give 95% confidence interval (ci). 3.4.4. risk of bias assessment. risk of bias in the included studies will be assessed by the cochrane risk of bias tool [22] according to the cochrane handbook 5.1.0 for systematic reviews of interventions, which consists of 7 items of bias relevant to the quality of rcts. the criteria to be assessed include the following domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. an assessment of risk of bias will be made for the included studies based on the following 3 levels: "low risk of bias," "unclear risk of bias," "high risk of bias." such an evaluation process will be independently performed by 2 researchers (ml and yx), and when differences arise, a third person (ww) will be required to participate in the discussion to determine the risk of bias. 3.4.5. data analysis. using review manager 5.3 software provided by cochrane collaboration network, meta-analyses will be carried out for the included researches. when p > .05, we generally determined that there is no heterogeneity among the studies, fixed-effects model is selected for analysis, otherwise random-effects model is selected. in addition, we also use i 2 for quantitative analysis of heterogeneity, [23] it is generally considered that i 2 > 50% indicates the existence of substantial heterogeneity. when there is homogeneity among the studies, the fixed-effects model analysis is used; when there is heterogeneity between the studies, the random-effects model analysis is used. if we find a significant level of heterogeneity, a descriptive analysis will be performed instead. 3.4.6. subgroup analysis. if the included evidence is rich, we will conduct a subgroup analysis of the factors that influence the outcome, such as: disease types of covid-19 and whether accompanied by underlying disease. considering that the diversity of included studies will lead to a certain degree of heterogeneity and inconsistency, we will conduct a sensitivity analysis. this process will be carried out by eliminating each included study. if the heterogeneity does not change after excluding each literature, we think our conclusion is stable; otherwise, if the heterogeneity changes, the excluded literature may be the source of heterogeneity. 3.4.8. assessment of publication bias and quality of the evidence. where a sufficient number of trials per comparison are available in a result of meta-analysis, the funnel plot will be drawn to analyze the publication bias of the included studies. if the included studies were distributed symmetrically on both sides of the equivalent line, the possibility of publication bias will be small. the evidence quality of the study will be assessed by the grading of recommendations assessment, development and evaluation (grade) framework. [24] the 4 levels of the grade for the quality of evidence are very low quality, low quality, moderate quality, and high quality. covid-19, as a global health hotspot that continues to ferment, has attracted wide attention for its therapeutic methods and drugs. since the outbreak of the epidemic, chinese medicine has been widely used in the treatment of covid-19 and has played a prominent role in disease prevention and control. the purpose of this study was to evaluate the efficacy and safety of chinese patent medicine injection in the treatment of covid-19 and to explore the role of chinese medicine in the treatment of covid-19. at present, relevant studies have reported that integrated chinese and western medicine treatment can safely and effectively reduce the clinical symptoms of patients, reduce the case fatality rate and the conversion rate of critically ill patients. [25, 26] therefore, traditional chinese medicine is a potential treatment method for covid-19. this study will systematically evaluate the efficacy and safety of chinese patent medicine injection for covid-19 based on available evidence. the presentation of these results will provide better options and more compelling evidence for clinical treatment. considering that there may be many studies that have not yet been published, more high-quality clinical evidence will need to be updated to ensure the integrity of the evidence in this study. clinical features of patients infected with 2019 novel coronavirus in wuhan, china 2019-ncov (wuhan virus), a novel coronavirus: human-to-human transmission, travel-related cases, and vaccine readiness the epidemiology and pathogenesis of coronavirus disease (covid-19) outbreak covid -19 -the search for effective therapy covid-19 in spain: transplantation in the midst of the pandemic covid-19 and italy: what next? the epidemiological and clinical features of covid-19 and lessons from this global infectious public health event early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia potential of large "first generation" human-tohuman transmission of 2019-ncov clinical manifestation, diagnosis, prevention and control of sars-cov-2 (covid-19) during the outbreak period review article: gastrointestinal features in covid-19 and the possibility of faecal transmission epidemiology and clinical characteristics of covid-19 medication for covid-19-an overview of approaches currently under study treatment options for covid-19: the reality and challenges sars-cov-2 vaccines: status report clinical observation on lianhua qingwen granules combined with western medicine conventional therapy in the treatment of 63 suspected cases of coronavirus disease 2019 clinical effectiveness and case analysis in 54 ncp patients treated with lanhuaqingwen granules refection on effects of integrated traditional chinese and western medicine on coronavirus disease 2019 (covid-19) early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia application and research progress of traditional chinese medicine in prevention and treatment of corona virus disease 2019 preferred reporting items for systematic review and meta-analysis protocols(prisma-p) 2015: elaboration and explanation cochrane handbook for systematic reviews of interventions version 5.1.0 [updated analysing data and undertaking meta-analyses: cochrane handbook for systematic reviews of interventions grade guidelines: 1. introduction-grade evidence profiles and summary of findings tables clinical observation on 49 cases of noncritical covid-19 in shanghai treated by integrated traditional chinese and western medicine clinical practice of the combination of chinese and western medicine in the treatment of a patient with the coronavirus disease medicine (2020) 99:25 www.md-journal key: cord-350443-ca5avyjf authors: zhang, lei; wilson, david p. title: trends in notifiable infectious diseases in china: implications for surveillance and population health policy date: 2012-02-16 journal: plos one doi: 10.1371/journal.pone.0031076 sha: doc_id: 350443 cord_uid: ca5avyjf this study aimed to analyse trends in notifiable infectious diseases in china, in their historical context. both english and chinese literature was searched and diseases were categorised according to the type of disease or transmission route. temporal trends of morbidity and mortality rates were calculated for eight major infectious diseases types. strong government commitment to public health responses and improvements in quality of life has led to the eradication or containment of a wide range of infectious diseases in china. the overall infectious diseases burden experienced a dramatic drop during 1975–1995, but since then, it reverted and maintained a gradual upward trend to date. most notifiable diseases are contained at a low endemic level; however, local small-scale outbreaks remain common. tuberculosis, as a bacterial infection, has re-emerged since the 1990s and has become prevalent in the country. sexually transmitted infections are in a rapid, exponential growth phase, spreading from core groups to the general population. together human immunodeficiency virus (hiv), they account for 39% of all death cases due to infectious diseases in china in 2008. zoonotic infections, such as severe acute respiratory syndrome (sars), rabies and influenza, pose constant threats to chinese residents and remain the most deadly disease type among the infected individuals. therefore, second-generation surveillance of behavioural risks or vectors associated with pathogen transmission should be scaled up. it is necessary to implement public health interventions that target hiv and relevant coinfections, address transmission associated with highly mobile populations, and reduce the risk of cross-species transmission of zoonotic pathogens. china has experienced a large decline in the spread and burden of infectious diseases since the early 1960s, associated with effective and large-scale public health interventions and large populationbased vaccination programmes. china successfully eliminated 11 infectious diseases -including smallpox from the general chinese population in early 1960s [1] , 19 years before its global eradication -and another 10 infectious diseases, including poliomyelitis, have more recently been eliminated [2] . a further 13 diseases, including measles, are thought to be contained well at low endemic levels [3] . surveillance systems for infectious diseases in china are mainly hospital based. the latest available statistics (from 2006) indicate that china has 18,703 county hospitals, 40,907 township hospitals and 201,562 medical clinics [4, 5] . hospitals at the prefecture level or above are usually equipped with reference laboratories that are capable of carrying out molecular surveillance for cases. together with laboratories from academic institutions, they form the front line of surveillance for outbreak detection and notification of infectious diseases in china. all hospitals and clinics are obliged to report both suspected and confirmed cases of notifiable infectious disease to their nominated county centre for disease control (cdc). after recording the details of the reported cases (including their geographical location, demographicl information and infection status), county cdcs send the information to the country's central cdc, through the national infectious diseases monitoring information system database, which was established in 2004 [6] . this reporting mechanism bypasses the previous stepwise hierarchical reporting framework, thus allowing information to flow directly from grassroots cdcs to china's central disease database. however, regional, provincial and national cdcs do not have equal access to all of the data in the database: their access rights are limited to their own administrative regions, and only national cdcs has the full access to all data [7] . in addition to their responsibility for verifying the disease information from their administrative regions, municipal and provincial cdcs are required to report to the appropriate level of the bureaus of health or department of health and to form networks with local research bodies, universities and other health organisations. at the top of the hierarchy, china's central cdc is the overseeing organisation with responsibility for assembling and analysing diagnostic data for all diseases and then presenting a final report to the ministry of health, which is the main public health policymaker in china. the central cdc is also the only legitimate office for disseminating infectious disease information to the public, but provincial and municipal cdcs are also authorised to publicise the information to people in their jurisdiction, under the supervision of the ministry of health [8] . in contrast to disease surveillance systems in europe, the chinese surveillance system uses a multilayer administrative mechanism that enables rapid and efficient upward flow of epidemic information. china is a populous country of 1.3 billion people [9] . over the last 30 years of economic reform in the country, there have been environmental, demographic, social and behavioural changes in the population. as china's ties with the rest of world become increasingly strong, infectious diseases in china no longer remain a domestic issue. a thorough review of infectious disease surveillance in china is timely and important for the country's disease prevention and control strategies. currently, 39 infectious diseases are classified as notifiable in china. this study reviews trends in notifiable infectious diseases in china, in their historical context, discusses the current epidemiological state of these infections and their implications for disease surveillance and public health interventions. the review is structured by category of disease or transmission route. currently, 39 infectious diseases are notifiable in china, classified as a, b or c according to their epidemic levels and potential population threats. groups a and b (total 28 diseases) represent categories of diseases with high risk of outbreaks or that are likely to result in rapid spread once an outbreak occurs. mortality and morbidity related to group a and b diseases are reported and published by the chinese ministry of health on a monthly basis. group c diseases are less infectious and, when outbreaks occur, are epidemiologically less severe. they are required to be reported only when outbreaks occur. in this review, we searched published peer-reviewed research articles as well as online reports and grey literature from 1985 to 2010 relevant to disease surveillance in china in the following databases: pubmed, chinese scientific journals fulltext database (cqvip), china national knowledge infrastructure (cnki) and wanfang data. keywords used in the database search included ['chinese' or 'china'] and ['infectious diseases surveillance' or 'surveillance system' or 'infectious diseases monitoring' or 'infectious diseases information' or the type of infectious disease or the name of individual infectious diseases]. we also searched governmental reports, reports of non-governmental organisations and other grey literature from online sources. we then collated data on notified cases and mortality related to these diseases, using the latest available information from the ministry of health [10] . notifiable infectious disease data, including morbidity and mortality rates, was summarised by chinese ministry of health and published annually in chinese health yearbook and online accessible through cnki database. notably, this dataset does not contain data on sars and influenza a(h5n1) virus infection. hence we did not include them in our statistical analysis, but describe them in the text. the selected diseases were categorised into eight major types according to their diseases characteristics and origins. the morbidity and mortality for each disease type were calculated as the sum of the corresponding rates of individual diseases. the total number of diagnosed and death cases were estimated by multiplying morbidity and mortality rates by the overall chinese population in the study years. case fatality rate was defined as the percentage of persons diagnosed with the disease who die as a result of the illness during the calendar year, and was estimated by dividing mortality rate by morbidity rate of the diseases. further, for each individual disease, we calculate the disease-specific mortality rates among the chinese population in five-year intervals (1999-2003 and 2004-2008) . for each disease, the mean annual increase or decrease during 1999-2008, with 95% confidence intervals, is estimated, based on linear regression of logarithmic values of the number of annual death cases. trends in infectious diseases in china, 1999 china, -2008 morbidity of notifiable infectious diseases in china, represented by estimated numbers of new cases, declined substantially (.90%) from 22,000 cases per million in 1975 to a nadir level of 1,800 cases per million in 1995 (figure 1a ). since then, the rate of new infectious disease cases gradually reverted and maintained an upward trend. in 2008, the estimated rate of infectious diseases among the general chinese population reached over 3000 cases per million population. the composition of diagnosed diseases cases also changed substantially, in 1975, the three most reported diseases were gastrointestinal diseases (41.9%), vector-borne diseases (30.8%) and vaccine-preventable diseases (21.1%), corresponding to a total of 93.8% of all diagnosed cases ( figure 1a ). additionally, these three types of diseases account for 35.5, 21.7 and 18.4 million reported cases respectively during the period 1975-1979 (table 1 ). in contrast, in 1995, although gastrointestinal diseases remained the dominating disease type (41.6%), the proportion of all cases that were due to viral hepatitis quickly rose to 35.7%. sexually transmitted diseases re-emerged, and together with hiv, consisted of a substantial 6.3% of all reported cases. in 2008, the three most frequently reported disease types included viral hepatitis (38.3%), bacterial infections (33.3%) and stis and hiv (9.8%), which account for 5.4, 4.8 and 1.4 million diagnosed cases respectively during the period 2005-2008 (table 1) . rapid declines in infectious diseases mortality and its similar saddle pattern were also observed in the past 35 years. the overall mortality rate in china decreased from 66 cases per million in 1975 to 5 cases per million in 1995, then it gradually reverted to 10 cases per million in 2008 ( figure 1b ). vaccine-preventable diseases, bacterial infections and gastrointestinal diseases were the greatest causes of death, accounting for 30.0%, 24.0% and 19.5% of reported infectious diseases death cases among chinese population in 1975 ( figure 1b) . however, the rank of composition shifted to zoonoses (22%), viral hepatitis (17.3%) and quarantinable diseases (15.3%) in 1995. since then, the proportion of deaths caused by stis and hiv, and bacterial infections rapidly increased. by 2008, stis and hiv (39.5%) has become the mostly deadly infectious disease, followed by bacterial infections (24.7%) and zoonoses (20.0%). during the period 2005-2008, these three types of diseases have led to approximately 12,500, 13,300 and 11,400 deaths in china, respectively (table 1) . case fatality rate measures the percentage of deaths among people who contracted a disease. during 1975-2008, the disease type with the highest fatality rate is zoonoses, consistently causing 5-15% of deaths among the infected population. following that, quarantinable diseases killed 1.4-5.6% of its infected population during the same period. in comparison, fatality rates in vaccinepreventable (0. (table 1) . plague, cholera and epidemic haemorrhagic fever (which is caused by hantaviruses and mainly transmitted by rodents) have had diverse impacts on the chinese population at different stages of recent history. during 1944 to 1949, there were 179 notified outbreaks of plague across china, which resulted in an estimated 2.4 million deaths. from 1950 to 1954, the mean number of annual notifications of plague infection was 1,373 cases per year [11, 12] . this was then substantially reduced to 20 cases per year over the following 30 to 40 years. since 1990, the number of annual reported plague cases has increased to approximately 52, which is equivalent to 0.004 per 100,000 population per year [11, 12] . there is no observed trend in the table 1 . estimated number of diagnosed cases, death cases and case fatality rate of eight major infectious disease types in china in 5-year intervals. period 1975 period -1979 period 1980 period -1984 period 1985 period -1989 period 1990 period -1994 period 1995 period -1999 period 2000 period -2004 period 2005 period -2008 quarantinable diseases mean annual mortality due to plague during 1999-2008 (table 2) . cholera has caused two major outbreaks in china in recent decades: the first started in 1973, leading to a large peak in the number of cases in 1980, with an annual notification rate of four cases per 100,000 population ( figure 2a ). the rate then gradually subsided but there was a second major outbreak in the early 1990s. during 2004 to 2008, cholera cases were reported at relatively low incidence levels: the disease is well controlled, with a mean annual decline in mortality due to the disease of 48% (95% ci, 12-70%, table 2 ). despite a 13-fold decrease in the epidemic haemorrhagic fever notification rate since 1987 and continuous decline in the diseasespecific mortality rate, china is still the country most severely affected by this disease, with 90% of the global cases of haemorrhagic fever with renal syndrome (hfrs) occurring in china [13, 14] . hfrs remains an important public health issue in china, as an estimated 20,000-50,000 new cases are reported each year [15] . it is important to establish effective strategies to reduce the incidence of hfrs. the mean annual decline in mortality due to this disease is 12% (95% ci, 3-20%, table 2 ). persistent public health campaigns have been effective in reducing the number of rodents, which has been largely responsible for the decreasing trend in plague and epidemic haemorrhagic fever notifications. improved hygiene and sanitary conditions have also led to the decline in incidence and mortality due to cholera. overall, these quarantinable diseases persist at low endemic levels, but still pose potential threats. in the early 1960s, a nationwide vaccination programme was implemented to eradicate smallpox, measles, poliomyelitis, tuberculosis (tb), pertussis, diphtheria and tetanus. measles vaccine (one-dose schedule) was introduced in the country in 1965, and from 1978 it has been administered routinely to all infants through the country's expanded programme on immunisation [16] . measles mortality and morbidity has declined continuously and substantially since 1978. during 1995 to 2007, the incidence was less than one per 100,000 population (figure 2b), with fewer than 250 deaths due to measles reported annually [17] . however, limited small-scale outbreaks continue to occur among susceptible children in rural areas with low routine immunisation coverage and among susceptible children of 'floating immigrants' (the relatively large population of internal chinese immigrants who leave their rural hometown and move to urban areas to seek better employment opportunities) [18] . in addition, although a two-dose measles vaccination schedule has been recommended in china since 1986, the second dose is widely perceived as a nonmandatory booster. coverage of the second dose is not reported, but is thought to be low [19] . a global effort to eradicate polio began in 1988 [20] ), wild-type poliovirus was eradicated in china in 1994 [21, 22] ; extensive surveillance for acute flaccid paralysis is thought to have strongly contributed to polio eradication in the country [23] . vaccination against diphtheria, pertussis and tetanus was also made mandatory for all infants under the country's expanded immunisation programme since 1960s. in 2006, vaccination coverage of the vaccine against the three diseases reached 99.0%, comparable with polio vaccination (99.0%) and measles vaccination (98.6%) [24] . since 2006, the total annual incidence of reported cases of diphtheria, pertussis and tetanus decreased to below 0.5 cases per 100,000 population ( figure 2b ). widespread vaccination against these diseases is one of the important contributors to improvements in child health in china: infant mortality rate dropped from 20% in 1950 to 1.7% in 2006 [24] . mandatory vaccination of children throughout the past decades has been demonstrated to be successful in containing the spread of these diseases in china. it is estimated that polio vaccination alone has saved a total of 1,128,000 children in china from disabling disease and suffering [24] . mortality due to pertussis and tetanus experienced significant annual decays at rates of 44% (95% ci, 23-59%) and 12% (95 ci%, 30-65%) ( table 2) . trends in tb are discussed in the section on bacterial infections. the number of reported cases of bacillary and amoebic dysentery has declined rapidly since 1975 in china (figure 2c ). an initial large decline occurred in the mid-1970s, largely due to substantial improvements in sanitary conditions and quality of drinking water. however, approximately 84 million diarrhoeal episodes were still reported in china each year at the end of the 1990s: 25% of the episodes were in children under five years of age [25] . shigella bacilli and entamoeba histolytica have been found to be the main aetiological organisms [25] . a live oral shigella vaccine was then developed in 1997 in china, which provided 60-70% protection against s. flexneri serotype 2a and s. sonnei infection [26] . between 1999 and 2008, reported deaths due to dysentery decreased by a mean of 10% (95 ci%, 1-18%) per year ( table 2 ). the number of notified cases of typhoid and paratyphoid fevers is very low in china, with an annual rate of 1.2 notifications per 100,000 population in 2008 (figure 2c ). the number of reported deaths due to these infections has decreased at a mean rate of 22% (95% ci, 2-39%) per year (table 2) . however, these infections remain endemic in some rural areas of southern china, where there is a lack of adequate sewage disposal and safe water supplies [27] . a large, localised outbreak occurred during 1996 to 1998 in xing-an county in the southern province of guangxi, which resulted in an annual incidence rate of 39 to 103 cases per 100,000 population [28] . subsequently 61,030 doses of vi polysaccharide vaccine were administered in 1999 and the epidemic quickly subsided. no further typhoid fever outbreaks were reported in china. national public health campaigns since 1949 in china effectively improved hygiene and sanitary conditions, which substantially reduced most of vector-borne infectious diseases. in 1955, a total of 5,970,000 malaria cases were reported nationally, accounting for 68% of the total number of reported infectious disease cases and an incidence of 1,028 per 100,000 population. malaria disproportionately affected some regions, with incidence rates as high as 10,360 per 100,000 population in hainan province [29] . in 1960 and 1970, there were major outbreaks of the disease, leading to a national incidence of 1,554 and 2,961, respectively, per 100,000 population [29] . it took considerable time for the incidence to fall: the number of cases did not decrease to 1955 levels until 1982, but it has since continued to decrease. by 1998, the rate of notifications decreased to 31.3 per 100,000 population, corresponding to more than a 99% reduction and accounting for only 1.3% of the total number of reported cases of notifiable conditions [29] . data for 2004 to 2008 indicate that the mean annual mortality rate due to malaria was reduced to 0.004 per 100,000 population (table 2) , corresponding to only 52 reported deaths per year countrywide. malaria no longer represents a major threat to the chinese population. the ongoing governmentmobilised mass movement for vector control is probably an effective method for eliminating mosquitoes and their habitats and consequently reducing the disease burden due to malaria in the country. the universal healthcare system provided an effective base for the implementation of countrywide interventions [6] . as a result of the national public health campaigns to eliminate infectious disease vectors, forest encephalitis (also named russian spring-summer encephalitis), tick-borne relapsing fever, tsutsuga-mushi disease (also known as scrub typhus) and epidemic typhus were reduced to very low levels by the late 1980s and were then no longer notifiable. the number of visceral leishmaniasis (also known as kala-azar), japanese encephalitis, malaria and dengue fever epidemics has also decreased, with few cases per year (figure 2d) . however, there are signs that climate change may have led to local outbreaks of some these vector-borne diseases in the past decade in china [30] . rabies is one of the zoonotic diseases on the rise in china. during a 58-year period between 1950 and 2007, a total of 117,530 human rabies cases were reported, corresponding to an incidence rate of 9.1 cases per 100,000 population. three major epidemics were observed [31, 32] : the first occurred in the mid-1950s when the annual number of reported cases reached a peak of about 2,000. the epidemic subsided in the 1960s and then started to surge again in the early 1970s. after reaching a sustained peak from 1982 until the end of the decade, at a level of 5,000 to 6,000 cases per year [33] , in 1996 the number of cases was at its lowest, with 159 reported cases [33] . as the disease in humans is closely associated with transmission of rabies virus by infected dogs, in the past epidemics, strict policies for vaccination of owned dogs and elimination of stray dogs were put in place, resulting in effective control of the epidemic. however, since 2000, due to a new wave of rapid expansion of the pet dog population in urban china, there has been a third outbreak, in which the number of cases has increased rapidly: in 2007, the number of notified cases climbed to 3,250 [34, 35] . the rabies-related mortality rate increased during 1999 to 2008 by a mean of 26% (95% ci, 14-37%) per year ( table 2 ). this should serve as a call for action to prevent the further spread of rabies in china. severe acute respiratory syndrome (sars), caused by a coronavirus that was transmitted to humans through close contact with civet cats, spread from guangdong, china, quickly leading to a worldwide epidemic in 2003. china reported 5,327 (66%) of the 8,071 sars cases globally and 349 sars-related deaths during the epidemic, which lasted for approximately a year [36] . the first human case of highly pathogenic avian influenza a (h5n1) virus infection was reported in hong kong in 1997. by 2009, mainland china had 88 avian influenza outbreaks among birds in 23 provinces and a total of 38 human cases and 25 deaths had been reported [37] . in 2010, the epidemic had spread to 15 countries and resulted in 296 deaths, out of 500 cases [38] . in comparison, the 2009 influenza a(h1n1) pandemic caused more than 154,000 human cases and 842 deaths in china alone [39] , despite the virus being much less virulent than influenza a(h5n1) virus. china, with concentrated human activity in its fast-growing major cities that may lead to effective transmission of human-tohuman transmission of h1n1, is very vulnerable to the transmission of respiratory infectious diseases of zoonotic origin. during the mid-to-late stages of the sars outbreak and, more apparently throughout the course of the 2009 influenza pandemic, the chinese government responded swiftly with openness and transparency to control both diseases and prevent further episodes. in both cases, the epidemics caused widespread social panic. instead of the ministry of health, the state councilsrepresenting the highest administrative authority of the chinese government -assumed direct leadership in combating the epidemics. case notifications for leptospirosis, anthrax and brucellosis have remained at low levels since 2000. there was an increase in the number of notified case of brucellosis from 0.17 per 100,000 population in 2000 to 1.50 per 100,000 population in 2007, but this was probably due to improved surveillance and is believed not to reflect an increase in incidence [40] . the annual number of notified cases of leptospriosis and anthrax dropped below 0.01 per 100,000 population in 2008. the mortality rate due to brucellosis remains very low and stable, whereas the rates due to leptospriosis and anthrax have dropped significantly, by 20% and 31%, respectively, during 1999 to 2008 (table 2) . china has the second largest tb epidemic in the world (after india) [41] . in 2008, some 4,500,000 patients were living with pulmonary tb in china, corresponding to an incidence of 111 per 100,000 population, and resulting in 130,000 deaths from tb in the same year [42] . since 2005, an estimated 20,000 additional tb reactivation cases have arisen per annum in china due to human immunodeficiency (hiv) coinfection [42] . the tb epidemic has spread unevenly in china: in 2005, china reported a national tb prevalence of 0.2% [41] , whereas the southern province of guangxi, which borders vietnam, reported a much higher prevalence of 0.65% [43] . in 1991, in adopting dots -the internationally recommended tb control strategy -china launched a 10-year infectious and endemic disease control project in an effort to curb its expanding tb epidemic in 13 of its 31 provinces [44, 45] . it is estimated that the number of chinese people infected with tb between 1990 and 2000 decreased by 30% and that 300,000 tb deaths were averted. with a success rate greater than 90% [45] , dots has led to the avoidance of an estimated 1.5 million tb cases [44, 45] . however, since 2000, multidrug-resistant (mdr) tb and extensively drug-resistant (xdr) tb have emerged as a severe public health issue in the country. in 2004, china reported approximately 140,000 mdr tb cases, accounting for about one third of the estimated global burden of mdr tb [46] . in some provinces, the proportion of mdr tb among newly notified tb cases and previously treated cases was found to exceed 10% and 30%, respectively [47] . the latest study indicates that the prevalence of mdr tb among tb patients is as high as 19.4%, and 14.9% of mdr tb cases were xdr during 2007 to 2009 [48] . the mortality due to tb increased at a rate of 28% (95% ci, 14-43%) per year. hydroelectric projects that led to the formation of a large number of dams in china, as well as climate change, have substantially increased the risk of schistosomiasis occurring and its spread to non-endemic areas of the country, leading to small-scale outbreaks and increases in rates of case notifications near the affected areas [49, 50] . the incidence of schistosomiasis has increased from 0.10 cases per 100,000 population in 2004 to 0.26 per 100,000 population in 2008 (figure 2f ). since the founding of china in 1949, laws have been enacted to make commercial sex illegal. brothels were closed down and sex workers were sent to camps to be 're-educated'. special institutions for treatment of sexually transmitted infections (stis), at the time mostly syphilis, gonorrhoea and chlamydia, were established for the training of medical personnel, who were then sent to areas previously associated with large sex industries to treat stis at beginning of 1950s. during 1950s, a universal healthcare system was established that provides treatment for sti patients free of charge. designated laboratories for stis were built for diagnosis and research [51] . more importantly, population-based health education campaigns about stis were carried out, and detection and treatment of stis were portrayed as patriotic actions [52] . as a result, the number of cases of notifiable stis decreased from 10 million in 1950 to reportedly eliminated from 1964 [51, 53, 54] . however, notifiable stis have re-emerged, leading to a fastspreading epidemic in the country. in 1987, the incidence for stis was 6.64 per 100,000 population and in 1996, the rate increased to 34.6 per 100,000 population, which corresponded to 1.8 million new sti cases [52] . the annual growth rate of the number of sti cases in china exceeds 20% [52] . the rise of sti incidence is mainly due to unprotected sexual acts and other high-risk behaviours [55, 56] . since early 1980s, underground prostitution has again become rampant in major cities in china [57] . the number of chinese men, increased purchasing power of urban residents and trends away from traditional chinese family values of fidelity all led to an increased number of male clients for commercial sexual services [58] . in addition, lack of sexual health knowledge among commercial sex workers and their inability to effectively negotiate condom use during sexual acts substantially increased the risk of sti transmission [57, 59] . the previously hidden population of men who have sex men (msm) is becoming more overt due to increasing acceptance in society. high-risk sexual behaviours, including a low percentage of condom use, in this population is also contributing to the fast transmission of stis [60] . for example, in 1998, the incidence of syphilis in china was 0.17 per 100,000 population: it increased 20-fold to 4.31 cases per 100,000 population in 2002 and further to 15.88 cases per 100,000 population in 2007 [10, 51] (figure 2g ). in particular, msm, injecting drug users (idus) and female sex workers have the highest syphilis prevalence in china, of 10-20% [61, 62] , 5.4% [63] and 7-12% [64] , respectively. the first case of acquired immunodeficiency syndrome (aids) in china was reported in 1985, but a local hiv epidemic was not detected until 1989 when a cluster of infections was diagnosed among idus in yunnan province [65] . before 2000, china had fewer than 20,000 reported hiv/aids cases, but in 2007, the number rose to 200,000. the latest estimates are that 700,000 people were living with hiv/aids in china at the end of 2007, with 70,000 new infections added every year since then [66] and 20,000-30,000 annual aids-related deaths [67] . although the hiv/aids epidemic first began and predominated among idus, it rapidly spread to other population groups through both heterosexual and homosexual transmission. the latest figures demonstrate that heterosexual transmission has accounted for approximately 38-50% of new hiv infections since 2005 [68] , which may level at or exceed the percentage (30-49%) caused by transmission due to the sharing of injection equipment among idus [69, 70] . notably, hiv infection has become more prevalent among msm, as male homosexual activities account for approximately 10% of new infections [71] . aids mortality rate increased from 0.10 in 1999 to 1.01 cases per million in 2005, then to 4.58 cases per million in 2008, corresponding to an annual growth rate of 44% (95% ci, 30-58%) the rate is expected to increase sharply if the epidemic remains uncontrolled and there is no large procurement of antiretroviral drugs. cumulatively, over 9000 infants were infected through mother-to-child transmission by 2005 and it was estimated that about 500 million chinese were carriers of mycobacterium tuberculosis in 2003 [72] : coinfection of hiv and m. tuberculosis could therefore have a large epidemiological impact, in the absence of appropriate public health interventions. viral hepatitis is prevalent in china, but the prevalence differs according to the type of virus. before the 1990s, hepatitis a virus (hav) was the most prevalent. in the early 1990s, the annual number of reported hav diagnoses was more than 50 per 100,000 population. this dropped by 90% to 5 per 100,000 population in 2005 to 2006 [73] (figure 2h ). the mean annual death rate due to hav decreased at a rate of 21% (95% ci, 8-32%) during 1999 to 2008 ( table 2 ). the decrease is probably a result of mass vaccination efforts in introducing the hav vaccine (h2 strain) in the 1990s and improvement of hygiene and sanitary conditions that broke the cycle of food and water contamination [73] . according to 2008 data [74] , hav persists at low, endemic levels ( figure 2h ). in comparison, infections of hepatitis b virus (hbv), which is transmitted mainly through body fluid from mother to child, and hepatitis c virus (hcv), transmitted predominantly by intravenous injections or blood transfusion, are becoming alarmingly widespread in china. the annual number of new hbv cases increased rapidly from 20 per 100,000 population in 1990 and reached 100 per 100,000 population in 2008, despite an increasing vaccination coverage of newborns from 30% in 1992 to 93.4% in 2005 [75] . hcv infections followed a similar trend and in 2007, the annual notification rate was about 8.8 per 100,000 population. the 2007 hcv and hbv prevalence among the general population was 0.5% and 6%, respectively [74] . mortality due to hbv and hcv increased at annual rates 9% (95% ci, 1-20%) and 30% (16-46%) respectively. in contrast to hav infection, which always causes acute hepatitis but never develops into a chronic condition, hcv and hbv infections often cause chronic hepatitis and may develop into cirrhosis and hepatocellular carcinoma [76] . coinfection of hbv or hcv with other pathogens causing chronic infections, such as hiv, results in substantial increases in the disease burden on individuals, accelerates disease progression and complicates treatment [77, 78] . since hbv and hcv can both be transmitted through exchange of body fluids, coinfection of these hepatitis viruses with hiv is common in at-risk groups in china. approximately 67-71% of the 700,000 registered idus in china are infected with hcv [79, 80, 81] and 17-26% of them are infected with hbv [79, 82] . the prevalence of hiv/hcv coinfection is 6.45% in idus [80] . among blood donors, the prevalence of hiv/hcv coinfection is 5.8-6.5% [80, 83] , whereas the figure for hiv/hbv coinfection is 3.7% [84] . in comparison, coinfection of hiv and hcv among the general population remains unknown as there is currently no reports on its prevalence. however, coinfection is expected to be increasingly noticeable as the hiv epidemic transforms into a generalised epidemic in china [6] . overall, this study investigated the temporal trends of major types of notifiable infectious diseases in china. our analysis indicated that while the morbidity and mortality of most infectious diseases reduced substantially during 1975-1995, there is an increasing trend of re-emergence of previously prevalent diseases and emergence of new infectious diseases since 1995, in particular, stis and hiv, viral hepatitis and zoonoses diseases. these diseases accounted for the majority of deaths associated with infectious diseases in china since 2005. consistent with this, analysis of case fatality rates indicated a higher percentage of deaths among zoonotically infected people (5-15%) and an elevated proportion (0.894%) among stis and hiv-infected individuals. our study has important implications for the surveillance and control of infectious diseases in china. first, the persistent small outbreaks of particular infectious diseases across the country indicate that any decrease in prevention efforts will probably trigger re-emergence of the diseases. surveillance activities are therefore essential to inform and prioritise public health responses. although efficient and well-developed disease surveillance systems have been implemented in many urban areas, hygiene conditions, health services and monitoring of patterns of spread and disease burden are largely lacking in rural china [6] . second, the rapid rise in the number of notified cases of stis, especially hiv infection, and viral hepatitis in china is associated with growth of the sex industry, increasingly frequent risky sexual behaviours and an increasing number of sexual partners in the general chinese population. the newly implemented internetbased national infectious diseases monitoring information system database not only provides a platform for integrating epidemiological data on hiv infection and other stis, but also initiated second-generation behavioural surveillance of the at-risk populations [70] . our analysis indicates that both epidemiological and behavioural surveillance of hiv infection and other stis is essential to understand and forecast the trends in these epidemics. extending surveillance efforts into population groups that were previously considered to be less at risk may further improve the quality and reliability of surveillance data. third, coinfections, especially those involving hiv, are likely to become major public health issues in the future. we demonstrate that tb/hiv, hbv/hiv and hcv/hiv coinfections have become increasingly prevalent in china and the trend is likely to continue in the absence of strong public health interventions. thus, inclusion of testing for tb and viral hepatitis coinfections as part of hiv voluntary counselling and testing could be useful among at-risk populations. scaling up of free-of-charge antiretroviral therapy should also include treatment for these coinfections. fourth, surveillance of zoonotic infections becomes increasingly important due to the interactions between humans and animals in china. china has established an efficient surveillance system for human infectious diseases [6, 85] : a parallel national centralised system for surveillance of disease in animals may be useful for reducing the risk of animal-to-human transmission. one of the potential limitations in our investigation may be poor data quality in the passive notification-based surveillance system. it is widely perceived that underreporting exists in the chinese infectious diseases surveillance system, but little is known about the extent of underreporting as systematic evaluations have never been conducted [6] . this issue requires further consideration in the future. an overview of prevalence studies would be useful for comparison with numbers of notified cases in order to estimate numbers of undiagnosed cases. a comprehensive evaluation would also involve assessments of the efficiency and effectiveness of the surveillance system, both quantitative and qualitative. understanding changes in testing rates in various population groups will also be useful for interpreting trends in notification data. but such investigations are beyond the scope of this review. infectious disease surveillance and interventions in china face several major challenges. the country's major economic reform in 1979 has created a large economic disparity between rural and urban areas, resulting in a large population of floating immigrants (also known as 'peasant workers'). this accounts for 10% of the total chinese population in 2005 [86] . the vast majority of these immigrants are from rural environments but work in urban areas, away from their families, and hence regularly travel between the two sites. in addition to the natural population growth of major cities, the inflow of internal immigrants substantially increases the population size and density in urban areas. these immigrants often live in overcrowded residential areas with compromised hygiene conditions. female immigrants often become targets of those seeking to recruit them for commercial sex work [57, 87] . these floating immigrants are often more disadvantageous than the local residents. they tend to be less educated compared with others in urban areas who have permanent resident status and less likely to seek medical treatment when sick due to financial constraints or lack of health insurance [6] . not surprisingly, the population of floating immigrants has been found to be more vulnerable to infectious diseases, especially stis, hiv and viral hepatitis [6] . additionally, their high-risk behaviours and mobility promotes transmission of infectious disease agents and creates a major challenge for disease detection and control. given the characteristics, behaviours and the increasing population size of floating immigrants, it becomes apparent that the capacity of current chinese healthcare system cannot meet the needs of both the surveillance activities and health problems of these migrant workers. the infectious disease surveillance system needs to be tailored for its high mobility, and a dramatic expansion of the private health sector is required to address the health needs of this population. transmission of zoonotic infectious agents relies on close interaction between infected animals and humans. as a result of the increasing social trend of keeping house pet dogs, it is estimated that the number of pet dogs in china reached 80-200 million in 2004 [88] . however, only 30% of dog owners register their animals with government authorities and only 2-8% of dogs are vaccinated against rabies [31, 89] -coverage of greater than 70% is needed to sufficiently control rabies, as determined by the world health organization (who) [90] . the high rabies prevalence (6.4%) among dogs and the expanding number of pet dogs pose a continual and increasing threat of transmission of rabies virus from dogs to humans in china [89] . in addition, the consumption of game meat, especially in southern china, is one of the important sources of zoonotic diseases [91] . markets in guangdong provinces sell live poultry, fish, reptiles and mammals, including dogs and civet cats, for food [92] : the housing of these live animals, often in packed conditions, together with human activities, makes such markets the ideal hub for cross-species transmission of zoonotic agents [91] . since there is no systematic surveillance of these live markets, it is difficult to estimate the number of such markets and the amount of game meat consumed by residents in southern china. the sars epidemic in 2003 demonstrates that transmission of pathogens originally associated with animals can cause worldwide outbreaks in human populations. the current absence of both epidemiological and behavioural data, including their frequency of contacts and means of animal handling, on animal infectious diseases is a strong barrier to effective surveillance and control. environmental changes facilitate the emergence and transmission of bacterial infections. the formation of a large number of dams in china, as a result of the increasing implementation of hydroelectric projects, have substantially increased the risk of schistosomiasis emergence and its spread to non-endemic areas of the country. further, the dense population conditions in urban china and the high mobility of its floating migrants substantially promote the rapid transmission of tuberculosis [93] . strengthening infectious diseases surveillance for bacterial infections among these specific affected populations should be a priority for the chinese government. conceived and designed the experiments: lz dw. analyzed the data: lz. wrote the paper: lz dw. establishment and amelioration of planned immunization in china disease control and prevention in china in the 20th century and prospects for the new millennium study on the strategy for shanghai disease control and prevention web-based infectious disease reporting using xml forms yearbook of chinese health 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infectious diseases in floating population: prevalent features and control migration and health in china: problems, obstacles and solutions. singapore: asian metacentre for population and substainable development analysis pivotal role of dogs in rabies transmission inferior rabies vaccine quality and low immunization coverage in dogs (canis familiaris) in china world health organization (1996) world health organization expert consultation on rabies the role of the legal and illegal trade of live birds and avian products in the spread of avian influenza severe acute respiratory syndrome analysis of factors affecting the epidemiology of tuberculosis in china key: cord-333119-vu4qbcy1 authors: zhang, xiao-rui; li, ting-na; ren, yuan-yuan; zeng, yi-jia; lv, hong-yang; wang, jin; huang, qin-wan title: the important role of volatile components from a traditional chinese medicine dayuan-yin against the covid-19 pandemic date: 2020-09-25 journal: front pharmacol doi: 10.3389/fphar.2020.583651 sha: doc_id: 333119 cord_uid: vu4qbcy1 aromatic chinese herbs have been used to prevent plagues since ancient times. traditional chinese medicine has unique advantages in the prevention and treatment of epidemic diseases. according to the traditional chinese medicine treatment plan in the national covid-19 diagnosis and treatment plan (trial seventh edition) of the national health commission, chinese patent medicines or prescriptions rich in aromatic chinese herbs are selected for prevention and treatment during the period of medical observation, clinical treatment, and recovery of confirmed covid-19 patients. some local health committees or traditional chinese medicine administrations recommend a variety of other ways of using traditional aromatic chinese herbs to prevent and cure covid-19. these involve external fumigation, use of moxibustion, and wearing of sachet. the efficacy of aromatic chinese herbs plays a decisive role in the prevention and treatment of covid-19. the unique properties, chemical composition, and mechanism of action of aromatic chinese herbs are worthy of extensive and in-depth experimental and clinical research. the findings are expected to provide a reference for follow-up treatment of novel coronavirus and the development of corresponding drugs. in 2003, dayuan-yin produced excellent results in the treatment of the sars virus. individually, 112 confirmed cases were administered this drug between january and april 2003, and more than 93.7% of the patients showed noticeable mitigation of the symptoms, as well as recovery. dayuan-yin also was selected as one of the nationally recommended prescriptions for the covid-19. based on the national recommendation of dayuan-yin prescription, this review discusses the role of volatile components in the prevention and treatment of covid-19, and speculates the possible mechanism of action, so as to provide a basis for the prevention and treatment of covid-19. most of the volatile components of dayuan-yin have been elucidated, and their structures are well established (table 1) . however, there are no data on volatile components extracted from areca catechu l. based on clinical evidence of therapeutic results with dayuan-yin, we summarized its potential bioactive volatile components in the treatment of covid-19. the biological benefits of dayuan-yin seem to involve anti-inflammatory, antiviral, antibacterial, and immunomodulatory effects ( table 2) . in autopsy studies and animal models, covid-19 manifests mainly as acute viral pneumonia leading to respiratory failure (chan et al., 2020; yao et al., 2020) . antiviral drugs have been used to treat common cold, fever and influenza viruses by destroying the viral surface structure and inhibiting its entry (hsieh et al., 2012) , suggesting that antiviral drugs can be used for covid-19. unfortunately, no specific antiviral treatment has been recommended for covid-19 treatment because of insufficient evidence from randomized trials (hung et al., 2020) . it has been shown that many re-purposed drugs have effects against close relatives of sars-cov-2, such as bcoronavirus, in vitro. furthermore, lopinavir and many interferons, especially interferon beta, have moderate effects against sars-cov in vitro and can be used in combination with ribavirin (chen et al., 2004; chan et al., 2013) . administration of antiviral drugs soon after symptoms appear reduces the release of virus in respiratory secretions of patients with covid-19, thereby decreasing their infectivity to others. targeted preventive treatment for contacts reduces their risk of infection (welliver et al., 2001; oriol and bonaventura, 2020) . patchouli oil is extracted from pogostemon cablin (blanco) benth. some studies in vitro have shown that patchouli oil exerted anti-viral effects against coxsackie virus (ic 50 = 0.081 mg/ ml, ti 1.25), adenovirus(ic 50 = 0.084 mg/ml, ti 1.20), influenza a virus (ic 50 = 0.088 mg/ml, ti 1.15), and respiratory syncytial virus (ic 50 = 0.092 mg/ml, ti 1.10) (wei et al., 2012) . evaluation of the antiviral properties of six chemical compositions of atractylodes lancea (thunb.) d dpph.c. revealed that atractylodin produced the most significant effect at doses of 10-40 mg/kg for five days, and attenuated iav−induced pulmonary injury via regulation of the tlr7 signaling pathway (cheng et al., 2016) . moreover, 1,8-cineole, the major constituent of the essential oil of lanxangia tsao-ko (crevost & lemarie) m.f.newman & skornick., is commonly applied for treating inflammatory diseases of the respiratory tract caused by viruses since it potentiates the antiviral effect of irf3, in addition to its inhibitory effect on proinflammatory nf-kb signaling (müller et al., 2016) . the levels of proinflammatory factors i.e. il-2, il-7, il-10, gcsf, ip10, mcp1, mip1a, and tnf -a in the plasma of critically-ill patients were higher than those in plasma of patients who were not in intensive care, suggesting that "cytokine storm" is closely related to the severity of covid-19 . cytokine storm is a very prominent pathophysiological feature of covid-19 infection (lin et al., 2020) . extensive endothelial barrier disruption and uncontrolled cytokine storm promote uncontrolled inflammatory response which is the basis of the core mechanism underlying acute respiratory distress syndrome (ards) (huang et al., 2017) , although this phenotype varies among individuals. experimental models of acute lung injury (ali) and human genome-wide association studies of ards indicate that cytokine storm plays an essential role in the pathophysiology of ards ( biondi et al., 1986; huang et al., 2017) . moreover, the most common and severe complication of covid-19 is ards (huang et al., 2017) . therefore, an understanding of the cytokine storm that aggravates ards in covid-19 may lead to early