The Role of CAM in Public Health, Disease Prevention, and Health Promotion

Evidence-Based Complementary and Alternative Medicine

Guest Editors: Cheryl Hawk, Jon Adams, and Jan Hartvigsen The Role of CAM in Public Health, Disease Prevention, and Health Promotion Evidence-Based Complementary and Alternative Medicine

The Role of CAM in Public Health, Disease Prevention, and Health Promotion

This is a special issue published in “Evidence-Based Complementary and Alternative Medicine.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board

Mona Abdel-Tawab, Germany Kevin Chen, USA Jian-Li Gao, China Jon Adams, Australia Evan P. Cherniack, USA Mary K. Garcia, USA GabrielA.Agbor,Cameroon Salvatore Chirumbolo, Italy Susana Garcia de Arriba, Germany Ulysses P. Albuquerque, Brazil Jae Youl Cho, Republic of Korea Dolores García Giménez, Spain Samir Lutf Aleryani, USA K. B. Christensen, Denmark Gabino Garrido, Chile M. S. Ali-Shtayeh, Palestine Shuang-En Chuang, Taiwan Ipek Goktepe, Qatar Gianni Allais, Italy Y. Clement, Trinidad And Tobago Michael Goldstein, USA Terje Alraek, Norway Paolo Coghi, Italy Yuewen Gong, Canada Shrikant Anant, USA Marisa Colone, Italy Settimio Grimaldi, Italy Isabel Andújar, Spain Lisa A. Conboy, USA Gloria Gronowicz, USA Letizia Angiolella, Italy Kieran Cooley, Canada Maruti Ram Gudavalli, USA Virginia A. Aparicio, Spain Edwin L. Cooper, USA Alessandra Guerrini, Italy Makoto Arai, Japan Olivia Corcoran, UK Narcis Gusi, Spain Hyunsu Bae, Republic of Korea Muriel Cuendet, Switzerland Svein Haavik, Norway Giacinto Bagetta, Italy RobertoK.N.Cuman,Brazil Solomon Habtemariam, UK Onesmo B. Balemba, USA Vincenzo De Feo, Italy Abid Hamid, India Winfried Banzer, Germany Rocío De la Puerta, Spain Michael G. Hammes, Germany Panos Barlas, UK Laura De Martino, Italy Kuzhuvelil B. Harikumar, India Vernon A. Barnes, USA Nunziatina De Tommasi, Italy Cory S. Harris, Canada Samra Bashir, Pakistan Alexandra Deters, Germany Thierry Hennebelle, France Jairo Kennup Bastos, Brazil Farzad Deyhim, USA Lise Hestbaek, Denmark Arpita Basu, USA Manuela Di Franco, Italy Eleanor Holroyd, Australia Sujit Basu, USA Claudia Di Giacomo, Italy Markus Horneber, Germany George David Baxter, New Zealand Antonella Di Sotto, Italy Ching-Liang Hsieh, Taiwan André-Michael Beer, Germany Luciana Dini, Italy GanS.Hua,Malaysia Alvin J. Beitz, USA Tieraona L. Dog, USA BennyT.K.Huat,Singapore Louise Bennett, Australia Caigan Du, Canada Roman Huber, Germany Maria Camilla Bergonzi, Italy Jeng-Ren Duann, USA Helmut Hugel, Australia Anna R. Bilia, Italy Nativ Dudai, Israel Ciara Hughes, UK Yong C. Boo, Republic of Korea Thomas Efferth, Germany Attila Hunyadi, Hungary Monica Borgatti, Italy Abir El-Alfy, USA Sumiko Hyuga, Japan Francesca Borrelli, Italy Tobias Esch, USA H. Stephen Injeyan, Canada Gloria Brusotti, Italy Giuseppe Esposito, Italy Chie Ishikawa, Japan Arndt Büssing, Germany Keturah R. Faurot, USA Angelo A. Izzo, Italy Rainer W. Bussmann, USA Nianping Feng, China Chris J. Branford-White, UK Andrew J. Butler, USA Yibin Feng, Hong Kong Suresh Jadhav, India Gioacchino Calapai, Italy Patricia D. Fernandes, Brazil G. K. Jayaprakasha, USA Giuseppe Caminiti, Italy Josue Fernandez-Carnero, Spain Zeev L Kain, USA Raffaele Capasso, Italy Antonella Fioravanti, Italy Osamu Kanauchi, Japan Francesco Cardini, Italy Fabio Firenzuoli, Italy Wenyi Kang, China Opher Caspi, Israel Peter Fisher, UK Shao-Hsuan Kao, Taiwan Subrata Chakrabarti, Canada Filippo Fratini, Italy Juntra Karbwang, Japan Pierre Champy, France Brett Froeliger, USA Kenji Kawakita, Japan Shun-Wan Chan, Hong Kong Maria pia Fuggetta, Italy Deborah A. Kennedy, Canada Il-Moo Chang, Republic of Korea Joel J. Gagnier, Canada Cheorl-Ho Kim, Republic of Korea Youn C. Kim, Republic of Korea Giovanni Mirabella, Italy Paolo Roberti di Sarsina, Italy Yoshiyuki Kimura, Japan Francesca Mondello, Italy Mariangela Rondanelli, Italy Toshiaki Kogure, Japan Albert Moraska, USA Omar Said, Israel Jian Kong, USA Giuseppe Morgia, Italy Avni Sali, Australia Tetsuya Konishi, Japan Mark Moss, UK Mohd Z. Salleh, Malaysia Karin Kraft, Germany Yoshiharu Motoo, Japan Andreas Sandner-Kiesling, Austria Omer Kucuk, USA Kamal D. Moudgil, USA Manel Santafe, Spain Victor Kuete, Cameroon Yoshiki Mukudai, Japan Tadaaki Satou, Japan Yiu W. Kwan, Hong Kong Frauke Musial, Germany Michael A. Savka, USA Kuang C. Lai, Taiwan MinKyun Na, Republic of Korea Claudia Scherr, Switzerland Ilaria Lampronti, Italy Hajime Nakae, Japan Guillermo Schmeda-Hirschmann, Chile Lixing Lao, Hong Kong Srinivas Nammi, Australia Andrew Scholey, Australia Christian Lehmann, Canada Krishnadas Nandakumar, India Roland Schoop, Switzerland Marco Leonti, Italy Vitaly Napadow, USA Sven Schröder, Germany Lawrence Leung, Canada Michele Navarra, Italy Herbert Schwabl, Switzerland Shahar Lev-ari, Israel Isabella Neri, Italy Veronique Seidel, UK Chun-Guang Li, Australia Pratibha V. Nerurkar, USA Senthamil Selvan, USA Min Li, China Karen Nieber, Germany Felice Senatore, Italy Xiu-Min Li, USA Menachem Oberbaum, Israel Hongcai Shang, China Bi-Fong Lin, Taiwan Martin Offenbaecher, Germany Karen J. Sherman, USA Ho Lin, Taiwan Junetsu Ogasawara, Japan Ronald Sherman, USA Christopher G. Lis, USA Ki-Wan Oh, Republic of Korea Kuniyoshi Shimizu, Japan Gerhard Litscher, Austria Yoshiji Ohta, Japan Kan Shimpo, Japan I-Min Liu, Taiwan Olumayokun A. Olajide, UK Yukihiro Shoyama, Japan Yijun Liu, USA Thomas Ostermann, Germany Morry Silberstein, Australia Víctor López, Spain Siyaram Pandey, Canada Kuttulebbai N. S. Sirajudeen, Malaysia Thomas Lundeberg, Sweden Bhushan Patwardhan, India Graeme Smith, UK Filippo Maggi, Italy Berit S. Paulsen, Norway Chang-Gue Son, Republic of Korea Valentina Maggini, Italy Philip Peplow, New Zealand Rachid Soulimani, France Gail B. Mahady, USA Florian Pfab, Germany Didier Stien, France Jamal Mahajna, Israel Sonia Piacente, Italy Con Stough, Australia Juraj Majtan, Slovakia Andrea Pieroni, Italy Annarita Stringaro, Italy Francesca Mancianti, Italy Richard Pietras, USA Shan-Yu Su, Taiwan Carmen Mannucci, Italy Andrew Pipingas, Australia Barbara Swanson, USA Arroyo-Morales Manuel, Spain Jose M. Prieto, UK Giuseppe Tagarelli, Italy Fulvio Marzatico, Italy Haifa Qiao, USA Orazio Taglialatela-Scafati, Italy Marta Marzotto, Italy Waris Qidwai, Pakistan Takashi Takeda, Japan James H. McAuley, Australia Xianqin Qu, Australia Ghee T. Tan, USA Kristine McGrath, Australia E. F. Queiroz, Switzerland Hirofumi Tanaka, USA JamesS.McLay,UK Roja Rahimi, Iran Lay Kek Teh, Malaysia Lewis Mehl-Madrona, USA Khalid Rahman, UK Norman Temple, Canada Peter Meiser, Germany Cheppail Ramachandran, USA Mayank Thakur, Germany Karin Meissner, Germany Elia Ranzato, Italy Menaka C. Thounaojam, USA Albert S Mellick, Australia Ke Ren, USA Evelin Tiralongo, Australia A. G. Mensah-Nyagan, France Man Hee Rhee, Republic of Korea Stephanie Tjen-A-Looi, USA Andreas Michalsen, Germany Luigi Ricciardiello, Italy Michał Tomczyk, Poland Oliver Micke, Germany Daniela Rigano, Italy Loren Toussaint, USA Roberto Miniero, Italy José L. Ríos, Spain Yew-Min Tzeng, Taiwan Dawn M. Upchurch, USA Shu-Ming Wang, USA Nobuo Yamaguchi, Japan Konrad Urech, Switzerland Yong Wang, USA Eun J. Yang, Republic of Korea Takuhiro Uto, Japan Jonathan L. Wardle, Australia Junqing Yang, China Sandy van Vuuren, South Africa Kenji Watanabe, Japan Ling Yang, China Alfredo Vannacci, Italy J. Wattanathorn, Thailand Ken Yasukawa, Japan S. Vemulpad, Australia Michael Weber, Germany Albert S. Yeung, USA Carlo Ventura, Italy Silvia Wein, Germany Armando Zarrelli, Italy Giuseppe Venturella, Italy Janelle Wheat, Australia Christopher Zaslawski, Australia Pradeep Visen, Canada Jenny M. Wilkinson, Australia Ruixin Zhang, USA Aristo Vojdani, USA D. R. Williams, Republic of Korea Marie-Geneviève Dijoux-Franca, France Dawn Wallerstedt, USA Christopher Worsnop, Australia Chong-Zhi Wang, USA Haruki Yamada, Japan Contents

The Role of CAM in Public Health, Disease Prevention, and Health Promotion,CherylHawk, Jon Adams, and Jan Hartvigsen Volume2015,ArticleID528487,2pages

Knowledge, Attitudes, and Usage of Apitherapy for Disease Prevention and Treatment among Undergraduate Pharmacy Students in Lithuania, Sonata Trumbeckaite, Jurgita Dauksiene, Jurga Bernatoniene, and Valdimaras Janulis Volume 2015, Article ID 172502, 9 pages

The Effects of Guided Imagery on Patients Being Weaned from Mechanical Ventilation, LeeAnna Spiva, Patricia L. Hart, Erin Gallagher, Frank McVay, Melida Garcia, Karen Malley, Marsha Kadner, Angela Segars, Betsy Brakovich, Sonja Y. Horton, and Novlette Smith Volume 2015, Article ID 802865, 9 pages

Association between Albuminuria and Different Body Constitution in Type 2 Diabetes Patients: Taichung Diabetic Body Constitution Study, Cheng-Hung Lee, Tsai-Chung Li, Chia-I Tsai, Shih-Yi Lin, I-Te Lee, Hsin-Jung Lee, Ya-Chi Wu, and Yi-Chang Su Volume2015,ArticleID603048,8pages