and effective intervention in critically-ill covid-19 patients. it seems necessary to directly inhibit inflammatory response in the lungs because cytokine storm can be alleviated with inflammatory therapy (cao p. et al., 2020) . previous studies have shown the benefits of antiinflammatory drugs in lung disease: they slow down impairment of lung function, reverse the inflammatory parameters nearly back to normal values, and improve patients' survival (konstan et al., 2011; lubamba et al., 2011) . ibuprofen, a popular antiinflammatory drug, is recommended for airway inflammation in cystic fibrotic lung disease (flume et al., 2007) . studies have shown pogostemon cablin (blanco) benth. volatile oils patchoulene: cyclin e↓, cyclin b↓, cdk1↓; the subsequent s-phase arrest, ifn-gamma↓, il-10↓ pogostemon cablin (blanco) benth. volatile oils: tnf-a↓, il-6↓, il-10↑, np-sh↑ (chen et al., 2015) patchoulene: regulates on the balance between nrf2 and nf-kb p65 signaling pathways (yang et al., 2018) patchoulene: vitro neutrophil fmlp chemotaxis↓, phagocytic activity↑; ear edema↑, myeloperoxidase (mpo) activity↑ that long-term prediagnostic use of nonaspirin nsaids (e.g., ibuprofen) is associated with a significant reduction in lung cancer survival (brasky et al., 2012) . in addition, barictinib, fedratinib, and ruxolitinib are active and selective jak inhibitors which have been approved for rheumatoid arthritis and myelofibrosis. all three drugs are effective anti-inflammatory agents, and as jak-stat signaling inhibitors, they may be effective against the consequences of elevated levels of cytokines (including interferon-g) usually observed in patients with covid-19 (stebbing et al., 2020) . the uk is currently conducting a randomized evaluation of covid-19 treatment (recovery) trial, based on the announcement on june 16, 2020, that dexamethasone had been shown to significantly improve the prognosis of covid-19 patients receiving respiratory support (recovery, randomised evaluation of covid-19 therapy trial, 2020). dexamethasone is a glucocorticoid which can be used as a synthetic form of the natural hormone cortisol (cain and cidlowski, 2017) . it has the same anti-inflammatory effect as cortisol. it inhibits the release of inflammatory chemokines by immune cells, thereby improving the prognosis of patients by reducing the severity of ards (lester et al., 2020) . in european patients, low-dose dexamethasone reduces mortality by 33% in critically patients requiring invasive ventilation (lim et al., 2020) . however, the implementation of appropriate dexamethasone use in low-and-middle-income countries has been a challenge. for example, corticosteroids may cause sepsis in some prevalent parasitic infections in africa (nutman, 2020) . therefore, the use of dexamethasone in african patients who have not been b-eudesmol has two-way regulation of gastrointestinal motility, which may be anticholinergic or directly acting on gastrointestinal smooth muscle. (wang et al., 2002) hinesol: h + , k + -atpase activity↓ (kanako et al., 2000 (guo et al., 2005) falcarindiol inhibited dc maturation by blocking the canonical pathway of nuclear factor-kappab and phosphorylated p38. (mitsui et al., 2010) falcarindiol inhibit pseudomonas aeruginosa by repressing virulencerelated genes, including the t3ss; quorum sensing synthase genes lasir and rhlir; lasb; motility-related genes flic and flig; and phenazine synthesis genes phza1 and phza2. diagnosed with covid-19 may lead to unexpected consequences (brotherton et al., 2020) . during the treatment of covid-19, dayuan-yin also reduces the severity of ards by inhibiting the release of inflammatory chemokines from immune cells. as a classic prescription in ancient china, dayuan-yin can play a safe and effective role in the treatment of respiratory infections in a more adverse environment. thus, it can avoid such problems in a large extent. anti-inflammatory property is widespread in various sources of volatile components. several data have found that 1,8-cineole significantly improved lung function and health conditions, and reduced dyspnea in patients with asthma, acute bronchus, and chronic obstructive pulmonary disease (copd). moreover, it significantly reduced the frequency of cough in patients with acute bronchitis, and alleviated frequent exacerbations in patients with copd and frequent exacerbations, notably (worth et al., 2009; worth and dethlefsen, 2012; fischer and dethlefsen, 2013; vogelmeier et al., 2018) . in a mouse model of lps-induced acute pulmonary inflammation, 1,8-cineole upregulated il-10 in lung tissues, and decreased the expressions of tnf-a, il-1b, nf-kb's subunit p65 and tlr4 (zhao et al., 2014) . moreover, 1,8-cineole was shown to inhibit ltb4 and pge2 (pathways of aa-metabolism in human blood monocytes) in bronchial asthma in vitro (juergens et al., 1998b) . in addition, 1,8-cineole decreased levels of tnfa, il-1b, leukotriene b4, and thromboxane b2 in human blood monocytes in vitro (juergens et al., 1998a) . pogostone, a bioactive component extracted from pogostemon cablin (blanco) benth., reduced the total population of t cells under cona stimulation by blocking t cell proliferation via downregulation of cyclin e, cyclin b, and cdk1. subsequent s-phase arrest inhibited the production of ifn-gamma and il-10 . simultaneously, pogostone pretreatment mitigated ethanolinduced gastric ulcer in rats by downregulation of il-6 and tnfalpha, and upregulation of il-10 and non-protein-sulfhydryl (np-sh) groups in the gastric mucosa (chen et al., 2015) . in lung disease, pogostone exerted potent protective effects against lipopolysaccharide-induced acute lung injury in mice by decreasing tnf-a-induced cell injury in a549 cells through modulation of the balance between nrf2 and nf-kb-p65 signaling pathways (yang et al., 2018) . pogostone significantly inhibited the protein and mrna expressions of proinflammatory mediators such as tnf-a, il-6, il-1b, no, and pge2. pogostone also significantly reduced lps-induced mortality in mice, suppressed the production of proinflammatory mediators in serum. and it attenuated liver and lung injury via downregulation of the mrna expressions of inflammatory mediators in multiple organs due to inhibition of activation of nf-kb and phosphorylation of p38 mapk (li et al., 2014) . pre-treatment with pogostone markedly mitigated lps-induced acute lung injury in mice, improved survival, attenuated histological alterations in the lungs, reduced mpo and mda levels, decreased the wet/dry weight ratio of lungs, and down-regulated proinflammatory mediators, such as tnf-a, il-1 beta and il-6. furthermore, pretreatment with pogostone enhanced the nrf2dependent genes nqo-1, gclc, and ho-1, but suppressed the nf-kappa b regulated genes tnf-alpha, il-1 beta, and il-6. the mechanism involved in the protective effect of pogostone was correlated with its regulation of the balance between keap1-nrf2 and nf-kappa b signaling pathways . moreover, volatile oils from pogostemon cablin contain a bioactive component named b-patchoulene which has been shown to significantly decrease mortality and lung wet/dry weight ratio of mice, and mitigate pathological changes in lungs, when compared to model group. it suppressed lps-induced activation of nf-kappa b, and markedly upregulated nrf2 and mir-146a (chen et al., 2017) . oxidative stress and inflammation form a positive feedback cycle (mittal et al., 2014) . in lung disease, excessive inflammation and oxidative stress lead to adverse outcomes. for instance, patients with copd are usually affected by other diseases (rabe and watz, 2017) . several mechanisms in lung inflammation and oxidative stress destroy dna and lead to an imbalance between tissue repair and cell proliferation, which seems to promote the link between copd and lung cancer (wilson et al., 2008; houghton, 2013; durham and adcock, 2015) . under normal conditions, the production and elimination of ros maintain a crucial balance between oxidation and antioxidation (cao et al., 2019) . in such a balance, the signal pathways are regulated, and cell proliferation can be guaranteed. when inflammatory factors destroy this balance, oxidative stress enhances the maturation of proinflammatory factors, leading to oxidative damage to cells and multisystem diseases (sies, 2015; kruk et al., 2019) . antioxidant drugs have been used in lung diseases. for example, antioxidants have been recommended for reduction of mortality or prevention of organ damage in animal models of acute lung injury induced by lipophilic acids (hsu et al., 2006; zhu et al., 2020) . vitamin c has also been shown to reduce the incidence of pneumonia in several controlled trials for human subjects (hemila, 2017) . the essential oil of magnolia officinalis rehder & e.h. wilson exerts antioxidant effect by scavenging 1,1-diphenyl-2picrylhydrazyl (dpph) radical and superoxide anion radical. the essential oil contains b-eucalyptol with a hydroxyl group which can provide hydrogen atom for scavenging dpph radical. moreover, with increase in volatile oil concentration, the antioxidant capacity gradually increased (guo, 2012) . the essential oil from atractylodes lancea (thunb.) dc. showed a strong antioxidant effect in vitro and indicated by dpph-radical scavenging property, with an ic 50 of 288.7 mg/ml. moreover, it inhibited lipid peroxidation, and affected total antioxidant capacity (t-aoc) in the serum and organ tissues of mice . in short-term cigarette smoke (cs)induced acute lung inflammation, 1,8-cineole decreased oxidative stress involving reactive oxygen species, by increasing superoxide dismutase and catalase, while reducing levels of malondialdehyde, inflammation, and the nf-kappa b p65 subunit (kennedy-feitosa et al., 2016) . the major components of pogostemon cablin (blanco) benth. are carvacrol (47.5%) and p-cymene (15.2%). it completely inhibits the growth of e. coli at a level of 0.05% (lin et al., 2016) . the essential oil of atractylodes lancea (thunb.) dc. exhibited antibacterial effects against gram-positive and gram-negative bacteria due to the cell membrane . in chronic zhang et al. dayuan-yin against the covid-19 pandemic frontiers in pharmacology | www.frontiersin.org september 2020 | volume 11 | article 583651 rhinosinusitis, 1,8-cineole suppressed the growth of s. aureus, escherichia coli, moraxella catarrhalis due to downregulation of significant and critical players in biofilm generation (agra, sara, and s b ) (schürmann et al., 2019) . on the other hand, the major constituent of the essential oil of atractylodes lancea (thunb.) dc. is b-eudesmol. in terms of intestinal flora, b-eudesmol has two-way regulation for gastrointestinal motility: anticholinergic pathway and direct effect on gastrointestinal smooth muscle. antibacterial effect is an essential pharmacological property of volatile compounds (houdkova et al., 2017; riad et al., 2020) . secondary bacterial co-infection is common in patients with covid-19 infection, and it leads to adverse prognosis (macintyre et al., 2018) . at present, many antibiotics have been used in the treatment of covid-19. for example, shufeng jiedu capsule (sfjd) prevents acute upper respiratory tract infection and positively affects fever, cough, and headache. studies have shown that sfjd significantly reduced the levels of serum pge2, il-1 b, and tnf-a in rats with acute pharyngitis (qian, 2019) . being a popular antiviral and antibacterial drug, sfjd is one of the drugs for covid-19 treatment in china (pan x. et al., 2020) . in addition, shuanghuanglian (shl) is a popular anti-bacterial drug. it has various pharmacological potential such as antibacterial, antiviral, and immune-enhancing properties which can be exploited in the treatment of acute upper respiratory tract infection (zhang et al., 2013) . preliminary studies in vitro showed that shl oral liquid inhibited sars-cov-2. indeed, shl has been used to carry out clinical research on covid-19 in shanghai public health clinical center and tongji hospital affiliated to huazhong university of science and technology (pan x. et al., 2020) . the antibacterial effects of volatile components of dayuan-yin are not limited to upper respiratory tract infections: these volatile components also regulate intestinal flora, treat gastric ulcers, and improve gastrointestinal symptoms. human gut microbes are the "second genome" of the human body (backhed et al., 2005; gill et al., 2006; cani and delzenne, 2007) . the composition of intestinal flora is closely related to human health status, and it plays an essential role in maintaining physiological balance (schuijt et al., 2016) . it has been confirmed that intestinal flora reduces ventilatorassociated pneumonia and enteritis by enhancing the function of primary alveolar macrophages (bradley et al., 2019) . patients with covid-19 showed intestinal microbial malnutrition and decreased microbial flora levels of some probiotics such as lactobacillus and bifidobacterium. the latest version of novel coronavirus pneumonia diagnosis and treatment plan released by the people's republic of china national health council suggests that intestinal microbiota should be used in severe and critical cases to maintain intestinal micro ecological balance (general office of the national., health commission of the people's republic of china. et al., 2020) . apart from the biological effects of the volatile components mentioned above, other non-volatile components of dayuan-yin also have abundant pharmacological properties. (zhang t. t. et al., 2014) (mitsui et al., 2010) . falcarindiol inhibited the growth of pseudomonas aeruginosa by repressing virulencerelated genes, including the t3ss; quorum sensing synthase genes lasir and rhlir; lasb; motility-related genes flic and flig; and phenazine synthesis genes phza1 and phza2 . it is obvious that dayuan-yin exerts extensive biological properties such as antiviral, anti-inflammatory, antioxidative, and antibacterial effects. it can be inferred that dayuan-yin may play an essential role in preventing covid-19 pandemic. at present, there are no conventional drugs that can cure covid-19 (cao b. et al., 2020) . however, according to data collected by the national health commission of the people's republic of china, clinical practice in chinese hospitals have reported that traditional chinese medicine has a definite therapeutic effect in the early stages of covid-19 infection . as a significant part of medical practice, chinese medicine has been used to treat human diseases for more than 5,000 years (li and kan, 2017) . in recent decades, volatile compounds extracted from medicinal plants have attracted more and more attention due to their important biological effects such as antiviral, anti-inflammatory, and antibacterial properties. besides, they are non-toxic and have few side effects, making them suitable for use as drugs. this review discussed the potential role of traditional chinese medicine in terms of volatile components. the antiinflammatory, antiviral, antibacterial and immunomodulatory effects of these volatiles seem to play the most critical roles in treating patients infected with covid-19. however, there are still lack of clinical trials on dayuan-yin. these need to be done in future. in china, the situation of covid-19 pandemic prevention and control has improved. the national pandemic situation has been controlled. however, with the resumption of factory work, re-opening of shopping malls, and resumption of transportation, the cross-flow of personnel has increased significantly, and the probability of close contact between people has increased tremendously too. in particular, with likelihood of increase in imported cases from abroad, the epidemic prevention and control should not be relaxed. it is essential to improve the ability of the human body to withstand infection. in addition to frequent washing of hands, wearing masks, social distancing and other measures, the "chinese medicine sachet" can be used as an essential means of prevention. this stems from a very important theory of traditional chinese medicine, namely "treating predisease". this idea in traditional chinese medicine originated in the yin and shang dynasties, took shape in zhouyi, and formed in huangdi neijing . chinese doctors in the past dynasties attached great importance to the prevention and treatment of diseases. they emphasized the prevention of diseases first, especially infectious diseases (lian et al., 2020) . wearing chinese medicine sachet is another special treatment of "treating pre-disease" . chinese medicine sachet has been used to prevent disease since ancient times. in this method, aromatic chinese medicine is put into a unique bag and worn on the chest to prevent respiratory diseases. this is known as "xiangpei therapy" (zhang q. et al., 2014) . from the perspective of modern medicine, the medicinal fragrance (i.e., volatile oil components) of chinese medicine sachet stimulates the nasal mucosa, promotes the secretion of immunoglobulins, and kills all kinds of viruses at the same time, thereby playing multiple roles in regulating immune function, and exerting antibacterial and anti-viral effects (lvy and bai, 2017) . interestingly, early intervention with aromatic chinese medicine blocks the course of diseases and relieves symptoms in clinical practice through oral administration, external fumigation, and moxibustion (lun and chen, 1987; chen et al., 2013) . aromatic chinese medicine dispels exterior pathogenic factors, regulates qi, activates blood circulation, breaks blood stasis, and disperses nodules. the application of aromatic chinese medicine embodies the theory of "internal disease and external treatment" of traditional chinese medicine (hu et al., 2010) . since the outbreak of covid-19, fumigation has been used for air disinfection to prevent the spread of the virus. in the clinical treatment period, the application of moxibustion plays the role of anti-inflammatory agent, regulates immune function, and prevents deterioration of the patients (zhang, 2012; liu k. et al., 2020) . some local health committees or chinese medicine administration bureaus are actively involved in promoting aromatic traditional chinese medicine as an anti-epidemic, as well as the use of fumigation or chinese medicine sachet to prevent and control covid-19 . there is no doubt that the pharmacological effects of volatile components of traditional chinese medicine are beneficial in the global fight against covid-19. however, each tcm prescription has multiple goals and links in the treatment of diseases, making it difficult to clearly and thoroughly explain its mechanism in a short period. more research should be carried out on volatile components of traditional chinese medicine to elucidate the associated regulatory mechanism, evaluate possible side effects, and conduct standard clinical trials. the insights provided in this review may help ease the covid-19 pandemic worldwide. q-wh and jw are the corresponding authors on the study. x-rz and t-nl are first authors and responsible for collecting materials and writing the paper. y-yr, y-jz, and h-yl helped in organizing the information and edited the article pictures. all authors contributed to the article and approved the submitted version. this work is financially supported by the xinglin scholar talent promotion plan of chengdu university of traditional chinese medicine (qnxz2018023, xsgg2019008). we are indebted 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(covid-19) in golden syrian hamster model: implications for disease pathogenesis and transmissibility the quality of chinese medicine and its rational application in vitro susceptibility of 10 clinical isolates of sars coronavirus to selected antiviral compounds protective effects of pogostone from pogostemonis herba against ethanol-induced gastric ulcer in rats b-patchoulene from patchouli oil protects against lps-induced acute lung injury via suppressing nf-kb and activating nrf2 pathways discussion on role of aromatic chinese herbs in prevention and treatment of covid-19 based on theory of traditional chinese medicine antiviral activities of atractylon from atractylodis rhizoma insecticidal compounds from the essential oil of chinese medicinal herb atractylodes chinensis anti-infectious efficacy of essential oil from caoguo (fructus tsaoko) anti-inflammatory effects of essential oils of amomum aromaticum fruits in lipopolysaccharide-stimulated raw264.7 cells chemical composition and in vitro inhibitory effects of essential oils from fruit peel of three citrus species and limonene on mycelial growth of sclerotinia sclerotiorum the relationship between copd and lung cancer a comparative study on chemical composition and antioxidant activity of ginger (zingiber officinale) and cumin (cuminum cyminum) efficacy of cineole in patients suffering from acute bronchitis: a placebo-controlled double-blind trial cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health metagenomic analysis of the human distal gut microbiome impact of air pollution on the burden of chronic respiratory diseases in china: time for urgent action the anti-viral studies of notopterygium incisum headspace solid-phase microextraction-gas chromatography-mass spectrometry for the analysis of volatile compounds from a.lancea research about effective ingredients of magnolia officinalis based on their antioxidant activity inhibitory effects of atractylone on mast cell-mediated allergic reactions antioxidant and antibacterial activities of essential oil from atractylodes lancea rhizomes vitamin c and infections evaluation of antibacterial potential and toxicity of plant volatile compounds using new broth microdilution volatilization method and modified mtt assay mechanistic links between copd and lung cancer mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus attenuation of endotoxin-induced oxidative stress and multiple organ injury by 3,4-methylenedioxyphenol in rats application of aromatic herb in external therapy experimental lung injury reduces krüppel-like factor 2 to increase endothelial permeability via regulation of rapgef3-rac1 signaling clinical features of patients infected with 2019 novel coronavirus in wuhan triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with covid-19: an open-label, randomised, phase 2 trial dayuan-yin against the covid-19 pandemic frontiers in pharmacology | www metabolite profiles of essential oils in citrus peels and their taxonomic implications covid-19 dashboard by the inhibition of cytokine production and arachidonic acid metabolism by eucalyptol (1.8-cineole) in human blood monocytes in vitro antiinflammatory effects of euclyptol (1.8-cineole) in bronchial asthma: inhibition of arachidonic acid metabolism in human blood monocytes ex vivo inhibition of h+,k+-atpase by hinesol, a major component of so-jutsu, by interaction with enzyme in the e1 state eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse exhibits anti-inflammatory activity through the suppression of mapks and the nf-kb pathway in mouse peritoneal macrophages atractylone, an active constituent of kmp6, attenuates allergic inflammation on allergic rhinitis in vitro and in vivo models clinical use of dornase alpha is associated with a slower rate of fev1 decline in cystic fibrosis oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis analysis of tetramethylpyrazine in ephedrae herba by gas chromatography-mass spectrometry and highperformance liquid chromatography the use of dexamethasone in the treatment of covid-19 traditional chinese medicine for pulmonary fibrosis therapy: progress and future prospects pogostone suppresses proinflammatory mediator production and protects against endotoxic shock in mice 1, 8-cineol protect against influenza-virus-induced pneumonia in mice two cases of covid-19 treated effectively with modified da yuan drinking review of classical famous prescription "dayuanyin" used for the treatment of covid-19 and analysis of pulmonary classical famous prescriptions discussion on tcm theories of "qingwen pihui san" to prevent new coronavirus pneumonia effect of dexamethasone in hospitalized patients with covid-19 -preliminary report essential oils from taiwan: chemical composition and antibacterial activity against escherichia coli cytokine storms, hyper-inflammatory phenotypes, and acute respiratory distress syndrome. genes dis attach importance to research and development of chinese materia medica based on prevention and control needs of sars-cov-2 infection feasibility analysis of moxibustion whole process intervention in the prevention and treatment of covid-19 70 vardenafil as anti-inflammatory drug in the treatment of cystic fibrosis lung disease prevention and treatment of aromatic chinese medicine study on the mechanism of aromatic traditional chinese medicine compound on prevention and treatment of new coronavirus pneumonia discussion on the effect of air disinfection for aromatic smell of traditional chinese medicine sachet the role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(h1n1)pdm09 retinal findings in patients with covid-19 supercritical co2 extracts and essential oil of ginger (zingiber officinale r.): chemical composition and antibacterial activity the herbal medicine compound falcarindiol from notopterygii rhizoma suppresses dendritic cell maturation reactive oxygen species in inflammation and tissue injury 1,8-cineole potentiates irf3-mediated antiviral response in human stem cells and in an ex vivo model of rhinosinusitis effect of some volatile oils on the affinity of intact and oxidized lowdensity lipoproteins for adrenal cell surface receptors general office of china., health commission of the people's republic of and medicine human infection with strongyloides stercoralis and other related strongyloides species use of antiviral drugs to reduce covid-19 transmission qualitative study on volatile components of different reticulatae pericarpium products based on gc-ms potential drugs for the treatment of the novel coronavirus pneumonia (covid-19) in china antiinflammatory effects of ginger and some of its components in human bronchial epithelial (beas-2b) cells dayuan-yin against the covid-19 pandemic frontiers in pharmacology | www effect of shufeng jiedu capsule on serum pge2, il-1b and tnf-a in rats with acute pharyngitis and clinical efficacy observation chronic obstructive pulmonary disease traditional chinese medicine for covid-19 treatment chemical screening and antibacterial activity of essential oil and volatile fraction of dictyopteris polypodioides mechanism of dayuanyin in the treatment of coronavirus disease 2019 based on network pharmacology and molecular docking the gut microbiota plays a protective role in the host defence against pneumococcal pneumonia the therapeutic effect of 1,8-cineol on pathogenic bacteria species present in chronic rhinosinusitis oxidative stress: a concept in redox biology and medicine effect of patchouli (pogostemon cablin) essential oil on in vitro and in vivo leukocytes behavior in acute inflammatory response covid-19: combining antiviral and anti-inflammatory treatments immunosuppressive activity of pogostone on t cells: blocking proliferation via s phase arrest 1,8-cineol reduces mucus-production in a novel human ex vivo model of late rhinosinusitis modern enlightenment on aromatic drugs in the prevention and treatment of epidemic diseases in ming and qing dynasties protective effects of pogostone against lps-induced acute lung injury in mice via regulation of keap1-nrf2/nf-kb signaling pathways atractylodin attenuates lipopolysaccharide-induced acute lung injury by inhibiting nlrp3 inflammasome and tlr4 pathways comparative study on chemical composition and antibacterial activity of essential oils from patchouli and magnolia officinalis alone and combination low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of covid-19 limonene: aroma of innovation in health and disease guideline for the diagnosis and treatment of copd patients -issued by the german respiratory society and the german atemwegsliga experience in treatment of covid-19 by elimination of pathogens through purgation and diuresis effects of beudesmol, an active constituent from rhizoma atractylodis on small intestine movement in rats study on the molecular mechanism of pogotone against staphylococcus aureus a case of dayuan yin and liujunzi decoction treating with covid-19 study on the effect of anti-respiratory viruses of patchouli oil in vitro effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial the pittsburgh lung screening study (pluss): outcomes within 3 years of a first computed tomography scan patients with asthma benefit from concomitant therapy with cineole: a placebo-controlled, double-blind trial concomitant therapy with cineole (eucalyptole) reduces exacerbations in copd: a placebo-controlled double-blind trial new guaiane sesquiterpenes and furanocoumarins from notopterygium incisum a new coronavirus associated with human respiratory disease in china orthogonal array design for the optimization of supercritical co 2 extraction of volatile oil from amomum tsaoko fruits theoretical origin and practical thinking of the theory of chinese medicine preventive treatment of disease analysis of volatile components of ephedra from different places based on gc-ms cytotoxic, apoptotic and antioxidant activity of the essential oil of amomum tsao-ko pogostone attenuates tnf-a-induced injury in a549 cells via inhibiting nf-kb and activating nrf2 pathways gc-ms analysis of volatile oil from atractylodes chinensis a pathological report of three covid-19 cases by minimal invasive autopsies. zhonghua bing li xue za zhi = chin limonene suppresses lipopolysaccharide-induced production of nitric oxide, prostaglandin e2, and pro-inflammatory cytokines in raw 264.7 macrophages chinese medicine injection shuanghuanglian for treatment of acute upper respiratory tract infection: a systematic review of randomized controlled trials effect of miao medicine fanggan sachet on expression of nkp46 in peripheral blood of mice bioactivity evaluation of ingredients identified from the fruits of amomum tsaoko crevost et lemaire, a chinese spice dayuan-yin against the covid-19 pandemic frontiers in pharmacology | www pseudomonas aeruginosavirulence-inhibiting herbal compound falcarindiol significantly reduced mortality in mice infected with the antibacterial effect of cangzhu and its application in the disinfection of hospital environment 1,8-cineol attenuates lps-induced acute pulmonary inflammation in mice effect of alpha-pinene on nuclear translocation of nf-kappa b in thp-1 cells effect of patchouli oil on acute bacterial upper respiratory infections model mice alphalinolenic acid protects against lipopolysaccharide-induced acute lung injury through anti-inflammatory and anti-oxidative pathways the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 zhang, li, ren, zeng, lv, wang and huang. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-353185-aapg75af authors: tambo, ernest; tang, shenglan; ai, lin; zhou, xiao-nong title: the value of china-africa health development initiatives in strengthening “one health” strategy date: 2019-09-24 journal: global health journal doi: 10.1016/s2414-6447(19)30062-4 sha: doc_id: 353185 cord_uid: aapg75af implementing national to community-based “one health” strategy for human, animal and environmental challenges and migrating-led consequences offer great opportunities, and its value of sustained development and wellbeing is an imperative. “one health” strategy in policy commitment, partnership and financial investment are much needed in advocacy, contextual health human-animal and environmental development. therefore, appropriate and evidence-based handling and management strategies in moving forward universal health coverage and sustainable development goals (sdgs) are essential components to the china-africa health development initiatives. it is necessary to understand how to strengthen robust and sustainable “one health” approach implementation in national and regional public health and disaster risk reduction programs. understanding the foundation of “one health” strategy in china-africa public health cooperation is crucial in fostering health systems preparedness and smart response against emerging and re-emerging threats and epidemics. building the value of china-africa “one health” strategy partnerships, frameworks and capacity development and implementation through leveraging on current and innovative china-africa health initiatives, but also, mobilizing efforts on climatic changes and disasters mitigation and lifestyle adaptations strategies against emerging and current infectious diseases threats are essential to establish epidemic surveillance-response system under the concept of global collaborative coordination and lasting financing mechanisms. further strengthen local infrastructure and workforce capacity, participatory accountability and transparency on “one health” approach will benefit to set up infectious diseases of poverty projects, and effective monitoring and evaluation systems in achieving african union 2063 agenda and sdgs targets both in africa and china. the china-africa partnership is one of the most important geopolitical and economic relationships of the 21st century that has ushered a new era of investment in mutual health development [1] . china has become the world's second-largest economy and offered africa various based on win-win cooperation. traditionally, china is willing to work together with africa to achieve mutual benefits by taking advantage of its status as assistanceprovider in tackling infectious diseases of poverty [2, 3] . furthermore, since africa is home to seven of world's ten fastest growing economies, chinese investments in the health sector in the continent can produce substantial financial gains and generate invaluable public health commodities and other goods that are much needed [4, 5] . the need for an african centre for disease control and prevention (cdc) was recognized at the african union special summit on hiv and aids, tb and malaria held in abuja, nigeria, in july 2013. the africa cdc has launched year with the establishment of an african surveillance and response unit, which will include an emergency operations center and exchanges on china's national disease surveillance and reporting system [4] . currently, africa continent is experiencing a rapid economic growth, with a gross domestic product (gdp) of $ 2.4 trillion usd in 2013 and is estimated to increase to $ 3.3 trillion usd by 2020. health-care spending rose from $ 28.4 billion usd in 2000 to $ 117 billion usd in 2012 across african countries [6] [7] [8] . the fact that sub-saharan africa accounts for 14% of the world's population and 24% of the global burden of infectious diseases caused by poverty, millions of people could be lifted out of poverty through bilateral trade and cooperation between china and africa. increasing and robust new commitments of outbreak and accounts for about 85% of all deaths recorded (a total of 585 suspected cases, 56 confirmed cases and 73 deaths recorded since disease onset in august 2015. in 2014, us cdc estimated the yearly number of lf cases to be between 300,000 to 500,000 resulting in about 5,000 deaths across west africa. lf is endemic in most parts of west africa with sporadic cases occurring in other african countries every year. studies have predicted approximately 80% of liberia and sierra leone, 40% of nigeria, and 30% of benin to be at risk of lf through spatial analysis. in nigeria, approximately 4883 cases and 277 deaths have been reported from 2012 to date. due to a paucity of data, the actual number of cases in other west african countries to date is still unknown. however, seroprevalence studies in the past have shown a prevalence of lassa igg antibodies in 8% to 52% of the general population in sierra leone and in guinea, and as high as 25% to 55% among inhabitants of tropical rain forest and 29% to 40% in hospital staff of gueckedou and lola prefectures in guinea. direct transmission from rodent to humans mainly occurs through inhalation of primary aerosols from infected rodent urine, ingestion of food contaminated with rodent excreta or by direct contact with broken skin. regional and nosocomial outbreaks of lf are commonplace in lf endemic countries and played a major role in recent outbreak. in nigeria, the 2016 lf outbreak has been estimated to have an overall case fatality rate of 48% and 60% in confirmed cases; the impact on healthcare workers due to inadequately equipped, weak preventive measure for hospital associated infections (hai) and well trained staff and facilities with poor laboratory and clinical management practices were the main reasons for a dearth of data. while there is no known vaccine for lf, early supportive care and treatment with ribavirin. prevention efforts include isolation of cases, implementing infection control measures such as barrier nursing supplies, rodent control and practicing adequate food hygiene (storing grain and other foodstuffs in rodent-proof containers) and personal hygiene. although treatment for lf is available, early diagnosis, prevention and prompt management of infection are necessary (table 1) . these growing public health emergencies and challenges prompted a memorandum on building the africa cdc that was signed by the african union with two parties are including chinese and us govemrnents. this cooperation exploring ways of further cooperation and lessons learning from china's national disease surveillance and reporting system model [1, 4] . based on a unified and integrated plan, china and us government are willing to leverage their respective strengths to support the african union in building this system, which will be the first regional disease surveillance system on the african continent from the ebola crisis. it is important to strengthen disease surveillance and monitoring efforts at the regional level in providing technical expertise and response coordination in future health emergencies, address complex health challenges, and build needed capacity responses, responsible for disease surveillance, investigations, analysis, and reporting trends and anomalies. this is a landmark event in african ownership of improving health across the continent. the us cdc looks forward to engaging in this partnership for many years to come to advance public health across africa and global health security [1, 4] results from the first and second china-africa ministerial health development forum held in beijing, china and cape town, south africa in 2013 and 2015, respectively, showed that china-africa health development partnership had entered a new collaborative paradigm with great global health opportunities [1, 5, 8] . chinese and african health ministers have adopted a declaration to increase access to facilities, medication, health workers and training, linking chinese scholars with those in africa into shared responsibility and global solidarity [5] . importantly, china-africa collaboration in health development will use "one health" approach to set the collaborative priorities, such as developing innovative information and communication technology for health, building regional surveillance systems, improving the core capacities of international health regulations and enhancing the using regulation of traditional medicines, etc [1, 6, 9] . the significance of africa-china cooperation health development initiative milestone was the broad consensus mou aimed to support the establishment of africa cdc signed on april 2015, as part of the agreement and of the pledge made at the summit that was held under focac in johannesburg, south africa december 2015 [1] . this laudable mutual commitment was realized through the full operationalisation of the africa cdc in early 2016 supported by the chinese government, including providing infrastructure construction, equipment, information system, expertise, and professional training, etc. as well fostering continuous strengthening african states public health prevention and control system under the chinese supports are also provided through comprehensively capacity building (e.g., staff, postdocs and students) and providing technical assistance and technology transfering to africa cdc sub-regional centres. the benefits of the translation of the immense mutual public health priority aligns "africa union health vision 2063" in the fields of infectious diseases of poverty surveillance and elimination, emergency preparedness timely response to early alert and risk communication capabilities against public health emergencies and disaster crises events. previously, china has already provided two million us dollars cash aid for the africa cdc in terms of capacity building and the on-site chinese experts visit for the regional collaboration with other partners' support [4] . africa cdc has now developed a five year strategic plan to improve surveillance, emergency response, prevention and resilience against infectious diseases threats and outbreaks, man-made and natural disasters, antimicrobial resistance and chronic diseases public health events of regional and international concerns. africa cdc focus on strategic priority areas and innovative programs aiming at improving evidence-based decision making and practice in event-based capacity development for surveillance, disease prediction, and improved functional clinical and public health laboratory networks and actions in minimizing health inequalities, and promoting quality care delivery, public health emergency preparedness and response best practices in achieving regional [1, 4, 10] . africa cdc collaborating sub-regional centres in five countries provides an opportunity for effective collaboration, integration and coordination in harnessing existing public health assets, epidemiological surveillance, strengthening existing networks of quality laboratories for early detection and response. infectious public health preparedness and emegergency response cannot deliver effectively if we do not implement "one health and biosecurity" approach bringing human, animal and environmental health. building evidence-based and adequate capacity building need to support integrated "one health" surveillance, laboratory systems and networks, emergency preparedness and response, and public health research for evidence-based heath programing and ample resource allocation. greater commitment to strengthen local and regional operationalization of integrated disease surveillance and response, public health systems and core capacities have been documented to critically address public health emergencies, biosecurity and disaster risk across the continent. national and regional public health emergencies, biosecurity surveillance, preparedness, rapid response, and recovery policy and strategies are robust and sustainable assets for socioeconomic transformation in line with africa health strategy (2016-2030), the africa union 2063 agenda and in attaining sdgs [1, 4, 10, 11] . firstly, developing innovative information and communication technology for health will provide opportunities to avert thousands of deaths and disability by improving access to good-quality essential drugs, by increasing coverage of vaccines immunization and use of other pharmaceutical and medical commodities nationwide [1, 10, 11] . in addition, leveraging on the unique "one health" approach to transform health care and health policy and to prioritize collaborative programs can be extended from infectious diseases to maternal and child health and health disparity in the poorest populations in africa [1, [10] [11] [12] . secondly, building regional surveillance systems is another way to enhance the local health system. the importance of implementing a local and national "one health" policy and programs holds tremendous prospects, such as co-tackling the epidemiological and environmental challenges, and accelerating in the transition from control to elimination of infectious diseases under china-africa collaboration [5, 15] . furthermore, it has potential to revolutionize national health systems, policies and strategic priorities and the patterns in health financing and resources allocation of african countries that require careful understanding of the local context of diverse stressors and drivers [21, 13] . these will continue to dominate the performance and effectiveness of "one health" in threats and epidemics prevention strategies and policies on healthcare and health outcomes. thus, assessing health impact especially how greenhouse gas and ozone emissions, rising temperature and environmental pollution resulted in climate change impacts to health ecosystem, such as population movement, animal trading and ecology of vectorborne disease and ill health, aging, chronic disease, drug use and domestic violence, inequity and poverty [16] . thirdly, improving the core capacities of international health regulations is the sustained efforts to improve the human welfare. for example, china's response impacting the global health fund (e.g., malaria, hiv/aids, schistosomiasis, ebola, influenza, tb, hepatitis, etc.) has shown robust global health leadership engagement [1, 2, 3] . the leadership reflected in the strategic mobilization and investment of resources fostering more easily accessible, availability and cost effectiveness of prevention and treatment interventions to resources limited countries including african countries [1] . the growing mutual china-africa win-win collaboration spans to technical expertise, technology transfer and capacity development using scientific and advanced methods to tackle the disease, and have enhanced their commitment to respect the dignity of the people such as chinese ebola outbreak emergency response in west africa. fourthly, enhancing the use and management of traditional medicines could improve the community involvement in health care and extend the trade among countries. so far, trade between china and africa is projected to reach $ 385 million usd a year by 2015. increasingly, embracing "one health" strategy to increase universal coverage of healthcare is significant as sharing china's rich expertise and lessons learnt in strengthening health systems and tackling public health burden both in china and africa communities. thus, africa has the opportunity to improve capacity of community health workers to reach remotes rural communities living beyond the margins of traditional health care systems [5, 10] . therefore, china's advancements in research and development, technical and scientific capacity transferring can support african next generation of proactive scientists to develop more sensitive simplified diagnostic tools and reduce the costs of laboratory diagnosis and medical equipment. furthermore, research and development (r&d) is needed in examining the biological mechanisms of stressors or risk factors exposure and health effects, assessing evidence-based mitigation or adaptation interventions and benefits [1, 11, 12] . innovative solutions and breakthroughs in human-animal-environment fields would not only enable africa to meet its own growing needs, but also support integrating health systems, including strengthening the capacities of laboratory diagnostics and medical care, as well as establishing the china-africa platforms that could generate evidence-based low-cost, available and easy-to-use health packages and solutions for the reduction of public health burden. the present paper has analyzed the values of implementing national to regional "one health" strategy for dealing with human, animal and environment related public health threats, diseases outbreaks emergencies and disaster risk challenges, and promote healthy mitigation measures and resilient management approaches in advancing targeted local, national and global health agenda. also, understanding how to develop, package and implement evidence-based and sustainable "one health" approach needs partnerships and investment for strategic priorities and resource mobilization. in addition, it also needs better financing mechanisms and participatory coordination in building capacity and technical assistance, monitoring, performance and effectiveness metrics evaluation for one health indicators. understanding the foundation of "one health" strategy in china-africa public health needs and challenges although significant progress has been made in improving health and safety of vulnerable population in low and middle-income countries (lmics), there is growing unprecedented public health emergencies crises due to natural disasters (such as disease outbreaks, floods, climate change, droughts and mud-/land-sliding) and man-made disasters including armed conflict and resulting forced refugees and displaced populations in lmics and mainly in africa as well as china. these have been resulting in significant direct and indirect health impacts including limited access to food, clean water, medicines, pre-existing mental health and other health services. conflict-affected countries have not achieved a single millennium development goal and have significantly higher maternal and infant mortality rates compared to stable and peaceful countries. natural disasters affect nearly 160 million people each year, with a disproportionate effect on populations and environment. there is also limited quantity of highquality and integrated research to build evidence "one health" approach response. for example, recent emerging zika virus is known to be circulating in latin america, america, africa, asia-pacific and middle east regions due to climate change and rapid urbanization, intense regional and global travel and trade impact on zika virus risk transmission and documented congenital complications on fetal and maternal health. efforts to strengthen regional and global public health emergencies surveillance and preparedness should be maintained in order to better characterize the intensity of aedes and culex vectorial capacity, asymptomatic or syndromic viral circulation and geographical infection spread, epidemiology and laboratory monitoring of zika virus related complications in vulnerable settings. we found that most existing and emerging infectious diseases of poverty and chronic diseases public health programs are based more on top-down and anecdotal experiences rather than accurate research in fostering an integrated humananimal and environment or "one health" community practice in most vulnerable settings in africa and china (table 1) . "one health" approach was officially adopted by international organizations and scholarly bodies in 1984 in response to the growing global human-animal and environment inter-dependence challenges and issues including climate change which needed new approaches. in such, "one health" broader interconnections understanding offers tremendous advantages and manifold benefits in tackling emerging zoonotic diseases and chronic diseases to disaster risk consequences, but also in improving safety health of people and animals, and safeguarding environment against pollutants and pollution. it aims to enhance across disciplinary and interagencies assessment complex including human-animal health systems vis-a-vis environmental and climatic determinants of health, development of contextual health or disease detection and surveillance-response systems, data sharing and communication; partnerships and mutual learning for positive transformation and behavioral changes outcomes. hence, strengthening firmer foundation in building evidence-based integrated healthy approach decision making, health programming and actions plans implementation, training and research practice to community-based programs ownership, shared values and experiences in integrated cost effective and beneficial china-africa "one health" strategy initiatives for mutual wellbeing and economic prosperity. prioritizing "one health" approach in emerging and current infectious diseases public health emergencies and disaster risk reduction is essential in attaining the regional africa union and global health agenda promises and benefits. it requires promoting and implementing evidence-based, effective and sustainable national "one health" strategy advocacy and mitigation strategies in most africa countries and worldwide [5] [6] [7] . strengthening evidence-based, consistent and reliable community, national and regional 'one health' and biosecurity people's medical publishing house co., ltd. partnerships, leadership, road maps commitment, approaches and strategies is a crucial for zoonotic diseases threats and outbreaks public health emergencies and other disasters risks humanitarian crises. integration "one health" principles and frameworks in health and relating multisectorial units or agencies planning and actions plans in generating comprehensive, consistent and real time knowledge and information in guiding evidence-based decision-making policy and participatory commitment and investment [6, 7, 10] . articulated interest and reliance of all stakeholders will cover communities and public articulated actions in preparedness and response to climate changes, infectious and zoonotic threat and epidemics public health burden has provided [10, 17, 18] . the extent and nature of "one health" approach through political engagement and funding is critical in advancing community social mobilization and awareness on "one health" strategy integration in public health systems and primary health care. the needs and value is prerequisite in sustainable public emergencies and disaster risk reduction priorities, preparedness, preventive and control programs and activities. while, providing the enabling health-animal and environment interface biosecurity and protection of legislative and technical assistance support to policy makers, planners and implementers including the local vulnerable communities in transforming contextual positive knowledge, behavioural and attitudes changes [4, 6] . understanding the climate change, global migration and country-specific complexities of emerging and current infectious diseases of poverty is needed in tackle operational programs challenges and bottlenecks, improved sustained control into elimination. for example national immunization programs hesitancy and resistance issues, such as misconceptions and mistrust or fear, weak coverage and non-adherence, persistent resurgence of zoonotic threats and emerging epidemics, continue to place a huge toll of maternal and child health morbidity and mortality on burden and coupled with the rising trend of chronic diseases related inequities and poverty vicious cycle [8, 9, 10, 13, 15] . building china-africa "one health" strategy partnerships, frameworks and capacity development china's global health approach is an unique and distinctive path. this approach based on contextual policies and realities-based on their history, driveninter sectoral and multidisciplinary government related ministries strengthen health systems in different african countries [1, 7, 9, 19, 20] . there is a steadily growth in depth and strength of china's global engagement and collective participation in fostering global health agenda through china-africa health development strategies. event-based preparedness and transparent support management and technical assistance on transferable chinese lessons in infectious diseases elimination and eradication including measles, filariasis, schistosomiasis, malaria, sars and ebola, etc. for example, the china-tanzania pilot project of community-based and integrated malaria control strategy and applications funded by china-uk partnership aimed at assessing the feasibility and transferability of chinese malaria skills in strengthening malaria health education, awareness knowledge and access to vector control interventions (e.g., rdt, llin, acts) to reduce the risk of malaria infection in tanzania [1, 20] . moreover, in the absence of specific ebola infection treatment, the partners or organizations, including african governments, who, the gavi alliance and "ebola ça suffit ring vaccination trial consortium" should accelerate on joint consensus for the adoption and "expanded access" to proven efficacious and safe rvsv-zebov vaccine ring ebola immunization strategy implementation to boost immune response and protect vulnerable populations and global travelers from potential ebola outbreaks [1, 10, 11] . china-africa mutual and comprehensive partnership in health and pharmaceutical has been encouraging and promoting the use of community-based health services; and increasing government investment in public health interventions [7, 19, 21] . china has been very supportive on african countries' efforts in building medical facilities and health service. for example, in 2013, the chinese government constructed 38 medical facilities and provided 50 batches of medical equipments and supplies to african countries. chinese enterprises