Characterizing Herbal Medicine Use for Noncommunicable Diseases in Urban South Africa, Gail D. Hughes, Oluwaseyi M. Aboyade, Roxanne Beauclair, Oluchi N. Mbamalu, and Thandi R. Puoane Volume2015,ArticleID736074,10pages

Effects of Tai Chi and Walking Exercises on Weight Loss, Metabolic Syndrome Parameters, and Bone MineralDensity:AClusterRandomizedControlledTrial, Stanley Sai-Chuen Hui, Yao Jie Xie, Jean Woo, and Timothy Chi-Yui Kwok Volume2015,ArticleID976123,10pages

A Systematic and Narrative Review of Acupuncture Point Application Therapies in the Treatment of Allergic Rhinitis and Asthma during Dog Days,Cai-Yu-ZhuWen,Ya-FeiLiu,LiZhou,Hong-XingZhang, and Sheng-Hao Tu Volume2015,ArticleID846851,10pages

Development and Preliminary Validation of the Questionnaire (the First Edition) Based on TCM for Detecting Health Status in China,XuanZhou,FangXu,JianGao,ShanCao,ZiweiZhao,MingliHeng, Huaien Bu, Liqun Yin, and Hongwu Wang Volume 2015, Article ID 863685, 12 pages

Resistance to Antibiotics and Antifungal Medicinal Products: Can Complementary and Alternative Medicine Help Solve the Problem in Common Infection Diseases? The Introduction of a Dutch Research Consortium, Esther T. Kok, Miek C. Jong, Barbara Gravendeel, Willem B. Van Leeuwen, and Erik W. Baars Volume 2015, Article ID 521584, 6 pages

Postmarketing Safety Surveillance and Reevaluation of Danhong Injection: Clinical Study of 30888 Cases, Xue-Lin Li, Jin-Fa Tang, Wei-Xia Li, Chun-Xiao Li, Tao Zhao, Bu-Chang Zhao, Yong Wang, Hui Zhang, Xiao-Fei Chen, Tao Xu, and Ming-Jun Zhu Volume 2015, Article ID 610846, 9 pages Antitumor Efficacy and Mechanism in Hepatoma H22-Bearing Mice of Brucea javanica Oil, Wen-Rong Shi, Yan Liu, Xiao-Ting Wang, Qiong-Ying Huang, Xue-Rong Cai, and Shao-Rong Wu Volume 2015, Article ID 217494, 8 pages

Traditional Chinese Medicine Decreases the Stroke Risk of Systemic Corticosteroid Treatment in Dermatitis: A Nationwide Population-Based Study, Kao-Sung Tsai, Chia-Sung Yen, Po-Yuan Wu, Jen-Huai Chiang, Jui-Lung Shen, Chung-Hsien Yang, Huey-Yi Chen, Yung-Hsiang Chen, and Wen-Chi Chen Volume 2015, Article ID 543517, 8 pages

From Body to Mind and Spirit: Qigong Exercise for Bereaved Persons with Chronic Fatigue Syndrome-Like Illness,JieLi,JessieS.M.Chan,AmyY.M.Chow,LaiPingYuen,andCeciliaL.W.Chan Volume 2015, Article ID 631410, 7 pages

Using the Theory of Planned Behaviour to Explain Use of Traditional Chinese Medicine among Hong Kong Chinese in Britain, Tina L. Rochelle, Steven M. Shardlow, and Sik Hung Ng Volume 2015, Article ID 564648, 6 pages

Efficacy of Compound Kushen Injection in Relieving Cancer-Related Pain: A Systematic Review and Meta-Analysis, Yu-ming Guo, Yi-xue Huang, Hong-hui Shen, Xiu-xiu Sang, Xiao Ma, Yan-ling Zhao, and Xiao-he Xiao Volume2015,ArticleID840742,8pages Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 528487, 2 pages http://dx.doi.org/10.1155/2015/528487

Editorial The Role of CAM in Public Health, Disease Prevention, and Health Promotion

Cheryl Hawk,1 Jon Adams,2 and Jan Hartvigsen3

1 Northwest Center for Lifestyle and Functional Medicine, University of Western States, Portland, OR 97230, USA 2Australian Research Centre in Complementary and Integrative Medicine (ARCCIM), University of Technology Sydney, Sydney, NSW 2007, Australia 3Department of Sports Science and Clinical Biomechanics, Nordic Institute of Chiropractic and Clinical Biomechanics, University of Southern Denmark, 5230 Odense M, Denmark

Correspondence should be addressed to Cheryl Hawk; [email protected]

Received 3 December 2015; Accepted 8 December 2015

Copyright © 2015 Cheryl Hawk et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

As the worldwide burden of chronic disease continues to rise, public health importance and disease prevention through risk disease prevention and health promotion become increas- factor reduction. A smaller number of articles address issues ingly important components of public health. Although many related to traditional medicine use among the general public. complementary and alternative medicine (CAM) practices Articles on treatment of conditions include a large clinical have emphasized health promotion and the area of CAM study by J.-F. Tang et al. on safety and evaluation of Danhong health care holds much opportunity and challenge for issues injection; a basic science study on Brucea javanica oilbyY.Liu of public health, CAM research to date has been dominated et al.; a systematic review and meta-analysis of the efficacy of by more clinically restrictive issues [1, 2]. However, CAM compound kushen on cancer pain by X. Ma et al.; an analysis practitioners can constitute a public health resource to of Qigong’s effect on chronic fatigue syndrome by L. P. Yuen increase the population’s access to certain clinical preventive etal.;asystematicreviewofacupunctureforallergicrhinitis services if integrated into mainstream public health practice. and asthma by L. Zhou et al.; and an analysis of the effects of As part of this integration of CAM practices, it is important guided imagery on patients on mechanical ventilation by B. to investigate methods of effective interprofessional collabo- Brakovich et al. ration involving both CAM and mainstream professions. It Articles on prevention and risk factor reduction were is also essential to identify issues that might be challenging a randomized controlled trial of Tai Chi on weight loss, to integration from the perspective of both mainstream and metabolic syndrome, and bone mineral density by T. C.- CAM providers such as professional biases on both sides, Y. Kwok et al.; an analysis of body constitution through differences in perception of health and disease, common Traditional Chinese Medicine by C.-H. Lee et al.; a survey language, and adherence to evidence-based principles. of apitherapy use for disease prevention by S. Trumbeckaite This special issue includes original research papers and et al.; an exploration of the possible effect of CAM on systematic reviews investigating the issues related to CAM antibiotic resistance by W. B. V. Leeuwen et al.; and a survey practices in the public health arena as well as outcomes of the effect of Traditional Chinese Medicine on decreasing of CAM treatment for chronic disease prevention and/or stroke risk among users of corticosteroids for dermatitis by management (tertiary prevention). J.-L. Shen et al. There are 14 articles in this issue, from six countries and Finally, F. Xu et al. described the validation of a question- on a wide variety of topics. The topics addressed are almost naire based on Traditional Chinese Medicine to assess health equally divided between treatment of specific conditions of status;S.H.Ngetal.describeduseoftheTheoryofPlanned 2 Evidence-Based Complementary and Alternative Medicine

Behaviour related to Traditional Chinese Medicine use; and G. D. Hughes et al. characterized the use of herbal medicines for noncommunicable disease. These articles tended to focus more on single herbal or other traditional preparations or procedures for both treatment and prevention, with very little emphasis on health behaviour, which is typically a cornerstone of public health programs. Behaviours related to diet, physical activity, and stress reduction are known to be increasingly important factors in determining the health of the public and are also areas of importance and emphasis for many CAM practitioners. It is necessary for CAM professions to become visible in this arena and for CAM research to extend into this direction rather than focusing narrowly on specific therapies if these efforts are to be recognized and utilized for the benefit of populations. Cheryl Hawk Jon Adams Jan Hartvigsen

References

[1] J. Adams, G. Andrews, J. Barnes, A. Broom, and P. Magin, Eds., Traditional, Complementary and Integrative Medicine: An International Reader,vol.2012,PalgraveMacMillan,London, UK. [2]J.Adams,E.Sommers,andN.Robinson,“Publichealthand health services research in integrative medicine: an emerging, essential focus,” EuropeanJournalofIntegrativeMedicine,vol.5, no. 1, pp. 1–3, 2013. Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 172502, 9 pages http://dx.doi.org/10.1155/2015/172502

Research Article Knowledge, Attitudes, and Usage of Apitherapy for Disease Prevention and Treatment among Undergraduate Pharmacy Students in Lithuania

Sonata Trumbeckaite,1 Jurgita Dauksiene,2 Jurga Bernatoniene,2 and Valdimaras Janulis1

1 Department of Pharmacognosy, Faculty of Pharmacy, Academy of Medicine, Lithuanian University of Health Sciences, Eiveniu Street 4, LT-50009 Kaunas, Lithuania 2Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Academy of Medicine, Lithuanian University of Health Sciences, Eiveniu Street 4, LT-50009 Kaunas, Lithuania

Correspondence should be addressed to Jurgita Dauksiene; [email protected]

Received 2 July 2015; Accepted 9 November 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Sonata Trumbeckaite et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Traditional medicine therapies are historically used worldwide for disease prevention and treatment purposes. Apitherapy is part of the traditional medicine based on bee product use. Complementary medicine practices which incorporate use of some traditional herbal, mineral, or animal kind substances very often are discussed with pharmacy professionals because these products are often sold in pharmacies as dietary supplements. This study is aimed at determining the attitude, knowledge, and practices of apitherapy among undergraduated pharmacy students (Master of Pharmacy) who already have a pharmacy technician diploma and from 1 to 20 years of practice working in a community pharmacy as pharmacy assistants. A method of questionnaire was chosen. The questions about attitudes, experience, knowledge, and practices for disease prevention and treatment of different bee products, their safety, and informational sources were included. Respondents shared opinion that use of bee product is part of the traditional medicine. Most of them had experience on honey product use for treatment and disease prevention for themselves and their family members (62%) although the need of more evidence based information was expressed. The most known bee products were honey, propolis, and royal jelly. They are widely used for enhancing the immune system and prevention of respiratory tract infection.

1. Introduction Chinese medicine: The famous ancient prescription book with fifty-two prescriptions dating back to the third century Apitherapy (Apis is a Latin word that means bee) is the B.C.foundinChangsha,HunanProvince,containstwo practice of using bee products such as honey, pollen, propolis, prescriptions involving bees, one of which uses honey to treat royal jelly, and bee venom for disease prevention or treatment diseases [1–4]. proposes. It can be also described as “the science (and art) of More recently, the bee products have been incorporated the use of honeybee products, to maintain health and assist into modern medical practice, where the focus of attention the individual in regaining health when sickness or accident ismainlytheillnessanditsprevention[5].Amongthe interferes” [1, 2]. complementary and alternative medicine (CAM) modalities, In the past, the apitherapy products were frequently some dietary supplements show relatively strong positive used as natural remedies for health maintenance. In many evidence for being effective in the prevention of some countries, bee products are part of traditional medicine. common diseases [6, 7]. Some findings suggest that those The roots of apitherapy can be traced back to more than who use alternative therapies, including herbal, mineral, 6000 years of medicine in ancient Egypt. The ancient Greeks and biological (including apitherapy) dietary supplements, and Romans also used bee products for medicinal purposes. appear less likely overall than nonusers to receive standard There is also evidence that honey was part of traditional preventive care. In addition, users of dietary supplements are 2 Evidence-Based Complementary and Alternative Medicine more likely to engage in healthy behaviours and appear to be a Professional Bachelor degree as pharmacy technicians and a more health-conscious group [8]. most of them declared from 1 to 20 years of practice in Lithuania has very old beekeeping traditions and for community pharmacy as pharmacist’s assistants (the demo- centuries bee products have been used in folk medicine graphic characteristics of the sample are presented in Table 1). for treatment of wounds, cough, ulcers, tuberculosis, and In Lithuania, pharmacy technicians after registration in the other diseases. Scientific research on apitherapy in Lithuania List of Pharmacy Assistants at Lithuanian State Medicines started more than 50 years ago when fresh royal jelly was ControlAgencycanworkincommunitypharmaciesas applied at the Cardiology Department for patients suffering pharmacist’s assistants and consult pharmacy patients under from cardiovascular diseases [2, 9]. From 1971, Lithuanian pharmacist’s supervision [12]. scientists have been focusing on investigation of propolis From the year 2013, the curricula of MPharm program qualities and propolis preparations development. Nowadays, of Lithuanian University of Health Sciences have a special bee products, particularly honey and propolis and its prepa- course on integrated evidence based CAM education. The rations (tablets, suppositories, ointments, mouth sprays, and courseisgiventothelastyearstudentsbeforegraduation. others), are quite popular among consumers and are available in most of the Lithuanian community pharmacies usually 2.2. Data Collection. Data were collected by cross-sectional positioned as dietary supplements. survey. The questionnaires were distributed during the 2014- The changing role of pharmacists encourages them to 2015 academic year at the Lithuanian University of Health discuss with pharmacy patients not only the correct usage Sciences to the intensive 3-year MPharm course students. of medication but also disease prevention and public health The respondents of all three years were invited to take part issues. The provision of information on disease prevention is in a survey. Third-year students answered questions before partofthepublichealthissuesandmayempowerpeopleto the beginning of special course on integrated evidence based increase control over and to improve their health [10, 11]. CAM education on use of dietary supplements with a special The community pharmacists are recognized as the most focus on traditional Lithuanian medicine: herbal, mineral, accessible to the public health care professionals. They are like and biological (including bee products) dietary supplements. gatekeepers when giving advice for patients who enter com- This ensured that the answers were not influenced by lectures munity pharmacy to obtain medication, dietary supplements, of apitherapy and expressed earlier students’ attitude, knowl- or medicine goods [11]. In Lithuania, like in many other edge, and practice of bee product use. countries, the community pharmacy is the only legal place The questionnaires were distributed to each student to obtain medication and the pharmacist consultation is an together with a written consent form with the explained aim obligatorypartofthepurchase[12].Thepatientswhomake of the survey and they were informed of confidentiality. All decisions about their health often use integrative practice and participants were assured that their refusal to participate in combine both conventional and complementary medicine theresearchwillnothaveanyinfluenceontheirevaluation practices [6, 8]. Complementary medicine practices which grades during upcoming courses. The signature on the incorporate use of some traditional herbal, mineral, or animal consent form was accepted as an indicator that a student kind substances very often are discussed with pharmacy wishes to participate in a research. It took from 10 to 20 professionals because these products are often sold in phar- minutes for every participant to fill up the questionnaire. All macies as dietary supplements. Pharmacy professionals often filledformswerecollectedbytheclassleaderandreturnedto encourage people to use dietary supplements because (1) theleadinginvestigator.Thereturnrateofthequestionnaire there is no prescription need for them, (2) this gives addi- was more than 90%. tional income for pharmacy, and (3) pharmacists value their knowledge on dietary supplements. Dietary supplements are often used for disease prevention purposes [13, 14]. The 2.3. Study Questionnaire. The questionnaire consisted of8 1 correct knowledge on common complementary medicines sections. Section consisted of questions about general practices is necessary to assist patient needs and answer the attitudes toward apitherapy, everyday personal practices, 2 6 questions. This includes providing information that allows and informational sources. Sections – were formed up thepatienttomaketheinformeddecisionsabouttheirhealth. with questions about knowledge and practices for disease The aim of this study was to investigate the experience, prevention and treatment for different bee products: honey, knowledge, attitude, and practices of undergraduate phar- propolis, royal jelly, bee pollen/bee bread, and bee venom. 7 macy students towards bee products for disease prevention Section consistedofattitudetowardsapitherapysafetyques- and treatment purposes. tions. The last section was with questions for demographic characteristics of the respondents. Most of the questions were closed, with the proposed choices of answers with “tick” box 2. Methods possibilities. Likert scale was used to evaluate the general 2.1. Setting and Sample. This study was conducted among attitude towards apitherapy and disease prevention practices undergraduated pharmacy students at the Lithuanian Uni- among respondents with different bee products. versity of Health Sciences (LUHS). The sample of undergraduate Master of Pharmacy (MPharm) intensive course 2.4. Data Analysis. SPSS (version 22.0) was used for data students was chosen for the cross-sectional study. All analysis. Descriptive statistics such as frequencies, means, participants of intensive MPharm course already have and ranges were calculated to summarize the data. For Evidence-Based Complementary and Alternative Medicine 3

Table 1: Sociodemographic characteristics of the respondents (𝑛=72).

Demographics 𝑛 (%) Year of study First year 23 (31.9) Second year 23 (31.9) Third year 26 (36.2) Gender Male 10 (13.9) Female 62 (86.1) Age group ≤22 14 (19.4) 22–26 38 (52.8) 27–32 3 (4.2) ≥33 17 (23.6) Birth place City 47 (65.3) Town 19 (26.4) Countryside 6 (8.3) Work place City 62 (13.9) Town 10 (86.1) Countryside 0(0) Work experience at the community pharmacy ≤1year 18 (25.0) 1–4 years 34 (47.2) ≥5years 17 (23.6) No experience 3 (4.2) Experience and expectation towards beekeeping of the family members Presence of beekeepers among parents Yes 5 (6.9) No 66 (91.7) Iamnotsure 1 (1.4) Presence of beekeepers among grandparents Yes 15 (20.8) No 50 (69.5) Iamnotsure 7(9.7) Expectation towards children beekeeping Yes 9(12.5) No 41 (56.9) Iamnotsure 22 (30.6)

the Likert scale responses, all responses with any level of 3. Results degree of agreement were grouped together as positive responses and all responses with any degree of disagreement 3.1. Pattern of Awareness and Use of Apitherapy. All 72 (100%) were grouped as negative respondent. For knowledge and respondents indicated that they use and are aware of at least useofbeeproductsfordiseaseprevention,theLikertscale one of the bee products. Honey was the most popular choice responses were transformed into Index score which was for all indicators (“I know”; “I use by myself and encourage calculatedasanaverageofallresponsesof5-pointLikert my family members to use for treatment purposes”; “I use scale evaluation (5: strongly agree; 4: agree; 3: neutral; 2: by myself and encourage my family members to use for disagree;1:stronglydisagree).𝑡-test and chi-square were disease prevention”; “I recommend it to pharmacy patients used to analyze the differences among groups. Results were for treatment”; “I recommend it to pharmacy patients for considered significant when the 𝑝 value was less than 0.05. disease prevention”). More than half (62%) were convinced 4 Evidence-Based Complementary and Alternative Medicine

Table 2: The attitude towards apitherapy.

Strongly agree Agree Neutral Disagree Strongly disagree Statement (%) (%) (%) (%) (%) Apitherapy is part of our traditional medicine 31.4 42.9 24.3 1.4 0 Apitherapy is very popular nowadays in our country 0 16.7 43.1 37.5 2.8 Physicians have sufficient knowledge on apitherapy 0 8.5 36.6 52.1 2.8 As a future pharmacist I have sufficient knowledge on apitherapy 45.7 35.7 18.6 0 As a pharmacist I am an apitherapy expert 0 9.9 29.6 46.5 14.1 Apitherapy has less contraindication than other remedies 6.9 36.1 45.8 11.1 0 Apitherapy has less side effects than other remedies 5.6 43.1 43.1 8.3 0 The use of apitherapy products should be encouraged 11.1 36.1 47.2 5.60 Apitherapy products should be available in every community pharmacy 26.4 45.8 22.2 4.2 1.4 of the usage of bee products by themself and almost one- Table 3: Sources of information. third (34%) reported recommendation to pharmacy patients. Question (%) The most popular choice for “disease prevention” purposes was “honey” for family members (28%) and propolis (16%) What are the main sources of the information on or “royal jelly” (13%) for pharmacy patients. “Bee venom” was apitherapy for you? the rarest choice for all statements. It was mentioned only by Parents/grandparents 41.7 4 respondents. Friends/community members 9.7 Journals 59.7 3.2. Attitudes towards Apitherapy. In Table 2, the attitudes of Internet sources 62.2 the respondents towards apitherapy are summarized. Most Other health professionals 5.6 of the respondents think that apitherapy is part of the Media 18.1 Lithuanian traditional medicine and as future pharmacists Formal lectures 52.8 they must have sufficient knowledge on apitherapy, but only 10% confirmed themselves already as apitherapy experts. Other 11.1 The statistical analysis demonstrated that more confident Who is supposed to be the main informational source on about their apitherapy knowledge are those who are older apitherapy to the patients? than 26 years, who have more than 5 years of experience Physician 47.2 working as pharmacist assistant and also those who have Pharmacist 61.1 beekeepers among their parents or expect their children to Beekeepers 44.4 𝑝 < 0.05 be beekeepers ( ). There was no significant differ- Traditional healers 26.4 ence among other demographic groups although students Apitherapist 80.6 of third year and those who declared to have beekeepers among their grandparents rated their knowledge as sufficient. Scientists 20.8 All 7 respondents who declared themselves as experts of Other 1.4 apitherapy had beekeepers among their ancestors and more than 5 years of working practice as pharmacy assistant. More than half (72.2%) agreed that apitherapy products should be 3.4. The Knowledge and Use of Bee Products for Disease Pre- available at every community pharmacy whereas only 5.6% vention. The undergraduate pharmacy students experience disagree. About the extra question whether the pharmacist onknowledgeanduseofbeeproductsfordiseaseprevention should promote apitherapy, 69% of all respondents answered is summarized in Table 4. Thus, only “enhancing immune positively,andtheratewashigherinbeekeepersamong system” and “respiratory tract infections” (all four types of ancestors group (89%). bee products: honey, propolis, royal jelly, and bee pollen/bee bread, except for bee venom) were evaluated with Index 3.3. Sources of Information on Apitherapy. In Table 3, the averagemorethan3—thismeansthatmostoftheparticipants most important sources of information on apitherapy are believe honey products to be effective for this purpose. presented. The main sources were the Internet (62.2%), Respondents thought that, for prevention of respiratory tract journals (59.7%), and formal lectures of continuing education infection, the best among bee products are honey (the range (52.8%). Even 41.7% said that parents and grandparents of the scale 3.57,i.e., 62.5% “strongly agree”) and propolis (the were source of information on apitherapy. The respondents range of the scale 3.42, i.e., 53.5% “strongly agree” and about expressed opinion that health care providers as pharmacists 30% of respondents “agree”). (61.1%) and physicians (47.2%) should provide information BeepollenalsogothighcumulativeIndexscoreof3for on apitherapy and only 26.4% said that it should be done by increasing male and female fertility. Also, the respondents traditional healers. demonstrated positive attitude towards the bee products Evidence-Based Complementary and Alternative Medicine 5

Table 4: The knowledge and use of bee products for disease prevention.