and nongovernmental organizations have helped african people get quality medical services by means of building and running hospitals, investing in pharmaceutical factories and localizing medicine production in improving health management and well-being, including maternal and child health, and emerging pandemic threat programs, etc. moreover, chinese medical assistance to africa has been sustained and operative win-win mutual support tailored to local settings, which could enhance research priorities in dynamic mapping of vectors and infectious diseases transmission with interaction of human-animal-environment, and provide evidence-based strategies in national or regional diseases control programmes and effective response packages [7, 8, [19] [20] [21] . good progress remains in developing and implementing these policies and strategies coupled with shared lessons learnt and experiences against unprecedented infectious diseases public health emergencies and rising non-communicable diseases (ncds) challenges, such as obesity, cardiac arrest and stroke, hypertension, diabetes, cancer, kidney disorders and mental health, etc. there is a shortage of qualified health professionals at grassroots health facilities. it is also shortage in accessing to basic health control and elimination packages and service delivery including vaccine preventable diseases immunization programs coverage inadequacies in most rural and remote settings across africa compared to china, insufficient public and private sector funding to r&d on safety and effective vaccines or drugs against most emerging coupled with unattended public health diseases threats and epidemics impact preparedness, and strategies mutually gains and economic benefits [12] . remarkable results and outcomes have been documented from chinese medical assistance in 51 of 57 african countries, ranging from health workers, implementers and policy-makers. capacity development and skills acquisition were achieved in over 115 health-related training courses to 2,200 health implementers and health workers since 1963. chinese medical teams friendship and health cooperation, including construction of ophthalmic center where more than 2,000 free cataract surgeries were completed in four african countries and construction of more than six other chinese medical hospitals in the last 2 decades [3, 5, 23] . it is also worth noting the robust and efficient participation and contribution of twenty-seven chinese provinces, autonomous regions and municipalities with accumulated more than 24,000 chinese medical workers in 120 medical centers since 1963, and currently over 1,200 medical workers are working in 51 african countries. continuous support in building medical facilities, africa cdc reference laboratories per excellence and health service capacity has been appraised in embarking on assessing public health emergencies needs, risk factors and determinants in understanding the perception, knowledge, attitude and practice in evidence-based promotion of integrated "one health" approach and biosecurity decision-making approach. this also provide priority and targets, methodologies and programs through effective indicators surveillance and monitoring. for examples, chinese government dispatched over 38 medical facilities and over 50 batches of comprehensive medical equipment for early diagnostics and prompt treatment or response, and supplies across africa since 2013 [3, 9] . chinese partnerships with local firms and communities have helped medical services delivery to remote and rural vulnerable populations through joint activities in building and running hospitals, investing in improving and scaling up localized production in pharmaceutical and biotechnologies industries in africa. in addition, we also recorded the establishment of more than 10 clinics of standard traditional chinese medicine (tcm) integrated to africa traditional medicine (atm) [8, 24] . in achieving universal coverage and healthcare for all, upgrading china-africa mutual health development cooperation and collaboration through independent and joint institutional research project and capacity development in health services delivery and in promoting science and technology capabilities, joint projects and activities have been increasingly developed and implemented. these projects and activities aim at tackling the persistent and growing burden of infectious diseases of poverty, maternal and child morbidity and mortality, and responding timely to the global health concerns and emergency response called on emerging threats and epidemics in the continent. some examples of the landmark achievements include the china-zanzibar and china-tanzania projects on sharing chinese lessons and experiences in infectious diseases to support schistosomiasis and malaria prevention and control in african countries respectively, as well as chinese maternal-child heath safety and children nutrition, dissemination and transfer experiences in ghana [9, 25, 26] . furthermore, china-comoros support to national malaria elimination that led to interruption of transmission and reducing in malaria mortality to zero in the last eight years in comoros [8, 9, 10] . likewise, understanding strategic public health financing and human resources systems capacity is necessary in promoting uptake and efficiency of chinese global health initiatives and innovations in strengthening healthcare delivery system and quality outcomes in lmics including africa, asia-pacific, middle east and latin american countries. strikingly again, during the west africa ebola outbreaks in 2014-2015, the chinese assistance in response valued at $ 120 million usd and more than 1,200 experienced medical professionals were deployed in the frontline affected and neighboring communities to combat and contain the rapid spread of the ebola virus epidemics [8] . in addition to the mobile biosafety laboratory, china also built permanent and well-equipped public biosafety laboratory in seirra leone and dr congo to improve the national capacity to detect, prevent and respond to future threats and epidemics. over 30 batches of public health, clinical medicine and laboratory experts were dispatched in 11 african countries in scaling up public healthcare delivery capacity and training of health workers and communities in risk assessment, communication, and response measures in effective ebola, malaria, schistosomiasis prevention and containment, amongst other shared responsibility and mutual commitment [1, 4, 8, 9, [25] [26] [27] . future expansion of china-africa health development initiatives offers immense opportunities in increasing mutual benefits and growth to both continents' several domains not only limited to health, technology and trade. the scale and sustainability of existing and forthcoming programs and plan of actions will require aligning of national priorities and defining contextual performance and effectiveness indicators, but also mutual respect and trust, accountability and transparency with good governance and proactive stewardship. it is imperative that efforts should also be made in strengthening evidence-based translation to the benefits of vulnerable populations and global community through sharing of lessons learnt and care knowledge experiences and information for all generations in combating infectious diseases and rising burden of noncommunicable diseases. fostering health systems preparedness and smart response against emerging and re-emerging threats and epidemics chinese and african rapid economic growth and the importance of strengthening the local and national public health laboratory systems in both continents have been recognized in tackling the rising healthcare needs, challenges and issues [1, 2, 26] . globalization of travel and trade is ever increasing local, national and global emerging and re-emerging infectious diseases threats and their impacts on human and animal health. resolving the persistent and unprecedented rising of emerging and reemerging epidemics, and new priorities of ebola, zika, hiv/aids, tuberculosis, malaria and neglected tropical diseases (ntds) requires collaborative and mutual cooperation with governments, bilateral and multilateral initiatives, including boosting private-public partnerships, regional and international organizations in achieving the global health security threat and agenda 2030 [2, 3, 5, 6, 7] . for example, china has dispatched more than 1,000 medical experts to resist west africa ebola epidemics through contributions to coordinated international emergency response efforts that helped to contain ebola virus transmission dynamics and spread that retrieved lives of over 12,200 people [1, 5, 6] . similarly, zika virus belongs to the family flaviviridae, genus flavivirus, and includes africa subtype and asia subtype. it is a mosquitoborne virus primarily transmitted by aedes aegypti mosquitoes, sexual transmission; blood transmission and mother-to-fetus transmission have been also reported. zika virus can go through blood-brain barrier and infect central nervous system. symptoms are generally mild and self-limited, but recent evidence suggests a possible association between maternal zika virus infection and adverse fetal outcomes, such as congenital microcephaly, as well as a possible association with guillain-barré syndrome. in absence of safe vaccine or effective antiviral zika medication for prevention and control zika virus infection, early laboratorial diagnosis includes nucleic acid detection, serological test, and isolation of virus and epidemiology and clinical risk assessment and syndromic surveillance is crucial [1, 3, 13] . nevertheless, there remains a need to build a platform with function of effective surveillance, recovery, preparedness, consultation and communication, and to share surveillance based on the principle of sincerity, real time problem-solving and results-giving, and good faith towards collaborative global health solutions [4, [14] [15] [16] . fostering surveillance capacity in laboratory, clinical, veterinary and allied health sciences in the africa continent are critical to overcoming the growing burden of diseases and ensuring a healthy future of its citizens [14, 15] . meeting the urgent growing healthcare needs in africa requires strategic and technical approaches in the development and integration of sound and harmonized regulatory systems for diagnostic products, new drugs and vaccine r&d. while reinforcing the national and international public health laboratories networks are able to improve collaborative and participative early disease detection, early warning and surveillance research in guiding proactive vigilance and smart response activities. effective good governance and leadership coordination of sustainable strategies on emerging outbreak preparedness and response capacity is necessary towards the transformation from traditional to modernized digital laboratory systems in timely and effective quality service delivery. however, the need for laboratories quality improvements and accreditation of methods, tools and programs are critical in upholding the gains preparedness, and emergency response in various infectious diseases programs and strategies should be supported through both national and international initiatives. bilateral and multilateral cooperation with the world bank, un and who, global fund to fight aids, tuberculosis and malaria, worthy philanthropic individuals and organizations efforts can enable country to be ready and capable of early detection, prognosis, prevention, and smart response or management in any detrimental natural or man-made epidemics eventuality, while facing operational challenges and setting new research priorities [5, 7, 21, 22] , for contextual "one health and biosecurity" programs, are also need to be supported with appropriate regulations and guidelines. there is an urgent need to invest in basic and operational research on climatic, ecological and evolutionary changes for understanding and forecasting persistent and future emerging threats dynamics and epidemics. timely evidence-based translation into policy programs and interventions is imperative to defeat the budding threat and burden through coordinate robust actions and better stakeholders leadership in response advocacy and mitigation in line with the paris climate change declaration in december, 2015 [16, 17] . fostering integrated approaches with cuttingedge inter-sectoral and trans-disciplinary partnership is also needed evidence-based nationwide scaling up contextual surveillance and response capacity. moreover, with improvement of targeted strategies to deal with emerging outbreaks and infectious diseases of poverty elimination, understanding human-animal interface with increasing urbanization, globalization of trade and travel are necessary. hence, china-africa "one health" strategy sustainable implementation and alignment with local and national priorities hold great promises. integrating collaborative human-animal-environmental projects and programs have substantial prospects in increasing local and national food production and global food security [28, 29] . this is critical in averting or reducing the persistent malnutrition, under-nutrition and related health complications and diseases (e.g. malnutrition linked kwashiorkor or rickets, obesity, typhoid, diarrhea, dysentery) resulted in children and youth developmental retardation, poor educational performance, poor quality of life and living including high daly and low qaly short life expectancy, worsening the vicious cycle of poverty and premature death documented in africa countries [4, 9, 11, 13, 14] . similar high public health challenges and burden in africa were recorded in china before 1980s, mainly in chinese rural communities circumventing with the implementation of the chinese rural cooperative medical insurance schemes. however, more investment is still needed in achieving food autosufficient and balanced food and nutrition/diet for all in both continents [15] . developing and integrating climate changes resilience , mitigation and adaptation measures in allied health programs is vital in protection, conservation and management of the adverse socio-demographic, ecological, health and economic effects of greenhouse gas emissions and changes consequences, and in securing the future benefits of green and eco-friendly environment. the value of china-africa "one health" strategy implementation financial support from governments and various levels, advocacy and social mobilization to develop supportive community environment for infectious and emerging zoonoses threats and epidemics in population-based public health control and elimination interventions is imperative through implementation of evidence based and cost-effective "one health" surveillance and response strategy, in order to integrate human, animal, and environmental landscape, continue health education promotion, improve awareness and quality public health service delivery performance and effectiveness metrics across africa. enhanced disease surveillance response, community capacity development and strain capacity can provide significant opportunities in health education and promotion, shared responsibility, positive behavior changes and best practices by different health facilities, training health practitioners of diagnosis, treatment and rehabilitation services. identification of local and national health needs and evidence-based effectiveness of "one health" solutions are urgently needed to improve appropriate and sustainable resource development policies and strategic programs across africa. such new partnership initiatives linked to china belt and silk initiative action plan should attract more indigenous and international partners and stakeholders, more qualified multidisciplinary professionals to work, communicate and share experiences and lessons collectively. building local and national trans-disciplinary and trans-sectoral research teams towards improved understanding the genetic and molecular mechanisms of invasive pest and drug resistance, and control of complex disease systems and in strengthening continuous improvements of human, animal, ecosystem health and well-being [22] [23] [24] [25] . robust evidence in comprehensive control for multiple risk factors including health guidance on diet, fitness activity and promoting individual and community self-management model is important to services by general practitioners and mainly in translational research directed toward sustainable development activities and global environmental health. to support integrated veterinary, medical and ecosystem education, and to provide more professional career development opportunities, the governments need to continuously increase its investment in public health intervention programs and financial support to health insurance schemes. increased funding from both central and local governments needs to be directed to the underdeveloped regions and poorer rural areas to support global and national programes on infectious diseases of poverty and sustain control and elimination agenda for emerging epidemics tackle maternal and child health challenges, improve ncds mitigation interventions, and set up better health insurance schemes. in addition, it is equally important to strengthen monitoring of the use for public health interventions. "one health and biosafety" systems research projects development and implementation are also urgently needed in improving training programs and educational empowerment in guiding human-animal health and environment programming and technical assistance. addressing the existing and unprecedented public health emergencies or disaster risks requires optimizing the "one health and biosecurity" targets and interventions which will benefit indicators metrics monitoring in routine public health programs and humanitarian emergencies crises response [27, 28] . there is need to promoting "one health and biosecurity" youths voices in healthy and ecofriendly "one health" community advocacy, engagement and participation. strengthening and sustaining "one health and biosecurity" strategy will improve the cost-effectiveness surveillance and communication interventions through continuous awareness, and knowledge improvements for the overall china-africa and global health security benefits [15, 26, 29, 30] . robust and sustainable leadership commitment and investment is needed in integration of "one health" and global health security. advocacy and mitigation programs is needed in china-africa health development initiatives. to establish public emergencies indicators and metrics for early and timely community engagement and effective risk communication, following actions need to be handled to achieve sdgs and global health agenda: (1) community-based partnerships and programs ownership, (2) assessment for evidence based "one health", (3) identification of the various stressors or risk factors, (4) programmatic and proactive development and implementation of appropriate and sustainable "one health", (5) resource mobilization mechanisms and solutions based on animal-humanenvironment interface challenges and impacts surveillance, preparedness, and timely collective response to public health threats and humanitarian emergency crises. china-africa health development initiatives: benefits and implications for shaping innovative and evidenceinformed national health policies and programs in subsaharan african countries enhancing collaboration between china and african countries for schistosomiasis control china-africa cooperation initiatives in malaria control and elimination establishing the africa centres for disease control and prevention: responding to africa's health threats tackling the challenges to health equity in china china's distinctive engagement in global health implementing a one health approach to emerging infectious disease: reflections on the sociopolitical, ethical and legal dimensions one health: an opportunity for an interprofessional approach to healthcare new orientation for china's health assistance to africa elimination of tropical disease through surveillance and response global implications of china's healthcare reform rift valley fever epidemic in niger near border with mali. the lancet inf diseases deciphering emerging zika and dengue viral epidemics: implications for global maternal-child health burden joint china-us call for employing a transdisciplinary approach to emerging infectious diseases china harvard africa network (chan) team. china, africa, and us academia join hands to advance global health china-africa cooperation initiatives in malaria control and elimination global health security: the wider lessons from the west african ebola virus disease epidemic one health: the hong kong experience with avian influenza genetic diversity and evolutionary dynamics of ebola virus in sierra leone building international genomics collaboration for global health security china's role as a global health donor in africa: what can we learn from studying under reported resource flows? the ebola threat: china's response to the west african epidemic and national development of prevention and control policies and infrastructure china's distinctive engagement in global health china takes an active role in combating an ebola outbreak: on-site observations and reflections from a chinese healthcare provider schistosomiasis control: experiences and lessons from china a strategy to control transmission of schistosoma japonicum in china schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk surveillance-response systems: the key to elimination of tropical diseases rebuilding transformation strategies in post-ebola epidemics in africa evidence on public health interventions in humanitarian crises thanks to nipd, china cdc, shanghai, and universite des montagnes for the enabling environment to complete this review. data are freely available and accessible. the authors have no conflict of interests. not applicable. key: cord-014597-66vd2mdu authors: nan title: abstracts from the 25th european society for animal cell technology meeting: cell technologies for innovative therapies: lausanne, switzerland. 14-17 may 2017 date: 2018-03-15 journal: bmc proc doi: 10.1186/s12919-018-0097-x sha: doc_id: 14597 cord_uid: 66vd2mdu nan . a schematic representation of crispr based synthetic transcription factor technology. b mrna expression levels of protein transport related genes (napg, rab5a and arpc1b). background an increasing number of biologics are entering the development pipelines of pharmaceutical companies [1] . today, the preferred production host for therapeutic proteins is the cho cell line. however one of the major hurdles, especially for the production of non-antibody glycoproteins, is host cell-related proteolytic degradation which can drastically impact developability and timelines of pipeline projects. material and methods spike-in: cho cells were cultivated in a chemically defined culture medium at 36.5°c/10% co 2 in shake-flasks. when the cells reached their maximum viable density, they were removed by centrifugation and the conditioned medium was collected. a model mab was spiked into the conditioned medium and incubated at 37°c ± protease inhibitors. the amount of proteolytic degradation was analysed by western blot and lc-ms. transcriptomics: total rna was extracted after 3 days of cell cultivation. rna sequencing libraries were constructed and processed on the hiseq 2000 platform from illumina. generation of matriptase knockout: cho-k1 cells were transfected with mrna encoding "transcription activator-like effector nucleases" or "zinc finger nucleases" targeting matriptase exon 2. the transfected cells were subsequently sorted into single cells and analysed for frameshift mutations in both alleles via sanger sequencing. cell cultivation: fed batch cultivation was performed in 15-ml miniaturized bioreactors (ambr15). approximately 700 proteases are known in rodents. to reduce the number of candidate proteases we showed first that a model mab (prone to proteolytic degradation) incubated in conditioned medium of cho-k1 cells resulted in clipping of the mab, demonstrating the involvement of secreted/shedded proteases (fig. 1a) . broad spectrum inhibitors of the different protease classes revealed that only serine protease inhibitors prevented clipping. serine protease inhibitors of higher specificity highlighted the group of "s1a trypsin-like proteases" (fig. 1a) . comparison of the proteolytic degradation profile of several therapeutic proteins between cho-k1 with another cho cell line (cho-a) revealed less degradation in cho-a. therefore expression of the involved protease(s) is likely lower in cho-a. gene expression profile analysis of both cell lines showed five secreted/shedded "s1a trypsin-like serine proteases" more than 1.5 fold lower expressed in cho-cho-a versus cho-k1 (fig. 1b) . surprisingly, sirna knockdown experiments of these five candidates identified "matriptase" as the major protease involved in degradation of recombinant proteins expressed in cho-k1 cells ( fig. 1c upper panel) . next, we generated a cho-k1 matriptase knockout (ko) cell line. no proteolytic degradation product was detected when the model mab was spiked into conditioned medium of the ko cell line (fig. 1c lower panel) . also, stable expression of the model mab in the ko cell line resulted in no/significantly less clipping (fig. 1e) . the protein titer and the cell growth behaviour of the matriptase ko cells were similar to the corresponding wildtype (wt) cells (fig. 1d) as shown by comparative cultivation in ambr system. conclusions one major challenge for the production of recombinant proteins is cho host cell mediated proteolytic degradation which can negatively impact or even result in termination of projects [2; 3] . using a variety of techniques such as applying protease inhibitors, transcriptomics and sirna mediated knock-down we were able to identify "matriptase" as the major protease involved in degradation of recombinant proteins expressed in cho-k1 cells. subsequently we generated a matriptase deficient cho cell line. protein candidates of diverse formats, severely degraded in wt cho-k1 cell line, were not or significantly less cleaved in the matriptase ko cell line. furthermore cell growth, viability and productivity levels were comparable between the wt and the matriptase ko cell line. in summary, we have generated a superior platform-compatible cho production host cell line with the same favourable productivity properties as the parental host cell line [4; 6] , allowing expression of complex glycoproteins prone to clipping. background cho cell lines are common hosts for the production of biopharmaceutical proteins. so far, considerable progress has been made increasing productivity of cell culture to meet the rapidly growing demand for antibody biopharmaceuticals through increased cell densities and longer culture times. the downside is the increase of the process related impurities, bringing new challenges for process and harvest development. among the process related impurities such as host cell proteins (hcps) or dna the potential impact of lipids production and release during cell culture is still poorly understood due to the complex nature and diversity of this class of molecules. thanks to recent advances in analytical tools especially mass spectrometry, the advent of lipidomics offers now the feasibility to study several thousands of lipid species thus unraveling the possibility to understand and potentially control the interactions between high performance bioreactor processes, harvest conditions and purification. in order to analyze and quantify lipids, we developed a three steps method. in a first step, lipids were extracted with methyl tert-butyl ether (mtbe) according to matyash method [1] . lipids were then separated by liquid chromatography using either hilic of reverse phase column prior to detection and quantification by mass spectrometry. all lipid classes were detected by esi-ms/ms excepted cholesterol (apci-ms/ms). finally we applied this method to analyze the lipid content of different cell lines each expressing a different recombinant protein, during a 14 days fed batch process. lipid from cho cells were successfully extracted with a yield between 80% and 95% depending on the different lipid classes. stable isotope labeled lipids were used as internal standard in order to have comparable results between batches. the obtained results (fig. 1) show that for a given cell line, lipid distribution is changing over the process. moreover, this distribution may vary significantly depending on the cell line: cl-1 and in a lower extend, cl-3, show an accumulation of triglycerides from day 6 to the end of the process, while cl-2 doesn't seems to follow this trend. conclusion interestingly, in some cell lines/experimental conditions, we highlighted an overproduction of triglycerides and cholesterol leading to the accumulation of lipid droplets known as energy storage sink. at the metabolic level, these findings suggest a relative overflow of the carbon metabolism. from a process development perspective these findings can be considered on the one hand as a resource waste since the stored energy is not used for protein/biomass biosynthesis and on the second hand as the root cause of additional process challenges especially during the harvest and the first capture steps given the hydrophobic nature of these molecules. implementation of lipidomics analysis enables us to highlight a new type of process variability and to anticipate potential problems for the downstream steps. the application of this methodology on our platform has helped us to design tailor made solutions (pretreatment selection, filter selection,…) at the clarification step which are now implemented in our harvest development platform approach. . matriptase knock-out in cho cells prevents clipping of recombinant proteins. a serine protease inhibitors protect model mab from proteolytic degradation in cho-k1 cell derived conditioned medium. the model mab was incubated in conditioned medium for 0h or 48h at 37°c, subsequently samples were analyzed by western blot. broad spectrum serine protease inhibitors (aprotinin, leupetin) were added during incubation. aprotinin and leupetin are inhibiting proteolytic degradation. the intact mab (upper band) and the clipped mab (lower band) are indicated by arrows. b gene expression profiling of cho-k1 versus cho-a by ngs. shown is the gene expression profile of "secreted/shedded members of the s1a trypsin-like serine protease family" for cho-k1 and cho-a cell lines using next generation sequencing. the gene expression analysis highlights that five proteases were more than 1.5 fold higher expressed in cho-k1 cells (labelled with a red asterix). the y-axis shows the transcript abundance as rpkm (reads per kilobase of exon model per million mapped reads). c sirna knock-down identifies matriptase as major clipping protease and cho matriptase ko clone shows no detectable clipping activity. upper figure: sirnas directed against the five protease genes and scrambled (scr.) sirna were transfected and conditioned medium was collected three days after transfection. the model mab was incubated in fresh medium as control (first lane) and conditioned medium from the sirna transfected cells. samples were analyzed by western blot. only sirna targeting matriptase (st14) showed reduced proteolytic degradation. the intact mab (upper band) and the clipped mab (lower band) are indicated by arrows. lower figure: the model mab was incubated for 48h in conditioned medium collected from wt cho-k1 as well as the matriptase knockout clone. samples were analyzed by western blot. the intact mab (upper band) and the clipped mab (lower band) are indicated by arrows. no proteolytic degradation could be detected in the samples originating from the matriptase ko clone. d cell growth, viability and productivity in ambr (fed batch with temperature shift). cell growth, viability and volumetric productivity profiles of wt cho-k1 (red circles, n=2) and matriptase ko clone (blue squares, n=1) cultivated in 15-ml ambr. no significant differences were seen between wt and matriptase ko clone regarding cell growth and viability. comparable or slightly higher productivity was detected for the matriptase ko clone compared to the wt. e significant reduced proteolytic clipping applying matriptase ko clone. the model mab was stable expressed in cho-k1 (wt) as well as the cho-k1 matriptase ko clone. samples were analyzed by western blot. the intact mab (upper band) and the clipped mab (lower band) are indicated by arrows. significant reduced proteolytic degradation could be detected in the samples originating from the matriptase ko clone (3 samples each is shown for wt and ko cells) the glycosylation of therapeutic proteins is a critical quality attribute (cqa) and needs to be analyzed during cell line and bioprocess development. the current methods for analyzing glycosylation are mainly based on the enzymatic release of glycans. they are tedious and offer only limited throughput, which makes them unsuitable for cell line development work. in this study we evaluated a novel paia assay for measuring intact glycoproteins with capture beads and fluorescence labeled plant lectins to analyze glycans in a high throughput 384-well plate format. material and methods analytes: erbitux © , mabthera © , arzerra © and avastin © . two glycoengineered variants of one igg were kindly provided by merck (vevey, switzerland). all analytes were spiked into cho-k1 cell culture supernatant or buffer, diluted 1:1 with a denaturation solution and incubated at 65 or 70°c for 20 minutes to expose the fc glycans. erbitux samples were analyzed under denaturing conditions to detect fab-and fc-glycosylation and in native conditions for fab glycosylation only. 10μl of pretreated sample was added to each well of the special 384-well paiaplate, containing labeled lectin and capture beads. the microplate was incubated for 45 minutes at 1800 rpm on an orbital shaker at room temperature and spun down at 500 xg. the read-out was done on a fluorescence microscope (synentec, elmshorn, germany) in less than five minutes. results figure 1a : lectin binding profiles of different iggs. the analysis of different igg results in lectin binding profiles which show the different degrees in glycosylation. high abundance of sugars leads to high binding rates of the lectin for the respective sugar. avastin has a very low degree of galactosylation and high mannose species compared to mabthera and arzerra (fig. 1a) . only arzerra is carrying glycans with 2-6 linked sialic acids. these findings are in line with results from literature [1] . figure 1b : distinction between fc and fab glycosylation in erbitux. without denaturation only the fab glycans are detectable in erbitux. denaturation leads to additional exposure of the fc glycans and thus higher lectin binding rates compared to native erbitux. gna and npl only bind to denatured erbitux indicating that the high mannose glycans are only present on the fc part. the equal sna binding rates for both conditions confirm that the 2-6 linked sialic acids are almost exclusively found on the fab part. this is in agreement with published data [2] . figure 1c : lectin binding rates correlate with the levels of galactosylation and fucosylation. increasing degrees of glycosylation in the mixtures of the glycan variants from merck lead to higher lectin binding rates for all galactose and fucose markers proving that quantitative analysis can be performed with these assays. the cona lectin which binds to the common core mannose glycan motive remains at the same level, suggesting that the fc glycans were similarly exposed in all samples. the results demonstrate that paia assays are capable of quickly detecting differences in glycan patterns of different antibodies. in addition it was shown that glycan variants of the same igg can be analyzed quantitatively. and finally we could confirm the differences in fab and fc glycosylation in erbitux. we believe that bead-based assays with lectins have a great potential for monitoring product quality early in the development process. background gene-and cell therapy-based medicines are experiencing resurgence due to the introduction of "next generation" transfer viral vectors, which have demonstrated improved safety and efficacy. adeno associated viruses (aav) and lentiviruses are very commonly used in therapeutics and often produced by transient gene expression, using pei-mediated transient transfection in hek-293 or hek-293t cells [1] . the critical raw materials needed for cgmp vector production must be sourced from approved suppliers and should have gone through a rigorous testing program to reduce the risk of introducing adventitious agents into the production process. correspondingly, the pei transfection reagent must also be sourced from a qualified supplier, and have gone through rigorous testing to ensure reliable transfection efficiencies, and hence reproducible virus production yields. here, we present peipro® and peipro®-hq, the unique pei-based transfection reagents suitable for use in process development and in cgmp biomanufacturing, respectively. unlike commercially available peis, peipro® benefits from extensive research and development in polymer chemistry and formulation for mammalian cell transfection. we further demonstrate that peipro® and peipro®-hq are the reagents of choice for virus production runs in most cell culture systems, hence facilitating the transition from initial optimization during process development up to large-scale therapeutic viral vector production in adherent or suspension cells. manufacturing process of peipro® and peipro®-hq reagents. peipro® and peipro®-hq are fully synthetic reagents, free of any animal-origin components. in comparison to peipro®, a more extensive number of quality controls are performed on peipro®-hq to enable its use as a qualified raw material in gmp processes for the manufacturing of clinical batches of therapeutic products. lentivirus and aav production. irrespective of the cell culture vessel type, transfection using peipro® was performed following our recommandations. as an example, hek-293t (lentivirus) and hek-293 (aav) cells were thawed directly into each medium and passaged every 3 to 4 days before going into a 2 liter benchtop bioreactor. cells were resuspended and cultured for 3 days before transfection with peipro®. hek-293t cells were transfected with a third-generation system (four plasmids) for lentivirus production. hek-293 cells were co-transfected with three plasmids for aav production. lentiviral and aav titers were measured 48 and 72 hours post-transfection (data kindly provided by généthon). peipro® is the reagent of choice for virus production runs in most adherent and suspension cell culture systems from process development up to large scale clinical-grade virus production. irrespective of the cell culture-based system and production scale, peipro® and peipro®-hq have led to efficient viral vector yields in standard laboratory cell systems, such as in flasks, cell factories, and roller bottles, as well as in multilayers flasks or fixed-bed culture systems that take into account time and space concerns for the scaling-up process (table 1) . for example, high viral vector yields superior to 10 7 ig/ml and 10 11 -10 12 vg/ml were obtained respectively for lentiviruses and aavs in suspension hek-293t and hek-293 cells cultured in one of the commercially available synthetic cell culture medium balancd® hek293 (irvine scientific®). conclusion peipro® and its higher quality grade peipro®-hq are the unique pei suitable for efficient and reproducible production of therapeutic viral vectors. efficient viral vector production yields can be achieved in most cell culture systems, irrespective of the production scale. with appropriate and advanced quality controls, the highest quality grade peipro®-hq is commercially available to accompany academics and biopharmaceutical companies in terms of qualified raw material for their gmp-grade viral vector production needs. b distinction between fc and fab glycosylation in erbitux. erbitux was diluted to a concentration of 200 μg/ml in tris buffer and measured in native and denatured conditions to distinguish fab glycosylation (native erbitux) from fab and fc glycosylation (denatured erbitux). it could be confirmed that sialic acids are almost exclusively present on the fab part of erbitux and that the high mannose glycans are only found in the fc part. c lectin binding rates correlate with the levels of galactosylation and fucosylation. two glycan variants samples of the same igg from merck were mixed in different ratios to yield glycosylation rates of 9 to 55% in terminal β-galactose and 8 to 100% in core-fucose, based on data from 2-ab uplc analysis. the mixtures all contained 0.5 μg igg per well. the measured lectin binding rates for all galactose and fucose markers correlate very well with the respective degree of glycosylation in the mixtures. all measurements were performed in triplicates (irvine scientific®) . hek-293t (lentivirus) and hek-293 (aav) cells were thawed directly into each medium and passaged every 3 to 4 days before going into a 2 liter benchtop bioreactor. cells were seeded and cultured for 3 days before being transfected by peipro® (polyplus). for transfection, four plasmids were used for lentivirus and three plasmids were used for aav. lentiviral and aav titer were measured 48 and 72 hours post transfection (data kindly provided by généthon) table 1 (abstract p-004). peipro®, the reagent of choice for virus production runs in most cell culture systems in both adherent and suspension cells. irrespective of the cell culture-based system and production scale, peipro® and peipro®-hq have led to efficient viral vector yields superior to 10 7 ig/ml and 10 9 vg/ml, respectively for lentiviruses and aavs background continuous perfusion process is making a comeback as a competing upstream manufacturing technology for the production of biopharmaceuticals compared to the standard fed batch processes. this is primarily because of cost advantages such as reduced capital cost and increased product yield. the change in status of perfusion process from older perfusion to the new-age perfusion is due to availability of better cell retention devices leading to more efficient processes, improved cell lines, cell culture medium capable of supporting high cell densities and better bioreactor control strategies. in this work, we present the advantages, limitations and challenges of fed batch and perfusion type of processes through case studies. table 1 results the perfusion run yielded 5-fold higher titer compared to fed batch run (fig. 1a) . considering the number of runs that could be executed in a manufacturing facility within the same calendar days, about 1fold increase in product output can be achieved with the perfusion process (fig. 1a) . this difference is attributed to higher ivcc, higher pcd and longevity of cells because of decreased level of toxic metabolite concentrations such as lactate and ammonia. case 2: understanding product retention in perfusion process the new-age perfusion processes utilize hollow fiber filters. this has been observed to cause retention of product within the bioreactor especially towards the end of the production run. two types of experiments were conducted to study the factors contributing to product retention: -spiking studies: -role of product titer: product was spiked into chemically defined media -role of different cell viability: different broths with varying viability spiked with same product titer -evaluation of different hollow fiber membrane (m1, m2 and m3) on product retention. from spiking studies, it was evident that cell debris and poor quality cell broth (lower viability) were the major factors contributing to product retention (fig. 1c) . from the different membranes experiments, it was identified that at pilot scale, m1 showed much higher retention from the first perfusion cycle itself and it increased to more than 75% towards the end of the batch. however, with m2 membrane, product retention started only late (after 50% of batch duration) and it remained low (~20-40%). on the contrary, this difference was not observed at 1l scale due to the usage of membranes with larger filter area (2-3 folds higher compared to pilot scale). when the filter area per unit volume of perfusate was decreased by half (m2_batch 4) for the pilot scale, even m2 showed retention profile similar to m1 (fig. 1d ). we presented data to show that perfusion process has 5-fold increase in product yield on a per-batch basis and a 3-fold increase when facility throughput is considered. product retention is a technical challenge that requires optimization (perfusion rates and filter membrane types). we believe it is imperative that labs that develop processes for biologics can now consider both perfusion and fedbatch based processes as both these technologies can now closely compete with each other. the choice of the process format going forward should now solely be dependent on the requirement for the biologic rather than the earlier perception that fed-batch is the preferred choice because of its simplicity. background chinese hamster ovary (cho) cell culture has been widely used for production of monoclonal antibodies in the pharmaceutical industry. previous studies have shown that the cell specific productivity in cho cells can be increased by glucose limitation [1] . introducing a productivity enhancing effect it is possible that this also affects the quality of the product such as glycosylation or other posttranslational modifications. in this work, we are focusing on the impact of glucose limitation and increased productivity on the product quality of a monoclonal antibody produced in a fed-batch cultivation of cho cells. materials and methods cho cells were cultivated both under limiting and non-limiting nutrient conditions in fed-batch. for fed-batch cultivation the reduced range for glucose concentration was chosen between 0.2 and 0.5 g/ l. reference cultivation was performed between 1.5 and 3.0 g/l. both cultures were fed with similar volumes of a complex nutrient supplement. all cultivations were performed in chemically-defined, animalcomponent free cho growth media (xell ag). viable cell density and viability were determined using the automated cell counting system cedex (roche diagnostics), glucose and lactate concentrations were detected via ysi (ysi life sciences). amino acid were quantified using hplc-fld, vitamins were quantified using reversed phase chromatography coupled to a triple quadrupol mass spectrometer (varian 320, selected reaction monitoring). amounts of igg1 were quantified via protein a hplc, mab purified from another cho cell clone was used as a standard. the analysis of product quality was performed by intact mass analysis using reversed phase chromatography coupled to a microotof-q ii mass spectrometer (bruker daltonik). the cho cell culture cultivated under low nutrient conditions reached a 54% higher viable cell density than the reference culture (fig. 1a) . the product titer was even increased by 109% (fig. 1b) . the spent media analysis shows that some amino acids and vitamins were present at presumably limiting concentrations after day 5/6, mostly in the low nutrient level culture (down to 40 to 190 μm for tyr, gln, arg, and asn, below 1 μm for pyridoxine, data not shown). the product quality showed significant changes for the changed feeding strategy ( fig. 1c and d) . as expected, the glycation level decreased from 3% to 1% compared to the reference culture. the truncation level of c-terminal lysine at the heavy chain of the mab increased from 79% to 88%. the glycosylation was also significantly influenced by the low nutrient level (fig. 1e) : the nonfucosylated variants increased from 3% to 6% (fig. 1f) , the degree of galactosylation increased from 31% to 39% (fig. 1g) . cultivation under low nutrient level led to 54% higher viable cell density and a product titer increased by 109% when compared to reference culture grown under non-limiting nutrient conditions. the analysis of product quality reveals 75% less glycation of light chain for cho cells grown under low nutrient conditions (0.7% vs 2.7% in reference culture). the truncation of c-terminal lysine decreased by 10% (from 88% to 79%), the degree of galactosylation increased by 23% (from 31% to 39%, also observed by takuma et al. [2] ) and non-fucosylated glycans increased by 105% (from 2.8% to 5.8%) under low nutrient conditions. the product quality analysis by intact mass proved to be highly robust (average cv for four replicates = 2%). in summary, cultivation with alternative feed led to higher igg product titer and better product quality (glycation unwanted, higher amount of non-fucosylated glycans leads to higher antibody-dependent cellmediated cytotoxicity (adcc), higher amount of galactosylation to higher complement-dependent cytotoxicity (cdc) and adcc [3, 4] ). background we developed an automated, multiwell plate (mwp) based screening system for suspension cell cultures (fig. 1a) which is now routinely used in cell culture process development. it is characterized by a fully automated workflow with integrated analytical instrumentation. it uses shaken 6-24 well plates as bioreactors which can be run in batch and fed-batch mode with a capacity of up to 768 reactors in parallel [1] [2] [3] . a wide ranging analytical portfolio to monitor cell culture processes and also a cooperation with internal high throughput (ht) analytic groups to characterize product quality are available. in addition the use and the benefits of spectroscopic methods for cell culture automation were shown in the past [4, 5] . automated cell culture systems enable broader screening within a shorter time frame for many applications in upstream process development. the higher degree of parallelization and automation helps to screen for most promising parameters in a shorter time. the use of broad doe screening design allows in addition the identification of parameters that support high titers while keeping high product quality (multiple factors at the same time). the illustration (fig. 1b) shows an example how this combination can speed up process development steps. main applications of the cell culture automation are for example the identification of product quality levers and media or feed optimization. the application of the cell culture automation is shown for two examples. the goal in the first application was to identify levers to reduce trisulfides. by a screening of 39 conditions in parallel (in 4-fold replication, 158 wells in sum) the reduction of trisulfides by 97.5 % (normalized to start level) was possible. in addition the levers for trisulfide reduction were identified. the best and start conditions were verified in bioreactor scale (fig. 1c) . the goal in the second application was to increase product concentration without an impact on product quality. by a screening of 54 conditions in parallel (in 4-fold replication, 216 wells in sum) the increase of titer from 1.5 g/l to 3.7 g/l (> factor 2) was possible by media platform change and media optimization. an impact on product quality could not been shown. the best conditions were also verified in bioreactor scale (fig. 1d) . the benefits of using cell culture automation in late stage process development were shown based on two examples of current applications. for this purpose the experimental results of the development work of two late state projects using the in-house developed automated cell culture system were shown. the first example shows the capability of the automated cell culture system by reducing trisulfides significantly in just one experiment. for the other project the final product concentration could be increased by factor 2.5 by a media screening and changing to the in-house media platform. these two examples show the potential of cell culture automation as a routine tool in process development. the cell line development process has become faster and is simultaneously generating more clone-and product-related analytical data. in order to select the best producer cell line, extremely heterogeneous data types need to be systematically compared. the timely availability of all data needed to decide which cell line to pursue has become a bottleneck in the cell line development workflow. to ensure sound decision making, new integrated workflow support and data analysis methods are needed. we have developed a new end-to-end platform for bioprocess development, which includes a cell line development workflow system supporting seeding, selection, passaging, analyzing, cryo-conservation, and processing in (micro-) bioreactors. this platform, genedata bioprocess™, enables partially or fully automated cell line selection and assessment processes, and it increases process efficiency and quality. the system tracks the full history of all clones -from initial transfection all the way to their evaluation in bioreactor runs -and combines this information with analytics data on molecules, clones, and product quality. it can directly integrate with all instruments, such as pipetting robots, bioreactors, and bioanalyzers. the system is designed for a wide range of . a schematic illustration of the automated cell culture system. only the core system is shown with a robotic plate handler as key device connecting cultivation, processing and analytical parts. b illustration of an example how cell culture automation can speed up process development steps. c application in the identification of product quality levers. d application in titer optimization biologic molecules, including antibodies (iggs, novel formats) and other therapeutic proteins (e.g., fusion proteins). highlighted use cases describe the identification of top producer cell lines, decision making support, bioreactor data management, and full clone history report documentation (fig. 1 ). genedata bioprocess, which was developed in collaboration with top pharmaceutical companies, can flexibly support various (non-linear) workflows and structure the collected information in a way that fosters collaboration across an organization. while increasing throughput is crucial to ensure the timely availability of optimal producer cell lines, high-throughput is only possible when automated processes in the laboratory and the resulting data collection and aggregation can be streamlined. genedata bioprocess helps to establish more productive processes by offering support and integration for automation stations and measurement devices. thanks to the comprehensive workflow support and the possibility to integrate results from cell line stability experiments, product quality assessment, and bioreactor suitability tests, genedata bioprocess provides a unique way to evaluate cell lines. comprehensive analysis of all data collected in the process helps to ensure the highest possible quality and minimize the time and resources needed for data analysis and management. integration of bioreactor data analysis and visualization with other parameters measured in cell line development, streamlines clone evaluation in micro-bioreactors and supports highthroughput operations. genedata bioprocess comprehensively tracks the full clone history from the origin of the host cell line to the generation of the validated monoclonal producer cell line. for promising clones, the clone history report can be generated with one click. besides supporting cell line development, genedata bioprocess is a comprehensive platform capable of tracking the complete bioprocess development process. in 2012, 14.1 million people suffered from cancer [1] making it to a major concern of our society. since common cancer treatment is limited and not effective for late stage carcinoma, alternative methods are needed to reduce the high mortality rate of cancer patients. one alternative approach is the application of the oncolytic measles virus (omv), because omv has a natural affinity against cancer cells. the major drawbacks of omv is to produce the extremely high amount of at least 10 11 tcid 50 (50 % tissue culture infective dose) per dose [2] which is needed. to solve this problem, a high titer process must be established including an efficient downstream processing (dsp). we developed an appropriate upstream processing and are able to produce 10 10 -10 11 tcid 50 ml -1 in a bioreactor with 0.5 l working volume [3] . now, we focus on the dsp part. the following study tested the application of charged depth filters for the omv clarification. in contrast to common dsp schemes, a depletion of virus particles or a loss of infectivity is not desired. the aim is a reduction of protein content and dna with