Prevention area Honey Propolis Royal jelly Bee pollen and bee bread Bee venom ∗ Enhancing immune system 3.86 3.54 3.46 3.48 2.01 Respiratory tract infections 3.57 3.42 3.16 3.2 1.98 Cardiovascular diseases 2.02 2.2 2.4 2.28 1.66 Cancer prevention 1.9 2.1 2.03 2.03 1.71 Endocrine system disorders 1.82 1.93 2.1 2.14 1.68 Allergy 1.36 1.68 1.73 1.6 1.55 Skin aging 2.54 2.51 2.42 2.27 1.57 Anemia 1.98 2.11 2.2 2.18 1.55 Increasing of male/female fertility 2.25 2.12 2.24 3 1.55 Enhancing mental activity 2.64 2.48 2.48 2.34 1.61 ∗ Index score is calculated as an average of 5-point Likert scale evaluation (5: strongly agree; 4: agree; 3: neither agree nor disagree; 2: disagree; 1: strongly disagree). The max Index meaning is 5 and minimum is1.

(except for bee venom) usage for fertility increasing proposes 3.6. Safety Issues of Apitherapy Products. The experience and (40.6%,34.3%,38%,and34%agreedthathoney,beepollen, knowledge on safety issues of bee products are presented royal jelly, and propolis might help, resp.). Bee venom has in Table 6. Participants of the study indicated that bee not been considered by respondents as a possible product for products have less contraindications than other remedies. prevention of all indicated areas in the table. 48.7% of the respondents agree or strongly agreed with this Respondents did not have much experience and knowl- statement and none (𝑁=0) strongly disagreed (Table 2). edge on bee product use for such prevention areas as They also indicated the attitude about fewer side effects cardiovascular diseases, cancer, and disorders of endocrine than conventional remedies. The most known side effect is system. The range of scale for the usefulness of various bee allergy (97.2%)and bee product use should be recommended products (honey, propolis, royal jelly, and bee pollen/bee with warnings to allergic patients (90.3%), pregnant woman bread) varied between 1.8 and 2.54. Thus, about 60% of (61.1%), or children under 3 years of age (62.5%). respondents did not agree that these products could be usedforpreventionofcardiovasculardiseases,cancer,or endocrine system disorders. 4. Discussion Regarding prevention of skin aging, only about 20% of The undergraduate pharmacy students of LUHS who have the respondents strongly agree and about 30% agree that bee already from 1 to 20 years of experience as consulting products, honey, propolis, and royal jelly, could be helpful pharmacy assistants demonstrated a positive attitude towards whereas more than 40% disagree. apitherapy. According to them, apitherapy is part of the tradition medicine though not so very popular nowadays. 3.5. The Knowledge and Use of Bee Products for Treatment Still they are positive about having a wide spectrum of bee of Diseases. Table 5 shows that bee products such as honey, products at community pharmacies. 62% of the respondents propolis,royaljelly,andbeebreadarewidelyusedand reported the use of bee products for themselves or their family recommended to pharmacy patients. The main indication is members. This repeats the results of pharmacy students respiratory tract infections: Every third respondent would use surveys towards attitude and use of complementary and alter- and recommend to the pharmacy patients honey or propolis native medication in Australia [15], Great Britain [16], Kuwait as main therapy and more than half of all respondents choose [17],Malaysia[18],andSierraLeone[19].InanAustralian honey, propolis, royal jelly, and bee bread as an additional survey [15], about 90% of all-years students declared that clin- therapy. Only less than 10% of the respondents indicated ical care should integrate the best of conventional and CAM “nouse”or“noknowledge”abouthoneyuseforrespiratory practices; 60% of undergraduate British pharmacy students tract infections. 37.1%of the respondents indicated bee venom stated that they were very interested in complementary and as a main therapy among all bee products for treatment of alternative medicine [16]; 79.7% of Kuwait students believed arthritis and 22.9% as an additional therapy. that CAM includes ideas and methods from which conven- According to 22.1% of undergraduate pharmacy students tional medicine could benefit [17]; 77.6of the Malaysian study for skin diseases propolis could be a main therapy among participants had used CAM previously [18]; and 55.6% of bee products and according to 55.9% an additional therapy. Sierra Leones respondents indicated that CAM therapies are 53.7% of the respondents believed honey and 44.9% propolis effective and not harmful [19]. The comparable studies in as an additional therapy for herpes treatment and only 16% USA [20] or Germany [21] made with undergraduate medical bee venom. About 34–36% thought that royal jelly and bee students also demonstrated positive attitudes towards CAM: pollen could be used as an additional therapy. medical students in USA survey declared earlier experience 6 Evidence-Based Complementary and Alternative Medicine

Table 5: The knowledge and use of bee products for treatment. Honey Propolis Royal jelly Bee pollen and bee bread Bee venom Treatment area (%) (%) (%) (%) (%) Arthritis Main therapy 4.7 6.0 3.1 4.5 37.1 Additional therapy 39.1 37.3 32.3 26.9 22.9 No knowledge 43.7 47.7 58.5 59.7 32.9 No use 12.5 9.0 6.2 9.0 7.1 Respiratory tract diseases Main therapy 29.8 34.8 15.7 19.1 4.4 Additional therapy 62.7 52.2 53.1 54.4 23.5 No knowledge 4.5 11.6 28.1 23.6 60.3 No use 3.0 1.4 3.1 2.9 11.8 Skin diseases Main therapy 18.4 22.1 10.8 13.2 4.4 Additional therapy 55.4 55.9 46.1 33.9 29.0 No knowledge 23.1 20.5 40.0 50.0 53.6 No use 3.1 1.5 3.1 2.9 13.0 Gastrointestinal disorders Main therapy 10.1 13.4 12.3 9.8 1.5 Additional therapy 52.2 41.8 38.5 42.3 13.6 No knowledge 33.3 35.8 44.6 42.3 71.3 No use 4.4 9.0 4.6 5.6 13.6 Tuberculosis Main therapy 1.5 1.5 1.5 2.9 0.0 Additional therapy 28.8 28.8 23.5 19.1 11.9 No knowledge 53.0 59.1 66.2 67.6 73.2 No use 16.7 10.6 8.8 10.4 14.9 Oncology Main therapy 1.5 4.5 1.5 2.9 1.5 Additional therapy 36.8 25.4 24.6 20.6 14.7 No knowledge 47.0 61.1 65.2 64.7 70.6 No use 14.7 9.0 8.7 11.8 13.2 Anemia Main therapy 4.4 4.5 5.8 4.3 0.0 Additional therapy 36.7 25.8 29.0 31.9 12.0 No knowledge 51.5 60.6 62.3 56.5 74.6 No use 7.4 9.1 2.9 7.3 13.4 Herpes Main therapy 6.0 11.5 4.5 1.5 0.0 Additional therapy 53.7 44.9 34.3 36.2 16.2 No knowledge 32.8 37.7 55.2 56.5 70.6 No use 7.5 5.8 6.0 5.8 13.2 Gynecological inflammations Main therapy 1.5 3.0 0.0 4.3 1.5 Additional therapy 26.5 27.3 20.9 21.8 11.7 No knowledge 58.8 59.1 74.6 66.7 72.1 No use 13.2 10.6 4.5 7.2 14.7 Benign prostatic hyperplasia Main therapy 0.0 0.0 0.0 2.9 2.9 Additionaltherapy 19.4 21.5 17.9 17.4 10.3 No knowledge 67.2 63.1 76.1 72.5 70.6 No use 13.4 15.4 6.0 7.2 16.2 Ophthalmologic disorders Main therapy 6.0 15.1 3.1 0.0 0.0 Additional therapy 46.3 37.9 18.5 21.2 0.0 No knowledge 40.3 39.4 72.3 68.2 64.3 No use 7.5 7.6 6.1 10.6 35.7 Evidence-Based Complementary and Alternative Medicine 7

Table6:Safetyissuesofbeeproducts. program curriculum. It was observed also in other studies [22]. Question (%) Mostofourrespondentsthinkthatpharmacistshould What group of patients should not use the bee products? have sufficient knowledge towards apitherapy but only a small Pregnant women 61.1 part of them think about themselves as experts. This strongly Children under 3 years of age 62.5 correlates with traditions of beekeeping in the family [2, 9]. Teenagers 18.1 The German survey of beekeepers [3] showed that most of Oncology patients 15.3 them had positive experience in using honey, propolis, pollen, Allergic patients 90.3 and royal jelly which they employ for various indications. ≥65 years of age 1.4 Common cold, wounds, sore throat, and gingivitis were one Other 4.2 of the most often mentioned indications for treatment purposes. In our survey, more than 90% of respondents indicated What are the possible side effects of the bee products? the use of honey for respiratory tract infections as main Allergy 97.2 or additional therapy. Also, propolis and bee pollen were Bleeding 2.8 indicated. All bee products were also chosen for prevention Headaches 13.9 reasons. “Enhancing immune activity” and “prevention of Weightlossorincrease 1.4 respiratory tract infection” were also very popular choice of Vomiting 45.8 our respondents as area of all bee products use except bee Vision disorders 0.0 venom. Other 0.0 Propolishasbeenreportedtoexertawiderangeofbiolog- ical activities: antibacterial, antiviral, anti-inflammatory, an immunomodulatory properties as demonstrated in in vitro and in vivo studies [23, 24]. Nowadays, propolis and its preparations in various forms for use (mouth sprays, tablets, of a wide spectrum of CAM modalities [20] and almost 68% capsules, etc.) are used in human medicine to treat common of German medical students indicated “earlier experience” cold, flu-like infections, wounds, sore throat, and herpes as “source of information” for knowledge on CAM [21]. simplex infection [24, 25]. WHO supports the idea about integration of conventional According to the study of Paul [26], “honey may be and complementary practice in order to reach the best results a preferable treatment for the cough and sleep difficulty for the patient and society [5]. associated with childhood upper respiratory tract infec- The respondents of our study more often tend touse tion.” Honey is used as a common ingredient or alone in the apitherapy by themselves rather than offering it to the folk medicine for relieving of cough. Royal jelly and bee pharmacy patients. The same findings were in USA study [20] pollen/bee bread were also mentioned by respondents among where more students used herbs or supplements rather than other bee products to enhance the immune system. It has recommending herbs or dietary supplements to the patients. been shown that royal jelly possesses immunomodulatory Some studies conclude that, due to the current popularity activity [27, 28], antioxidant properties [29], and antimicro- of complementary and alternative medicine (CAM) among bial activities [30]. patients, many pharmacists will be faced with questions Regarding bee products for prevention of cardiovascular from the public regarding natural products and other CAM or cancer diseases, the students did not express united therapies and there is a great need for exact knowledge [13, position: 29–40% of the respondents agreed or strongly 14]. agreedthatpropolis,honey,royaljelly,orbeepollencould In our study, the most important sources of information be useful for disease prevention purposes and, respectively, on apitherapy were the Internet (62.5%), journals (59.7%), 24–32% for cancer prevention. Current in vitro studies show a and formal lectures of continuing education (52.8%). Even potential of selective bee products against tumor cells [31, 32]. 41.7% obtained information from parents and grandparents Regarding bee venom, 60% of undergraduated pharmacy and only 18% from media. In a German [21] study, the students think that in case of arthritis bee venom could “practical experience” (68%), media (48%), and also “other be used as a main or additional therapy; however, they publications and congresses” and “medical education” were reportednoorlessknowledgeonbeevenomtherapyfor named. Pharmacy students of Sierra Leone listed media other listed diseases. Bee venom is mostly known as anti- (58.9%), books (35.6%), and CAM practitioners (43.3%) [19]. inflammatory and pain-reducing agent and, in form of bee Moreover, the results of the survey revealed that under- stings, apipuncture, injections, and so forth, is used by graduate pharmacy students believe that one of the main apitherapy practitioners in some countries to treat arthritis information sources to the public about apitherapy should [4] or other diseases, but there is still a great need for evidence be pharmacist (62.5%) or physician (47.2%). 80.6% of the based knowledge. respondents have chosen “apitherapist” as the answer for this Animportantfactorbyusingbeeproductsishuman question but there is no apitherapists activity regulation in safety. Most of our respondents named allergy as the main Lithuania. The choice of health care providers as expected possible side effect and also stated that generally allergic source for information on apitherapy also reports the need patients should avoid this therapy. This fact is supported by of evidence based information integrated in the pharmacy other studies [33, 34]. 8 Evidence-Based Complementary and Alternative Medicine

5. Conclusions [13] H.-L. Koh, H.-H. Teo, and H.-L. Ng, “Pharmacists’ patterns of use, knowledge, and attitudes toward complementary and alter- Pharmacy students in Lithuania showed interest towards bee native medicine,” The Journal of Alternative and Complementary product use for diseases prevention and treatment purposes. Medicine,vol.9,no.1,pp.51–63,2003. They self-reported use and awareness of apitherapy prod- [14] L. A. Braun, E. Tiralongo, J. M. Wilkinson et al., “Perceptions, ucts which are part of traditional medicine in Lithuania. use and attitudes of pharmacy customers on complementary According to them, the pharmacist as the easiest accessible medicines and pharmacy practice,” BMC Complementary and health care professional is the one who can support phar- Alternative Medicine,vol.10,no.1,article38,2010. macy patients with appropriate information on apitherapy [15] E. Tiralongo and M. 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Research Article The Effects of Guided Imagery on Patients Being Weaned from Mechanical Ventilation

LeeAnna Spiva,1 Patricia L. Hart,2 Erin Gallagher,3 Frank McVay,3 Melida Garcia,4 Karen Malley,5 Marsha Kadner,5 Angela Segars,5 Betsy Brakovich,6 Sonja Y. Horton,6 and Novlette Smith5

1 WellStar Health System, Center for Nursing Excellence, WellStar Development Center, 2000 South Park Place, Atlanta, GA 30339, USA 2Kennesaw State University, 1000 Chastain Road, Prillaman Hall Building 41, Kennesaw, GA 30144, USA 3WellStar Health System, Center for Nursing Excellence, 2000 South Park Place, Atlanta, GA 30339, USA 4WellStarCobbHospital,3950AustellRoad,Austell,GA30106,USA 5WellStar Kennestone Hospital, 677 Church Street, Marietta, GA 30060, USA 6WellStar Windy Hill Hospital, 2540 Windy Hill Road, Marietta, GA 30067, USA

Correspondence should be addressed to LeeAnna Spiva; [email protected]

Received 17 June 2015; Revised 19 October 2015; Accepted 21 October 2015

Academic Editor: Tadaaki Satou

Copyright © 2015 LeeAnna Spiva et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The study purpose was to assess the effects of guided imagery on sedation levels, sedative and analgesic volume consumption, and physiological responses of patients being weaned from mechanical ventilation. Forty-two patients were selected from two community acute care hospitals. One hospital served as the comparison group and provided routine care (no intervention) while the other hospital provided the guided imagery intervention. The intervention included two sessions, each lasting 60 minutes, offered during morning weaning trials from mechanical ventilation. Measurements were recorded in groups at baseline and 30- and 60- minute intervals and included vital signs and Richmond Agitation-Sedation Scale (RASS) score. Sedative and analgesic medication volume consumption were recorded 24 hours prior to and after the intervention. The guided imagery group had significantly improved RASS scores and reduced sedative and analgesic volume consumption. During the second session, oxygen saturation levels significantly improved compared to the comparison group. Guided imagery group had 4.88 less days requiring mechanical ventilation and 1.4 reduction in hospital length of stay compared to the comparison group. Guided imagery may be complementary and alternative medicine (CAM) intervention to provide during mechanical ventilation weaning trials.

1. Introduction consequences including but not limited to anxiety and inability to relax [6, 7], psychological and emotional distress at Mechanical ventilation is a life-sustaining treatment for being unable to communicate [8], and delusional memories respiratory compromised patients by reducing the work to [7]. Analgesic and sedatives are commonly administered breathe,oxygenatetissue,andeliminatecarbondioxide[1]. to reduce these symptoms. Consequently, pharmacologic It is a costly treatment estimated at $27 billion a year repre- senting 12% of hospital costs [2]. Therefore, early assessment interventions including sedatives and analgesics have notable of weaning readiness and implementation of standardized side effects and are found to prolong mechanical ventilation weaning trials to transition patients from full ventilator and contribute to a higher hospital and/or intensive care supporttospontaneousbreathingwiththegoalofearly unit (ICU) length of stay [9–11]. As mechanical ventilation extubation [3, 4] are essential to prevent unintended conse- duration increases, risk of hospital-acquired complications quences from prolonged ventilation and weaning [5]. Patients increases contributing to higher mortality and morbidity requiring mechanical ventilation may experience unintended rates [2, 12–14]. 2 Evidence-Based Complementary and Alternative Medicine

Further work is needed to explore the effects of guided 2. Methods imagery, a complementary and alternative medicine (CAM) technique, used to optimize a mind-body connection. 2.1. Participants. Patients were recruited from an integrated Guided imagery is used to focus on pleasant mental images healthcare system that included two community acute care to promote healing and relaxation, manage symptoms, and hospitals with seven ICUs located in the southeastern United ultimately contribute to critically ill patients’ well-being [15– States from August 1, 2012, to March 10, 2014. One hospi- 18]. Guided imagery may have the potential to reduce the tal served as the comparison group and provided routine frequency and severity of symptoms in patients weaning care (no intervention), while the other hospital provided from mechanical ventilation. Guided imagery may assist with theguidedimageryintervention.Thetwohospitalswere shifting focus away from the weaning trial to acquiring a level chosen based on similar patient population (age, reason of relaxation. Therefore, we conducted a study to determine for ICU admission, severity of illness, etc.), and evidence- the effects of guided imagery in mechanically ventilated based mechanical ventilation order set was followed for patients undergoing active ventilator weaning on sedation daily spontaneous breathing trials used to decrease practice levels, sedative and analgesic volume consumption, and phys- variation. Additionally, the four researchers conducting the iological responses. Additionally, we assessed nurse percep- intervention were based at the hospital receiving the inter- tion of the feasibility and satisfaction of using guided imagery vention. Patient inclusion criteria were (a) age greater than as an intervention. 18 years, (b) actively weaning from mechanical ventilation Guided imagery has been used in a variety of patient (the process of gradual reduction of ventilator support) per populations including preoperative patients [19], antepartum the hospital’s standard weaning criteria, and (c) no hearing patients [20], community-dwelling older adults [21], patients impairment. Nurse inclusion criteria included directly caring with cancer [22, 23], cardiac patients [24–26], and patients for a patient receiving the intervention. With a power of withchronicpain[27,28].Patientsrecoveringfromsame .80, an alpha value of .05, and a medium effect of 0.25, 34 day head and neck surgery had a significant reduction in participants were needed for the study [31, 32]. anxiety and pain levels and postanesthesia care unit (PACU) The study was reviewed and approved by Kennesaw State length of stay was nine minutes less compared to the control University Institutional Review Board and the study site’s group [19]. There is evidence that guided imagery is an nursing research council. Informed consent was obtained at effective intervention to reduce maternal stress, fatigue, and the beginning of the study by one of the study researchers anxiety for pregnant African American women in the second from each patient’s surrogate due to the patient consumption trimester [20]. Guided imagery was shown to improve self- of sedatives and analgesics. In order to protect confidentiality, reported leisure time behavior, reduce mobility test time, and each participant was assigned a unique identifier. reduce the fear of falling in older adults [21]. Researchers found lower respiratory and heart rates and 2.2. Intervention. If patient was receiving continuous infu- blood pressure measurements and felt the sessions were sions of sedation and/or analgesic, the infusions were stopped beneficial for patients undergoing radiation therapy for breast in order to assess patient readiness for weaning and extu- cancer [23]. Similarly, thyroid patients undergoing radioac- bation. Prior to the intervention, patient’s sedation level tive iodine therapy had reduced fatigue and stress levels [22]. was assessed before weaning to ensure patient was rested, Guided imagery has been used as an intervention with comfortable, and not lethargic, when weaning started. For cardiac patients including post-open heart surgery patients patients enrolled in the guided imagery group, two separate [24,26]andhasshowntoreducelengthofstay,anxiety,and sessions were held on two consecutive days, each lasting pain levels. In addition, percutaneous transluminal coronary 60 minutes and offered during morning weaning trials. The angiography patients [25] had reduced anxiety and pain levels structured, guided imagery, produced by Guided Imagery, and improved heart and respiratory rates and blood pressure Inc., was delivered via PLAYWAY device, 5 × 7inches’ after listening to a guided imagery cassette for 18 minutes. plastic case. The case included a four-track preloaded 60- In addition, guided imagery has been shown to reduce minute audio book that required AAA battery. Disposable musculoskeletal pain and medication usage, including anal- earphones were connected to the device. The guided imagery gesics, in osteoarthritis patients from baseline to four months [27]. Similarly, patients with fibromyalgia who received was narrated with a faint, soft voice, instructing the patient guided imagery as an intervention had lower pain and to relax. The session started approximately 20 minutes prior depression levels compared to usual care [28]. However, to weaning. Patients listened to the content for 60 minutes two systematic reviews concluded that guided imagery used during the spontaneous breathing trial from mechanical for musculoskeletal pain [29] and nonmusculoskeletal pain ventilation. Four study researchers delivered the intervention [30] were inconclusive due to lack of methodological rigor. and remained with the patient throughout the session. The Furthermore, the beneficial effects of guided imagery have length of time of the intervention was based on the hospital’s not been studied as an intervention to provide to patients average duration of a weaning trial (30 to 120 minutes); weaning from mechanical ventilation. Therefore, the specific andtheperiodofthedeliveryoftheinterventionwas aims of this quasi-experimental, repeated measure with based on the weaning process occurring each morning. For intervention and comparison groups study were to assess the patients enrolled in the comparison group, the intervention effects of guided imagery on patients being weaned from did not occur and routine patient care management was in mechanical ventilation. accordance with institutional standards. Routine monitoring Evidence-Based Complementary and Alternative Medicine 3 included pulse oximetry, five-lead electrocardiography, heart A Friedman test was conducted to determine changes over rate, respiratory rate, and blood pressure measurements. time with the RASS scores and sedative volumes followed by a post hoc analysis with Wilcoxon signed-rank test with a 2.3. Measurement. The Richmond Agitation-Sedation Scale Bonferroni correction applied. One-way repeated measures (RASS) was developed to titrate sedation and pain control analysis of variance (ANOVA) was conducted to test the effect [33]. The 10-point scale ranges from unresponsive− ( 5) to of guided imagery on critically ill ventilated patients’ and calm and alert (0) to combative (+4). The RASS scale has physiological responses during both sessions at baseline, 30 undergone extensive reliability and validity testing and is minutes, and 60 minutes. To detect differences with analgesic use, 𝑡-tests were conducted. Significance level was set at 𝑃< sensitive to detect changes in sedation status against level of .05 consciousness and delirium and correlated with sedative and . Post hoc tests were conducted to determine where the analgesic medication doses [34]. The RASS score is used to difference in means occurred. titrate sedation and pain control for ICU patients at the study hospitals [33, 34]. 3. Results The Acute Physiology and Chronic Health Evaluation (APACHE II) provided an estimate of illness severity and 3.1. Sample. Sample demographic characteristics are pre- in-hospital mortality of ICU patients. Twelve variables are sented in Table 1. All variables between the groups were used to calculate APACHE II score. Extensive reliability normally distributed except gender, race, RASS scores, and and validity testing has been conducted on APACHE II. sedation volume. Initially, 54 patients were screened, and The researchers conducted a retrospective chart review and 42 patients receiving mechanical ventilation supported via recorded the worst APACHE II score during the initial 24 oral endotracheal tube met study criteria and participated hours of the ICU stay [35]. (Figure 1). Twenty-one patients received two 60-minute The researchers developed a survey including four ques- guided imagery sessions (intervention). The first session tions addressing feasibility and satisfaction of using guided occurred within 24 hours of initial intubation and the second imagery as an intervention. The survey is rated on a 5- session followed 48 hours later. Another 21 patients served point Likert scale (1 = strongly disagree and 5 = strongly as the comparison group with no intervention and only data agree). Nurses directly involved with patients receiving the collection occurred within 24 hours of intubation and 48 intervention completed the surveys immediately after the hours later. The majority were white (69%) females (54.8%) intervention session. Completion of the survey by the nurse with a mean age of 64.6 (SD, 13.25). Most patients were served as his or her consent to participate. being treated with assist control (66.7%) and primary reasons for ICU admission included respiratory (59.5%), cardiac 2.4. Procedures. Several times each week, the researchers (28.6%), or other (11.9%) reasons. All patients who received communicated with the ICUs to identify potential study the intervention were receiving one or more continuous participants. All eligible patients were enrolled if patient met intravenous sedative and/or analgesic infusions compared to 𝜒2 =5.76𝑃=.02 the study’s inclusion criteria. Measurements were recorded only 16 patients in the comparison group ( ; ). bythestudyresearchersatbaselineand30-and60-minute The APACHE mean score was 24.36 (SD, 7.42). intervals and included heart rate, systolic and diastolic blood pressure, respiratory rate, oxygen saturation, and 3.2. Sedation and Analgesics. The most significant effects RASS scores. Vital signs were measured indirectly from the of the intervention included improved RASS scores and noninvasive module on the monitor. Prior to data collec- a decrease in sedative and analgesic volume consumption 2 tion, the bedside monitors were tested and calibrated by (Table 2). During the first (𝜒 (2) = 17.45, 𝑃 = .000)and 2 the bioengineering department. Total amounts (volume) of second (𝜒 (2) = 7.65, 𝑃 = .022) sessions there was a continuous intravenous sedatives and analgesics adminis- statistically significant difference in the RASS scores over tered in a 24-hour timeframe were converted into milliliters the three time points. For the first-session median (IQR) and recorded from the electronic documentation system by baseline and 30-minute and 60-minute RASS scores were the study researchers. Sedative and analgesic amounts were −1.00 (−2.00 to 0), −1.00 (−1.25 to 0), and −1.00 (−2.00 to 0), evaluated during a continuous 24-hour period before and respectively. There were significant differences between first- after the intervention. Commonly administered sedatives session baselines and 30-minute RASS scores (𝑍 = −3.380, included Diprivan (propofol), dexmedetomidine (Precedex), 𝑃 = .001) and baseline and 60-minute RASS scores (𝑍= midazolam (Versed), and lorazapam (Ativan). Commonly −3.252, 𝑃 = .001). The second-session median IQR baseline administered analgesics included fentanyl and morphine. The and 30-minute and 60-minute RASS scores were −1.00 (−2.00 researchers reviewed the patient’s medical record to collect to 0), 0 (−1.00 to 0), and 0 (−1.00 to 0), respectively. There were demographic data and data to calculate APACHE II. significant differences between first-session baselines and30- minute RASS scores (𝑍 = −2.524, 𝑃 = .012) and baseline and 2.5. Data Analysis. Data were analyzed using SPSS 22.0 soft- 60-minute RASS scores (𝑍 = −2.480, 𝑃 = .013). As shown ware for Windows (SPSS, Inc., IBM Company, Armonk, NY, in Table 2, over time the intervention group’s RASS scores USA). An independent 𝑡-test, Chi-square test, and Mann- decreased significantly from baseline (M = −2.10)to30 Whitney 𝑈 test were conducted to examine if any differences minutes (M = −1.57;MDifference=−.53; 𝑃 = .01)andfrom existed between the comparison and intervention group. baseline to 60 minutes (M = −1.19;MDifference = −.91; 4 Evidence-Based Complementary and Alternative Medicine