minimal loss of infective omv. further, we investigated the influence of the cell culture medium on the depth filtration process. to explore the influence of the surrounding cell culture medium on the depth filtration performance, omv was either produced in serum-free medium (vp-sfm) or serum-containing medium (dmem + 10% fcs). the production was done in a str with a working volume of 0.5 l as described in [3] . cells and carriers were separated with an opticap xl 1-module (polygard-cr; 5 μm; merck). for the depth filtration millistak+ ce50 filters (merck) were used. the filter material was autoclaved and rinsed with 25 ml of 20 mm tris-hcl (ph=7.4). the virus suspension was filtered with a load of 50 l m -2 using a peristaltic pump (ism931c; ismatec) applying a flux of 150 l m -2 h -1 (fig. 1 ). samples were collected at the beginning and end of a filtration run. the omv titer (tcid 50 ml -1 ) of the samples was determined according to kärber and reed [4, 5] . protein content was measured with the pierce bca protein assay kit (thermofisher scientific) according to the manufacturer's instructions. dna was measured by a microtiter assay using quant-it picogreen dsdna reagent (thermofisher scientific) according to the manufacturer's instructions. we found that positively charged depth filters were suitable to clarify omv suspensions. the cell culture medium, in which the omv was produced, influenced the outcome of the depth filtration. a log reduction value (lrv) of 0.87 was determined for omv present in serum-containing medium (scm), whereas the titer of omv in serumfree medium (sfm) was reduced 1.63 log levels. this indicates that without serum in the surrounding liquid, omv will adsorb to the filter material. however, we must evaluate if the missing serum or other components present in sfm are responsible for this effect. total protein was not relevantly reduced by the clarification using charged depth filters. for omv present in scm, the residual protein content was slightly less compared to omv present in sfm (table 1 ). in contrast, host cell dna (hcdna) was bound to the filter material. we achieved a 33% reduction of hcdna for an omv suspension in sfm. after clarifying an omv suspension in sfm, the remaining hcdna content was even lower being only 42 %. conclusions charged depth filters are suitable for the first clarification step of omv downstream processing. residual protein could pass the depth scheme of the complete cell line development workflow support in genedata bioprocess. showcasing integration of data from diverse measurement instruments, data visualization for decision making support as well as, tracking of full clone history filter almost unhindered, whereas the hcdna content was already reduced to 42% at maximum. however, the omv titer was also reduced by the depth filtration. this undesired effect was stronger for the omv present in sfm. because the agencies require avoiding serum in clinical-grade production processes, this is disadvantageous. nonetheless, because sfm will be soon standard for omv production, further experiments have to be done preventing the omv reduction during clarification. one option can be to reduce the adsorption strength of the virus to the filter material by the addition of salt. moreover, it is important to establish a standardized protocol for the upstream processing. we determined batch-to-batch variations within the clarification indicating a strong impact of upstream processing (usp) on the outcome of the dsp. therefore, further studies must investigate the influence of usp parameter e.g. time of harvest and ph of the harvest solution on the omv. fed-batch culture is commonly employed to maximize cell and product concentrations in upstream mammalian cell culture processes. typical standard platform processes rely on fixed-volume bolus feeding of concentrated feed supplements at regular intervals. however, such static approaches might result in over-or underfeeding. to mimic more closely the dynamics of a fed-batch culture, we developed a dynamic feeding strategy responsive to the actual nutrient needs of a mab-producing recombinant cho cell line. results and discussion improvements made at different steps during fed-batch development are shown in fig. 1 . at step 1, all eight cell boost supplements were added to cdm4ns0 according to a doe approach, and batch cultures were performed. this evaluation allowed us to select only those cell boost supplements that were beneficial to the overall culture performance. non-performing cell boost supplements were removed and not considered further. at step 2, the selected cell boost supplements were added daily to the cultures at different ratios according to a doe approach, and fedbatch cultures were conducted. as expected, daily feed additions to replenish consumed nutrients substantially improved mab and peak cell concentrations as well as viable cumulative cell days (vccd) compared to batch cultivation. further, the results enabled us to fine-tune the feed ratio of selected cell boost supplements. at step 3, we further optimized the best performing feed ratio by investigation of static and dynamic feed protocols. most fed-batch protocols rely on constant feed additions on distinct days. however, these approaches often lead to substantial over-or underfeeding during bioprocessing. to improve such "static" protocols, we investigated three different "dynamic" approaches as shown in table 1 by applying the selected cell boost supplements with the optimized feed ratio. this investigation allowed us to further improve the bioprocess performance. the best performing approaches, constant and retrospective feed, were further investigated in fully automated bioreactors under controlled conditions. in general, constant cultivation parameters in the bioreactor slightly enhanced mab titers compared to shake flask cultivation. the retrospective feed strategy yielded 10% higher titers than the constant strategy. overall, the established methodology for fed-batch development allowed us to obtain 2.5× higher mab titers (batch mean: 1.9 g/l vs. fed-batch 4.9 g/l) in a short time and three simple steps. in addition, the product quality was investigated. compared to the legacy fedbatch process, fed-batches that were conducted with the newly selected basal and feed media altered the distribution of charge and glycan variants. the amount of aggregated product was not altered. the established methodology for fed-batch development is a rapid protocol to select well-performing feed supplements and optimize their ratio to the culture requirements. in three steps, mab titers were boosted 2.5x from 1.9 g/l to 4.9 g/l. product glycosylation and charge variants could be influenced by the newly selected basal and feed media compared to a legacy fed-batch process. the amount of aggregated product was not altered. the present study investigates the beneficial effect of spiking hyclone™ actipro™ basal medium with hyclone cell boost™ 7a and cell boost 7b feed supplements on growth and productivity of a recombinant cho cell line. to evaluate the impact of feed-spiking compared with cultivation in basal medium only, the cell line was grown in bioreactors under controlled conditions to determine cellspecific metabolic rates, nutrient consumption, and byproduct accumulation over the process time. transcriptome analysis of the cultivated cells, using microarrays on four consecutive days to investigate differential gene expression, revealed the beneficial effect of feed-spiking compared with cells grown in basal medium. model cell line was a mab-expressing cho dg44 (licensed from cellca gmbh) cultivated either in actipro basal medium only (ge healthcare) or in actipro basal medium feed-spiked with additional supplementation with 7% cell boost 7a and 0.7% cell boost 7b (ge healthcare). both cultures were grown in batch mode using dasgip™ cellferm-pro™ stirred-tank bioreactors (eppendorf). the beneficial effect of feed-spiking was analysed by transcriptome analysis using microarray technology (8×60 k design, agilent). both basal and feed-spiked processes lasted for seven days with viabilities above 95% until day 6. on day seven, a sharp decline in viability indicated the end of the batch process (fig. 1a) . in feed-spiked medium, cells initially grew slower but reached almost twice as high peak cell concentrations (17.6 × 10 6 c/ml) than in basal medium only (9.79 × 10 6 c/ml). remarkably, the integral of the viable cell concentration over the total process time (viable cumulative cell days [vccd] ) was similar between both process strategies (fig. 1c) . while mab production plateaued after day 4 in basal medium only (final titer 0.8 g/l), a continuous increase to three-fold higher final titers (2.4 g/l) was observed in feed-spiked medium (fig. 1b) . the higher titers could be attributed to generally higher cell-specific productivities (qp), which remained rather constant (~70 pg/cell/day) in feedspiked cultures. in basal medium, the qp continuously dropped by 20% (day 0 to 3), 50% (day 4), and > 90% (day 5 to 7) from 70 to 10 pg/cell/day in basal medium cultures. in average, the qp was 70% higher in feed-spiked cultures (fig. 1d ). transcriptome analysis of differentially expressed genes between cells grown in basal medium or feed-spiked medium were used to identify relevant go terms that indicated a more active proliferative state for feed-spiked cultures (data not shown). the top go terms significantly related to cell cycle and primary metabolism, cellular division, as well as nucleobase formation or regulation. furthermore, gsea revealed several significantly enriched set of genes related to gene transcription, dna replication and repair, cell growth and proliferation, as well as inhibition of apoptosis in feed-spiked cultures. thus, feed-spiking increased the proliferative activity of cultivated cells. several of the identified genes appear as promising targets for cell line engineering, but have not yet been described in relation to high-producing recombinant cell lines and will need to be evaluated in future studies. feed-spiking of basal medium is a convenient and easy way to considerably increase product concentrations in a simple batch culture. differential gene expression revealed genes that appear important for high cell-specific production rates, and this knowledge can be leveraged into cell line engineering approaches or the design of high producing cho cell media. in the latter case, a maximized supply of high biosimilarity must be demonstrated by physicochemical and functional characterization for approval requirements of phase i and phase iii studies in terms of efficacy, safety and immunogenicity. in this study, rounds of upstream and downstream processes were run to reach the cqa limits of the originator molecule. after conducting many different development strategies, the mirror plot images of the intact deconvoluted mass were found to be identical corresponding to similar levels of glycoforms. the uv chromatogram of reversed phase ultraperformance liquid chromatography (rp-uplc) of tryptic peptide mapping demonstrated that the primary structure of tur01 is identical to the originator as shown in fig. 1a . post-translational modifications (ptms) such as oxidation, deamidation, n-terminal pyroglutamic acid, c-terminal lysine truncation levels were also comparable for two products. the glycosylation site (hc-asn301) was confirmed by peptide mapping analysis and 100% glycan site occupancy was proven for tur01 and originator. the glycosylation pattern for two products were highly similar in terms of major glycans (g0f, g1f, g0f-gn and etc.). man5 level was lower in tur01 compared to the originator product which may not have any clinical effect on the molecule. the secondary structure was determined by atr-ftir spectroscopy. absorption bands (amide i and amide ii) were overlapped completely and amounts of α-helix and β-sheet structures were comparable. furthermore; size-exclusion chromatography (sec) analysis revealed that both products have the same level of purity (>99%) and aggregate (<1%) levels. the level of impurities were determined as below 4% by ce-sds. the capillary isoelectric focusing (cief) experiments showed that the charge variant profiles of two products are indistinguishable and the isoelectric point of main peak is observed at 8.3 for both products. the association/dissociation rate constants and binding affinity for both tur01 and originator were highly similar and similarity score was calculated greater than 99%, as shown in fig. 1b . in this study, state-of-art analytical techniques were used to assess the biosimilarity of tur01 to the originator adalimumab. head-tohead comparison data clearly demonstrated that tur01 is highly similar to the originator adalimumab in terms of physicochemical and functional characteristics. based on the analytical similarities, we . process performance of basal medium (black) and feed-spiked (red) bioreactor batch cultures: a cell concentrations and viability, b viable cumulative cell days and specific growth rate, and c antibody concentrations and cell-specific productivity. error bars indicate standard deviation from three independent experiments. the black arrows on day 4 indicate the beginning of decreasing cell-specific productivities and lower cell-specific growth rates in basal medium cultures believe that tur01 will have comparable pk/pd, potency, and efficacy results to the originator adalimumab. the expanded interest in intensified continuous bioprocessing has highlighted the need to develop a small scale model for perfusion cell culture. the direction in the industry has been to increase target cell densities to ≥50x10 6 vc/ml and decrease perfusion rates to ≤3vvd. in order to increase the throughput of our perfusion media development capabilities we sought to develop a small scale model of perfusion using the ambr®15 instrument (sartorius, germany). we used a modified cell settling model from the previously published by kreye et. al. to achieve the cell retention necessary to reach perfusion relevant viable cell concentrations [1] . in this work, we will show the application of this small scale model for: (1) identification of specific productivity performance over a steady-state for tested media, (2) identification of cspr min for a specific cell line and medium combination, and (3) confirmation of consistent product quality profiles between the small scale model and benchtop perfusion (data not shown). a chozn® cell line producing an igg1 was evaluated in several proprietary chemically defined media prototypes generated during the development of the catalog excell® advanced hd perfusion medium: "fed batch medium", "early prototype", "mid prototype", "intermediate prototype" and "late prototype" [2] . small scale simulation of perfusion experiments were run in ambr®15. media exchange was performed 3 times per day in equal amounts. agitation, gassing, and liquid handling were stopped for an optimized period of time to allow cells to settle to the bottom. spent media was removed in an amount proportional to 1/3 rd daily exchange volume. agitation, gassing, and liquid handling were resumed and fresh media was added back to the vessels. for benchtop perfusion, cells were inoculated in 3l applikon bioreactors (applikon, netherlands). at a concentration of~6.0x10 6 vc/ml, perfusion was initiated using the atf2 (repligen, massachusetts). perfusion rate was limited at 1.2vvd during steady-state. using the cell settling method described above we have been able to achieve ≥90% cell retention efficiency. all media tested in this work were able to reach and maintain the 30x10 6 vc/ml target cell density at 1vvd (fig. 1) . performance of each media formulation was ranked based on specific productivity (table 1) . using "intermediate prototype", minimum steady-state cspr was determined to be 33.3pl/c/d for this cell line. n-glycan analysis of ambr®15 and bioreactor samples via intact mass spectrometry displayed only slight differences in product quality profile (data not shown). our work has shown a clear distinction between various prototype perfusion media and demonstrated a 50% increase in specific productivity over "fed batch medium" used in perfusion. additionally, we have shown the application to further characterize the process using this model to determine cspr min for a given medium and cell line. the transient process has been successfully operated at 500l in a sartorius biostat single use bioreactor (sub), yielding 0.4kg of crude product from a two-week expression culture (table 1) . successful scale up of the process to 500l creates the potential to supply transiently expressed products to support toxicology studies or even early gmp clinical supply, enabling accelerated biopharmaceutical development project timelines. the scale up from rocking bioreactors (rbr) to sub scale identified some scalability issues. lower specific productivity due to increased cell growth and decreased titres were observed in the sub ( fig. 1 iii & iv). to improve the predictability of scale up, a new process was developed and evaluated in the sub vessels utilising a modified transfection method, which resulted in comparable expression levels and specific productivity between rbr and sub scales. two sets of expression vectors comprising heavy chain and light chain plasmids expressing a human igg1 kappa mab, as previously described [1, 2] were used in the process optimisation study. the cell line used for transient expression and the pei mediated transfection method has been described previously [1] . transfected cultures were run under fed batch conditions for 14 days in 22l ge healthcare wave bioreactors (rbr), hyclone sub using 50l and 250l hyclone bioreactor bags (thermo scientific). the transfection process was modified to address the reduced titres and higher viable cell density (vcd) seen in the sub cultures. shake flask cultures were used to assess the standard (a) and modified transfection processes (b and c) (fig. 1 , i & ii). process c was identified as the process to be studied at sub scale, offering the potential to mitigate the high viable cell densities (vcd) observed. scaling up process c to 50l and 250l sub resulted in cultures producing titres exceeding 1g/l with desired cell growth profiles. scale up of process a into sub vessels resulted in decreased productivity compared to the rbr scale. after optimisation, the sub process c yielded increased specific productivities and expression titres comparable to those seen at rbr scale (table 1) . medimmune has successfully completed the first known successful cho transient culture at 500l scale producing > 800mg/l of mab at harvest. process optimisation has subsequently demonstrated reproducible titres at 50l to 250l scale exceeding 1g/l with comparable glycosylation profiles between sub and rbr cultures across scales. comprehensive analysis of the impact of trace elements in media on clone dependent process performance and product quality background state-of-the-art biopharmaceutical processes are accounting concomitantly for process performance and product quality. even though high yielding, robust processes are the cornerstones of any process development, product quality parameters such as structural integrity, charge variances and post-translational modifications are progressively becoming the focus of the developmental work. in conjunction with host cell line selection and process performance parameters, media components are crucial for the continued progress in rational modulation of product quality attributes affecting biological activity, immunogenicity, half-life or stability. among media components, trace elements (te) are of particular interest as they play a pivotal role in various cell metabolism pathways. based on a comprehensive doe approach, extensive process performance-and product quality evaluation combined with metabolic flux analysis, the impact of several trace elements on the biopharmaceutical process is assessed. in a comprehensive i-optimal doe approach ( fig. 1) , the effect of six te in various concentration levels and combinations in serum-free media was studied for four different cho-k1 cells lines in an ambr® 15 setup. a scrutiny of the process performance parameters such as cellular growth, productivity, amino acids and vitamins consumptions rates for each of the conditions was performed. the process performance evaluation was accompanied by extensive product quality analysis including size and charge variants, glycosylation patterns, oxidation and methylation. furthermore, a metabolic flux analysis was performed based on the nitrogen balance. based on extensive analytical data, the obtained response surface model provides a clear insight into the impact of particular te and their combinations on process performance and product quality. the high model quality enables discriminations between clone dependent and clone independent effects. with an elevation in titer up to 25% in the best condition of the cell lines clearly show, that even state-of-the-art media can be outperformed by trace element rebalancing. analyzing specific rates in combination with metabolic flux analysis improves the understanding of metabolic restructuring of the cell lines under distinct te levels and combinations. modulation of trace elements levels had a tremendous effect on the charge heterogeneity and glycosylation structure of the different proteins. this provides a toolbox for the fine tuning and control of product quality parameters. taken together, the data further paves the way to the rational fine tuning of process performance and product quality attributes. background due to regulatory concerns and economic impact, ensuring product quality and consistency is now one of the main challenge faced by the biopharmaceutical industry. for monoclonal antibodies (mab), glycosylation is one of the most important quality attributes as it impacts on mab structure integrity, and ultimately on both clinical efficacy and safety. many factors affect mab glycosylation and its inherent heterogeneity, including the host cell, the culture medium, the mode of operation and the operating conditions. in this context, the capacity to monitor and control on-line the antibody glycosylation, from early-to late-stage process development, would be of salient interest to reduce the time and cost to market. in order to address this unmet need, we have designed an improved spr biosensor assay to measure the kinetics of interaction between a mab and the extracellular domain of the fcγriiia receptor bound at the biosensor surface [1, 2] . of salient interest, we also demonstrated that various binding kinetic signatures, especially different dissociation kinetics could be correlated with distinct mab glycosylation patterns and with therapeutic efficacies, as deduced from mass spectrometry and a surrogate adcc assay, respectively. in parallel, we have also harnessed a spr biosensor directly to a bioreactor, which permitted the at-line determination of the concentration of antibodies by hybridoma cells during a bioreactor culture. we now plan on combining both approaches to determine on-line the glycosylation profile of the produced mabs. our ultimate goal is to design a unique and highly innovative bioprocess control tool that can be readily applied in an industrial bio-manufacturing setting. reducing timelines and costs are key factors for bio-pharmaceutical industries to accelerate process development and drug delivery to patients. enhancing throughput of bioprocess development has become increasingly important for the screening and optimization of cell culture processes. this challenge requires high throughput tools. in a previous study [1] , we showed that ambr® 15, a robotically driven mini-bioreactor system developed by tap-sartorius, could be advantageous to accelerate process development. the use of ambr® 15 system allows us to test a large number of experimental conditions in a single experiment. therefore, the large amount of production samples to be characterized for product quality attributes (pqa) increases as well: the bottleneck has moved from the generation of samples at the production bioreactor step to in-process analysis. for product quality attribute analysis at lab scale, protein purification is generally carried out on >5ml columns which is incompatible with the size of ambr® 15 bioreactors. moreover, the applied methods are relatively low throughput. the development of a high binding capacity resin (up to 70 mg/ml) [2] , combined with high performing new cell lines which are able to produce up to 5 g/l of recombinant monoclonal antibodies, allow require the development of an efficient and high throughput (hts) purification method robot. the use of robotic equipment for small scale purification purposes is a great opportunity for us to tackle this bottleneck, by enabling highthroughput sample purification at smaller scale (200μl). recombinant monoclonal antibodies were produced by a genetically engineered dihydrofolate reductase (dhfr)-/-dg44 chinese hamster ovary (cho) cell line. clarified cell culture fluid (cccf) was obtained from 2 and 2k liter bioreactors after three filtration steps. minipurifications were performed on tecan freedom evo® robot with predictor robocol-umns® containing 200μl mabselect sure® resin. larger scale purification were executed using an aktaxpress using hitrap column prota. to assess monoclonal antibody purification at small scale, we first tested the repeatability of the minipurification, purifying the samples 8 times on the same columns and using different columns, focusing on the yield of the purification and the impact on product quality attributes, especially the hmws. then, we compared those results to those obtained with the aktaxpress at larger scale purification, comparing the yield of the purification and the pqa of the protein-a eluates obtained with both purification systems. finally, we assessed the capability of the robot to perform hts of buffer and purification conditions, evaluating three different buffers at different concentrations and ph values, and also testing different loading column capacities. in this study we established that the tecan can be used as a robust platform for purification at small scale. we observed similar purification yields, intra and inter run. the analysis of the pqa1a level showed there is also very high reproducibility. and the ph of the eluate showed as well strong comparability as well. table 1 shows the coefficient of variation (cv) of the yield, hmws and eluate ph are low, demonstrating the good reproducibility of the purification. the strong reproducibility obtained between the different purifications showed that the tecan and the aktaxpress are similar in terms of purification performance and pqa (fig. 1a, b) . the tecan is a versatile automated liquid handler allowing the screening of huge purification conditions (fig. 1c) , the possibility to purify large quantities of samples, while the samples amount is limited. the tecan has the potential to purify more than 150 samples/day, reducing timelines and allowing us to deliver faster to the patients. viable cell density monitoring in bioreactor with lensless imaging geoffrey monitoring cell density and viability of mammalian cell culture bioreactors is a necessary task that presents today a number of remaining challenges. the traditional measurement for bioreactor cell count and viability rely on using the trypan blue exclusion method once a day. while automatic cell counters have reduced the statistical manual error, sampling the bioreactor remains a contamination risk and is prohibiting process control as the sampled volume becomes siginficant. lensless imaging technology is a new method for accurately determining cell concentration and viability without staining. this technique directly acquires the light diffraction properties of each individual cells through their holograms images without any objective, lens or focus settings. living and dead cells have significant holographic patterns that can be distinguished and precisely counted. lensless imaging technique directly acquires the light diffraction properties of each individual cells through their holograms images without any objective, lens or focus settings. living and dead cells have significant holographic patterns that can be distinguished and precisely counted. we compare cell counts and viability between the reference method and our lensless imaging device, the cytonote counter. measures are performed once a day on samples from 12 bioreactors, from the inoculation to the end of the culture. we also assessed the repeatability of our method. another lensless imaging prototype is setup as a measurement chamber directly connected to a perfusion bioreactor, for continuously receiving the bioreactor broth, and therefore reproducing an in situ measure. with a concentration range up to 40x10 6 cells/ml ( fig. 1) and viability range at 75-100%, we obtained a correlation factor of 0.98 between the two compared methods. the large field of view allows the analyze of several thousand cells within a single image, keeping the statistical variability of the measure as low as 3%. our measurement chamber prototype has demonstarted its capability for continuous viable cell density and viability monitoring. we are now working at designing a steam strerilizable probe, and we envision lensless imaging to become the future method of choice for on-line monitoring of suspension cells cultures. lensless imaging technology is capable of accurately and precisely monitoring viable cell density and viability with a combination of significant advantages starting from low sample volume use, label free detection, quick measure, simple device, to high number of cell analyzed which let us think that it is a good candidate for very smallcomparison between both purification systems and the ability of the system to be used as a high throughput tools for buffers screening. a purification yield (%). b pqa1.a (normalized). c impact of the ph and buffer concentration on the pqa1.a scale bioreactor and high-throughput measures. its high repeatability is also a key parameters in the effort to narrow batch to batch deviations. in addition we demonstrate that this technique is potentially powerful for in-line and continuous monitoring of a lab bioreactor. we envision lensless imaging to become the future method of choice for on-line and in-situ monitoring of suspension cells and a perfect tool for process control in fed-batch or perfusion mode in single-use bioreactors or traditional steam sterilized vessels. it can certainly become the first vcd measurement technique to work from cell line engineering, to process development, pilot scale, and up to manufacturing scale. time-dependent product heterogeneity in mammalian cell fermentation processes background a consistent product quality is a major goal in the production of biotherapeutics, especially recombinant glycoproteins. whereas it is unlikely that the polypeptide chain changes during a production process, posttranslational modifications and protein folding are sensitive to fluctuations in parameters and conditions. here we focus on protein glycosylation as one important indication for product quality [1] . during a batch process conditions change continuously. at the beginning, the supply situation for the cell is excellent, but the secreted material stays a long time in the culture fluid. later during cultivation substrate provision decreases, whereas the exposition time of the protein to the culture fluid is much shorter. altogether this leads to product heterogeneity of the secreted protein during a batch culture. four different cell lines, two of human origin and two cho clones, producing four different recombinant glycoproteins were investigated in this study. together with their respective parental cell line the clones were cultured in three replicates in shakers. supernatant from the cultures were harvested at four time points. the removed culture volume was replaced by culture supernatant of the identically cultured corresponding parental cell line. the product was isolated from the supernatant and the glycans were released. one part of the released glycans was labeled with 2-ab and separated by hilic-fld. the other part of the glycans was permethylated and analyzed by maldi-tof mass spectrometry (fig. 1a) . the investigated proteins were antibody, antithrombin iii from cho clones and α1-antitrypsin, c1-inhibitor from human clones. the antennarity of the glycans is quite stable in all production phases. the degree of core fucosylation is very high in all products. a low fucosylation degree of antibodies may be favorable for a higher adcc performance [2] . some of the products showed an antennary fucosylation, which seemed to change not very much in different cultivation phases. nevertheless, this might be an issue due to an antigenic impact in the patient. the antennary galactosylation changes noticeable for the antibody and α1-antitrypsin. in both cases the degree is highest in the first phase. an incomplete galactosylation leads to truncated glycans. this leads inevitable to undersialylated antennas to be seen for α1-antitrypsin. the sialylation is the highest in the early phases and decreases during cultivation time. sialylation of a therapeutical protein is important for the half-life in the patient. therefore highly sialylated products are desired [3] . in further studies the consistency of the galactosylation and the sialylation will investigated for fed batch and long term continuous cultures in comparison to batch cultures. due to the feed solution or the fresh media being present during such processes, the supply situation should be excellent for the whole cultivation time. the differences between the maldi-tof and hilic-fld data originate from complex and unresolved chromatograms (fig. 1b , chromatograms not shown). for that reason coupling of hilic-fld and ms is very much recommended. background novel biologics are often selected from a large library of lead candidates in the initial stage of preclinical and clinical developments. for this selection, there is a demand for high-throughput production of recombinant proteins of high quality and in sufficient quantity. transient gene expression offers a rapid approach to the production of numerous recombinant proteins for the initial-stage developments of biologics. mammalian cells are major host cells for transient gene expression, but they have the disadvantages of complicated operations and high cost of culture. insect cells are easy to handle and can be grown to a high cell density in suspension with a serum-free medium. insect cells can also produce large amount of recombinant proteins through post-translational processing and modifications of higher eukaryotes. hence, insect cells have been recognized as an excellent platform for the production of functional recombinant proteins [1, 2] . in the present study, the production of an antibody fab fragment through transient gene expression in lepidopteran insect cells was examined. the dna fragments encoding the heavy chain (hc) and light chain (lc) genes of an fab fragment of mouse anti-bovine rnasea [3] were respectively cloned into the plasmid vector pihaneo, which contained the bombyx mori actin promoter downstream of the b. mori nucleopolyhedrovirus (bmnpv) ie-1 transactivator and the bmnpv hr3 enhancer for high-level expression [4] . trichoplusia ni bti-tn-5b1-4 (high five) cells were co-transfected with the resultant plasmid vectors using linear polyethyleneimine (pei; mw 40,000). before transfection, the plasmids and pei were prepared in 150 mm nacl, ph 7.0 and incubated at room temperature for 5 min. when the transfection efficiency was checked, a plasmid vector encoding the enhanced green fluorescent protein (egfp) gene was also co-transfected. transfected cells were incubated with a serum-free medium in a static or shake-flask culture. culture supernatants were analysed by western blotting and enzyme-linked immunosorbent assay (elisa). the numbers of green fluorescent cells and total cells in culture broth was determined using a flow cytometer. western blot analysis and elisa of culture supernatants showed that transfected high five cells secreted the fab fragment with antigenbinding activity. in static cultures, transfection and culture conditions, such as hc:lc gene ratio, a serum-free medium, dna:pei ratio, and dna amount per cell, were successfully optimized by flow cytometry of egfp expression in transfected cells and the yield of the secreted fab fragment measured by elisa. the effects of culture temperature and initial cell density were also examined by comparing the cell growth and the production of fab fragments in shake-flask cultures. under optimal conditions (medium, psfm-j1 (wako pure chemical industries, japan); hc:lc gene ratio, 3:7; dna, 5 μg/(10 6 cells); pei, 10 μg/(10 6 cells); initial cell density, 1 x 10 6 cells/cm 3 ; temperature, 24°c), the yield of more than 100 mg/l of fab fragment was achieved in 5 days in a shake-flask culture ( fig. 1) . transfection did not significantly affect the growth of high five cells as compared with untransfected cells. transient gene expression using insect cells may offer a promising approach to high-throughput production of candidate proteins for the development of biologics. the increasing demand for biopharmaceuticals produced in mammalian cells has led industries to increase volumetric productivity of bioprocesses through different strategies [1, 2, 3] . in this context, fedbatch and perfusion cultures have attracted more interest than conventional batch processes. the efficient application of such alternative processes requires the availability of reliable on-line measuring tools for cell density and cell metabolic activity estimation [4] . the comparison of different culture strategies for hek293 cell line producing ifn-γ are presented below: batch, fortified batch and fed-batch. in this context, a new robust feeding strategy based on the monitoring of alkali buffer addition was applied for the estimation of nutrient requirements. this method allows to increase cell density and product titer compared with the other strategies assessed. three different culture strategies were carried out in 2-litre biostat b-dcu ii bioreactor. first, a reference batch and a batch using fortified medium (nutrient enriched medium) were run and assessed in terms of viable cell density (vcd) and product titer, and set as initial references. then, a fed-batch was performed applying a feeding strategy based on the nutrient requirements estimation by monitoring the alkali buffer addition used for the control of ph. results vcd and product titer achieved for the different culture strategies assessed (batch, fortified-batch and fed-batch) are presented in table 1. in fortified batch an increase in vcd of 145% and also 350% in product titer were obtained compared with batch. in the fed-batch culture carried out (fig. 1) , we observed that alkali buffer addition profile matched the vcd evolution trend. thus, the monitoring of alkali buffer addition was used for estimating the nutrients requirements (i.e. the volume of feeding medium) at any time during the fed batch phase. the feeding strategy based on alkali buffer addition enabled to maintain glucose concentration set point therein a narrow range during fed-batch phase (around 20 mm). as a result, higher vcd (16.6·10 6 cells/ml) was obtained when compared with both batch references: vcd was enhanced to 241% and 39% and an increase up to 381% and 7% in product titer in respect to batch and fortified batch respectively. the results prove that fed-batch strategy based on the alkali buffer addition is a robust on-line monitoring method that enables to optimize the feeding strategy in a fed-batch cultures. three different culture strategies have been tested in bioreactor with a hek293 cell line producing ifn-γ. results show as the higher vcd is reached, the higher product concentration is achieved. therefore, from bioprocess development point of view, it is very interesting to implement strategies with higher vcd outcome, such as fed-batch operation mode. in this context, a new robust method for vcd estimation in fed-batch was applied. the alkali buffer addition necessary for maintaining the ph set-point is an on-line reliable and easy measuring variable that provides information about by-products formation (mainly lactic acid). the monitoring of this variable can provide information about the cell concentration, activity and metabolism, to detect changes in culture. besides that, a relationship between alkali buffer addition and vcd can be established since the first is strongly correlated with cell growth and metabolites consumption/formation. the application of alkali buffer addition measure to implement an optimal feeding strategy in fed-batch permits to enhance vcd and product titer when comparing with batch strategies. a novel approach to high throughput screening for perfusion background perfusion systems for suspended mammalian cells raise growing interest in the biomanufacturing industry. continuous manufacturing is growing in the field and is encouraged by health authorities [1, 2, 3] . this work addresses scale down limitations inherent to continuous media exchange and cell retention by using a semi-continuous system. data was generated with a set of different clones that were previously studied in fed-batch mode [4] . materials and methods 4 cho-k1 cell lines expressing the same monoclonal antibody (mab) and issued from the same transfection were used as models. 3.5l bioreactors (sartorius) were used for fed-batch and perfusion production runs. the perfusion bioreactors were run using an alternating tangential flow filtration device (repligen, xcell™ atf 2 system). the cell biomass was controlled by removing cells through a bleed line and was controlled using a biocapacitance probe (hamilton, incyte). the perfusion rate (d) was fixed to one vessel volume a day (vvd -1 ). the semi-continuous runs were made in 50 ml shake tube (tpp, tubespin® bioreactor 50). once a day, the tubes were centrifuged (5 min, 200 g), the supernatant removed (to mimic a perfusion rate of 1 vvd -1 ), replaced with fresh media and cells were re-suspended. the clone's growth potential were preserved across the systems (fig. 1 ). clone #3 always reached the highest viable cell density (vcd), followed by clone #1. clone #2 and #4 showed similar growth characteristics. it is interesting to note that in the perfusion bioreactor different patterns in terms of vcd were observed although the cell biomass signals were similar for all 4 runs. this reflects the fact that the capacitance measures the biomass and not the absolute cell count [5] . to estimate the minimum cell specific perfusion rate (cspr min ) in the semi-continuous experiment, the perfusion rate was divided by the maximum viable cell density (vcd max ). this value was compared to the cspr obtained during the 4 th set-point (sp4) of the perfusion runs. as expected, the bleed fraction decreased when the capacitance set-point was increased and went down to 5% or less of the total perfusion rate (data not shown). since the bleed removes the excess biomass, it is an indication of how close to a limitation the system is. therefore, the cspr calculated at sp4 was considered as the minimum cspr. the cspr min obtained in both systems were very close ( table 1 ). the semi-continuous system can therefore be used to identify the cspr min before running a continuous bioreactor, it therefore facilitates the decision making early in the development (to define the target cell density for a defined perfusion rate). the specific productivity (q p ) of the 4 clones was quantified at the maximum vcd (semi-continuous) or at sp4 (perfusion). absolute values are not representative since the cell environment is so different in both systems. nevertheless, a relative ranking proved to be indicative of the respective performances ( table 1 ). the maximum cell growth in fed-batch, semi-continuous and perfusion were also compared, their ranking was always preserved. both indications can be used to assess a performance ranking for different clones. the performance of 4 clones was studied in 3 different cultivation systems: fed-batch/perfusion bioreactors and semi-continuous shake tube. the semi-continuous system was able to precisely predict the cspr min , an important process parameter for perfusion. specific productivity and maximum cell density ranking was preserved across the systems, therefore the scale down experiment can be used to assess a performance ranking for perfusion clone screening. modulating antibody galactosylation through cell culture medium for improved function and product quality jenny y. bang, james-kevin y. tan the production of therapeutic antibodies (abs) requires high titers and excellent product quality to ensure efficient manufacturing and potent drug efficacy. glycosylation, or the attachment of sugars to organic molecules, is a critical quality aspect that can significantly alter ab binding, function, and therapeutic effect [1] . galactose is a key sugar of interest due to its significant impact on ab function and the ability to control galactosylation through cell culture medium. herein, irvine scientific assessed the ability of media components to modulate galactose levels on a model therapeutic ab. various media compositions were able to modulate galactosylation levels without compromising cell growth and ab titers. in addition, an in vitro assay was utilized to evaluate the functional ability of abs to bind and activate complement-dependent cytotoxicity (cdc). differences in galactosylation significantly altered the abs' ability to induce cell cytotoxicity. furthermore, design of experiment analysis determined the optimal ratio of supplements to maximize galactosylation. this "optimized supplement" was verified and evaluated against other suppliers' galactosylation supplements in terms of growth, titer, glycan analysis, and ab function. the optimized supplement outperformed all other suppliers' supplements and resulted in the best overall cell growth, titer, galactosylation, and ab function. ab against cd20 were grown in balancd® cho growth a and were fed with balancd® cho feed 4 on days 3-7 of the cultures. viable cell density and cell viability were assessed by a beckman coulter vi-cell xr, ab titer was assessed by a pall fortébio qk e , and glycan analysis was assessed by a perkinelmer labchip gxii. for the functional cdc assay, abs were incubated with daudi b lymphoblast cells and normal human complement serum. cell cytotoxicity was assessed with a promega cytotox-glo kit. various supplements were evaluated in fed-batch cultures and resulted in 15-45% ab galactosylation without compromising cell growth and ab titers. design of experiment analysis determined an optimal composition, deemed "optimized supplement," which was evaluated against a panel of galactose-modulating supplements from other suppliers. the optimized supplement resulted in a similar viable cell density (vcd) and cell viability compared to the fed-batch culture control which had no supplements (fig. 1a) . supplements from supplier 1 resulted in similar to half the vcd of the control while supplements from supplier 2 resulted in very low vcd and percent viability. all of the supplements except those from supplier 2 resulted in ab titers similar to the control (fig. 1b) . due to the poor growth and subsequently low titer from supplier 2's supplement, supplier 2 was not further evaluated. the glycan profiles were analyzed and are presented in (fig. 1c ). all the evaluated supplements were able to raise galactosylation; however, only the optimized supplement and the 2x supplier 1 supplement resulted in over 40% galactosylation. the function of the abs was further evaluated in a cdc assay (fig. 1d) . abs from the optimized supplement were more effective than the control abs and had a significantly lower half-maximal effective concentration (ec 50 , 1.19 μg/ml) than the control (1.71 μg/ml). abs from the 2x supplier 1 supplement had a similar ec 50 to the control which may be due to the higher man5% of the abs. an optimized supplement was produced through fed-batch evaluation and design of experiment analysis. the optimized supplement outperformed all other supplenments from other suppliers and resulted in the best overall cell growth, glycan profile, and functional ab activity (table 1) . industry practice for mammalian cell culture media and feed development typically employs a high-throughput screening (hts) platform along with large sets of experiments [1] . modern hts systems often include robotic liquid handlers to replace labor intensive steps. to align with advancements in the field, a semi-automated hts platform was developed to facilitate in-house media and feed development for early stage biologics projects. selecting appropriate instruments and integrating them into a seamless system are the keys to a hts platform. the developed hts platform uses 24 deep well plates (dwps) for culture vessels, the liquid handler of the advance microscale bioreactor (ambr15) for media/ feed formulation preparation in an aseptic environment, nyone cell imager for viability and cell growth analysis, tecan freedom evo's liquid handler for activity assay sample preparation, and cedex bioht for high-throughput metabolite analysis. 