Table 1: Demographic characteristics.

Characteristic Comparison group Guided Imagery Total 𝑃 (𝑛=21) (𝑛=21) (𝑁=42) Age, y Mean (SD) 64 (14.1) 65.2 (12.7) 64.60 (13.25) .78 Median, range 61, 35–93 66, 39–89 64.50, 35–93 Female sex, % 15, 71.4% 8, 38.1% 23, 54.8% .03 Race, % .05 White 12, 57.1% 17, 81% 29, 69% African American 7, 33.3% 1, 4.8% 8, 19% Others 2, 9.5% 3, 14.3% 5, 11.9% Marital status, % .87 Married 6, 28.6% 14, 66.7% 20, 47.6% Single 6, 28.6% 2, 9.55 8, 19% Others 9, 42.9% 5, 23.8% 14, 33.3% Number of comorbidities Mean (SD) 5.9 (2.8) 4.7 (2.6) 5.29 (2.7) .14 Median, range 6, 1–15 4, 1–10 5, 1–15 Acute physiology and chronic health evaluation (APACHE) score Mean (SD) 22.9 (8) 25.8 (6.7) 24.36 (7.42) .21 Median, range 24, 10–39 24, 9–38 24, 9–39 Primary reason for ICU admission, % .09 Respiratory 14, 66.7% 11, 52.4% 25, 59.5% Cardiac 4, 19% 8, 38.1% 12, 28.6% Others 3, 14.3% 2, 9.5% 5, 11.9% Hospital length of stay Mean (SD) 21.33 (15.9) 19.90 (11.1) 20.63 (13.6) .74 Total days on ventilator Mean (SD) 13.14 (15.2) 8.26 (7.3) 10.7 (12.1) .20 Median, range 7, 2–56 7, 1–29 7, 1–56 Ventilator mode .06 Assist control, 𝑛% 18, 85.7% 10, 47.6% 28, 66.7% Synchronized intermittent mandatory, 𝑛% 2, 9.5% 3, 14.3% 5, 11.9% Pressure control, 𝑛% 1, 4.8% 8, 38.1% 9, 21.4%

𝑃 = .00). Additionally, a significant decrease in RASS scores The intervention group had a significant reduction in sedative was noted (M Difference = −.38; 𝑃 = .02) between the 30- volumes (24 hours’ cumulative amount) before and after the minute interval (M = −1.57) and the 60-minute interval first and second intervention sessions. The 24-hour cumu- (M = 1.19). During the second session, the intervention lative volume was reduced by 140.06 mL. Additionally, the group’s RASS score decreased from baseline (M = −1.67) intervention group had a significant reduction in analgesic to 30 minutes (M = −1.08;MDifference= −.59)andfrom volumes before and after the first intervention session (𝑡20 = baseline to 60 minutes (M =0,MDifference= −1.67). 2.77; 𝑃 = .01) and a decrease during the second intervention There was a statistically significant difference inthe but not significant (Table 2). 2 sedative volumes over the four time points (𝜒 (3) = 9.90, 𝑃 = .019). The median (IQR) 24 hours prior to (session 1), 3.3. Physiological Responses. The intervention group mean 24 hours after (session 1), 24 hours prior to (session 2), and heart rate, respiratory rate, and oxygen saturation remained 24 hours after (session 2) cumulative sedative volume totals well below the comparison group (Table 3). For the first were145(10to232),42(0to152.65),3(0to208),and0.5 intervention session only, heart rate differed significantly over (0 to 115.17), respectively. There were significant differences the three time periods (𝐹2,80 = 3.91; 𝑃 = .02). Respiratory between first sessions’ prior and after 24-hour cumulative rate differed significantly over time during sessions one volume sedative totals (𝑍 = −3.009, 𝑃 = .003)andfirst (𝐹2,80 = 4.45; 𝑃 = .02)andtwo(𝐹2,60 =3.02; 𝑃= sessions’ prior and session 2 after (𝑍 = −2.633, 𝑃 = .008). .05). Both groups’ heart and respiratory rates increased from Evidence-Based Complementary and Alternative Medicine 5

Enrollment

Assessed for eligibility (n = 54)

Excluded (n = 7) (i) Not meeting inclusion criteria (n = 3) (ii) Declined to participate (n = 4) (iii) Other reasons (n = 0)

Patients (n = 47)

Allocation Allocated to intervention (n = 26) Allocated to usual care (n = 21) (i) Received allocated intervention (n = 26) (i) Received allocated intervention (n = 21)

Attrition Discontinued intervention (patient extubated Lost to follow-up (n = 0) before second session delivered) (n = 5)

Analysis

Analyzed (n = 21) Analyzed (n = 21)

Figure 1: Flow diagram of patient enrollment. Adapted from Schulz K. F., Altman D. G., and Moher D. (2010). For the CONSORT Group. baseline to 60 minutes; however, the intervention group had a the intervention met the intended purpose (M = 4.09, SD = lower heart and respiratory rate compared to the comparison 1.08). group over the three time intervals. During the second intervention, there was a significant difference between the 4. Discussion two groups’ oxygen saturation levels (𝐹2,60 = 3.11; 𝑃 = .05). The intervention group had higher oxygen saturation levels To date, research conducted has focused on deployment during all three time periods compared to the comparison of interventions with no research identified using guided group. Furthermore, the guided imagery group had 4.88 less imagery as an intervention in patients who are being actively mechanical ventilation days compared to the comparison weaned from the ventilator. This study is unique in using group (𝑡39 = 1.33; 𝑃 = .193). The guided imagery group guided imagery as an intervention in mechanically ventilated hospital length of stay was 1.4 less days compared to the patients who were being actively weaned from the ventilator. comparison group (𝑡40 = .33; 𝑃 = .74). Despite the intervention group having higher RASS scores and receiving continuous sedative and analgesic infusions, we demonstrated improved RASS scores, reduced sedative and 3.4. Staff Perception. Of the 42 surveys that were distributed, analgesic volume consumption, and higher oxygen saturation 23 nurses (55%) completed the survey with mean scores levels. Furthermore, we found that patients who received the for each question ranging from 4.09 to 4.83. Nurses felt intervention had a shorter time on the ventilator and shorter that guided imagery was an effective nursing intervention length of stay. We were able to demonstrate a significant (M = 4.83, SD = .39). Nurses felt that the intervention was improvement in actual sedative and analgesic volume intake successfully incorporated into the weaning process (M = 4.09, in relation to using guided imagery as an intervention despite SD = .95) and simple to implement (M = 4.13, SD = 1.0) and 24% of the interventions groups’ baseline RASS score being 6 Evidence-Based Complementary and Alternative Medicine

Table 2: Sedation levels, sedative, and analgesic outcomes.