24 dwps offer comparable cell growth to shake flasks and compatible layout to ambr15, which makes the 24 dwp an ideal candidate for the platform. in addition, the user friendly design of experiments (does) interface and liquid handler function of the ambr15 expediates the formulation preparation of varying doe conditions [2] . a macro program was written and developed in excel to enable the easy import of does design from major statistics software packages, such as jmp and simca, into ambr15. performance qualification of each component were performed prior to implementing the hts platform. comparable cell growth profile and productivity were achived between shake flasks and 24 dwps (fig. 1a ), indicating compatable cell culture environment for the cells. cell counts using nyone gave identical cell growth ranking as the traditional count from vi-cell xr (fig. 1b) . freedom evo's liquid handler was optimized to produce comparable activity results to manual operation while expediting the sample preparation with improved consistency (fig. 1c) . finally, implementing the liquid handler function of ambr15 to support media and feed formulation significantly reduced the labor for each experiment. summary of the capability comparison between the hts platform and the traditional method are listed in table 1 . a case study of a complex feed screening with definitive screening design was completed using the semi-automatic hts platform. this experiment, containing more than 60 feed formulations in duplicates, was handled by one operator and delivered a 40% improvement in productivity within a 4 week period (data not shown). in addition, implementing the hts platform for this study also resulted into~80% reduction in labor while improving the traceability of formulation preparation. a semi-automated hts platform was developed to support media and feeds screening and development for early stage biologics projects. the platform utilizes 24 dwps, nyone cell imager, ambr15, freedom evo liquid handler system, and bioht metabolic analyzer to accelerate the screening process. this screening platform not only improves process throughput, operational precision, and traceability of formulation preparation, but also reduces the labor for the media and feed formulation preparation. background a perfusion medium requires high concentrations of specific nutrients while balancing other components to support intensified perfusion processes. using a combination of design of experiment (doe), multivariate analysis (mva), and spent media analysis, we developed a catalog "de novo" perfusion medium by working with multiple cho cell lines and proteins. the optimization of the medium in bioreactors using alternating tangential flow (atf) cell retention devices reduced the minimum cspr from over 80pl/cell/d to under 35pl/cell/d for most cell lines while increasing specific productivity during 30 day steady states with stable growth rates, viability, volumetric productivity and product quality. high throughput screening (hts) was performed with seven cell lines, while four were used in bioreactors: cho-s, dg44, and two chozn® gs lines, each producing different monoclonal antibodies and include a fusion protein. for hts experiments, cells were inoculated at 2.0x10 6 vc/ml with a 30 ml working volume in 50 ml tpp® tubes and cultured for 7 days in a multitron shaken at 200rpm, 37°c, 80% rh, and 5% co 2 . for benchtop perfusion, cells were inoculated at 0.4-2.0x10 6 vc/ml in 3l applikon bioreactors (applikon, netherlands) with a 2l working volume. bioreactors were operated at 350 rpm, 37°c, 40% do, and a ph of 6.9 or 7.1±0.05 depending on the cell line. oxygen was supplied through an l-sparger or microsparger as needed, and excell® antifoam (milliporesigma, germany) was added at a maximum rate of 0.25% v/v to control foam. at a cell concentration of~6.0x10 6 vc/ml, perfusion was initiated using the atf2 (repligen, massachusetts), with a bleed set to maintain cell concentrations at 50 or 80*10 6 vc/ml. two "de novo" prototype media were developed using doe and mva in hts with tpps and an ambr®15 [1] and one was chosen for further development after comparing to a basal medium enriched with feed in bioreactors. eleven components were identified as significant effectors of critical parameters for perfusion processes across evaluated cell lines. doe central composite experiments were run and component concentrations were optimized in the selected prototype. in parallel, amino acid specific consumption rates were calculated from bioreactor spent media samples and used to adjust the concentration of amino acids to target a reduced cspr. increasing specific amino acids concentrations resulted in a significant reduction of the minimum cspr across all tested cell lines -for example the cspr of cho-s was reduced from 60 to 39pl/cell/day (table 1 ). however, even at the lower cspr, spent media analysis revealed excess concentration of some amino acids, so specific accumulating amino acids were reduced and components were streamlined for the final medium: excell® advanced hd perfusion medium. using this medium, a cho-s and a chozn® gs cell line producing a fusion protein were cultured at a cspr of less than 40pl/cell/day with a vcd of 50*10 6 vc/ml. metabolic profile, productivity, and product quality were constant over the 30 day steady state. the chozn® gs cell line was also tested at 80*10 6 vc/ml with a cspr of 33pl/cell/day (fig. 1 ). we have developed a catalog perfusion medium from first principles, ensuring broadness of application by using seven cell lines in scaleddown systems and four in perfusion bioreactors. the final catalog medium showed significant improvements in productivity across all cell lines, with reduced csprs when compared to enriched fed-batch medium or initial prototypes (table 1) . there is a rising demand for accelerated process development, increased efficiency and economics for biopharmaceutical production processes. furthermore, increased process understanding have evolved from the process analytical tool initiative (pat) and the quality by design (qbd) methodology. in contrast to one-factor-at-atime methods, statistical design of experiment (doe) methods are widely used to develop biopharmaceutical processes. even if highthroughput systems can handle these numbers of experiments in parallel, the heuristic restriction of boundaries and the high number of factors results in stepwise iterations with multiple runs. therefore, the combination of model-based simulations with doe methods (mdoe) for the development of sophisticated cell culture processes is a novel tool for process development [1] . it is used to reduce the number of experiments during doe and the time needed for the development of more knowledge-based cell culture processes. this concept was applied to the optimization of the initial glutamine and glucose concentrations of a cho batch process. a mechanistic model was adapted and modified from [2] and used to describe the dynamics of cell metabolism and antibody production of an il-8 antibody producing cho cell line (see abbreviation of fig. 1 for cultivation details). experiments were simulated and compared to a fully experimental doe. as can be seen from table 1 , user defined constraints were chosen to get a stable and reproducible process with the aim of maximizing the cell density but decreased lactate and ammonia production. at first, the experimental space was estimated by simulating the responses for broad concentration ranges and calculating the multiple response desirability function (fig. 1a) . this results in a small area (turquoise) suggested as experimental space. experiments were planned within these boundaries and responses were either simulated ( fig. 1b, 4 cultivations for fitting the model) or compared with the purely experimental responses (fig. 1c, 16 cultivations). optimal concentrations for glutamine and glucose with respect to the constraints are in the lower right corner and similar for both methods (red frame, fig. 1 ). compared with the fully experimental design, mdoe results in a reduction of 75 % in the number of experiments (4 experiments for modelling vs. 16 experiments in experimental doe). the method is intended to optimize cultivation strategies for mammalian cell lines and evaluated these before experiments have to be performed in laboratory scale. this results in a significant time and cost reduction during process development and process establishment. the strategy is especially intended for the use in multi-single-use-devices to speed up process development. . at a target cell density of 50*10 6 vc/ml, volumetric productivity was stable for a 30 day steady state with excell® advanced hd perfusion medium. shorter steady states were tested at 80*10 6 vc/ml background for the large-scale production of therapeutic glycoproteins, fedbatch culture has been widely used for its operational simplicity and high titer. however, repeated feeding of medium concentrates and/ or addition of a base to maintain optimal ph during fed-batch culture lead to increase in osmolality. the hyperosmolality affects glycosylation in a protein-specific manner. however, the mechanism behind such osmolality-dependent variations in glycosylation in recombinant chinese hamster ovary (rcho) cells remains unclear. in this study, to better understand the effect of hyperosmolality on the glycosylation of a protein produced from rcho cells, we investigated 52 n-glycosylation-related gene expression and n-linked glycan structure in fc-fusion protein-producing rcho cells exposed to hyperosmotic conditions. furthermore, to validate the effect of hyperosmolality on protein glycosylation, we performed hyperosmotic culture supplemented with betaine, an osmoprotectant, and then analyzed the n-linked glycan structure and mrna levels of n-glycan branching/antennary genes. after three days of hyperosmotic culture, nine genes (ugp, slc35a3, slc35d2, gcs1, manea, mgat2, mgat5b, b4galt3, and b4galt4) were differentially expressed over 1.5-fold of the control, and all these genes were down-regulated. n-linked glycan analysis by anion exchange and hydrophilic interaction hplc showed that the proportion of highly sialylated (di-, tri-, tetra-) and tetra-antennary n-linked glycans was significantly decreased upon hyperosmotic culture. addition of betaine, an osmoprotectant, to the hyperosmotic culture significantly increased the proportion of highly sialylated and tetra-antennary n-linked glycans (p ≤ 0.05), while it increased the expression of the n-glycan branching/antennary genes (mgat2 and mgat4b). thus, decreased expression of the genes with roles in the n-glycan biosynthesis pathway correlated with reduced sialic acid content of fc-fusion protein caused by hyperosmolar conditions. conclusions taken together, the results obtained in this study provide a better understanding of the detrimental effects of hyperosmolality on n-glycosylation, especially sialylation, in rcho cells. the identified genes, particularly mgat2 and mgat4b, are potential targets for engineering in cho cells to overcome the impact of hyperosmolality on glycoprotein sialylation. disruptive cost-effective antibody manufacturing platform based on cutting-edge purification process v. medvedev, m. duyck, t. albano, j. castillo univercells sa, gosselies, belgium correspondence: v. medvedev (v.medvedev@univercells.com) bmc proceedings 2018, 12(suppl 1):p-093 background demand for high-quality monoclonal antibodies is growing exponentially, calling for new production capacities. overcoming current limitations of conventional manufacturing strategies, namely the high capital investment and production cost, can only be achieved through innovative process designs based on the latest technologies. this study presents a process design combining batch-fed technology with continuous multi-column capture. an advanced cell culture clarification method was introduced to simplify downstream operations and increase overall cost-effectiveness of the process, for an optimized production of recombinant proteins. this study was performed with cho cells expressing a monoclonal antibody targeted against the coronoavirus responsible for the middle east respiratory syndrome (mers), developed by organic vaccines tm and the nih, kindly provided to univercells. upstream process: -fed-batch, 12 days culture at 10l scale with cd-cho chemically defined media and feeds. harvest treatment: -precipitation of impurities in the production bioreactor using organic compounds (<1% v/v) and flocculation by electropositive organics (<0.1% w/v). -acidic ph and physiological conductivity. upstream processing and harvest treatment: culture reached 0.5 g/ l (8x10 6 cells/ml; 90% viability), harvest treatment was found to be very effective in terms of impurities clearance. capture: capture strategies were evaluated from the point of view of simplification of downstream operations, with hcp impurities content monitored as a key performance indicator. -protein a affinity chromatography: advanced harvest clarification enabled major improvements in affinity capture, in terms of eluate purity and reduction of host cell impurities (<35 ppm in all conditions tested). (fig. 1 ). -cation exchange chromatography: cex allows higher capacities (>100 g/l) than protein a, whilst being more affordable (from 2-to 6-fold cheaper). low residual hcp (<500 ppm) was observed with all cex resins tested. without harvest treatment and clarification preceding the capture studies (either affinity or cex), results showed a lower binding capacity of the resin, a higher content of hcp in the eluate (up to 2000 ppm), a higher content of hmw species in the elution fraction (up to 3-fold higher) and a significant turbidity of the neutralized eluate. -continuous multicolumn chromatography: further options to increase cost efficiency include using a continuous multicolumn setup (table 1) . two models were assessed based on two different static binding capacities (sbc), demonstrating that 4 to 6 columns of 100ml were able to process a 200l production in less than 24h. this method provides a great opportunity for designing simplified and low footprint mabs dsp processes, while maintaining similar or achieving superior quality profile compared to standard approaches: -harvests treatments followed by depth filtration proved to be a cost-efficient way to obtain pretreated feed and minimize the burden on downstream operations. -protein a resins exhibited advantages of extracting key contaminants during harvest treatment, while caex confirmed to be a competitive capture strategy. -switching from batch to continuous multicolumn mode allowed to process a complete batch in less than 24 hours, requiring lower media and resins volumes. followed by a single polishing step, such process set-up strongly supports the reduction of operations required to deliver a high-quality product. analyses of product quality of complex polymeric igm produced by cho cells background immunoglobulin m (igm) antibodies are secreted by b cells as the first defense against invading pathogens during primary immune response. some igm antibodies already gained the orphan drug status, which shows their unique capability in therapy of rare diseases. potential fields for applications are discovered with increasing knowledge about these molecules. it seems that the most active forms are pentameric and hexameric igms. unfortunately, recombinant production of igms is rather difficult as secretion and correct polymer formation results in low expression yields and mixtures of polymers. we established stable producing chinese hamster ovary (cho) dg44 cell lines to analyze cellular and extracellular factors that influence quantity and quality of the produced recombinant polymeric igm in future studies [1] . one quality parameter is polymer distribution, which can be measured directly in cell culture supernatant using densitometric analyses [2] . additionally, we developed a very efficient single-step-affinity purification strategy using the poros captureselect igm affinity matrix to analyze pure igms. for more precise measurements of the igm isoform distribution we separated the purified polymers by high performance liquid size exclusion chromatography (sec hplc). our cho dg44 cell lines grow to peak cell concentration of 4.5x10 6 cells/ml in erlenmeyer flasks and 4.0x10 6 cells/ml in bioreactors. similar productivity of approximately 50 mg/l was observed for cells cultivated in both cultivation vessels in a nonoptimized batch culture using chemically defined media. analysing how cultivation conditions affect the fraction of polymers may offer clues about the assembly of polymers and the challenges of igm production. we quantified polymeric distribution of igm directly in the supernatant using a densitometric method [2] . cultivated under standard conditions (37°c, ph 7) igm012 is produced as 90% pentamers, whereas igm012_gl only consists of approximately 80% pentamers. the purified igm012_gl was analysed with sec-hplc and contained 81 % pentamer and 19 % dimer, which is comparable to the results achieved with densitometry. the purification of the igm antibodies was quite challenging as the manufacturer recommend acidic elution, which led to aggregation and inefficient elution of our model igms. therefore, we screened for different elution buffers that prevent denaturation and aggregation. by combining high salt concentrations with moderate ph reduction we optimized elution conditions to 88-99% igm recovery, which corresponded to a five to six fold improvement compared to the manufacturers' conditions. sds-page analysis and sec-hplc showed that our elution strategy resulted in a very pure product after a single chromatographic step. the purification strategy was verified with the igm103, igm104 and igm617. our model igms were produced in a ratio of approximately 4:1 pentameric to dimeric igm, measured concordantly with both analytical methods. process development on igm purification using the poros capture select human igm affinity matrix enabled the recovery of highly pure fractions. through optimization, by combining mild ph and high salt concentrations, the relatively low elution yields were increased by a factor of 5-6. applying densitometry and sec-hplc we will investigate how culture conditions influence polymer formation in future. currently, no small scale (<0.5l) cell culture system is commercially available for high cell density perfusion cultivations to use in high throughput screening studies. to increase throughput for process characterization activities at janssen vaccines and prevention, a shaker flask-based scale down model was developed. though, the control possibilities of shaker flask cultures are technically very limited and different compared to a bioreactor controlled process. in addition, the sensitivity of the shaker flask model should allow the detection of the effects of process parameters on critical quality attributes (cqas) of the vaccine produced at large scale. iterative experiments were performed in shake flasks to evaluate the influence of cultivation parameters such as shaking speed, working volume, co2% in the incubator and daily base additions on cultivation parameters (as cell growth, ph and do). in addition, a medium exchange was tested to mimic the perfusion mode used in the bioreactor process. the presens shake flask reader was implemented to allow for ph and do monitoring. the conditions for which the performance as reflected in specific virus titer showed the best fit were selected. at these conditions, a series of parallel shaker flask infections were conducted to demonstrate statistical equivalence of performance parameter and cqas (as cell specific iu titer and vp/iu ratio) between the production scale and reduced scale processes and thus to qualify the shake flask as a scale-down model. a daily medium exchange by centrifugation was implemented and cultivation parameters for shake flasks were identified. based on performance parameter (cell specific vp titer) and the cqas of the vaccine (cell specific iu titer and vp/iu ratio), equivalence between the production-scale and scale down systems was confirmed. the scale down model data fall into the 95% prediction intervals calculated on manufacturing data whereas scale down model data from batch mode experiments (using non optimized cultivation conditions) do not. the shaker flask as a scale down model for the 10l bioreactor perfusion process was qualified. this model is a tool to screen a subset of process parameters at a higher throughput, thereby reducing process characterization timelines. background until today, the market for therapeutic proteins, especially monoclonal antibodies, is gaining more and more importance in the pharmaceutical field. to meet the increasing demand for these products, the industry made tremendous efforts to generate highly efficient production systems. one of the pharmaceutical industry's research focuses is the improvement of the secretion process in eukaryotic cells. in mammalian cells, the efficiency of protein transportation strongly depends on the translocation of a nascent protein into the er, which is mostly conducted by the signal peptide (sp) coupled to the nterminus. through the interchangeability of signal peptides between products and even species, a large variety can be used to enhance protein expression in already existing production systems materials and methods at first the influence of four different natural sps (sp (7), (8), (9) and (10)) was compared on the secreted amount of an igg4 model antibody (product a) in fed batches using a cho dg44 host cell line. in the second part, one promising sp-candidate showing improved secretion (sp (9)) was identified and the influence of this sp on four additional antibody products, which varied in their expressability from good to mid/bad, was investigated. in both approaches, the standard sp was implemented for comparative reasons. in the first approach, four signal peptides sp (7), sp(8), sp(9) and sp(10) were screened for their potential to improve the product secretion of cho dg44 cells expressing a model antibody (product a). the results revealed a 2.4-fold increase in average final fed-batch antibody titer of sp(9) when compared to the standard sp approach (standard sp = 0.44 g/l; sp(9) = 1.50 g/l). in the second approach, the enhancing capacity of sp(9) on secretion of four other igg products (named product b to e, table 1 ) was further evaluated. an improved performance was observed for all products when comparing sp(9) and the standard sp in a fed batch process (fig. 1) . with an increase in average final fed-batch titers ranging from 28 to 354 % and up to 290 % in cell-specific productivities. taken together, with a positive influence on the final concentrations of all tested products, the results obtained with sp(9) contribute to -signal peptide sp(9) was identified as a promising candidate with an average 2.4-fold titer increase during screening of four signal peptides. -sp(9) was able to improve production titers up to 354 % compared to standard sp. -sp(9) was able to improve cell-specific productivities up to 290 % compared to standard sp. -future usage of sp (9) contributes to the further optimization of sartorius stedim cellca's standard cell line development process. new platform for the integrated analysis of bioreactor online and offline data lukasz gricman 1 , milan ganguly 2 , amanda fitzgerald 3 , hans peter more and more experiments are used to assess bioreactor suitability and stability of clones, to evaluate media composition and other process parameters, and to start upscaling campaigns. this has resulted in a major bottleneck due to the increase in data capturing, processing, aggregation, visualization, and statistical analysis. in addition, the association of the data with the experimental context (e.g., fermentation protocols, media recipes, bioreactor control parameters) is not easily accomplished in high throughput. the data generated in the process must not only be analyzed, but also managed and stored to enable easy tracking and relating to historical records. furthermore, the processes are often developed by global teams interacting in complex enterprise it ecosystems. therefore, new and high performing systems for data capture, processing, and analysis need to be integrated in order to enable storage and correlation of experimental context information and various types of time course analytics data. we have developed genedata bioprocess™, a new enterprise platform for bioprocess development. the platform enables automatic capture and visualization of all online and offline data (e.g., ph, o2, metabolic data), auto-calculations and aggregations (e.g., ivcd, qp, consumption rates) and multi-parametric assessment of any type of time-series bioreactor data in the context of experimental protocol data (e.g., process parameters, feeds). genedata bioprocess comes with dedicated interfaces for integrating with relevant laboratory instruments, control systems, statistical analysis software packages and custom enterprise solutions. it enables the modeling and tracking of complex nonlinear workflows and supports decision making in bioprocess development. the data can be analyzed in the context of upstream process development, and also be correlated to other unit operations. automation support assists the ever increasing throughput of bioprocess development operations, and the analysis of experimental data and process parameters across unit operations or even different projects. this overall integration enhances process development workflows. highlighted use cases describe the selection of the best producer clones (fig. 1a) , the identification of optimized media feeding strategies (fig. 1b) , and the comparison of clone performance across different fermentation scales (fig. 1c) . a special focus is on the analysis of data from micro-and bench-top bioreactors (such as the ambr15™ and dasgip™ systems) operated in parallel. these bioreactors allow for increased throughput of clone selection and process optimization studies, which in turn leads to an increase in data generation. genedata bioprocess supports integration with such systems and enables a comparison of data regardless of the instrument provider or scale. automated bioreactor data analysis allows development groups to take advantage of even richer datasets and, as data management is built-in to the system, the data can be easily tracked and associated to historical records. another focus is on cross-reactor scale comparisons. data coming from different bioreactor scales can be easily imported into the platform and analyzed to establish the best conditions for upscaling. genedata bioprocess enables the correlation of process parameters (e.g., fermentation protocols, media recipes, bioreactor control parameters), with key performance indicators of the processes (e.g., titer, qp) and the product quality attributes (e.g., aggregation, glycosylation profiles). finally, bioreactor time course data can be tracked together with clone analytics and product quality parameters, which makes the platform uniquely able to support end-to-end biopharma development. upstream bioprocesses are at particular risk of contamination from adventitious agents. the typical 0.1 μm filters used at this step protect bioreactors from bacteria and mycoplasma but offer no protection from viral contaminations. a new polyethersulfone (pes) upstream virus filter, viresolve® barrier, has demonstrated high levels of microorganism retention -full retention for bacteria and mycoplasma (>8.0 lrv -log reduction value) and~5 lrv for small viruses, such as parvoviruses. it also has improved flow and capacity as compared to virus removal filters designed for monoclonal antibody purification. given the small pore size of virus retentive filters, implementing a virus filter upstream of the bioreactor raises the question of whether critical cell culture media components are removed. therefore, it is important to evaluate the cell culture performance and protein quality attributes using virus-filtered media to ensure that filtration does not negatively impact the process. materials and methods ex-cell® cho media and corresponding feeds were processed through either viresolve® barrier filters or 0.22 μm filters (control). media composition post-filtration was evaluated by high performance liquid chromatography (hplc), inductively coupled plasma/ optical emission spectrometry (icp-oes), and nuclear magnetic resonance (nmr). recombinant cho cells were cultured in fed batch culture. cell density and viability were measured by vi-cell tm cell viability analyzer while metabolites were analyzed by bioprofile® flex analyzer. shake flasks and bioreactors were utilized to verify that surfactants, such as poloxamer, (which are essential for shear protection in stirred tank bioreactors and can be difficult to filter) have not been removed during filtration. monoclonal antibody titer was quantitated by protein a hplc. characterization of the antibody product quality was assessed via weak cation-exchange chromatography (charge heterogeneity), size exclusion chromatography (aggregate profile), and 2-ab fluorescent labeling with np-uplc (glycan species). media and feed compositions were unaffected by filtration through the virus barrier filter. no significant differences in concentrations were observed with icp-oes (trace metals) or hplc (amino acids and water soluble vitamins). nmr showed no change in the organic composition of the media including poloxamer. the aromatic region with vitamin and amino acid signals is shown (fig. 1a) . cell cultures showed no differences in cell growth or titer, in either shake flasks or bioreactors (fig. 1b) . cell viability was unaffected, metabolite levels were within limits, and titer was consistent. the protein quality of the secreted antibodies showed no differences in the glycosylation pattern (fig. 1c) , amount of aggregates or charge variants. the risk of virus contamination in the bioreactor remains a concern for biotherapeutic manufacturers as there is no universal technology that provides a reliable, cost effective solution for virus removal that can be applied to all components of cell culture media. this study evaluated the viresolve® barrier filter that provides an efficient and easy way to protect bioprocesses from adventitious virus contamination. study results demonstrated that media and feed compositions, cell culture performance, and product quality were unaffected by filtration through the viresolve® barrier filter. implementation of vire-solve® barrier filters provides efficient filtration performance, high virus retention, and minimal cell culture impact and offers a viable option to improve the overall virus risk mitigation strategy for the manufacture of biotherapeutics. b tracking of process conditions together with online and offline performance analytics. the system allows to flexibly define tracked parameters and select optimal process conditions. c comparison of process performance across different reactor scales. the open architecture makes genedata bioprocess a provider agnostic system which allows to aggregate and compare data regardless of provider background bi-and multi-specific antibodies, antibody-cytokine fusion proteins, nonimmunoglobulin scaffolds, chimeric antigen receptors (cars), engineered t-cell receptors (tcrs) and tcr-based bispecific constructs can provide significant advantages for use in cancer immunotherapy. however, as highly engineered molecules they pose new challenges in design, engineering, cloning, expression, purification, and analytics. we have thus implemented an infrastructure that addresses these challenges and enables the industrialization of these various novel therapeutic platforms. in close collaboration with leading biopharmaceutical companies, we implemented a workflow, data management and analysis support system, genedata biologics™, enabling the automated design, screening, and expression of large panels of therapeutic candidates using these novel technologies. we have also built tools for developability and manufacturability assessments of these complex molecules. we have ensured that there is a seamless integration of all data generated and that functionalities such as bulk protein and vector generation using our in silico cloning engine, configurable library of template vectors and cloning strategies, fully annotated in silico protein molecules and dna constructs, and dna synthesis verification support, can be used for the newest protein formats and molecule topologies. we implemented data structures and data handling systems, which mirror how these complex next-generation biologics molecules and cell lines are being designed, screened, and analyzed. the result successfully addresses workflows for tcr optimization and engineering. we exemplified this with the generation and evaluation of a panel of engineered tcrs with an alpha chain cdr3 randomization and successfully supported the analysis and selection of beneficial mutations. the system also successfully supported workflows for the design and generation of a panel of tcr-based bispecifics (tcr coupled with anti-cd3) using automated molecule registration and in silico cloning tools and subsequent capture of expression, purification, and functional and analytical characterization data. on the car-t cell front, the system is able to provide traceability of the work from antibody generation, optimization, car engineering (e.g., attachment to the scfv with cd3-zeta and co-stimulatory domains to mimic the natural tcr complex) to the engineering of the t-cell. the genedata biologics platform successfully enabled automation, increased data integrity and traceability during research and development work, and will contribute towards the industrialization of these very exciting novel approaches for cancer immunotherapy. optimal selection of therapeutic antibodies and production cell lines by assessment of critical quality attributes and developability background the increasing cost of bringing a new drug to the market has put significant pressure on biopharma organizations. to increase efficiency in r&d processes and reduce costs, organizations need to evaluate potential drug candidates earlier in the r&d process, eliminate those with undesirable characteristics, and focus on the most promising candidates. after designing and thorough testing of successful candidates, efficient production of new biological entities in mammalian cell lines is necessary. the main goal here is to find a suitable cell line and optimal upstream and downstream processing conditions that not only lead to a satisfactory product yield, but also to a product with the desired biochemical properties. the evaluation of production cell lines, processes, and product quality attributes is performed earlier and in higher throughput for an increasing number of drug candidates. in addition, new methods in molecular and cell biology (e.g., novel genome engineering approaches such as crispr/cas9), in analytics [e.g., process analytical techniques (pats)], in process miniaturization, and in automation promise to make process development more efficient. however, the management and analysis of the increasing amount of experimental data during candidate selection and cell line and process development has become a bottleneck. in addition, quality-compromising steps in biopharma organizations can negatively impact the cost of goods and substantially prolong the drug candidate's time to market. therefore, systems for integrated management and analysis of wellstructured and curated data that comprehensively integrate molecule and sample information, manufacturing process parameters, and process and product quality attributes are needed. critical quality attribute (cqa) assessment should be enabled along the whole bioprocess development workflow, including cell line development, upstream and downstream process development, as well as analytical and formulation development. we have developed a comprehensive platform, genedata bioprocess™, which supports drug candidate developability and manufacturability assessment and bioprocess development. the platform captures and structures the cell line and process parameters together with analytical data for cell lines, processes, and protein products. the protein analytical data being tracked include biological data (such as bioactivity, immunogenicity), and physicochemical properties. these properties include glycosylation, chemical liabilities (such as deamidation and oxidation), aggregation, stability under different conditions (low ph, low and high temperature), solubility, and impurities. genedata bioprocess™ simplifies and streamlines laborious, manual process and supports tools for molecule, clone and process selection. furthermore, the platform allows for seamless integration with laboratory instruments, statistical software packages, and custom solutions. here, we present use cases showing how to identify and annotate liability sites prone to chemical modifications (fig. 1a) and how to monitor cqas of molecules allowing to assess developability more efficiently. we show how the analytical data generated in the course of a developability assessment are compiled to select the best drug candidate (fig. 1b) . implemented traffic-light systems indicate where molecules harbor issues such as in case of the antibody tpp-86, which is compromised by low temperature and repeated freeze-thaw operations. the same assessment views can also be applied on batches and cell lines. the underlying data can be visualized graphically. as an example, we show glycan types of products obtained from different cell line clones generated in a cell line development campaign for the molecule tpp-86 (fig. 1c) . even though the selected clone cli-35 meets the glycosylation criteria (e. g., <13% afucosylation, <40% galactosylation, <2% sialylation), the produced next-generation biologics molecules are composed from a number of specific subdomains. each type of molecule is composed of a specific set of domains, which must be mirrored in the registration and further research and development workflow. molecule registration and hit-selection using data from a number of assays is shown here using the example of car-t cells. the image is a screenshot from the genedata biologics™ software molecule harbors some stability issues as mentioned above. therefore, more attempts would be needed either in formulation or in reengineering of the complimentarity determining regions (cdrs) in order to provide a developable ttp-86-like drug candidate. background environmental process variables are often used as tools to optimize the performance of mammalian cell cultures to achieve higher cell densities and high productivities of r-proteins (q p ). the manipulation of culture temperature in the range of mild hypothermia (mh) (35-30°c) [1, 2] , as well as different glucose availability scenarios [3, 4] , has been shown to improve productivity in different cell lines. however, the manipulation of these variables individually or together has a concomitant effect on the rate at which cells grow, masking the net response exhibited by the cells. in order to identify the effects of these variables, we have taken advantage of the use of the chemostat culture. chemostat cultures were performed at two dilution rate (d)(0.010 or 0.018(h-1)), two temperatures (33 or 37°c) and three feed glucose concentrations (20, 30 or 40 mm). the response was analysed considering r-protein production, cell growth and key metabolites. r-tpa protein concentration was determined by immunoassay (trinilize tpa kit); cells were counted using a hemocytometer and cell viability was determined by the method of exclusion using trypan blue (t8154, sigma, usa); glucose, lactate and glutamate were determined by enzymatic assay using a biochemical analyser ysi (yellow spring instruments). statistical analysis of the results was performed by anova (design-expert 7 for windows). a decrease in cell density was observed in response to an increase of glucose feeding concentration, regardless of temperature or specific growth rate (in this case μ=d) evaluated. the maximum cell densities were reached at 20mm, achieving 1.65 and 1.50 x10 6 cells/ml at 37/33°c and 0.018(h -1 ); and 1.10 and 1.33 x 10 6 cells/ml at 37/33°c and 0.010(h -1 ) respectively (fig. 1a) . the increase in glucose concentration from 20 to 40mm resulted in an q p increase of 3 and 3.3 fold at 33°c/0.018(h -1 ) and 37°c/0.018(h -1 ) respectively. a lower increase of 2.4 and 1.8 fold was reached at 33°c/0.010(h -1 ) and 37°c/0.010(h -1 ) respectively (fig. 1b) . the highest q p s were reached at 37°c and 0.010(h -1 ). however, a positive effect of mh was not observed, in contrast to that observed in batch culture [1, 2, 3] . this behaviour suggests that low μ is a main factor on increased r-protein production in batch cultures exposed at mh condition. the specific consumption rate of glucose was significantly increased by the glucose increase from 20 to 40mm and reduced by mh (fig. 1c) . at 0.010 (h -1 ) the specific production rate of lactate (q lac ) was increased by glucose increase, independent of the culture temperature used. while at 33°c/0.018(h -1 ) the q lac decreased with increasing glucose concentration and at 37°c/0.018(h -1 ) a maximum consumption was observed at 30 mm glucose (fig. 1d) . the lactate-glucose yield ( fig. 1e ) not showed relevant changes at 0.010(h -1 ), while at 0.018(h -1 ) this yield showed a more efficient utilization of glucose, as glucose concentration was increased. however, this last behaviour was not reflected in an increase of r-protein production. the concentration of glucose has the greatest impact on the behaviour of the culture, and its increase affects positively the protein productivity. the mh did not improve proteins productivity of cho cells producing tpa under the different conditions evaluated; low dilution rate and at high glucose concentration impact positively the protein productivity and the metabolism exhibited by the cells. background mammalian cell cultures are the most commonly used bioprocess for the production of therapeutic recombinant proteins such as monoclonal antibodies (mabs). facing to the increasing demand of these biopharmaceuticals, the fda has initiated the process analytical technology (pat) framework in order to encourage pharmaceutical industries to use innovative technologies to monitor in real time the critical process parameters (cpps), and to ensure the final product quality [1] . one of the most important cpps for cell culture bioprocesses is the specific growth rate (μ), which is a direct indicator of cellular physiological state. indeed, μ is sensible to culture conditions and its value decreases when cells are in the unfavourable environment for growth [2] , which may greatly influence mab production and quality. however, until this day, the online monitoring of μ remains a great challenge for mammalian cell culture bioprocesses. igg-producing cho cells were cultured in 2 l stirred bioreactors equipped with an in situ dielectric spectroscopy (hamilton). operating conditions were fixed at 90 rpm, 50% of air saturation, ph 7.2 and 37°c. permittivity of cell culture was measured every 12 min, which allowed to calculate in real time the vcd by using a previously established linear correlation. then, a model of online estimation of μ was developed based on vcd prediction and cell mass balance equations. several signal noise filters and various calculation methods were evaluated to reach better model stability. cell cultures were performed in both batch and feed-harvest modes. feed-harvest cultures consisted of sequential renewals of 2/3 volume of the culture medium by following different strategies. this study proposed an innovative methodology based on dielectric spectroscopy to monitor in real time the cellular physiological state, by online estimating the specific growth rate (μ) of cells. model of online estimation of μ was developed from cultures in batch mode, and was validated by comparing online estimated μ with the experimental ones calculated at the end of the culture. with this model, the moment when μ started to decrease significantly, which indicated that cells were no longer in the exponential growth phase, was identified as the critical moment. to demonstrate the interest of online estimation of μ, the developed model was applied to a feedharvest culture, where the medium renewals were performed at the critical moments indicated by the model. this culture was then compared with the traditional feed-harvest culture where medium renewals were performed by following offline measurements of glucose and glutamine. we found that the online strategy allowed to maintain the value of μ by renewing the medium at the right time, while the values of μ varied a lot when using offline strategy. moreover, by using the online estimation of μ, the glycosylation of igg was kept at a high level (about 95%) throughout the whole culture. however, for the culture using offline strategy, the glycosylation level decreased progressively and was only about 75% at the end of the culture (fig. 1) . model of online estimation of μ was developed by using dielectric spectroscopy, which allowed to monitor the physiological state of cells in cell culture bioprocesses. implementation of this model in feed-harvest cell culture led to better mab glycosylation, which demonstrates clearly the potential of this methodology in mab production bioprocesses. background monoclonal antibodies are normally synthesised from transfected mammalian cells as heterogeneous mixtures of glycoforms [1] . however, clinical efficacy may depend upon single glycoforms which have been difficult to isolate [2] . we have now developed an efficient method for generating single glycoforms by solid phase re-modelling which is superior to previous methods because it allows a sequential series of enzymatic changes without the need for intermediate purification of the antibody. solidphase binding exposes the antibody glycans to enable easier access of the transforming glycosylation enzyme. the antibodies subjected to modification were a chimeric human/ camelid monoclonal antibody (eg2), a humanized monoclonal antibody (il8), a full size chimeric antibody (cetuximab) and polyclonal antibodies obtained from pooled human serum. the antibodies were bound to a protein a column using conditions typical of mab purification (fig. 1 ). after washing out non-bound impurities by a neutral ph buffer, each antibody was subjected to enzymatic modification directed to a targeted glycan profile ( table 1 ). the antibodies were then eluted with a low ph buffer and neutralized. the glycan profiles were analysed following glycan removal with pngase f, labelling with 2-aminobenzamide and separation on a hilic-hplc column [3] . prior to enzymatic modification glycan analysis of all 4 antibodies showed variable galactosylation and sialylation typical of human abs. this included a distribution of fg0, fg1, fg2, fs1 and fs2 with galactosylation indices ranging from 0.22 for il8 to 0.64 for eg2. there was minimal sialylation in il8 but up to 11% in eg2. glycan modifications were made as each antibody was held on a protein a column in accordance with procedures shown in table 1 . agalactosylated glycans were enriched by treatment with the single addition of galactosidase and neuraminidase. this resulted in 83-95% of agalactosylated structures in the mabs and 65% in the polyclonal antibody. galactosylated antibodies (>95% yield) were produced by a single stage reaction involving sialidase and by galactosyltransferase with udp-gal. breakdown of the glycans to a trimannosyl core was accomplished by treatment of the agalactosylated structures with hexosaminidase. this produced a yield of 76-80% of the fm3 structure with a small remainder of fa1. sialylated antibodies (>95%) were produced by a 2 stage reaction involving sialidase, galactosyltransferase and finally treatment with 2,6 sialyltransferase in the presence of cmp-nana. the latter reaction produced equimolar quantities of monosialylated and disialylated cetuximab and polyclonal antibodies. the results suggest that for human antibodies (150 kda) there may be a limitation for sialylation given the steric constraints between the two ch2 domains of the dimeric structure. the ability to sialylate the smaller camelid antibody (80 kda) was greater resulting in a high (>90%) level of disialylated glycans. this suggests that the steric constraints for glycosylation may be lower. these sialylated antibodies have significant potential clinical importance for their ant-inflammatory activities. we have modified the glycans of antibodies following immobilization on an affinity ligand column. this allows enzymatic transformation in a solid state that has a distinct advantage over the equivalent transformation in solution because the enzymes and buffers can be washed out on completion of the modification leaving the antibody still attached to the affinity ligand. this enables repeated rounds of an enzymatic reaction or sequential reaction steps without the need for intermediate antibody purification. the antibody can be removed eventually from the column by application of an elution buffer once all desired glycan modification have been made. since affinity ligand purification of antibodies is performed routinely as an initial step of purification after cell culture, the glycan modification can easily be incorporated into this process. the enrichment of the resulting antibody for a targeted glycoform can enhance the potential therapeutic efficacy as it is known that specific glycoforms are required for certain biological effects. [1, 2] . this is mainly because microvesicles can be enriched/deprived for specific proteins, based on their functional purpose and their cellular origin. recently, microvesicles purified from the supernatant of t24 bladder cancer cells were reported to be enriched for bcl-2 and cyclin d1 (anti-apoptotic proteins), but deprived for bax and caspase-3 proteins (pro-apoptotic proteins) contributing towards immunity against programmed cell-death [2] . however, impact of microvesicles on cho-based bioprocess has not been evaluated yet. therefore, in this investigation, we aimed to evaluate their impact on cell growth and recombinant protein production from cho cells. materials and methods cho-k1 cells were grown in chemically-defined protein-free culture medium (life technologies-1835273) in shake flask (gx-00125p). the different fractions of spent-media (microvesicles and microvesicle-free spent media) were collected using ultracentrifugation method [1, 3] . quality of different fractions was ensured using western blotting for exosomal marker, cd63 (sc-15363) and coomassie stained gel for loading control (fig. 1a) . to evaluate impact on cell growth, cells were seeded with microvesicles and microvesicle-free fraction collected from log-phase of culture and cell counts were performed by vicell using trypan-blue dye exclusion method. for impact on productivity, cell-free supernatant, collected from microvesicle-treated human igg secreting cho culture from stationary-phase of culture with respective control, was evaluated using elisa (ab100547). microvesicles collected from 10% of media (by volume) from routine maintenance cultures compared to working volume for microvesiclesupplementation were used in each experiment. the growth of microvesicle-supplemented cultures had shorter lag-phase and achieved 1.2 fold higher maximum cell density (1.46x10 6 viable cells/ml) compared to untreated standard culture (1.21 x10 6 viable cells/ml) and maintained higher for the remaining period of batch culture (fig. 1b) . however, microvesicle-free fraction did not had significant impact on growth. the viability of microvesicle-supplemented cultures, similar to microvesicle-free media supplemented, was also higher compared to standard culture suggesting potential use of microvesicles for regulating cho growth in production cultures. this could be possibily because microvesicles have already been reported to be enriched with cell growth/death-regulating proteins and hence facilitating cell growth [2, 3] . we have also observed abundance of cell cycle regulators including cyclin d1 in microvesicle-fraction compared to microvesicle-free spent-media in our laboratory (data not shown); however, further investigation are required to prove the hypothesis. the overall productivity of human igg secreting cho cells was also observed to increase bỹ 4 fold following supplementation of microvesicles to the culture without significantly affecting per-cell productivity. since microvesicle-supplementation facilitates cell growth, increased number of viable producer cells in the culture could be expected to be the basis of observed increase in the overall productivity of the culture [2, 3] . the further work is ongoing to in-depth explore the potential of microvesicles for improving recombinant protein production from cho cells. the data indicate that microvesicles secreted from cho cells can improve cell growth and hence recombinat protein production in culture. therefore, strategies need to be developed for sterile isolation of cho microvesicles from routine maintenance cultures and their supplementation into the production culture for improving the performance of cho-based production process. the glycosylation profile of a recombinant protein is one of the most important attributes when defining product quality. producing a protein with desired characteristics requires the ability to modify and target specific glycosylation profiles. traditionally the approach to modify the glycosylation profile of a protein involves supplementing a culture with components that can improve galactosylation. experimentation using this supplemental approach resulted in a dramatic increase in terminal galactosylation, but lacked the ability to easily and repeatedly target specific glycosylation profiles. using novel and proprietary technology, we have developed a feed (glycantune™) and a unique feeding process that will maximize growth and titer while being able to modulate glycan profiles. this new feed can be added as a standalone process that can result in a significant shift from g0f to g1f and g2f (maximum galactosylation). using a unique fed-batch process, glycantune can also be used with a standard feed to dial in targeted glycosylation profiles. through process development, we created a method where a transition point is used to switch from a standard feed to a glycan modulating feed. the timing of the transition point will determine the specificity of the glycan profile. ) . n-linked glycans were digested with pngase f and quantified using 100pmole maltohexose/maltopentose internal standards labeled with 8-aminopyrene-1,3,6-trisulfonic acid (atps) as described by laroy et al [1] or the user guide for the glycan labeling and analysis kit (glycanassure™ user guide, thermo fisher scientific). all ce separations were performed using the applied biosystems™ 3500xl. the timing of transition from efc+ to gtc+ made it possible to target specific glycosylation profiles. modulating g0f from 75% down to 32%, while increasing g1f and increasing g2f (fig. 1) . transitioning to gtc+ early in culture resulted in a greater shift from g0f to g1f and g2f. transitioning midway or late in culture resulted in a greater proportion of g0f compared to g1f and g2f. supplementation based approaches using glycosylation modulating media components to modify and target specific glycosylation profiles proved to be difficult. these approaches were able to increase terminal galactosylation (g1f and g2f), but lacked the ability to fine tune glycan profiles. this could result in numerous rounds of titration experiments to target specific glycan profiles that would likely remain inconsistent between cell lines, culture media and feeds, and process scale. the development of a unique process made it possible to predictably target specific glycosylation profiles. transition from standard feeding to glycantune allowed for precise targeting of glycan profiles. transition to glycantune early in culture resulted in an increased shift from g0f to g1f and g2f. a transition late in culture resulted in increased g0f and decreased g1f and g2f. growth performance during precultures and batch curves in plain shaking flasks did not show any differences among tested surfactants or lots thereof, and cell densities reached 10-12·10 6 cells/ ml ( fig. 1a and b) . experiments with hek 293-f cells at elevated power input in baffled shaking flasks revealed distinct differences between pluronic® f-68, f-127 and kolliphor® p188, with f-127 showing the best performance. peak viable cell densities reached with lots a and b of pluronic® f-68 and f-127 were comparable to those in plain shaking flasks, while those for kolliphor® p188 and lots c and d of pluronic® f-68 were significantly lower. peak viale cell densities were of 2 -12·10 6 cells/ml (fig. 1c) . similar transient transfection efficiency and mean fluorescence of transfected cells independent of applied surfactant and lot thereof indicated no major impact of respective poloxamer (fig. 1d) . interestingly, experiments using fluorescein-labelled pluronic® showed a time-dependent uptake into hek cells. visual tracking revealed an endocytic uptake of poloxamers by the cells (>10fold increase in signal after 96 h) and its co-localisation with cell membrane and lysosomes. sec (fig. 1e) analyses showed differences between the tested poloxamers. especially tested lots of pluronic® f-68 revealed notable deviations in the low molecular weight fraction (peak 2, fig. 1e ), compared to the other poloxamers. cultures subjected to varying levels of shear stress showed distinct growth differences depending on used poloxamer. while experiments in plain shake flasks did not show any differences in growth, cultivations under elevated shear stress in baffled shake flasks resulted in lower peak viable cell densities with kolliphor® p188 and some pluronic® f-68 lots. it remaines unclear whether this can be explained by different membrane protective activities alone, or if other mechanisms, occuring during and after cellular uptake, contribute to this effect. especially for the tested lots of pluronic® f-68, sec of surfactants showed differences in the low molecular weight fraction. this fraction mainly represents polyethylen oxide (peo) (revealed by nmr), which is likely to be a remnant from synthesis. these observations indicate that the use of different poloxamers and lots thereof should be carefully evaluated, especially under elevated shear stress. further experiments will focus on investigating distinct sec fractions of poloxamers. overcoming (fig. 1) . aurintricarboxylic acid (endonuclease inhibitor; enhancer used in e.g. salivary gland transfection) and polyvinylpyrrolidone (polymer; beneficial in electroporation) were both found to negatively impact peimediated transfection of cho cells, while another tested polymer enhanced growth as well as transfection efficiency. the use of a strong chelator led to a high transfection efficiency, but impaired cell growth. based on the results of the independent substance testings, the medium formulation was modified by the addition of a weak chelator and further components including vitamins. different osmolalities between 280 mosmol/kg and 340 mosmol/kg were tested for the final formulation, but no major impact was seen neither on transfection efficiency nor on viability 2 days post-transfection. the final cho tf medium formulation supported high cell growth of finally tested cho cell lines 2 and 3 with peak viable cell densities above 10⋅10 6 cells/ml in batch cultivations with an overall cultivation time of 7-8 days (fig. 1) . further improvements of the process might be achieved by adapting the protocol, as the results shown are based on a simple precomplexing of dna-pei. moreover, product yields could potentially be increased by using feeds, temperature shifts or commonly used enhancers (e.g. valproic acids). scaling of a cell culture process is an essential part in its development. in a typical approach scaling [1] is performed by keeping a (critical) process parameter constant throughout the complete bioreactor range. this can lead to non-beneficial results either on the high or the low end of the range. for instance, the specific power input [p/v] of 30 w/m 3 might result in a good agitation in production scale whereas it leads to a nonturbulent mixing behavior in process development scale. to overcome this issue a new approach for an easy scaling procedure was developed. this "utility function" approach for agitation scaling is based on individual functions with a value-based mapping independent of bioreactor scale. process insight information (established either from doe process investigation or existing experience with a process platform) is directly formalized into a set of mappings which transform bioprocess values into perceived benefits (0 to 1). at each bioreactor scale, parameters (e.g. stirring and gassing) are then chosen to maximize the product of resultant utility functions. the model cho fed-batch process in this trial comprised a cho dg44 cell line that was transfected to produce a humanized antibody igg1. a chemically defined media system was used. the process, including cell line, medium and feeding strategy was designed and developed by sartorius stedim cellca. the aim of the gassing scale-up was to achieve similar cell densities when the addition of pure oxygen starts. for all flexsafe str® bags oxygen was sparged via the micro sparger part of the combi sparger. all other systems used a ring sparger with holes face up. the initial air flow rate was set to an oxygen transfer rate (k l a) of 8 1/h at the corresponding agitation rate and volume. all process engineering characterization parameters were determined according to dechema guidelines [2] . with the use of the utility functions the discrete agitation rate was determined (table 1) . the utility functions led to discrete agitation rates where not only homogeneous mixing but also a turbulent flow pattern and a suitable specific power input was guaranteed. the initial gassing rate of air supplied enough oxygen for 5 x 10 6 cells/ml in all bioreactors. due to the used scaling methods the growth patterns in all bioreactor scales were comparable. peak viable cell densities (vcd) of 20 -26 x 10 6 cells/ml were achieved and viability at the point of harvest was above 80 % in all scales. the final product concentration was in an acceptable range of 2.9 -3.6 g/l. product quality attributes show comparability over the complete bioreactor range (fig. 1) . the harvest criteria of 12 days gave a combination of viability and product concentration that made it easy to process the cell broth during cell removal and other downstream steps. the process implementation of the cho production system -expressing mab 2 was successfully performed with the use of utility functions. cell growth, productivity and product quality is comparable over the complete bioreactor range. background endoplasmic reticulum (er), the central part of the secretory pathways in eukaryotic cells, is responsible for controlling the quality of secreted and resident proteins through the regulation of protein translocation, protein folding, and early post-translational modifications [1] . a number of physiological conditions such as oxidative stress, hypoglycemia, acidosis, and thermal instability can disturb the er functions, which triggers er stress [2] . prolonged er stress induces apoptotic cell death [3] . oxidative stress that naturally accumulates in the er as a result of mitochondrial energy metabolism and protein synthesis can disturb the er function [4] . because er has a responsibility on the protein synthesis and quality control of the secreted proteins, er homeostasis has to be well maintained. when h 2 o 2 , an oxidative stress inducer, was added to recombinant chinese hamster ovary (rcho) cell cultures, it reduced cell growth, monoclonal antibody (mab) production, and galactosylated form of mab in a dose-dependent manner. antioxidants