Characteristic Comparison group Guided imagery 𝑃 (𝑛=21), mean (SD) (𝑛=21), mean (SD) Session I Baseline RASS score −.38 (1.1) −2.10 (1.4) .000 30-minute RASS score 0.1 (1.2) −1.57 (1.4) .000 60-minute RASS score −.29 (1.2) −1.19 (1.8) .086 24-hour cumulative amount (mL) of sedative infused before 133.18 (143.28) 218.66 (243.62) .284 (16 doses) (19 doses) 24-hour cumulative amount (mL) of analgesic infused before 48.92 (83.77) 95.28 (128.12) .173 (11 doses) (14 doses) 24-hour cumulative amount (mL) of sedative infused after 111.77 (156.24) 78.59 (93.61) .737 (13 doses) (13 doses) 24-hour cumulative amount (mL) of analgesic infused after 54.69 (89.28) 18.10 (51.36) .111 (11 doses) (8 doses) Session II Baseline RASS score −.55 (.8) −1.67 (2) .043 30-minute RASS score −.35 (.9) −1.08 (1.8) .162 60-minute RASS score −0.55 (.8) 0 (1.6) .181 24-hour cumulative amount (mL) of sedative infused before 109.24 (146.74) 166.54 (259.61) .803 (14 doses) (10 doses) 24-hour cumulative amount (mL) of analgesic infused before 24 (52.67) 2.52 (9.13) .073 (6 doses) (4 doses) 24-hour cumulative amount (mL) of sedative infused after 125.93 (188.45) 38.13 (75.78) .024 (15 doses) (3 doses) 24-hour cumulative amount (mL) of analgesic infused after 21.14 (56.36) .49 (1.53) .101 (4 doses) (3 doses)

greaterthanorequaltominusfour(−4) indicating that the measurements. We only looked at volumes of sedatives and patient was deeply sedated. analgesics, as most of these medications are weight based; Throughout the intervention, heart rate, diastolic blood comparing volume of medications infused between groups is pressure, and oxygen saturation levels remained within nor- a limitation. Additionally, before intervention the interven- mal range. Similar to other researcher findings that used tion group had higher cumulative amounts of sedative and guided imagery, we found that heart and respiratory rates analgesics that might have influenced the amount of sedatives were significantly lower over time for the intervention group and analgesics needed during and after the intervention. Both compared to the comparison group [23, 25]. The comparison hospitals’ ventilator weaning is assumed by the respiratory group’s respiratory rate increased and oxygen consumption therapist guided by standardized protocols. Daily weaning declined. We did not find significant improvements in blood occurred in the mornings and intervention effects may have pressure but other medications including cardiac medica- been different later in the day. Certain medications may tions could have masked the intervention effects. Similar have masked the intervention effects as we did not control to Deisch et al. [24] and Halpin et al. [26] patients who for prescribed medications such as cardiac medications. received the guided imagery intervention had reduced length Secondary to one hospital serving as the intervention hospital of hospital stay (1.4 less days) and 4.88 less mechanical and the other serving as the control hospital, any hospital ventilation days compared to the comparison group. effect is potentially confounded by the intervention effect. Complementary and alternative medicine therapy such as By carrying out the intervention at one hospital only, the guided imagery may be a part of the multimodal treatment researchers were hoping to lessen the threat of treatment approach and serve as a substitute to administering high diffusion. It is difficult to be blinded to the intervention doses of sedatives to assist with keeping the patient calm and when the researchers had to deliver the intervention to relaxed. Nurses perceived the intervention as effective and the patient. A randomized controlled trial (RCT) was not easily incorporated into the weaning process. conducted secondary to conditions that either occurred daily Our study had several limitations. The sample was pri- and/or were planned in the ICU that the researchers had no marily white females admitted to ICU with a respiratory control over things including but not limited to noise levels, problem. Sedation levels and sedative and analgesic use and patient volumes, ICU renovations, and transition from one practices may have varied between the hospitals and affected electronic medical record to another which would have added Evidence-Based Complementary and Alternative Medicine 7

Table 3: Physiological outcomes.

Characteristic Comparison group Guided imagery Total 𝑃 (𝑛=21) (𝑛=21) (𝑁=42) Session I Baseline, mean (SD) Heart rate 84.7 (16.8) 79.1 (19) 81.9 (17.7) .317 Systolic blood pressure (BP) 124.7 (22.9) 126.6 (19) 125.6 (21) .777 Diastolic BP 59.3 (11.8) 64.1 (17.4) 61.7 (17.9) .305 Respiratory rate 21.8 (4.5) 19.8 (4.8) 20.8 (4.7) .170 Oxygen saturation 97.6 (2.5) 97.6 (2.4) 97.6 (2.4) 1.000 30 minutes, mean (SD) Heart rate 89.3 (22.2) 81.6 (18) 85.5 (20.3) .220 Systolic BP 133.9 (17.4) 127.2 (20) 130.5 (19) .258 Diastolic BP 64.5 (12.2) 64.7 (16.1) 64.6 (14.1) .966 Respiratory rate 22.6 (4) 20.3 (6.8) 21.5 (5.7) .186 Oxygen saturation 97.1 (2.7) 97.2 (3) 97.1 (2.8) .915 60 minutes, mean (SD) Heart rate 90.3 (16.4) 82.7 (16) 86.5 (16.3) .130 Systolic BP 129.6 (24.4) 130.2 (25) 129.9 (24.3) .940 Diastolic BP 62 (11.9) 63.8 (20) 62.9 (16.2) .728 Respiratory rate 24.6 (4.7) 21.6 (8.1) 23.1 (6.7) .148 Oxygen saturation 97.2 (2.5) 97.1 (2.8) 97.1 (2.6) .818 Session II Baseline, mean (SD) Heart rate 86.5 (17.4) 77.4 (14.8) 83.1 (16.8) .141 Systolic BP 123.8 (25.8) 133.9 (20) 127.6 (24.1) .254 Diastolic BP 60 (12.3) 65.8 (21.3) 62.2 (16.2) .338 Respiratory rate 23.4 (3.6) 20.9 (4.6) 22.5 (4.1) .099 Oxygen saturation 96.6 (3) 96.9 (2.2) 96.7 (2.7) .733 30 minutes, mean (SD) Heart rate 94 (14.7) 82.8 (19.4) 89.8 (17.2) .073 Systolic BP 141.4 (25.8) 135.8 (13.7) 139.3 (22) .622 Diastolic BP 63.3 (10.8) 66.7 (17.7) 64.6 (13.6) .426 Respiratory rate 22.2 (4.8) 23.8 (7) 22.8 (5.7) .507 Oxygen saturation 96.9 (2.8) 97.2 (2.3) 97 (2.6) .427 60 minutes, mean (SD) Heart rate 92.4 (21.2) 81.5 (12.5) 88.3 (19) .119 Systolic BP 124.6 (21.7) 136.9 (21.7) 129.2 (22.2) .130 Diastolic BP 62.5 (14.9) 68.7 (15.6) 64.8 (15.2) .271 Respiratory rate 23.3 (5.5) 20.8 (5.6) 22.4 (5.6) .235 Oxygen saturation 95.6 (3.8) 97.9 (1.6) 96.5 (3.3) .024 to additional study limitations. It is suggested to replicate the the day prior to the actual intervention and/or the surrogate study randomizing the intervention at both hospitals to see if was not present during the entire weaning process and the findings of the present study are generalizable. intervention not meeting study criteria. Future investigators As we noted, weaning trials and intervention sessions may want to involve patients’ surrogate in intervention and occurred during the morning hours. We attempted to obtain weaning process to promote patient- and family-centered surrogates’ perceptions of ventilated patients who listened care. In addition, patients’ surrogates were not always present totheguidedimagery.Wedidnotcaptureenoughdatafor at the hospital with the patient and initial weaning trial analysis primarily due to low participation. Typically, the was unpredictable which at times made recruitment and patients’ surrogate consented for the patient to participate data collection a challenge for the researchers. ICU nurses’ 8 Evidence-Based Complementary and Alternative Medicine perception of guided imagery as an effective intervention to patients,” Cochrane Database of Systematic Reviews, vol. 11, implement was rather high; however, the four researchers Article ID CD006904, 2014. delivering the intervention may have inadvertently positively [5] American Association of Critical-Care Nurses (AACN), skewed the nurses’ perception of guided imagery. Further- “AACN PEARL: Implementing the ABCDE bundle at the bed- more, the intervention effect sustained beyond the study time side,”2013, http://www.aacn.org/wd/practice/content/actionpak/ is unknown. withlinks-abcde-toolkit.pcms?menu=practice. [6]L.L.Chlan,C.R.Weinert,A.Heiderscheitetal.,“Effectsof patient-directed music intervention on anxiety and sedative 5. Conclusions exposure in critically Ill patients receiving mechanical venti- latory support: a randomized clinical trial,” The Journal of the Guided imagery may be a CAM intervention to provide dur- American Medical Association,vol.309,no.22,pp.2335–2344, ing mechanical ventilation weaning trials. Guided imagery 2013. appeared to be effective, safe, and feasible intervention to use [7] L. Rose, M. Nonoyama, S. Rezaie, and I. Fraser, “Psycholog- in patients being weaned from mechanical ventilation. Future ical wellbeing, health related quality of life and memories of research is needed including a larger randomized controlled intensive care and a specialised weaning centre reported by trial examining the effect of guided imagery use with a larger survivors of prolonged mechanical ventilation,” Intensive and sample with a longer tracking period in relation to patient Critical Care Nursing,vol.30,no.3,pp.145–151,2014. outcomes. [8]R.Khalaila,W.Zbidat,K.Anwar,A.Bayya,D.M.Linton, and S. Sviri, “Communication difficulties and psychoemotional Disclosure distress in patients receiving mechanical ventilation,” American Journal of Critical Care,vol.20,no.6,pp.470–479,2011. Institution work was performed in WellStar Health System [9]C.R.Dale,D.A.Kannas,V.S.Fanetal.,“Improvedanalgesia, Kennestone and Cobb Hospitals. sedation, and delirium protocol associated with decreased duration of delirium and mechanical ventilation,” Annals of the American Thoracic Society,vol.11,no.3,pp.367–374,2014. Conflict of Interests [10]T.D.Girard,J.P.Kress,B.D.Fuchsetal.,“Efficacyand safety of a paired sedation and ventilator weaning protocol for The authors declare that there is no conflict of interests mechanically ventilated patients in intensive care (Awakening regarding the publication of this paper. and Breathing Controlled trial): a randomised controlled trial,” The Lancet, vol. 371, no. 9607, pp. 126–134, 2008. Funding [11] M. J. Grap, C. L. Munro, P. A. Wetzel et al., “Sedation in adults receiving mechanical ventilation: physiological and comfort The researchers received $150 to purchase the music and outcomes,” American Journal of Critical Care,vol.21,no.3,pp. guided imagery devices to use in this study through WellStar’s e53–e64, 2012. Nursing Research Fund. The researchers also received a [12] Y. Hayashi, K. Morisawa, M. Klompas et al., “Toward improved discountedpriceforthePLAYWAYdeviceatFindaway surveillance: the impact of ventilator-associated complications World. on length of stay and antibiotic use in patients in intensive care units,” Clinical Infectious Diseases,vol.56,no.4,pp.471–477, 2013. Acknowledgments [13]A.C.Lemay,A.Anzueto,M.I.Restrepo,andE.M.Mortensen, “Predictors of long-term mortality after severe sepsis in the The researchers acknowledge Amy Good, BSN, RN for her elderly,” AmericanJournaloftheMedicalSciences,vol.347,no. assistance with data collection. 4, pp. 282–288, 2014. [14] D. M. Needham, E. Colantuoni, P. 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Research Article Association between Albuminuria and Different Body Constitution in Type 2 Diabetes Patients: Taichung Diabetic Body Constitution Study

Cheng-Hung Lee,1,2,3 Tsai-Chung Li,4,5 Chia-I Tsai,6 Shih-Yi Lin,7 I-Te Lee,7,8,9 Hsin-Jung Lee,10 Ya-Chi Wu,10 and Yi-Chang Su1,3

1 Graduate Institute of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan 2 Department of Traditional Chinese Medicine, Han Ming Hospital, Changhua 50072, Taiwan 3 School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan 4 Graduate Institute of Biostatistics, China Medical University, Taichung 40402, Taiwan 5 Department of Health Administration, College of Health Science, Asian University, Taichung 41354, Taiwan 6 Department of Traditional Chinese Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan 7 Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan 8 Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan 9 School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan 10Division of New Drugs, Center for Drug Evaluation, Taipei 11557, Taiwan

Correspondence should be addressed to Yi-Chang Su; [email protected]

Received 3 July 2015; Accepted 4 October 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Cheng-Hung Lee et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. Albuminuria in type 2 diabetes mellitus (T2DM) patients increases the risk of diabetic nephropathy, the leading cause of end-stage renal disease worldwide. Because albuminuria is modifiable, identifying relevant risk factors could facilitate prevention and/or management. This cross-sectional study investigated whether body constitution (BC) independently predicts albuminuria. Method.PatientswithT2DM(𝑛 = 846) received urinalysis, a blood test, and diabetic retinopathy examination. Albuminuria was defined by an elevated urinary albumin/creatinine ratio≥ ( 30 𝜇g/mg). BC type (Yang deficiency, Yin deficiency, and Phlegm stasis) was assessed using a body constitution questionnaire (BCQ). Traditional risk factors for albuminuria were also recorded. Odds ratios (ORs) of albuminuria for BC were estimated using multivariate logistic regression. Results. Albuminuria was more prevalent in patients with Yang deficiency or Phlegm stasis (both 𝑃 < 0.01). After adjustment, patients with both Yang deficiency and Phlegm stasis exhibited a significantly higher risk of albuminuria (OR = 3.037; 95% confidence interval = 1.572–5.867, and 𝑃 < 0.001). Conclusion. BC is strongly associated with albuminuria in T2DM patients. Using a BCQ to assess BC is noninvasive, convenient, and inexpensive and can provide information for health care professionals to identify T2DM patients who are at a high risk of albuminuria.