can reduce the oxidative stress level and suppress the apoptotic cell death by scavenging oxygen free radicals, inhibiting chain reaction of oxidation, and detoxifying peroxide [5] . however, despite the importance of mass production of mabs, studies on the effect of antioxidants on the production and quality of mabs in rcho cell cultures have not been fully substantiated. to find a more effective antioxidant in rcho cell cultures, six different antioxidants including baicalein, which have used widely in mammalian cell cultures, were evaluated as chemical supplements with two different rcho cell lines producing the same mab in 6-well plates. then, batch and fed-batch cultures were performed in shake flasks with the supplementation of baicalein, which showed the best effect on culture performance among the 6 antioxidants. the reactive oxygen species (ros) and er stress levels were measured to study the effect of baicalein on mab production and quality. among these antioxidants, baicalein showed the best mab production performance. addition of baicalein significantly reduced the expression level of bip and chop along with reduced ros level, suggesting oxidative stress accumulated in the cells can be relieved using baicalein. as a result, addition of baicalein in batch cultures resulted in 1.7 -1.8-fold increase in the maximum mab concentration (mmc), while maintaining the galactosylation of mab ( fig. 1 and table 1 ). likewise, addition of baicalein in fed-batch culture resulted in 1.6-fold increase in the mmc while maintaining the galactosylation of mab. oxidative stress negatively affected the production and galactosylation of mab in rcho cell cultures. among the various antioxidants tested in this study, baicalein showed the best mab production performance in both batch and fed-batch cultures of rcho cells. baicalein addition significantly enhanced mab production while maintaining galactosylated forms of mab. thus, baicalein is an effective antioxidant for use in rcho cell cultures for improved mab production. background the production of many biopharmaceuticals (e.g. antibodies & proteins for diagnostic and therapeutic purposes) requires the cultivation of mammalian cell lines, which is demanding with respect to various aspects such as complex cell metabolism, variabilities in cell behavior, scale dependencies, influences of changes in cultivation conditions, medium composition etc. although an increasing number of measurement parameters is available, only a part of them is routinely utilized in industrial cell culture processes and their corresponding seed trains. nevertheless, the data base grows, statistical investigation of data gains importance and process data are more easily accessible in the context of industry 4.0. cell cultivation has to consider these complex requirements, e.g. for fed-batch control and seed train design. furthermore, cultivation strategies have to be adapted to new products, cell lines and clones as well as to different production plants when transferring processes. one approach to encounter the variabilities and to include actual information from the process and from data analysis is adaptive model-assisted control [1] . two software tools enabling adaptive model-assisted control applying unstructured, unsegregated models have been developed and implemented using matlab © , winers and fortran, one tool for fedbatch control and another one for seed train simulation and optimization. one key element of adaptive model-assisted control is the underlying process model. in order to provide an adaptive character, model parameters should be easily identifiable from routine cultivation data, which is available during seed train and fed-batch without additional sophisticated measurements. therefore, the usage of unstructured, unsegregated models is recommended. a) example of an unstructured, unsegregated cell culture model (for adaptive model-assisted control) one example, describing cell growth, cell death, uptake of substrates and production of metabolites via a first order system of ordinary differential equations and monod-type kinetics, is shown in table 1 . this mathematical model includes 13 cell specific model parameters [2] . ii) b) open-loop control sequence for seed train simulation and optimization [3] : using model, a priori identified model parameters and starting concentration values, the temporal concentration courses can be predicted for the first scale. subsequently, points in time for passaging and starting values for the next scale can be computed by adding a passaging strategy, seed train conditions and medium concentrations. prediction for the following scales can be obtained iteratively. integrating feedback from the process in terms of cultivation data enables increasing prediction accuracy and responding to possible changes in cell behaviour. process design and optimization, e.g. regarding seed train and fed-batch, is realized by adaptive model-assisted software tools using unstructured, unsegregated models. they enable feedback from the process via routine cultivation data and allow adaptation to diverse circumstances such as different cell lines, products, cultivation conditions, plant configurations etc. ) in polyelectrolyte capsules. significant advantages, such as great mechanical stability, good biocompatibility and good mass transfer properties characterized these capsules based on sodium cellulose sulfate/poly(diallyldimethyl) ammonium chloride (scs/pdadmac) [1, 2] . here, we present the possibility to cultivate human t cells, freshly isolated from blood, to high densities in similar semipermeable polyelectrolyte microcapsules within less than 10 days. cells were encapsulated in semipermeable scs/pdadmac polyelectrolyte microcapsules or confined in 1.5% alginate/poly-l-lysine (pll) beads, a standard approach for cell immobilization. the permeability of the microcapsules was estimated using dextran-based molecular weight standards (10 and 20 kda) and vitamin b12 (1.6 kda). gentle digestion with endocellulase allows an easy release of the cells out of the capsules. cell growth, cytokines production and phenotype were measured in non-encapsulated and encapsulated cells grown under standard culture conditions. moreover, we analyzed the interplay between the secreted cytokines and the scs within the capsules and its putative influence on cell growth. cells mixed in the cellulose sulfate solution under physiological conditions can be safely trapped within a liquid core during capsule formation. encapsulated cells can reached cell densities ≤ 40 x 10 6 cells ml capsule -1 , whereas cells confined in alginate/pll beads and non-encapsulated ones reached 11.3 x 10 6 cells ml bead -1 and 2.4 x 10 6 cells ml, respectively. one major advantage of these polyelectrolyte microcapsules (<1 mm) is the low mwco (<10 kda) (fig. 1a-b) . this restricted permeability allows for a conditioning of the capsule core by autocrine factors, which in turn permits the use of basal cell culture medium instead of expensive t cell specialized media, hence does not necessitate high amounts of rhil-2 and reduces the cultivation costs. moreover, co-encapsulation of rhil-2 had a beneficial effect on the growth kinetics in most cases (fig. 1c) . some evidence is presented that the scs used to form the polyelectrolyte microcapsules, specifically adsorbs il-2 (table 1 ) -a cytokine which provides an essential signal for t-cell proliferation and differentiation [3] . therefore, we postulate that the scs used for encapsulation has biomimetic properties, creating an artificial extracellular matrix mimicking heparin sulfate which in turn positively affect t cell proliferation via trans-presentation of il-2 (fig. 1d) [4] . primary t lymphocytes can be expanded under appropriate conditions outside the body. in the latter, t cells grow/expand in specific environments where the cells are tightly packed, leading to multiple cell-cell contacts and manifold interactions with the extracellular matrix. ex vivo suspension cultures of diluted cells cannot provide such a microenvironment. in the microcapsulesbased cultivation system presented, the cells are suspended in a viscous scs-solution. the low molecular weight cut off of the surrounding polyelectrolyte membrane assures that typical signaling molecules produced by the cells are retained thus facilitates the "conditioning" of the cellular microenvironment, while nutrients and metabolites can pass. expensive additives, such as interleukin-2 (il-2), can be co-encapsulated. expansion then no longer requires specialized t-cell media. moreover, the scs seems to have biomimetic properties, representing an artificial extracellular matrix mimicking heparin sulfate. we consider that the described method may be an appropriate alternative to expand t cells while creating a local microenvironment mimicking in vivo conditions. -175) . equations of balances and kinetics of an employed process model including x v viable cell density, x t total cell density, μ cell-specific growth rate, μ d cell-specific death rate, t time, k s and k monod kinetic constant and monod constant for uptake, k lys cell lysis constant, q cell-specific uptake rate or production rate, respectively, y kinetic production constant, c concentration, glc glucose, gln glutamine, lac lactate, amm ammonia, f feed rate, v volume balances with fed-batch terms kinetics ;uptake if c glc ≥ 0.5 mm : q lac,uptake = 0 if c glc < 0.5 mm : q lac,uptake = q lac,uptake,max q amm = y amm/gln • q gln background digital manufacturing (dm) is heightening the productivity and robustness of existing processes and facilities. it also enables the efficient development of previously unmanageable products or processes and provided the basis for a wave of innovations. dm is a resident and on-line source of continuous optimization of process performance. it relies upon the comprehensive, real-time interfacing of both human and machine sourced information through one centralized system. more than legacy distributed control system (dcs) and supervisory control and data acquisition (scada), it is an integral interconnection of real-time access to divergent sources of information. as such, it can promise deep analysis and predictions leading to shortened product cycle and advanced process control. this comprehensive analysis is extending beyond operations performance data from the production floor to data driving such activities as raw materials security of supply (sos) and business continuity management systems (bcms). digital biomanufacturing (db) can be viewed as yet another, larger, embodiment of digital biotechnology. db is similar to digital manufacturing in that it promotes innovations in the manufacturing of biologicals by using such things as computer aided design, manufacture, verification and deep process analysis using software sensors (fig. 1) . however, the fact that there are living components (cells) involved in the processes puts a distinctly different flavor to the systems employed. it is desirable to use a distinct term here to distinguish it because, as in the terms bioproduction and biopharmacology, db addresses many unique aspects of biologically-based activities. the reasons why the biotech and biopharma industry lags behind other sectors such as the automotive regarding the transformation to digital manufacturing are (i) the complexity and dissipative nature of biological systems, (ii) distributed heterogeneous data and (iii) limited at-line or on-line data sources. however, the costs of genomic sequencing, omics data generation, and computing resources are decreasing rapidly, and at the same time process analytical technologies, computational power and predictive modeling as well as data management infrastructures are greatly improving (table 1) . by removing roadblocks that used to limit approaches, these changes have paved the way to transforming the bioeconomy into an industry that is based on digital knowledge. such new and optimized manufacturing technologies as continuous biomanufacturing and 3d bioprinting can actually demand the interfacing of many sources of information, deep data prior to elisa, the various proteins were incubated at 37°c in scs prepared as for encapsulation. as control, the scs was replaced by pbs. shown are mean values ± sd, n = 3 analysis including software sensors for metabolic fluxes, and model-based predictions of digital biomanufacturing. the application of predictive models for bioprocess optimization greatly improves established platforms and finally leads to a massively increased mechanistic process understanding. four essential benefits result from the increased bioprocess understanding, development, and control of db. first, personnel are relieved of many manual and repetitive tasks. second, strategic planning and operational efficiency are improved. third, we see real-time optimization of end-to-end manufacturing based on such high-value criteria as projected product quality and profitability. fourth, it enables previously unmanageable operations and creates innovative solutions. monitoring between-batch behavior of real-time adjusted cellculture parameters xavier lories, jean-françois michiels arlenda, mont-saint-guibert, 1435, belgium correspondence: xavier lories (xavier.lories@arlenda.com) bmc proceedings 2018, 12(suppl 1):p-192 background cell-culture parameters (ccp), such as ph, may be continuously measured online and subject to real-time automated adjustment (e.g. automated addition of a base to prevent the ph to drop too low). this is an efficient method to maintain the parameter within specified limits. this type of control constraint the variability within the predefined limits and does not provide any information on the between-batch variability of the process. online measurements of ccp provide time-dependent curves presenting one or more transitions. different types of transition can be observed: -the process can shift from a state in which adjustment is needed to keep the ccp in range to a state in which it is not. typically, the ccp drifts away from a limit. -the process shifts from a state in which adjustment is not needed to one in which it is. for instance, a drifting ccp reaches the lower or upper limit of the accepted range. the timepoints at which those transitions take place are here called changepoints. those are aspects of the process and, as such, should be controlled. in the multiple changepoints cases, the approach allows the early termination of runs showing very early or very late first changepoint. the identification of the changepoints position is based on simple rules rather than complex statistical modeling to keep the identification methodology simple. once the changepoint are identified, a multivariate bayesian model is adjusted on the appropriately transformed data. prediction regions are obtained and used as control limits [1] . results obtained for a 2-changepoint case are shown on fig. 1 . points on the right-hand graph represent new batches. the red triangle represents a failed batch. it appears that the control strategy fails to identify the failed batch. two reasons can be considered: -the limits of the prediction region have been established based on 9 points, such a small sample size is likely to be insufficient for the definition of such a control chart. -the tested batches were produced out of set point. a control chart should be used on a stable process, ran in the same conditions, in order to be really relevant. this work was based on available historical data, which is never an ideal situation. the suggested strategy offers a simple approach to the monitoring of between-batch behavior for cell-culture. once the limits have been defined, the approach is quite straightforward and usable by nonstatistician. however, such strategy, as any other of this type, must be based on a sufficient number of batches for the definition of the control limits in order to have a good estimation of the batch-to batch variability. fig. 1 (abstract p-190) . intelligent software applications support digital biomanufacturing process development and control. • databases using data collected online, at-line, and offline from bioprocesses operating worldwide. • process data are used to generate metabolic network models that represent a specific host cell line in a bioprocess. • modelbased computational simulations improve process understanding and reduce experimental efforts for media design, clone selection, and metabolic engineering. • automated data import and processing allow for a streamlined and standardized metabolic process analysis. • identification of critical metabolic parameters is used for proactive steering and control of production processes background rabies is a zoonotic viral disease with a mortality close to 100% [1] . as there is not an efficacious treatment available, post-exposure vaccination is recommended for individuals in contact with the virus. on the other hand, the most common source of virus transmission is saliva of infected animals, mostly dogs, whereby mass vaccination of pets is the most cost-effective way to reduce human infections. in this context, availability of both human and veterinary vaccines is critical [2, 3] . our group had previously developed an effective vlp-based rabies vaccine candidate produced in high density hek293 cell cultures with serum free medium (sfm) [4, 5] . one of the aims in vaccine production process is the achievement of a good productivity with a low cost per dose, mainly in the case of vaccines for animal use in which case the sfm is one of the principal expenses. in this work, we show the adaptation of the producer clone to a non-expensive in-house developed culture medium, in order to reduce the global cost of the process and therefore the price per dose. experimental approach first, we compared a direct and a sequential adaptation protocol of our hek293 rv-vlps producer clone, from 100% of the commercial sfm (ex-cell293, safc) to a new formulation with only 50% of the sfm and a minimum essential medium (p2g), developed in our laboratory specifically for rv-vlps production. this new formulation was called rvpm (rabies vaccine production medium). the specific productivity of rv-vlps in culture supernatants was measured by sandwich elisa, using the 6 th international standard for rabies vaccine that quantify the glycoprotein content (nibsc, expressed in elisa units per ml). further, we evaluated both media for the production of the rabies vaccine, using stirred tank bioreactors operated in continuous mode (biostat qplus, sartorius). the production of the rv-vlps was daily evaluated by elisa and the obtained harvests analysed by the nih potency test for rabies vaccine. after the adaptation process, suspension cultures without aggregates or clumps were obtained, with the same specific growth rate. a lower maximum cell density with the rvpm was reached, achieving 5x10 6 cells.ml -1 , compared with the sfm that reach cell densities between 8 and 9x10 6 cells.ml -1 in batch mode. the specific rv-vlps productivity per cell was maintained, obtaining values of 0.88 and 0.90 eu.10 6 cells -1 .day -1 for the clone being cultured in sfm and rvpm, respectively. taking into account that this producer clone can be changed directly from one medium to the other without lag phase or cell damage, and that in rvpm the maximum cell density reached was lower, this medium was proposed to be analysed in high cell density in perfusion mode for a continuous culture in bioreactor. therefore, we performed two cultures in parallel to compare the efficacy of each media formulation in perfusion. as shown in fig. 1 , we obtained very similar culture performances in both bioreactors; 14.4 eu.ml -1 and 16.1 eu.ml -1 of rv-vlps for the commercial sfm and rvpm, respectively. after that, the harvests were evaluated by the nih potency test obtaining a rabies vaccine potency of 1.2 iu.ml -1 for both cultures (being 1 iu.ml -1 the minimum potency required for animal vaccine). thus, the results obtained represent an interesting advance in the optimization of this vaccine production process since the use of this new medium formulation represents a reduction of 40% of the total cost which will be reflected in a considerable reduction of the price of the vaccine dose. background vaccines are one of the most powerful and effective health inventions ever developedproviding tremendous economic and societal value; yet several factors hinder comprehensive immunization coverage. traditional methods of biologics production, based on stainless steel bioreactors, allow pharmaceutical companies to achieve economy of scale, but are limited by high capital expenditures. such approaches stifle manufacturing innovation and lack long-term cost-effectiveness and sustainability. current innovations can cut biologics' production costs to revolutionize the mainstream use of biologic treatments, focusing on developing fast, potent and cost-effective vaccine production. univercells' mission to make biologics affordable to all initiated a paradigm shift, targeting an innovative single-use manufacturing platform incorporating bioprocess into continuous operations. univercells employs process intensification, using high volumetric productivity bioreactors; and unit steps integration, coupling usp and dsp into continuous operations. the objective is a down-scaled high-productivity process for a cost-effective manufacturing solution. the resulting micro-facilities are easily-deployable in developing countries, breaking entry barriers to biomanufacturing (fig. 1) . manufacturing and distribution advancements, from centralized to distributed, foresee affordable treatments' obtainability via supplying local populations with local production units. -bench-scale fixed-bed bioreactor; -carriers made of 100% pure non-woven hydrophilized pet fibers; -vero cells grown in serum-free and serum containing media; -attenuated polio strains; -cell nuclei on carriers counted by the crystal violet method; -polio virus production estimated by elisa assay (d-antigen content). cultivation of vero cells in medium with serum and in serum-free medium, was carried out in bench-scale compact fixed-bed bioreactors, to determine which culture conditions result in the highest growth rate, the highest cell biomass by carriers and virus production. cells were inoculated at 0.05x10 6 cells/cm 2 and infected during the mid-exponential phase, following a complete media exchange. viral infection took place in serum-free media. in-line clarification and purification is targeted to be performed in only a few steps (maximum one of two) without intermediary diafiltration. in such configuration, we measured that vero cells can reach a cell density of 300-350x10 3 cells/cm 2 with pdl/day of 1.0-1.2 in serum-containing media. this new facility is expected to manufacture any type of viral vaccine at a very low cost and could be deployed at the site of the manufacturer in emerging countries, killing the two birds of cost of manufacturing and distribution with one stone. the presentation will feature the description of the engineering development, but also the preliminary results of cell growth, infections, and product quality, as well as a description of the cogs calculation. univercells developed a disruptive polio vaccine manufacturing technology exceeding expectations when compared to traditional methodsachieving a superior result via its all-in-one solution of a simple, scalable, and fully-disposable vaccine production platform resulting in long-term cost-effectiveness, flexibility and sustainability: -all upstream, downstream and inactivation steps take place within a closed system with all the equipment contained in a low footprint isolatorcreating a confined area for polio virus handling that facilitates the deployment of micro-facilities. -this leads to a dramatic reduction in capital investment, time required for development and increases production capacity. -in conclusion, this is a simple and elegant solution for the industrial production of human vaccines at a low cost in micro-facilities, making polio vaccines available to all. comparison of media formulations for the vaccine production in 1 l stirred tank bioreactors operated in continuous mode. both cultures were performed in parallel using the corresponding medium for the perfusion. a feeding was performed with the commercial sfm. b the first two days of perfusion feeding was performed with sfm until the cell density reach 10 7 cells.ml -1 and, after that, the bioreactor was fed using the rvpm formulation. (↓) on day number 10, 20% of the reactor volume was punctually bled maintaining the working volume background vectored vaccines based on modified vaccinia virus ankara (mva) are reported to stably maintain large transgenes, and to be safe, immunogenic and tolerant to pre-existing immunity. mva is usually produced on primary chicken embryo fibroblasts but continuous cell lines are being investigated as more versatile substrates. we have previously reported development of a continuous suspension cell line (cr.pix) derived from the muscovy duck and efficient production process for mva in chemically defined media [1, 2] . this process allowed isolation of an hitherto undescribed genotype (mva-cr19) that induced fewer syncytia in adherent cultures and replicated to higher infectious titers in the extracellular volume of suspension cultures [3] . replication of mva-cr19 remained restricted predominantely to avian cells, an important property of mva vectors. homologous recombination in cr.pix cells was used to generate viruses with various expression cassettes in deletion site iii [4] and combinations of the differentiating point mutations of mva-cr19 in a backbone of wildtype virus. all recombinant viruses were plaquepurified. successful introduction of the mutations was confirmed by sequencing and specifically designed restriction fragment length polymorphisms (rflps). viruses were analyzed by serial passaging, diagnostic pcrs accross deletion sites [4] , replication kinetics, plaque phenotype and electron microscopy. the genome was further investigated by anchored pcr and long pcr. efficiency of spread of recombinant viruses (fig. 1a) could be mapped to a point mutation in one of the genes, a34r. however, although mva-cr19 carries mutations in three structural proteins we detected no obvious differences to wildtype by electron microscopy (fig. 1b) . the replacement of the left viral telomere by the right counterpart was the most surprising result of our new study (fig. 1c) . this extensive rearrangement affects 15 % of the viral genome and has also increased the area of complementarity between the two telomeres. the recombination site was precisely located and shown via analysis of earlier and subsequent passages to be a stable property of mva-cr19. various viruses, including those with larger dual (dsred1 and gfp) expression cassettes, were serially passaged at least 20-fold. although the genotype of mva-cr19 is advantageous for replication, all genomic and genetic markers of wildtype and mva-cr19 were stably maintained in all passages of the recombinant viruses, independent of wildtype or mva-cr19 backbone. we confirmed our previous results that suggested that mva-cr19 replicates efficiently in single-cell suspensions and were able to connect this property with the d86y mutation in a34, a structural protein on the surface of the virions. mva-cr19 was also found to differ from wildtype mva by a recombination between left and right viral telomere. due to this event, several genes encoded at the left terminus have been deleted whereas the gene dosis of those originally encoded only at the right terminus may have increased. we do not currently know how much the various point mutations and changes in genomic structure combine to explain the improved replication of mva-cr19. as several of the affected genes have been reported in the literature to impact interaction of mva with the host we would expect that in vivo studies may reveal additional novel properties of mva-cr19. an extremely important distinction between our earlier study [3] and this one concerns the source of the viruses. here, we investigated plaque-purified viruses and confirm the high genetic and genomic stability of mva. different expression cassettes inserted into deletion site iii, all diagnostic rflps and pcrs over various sites of the genome and within the viral telomeres remained unchanged throughout at least 20 serial passages -independent of whether recombinant viruses with wildtype or cr19-derived backbones were characterized. fig. 1 (abstract p-225) . a one hallmark of mva-cr19 is a significantly reduced tendency to induce syncytia and an increased dispersion of plaques in cr.pix cell monolayers. this property appears to be supported by the mutation in a34r. b electron microscopy reveals no obvious differences between novel genotype and wildtype. background transient gene expression systems using polyethylenimine (pei) are considered to be fast, flexible and cost-efficient for recombinant protein production [1] . transfection efficiency depends on different factors; one of them is the type of media. production media support cell growth and protein production but not high transfection efficiency (te) mediated by pei [2] . therefore, media were selected for transfection followed by feeding of production media [3] to improve te and protein production. two different transfection strategies are compared: conventional transfection by preparing polyplex of a plasmid (pdna) and pei interaction before transfection and insitu transfection by direct addition both of them to the cell suspension and the polyplex formed spontaneously [4] . cells were seeded 24 hr in chomacs cd media before transfection. at transfection time point an equal amount of cells were resuspended in each media type. transfection was applied either insitu or conventional (polyplex prepared in 100 μl of 150 mm nacl and incubated for 20 min.), media addition was performed 5 hours post-transfection (hpt). media type and transfection condition were illustrated in table 1 . media screen result exhibits the highest transfection efficiency of around 50% transfected cells by opti-mem medium coming along with low cell growth and viability. to improve the transfection efficiency, basic parameters including cell density, pdna, and pei concentrations were varied and higher transfection efficiency was reached by reducing media or accordingly increasing cell density, pei and pdna concentration for transfection. further optimization results show that the transfection of cho-k1 cells in opti-mem (transfection medium) for 5 hours followed by addition of cho-macs cd (production medium) for further enhancing the transfection, cell count, and cell viability. the transfection efficiency (te) increased up to 85 ± 2.6% coincide with increases in viable cell concentration (vcc) in comparsion to transfection and cultivation in opti-mem media alone fig. 1a . both conventional and insitu methods are successfully transfected cho-k1 to the same similar high te as shown in fluorescence microscope images of fig. 1b . insitu transfection shows super-priority for suspension cell transfection concerning the reduction of handling steps (one step) compared to the conventional way (two steps). the insitu transfection avoiding the optimization step required for the incubation period to prepare transfection polyplex but require a higher amount of pdna and pei than conventional way as shown in table 1 . in order to deal with the growing demand of large quantities of therapeutic proteins in a timely fashion, expression systems are being optimized to reduce the time of generation of stable clones as well as to increase the levels of protein secretion. this can be achieved by a combination of expression cassette optimization, cell engineering and selection process. we have previously developed the cumate gene-switch, which is a very efficient expression system for protein production [1] . we have shown that the cumate-inducible promoter (cr5) was the strongest promoter we had tested so far in chinese hamster ovary (cho) cells. with this promoter, we were able to generate stable cho pools capable of producing high levels of a fc fusion protein (900 mg/l), outperforming by 3 to 4 fold those generated with cmv5 and hybrid ef1α-htlv constitutive promoters. besides the strength of the cr5 promoter, we demonstrated that the ability to control both the time and the level of expression during pool generation and maintenance gave a real advantage to the inducible expression system. indeed, we observed that keeping the expression off during selection enabled the generation of pools with superior productivity compared with the pools whose expression was maintained on. moreover, preliminary results suggest that keeping recombinant protein expression down increases the frequency of high producer clones [2] . knowing that one of the main bottlenecks of the successful bioprocessing of recombinant proteins using cho cells is the rapid isolation of a high producer, our data suggest that the cumate gene-switch system could be a valuable platform for the generation of stable clones. the main regulatory authorities and organizations demand proof of monoclonality for biotechnological producer cells. with increasing pressure to shorten timelines and to improve drug safety, technologically advanced methods have to be established to ensure that production cell lines are derived from a single progenitor cell. sartorius stedim cellca's single cell cloning approach is based on one round of fluorescence-activated cell sorting (facs) using becton dickinson (bd) facsariatm fusion cell sorter combined with photodocumentation by synentec cellavista microscopic imaging system. for the approach, critical process parameters such as different cell lines, viability and cell aggregation levels were investigated separately to assess their contribution to the probability of monoclonality. immediately after single cell cloning into 384-well plates (1 cell/ well) the plates were centrifuged followed by imaging using the cellavista (day 0). further cellavista images are taken on day 1, day 2 and on one day between day 5 and 7. outgrowth was defined at day 14. 8 cell lines expressing different recombinant products were investigated to calculate probability of having ≥ 2 cells/well after facs sorting p(d), the apparent probability p(i) of having ghostcells (cells that are out-of-focus and, thus, are not visible during initial microscopic imaging), and the apparent probability p(k) of having ghostcells that outgrow the 384-well stage (fig. 1 ). using these results, the probability of obtaining a monoclonal cell by using sartorius stedim cellca's single cell cloning approach was determined (table 1) by conservative examination: p(monoclonal, conservative) = 1 -(p(d) x p(i)) realistic examination: p(monoclonal, realistic) = 1 -(p(d) x p(k)) cell pools with low viability can theoretically impact the probability of monoclonality by e.g. diminishing microscopic imaging quality (cell debris). therefore, pool cell line 1 with very low viability (≥36 %) was used to demonstrate, that the probability of monoclonality is still 99.9 % in case of low viability on day of sorting: p(monoclonal, conservative) = p(d) x p(i) = 99.9 % p(monoclonal, realistic) = p(d) x p(k) = 99.9 % furthermore, cell pools with high aggregation levels can theoretically impact the probability of monoclonality by sticking together during facs sorting and therefore increase the probability p(d) of having ≥ 2 cells/droplet. therefore, pool cell line 8 with high aggregation levels (≥11.1 %) was used to demonstrate, that the probability of monoclonality is still ≥ 99.9 % in case of highly aggregated cell pools on day of sorting: p(monoclonal, conservative) = p(d) x p(i) = > 99.9 % p(monoclonal, realistic) = p(d) x p(k) = > 99.9 % conclusions in summary, there is no obvious correlation between protein product type and the determined probabilities for monoclonality. furthermore, pools with a viability as low as 36 % and pools with an aggregation level as high as 11.1 % can be used for scc resulting in acceptable probabilities of monoclonality. background ich guidance [1] requires that any cell line used to produce biopharmaceuticals originates from a single progenitor cell. recently, there has been increased scrutiny of the method(s) used to achieve this requirement. here, we review the suitability of the legacy capillary aided cell cloning (cacc) method in light of this changing landscape of expectations. the cacc method is based on the 'spotting' technique [2] and relies on independent visual conformation by two scientists of the presence of a single cell in a 1 μl droplet. this method achieves a high probability of monoclonality in one cloning round. although the method has since been replaced by facs single cell deposition for routine use, it remains a viable cloning method. -performed by trained scientists -dilute culture to 1500 ± 500 cells/ml with ≤2% doublets -draw cell suspension into pipette tip by capillary action; tap tip against the centre of the base of each well of a 48 well plate. -size of resulting droplet =~1μl (fig. 1a ) -two scientists independently view all wells using a microscope (initially use 40x magnification with the entire rim of the droplet visible within the field-of-view. next, examine particles using 100x or 200x magnification to confirm they are cells) and individually record the number of cells present in each well's droplet (fig. 1b to d) . -exclude droplet from further analysis if full visualisation is hindered (fig. 1e to h) . -add growth medium, and incubate plates. record all wells containing colonies; only progress colonies from wells that both scientists agree contains only one cell. -data analysis: -each scientist's observations categorised as: 0 cells, 1 cell or >1 cell -observed outcome for each well: growth or no growth -probability of monoclonality estimated from data using a statistical model cloning (ldc) increased accuracy of p(monoclonality) with cacc -ldc weakness: no visualisation after seeding (to check both well seeding and subsequent growth of colonies is well described by the poisson distribution), potentially overestimating p(monoclonality) -addressed by cacc: visual examination with colonies arising from wells seeded with 1 cell distinguished from those seeded with >1 cell -visualisation step further strengthened by: using controls for exclusion of wells; measuring errors based on the presence or absence of colonies in wells where two scientists independently reported 0 cells; and formally analysing the data using a suitable statistical model decreased time and resource requirements with cacc -high p(monoclonality) possible in single round as each well examined individually with only those containing a single cell progressed, and because the error rate for incorrect scoring is considered to be low two scientists miss a cell one cell sitting on top of another and the two thus appearing as one an experiment was performed to estimate error frequency [3] . conclusion -scientists miss a cell infrequently (in the range 0.4% to 1.3%, [3] ) -error frequency does not invalidate use of direct observation methods for cell cloning -single cell seen by both scientists is highly likely to be monoclonal -during method development, strategies established to control potential sources of error ( table 1 ) use of a contemporaneous visualisation approach, a strict control strategy, and a suitable statistical model (which takes into account potential errors) results in: -the cacc method being at least as robust as the ldc method -the cacc method being a reliable, single-step method for cloning to achieve a high p(monoclonality) background vector design is a key step in cell line development for the expression of therapeutic biologics. it is essential that the vector design results in high, stable expression of the encoded protein. other considerations include ease of cloning, stability for propagation in e. coli as well as in the mammalian host cell line, and ease of sequence amplification for verification of vector construction and for detection of insertion site and copy number in stably expressing cells. for these reasons, use of the same promoters and polya tails in dual cassette vectors, as is common for expression of the heavy and light chains of monoclonal antibodies, can be problematic. in order to minimize sequence similarities between the two expression cassettes, we have modified the promoters, introns, and polya tails of the light chain and heavy chain expression cassettes in the dual expression vector commonly used for the expression of therapeutic antibodies in the chozn® gs -/cell line development platform. gene synthesis and vector construction of igg1 and fluorophore-expressing vectors was done by atum. vectors were transfected into chozn® gs -/cells via electroporation. analysis of gfp and rfp expression was achieved using a macsquant instrument. selection and generation of stable pools and single cell clones from transfections with igg1-encoding vectors was performed as described in the chozn® platform technical bulletin. titer analysis was performed in static (96 well plate), in a 7 day tpp assay and in a 14 day fed batch assay using a qk fortebio. initial screening experiments identified a lead vector, #39, and a vector, #37, which produced very low titers and relatively few minipools expressing detectable levels of igg1. analysis of gfp and rfp expression from the modified vectors indicated relatively high expression from the rfp/hc expression cassette of vector #37. a stronger promoter resulting in overabundance of hc, known to be toxic to cells, provides a possible explanation for the poor results with this vector. interestingly, swapping the positions of the lc and hc in #37 resulted in a vector, #77, that outperformed the initially identified lead vector (fig. 1 ). this same change was made to vector #39 without any resulting improvement in titers (vector #78, fig. 1 ). interestingly, vector #39 had a smaller difference in relative promoter strengths, based on mean channel fluorescence ratio of gfp to rfp, suggesting that overabundance of hc was not an impediment to igg1 expression from #39. poor titers were also seen with a modified version of vector #39 (vector #79, fig. 1 ) in which the glutamine synthethase selection cassette was in the reverse orientation. this second screen identified vector #77 as the lead vector design (fig. 1) . a full comparative study of vector #77 and the control vector was performed, cumulating in the generation and comparison of single-cell clones from each. these studies have demonstrated the equivalence of these vectors in terms of igg1 titer. this work has resulted in the identification and characterization of a dual expression vector with minimized similarity between the two expression cassettes, easing the cloning, propagation and analysis of vector integration in stable cell lines while maintaining the high, stable expression of the encoded protein of the original vector design. background traditional cell line engineering strategies mainly include an antibiotics resistance selection. in this process, cells are transfected with the goi (gene of interest) together with an antibiotics resistance gene and those cells are selected that survive treatment with the respective antibiotic [1] . although the gene responsible for the survival of the cell is transfected together with the goi, resistance is not necessarily linked to high goi expression. thus, a significant proportion of resistant cells may not express the goi at all, necessitating the search for alternative, more closely linked selection systems. sirnas (silencing inducing rnas) are short, noncoding rnas that can bind to complementary mrna and inhibit their translation. this function has been used in many approaches to silence the expression of certain genes [2] . with their short length, sirnas can be hidden in introns (non-translating regions) of genes, making it possible to couple the expression of a sirna to a gene. this way a cell produces a correlating amount of sirna when transcribing the gene, without adding any further translational burden on the cell. the co-expression of the sirna can be used as a selective marker by one of the following methods: (1) knock-down of a suicide gene to enable a cell's survival after suicide gene mrna transfection, (2) down-regulation of a surface marker which is used in macs (magnetic cell separation) to filter out wanted or unwanted cells, and (3) inhibition of a fluorophore marker for selection using facs without product specific antibodies. for sirna based cell selection systems, sirnas replace the commonly used antibiotics resistance as a marker. cells that produce goi will also produce the sirna that protects the cell from a suicide gene. the selection protein (suicide genes, fluorophores, surface markers, etc.) is transfected as mrna and is only expressed during selection. the general process is outlined in fig. 1. (a) the traditional antibiotics resistance marker is replaced by an sirna, which is cotranscribed with the goi. unlike in antibiotic resistance, the marker here is not a protein, reducing the translational burden and providing more resources for goi production [3] . transfection with the suicide gene proved to be 100% lethal within 2 days, with no outgrowth over two weeks. protection by expression of the sirna was shown to be efficient. currently a comparison of stable cell line development programs based on sirna selection and neomycin selection is ongoing. conclusions the novel selection system should speed up cell line development, as the system kills rapidly and directly selects for cells transcribing the product gene on a high level. we expect to see more high producers earlier in the process, which will allow for an easier and faster selection in the following steps. sirna based selection offers great opportunities. by directly selecting based on goi transcription and not a proxy marker, we expect more relevant cells on a pool level. in addition, the elimination of an antibiotics resistance allows more cellular resources for goi production. the system offers multiple ways of application, either by enriching wanted, or depleting unwanted cells. background single-cell cloning is an essential step used in the upstream development of transformed cell lines for therapeutic protein production. while single-cell clones are typically used to ensure product consistency, such low cell density cultures present a survival challenge; cells grow more slowly or may even not survive at low densities in protein-free media, costing the industry time and money and limiting the pool of candidate colonies for choice of production clones [1, 2] . to address this problem, we aimed to develop a highly efficient serum-free medium suitable for optimising single-cell cloning efficiency by studying a range of conditioned media (cm) samples isolated from different chinese hamster ovary (cho) cell lines. materials and methods cho-s, dg44 and cho-k1 were adapted to cho-s sfm-ii (gibco) medium for a minimum of three passages. conditioned media was then collected when the cultures reached a cell density of 1x10 6 cells/ml (typically day 2-day 3 depending on the growth profiles of each cell line and whether they grew in suspension or attached conditions). samples were then centrifuged twice to remove cell pellet/debris and stored at -20°c. the ability of conditioned media to support cho colony formation was then assayed using 96-well plates, seeding the cells at low cell density (1-10cells/well) by diluting down cho cultures in media/conditioned media. after incubation at 37°c for 10 days, cloning efficiency was assayed using a standard xtt assay. initial screening of the nine cm samples was performed using cho-k1 cells due to their widespread use in industrial antibody production. successful media candidates were subsequently screened using additional cho cell lines. table 1) . the k1-sfmii-cm product improved cell cloning efficiency for dg44 cells (avg. increase>1.5-fold) and cho-s cells (avg. increase>3-fold) ( fig. 1) and also the adherent cho-k1 cell line growing in atcc +5%fbs. the ability of conditioned media to support cho growth in limiting-dilution conditions (1, 6 and 10 cells/ml) was investigated. from a range of nine conditioned media samples; four compelling products have been identified which improve low-cell density growth of cho-k1 cells, compared to sfm-ii control media. we feel that these early-stage conditioned media products may increase cloning efficiencies during upstream cho cell line development, resulting in financial savings for industry and increasing the possibilities of identifying particularly highperforming transformed clones. 12 (7):3496-3510. the main rate-limiting step in the upstream stages of protein biomanufacture is the isolation of stable, high producing cell clones. ubiquitous chromatin opening elements (ucoe®s) consist of at least one promoter region with associated methylation-free cpg island from housekeeping genes; they possess a dominant chromatin opening capability and thus confer stable transgene expression. ucoe®-viral promoter (e.g. cmv) based plasmid vectors markedly reduce the time it takes to isolate high, stably producing cell clones. although some ucoe®-viral promoter combinations have been tested, they have not been thoroughly evaluated in chinese hamster ovary (cho) cells. plasmid vectors containing combinations of either the human hnrpa2b1-cbx3 ucoe® (a2ucoe®) or murine rps3 ucoe® linked to different viral promoters (hcmv, gpcmv, sffv) driving expression of an egfp reporter gene were functionally analysed by stable transfection into cho-k1 cells and expression analysed by flow cytometry and qpcr to determine vector copy number. the results at 21 days post-transfection and selection clearly indicate that the rps3 ucoe®-gpcmv and -hcmv combinations give the highest transgene expression as shown in fig. 1 . the a2ucoe®-hcmv/gpcmv constructs were the next efficacious but 2-fold lower than the rps3 ucoe® vectors. the sffv promoter linked with either of the two ucoe®s was the least effective with expression levels 17-fold lower than the rps3-cmv constructs. the rps3 ucoe®-gpcmv/hcmv constructs are now being further modified to include elements that will provide optimal post-transcriptional pre-mrna processing (splicing, polyadenylation, transcription termination, mrna stability) thereby maximising stable cytoplasmic transgene mrna levels and protein production. in the last 20 years, growing number of innovator biologics and biosimilars have formed a competitive environment, where speed and efficiency of generating robust and highly productive cell lines needs to be improved continuously. through various advances, especially in media development and process optimization, product titers as high as 10 g/l were achieved in the pharmaceutical industry (kim et al., 2012) for standard products such as monoclonal antibodies. nevertheless, other proteins e.g. bispecific antibodies, fc-fusion proteins or fab-related products are difficult-to-express (dte) in chinese hamster ovary (cho) and may result in delays or even in termination of the cell line development process. we developed a new robust pool generation approach (cld 2.0) addressing both, easy-and difficult-to-express molecules, while reducing timelines down to 5 months (cld standard = 6 months), improving reliability of cell line development as well as clearly increasing obtained titers. in order to create stable cell lines, we transfected our cho dg44 host cells by electroporation. cells processed using the standard approach were cultivated in selective medium or medium containing additional 2.5 nm methotrexate (mtx) for three weeks. after an amplification step with 30 nm mtx for three weeks, stable individual cell pools were expanded and clones were generated by facs-sorting. clones were analyzed for growth performance and product concentration in fed-batch studies. in our new cld 2.0 approach, we increased mtx concentrations (2.5 nm, 5 nm and 10 nm mtx) during the first selection phase of three weeks. afterwards we omitted the 30 nm mtx amplification step. thereby, pool generation finished four weeks earlier than in the standard approach. to evaluate the stability of cell clones derived from mini pools (mps) generated according to the cld 2.0 approach, stability studies were performed for eight weeks, including stability fed batches at t=2 weeks and t=8 weeks. altogether three different proteins of interest with six cell clones each were tested. we adapted our cell line development process by increasing the initial selection during the first selection phase, thereby allowing the omission of the 30 nm mtx amplification step. we observed that the capacity of amplifiability varied for different products. cell lines with a protein titer ranging from >1 g/l to 1.5 g/l (dte) in shake flask fed-batch showed to be more susceptible to increased initial mtx levels and were thus not amplifiable with 30 nm mtx. in contrast, cell lines with high protein titer >1.5 g/l were observed to adapt to 30 nm mtx easily and were amplifiable. finale shake flask fed-batch data with cld 2.0 clones of highexpressing products showed comparable titers to clones from the standard approach. cld 2.0 clone titers for dte proteins revealed in average a 2.0-fold increase compared to clones generated in the standard approach. titers of top producing clones were in a range of 1.8 g/l to to 2.7 g/l (fig. 1) . furthermore, stability data of cld2.0 cell clones from different dte products showed a stable specific productivity in a range of +/-15 % over eight weeks cultivation. fed-batch titer from t=2 weeks and t=8 weeks were in a normal range of +/-20% of the standard 30 nm projects. our results demonstrate that cld 2.0 is a robust and reliable process for standard products (mab) and dte proteins. with our new process, we were able to increase titer of difficult-to-express proteins up to 200%. by omitting the amplification step (30 nm mtx) 96 % of generated clones were stable over eight weeks cultivation time. additionally using the cld2.0 approach, the time line from dna to rcb was reduced to 5 months. background cho cells have become the most popular platform for production of therapeutic proteins [1] . however, the generation of high-producer cells is a time-consuming and labor-intensive process that requires the screening of large amount of cells to get a clone of high titer and stability. since the expression titer and stability of clone is highly dependent on the site of integration, we demonstrated a new cell line development strategy by using ngs to identify the integration site and using crispr/cas9 to generate the target integrated high producing cell lines [1, 2] . to identify the high expression sites in the cho cells, we employed ngs to analyze the integration sites of a high producing cell line (titer > 3g/l). the pair-end reads with one read mapped to the vector and the other read mapped to the cho reference genome are extracted to identify the integration sites. to test the expression activity of the integration sites, we employed crispr/cas9 to specifically integrate the antibody gene into cho genome for expression. our data showed 4 integration sites are in the high producing cell line. among the 4 integration site, is1 integration site was tested by crispr/ cas9 for target integration of antibody gene for expression. the is1target integrated cell pool present higher expression titer than cell pool generated by target integration into other integration sites (fig. 1a) . the single cell clones derived from is1-target integrated cell pool had low copy number of goi (fig. 1b) . after normalization with copy numbers, the single cell clones derived from is1-target integrated cell pool showed high titer per copy (123~583 mg/l/copy) (fig. 1c) . this study demonstrated the generation of high-producing cell lines by crispr/cas9 mediated target integration. this approach will cost less time and labor than traditional method. the active integration site will serve as a platform like a cassette player for therapeutic antibody production. background cho, hek and sp2/0 are the dominant host cells for biologics drug production. achieving high level of recombinant protein production by these cell lines still remains a challenge. in order to understand the potential roles of lipids in protein production, secretion, vesicular transport and energy metabolism, we coupled high-throughput transcriptomics and lipidomics technologies. quantitative lipidomics is an emerging 'omics technology which can help us understand the physiological limitations of each cell line. the two types of major lipid groups in cells are non-polar and polar lipids. polar lipids such as glycerophospholipids (pls) include phosphatidylethanolamine (pe), phosphatidylcholine (pc), phosphatidylinositol (pi), phosphatidylserine (ps), phosphatidylglycerol (pg), and phosphatidic acid (pa). in this study; we integrated two dimensional high performance thin layer chromatography (2d-hptlc) and mass spectrometry (ms) lipid analysis of sp2/0, cho, and hek cell lines to understand the major differences in the lipid content of these hosts. bligh-dyer method was used to extract the lipids and extracts were analyzed by hp-tlc and ms. the polar lipids were separated into different categories by 2-d hp-tlc using a chcl 3 -meoh-h 2 o (71:25:2.5, v/v/v) solvent system in the first dimension and a chcl 3 -meoh-acetic acid-h 2 o (76:9:12:2, v/v/v/v) solvent system in the second dimension. non-polar lipids were separated by 1-d hptlc using hexane-diethyl ether-acetic acid. 2,7-dichlorofluorescein dye was used to visualize both polar and non-polar lipids. further detailed analysis was performed on a qqq mass spectrometer (thermo tsq vantage, san jose, ca) using negative-ion and positive-ion esi modes as well as negative-ion esi mode in the presence of lithium hydroxide. in this study, quantitative lipidomics was coupled with transcriptomics to further understand the physiological pathways of hek, cho-m and sp2/0 cells. initial hp-tlc analysis indicated that major lipids in these industrial cell lines were pe and pc. other polar lipids such as pi, ps, pg, pa, and sm were lower compared to pc and pe in exponential and stationary phases of each cell line. figure 1 represents 2d hp-tlc results of hek with the relative quantitation of polar lipids. in order to investigate the lipid subgroups, shotgun ms analysis was conducted for both exponential and stationary growth phases of the three cell lines. ms analysis indicated that lysophosphatidylethanolamine (lpe) and lyso-phosphatidylcholine (lpc) amounts were 4 -10 fold and 2-4 fold higher in hek cells compared to sp2/0 and cho cell lines. sphingomyelin (sm) was another lipid subgroup that was shown to have a major difference between sp2/0 and other mammalian cell lines. sm was 30-65 fold lower in sp2/0 cell line compared to cho and hek. to understand these metabolic differences, transcriptomics analysis using illumina highseq and gene expression omnibus was conducted on these mammalian cells. the kyoto encyclopedia of genes and genomes (kegg) database was used to map the transcriptomics data to the lipid synthetic pathways. transcriptomics data mapping to kegg pathways demonstrated that differences in lpe and lpc pathways correlate with the expression profiles of secretory phospholipase a2 (spla2), lysophospholipid acyltransferase (lpeat), lysophosphatidylcholine acyltransferase (lpcat), and lysophospholipase (lypla) [1] . the hp-tlc and lc/ms findings demonstrated that high levels of lpe and lpc existed in the hek cell line and low levels of sm were observed in the sp2/0 cell line. coupling lipidomics with transcriptomics provides us with an improved understanding of the physiological differences across sp2/0, cho, and hek cell lines that could be used to guide cell engineering efforts with the goal of increasing the recombinant protein expression capabilities of these three cell lines. biopharmaceuticals are a class of biological macromolecules that include antibodies and antibody derivatives, generally produced from cultured mammalian cell lines via secretion directly into the media. manufacturing at medimmune requires the generation of chinese hamster ovary (cho) clonal cell lines capable of producing the biopharmaceutical product at commercially relevant quantities with optimal product quality. the isolation of cell clones based on random single cell deposition via fluorescence activated cell sorting (facs) provides a heterogeneous panel of expressers. we hypothesize that the application of facs to provide an additional sorting step based on desirable cell attributes that correlate with productivity, product quality or cell growth attributes could lead to the isolation of higher producing cell lines with enhanced product quality attributes. a panel of 20 cell lines expressing a model recombinant monoclonal antibody were characterised in terms of growth, productivity, intracellular recombinant protein and mrna amounts. assays were also developed to investigate cell attributes using the commercially available imagestream instrument, an imaging flow cytometer, which enables the investigation of cellular characteristics that correlate with cell productivity at the single cell level. characterisation revealed the cell lines exhibited a range of values for productivity, growth, and intracellular (ic) antibody mrna and protein expression, ideal for further imagestream characterisation. western blot and qrt-pcr analysis demonstrated that final titre correlated with both ic heavy chain (hc) protein and mrna amounts (pearson correlation coefficient (pcc) = 0.70 and pcc = 0.80, respectively). to assess productivity at the single cell level, assays multiplexing ic hc protein and mrna with cell attributes were therefore developed. initial assay development focusing on hc mrna and protein amounts has revealed interesting results; four cell lines displayed two distinct populations, one producing the antibody and another nonexpressing population. the ratio of these populations varied amongst the cell lines. images obtained from the imagestream have shown the cellular localization and expression of hc and lc message and protein (fig. 1) . for both message and protein, hc and lc colocalize in the cell. whether there is any relationship between ic hc protein and cell attributes at the single cell level was then also investigated, as well as correlations with cell culture parameters at the population level. at the population level, correlations were found between titre and ic hc protein and mrna (pcc = 0.84 and pcc = 0.79, respectively) confirming the data obtained by western blot and qrt-pcr analysis. a panel of 20 cell lines has been characterised at the population level and show a wide range of antibody expression profiles at both the mrna and protein level. in parallel, assays have been developed for the imagestream to measure hc and lc message and protein amounts at the single cell level. protein and message quantification with the imagestream are consistent with more traditional approaches, such as western blots and qrt-pcr, that operate at the population level. the developed assays are now being used to investigate single cell productivity attributes and for the isolation of more productive clones. background productivity and stability are key factors for the selection of cell line in protein drugs production. large amount of target gene integrated in cell genome could lead to the instability of production. therefore, cells with low copies of target gene integrated in high yield sites could be an ideal production cells for manufacturing. it has been known that the transposon system can control the integrated copy number of target gene and can generate high yield producing cells, it could be a great approach to generate stable high yield producing cell lines carrying low copies of target gene through transposon system. we intended to develop a platform to generate high yield producing cell lines carrying 1-2 copy of the integrated target gene using transposon system. two cho cell lines, cho-s cells and dxb11 cells, have been applied. cells were co-transfected with transposon and target gene expression plasmids. after drug selection, the cell pool with highest productivity per target gene copy was applied to single cell cloning. the productivity and copy number of cell clones were determined, and the stability of cell clones was analysed after culture of about 60 generations. in the stable pools of cho-s and dxb11 cells, the productivities per integrated target gene copy were about 11-13 mg/l/copy and 68-75 mg/l/copy in a batch culture, respectively. after single cell cloning, the integrated copy numbers in most cell clones were less than three copies per cell. in cho-s and dxb11 cell clones, the productivities per integrated target gene copy were 20-60 mg/l/copy and 60-150 mg/l/copy in a batch culture, respectively. the productivity per integrated target gene in cell clones developed by the transposon system was much higher than that in cell clones developed by random integration (fig. 1a and b) . to evaluate the productivity stability of cell clones developed by the transposon system, ten cell clones at generation 0, 30, 60, and 100 were applied in the analysis. of interest, about 80% of cell clones were stable at generation 60, but lost the productivity at generation 100 (fig. 1c) , implying the most cell clones could maintain the stability within 2 months. using the optimized conditions of the transposon system to develop the stable gene expression cells, the productivity per integrated target gene was higher than random integration. these results suggested that our platform is capable to develop high yield producing cells with 1-2 copy of integrated target antibody gene and can be applied to identify high yield integration sites. background mammalian cells show an inefficient metabolism characterized by high glucose uptake and the production of high amounts of lactate, a widely known growth inhibition by-product [1] . recently, we have observed a different glucose-lactate metabolism in some cell lines. while some cell lines are unable to metabolize lactate, others can co-metabolize simultaneously glucose and lactate under certain culture conditions, even during the exponential growth phase [2] . these metabolic differences between different mammalian cell lines (cho, hek293 and hybridoma) have been studied by means of flux balance analysis (fba). three different cell lines were cultured in a 2-liter bioreactor: cho-s, hek293sf and hybridoma kb-26.5. for the fba, two adapted genome-scale metabolic models were used: a reconstruction of mus musculus for cho and hybridoma [3] , and a reconstruction of human metabolic model (recon 2) for hek293 [4] . in cultures where ph was not controlled, two different metabolic phases were observed for cho and hek293 cells. during the first phase both cell lines produced large amounts of lactate as a consequence of the high glucose consumption rates. interestingly, when ph dropped below 6.8, due to acid lactic secretion and accumulation, a second metabolic phase was identified, in which concomitant consumption of glucose and lactate was observed even during the exponential growth phase. conversely, hybridoma cells were unable to co-consume lactate and glucose simultaneously even under noncontrolled ph conditions. therefore, the hybridoma physiological data used for the fba corresponded to only phase 1 of phcontrolled cultures. a summary of the main cell growth and metabolic parameters obtained from the different experiments performed is presented in table 1 . fba shows ( fig. 1 for hek293 cell culture) that lactate is produced in phase 1 because pyruvate has to be converted to lactate to fulfill the nadh regeneration in the cytoplasm and only a small amount of pyruvate can be transported into tca through acetyl-coa. cell metabolism in phase 1 is highly inefficient, as the majority of the carbon source is not used for the generation of energy nor biomass. in phase 2, in which mitochondrial ldh was considered, tca fluxes could be maintained as in phase 1 at the maximal rate encountered; hence, the energy available for cells to grow was similar in both phases, obtaining similar growth rate. two different glucose and lactate metabolism behaviors have been observed in cho and hek293 cultures depending on the culture conditions: phase 1) glucose consumption and lactate production, and phase 2) glucose and lactate simultaneous consumption. in contrast, only phase 1 was observed in hybridoma cultures even when ph was non-controlled. fba showed that tca fluxes in phase 1 and phase 2 were similar, obtaining similar cell growth rate, but glucose uptake rate was much lower in phase 2 due to the lactate co-consumption. some authors hypothesize that cells metabolize extracellular lactate as a strategy for ph detoxification [2] . glucose and lactate co-metabolization resulted in a better-balanced cell metabolism, as can be seen from the metabolic fluxes calculated, with minor effects on cell growth. the observation of glucose and lactate co-consumption metabolic behavior and its deeper study and characterization could open the door of novel culturing strategies with the aim of increasing bioprocesses productivity. background transient protein expression in mammalian cell lines has gained increasing relevance as it enables fast and flexible production of high-quality eukaryotic protein. considerable efforts have thus been made to overcome existing limiting aspects of transient gene expression systems, in terms of cell lines, cell culture-based systems, and protein production in a cost-effective manner. milligram amounts of protein per liter can be produced within several days, allowing a significant shortening of the bioproduction process in comparison to protein production from stable clones. to ensure the robustness of the process, it is essential to have a reliable and easy-to-use transfection method. to palliate for the need of a reliable transfection reagent, we developed peipro®, the only commercially available pei optimised for mid to large-scale transient protein production during process development. peipro® is a non-polydiperse and fully-characterised polymer that has become the gold pei standard due to its reliability, reproducibility in high dna delivery efficiency and in ensuing high protein production yields. here, we present experimental data showing the benefits of using peipro® for protein production in comparison to other peis. we further demonstrate compatibility of using peipro® for recombinant protein production in most commonly used chemicallydefined media. materiel and methods suspension hek-293 and cho cells were cultured in shaker flasks in various synthetic media, as listed in table 1 . hek-293 and cho cells were resuspended at 1×10 6 cells/ml of serum-free medium, on the day before transfection. cells were transfected with 0.5-1 mg of plasmid dna encoding for the luciferase gene reporter using peipro®, pei "max" and l-pei 25 kda (polysciences, warrington, pa) resuspended at 1 mg/ml according to the manufacturer's recommendation. protein expression of the luciferase reporter gene was assayed 48 hours post-transfection by affinity chromatography using protein g (hplc). comparison of peipro® to other commercially available peis was achieved by transfecting suspension hek-293 and cho cells with plasmid dna encoding for the luciferase gene reporter. luciferase production yields obtained in hek-293 and cho cells were at least respectively 5-fold and 10-fold higher when using a similar amount of peipro in comparison to the other peis (fig. 1) . furthermore, peipro® was the only pei that led to similar luciferase production yields when decreasing the amount of plasmid dna per liter of cell culture. conversely, at least 1 mg of plasmid dna and 4-fold more of pei "max" and l-pei 25 kda were needed to obtain a similar luciferase expression range in both hek-293 and cho cells. we further assessed the compatibility and versatility of peipro® by measuring protein production yields obtained in most commonly used animal-free synthetic media. as shown in fig. 2 , peipro® leads to high protein production yieds in several commercially avaialble media formulations for hek-293 anc cho cell lines. peipro® is the only fully characterised pei transfection reagent that is suitable for reliable and reproducible recombinant protein production, irrespective of the scale of production and of the type of adherent and suspension cell culture system. fig. 1 (abstract p-274) . peipro® requires less reagent and similar to lower dna amount compared to other peis. suspension hek-293 and cho cells were seeded at 1×10 6 cells/ml in serum free medium and transfected with peipro®, pei "max" and l-pei 25 kda (polysciences, warrington, pa) resuspended at 1 mg/ml. luciferase expression was assayed 48 h after transfection using a conventional luciferase assay fig. 2 (abstract p-274) . peipro® is optimized for transfection of hek-293 and cho cells in several specific synthetic culture media. suspension hek-293 and cho cells were seeded following the recommended protocol in serum-free media and transfected with peipro® using the standard conditions. igg3-fc production was assayed 48 h after transfection using protein g affinity quantification (hplc) monoclonal antibodies (mabs), which are widely used in anticancer therapies, are mainly produced by mammalian cell lines. mab conjugation to biological molecules for enhancing their antitumor activity offers a new powerful tool for anticancer therapies. we have assessed the production of commercially approved anti-her2 therapeutic antibody trastuzumab (tzmb) [1] and also its fusion with interferon-α2b (ifnα2b). two cloning strategies consisting in transfecting cho-s and hek293 cell lines with two bicistronic or with a single tricistronic plasmids have been assessed. the in vitro efficacy of both antibodies has been tested and compared side by side. tzmb heavy and light chains were cloned in two bicistronic plasmids (pirespuro3 and piresneo3, clontech) and in a tricistronic plasmid derived from pirespuro3. ifnα2b was spliced to tzmb heavy chain by overlap extension pcr and the resulting tzmb-ifnα2b fusion protein was also cloned in the expression vectors in the same way than non-modified tzmb. selected cell pools were cultured in 125 ml shake flasks containing sfmtransfx supplemented with 10% v/v of cell boost 5 (hyclone), 4 mm of glutamax (gibco) and 2 μg/ml of puromycin and also with 700 μg/ml neomycin in the case of the cells transfected with pires-neo3. cells were cultivated in the same conditions as described elsewhere [2] . purified products (using protein a chromatography (hitrap mabselect sure, äkta avant 150)) were quantified by both elisa and sds-page. antigen binding test was performed in sk-br-3 breast cancer cell line by means of flow cytometry analysis. the biological activity of the different candidates was tested with mtt assay. both tzmb and the fusion protein tzmb-ifnα2b have been successfully expressed in cho-s and hek293, which use for heterologous protein expression have previously been optimized in prior works [3] . the tricistronic strategy resulted in the most efficient, showing a 3.5fold increase in terms of productivity with respect to the bicistronic double-transfection for tzmb in cho-s cells and a 5-fold increase in hek293 cells (fig. 1a) . in the case of tzmb-ifnα2b, the tricistronic strategy also allowed to achieve higher productivities than the bicistronic one (fig. 1b) . regarding the differences of specific productivity between both cell lines tested, hek293 emerged as the best production host candidate, for the two tested strategies (tricistronic and bicistronic) and for the two produced proteins, showing a 1.5-fold increase in terms of productivity with respect to cho-s cells for tzmb using the tricistronic strategy. tzmb and tzmb-ifnα2b were analysed in terms of their antigen binding capacity, and both were find to efficiently bind to her2+ skbr-3 cells (fig. 1c) . thus, the antibody affinity to her2 antigen has not been affected when fused to inf-α2b. finally, antiproliferative activity of tzmb and tzmb-ifnα2b were assessed on the same sk-br-3 cells. at a concentration of 500 nm of tzmb, and after a 72-hour incubation, sk-br-3 cells presented a 83% growth with respect to the untreated control. however, no antiproliferative effect was observed for tzmb-ifnα2b (fig. 1d) . the tricistronic strategy provides higher productivity yields in hek293 and cho-s cell lines for both recombinant proteins (trastuzumab and tzmb-ifnα2b). regarding which cell line is the best production host candidate, hek293 achieved higher productivity than cho-s cells for the two proteins tested. all constructions performed preserved the binding affinity to its antigen, trastuzumab and tzmb-ifnα2b bind efficiently to the her2 antigen present in skbr-3 cells. finally, tzmb-ifnα2b does not present an improved antiproliferative effect with respect to trastuzumab when compared by means of an in vitro assay. the genetic engineering of patient-specific t cells with lentiviral vectors (lvv) expressing chimeric antigen receptors (car) for late phase clinical trials requires the large-scale manufacture of high-titer vector stocks. the state-of-the-art production of lvv is based on 10-to 40layer cell factories transiently transfected in the presence of serum. this manufacturing process is extremely limited by its labor intensity, open-system handling operations, its requirements for significant incubator space plus costs and patience risk due to presence of serum. to circumvent these limitations, this study aims to develop a stable and serum-free process to produce lvv with pei-mediated transfection. in addition, this study also focuses on the development of a a c b d fig. 1 (abstract p-276) . expression of trastuzumab (a) and trastuzumab-ifnα2b (b) from bicistronic strategy (bc) and tricistronic strategy (tri) with cho-s and hek293 cells. relative specific productivity units are used for comparing the different strategies. c antigen binding analysis of trastuzumab and trastuzumab-ifnα2b. d antiproliferative activity of trastuzumab and trastuzumab-ifnα2b on sk-br-3 cells production system not only using a gfp marker but also a therapeutically relevant transgene (cd20-car) [1] . therefore, three different cell lines (hek 293, 293t, 293ft) were investigated concerning their productivity of lvv and their growing behavior in the in-house serum-free medium transmacs. as part of this, design of experiment was used to investigate the optimal conditions for pei/ dna-transfection. furthermore, this statistical approach was used focusing an ideal ratio between the 3rd generation plasmids (transfer plasmid cd20-car or gfp, envelope plasmid, packaging plasmids). in addition, different enhancers (sodium butyrate, lithium acetate, caffeine, trichostatin a, cholesterol, hydroxyurea, valproic acid) were investigated concerning their effects on productivity comparing hek cultures producing lvv encoding for gfp-marker or cd20-car. concerning productivity and growing behavior, hek 293t was the favored cell line for our serum-free lv manufacturing process. in addition, an additive screen revealed that sodium butyrate alone had the most promising effect on both gfp-lvv and cd20-car-lvv production. after pei/dna titration, we finally could increase lvv productivity by lowering pei/dna amount at higher cell densities referred to our standard transfection protocol. furthermore, the titration for the optimal plasmid ration revealed, that for large transfer constructs higher amounts of transfer plasmid are required than for smaller constructs to achieve a high productivity (fig. 1) . the outcome of these experiments enabled the development of a robust hek293t based process to produce clinical relevant lvv under serumfree conditions. furthermore, it provides an insight how therapeutic genes and the expression of its transgene can influence cell productivity. led to a vast increase in productivity, cho cells yield less than other expression systems like yeast or bacteria [1] . to improve yields and find beneficial bioprocess phenotypes, genetic engineering plays an essential role in recent research. the mir-23 cluster with its genomic paralogues (mir-23a and mir-23b) was first identified as differentially expressed during temperature shift, suggesting its role in proliferation and productivity [2] . the common approach to deplete mirnas is the use of a sponge decoy which, requires the introduction of reporter genes. as an alternative this work aims to knockdown mirna expression using the recently developed crispr/cas9 system which does not require a reporter transcript. this system consists of two main components: the single guide rna (sgrna) and an endonuclease (cas9) which induces double strand breaks (dsbs). these dsbs can result in insertion or deletion (indels) of base pairs which can disrupt mirna function and processing [3] . a cho-k1 cell line stably expressing an igg was used for knockdown experiments. sgrnas were designed to target the seed region of each mirna member and stable mixed populations were generated (fig. 1a) . total rna form each mixed population was reverse transcribed into cdna using mirna specific stemloop primers. the expression was quantified by rt-qpcr. to further analyse the range of indels the mir-23a and mir-23b clusters were amplified by a standard high-fidelity pcr. amplicons were cloned into pcr tm -topo® vector and positive clones were analysed by sanger sequencing. cell growth was monitored using viacount tm viability stain on a guava tm benchtop flow cytometer. productivity was assessed by elisa. students t-test was used for statistical analysis. it was shown that mirna expression was significantly reduced in mixed populations. a knockdown up to 95% was achieved for mir-23a, mir-23b and mir-24. the knockdown in mir-27a and mir-27b expression was considerably less -between 70-90% (n=3, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001) (fig. 1b) . furthermore, it was shown that various sizes of indels were generated by targeting the seed region. smaller indels (+1/ +2/-1/-2 bps) seemed to be more common but larger deletions were detected as well (fig. 1c) . mir-23a, mir-23b and mir-27b showed increased viability in late stages of the culture. depletion of mir-27a reduced growth significantly whereas knockdown of mir-24 showed increased proliferation as well as boosting igg titers (table 1) . in this work, we have shown that crispr/cas9 can be successfully applied as a tool to knockdown mirna expression in cho cells. the data was generated using mixed pools and it remains to be established if both alleles can be successfully targeted e.g. using nextgeneration sequencing of individual clones. background chinese hamster ovary (cho) cells are the most widely used host cell line for the production of therapeutic antibodies. pre-and posttranslational modifications and optimization of culture methods contributed to increase the productivity, resulting in a very high titre [1, 2] . however, it has been pointed out that the intracellular secretion process is a bottleneck in the production of therapeutic antibodies [3] . in addition, the details of the process of secretion of humanized recombinant antibodies from cho cells have not been well investigated. in this study, we thus analysed the detailed process of secretion of therapeutic antibodies using cho cell lines, which have already been established as high producers, with the aim of obtaining information for the more rational and efficient establishment of high-producer cells. we performed 1) chase assay, 2) immunofluorescent microscopy observation, and 3) size exclusion chromatography (sec) analysis to investigate the duration of secretion, bottleneck position, and formation of recombinant igg, respectively. high-producer cho cells expressing humanized igg1 [4] and igg3 were used. for the chase assay, cells were cultivated in shake flasks with serum-free medium containing 50 μg/ml cycloheximide (chx) to stop nascent peptide synthesis. the amounts of igg both remaining in the cell and secreted into the medium at each time point were measured by quantitative western blotting. for immunofluorescent microscopy observation, cells were cultivated on coverslips with chx for 4 h. immunofluorescent staining against the recombinant igg, endoplasmic reticulum (er), and golgi apparatus was performed after chemical fixation. for sec, cells cultured with chx were re-suspended in a buffer containing tritonx-100 and injected into a column. the amount of igg in each fraction was measured by quantitative western blotting. the amount of igg3 in the supernatant increased until 4-6 h after the inhibition of protein synthesis by chx; however, it hardly changed thereafter (fig. 1, upper panel) . at this point in time, however, around 40% of igg still remained in the cells (fig. 1, lower panel) , meaning that all of the synthesized igg could not be secreted into the medium and remained in the cells for several hours. this result was almost the same as that of studies using igg1-expressing cells [5, 6] . the localization of igg in the cells was checked before and after the addition of chx, with the results showing that igg1 remained in the er and was hardly seen in the golgi apparatus [5] [6] [7] ; igg did not seem to be efficiently transported to the golgi apparatus. the sec experiment showed that most of the igg1 remaining in the cell seemed to form full-sized antibodies [5, 6] , but it could not be secreted despite this. the high-producer cells could not secrete all of the synthesized igg, and around 40% of igg remained in the cells for several hours. this incomplete secretion is a common phenomenon among cho cells producing different types of recombinant igg. the igg could not be transported from the er to the golgi despite its formation of fullsized antibodies. solving this bottleneck in the transportation of igg from the er to the golgi and/or achieving more efficient glycosylation of igg after the formation of full-sized antibodies might be the next target to improve productivity. background humanized monoclonal antibodies (mabs) are among the most promising drugs, but defined strategies for their modification are still not available. our work deals with humanization of murine mab2/ 3h6. the superhumanization approach leads to a loss of binding affinity which was partially restored by a single human-to-mouse backmutation (t98hr). [1] this residue was selected by synergistic combination of sequence analyses of antibody framework regions and structural information using novel in silico simulations. for structural stabilization, a conglomeration of tyrosine residues surrounding t98hr was identified, the so called "tyrosine cage". [2] analysis of the "tyrosine cage" was done by alanine scanning mutations with a double mutation variant t98hr + y27ha (bm09) and a triple mutation variant t98hr + y27ha + y32ha (bm10). in a recent series of experiments we tried to enhance binding affinity by three new variants with backmutations in the variable light chain (vl). originating from t98hr, residues in the vl were selected based on their spatial proximity to the cdr3 loop of the variable heavy chain. affinity improvement of t98hr was evaluated by vl-double backmutation variants t98hr + f46ll (su01) and t98hr + q49ls (su02) and a triple backmutation variant t98hr + f46ll + q49ls (su03). all five variants were expressed transiently in hek293-6e cells and binding affinities were investigated in two individual settings with bio-layer interferometry. in the first approach concentrated cell culture supernatants were directly applied and mabs were captured on protein a tips, blocked with 3d6scfv-fc and the association and dissociation of 2f5 igg was measured. for the second approach, the culture supernatants were purified and the affinity was determined with streptavidin biosensors. first, biotinylated 2f5 igg was bound and then the association/dissociation of the purified 3h6 variants was measured. affinity evaluation of concentrated culture supernatants with protein a sensor tips showed a decrease of binding affinity of bm09 and a loss of binding of bm10. the protein a measurement showed an increased binding strength of su01, su02 and su03 compared to su3h6 and bm07. su01 and su03 result in a higher binding affinity compared to su02. these results can be confirmed with purified variants by the streptavidin bio-assay (fig. 1) . alanine scanning of the tyrosine cage demonstrated a reduction of binding affinity (bm09) and a severe loss of binding (bm10), concluding that the tyrosine cage plays an important role for supporting a correct cdr loop conformation. further affinity improvement of the single mutation variant t98hr could have been reached via mutations in the vl. it demonstrates the underestimated role of the vl for the interaction with its binding partner. although cho cells are a major expression system for production of recombinant biopharmaceuticals, the molecular and cellular background characterizing a high producer is largely unknown. it has been observed that in producer cell lines important signaling pathways like the akt-signaling are altered in characteristical ways. thus analyzing according signaling events should lead to identification of key elements characterizing high producer cells. to investigate this, our emphasis lies on the phosphorylation status of involved proteins as reversible switches in all signaling pathways. we aimed to establish a workflow for cho-specific phosphoproteomics and focused on igf signaling, as cell culture media often are supplemented with this growth factor. two producer cell lines and the according parental cells were cultivated in a stable isotope labeling with amino acids in cell culture (silac) experiment, followed by quantitative ms phosphoproteomic analysis including chospecific data evaluation. the chosen cho cell lines were cultivated in triplicates in silac media containing isotopically-labeled lysine/arginine (hlys/harg) and in parallel in identical standard media (llys/larg, tcx10d, xell). cell density, viability, metabolism and cell cycle distribution were monitored during 50 ml batch culture for 7-8 days. at day 3.25 igf was added into hlys/harg cultures. 5 min later a part of the cells was harvested. for ms analysis igf-treated (hlys/harg cultures) and control cultures (llys/larg cultures) were combined. the following ms sample preparation workflow included digestion of whole protein lysate and phosphopeptide enrichment via tio 2beads. nanolc-esi-orbitrap ms (q exactive plus, thermo fisher scientific) of phosphopeptides was excecuted with subsequent identification and quantification in maxquant [1] . in addition to silac quantification of h/l ratios for investigation of igf effects, aquired data was also used to perform label-free quantification (lfq) in maxquant [1] for comparison of cell lines. statistical significance was calculated via t-test (p<0.05) or anova (permutation-based fdr<0.05) in perseus [2] . results igf effects on growth and production the igf treatment resulted in a prolonged viability for all cell lines. however, an increased vcd was only observed for producer cell line 1, yielding in an enhanced integral of vcd (ivcd). for the parental cells growth was inhibited by igf, although s-phase cells were enriched at least temporary (fig. 1a) . regarding antibody production igf led to a decreased qp and product titer, concomitantly with an increase in s-phase cells (fig. 1a) . this inverse correlation of proliferation and cell specific productivity is known from different productivity enhancing molecules, like butyrate [3] . ms investigation of signaling events the phosphoproteomic experiment resulted in the identification of 10.485 class i-phosphorylation sites. statistical evaluation of phosphopeptide abundances in perseus showed up 144 significant differences between the cell lines and led to producer vs. parental classifications (fig. 1b) . the quantitative evaluation via silac yielded in about 2.408 quantifiable phosphosites in at least 6 biological replicates. rapid phosphorylation changes after growth factor treatment indicated signaling towards protein synthesis, cell cycle and regulation of actin cytoskeleton amongst others. for 201 phosphosites significantly different h/l ratios were calculated between the two groups parental vs. producer, four of them are listed (table 1) . the workflow to study phosphorylation states revealed differences in the related cell lines and gave insights into signal transduction as a response on igf. on the one hand, igf-treatment resulted in a fast and widespread upregulation of phosphorylation sites within aktand mapk-signaling. on the other hand, a different phosphorylation status for producer compared to parental cell lines uncovered distinctions in biological processes like rna-and dna-binding and regulation of cytoskeleton. in sum, our sucessfully established phosphoproteomic approach allows to detect important signaling key players in cho cells that subsequently can be targeted through cell engineering or small molecule treatment. to improve antibody production in the cho cell expression system, it seems to be useful to up-or downregulate gene expression including antibody folding, secretion, and cell metabolism. many cell engineering approaches, including gene introduction, knockout and knockdown, have been employed to enhance recombinant antibody production [1] . however, identifying production enhancer genes is the rate-limiting step for cho cell engineering, because the conventional method requires a series of experiments including genomic integration of the tested genes, selection of stable cell clones and cell culture experiments of several clones. in this study, we propose an approach for rapid evaluation of production enhancer genes based on an episomal expression system. plasmid vector carrying the epstein-barr virus (ebv) encoded nuclear antigen 1 (ebna1) was transfected into cho cell line producing igg1 antibody. after g418 selection and single colony isolation, ebna1 expression was checked with capillary electrophoresis system wes (proteinsimple). ebv ebna1-antibody (1eb12) was used for detection as the primary antibody. the expression vector for the gene of interest was prepared by inserting 1508 bp of an orip dna sequence into a plasmid vector carrying cag promoter, resulting in the potc vector. pei max (polysciences, inc.) and balancd transfectory cho (irvine scientific) were used for the transfection. the number of viable cells and gfp-positive cells were counted using countess ii fl automated cell counter (thermo fisher scientific). the transfected cells were cultured in cellstar cellreactor tubes. the tubes were incubated in a climo-shaker isf1-x (kuhner). antibody production was measured using biolayer interferometry with an octet qk system (fortebio). we constructed four cho cell lines stably expressing ebna1, termed igg1-eb01 to eb04. in capillary electrophoresis analysis, we observed a clear peak corresponding to the ebna1 expression in all four cell lines. we tested the transfection efficiency by potc-gfp plasmids. in the best transfection condition, pei/dna ratio of 1/1, igg1-eb01 cell showed the highest gfp-positive cell number (1.07×10 7 cell/ml) and transfection efficiency (95%) among the four cell lines. therefore, igg1-eb01 cell lines were selected for further study. after the transfection, the number of gfp-positive cells continued to increase even after the passage (fig. 1) , suggesting that the potc-gfp plasmid was stably retained and replicated by ebna1/orip system in igg1-eb01 cell lines. in preliminary experiments, we introduced three genes, mdh2, gss and gclm, into igg1-eb01 cell lines. cotransfection of these three genes led to an increase in igg1 production from 287±18 mg/l (control) to 334±21 mg/l at day 8 (p<0.05, t-test, n=3). this result suggests that these three genes work as production enhancer genes. conventional methods based on stable cells take up to 6 months to determine whether the gene of interest is beneficial for recombinant igg1 production. in contrast, identification of production enhancer genes is achievable within 10 days by our proposed method based on ebna1/orip system. the proposed method makes it possible to evaluate production enhancer genes in a rapid manner. the proposed method is a promising approach to identify genes enhancing recombinant antibody production. background 2g unic™ (2gun) technology comprises a set of protected genetic elements that improve protein production by acting on transcription as well as on translation. the elements can either be inserted into existing (platform) vectors or be provided as complete ready-to-use vectors. the technology can be used in stable and in transient transfection to boost protein production for product development and is being applied in cld for pharmaceutical proteins. in combination with antibiotic selection or dhfr selection, 2gun technology routinely results in 2-3 fold increase in expression of client antibodies or fusion proteins, both in pools and after clonal selection. previously, we have successfully combined 2gun technology with glutamine synthetase (gs) selection and the cho gs null cells of horizon discovery, resulting in clonal cell lines producing > 6 g/l of a biosimilar mab in fed-batch assay. here we present data on the successful application of the 2gun technology for the enhanced expression of a large (>300 kda) human heterotrimeric glycoprotein, a renowned difficult-to-express (dte) protein. all expression vectors comprised a hcmv promoter and bgh polyadenylation sequence in the expression cassettes for the gene of interest, and a selection marker gene with sv40 promoter and sv40 polyadenylation sequence. 2g unic™ vectors also contained genetic elements (2g unic™ technology, proteonic). cho gs null cells (horizon discovery) were transfected in duplicate with reference or 2gun expression vectors and selected in media lacking glutamine and containing the appropriate antibiotics. the bulk pools were seeded at equal viable cell density after obtaining maximum viability and cultured for 9 days without feeding (batch). expression of the target protein in cell culture supernatants of stable bulk pools was measured by elisa. the three protein subunit genes were expressed from vectors with different selection markers. in the reference constructs (without 2gun), the α, β, and γ chains were expressed from vectors with marker genes for zeocin, blasticidin, and gs, respectively. a similar 3 vector combination was also generated with 2gun elements integrated in each vector. in addition, 2 vectors with 2 subunits (γ-α and α-γ), each with a separate 2gun element, promoter and polyadenylation signal, were generated with a gs marker gene. cho gs -/cells were transfected with the 4 appropriate vector combinations in equimolar ratios and selected in bulk in medium lacking glutamine and 1 or 2 antibiotics. the 2-vector transfected cell pools recovered first, due to the presence of only 1 antibiotic in the medium (fig. 1a) . the pools transfected with three 2gun vectors recovered to maximum viability just a few days after the 2-vector 2gun pools. recovery of the reference pools took up to a week longer than the 2gun pools. production of each pool was assessed in a batch production run in shaker flasks. all 2-vector 2gun pools which recovered first produced titers around 0.1 g/l, which is almost 10-fold higher as compared to the production by reference pools (fig. 1b) . the highest titers of 0.5 g/l were obtained in the 3-vector 2gun pools. these data show that the 2g unic™ genetic elements can be successfully used to obtain a significant increase in the titer of difficult-to-express proteins. similar results have been obtained with other dte proteins, including fc-fusion proteins and bi-specific antibodies (not shown). the expression of a large, glycosylated multimeric difficult to express protein can be increased more than ten-fold in cho gs pools by application of 2g unic™ genetic elements. the highest expression of is obtained using a separate vector for each subunit. characterization of antibody-producing cho cells with chromosome aneuploidy noriko yamano 1,2 , sho tanaka background chinese hamster ovary (cho) cells are commonly used as host cells to produce biopharmaceuticals. however, the number of chromosomes in cho cells varies. previously, dg44-sc20 and dg44-sc39 cell lines with modal chromosome numbers of 20 and 39 were isolated from parental cho-dg44 cells, from which igg3-expressing cell lines named igg3-sc20 and igg3-sc39 were established, respectively. the igg3-sc39 cell pool showed a higher specific igg3 production rate than the igg3-sc20 cell pool [1] . even though all of the igg3-sc20 clones and half of the igg3-sc39 clones contained the same number of vector integration sites (single integration site), igg-sc39 cell clones produced more igg3 following the culture of single-cell clones than any of the igg3-sc20 clones [1] . in this study, we performed transcriptome analysis to investigate the characteristics of high-producer cells with chromosome aneuploidy. transcriptome analyses using amplified fragment length polymorphism (aflp)-based high-coverage expression profiling (hicep) and de novo mrna-seq were performed on dg44-sc20, dg44-sc39, igg3-sc20 and igg3-sc39. to compare cell lines with different numbers of chromosomes, transcriptome data from mrna-seq were adjusted for cell number using rna reference materials (nmij crm 6204-a; national institute of advanced industrial science and technology) mixed at equal amounts per cell. pathways related to differentially expressed genes were searched using keymolnet (km data). high-chromosome-number cho cells showed larger cell diameters, as determined by vi-cell (beckman coulter) measurement. the predicted volume ratios, based on these diameters, are 2.24 (dg44-sc39:dg44-sc20) and 1.59 (igg3-sc39:igg3-sc20). the levels of β-actin and the products of most other genes that were detected by mrna-seq differed by approximately 20% in the comparison between sc39 and sc20 (sc39 > sc20). based on the analysis of gene expression levels per cell volume, approximately 90% of detected genes showed lower expression in both dg44-sc39 and igg3-sc39 compared with the levels in dg44-sc20 and igg3-sc20, respectively. in addition, the number of genes whose expression level was decreased in igg3-sc39 compared with that in dg44-sc39 was larger than those showing the opposite pattern. the results of the comparisons between igg3-sc20 and igg3-sc39 indicate that differentially expressed genes were mainly related to cell growth (e.g. myc, smad), apoptosis (e.g. caspase), lipid metabolism (e.g. srebp, pparγ) and epigenetic histone modification (e.g. brca, hat) pathways. the mrna levels of myc, smad, caspase, brca and hat related genes were lower in igg3-sc39, while those of srebp and pparγ related genes were higher in igg3-sc39. the effects of these pathways on antibody production should be examined in future. in this study, we found that high-chromosome-number cho cells have lower amounts of mrna relative to their volume. a reduction per unit volume in the expression of genes that are required for survival might generate additional energy for recombinant protein production in high-chromosome-number cells. from an evolutionary perspective, an increased set of chromosomes underlies rapid evolutionary adaptation. although there are issues to be considered, such as stability, there may also be advantages to using high-chromosome-number aneuploid cho cells as a production host cells of recombinant proteins. background human growth factors have an enormous therapeutic potential. among them, the bone morphogenetic protein-2 (bmp-2) can induce de novo bone formation endowing the protein a high therapeutic potential. however, finding a suitable recombinant production system for such a protein still remains a challenge. recombinant expression of hbmp2 was investigated in transiently transfected hek-293 cells and in stable clones established in cho-k1 cells cultivated in excell and pro-cho5 medium, respectively. protein stability and interaction of the hbmp2 with the producer cells were investigated in vitro using commercially available rhbmp2. in addition, we investigated a cell-free protein synthesis system harboring translocationally active microsomal structures, hence having the potential to perform post-translational modifications, as an alternative production method. we showed that growth rates and viabilities of the rhbmp2producing cells were similar to those of the parent cell line, while entry into the death phase was delayed in case of the recombinant cells. the maximum rhbmp2 concentration detected in the culture supernatant was low for stable clones but can be greatly improved combining the hek-293 cells transient expression system and batch reactor cultivation which reflects a better compatibility of the codon usage in the human cells (table 1) . hbmp2 protein is sensitive to slightly acidic ph and to a lesser extend to proteases (fig. 1a ) and binds to both producers cell lines (fig. 1b) -all this could incidentally contribute to the low product titers. cell-free protein synthesis has been proposed as alternative for "difficult-to-express" proteins. since native hbmp2 is glycosylated, a cell-free system based on eukaryotic cell lysates is required for its production. cho cell lysates were chosen, since they had previously been established as the most productive eukaryotic system in our hands [1] , while concomitantly enabling a direct comparison to the production of hbmp2 in stable clones established in cho-k1. the ability to perform post-translational modifications is a major advantage of eukaryotic systems. the cho lysates prepared by the protocol used here have previously been shown to contain significant amounts of endogenous microsomes derived from the endoplasmatic reticulum during lysis [2] . to enforce translocation of the target protein into the microsomal structures, a melittin signal peptide was fused to the hbmp2 cdna. the glycosylation of the protein was assessed by enzymatic treatment (pngase, endoh) and confirmed using 14 c-mannose for the de novo protein synthesis. upon cell-free protein synthesis, the hbmp2 yield was 100-fold higher than the best one in the hek-293 cells. the difference becomes even more dramatic, when productivities are considered (table 1) , i.e. the fact that maximum product titers are reached within 3 h in the cellfree system compared to 120 h in the cell-based ones. this demonstrates that the cell-free expression system is most suitable compared to mammalian cell expression method for the production of glycosylated human bmp2 (table 1 ) [3] . human growth factors are complex molecules, which make their production in mammalian cells desirable. however, low product titers caused by a variety of both cell and process related effects may hinder the development of highly productive processes. in such cases, cell-free protein production using cho cell lysates containing endogenous microsomes for posttranslational processing, may eventually present an attractive alternative. in particular since these lysates can be used under tightly controlled conditions assuring a higher degree of reproducibility, than, e.g. transient transfection systems. cell-free systems are known to circumvent typical bottlenecks of cellbased ones, e.g. metabolic regulation and cell maintenance mechanisms. in consequence, the production of a recombinant protein is neither inhibited by its accumulation nor by any interaction with the cells, e.g. through the activation of inhibitory signaling pathways. core. preliminary studies showed that the corresponding polyplexes, but also some of the cells that came into contact with them, became magnetic and were manageable by magnetic fields [1] [2] [3] . here, we present a characterization of the influence of structure and composition on the function of these polymers using a library of highly homogeneous, paramagnetic nano-stars with varied arm lengths and densities [4] . the paramagnetic nano-stars library was synthesized by coating maghemite nanoparticles (γ-fe 2 o 3 ) with a thin silica-shell functionalized with an atomic transfer radical polymerization (atrp) initiator. pdmaema arms were grown from the core particles via atrp. in one case, the pdmaema arms was end-capped with pdegma blocks produced during a second atrp step. all nanostars were characterized by size exclusion chromatography and thermogravimetry to calculate number and length of the pdmaema arms. the core diameter was determined by transmission electron microscopy and dynamic light scattering (dls). the different variants (table 1) were analyzed for their ability to complex pdna (pegfp-n1) using various physicochemical methods (dls, zeta sizer). transfection efficiency/cytotoxicity in cho-k1 cells were determined by flow cytometry. transfected cells were placed in a magnetic field and the influence of the polymer architecture on the magnetic separation was investigated. nonparametric spearman analysis was used to correlate between arm length/arm densities, magnetic properties of the cells and transfection efficiency. based on the hydrodynamic radii of the polyplexes, the investigated nano-stars could be divided into three subgroups (table 1) . middle, but also high arm density nano-stars formed smaller polyplexes with hydrodynamic radii ≤ 300 nm, a size that is considered suitable for endocytosis and transfection. transfection efficiencies and cytotoxicities varied systematically with the nano-stars architecture, with viability showing a more pronounced dependency on the characteristics of the transfection agent than the transfection efficiency itself. the arm density was particularly important, with values of approximately 0.06 arms/ nm 2 yielding the best results (fig. 1a) . the end-capping the polycation arms with pdegma significantly improved the serum compatibility (fig. 1b) . the gene delivery potential of a given nano-star and its ability to render the cells magnetic did not correlate. although, compared to the non-separated cells, egfp-expressing cells were consistently more frequent in the magnetic cell fraction, while the non-magnetic fraction was slightly depleted. when the egfp-expressing cells were further divided into low, middle and high producers, a statistically significant shift towards the high producers was observed in the magnetic cell fraction (fig. 1c) . a nonparametric spearman correlation analysis was used to statistically evaluate possible links between the molecular characteristics of the nano-stars, the physicochemical properties of the corresponding polyplexes, the transfection conditions, and the cellular reactions. the resulting correlogram is shown in fig. 1d . transfection agents with magnetic properties enlarge the toolbox for studying non-viral gene delivery, since cellular magnetism is added as a new parameter. this allows, inter alia, a distinction between mere cellular interaction and actual uptake, which is otherwise difficult. viability showed a much more pronounced dependency on the characteristics of the transfection agent/polyplex than the transfection efficiency itself, which should be taken into account during method optimization. end-capping the polycationic pdmaema-arms with pdegma-blocks improved the compatibility of the polycationic nano-stars with serum components. in future optimized, blood-compatible, nano-stars, which can be retained/directed by magnetic fields, could become options for non-viral gene delivery in vivo. the increasing demand for monoclonal antibodies has necessitated the need to increase the productivity of current industrial cell lines. in our earlier study [1] , we had shown that treatment with er-stress inducer, tunicamycin significantly increased the titers and productivity in recombinant cho cell lines with a simultaneous upregulation of many genes from the unfolded protein response pathway (upr). however the loss in cell viability prevented a sustained increase in titers. in the current study we explore the effect of varying concentrations of tunicamycin and treatment times, such as to modulate the increase in protein folding capacity while preventing induction of apoptosis. anti-rhesus igg-secreting cho cells [2] were cultured in sf-cdm in 125 ml shake flasks. the cells were treated with varying concentrations (30-500 ng/ml) of tunicamycin in a batch culture. further, the effect of treatment with tunicamycin for short periods of time (24 hrs) was also evaluated. igg titers and mrna expression levels were quantified using elisa and qrt-pcr (illumina), respectively. results cho cells were treated with different concentrations of tunicamycin and cultured in a batch for 8 days (referred as continuous treatment/cte). figure 1a presents the maximum vcd and % drop in viability under treatment. a dose-dependent inhibitory effect is observed on growth and viability of cells in cte-cultures, with minimal inhibition as lower concentrations. contrastingly, igg titers (fig. 1b) were higher in treated cultures w.r.t. control in initial phase of the cultures at all the concentrations of tunicamycin. the per-cell productivity (fig. 1c) also showed a significant increase w.r.t control at all the concentrations of tunicamycin. however, the increased productivity due to tunicamycin was not sustained and levels become similar to control after day 3 (data not shown). to prevent loss of viability due to tunicamycin, the effect of short-term treatment (ste) with tunicamycin was explored. cells treated with tunicamycin for 24 hours were harvested (corresponding to day 2 of cte cultures) and inoculated in fresh media. the ste-cultures showed improved viability and higher maximum vcd as compared to cte-cultures (fig. 1a) . the fold increase in igg titers was not sustained beyond day 1-2 in stecultures ( fig. 1d ) but significant increase in productivity was seen in the initial phase (fig. 1e) . further, the cells were adapted over 25 continuous generations under 30ng/ml tunicamycin. the adapted cells had overall 1.3-fold higher productivity, as compared to control (fig. 1f) , in a batch culture. to understand the molecular basis of increase in productivity, mrna expression level of key genes was determined. xbp1s is a transcription factor involved in activation of chaperones (like grp78, calreticulin) and apoptotic genes (such as chop). significant increase in the levels of calreticulin was seen on treatment with tunicamycin (fig. 1g) . both xbp1s and grp78 were marginally induced when treated with 30ng/ml of tunicamycin in both cte-and ste-cultures (fig. 1h) , and significantly up-regulated when treated with 500ng/ml of tunicamycin. the chop mrna levels also increase with increasing tunicamycin concentrations, with levels in ste-cultures lower than cte-cultures (fig. 1h) . the results suggest that upr induction may be important to increase productivity in these cte/ste-cultures. note that, tunicamycin had no effect on the expression levels of igg heavy-chain, thus eliminating the involvement of igghc-mrna in increasing productivity (fig. 1i) . tunicamycin induced er-stress increased productivity in the initial phase of the culture and enhanced upr-mediated folding capacity can be attributed as one of the reasons for it. at lower concentrations of tunicamycin, a fine balance between optimum upr induction and apoptosis can be achieved, as seen in 30ng/ml tunicamycin ste-cultures. in summary, this study demonstrates an alternate approach to enhance productivity of current industrial cell lines. background chinese hamster ovary (cho) cells have been widely used for the large-scale production of biopharmaceuticals [1] . to construct antibody-producing cho cells, exogenous genes encoding antibodies are usually integrated into unspecified regions of chromosomes (random integration). however, the chromatin structure differs depending on the location of the chromosomal region, which affects the expression level of the gene of interest [2] . recently, gene-targeting methods that enable site-specific integration of expression vectors have been developed. however, the regions that are most efficient for exogenous gene expression have not been clarified. we previously constructed a cho genomic bacterial artificial chromosome (bac) library generated from the recombinant cho-dg44 cell line. it was expected to cover the entire cho genome five times. the 20 chromosomes in cho-dg44 cells were aligned in decreasing order of size and assigned letters from a to t [3] . three hundred and four bac clones were mapped to every chromosome of cho-dg44. among the karyotypes of cho-dg44, cho-k1 and primary chinese hamster cells, chromosomes a and b are considered as the sole paired chromosomes corresponding to chromosome 1 in primary chinese hamster cells. hence, chromosomes a and b are considered to be stable [4] . in this study, we constructed antibody-producing cells by using a gene-targeting method, which focused on the stable chromosomes. a gene map of chromosome 1 was constructed by combining the bac-fluorescence in situ hybridization (fish)-based chromosome physical map and sequence data of mapped bac clones. the sequences of bac clones were searched by blast with ncbi and chogenome.org databases. three different regions on chromosomes a and b were selected based on cho genomic bac library sequences as target sites. cho-k1 cells were stably transfected by lipofection. the target sequences were broken using the clustered regularly interspaced short palindromic repeats (crispr)/crispr-associated protein 9 (cas9) system and humanized igg1 genes were integrated by non-homologous end joining recombination. transfection without using the crispr/ cas9 system was also performed. these cell pools were cultivated for six days with serum-supplemented medium, and their levels of antibody productivity were evaluated by elisa. copy number analysis was also performed using real-time pcr. results and discussion construction of gene map of chromosome 1: eighty-three bac clones were mapped onto chromosomes a and b (each clone contained 100-150 kb of the cho genome sequence). as a result of annotations of 83 bac clone sequences, 91 genes were mapped on chromosome 1. investigation of the differences of productivity among antibodyproducing cells that were constructed by chromosome 1 targeting and/or random integration: cell growth was not affected by the gene targeting site. the specific production rates of antibodyproducing cell pools constructed by gene targeting of chromosome 1 were higher than those of the cell pool constructed by random integration. all cell pools constructed by gene targeting showed lower copy numbers of heavy chain and light chain in genomic dna than those in the cell pool constructed by random integration, despite showing high productivity. our results indicate that high productivity of the cells constructed by gene targeting of chromosome 1 does not depend on the increase of the antibody copy number, and that the environments around these target regions are suitable for exogenous gene expression. the approach of using gene targeting to chromosome 1 may be promising for constructing antibodyproducing cells. retroviral vectors have been widely used as gene delivery tools in various biotechnology fields. however, the random integration feature of retroviral vectors seems to cause problems such as insertional mutagenesis and gene silencing. we previously demonstrated cre-mediated retroviral transgene insertion into a pre-determined site of the founder cells using integrasedefective retroviral vectors (idrvs), where a cre expression plasmid was transfected into the cells prior to retroviral transduction [1] . recently, we reported novel hybrid idrvs (cre-idrvs) incorporating bioactive cre recombinase protein, and validated site-specific gene integration of an scfv-fc antibody expression unit into the chinese hamster ovary (cho) cell genome [2] . we also developed an accumulative site-specific gene integration system, which enables repeated integration of multiple transgenes into a pre-determined locus of the cell genome [3] . here, we attempted repeated integration of transgenes using cre-idrvs. a viral vector plasmid (pqmscv/hd[scfv-fc]) encoding reporter genes and an scfv-fc expression unit flanked with wild-type and mutant loxps was constructed for the production of idrvs. cre-idrvs were produced described previously [2] . results and discussion figure 1a shows a schematic drawing of each round of targeted transgene integration using cre-idrvs harboring an scfv-fc expression unit. (fig. 1b) . genomic dna extracted from the cells were subjected to pcr using specific primer pairs α and β, and γ and δ to confirm site-specific integration. dna fragments with expected sizes were amplified in each cell clone (fig. 1c) . these results indicate that site-specific repeated integration was achieved using cre-idrvs. in contrast, scfv-fc productivity in cho/hd[scfv-fc]×2 cells was slightly decreased compared with that of cho/ne[scfv-fc]×1 (data not shown). although the reason remains unclear, repeat-induced gene silencing might occur due to tandem repeat structure of expression units. we reported improved recombinant antibody production using a production enhancer element [4] . such a cis-regulatory element might be a feasible approach to enhance the productivity. we demonstrated site-specific repeated transgene integration into a pre-determined chromosomal locus using cre-idrvs for the production of an scfv-fc antibody. if lipids role in the cell have been reduced for a long time to cell membrane formation, it is now understood that lipids plays also a role into energy metabolism, vesicular transport, membrane structure, dynamics and signaling. however, the exact mechanism of how compositional complexity affects cell homeostasis remains unclear. thanks to recent advances in mass spectrometry, it is now possible to study a wide range of lipids, providing a better understanding of lipid homeostasis in high performance cell culture processes. the purpose of this work was to develop a robust lipidomics method applied to mammalian cell cultures in a three step method: extraction, separation and detection (fig. 1 ). both matyash [1] and folch [2] extraction method were performed on our cells to reach the highest yield. two separation techniques were also tested: hydrophilic interaction liquid chromatography (hilic) and reverse phase chromatography. finally lipid classes' identification was achieved by tandem mass spectrometry analysis thanks to structure-specific fragmentation ions. the yield obtained with matyash extraction method was higher than with folch method for each lipid class tested. besides, matyash method presents also the advantage to be less toxic and suitable for high throughput analysis since the organic layer is above the aqueous layer. lipids separation by hilic is based on their polar head. since lipid classes are defined by polar head, the lipids are eluted class by class, making their identification easier. the separation of lipids by reverse phase was correct but the method is longer and we observed a massive carryover of triglycerides on the column. finally each lipid class was screened in ms/ms parent ion mode. target daughter ion was set according to the lipid class structure and fragmentation pattern. this detection technique enabled the identification of 50 different lipids. to ensure the absolute quantification of the detected lipids and to guarantee comparable results between batches labeled internal standard were added prior to extraction. this method was optimized in a stepwise process to ensure a sensitive and selective measurement of the lipids. lipids were extracted by matyash method, separated by hilic and detected by tandem mass spectrometry. this method is suitable for both in process sample lipid analysis providing information on the cell lipid content, and for harvest samples, enabling to follow the lipid release during the different harvest steps. this non-targeted lipidomic quantitation method will enable us to better control lipid synthesis during biopharmaceutical fed batch production through clone selection, metabolomics studies and harvest development. background human mesenchymal stem/stromal cells (hmsc) can easily be isolated from e.g. bone marrow, fat tissue or umbilical cord blood and are therefore a central player in regenerative medicine, gene therapy and cell therapy [1] [2] [3] . the necessary gene shuttle is mainly provided by viruses associated with diseases, like retrovirus or adenovirus [4] [5] [6] [7] . these possible pathogen viruses demand for high safety standards. also, they are prone to genomic alterations and there is the possibility of virus inactivation, triggered due to pre-existing immunity in the patient [8] [9] [10] . in this context, the autographa californica multicapsid nucleopolyhedrovirus (acmnpv) is a safe alternative. the virus replication is hostspecific for insects [11] , but it is known since the mid-90s, that a temporary transduction of mammalian cells is possible [12] . some modifications of the virus increased the applicability in stem cells. pseudotyping the virus with the vesicular stomatitis glycoprotein (vsv-g) led to an expansion of the transducable cell [13, 14] and the integration of the woodchuck hepatitis virus post-transcriptional regulatory element (wpre) prolonged the recombinant protein expression [15, 16] . for achieving a baculovirus-induced differentiation of hmscs, the promotor and the expression strength of the recombinant protein are crucial factors. still, there are still few comparative promotor studies [17, 18] . however, a successful virus uptake is the prerequisite for a successful protein expression. we therefore investigated factors significantly influencing the transduction process by applying design of experiments (s. fig. 1a ). the experimental design comprises a two level factorial screening, set-up using design expert v9.for the transduction 60,000 c/cm 2 were seeded in 24-well plates with dmem + 10% fcs and incubated overnight at 37°c, 8% co 2 and humidified atmosphere. the recombinant baculovirus using an integrated ef1α promoter to control gfp expression, described elsewhere [18] , was diluted to the respective concentrations in the different surrounding fluids. after discarding the cultivation medium of the hmsc-tert, 1 ml of virus containing solution was added to the cells. the following incubation was varied in duration before replacing the virus solution with growth medium and an incubation overnight. 24 h post transduction (hpt) the cells were washed with pbs, trypsinized with 100 μl trypsin/edta and incubated for 5 min at 37°c. trypsination was then stopped applying 100 μl soybean trypsin inhibitor and the cells were analyzed using flow cytometry. as shown in fig. 1a , the virus concentration and incubation time exert the highest influence on the transduction efficiency. obviously, a higher concentration of viral particles and longer incubation of cells with virus increases the probability for hits between cells and virus particles. additionally, the surrounding fluid can have a negative impact on the transduction. this is due to the interaction of medium components with the baculovirus. therefore, pbs containing ca 2+ & mg 2+ is recommended as surrounding fluid for transduction experiments. in fig. 1b , the transduction conditions resulting in the highest percentage of gfp+ cells are displayed: 150 virus particles per cell (ppc) and an incubation time of 5 h with hmsc-tert. the experiments show, that especially the virus concentration and the incubation time of cells with virus influence the transduction efficiency. based on the results of the screening, further optimization of the transduction conditions will be done using a face centered central composite design with pbs containing ca 2+ & mg 2+ as surrounding fluid and at an incubation temperature of 37°c. background breast cancer is the second main cause of cancer related deaths for women worldwide and among them the triple negative subtype (tnbc) represents a clinical challenge by being associated with high mortality and having no effective therapies against it [1] , [2] . accordingly, there is an urgent need to design new and more effective drugs to treat breast cancer. notch signaling is an evolutionary conserved cell-to-cell communication pathway crucial during embryonic and breast development and tissue homeostasis. this pathway is often hyper-activated by overexpression of notch receptors and/or its ligands in several types of cancers, such as breast cancer (tnbc included), where it contributes to its development, progression and drug resistance [3] , [4] , [5] . our aim is to generate a function blocking antibody against the notch delta-like-1 (dll1) ligand with therapeutic efficacy against breast cancer. materials and methods dna of human dll1 full length extracellular domain (dll1-ecd) and a truncated version, containing the minimal binding region to the notch receptor (dll1-egf3), were cloned into pfuse-fc1-igg1, and expressed in hek293e6cells. recombinant proteins were purified from culture media by protein-a affinity and size exclusion chromatography. the human scfv phage display tomlinson i+j library was used to select specific scfv against peptides targeting dll1 binding regions to notch. the binding ability and specificity of the selected scfv clones was evaluated by scfv-on-phage elisa. our strategy allowed us to obtain 20 mg of pure (>95%) and stable dll1-ecd-fc as confirmed by sds page and thermofluor assay. dll1-egf3-fc yield was very low and buffer screenings are ongoing to optimize protein stability. functional studies performed in human breast cancer mcf7 cells showed that both ligands are biologically active as they increased the expression of the notch-dependent genes hes-1, hey-l and hey-1. recombinant dll1 and peptides were used to select for monoclonal antibodies by phage display. after three rounds of panning with dll1 peptides we identified 13 scfv positive clones, 2 of which presented high affinity to dll1-ecd-fc. currently we are performing more phage display selections to increase the number of positive clones. scfv with higher affinities will be reformatted into iggs and their ability to inhibit the notch pathway will be evaluated. the anti-oncogenic effects of anti-dll1 iggs will be assessed in breast cancer cells in viability/apoptosis, proliferation, migration, and invasion assays. an anti-dll1 igg with therapeutic efficacy against breast cancer will demonstrate that targeting dll1 could be one of the key factors for successfully targeting breast cancer. recombinant adeno-associated virus (raav) approaches have an outstanding reputation in gene therapy and are evaluated for cancer therapy [1] . advantages include long-term gene expression, targeting of dividing and non-dividing cells, and low immunogenicity. established raav production utilizes triple transfection of adherent hek 293 cells, which hardly meets product yield requirements for clinical applications. we transferred the aav production system to hek 293-f suspension cells. this process is scalable and uses serum-free media streamlining downstream procedures. after optimization of transfection efficiencies and shaker cultivations, we produced titers of 1×10 5 viral genomes per cell in a 2 l bioreactor. the suspension adapted hek-freestyle 293-f cell line was used for the experiments in chemically defined animal component free media (hek-tf, hek-gm (xell ag), freestyle f17 (thermo fisher scientific)). samples for viable cell density and viabilities were taken daily and analyzed using an automated cell counting system (cedex, roche diagnostics). transient transfection of 3×10 6 cells/ml was carried out with polyethylenimine max in a 1:4 dna-pei ratio (w/w) with 2 μg dna. three plasmids (pgoi, prepcap, phelper) were applied in a molar 1:1:1 ratio (fig. 1a) . pretests were performed in orbital shaking tube spin bioreactors. for scale-up, batch processes were carried out in 125 ml shake flasks as well as in 2 l stirred bioreactors at 30% air saturation and ph 7.1. transfection efficiencies and raav production were quantified by flow cytometry using a goi coding for a fluorescent protein and qpcr of genomic copies, respectively. by optimizing the dna amount for transfection of 293-f cells more than 90 % of the cells were reproducibly transfected. batch cultivations in shaker flasks revealed that raav were produced in the first 24-96 h after transfection. figure 1b shows viable cell densities and viabilities in relation to the genomic titer. genomic titers were determined from raw cell extracts and up to 10 9 copies/ml were repetitively achievable. a decrease in viability marked the decline in genomic copies per ml showing that a prolongation of the process e.g. by addition of a feed would probably not increase yield. in a first scale-up, the raav production was transferred to a 2 l bioreactor (fig. 1c) . transfection efficiencies in bioreactors of up to 55% were comparable to that obtained in a simultaneous shaker flask experiment. transfection efficiencies were lower compared to prior experiments due to controlled conditions in the bioreactor. nonetheless the titer with up to 1×10 5 genomic copies per cell was elevated compared to that of shaker flasks. first experiments with 293-f cells in hek tf medium showed promising results of transferring raav production from the adherent system to suspension. after improvement of transfections by the adjustment of dna amounts in small scale experiments, aav production was analyzed in shaker flasks. the batch process showed an expected increase in cell density with low variability between biological replicates (fig. 1b) . the genomic titer increased according to the viable cell density until day four where a sudden drop started. this observation was made for aav productions in hek-tf, hek-gm and freestyle f17 medium. for optimal yields, we assume that a slight decrease in viability marks the point in time for harvest. from optimized protocols, a batch process in a 2 l bioreactor was carried out. interestingly the bioreactor cultivation resulted in lower overall viable cell densities but in higher genomic copies per cell compared to shaker flasks (fig. 1c) . these results are comparable to already published data for suspension cells [2] . subsequent optimization of the bioreactor protocol will lead to further increase in raav yield. genethon and pall have collaborated to assess pall's single-use icellis fixed-bed bioreactor for viral vector production. clinical use of gene therapies to treat formerly incurable genetic diseases is advancing rapidly. viral vectors are an important tool for introducing genes into target cells. many gene therapies have been developed using adherent cells in 2-dimensional flatware or roller bottles but using these technologies to reach commercial-scale production represents a significant challenge. the icellis bioreactor enables large-scale viral vector production by providing a 3-dimensional matrix for cell growth in a compact configuration (fig. 1 ). up to 500 m 2 of surface area is available in a compact bioreactor measuring 88 mm in diameter in a total volume of 75 l with ph, do and temperature control. a key feature of the icellis bioreactor is that it scales by increasing the diameter of the fixed-bed while keeping the height constant with no change in aspect ratios. the height of the fixed-bed can be varied (2, 4 and 10 cm) as well as density of carrier packing (96 gm/l or 144 gm/l). the icellis system comes in two formats, the icellis nano bioreactor (0.53-4.0 m 2 ) and the icellis 500 bioreactor (66-500 m 2 ). processes developed in the bench top icellis nano bioreactor can be directly transferred to the corresponding icellis 500 system. the icellis nano bioreactor enables an efficient platform for process optimization. the genethon raav-8 process was transferred to an icellis nano bioreactor 0.8 m 2 (2 cm bed height, 144 gm/l density) bioreactor using freestyle media. the initial icellis nano process was established as (1) seed on day 1, (2) transfect at day 5, (3) harvest at day 8 and yielded <1x 10 9 vp/cm 2 (n=3). media exchange, cell density at transfection, pdna/cell ratio, and lysis method were then changed to determine the effect on productivity. the modified process was then scaled from 0.8 m 2 to 4.0 m 2 (10 cm bed height, 144 gm/l density) icellis nano bioreactor. -media: a media exchange at 5 hours post transfection with dmem substituted for freestyle medium resulted in an 8x increase in specific productivity. 1 (abstract p-349) . a schematic overview of raav production in hek293 cells with triple-transfection system. b viable cell densities (vcd), viabilities and genomic copies per ml (gc) of a raav production with 293-f batch cultivations in shaker flasks. genomic copies per ml refer to the titer determined in 1 ml culture volume. error bars represent biological and technical duplicate measurements of samples. c viable cell densities and genomic copies per cell of a raav production with 293-f batch cultivation in a 2 l bioreactor. for reasons of comparability between shaker and bioreactor data genomic copies are given per cell. error bars represent technical duplicate measurements of samples -cell density at transfection: cells were seeded at 6,000 cells/cm 2 and reached 200,000 cells/cm 2 at day 5 which was determined to be the optimal cell density for transfection. -pdna/cell ratio: reducing pdna by 50% had no significant effect on productivity. -lysis: use of trion x-100 at 0.5% with 100 mm nacl at ph 8 resulted in >100% virus recovery compared to sampled carriers. -scaling: specific productivity was maintained as the system was scaled from 0.8 m 2 to 4.0 m 2 . -overall, an average yield of 4x10 13 vg/m 2 was achieved. the icellis technology is being adopted widely for viral vector production. transferring a process to the icellis nano bioreactor can be easily achieved and once in place can be optimized to provide significant productivity increases and cost savings such as reduced pdna. the icellis nano bioreactor is an efficient bench-top system the results of which can be readily scaled to the icellis 500 system. background tissuse multi-organ-chip (moc) platform contributes to the ongoing advancement in systemic substance testing in vitro. current in vitro and animal tests for drug development are failing to emulate the systemic organ complexity of the human body and, therefore, often do not accurately predict drug toxicity. especially, cardiotoxicity is one of the main reasons why new compounds are failing in clinical trials. therefore, we aimed to establish an autologous dynamic multiorgan-device integrating cardiomyocytes for substance testing. generic 2d monolayer and 3d suspension ipsc derived cardiomyocytes differentiation protocols were established. beating cardiomyocytes were first seen on day 8 in monolayer as well as in spheroid culture. cardiomyocytes show up to 64% cardiac troponin t positive cells and 44% myosin heavy chain positive cells by flow cytometry (fig. 1g, h) . myosin ii heavy chain, α-actinin, myosin 9/10, myosin 11 and caldesmon expression was shown by immunohistochemistry ( fig. 1a-d) . due to the exclusion of a lactate enrichment of cardiomyocytes, cardiac fibroblasts are also expressed in the spheroids shown by vimentin staining. those cardiac fibroblasts lead to a physiological heterologous cell population similar to the human heart. beating spheroids were cultivated for 7 days under dynamic culture conditions in the multi-organ-chip. the integrated on-chip micropump provides physiological-like pulsatile circulation at a microliter scale and leads to better nutrition and oxygen supply. the next significant step is to combine multiple autologous 3d organ equivalents in our multi-organ-chip using ipsc differentiation technology. differentiating all cell types from one ipsc donor is crucial to overcome source and rejection problems. combining our multi-organ-chip platform with ipsc differentiation technology will eventually lead to a personalized system for drug and substance testing. lab as a service -automated cell-based assays lena schober, moriz walter, andrea traube laboratory automation and biomanufacturing engineering, fraunhofer ipa, stuttgart, germany correspondence: lena schober (lena.schober@ipa.fraunhofer.de) bmc proceedings 2018, 12(suppl 1):p-365 background the use of cell-based assays in pharmaceutical industry and academic research is a growing trend that is a driving force to reduce costs for drug development. academic research is gaining information about intracellular targets or functional mechanisms through the variety of different assays. these benefits can be used in preclinical studies and furthermore costly late-stage drug failures may be reduced by the use of cell-based assays. the use of automated systems is also in great demand and will change the testing of substances and research activities. nevertheless, there are a lot of barriers at the moment limiting the successful application of automated systems in this field. by the lack of flexibility and the demand for skilled computer scientists & engineers just the two main aspects stated by experts shall be mentioned. our strong background on automated cell culture technologies and expertise, gained in several projects, let us rethink the overall process chain and overcome established principles. a new service orientated platform for the execution of cell-based assays that are commonly used will be introduced. the main idea is to give access to automated infrastructure for academic research or spin-offs which cannot afford the special infrastructure. nowadays it is known that the development of inhibitory antibodies by hemophiliac patients is closely related with immunogenic epitopes present in the coagulation factors. these proteins are produced in hamsters cells [1 -4] which insert a different posttranslational modification profile when compared with the human profile. patients with high-titer/high-responding inhibitors must be treated with bypassing agents that can achieve hemostasis. activated factor vii (fviia) is an attractive candidate for hemostasis, independent of fviii/fix, making this coagulation factor an alternative for hemophilia patients with inhibitory antibodies. however recombinant factor vii is produced in bhk-21 cells (baby hamster kidney cells) and as well as the others coagulation factors, it may contain immunogenic epitopes [5 -7] . in this context, becomes extremely important to produce recombinant proteins with complex posttranslational modifications in a cell line not yet used [8 -10] . we have been using the sk-hep-1 human cell line for the production of recombinant fvii. to generate the recombinant cell line we have used a bicistronic lentiviral vector, 1054-gfp, containing a fvii gene and the gfp selection marker gene. a master cell bank and a work cell bank were generated in gmp conditions. the rfvii analyses were made by elisa assay, western blot, gene expression quantification and biological activity using the prothrombin time (pt) assay. rfvii purification by affinity chromatography using viiselect (ge) column. after purification the rfvii was formulated and dry froze to be used in in vivo experiments. in static conditions sk-hep-1 cells showed, for a period of 6 months, a stable fvii production with an average of 8,03 iu/ml of fvii, 83% of cell viability and 77% of cells expressing the gfp gene. after purification with viiselect column it was possible observe a recover of 65% of the purified protein with 95% degree of purity (fig. 1) . this recombinant purified fvii is being used in in vivo experiments to determine the pharmacokinetics parameters and to evaluate the posttranslation modifications profile. in conclusion, this study reports the use of sk-hep-1 cell line for high-level production of recombinant factor vii. these cells have proven to be effective in the production of recombinant protein and can be used as a new platform for the production of recombinant proteins. fig. 1 (abstract p-366) . a determination of protein yield of egfr (epidermal growth factor receptor) synthesized in a cho cecf system. analysis of egfr protein yield obtained in a various batches of cecf formatted reaction. cecf synthesis was performed in the presence of 14 c leucine for radio labeling of target proteins. radio labeled proteins were precipitated using tca followed by scintillation measurement. b detection of radio labeled egfr by autoradiography. a no template control (ntc) was prepared containing no egfr dna template background emergence of stem cell-based regenerative medicine recently leaded to the necessity to reach a sustained production of such cells [1] . hence, new bioreactors and carriers were designed for cell expansion. however, to meet this increasing demand, improvement of both quality and quantity of stem cells remains necessary. soft biocompatible microcarriers mimicking extracellular matrix in term of structure and stiffness should be of valuable utility as substrate stiffness strongly influence in vitro stem cell fate and differentiation [2, 3] . our expertise in the field of microbeads design using jetcutting technology [4] enabled us to engineer +/-200 μm alginate beads of various g/m monomer ratio. we used jetcutter (genialab gmbh) with 100 μm nozzle at max speed 12000 rpm. alginate solutions with concentrations 2% to 4% were gelifyed in 2% cacl2 etoh 50% solution. alginates with estimated viscosity (@1%) from 30 to 720 mpa were tested. a further surface treatment with gelatine (0,1%, 1%) and poly-l-lysine (0,1%) was carried out to reach an optimal cell anchoring of human adiposederived mesenchymal stem cells (atcc-psc-500-011) in mesempro rs medium (gibco). jetcutter technology allowed us to obtain alginate microcarriers with a good homogeneity in size around 200 μm and sphericity comparable to commercial carriers (table 1) . best adhesion of human adipose-derived mesenchymal stem cells was obtained on 0,1% gelatine coated alginate carriers (fig. 1) . we observed limited apoptosis and human adipose-derived mesenchymal cells stemness was conserved after 14 days in culture (data not shown). cellular bioassays developed with functionally immortalized cell lines aileen bleisch 1 , aleksandra velkova 3 , tom wahlicht 2 , dagmar wirth 2 , tobias may 1 1 inscreenex gmbh, braunschweig, germany; 2 msys, helmholtz centre for infection research, braunschweig, germany; 3 greiner bio-one gmbh, frickenhausen, germany bmc proceedings 2018, 12(suppl 1):p-381 background a major challenge of current research is the limited availability of physiologically relevant cells [1] . thus the development of relevant cellular bioassays that are robust, reproducible and scalable is hindered. to overcome current limitations we developed an immortalization strategy allowing the efficient and reproducible establishment of novel cell lines showing an in vivo-like phenotype. the main feature of our ci-screen technology is the ability to combine the advantage of cell linesthe unlimited cell supplywith the advantage of primary cellsthe physiological relevance. using this technology we have immortalized, amongst others, a human osteoblast cell line (ci-huob) [2] . in the present study, the in vivo-like phenotype and functionality of the novel ci-huob was examined. therefore, ci-huob cells were used to develop a 3d cell culture model by using the magnetic 3d bioprinting technology (nano3d biosciences, houston, tx, usa) [3] . the ci-huob cell line was recently described and cultivated in huob maintenance medium (inscreenex, germany). for spheroid creation ci-huobs were grown in a monolayer, magnetized by adding a magnetic nanoparticle assembly (nanoshuttle, ns, nano3d biosciences, houston, tx, usa) at a concentration of 4μl ns/cm 2 growth area. after an overnight incubation magnetized ci-huob were detached and seeded into cellstar® cell-repellent 96-well plates (greiner bio-one, frickenhausen, germany). with the help of mild magnetic forces cells were printed into spheroids within 2h. these consist of 1.000-50.000 cells and were cultured for a period of up to 50 days. the cell viability was analyzed by a propidium iodide (pi) and calcein am staining. to improve spheroid functionality spheroids were cultivated with huob differentiation medium (inscreenex, germany). "mini bone" tissue functionality and thus mineralization was analyzed by an alkaline phosphatase (alkaline phosphatase activity) and an alizarin red s staining (ca 2+ deposits). the combination of ci-huob cells with the magnetic 3d bioprinting technology enabled the establishment of reproducible and consistent 3d spheroids. single spheroids per well were formed independent of the amount of cells (1.000-50.000 cells) (fig. 1a) . formed spheroids were stable for a culture period of up to 50 days (fig. 1b) . neither cell death nor cell proliferation were observed in the bioprinted spheroids which is indicated by the stable size of the spheroids throughout the cultivation (fig. 1c) . after treatment with a differentiation stimulus the 3d bioprinted spheroids became fully functional "mini bones". this was highlighted by the alkaline phosphatase activity and the ca 2+ deposits within the 3d bioprinted spheroids (fig. 1d,e) . taken together, these results demonstrated that the functional immortalization technology provides physiologically relevant cells in sufficient numbers and that the magnetic 3d bioprinting technology enabled a fast, consistent cell aggregation and the formation of stable uniform spheroids. importantly, these immortalized cells are capable to differentiate when a suitable stimulus is provided. for differentiation into mini bones, 3d spheroid cultivation and additional stimulation by small molecules are required. the combination of physiologically relevant cell systems with three dimensional culturing will help to generate in vitro test systems which closely resemble the in vivo physiology and thereby supporting future drug discovery approaches. fig. 1 (abstract p-381) . characterization of spheroid "mini bones". a different number (1.000-50.000 cells) of ci-huob cells were printed into spheroids. b 20.000 ci-huobs were printed into spheroids and cultivated for indicated time points. c for analyzing spheroid sizes, pictures were taken and quantified by imagej. (d/e) 20.000 ci-huob cells were printed into spheroids and cultivated with (huob differentiation medium) or without a differentiation stimulus for two weeks. afterwards, bioprinted spheroids were sectioned by a cryo microtome and d stained for ca 2+ deposits (alizarin red s) or e stained for alkaline phosphatase activity crispr/cas9, a novel genomic tool to knock down microrna in vitro and in vivo degrontagged dcas9/cpf1 effectors for multi-directional drug-inducible control of synthetic gene regulation assessing the variability of an innovator molecule n-glycan profile correct primary structure assessment and extensive glyco-profiling of cetuximab by a combination of intact, middle-up, middle-down and bottom-up esi and maldi mass spectrometry techniques 2d-dige screening of high productive cho cells under glucoselimitation -basic changes in the proteome equipment and hints for epigenetic effects dependence on glucose limitation of the pco2 influences on cho cell growth, metabolism and 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selection from phage display libraries towards the development of a surface plasmon resonance assay to evaluate the glycosylation pattern of monoclonal antibodies using the extracellular domains of cd16a and cd64 biotinylation of the fc gamma receptor ectodomains by mammalian cell co-transfection: application to the development of a surface plasmon resonance-based assay ambr™ mini-bioreactor as a high-throughput tool for culture process development to accelerate transfer to stainless steel manufacturing scale: comparability study from process performance to product quality attributes maximizing binding capacity for protein a chromatography protein glycosylation and its role in protein folding afucosylated antibodies increase activation of fcγriiia-dependent signaling components to intensify processes promoting adcc sialic acids and other nonulosonic acids production of antibody in insect cells suitability and perspectives on using recombinant insect cells for the production of virus-like particles cloning of cdna and characterization of anti-rnase a monoclonal antibody 3a21 production of functional antibody fab fragment by recombinant insect cells optimization of hek-293s cell cultures for the production of adenoviral vectors in bioreactors using on-line our measurements enhancing heterologous protein expression and secretion in hek293 cells by means of combination of cmv promoter and ifnα2 signal peptide hek293 cell culture media study towards bioprocess optimization: animal derived component free and animal derived component containing platforms comparison of control strategies for fed-batch culture of hybridoma cells based on on-line monitoring of oxygen uptake rate, optical cell density and glucose concentration continuous bioprocessing: the real thing this time? mabs white paper on continuous bioprocessing fda perspective on continuous manufacturing. ifpac annu. meet screening and assessment of performance and molecule quality attributes of industrial 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improve recombinant protein production of cho cells effects of osmoprotectant compounds on ncam polysialylation under hyperosmotic stress and elevated pco 2 evaluating the bottlenecks of recombinant igm production in mammalian cells igm characterization directly performed in crude culture supernatants by a new simple electrophoretic method effect of culture ph on erythropoietin production by chinese hamster ovary cells grown in suspension at 32.5 and 37.0°c enhancing protein expression in hek-293 cells by lowering culture temperature relationship between tissue plasminogen activator production and specific growth rate in chinese hamster ovary cells cultured in mannose at low temperature a quantitative proteomic analysis of cellular responses to high glucose media in chinese hamster ovary cells process analytical technologies in the pharmaceutical industry: the fda's pat initiative effects of ammonium and lactate on growth and metabolism of a recombinant chinese hamster ovary cell culture glycosylation in cell culture structural mechanism of high affinity fcgammari recognition of immunoglobulin g inhibition of glycosylation on a camelid antibody uniquely affects its fcγri binding activity investigation of cho secretome: potential way to improve recombinant protein production from bioprocess bladder cancer cell-derived exosomes inhibit tumor cell apoptosis and induce cell proliferation in vitro exploring packaged microvesicle proteome composition of chinese hamster ovary secretome glycome mapping on dna sequencing equipment iron (iii) citrate inhibits polyethylenimine-mediated transient transfection of chinese hamster ovary cells in serum-free medium efficient high-throughput biological process characterization scale-up of a stirred single-use bioreactor family quality control: er-associated degradation: protein quality control and beyond pharmacological targeting of endoplasmic reticulum stress signaling in cancer when er stress reaches a dead end oxidative stress and antioxidant defense the antioxidant edaravone attenuates er-stress-mediated cardiac apoptosis and dysfunction in rats with autoimmune myocarditis advanced process and control strategies for bioreactors. book chapter model-based strategy for cell culture seed train layout verified at lab scale seed train optimization for cell culture. chapter high cell density cultivation of human leukemia t cells (jurkat cells) in semipermeable polyelectrolyte microcapsules. eng. life sci cell retention by encapsulation for the cultivation of jurkat cells in fixed and fluidized bed reactors the role of interleukin-2 during homeostasis and activation of the immune system creating a biomimetic microenvironment for the ex vivo expansion of primary human the era of digital biomanufacturing the multivariate normal distribution recovery from rabies: a call to arms the role of vaccination in rabies prevention eliminating canine rabies, the principal source of human infection: what will it take? rabies virus-like particles expressed in hek293 cells immunogenic virus-like particles continuously expressed in mammalian cells as a veterinary rabies vaccine candidate an avian cell line designed for production of highly attenuated viruses a chemically defined production process for highly attenuated poxviruses a genotype of modified vaccinia ankara (mva) that facilitates replication in suspension cultures in chemically defined medium easy and efficient protocols for working with recombinant vaccinia virus mva large-scale transfection of mammalian cells for the fast production of recombinant protein recombinant protein production by large-scale transient gene expression in mammalian cells: state of the art and future perspectives high density transfection with hek 293 cells allows doubling of transient titers and removes need for a priori dna complex formation with pei regulation of recombinant protein expression during chobri/rcta pool generation increases productivity and stability qc, canada; 2 department of microbiology, infectiology and immunology the cumate gene-switch: a system for regulated expression in mammalian cells rapid protein production from stable cho cell pools using plasmid vector and the cumate gene-switch christoph zehe sartorius stedim cellca gmbh, 88471 laupheim animal cell technology: from target to market recent advances in mammalian protein production molecular mechanisms of rna interference. annual review of biophysics ribosome profiling-guided depletion of an mrna increases cell growth rate and protein secretion ubiquitous chromatin-opening elements (ucoes): applications in biomanufacturing and gene therapy the art of cho cell engineering: a comprehensive retrospect and future perspectives a novel bxb1 integrase rmce system for high fidelity site-specific integration of mab expression cassette in cho cells high-troughput lipidomic and transcriptomic analysis to compare sp2/0, cho, and hek-293 mammalian cell lines single cell 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virusdirected enzyme prodrug therapy production of recombinant adenoassociated virus vectors using suspension hek293 cells and continuous harvest of vector from the culture media for gmp fix and flt1 clinical vector development of a cost-efficient scalable production process for raav-8 based gene therapy by transfection of hek-293 cells simon arias 2 , mustapha hohoud 1 , roel lievrouw 1 , fabien moncaubeig 1 b-1120 brussels, belgium; 2 généthon, rue de l'internationale 1 cell-free systems based on cho cell lysates: optimization strategies, synthesis of "difficult-to-express" proteins and future perspectives cell-free protein expression based on extracts from cho cells comparison of cell-based vs. cell-free mammalian systems for the production of a recombinant human bone morphogenic growth factor ires-mediated translation of membrane proteins and glycoproteins in production of recombinant factor vii in sk-hep-1 human cell line zip 14049-900, brazil; 3 department of clinical, toxicological and food science analysis, faculty of pharmaceutical sciences of ribeirão preto human cell lines for the production of recombinant proteins: on the horizon production of recombinant protein therapeutics in cultivated mammalian cells recombinant protein therapeutics from cho cells -20 years and counting establishment of a cell line expressing recombinant factor vii and its subsequent conversion to active form fviia through hepsin by genetic engineering method expression and fast preparation of biologically active recombinant human coagulation factor vii in cho-k1 cells implications of the presence of n-glycolylneuraminic acid in recombinant therapeutic glycoproteins uniquely human evolution of sialic acid genetics and biology production platforms for biotherapeutic glycoproteins. occurrence, impact, and challenges of non-human sialylation human cells: new platform for recombinant therapeutic protein production therapeutic glycoprotein production in mammalian cells 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submit your next manuscript to biomed central and we will help you at every step authors thankfully acknowledge the biotechnology and biological sciences research council for funding this research work. sns thanks esact 2017 for providing her with the opportunity to present her work at the meeting. we would like to thank moritz frei for his support for the generation of the ngs transcriptomics data. many thanks to valentine chevallier for her precious advices, to stefanos grammatikos for his support and to the whole upstream process sciences team. we thank david bruehlmann and thomas vuillemin from merck (vevey, switzerland) for providing the igg glycan variants and the 2-ab-uplc glycan data. polyplus-transfection would like to thank généthon for their kindly provided data.acknowledgements asmita mukerji, reetesh pm, sasi kumar k, pilot plant team acknowledgment to cedric allier from cea leti, grenoble, france. we would like to thank a. schemel and a. ehrlich for technical assistance. the authors would like to mention that this research was supported by the fi-dgr (2017) from spanish government and the project was led by prof. jordi joan cairó badillo. the authors want to thank the biotech process sciences team at merck in corsier-sur-vevey for their support and also the members of the morbidelli group at eth zürich for their input and collaboration. authors would like to thank dr. benjamin youn in manufacturing science and technology (msat) at biomarin for his help on coding the excel macro program for ambr15, and dr. donald l. traul from tap biosystems (now part of the sartorius stedim biotech group) for his assistance on ambr15 operations. thanks to the bioreactor team of dustin davis, amer al-lozi, and jana mahadevan. we organic vaccines tm and the nih, who kindly provided to univercells. we thank polymun scientific immunbiologische forschung gmbh for providing the antibodies igm103, igm104 and igm617 as a kind gift. this allison kurz and gian andrea signorell, genedata ag, basel, switzerland allison kurz, gian andrea signorell, genedata, basel, switzerland. allison kurz, gian andrea signorell, genedata ag high glucose concentration and low specific cell growth rate improve specific r-tpa productivity in chemostat culture of cho acknowledgements r. boraston for photographs in fig. 1 . we acknowledge atum for their contributions to vector design and construction. austrian bmwfw, bmvit, sfg, standortagentur tirol, government of lower austria and business agency vienna through the austrian ffg-comet-k2. this research is supported by sfi grant 13/ia/1841. financial support of the austrian science fund (fwf; grant number p 25056) is gratefully acknowledged. we would like to thank the australian institute for bioengineering and nanotechnology, university of queensland-brisbane, australia (aibn) for providing the cho clones. this research is partially supported by the developing key technologies for discovering and manufacturing pharmaceuticals used for next-generation treatments and diagnoses both from meti and amed, japan. this work was supported in part by grants for developing key technologies for discovering and manufacturing pharmaceuticals used for next-generation treatment and diagnoses, both from the ministry of economy, trade and industry (meti), japan and from the japan agency for medical research and developments (amed). many thanks stefanos grammatikos for his support and to the whole upstream process sciences team. the authors thank the hessen state ministry of higher education, research and the arts within the hessen initiative for scientific and economic excellence (loewe program) for the financial support. the authors thank xell ag, bielefeld, for providing hek serum-free media (hek gm and hek tf) and for fruitful discussions. the authors would like to thank dana wenzel for cho lysate preparation (fraunhofer izi, potsdam-golm, germany). this work is supported by the european regional development fund (efre) and the german ministry of education and research (bmbf, no. 031b0078a). the authors acknowledge são paulo research foundation -fapesp (2015/ 19017-6), centro de pesquisa, inovação e difusão (cepid), and national institute of science and technology in stem cell and cell therapy -inctc for financial support. this work was supported by grants from the niedersächsisches ministerium für wissenschaft und kultur (80029155) and the german ministry for economic affairs and energy (igf 16153 n). the infrastructure which was modularly built up, consists of automated liquid handling robots, plate and tube handling robots as well as incubators, refrigerator and analysis systems as for example an imaging system. the aim is to address the need on reproducibility and reliability of results and to offer access to a maximal controlled and automated environment. with the help of a web-based configurator assay selection as well as parameterization of the assays can be done in an easy way. after the order process, test items can be shipped to the lab. assays will be executed on the fully automated platform. by capturing in process data as well as environmental conditions, a real complete data set is leading to comprehensively results. as soon as results are available during the process, the view and analysing can be done in a secure cloud. the service can be used for single experiments in low throughput applications and is therefore a benefit for labs which cannot afford automated infrastructure or the staff for the maintenance for such platforms. extensive monitoring and data capturing during the run leads to a gapless data trail and the possibility of detailed result analysis. due to automated processing the reproducibility is increased associated with direct reduction of costs and time. the centralized service paired with specific know-how allows up-scaling of processes at any time. the web-based interface provides a flexible guidance for the user and the online order gives 24/7 access on the infrastructure, leading to a fast reliable result generation. furthermore the secure interaction with additional services e.g. other specific data analysis tool is possible. this dynamic access to automation offers high flexibility for low throughput experiments and will push high quality research and drug development in early stage. development of alternative animal cell technology platforms: cho based cell-free protein synthesis systems for the production of "difficult-to-express" proteins lena thoring 1, 2 background nowadays, animal cell technologies are commonly used for a broad range of medical and pharmaceutical applications. one main topic of these technologies is the production of proteins used for therapeutical purposes. these in vivo production processes are often time consuming and limited in production of so called "difficult-to-express" proteins including the pharmaceutical relevant class of membrane proteins. to overcome these issues, novel cell-free protein synthesis platforms were developed based on the industrial working horse cho cells [1] . cell lysates provide a basis for this technology by including all components of the translational machinery and enabling protein production within a few hours. microsomal structures present in cho cell lysates enable posttranslational modification of target proteins and insertion of membrane proteins into lipid bilayer. in this study a cell-free protein synthesis platform was developed based on a combination of cho cell lysates and a continuous exchange reaction format. the continuous exchange reactor consists of a twochamber system, a reaction and a feeding chamber, separated by a semipermeable membrane. due to concentration gradients, energy components can diffuse to the reaction chamber, while inhibitory byproducts are continuously removed. different classes of proteins were selected to evaluate the quality of the cho cecf system including a transmembrane receptor, a single chain variable fragment and an ion channel. cell-free protein synthesis was performed in the presence of 14 c leucine for radio labeling of synthesized proteins. protein yield was quantified by tca precipitation of radio labeled proteins followed by scintillation measurement and molecular mass was detected by autoradiography. posttranslational modifications and activities of proteins were estimated by kinase assays, elisa, endoglycosidase treatment and electrophysiological measurements. the demonstrated results showed a protein production of up to around 1 g/l while detecting correct molecular weights by autoradiography. analysis of the productivity using different lysate batches by the production of the membrane protein egfr revealed only minimal batch-to-batch variations (fig. 1a) . posttranslational modifications of proteins, including phosphorylation and glycosylation, were detected using western blot and autoradiography (fig. 1b) . evaluation of localization of membrane embedded eyfp fusion proteins by confocal laser scanning microscopy resulted in the detection of proteins in the microsomal fraction of cho cell lysate. produced single chain variable fragments showed binding specificity in elisa experiments. the activity of synthesized ion channels was underlined by electrophysiological measurements and detected single channel activities. a cell-free system based on cho cell lysates for high yield production of proteins was developed that provides a platform for efficient production of "difficult-to-express" proteins. the combination of a cho lysate based cell-free system and a continuous exchange cell-free system leads to be a highly efficient production system for various classes of "difficult-to-express" proteins. this approach opens up a fast and cost-effective process pipeline for the production of "difficult-to-express" proteins and shows a high potential for industrial applications including screening technologies, protein structure determination and just-in-time protein production processes.