1. Introduction renal disease (ESRD) in many countries [2, 3]. ESRD con- siderably influences public health and health care economy Global prevalence of diabetes, a chronic metabolic disease, [4–6]. According to the annual report of the United States has increased rapidly and is estimated to reach over 552 Renal Data System (USRDS), Taiwan had the world’s highest million by 2030 [1]. Diabetic nephropathy, a severe vascular incidence and prevalence of ESRD during 2002–2005 and complication of diabetes, is the leading cause of end-stage 2009,respectively[4,7].TheTaiwanSocietyofNephrology 2 Evidence-Based Complementary and Alternative Medicine demonstrated that the increasing prevalence of diabetes was all laboratory tests were excluded. A total of 846 participants themaincauseoftherisingprevalenceandincidenceof with T2DM were included in the final analysis. Figure 1 shows ESRD in Taiwan [8]. Albuminuria is a modifiable and crucial the recruitment flowchart of the study participants. risk factor for diabetic nephropathy [9, 10]. In addition, Ifthesamplesizeisfixedat800patientswithtype2 multinational and regional studies have revealed that Asian diabetes, the power would be 0.8891, given that the associ- diabetic populations have a higher prevalence of albuminuria ation between BC and albuminuria (OR) was 2 with two- [11, 12]. Hence, reducing the risk of albuminuria is a key sided type 1 error of 5% and prevalence of 12.5% for BC. treatment goal for renal protection in patients with type Thisiscalculatedwiththeuseofatwo-sidedproportion 2 diabetes (T2DM) to prevent the progression of diabetic test (𝑧 test) on the assumption that there is an albuminuria nephropathy. prevalence of 57.1%in patients with type 2 diabetes whose BC Despite the vast efforts devoted to managing the potential was Yang deficiency. This information came from our pilot risk factors for albuminuria, the global incidence of ESRD study and Yang deficiency was the primary predictor ofBC in patient with T2DM continues to rise [5, 8, 13]. This is for albuminuria in study design stage. probably because the pathogenesis of albuminuria is multifactorial, thus indicating an urgent necessity to discover other 2.2. Measurements potential risk factors. Traditional Chinese medicine (TCM) may provide a novel insight into this problem. TCM, a type 2.2.1. Body Constitution Measurement. All the participants of frequently used complementary and alternative medicine were self-administered a body constitution questionnaire (CAM) [14–16], emphasizes the concept of personalized (BCQ)toevaluatetheirBCstatus.TheitemsoftheBCQwere medicine based on body constitution (BC) theory [17–19]. generated from TCM textbooks and the published literature An individual’s constitution status is formed by the state [17, 21, 25]. The initial items were translated into colloquial of Yang and Yin in his body. Yin and Yang deficiency questions through a 2-stage Delphi process. The resulting BCs refer to the decrease of the material and energy level, questionnaire was tested to check for wording, sequencing, respectively, and the imbalance between Yin and Yang may grammar, and ease of comprehension. Then, intraclass con- cause Phlegm stasis [17]. People with different BC types sistency was done to reduce the items of the questionnaire are variously prone to certain diseases and differ in disease [17, 21, 25]. The BCQ demonstrates favorable factorial validity progression [20, 21], and TCM practitioners treat patients [21], and the Cronbach 𝛼 of each constitution subscale in with the same disease diagnosis differently according to each previous studies has been between 0.88 and 0.90 [21, 26, 27]. individual’s body constitution, which is known as tong bing yi The BCQ comprised 44 items on a 5-point Likert-type scale zhi in Chinese. Besides, to achieve optimal health promotion, from 1 (never happened)to5(always happens), including TCM practitioners used to adopt individualized preventive 19 items on Yang deficiency [17, 26], 16 items on Phlegm methods based on BC [22–24]. stasis [21], and 19 items on Yin deficiency [25, 27]. Some Distinguishing T2DM patients who have a higher risk items belonging to these three scales overlapped, and the final of albuminuria is essential for prevention or early treatment score of each constitution was calculated by summing the of diabetic nephropathy. In the current study, we sought to scores of all items on each subscale. A higher score implied determine whether BC could be an independent predictor a greater deviation from the constitution. The score range of of albuminuria in 846 patients with T2DM recruited from a Yang deficiency is between 19 and 95, and the participant was medical center with information of their BC status and data diagnosed with Yang deficiency when the score reached over from urinalysis, blood test, and diabetic retinopathy (DR) 30.5 [26]. For Phlegm stasis, the score range is 16 to 80, and examination. the cut point for diagnosis is 26.5 [21]. As for Yin deficiency, thescorerangeis19to95,andtheparticipantwasdiagnosed 2. Materials and Methods with Yin deficiency BC when the score is higher than 29.5 [27]. 2.1. Study Design and Participants. This cross-sectional study was conducted from February 2010 to February 2011 at the Diabetes Health Promotion Center of Taichung Veterans 2.2.2. Detection of Albuminuria. Spot urine samples were General Hospital in Taichung, Taiwan. The study protocol collected from each participant and the urinary albumin was approved by the Institutional Review Board of Taichung concentrations were measured using immunoturbidimetry Veterans General Hospital (C10007). A total of 887 partici- [28] at Taichung Veterans General Hospital. Daily urinary pants diagnosed with T2DM were referred by endocrinology albumin secretion was estimated by calculating an elevated and metabolism subspecialists from an outpatient clinic. urinary albumin/creatinine ratio (ALB/Cr) [29–31]. Albu- minuria was defined according to an elevated urinary albu- Written informed consent was obtained from each partici- ≥ 𝜇 pant. Every participant had to undergo the following tests for min/creatinine ratio ( 30 g/mg) [30, 31]. determining the risk factors for albuminuria: BC measurement, sociodemographic characteristics (including gender, 2.2.3. Detection of Diabetic Retinopathy. Each participant age, body mass index, and waist circumference), lifestyle received standardized central fundus photographic imaging behaviors, diabetic history, lipid profile, blood pressure, and both eyes of each participant were photographed using ∘ kidney function, and DR. All the tests were performed on anonstereoscopic45 digital nonmydriatic camera (CR- the same day. Forty-one participants who could not complete DGi, Canon, Inc., Tokyo, Japan). Experienced and trained Evidence-Based Complementary and Alternative Medicine 3

887 participants referred from endocrinology and metabolism subspecialists

Exclusion criteria: (i) Mental illness (ii) TCM use within past 2 months (iii) Pregnant women (iv) Age <18years old

Informed consent

Participants with incomplete laboratory work-up were excluded (n = 41)

846 participants completed the body constitution questionnaire, urinalysis, blood test, and diabetic retinopathy examination

Figure 1: The flowchart of the study. endocrinology and metabolism subspecialists examined the between groups, chi-square test and 𝑡-test were used for fundus photographs in a masked manner. The DR severity of categorical and continuous variables, respectively. each eye was graded according to the International Clinical In the other published paper from Taichung Diabetic Diabetic Retinopathy and Diabetic Macular Edema Disease Body Constitution Study (TDBS), the independent effects of Severity Scales [32]. Participants who had at least one eye with Yang deficiency, Phlegm stasis, and Yin deficiency on DR either nonproliferative DR or proliferative DR were assigned among T2DM patients had been explored [34]. In this study, to the DR group. we are interested in albuminuria, another diabetic microvas- cular complication. In addition to examining independent 2.3. Data Collection. Traditional risk factors for albuminuria effects of BCs, we further examined their joint effect of were derived to control for the confounding influence. The different BCs on albuminuria. sociodemographic characteristics (gender, age, height, and We used hierarchical models for covariant variables to waist circumference), lifestyle behaviors (smoking history, determine whether BC is an independent predictor of albu- alcohol consumption, and exercise habits), diabetes history minuria. First, crude ORs were calculated without adjust- (diabetes duration, oral hypoglycemia agent, and insulin ment. Subsequently, sociodemographic characteristics, life- usage), and systolic and diastolic blood pressure of all the style behaviors, blood pressure, lipid profile, diabetes history, participants were investigated through personal interviews at eGFR, and DR were sequentially entered into the model. the Diabetes Health Promotion Center of Taichung Veterans Finally, the joint effect of Yang deficiency and Phlegm stasis General Hospital. Fasting (>12 hours) blood samples were on albuminuria was examined. A two-sided significance level collected for measuring the level of fasting blood sugar, was set at 𝑃 < 0.05.AllanalyseswereperformedusingSAS glycosylated hemoglobin (HbA1c), total cholesterol, total version (SAS Institute Inc., Cary, NC, USA). triglyceride, high-density lipoprotein, low-density lipoprotein (LDL), and creatinine (Cr). The estimated glomerular 3. Results filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease four-variable equation: 186 × serum The study group comprised 366 (43%) females and 480 (57%) creatinine − 1.154 × age − 0.203 × 1.212 (if black) × 0.742 (if males with a mean age of 63.72 years (SD = 13.05 years), with female) [33]. a mean duration of diabetes of 8.92 years (SD = 7.92 years). Among the study participants, 232 (27.4%), 112 (13.2%), and 2.4. Statistical Analysis. Continuous and categorical variables 99 (11.7%) were diagnosed with Yin deficiency, Phlegm stasis, were presented as mean ± standard deviation (SD) and and Yang deficiency, respectively. Table 1 shows a compari- number (%), respectively. For comparing the differences son of sociodemographic characteristics, lifestyle behaviors, 4 Evidence-Based Complementary and Alternative Medicine † ∗ ∗ ∗ value 0.01 < 𝑃 ) ) 37.02 0.58 43.93 0.71 30.68 0.94 14.52 0.68 4.06 1.00 8.99 0.23 7.54 0.08 14.95 0.31 218.3 0.62 10.47 0.92 21.65 1.55 0.36 177.90 0.36 916.70 0.47 113.00 0.01 0.54 0.16 ± ± ± ± ± ± ± ± ± ± ± ± ± ± 𝑛 = 846 ± ± 𝑛 = 614 )No( 9.77 77.85 37.22 175.80 32.82 106.30 52.87 144.00 3.63 25.53 88.02 151.50 14.92 131.70 13.31 62.97 87.91 34.73 22.74 69.55 13.25 52.64 1.74 7.65 8.82 8.60 10.44 89.26 1235.80 229.10 0.60 1.15 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 𝑛 = 232 3 (1.29) 23 (3.75) 0.07 174 (75) 494 (80.46) 0.08 7. 7 7 100 (43.10) 236 (38.44) 0.23 116 (50.00) 250 (40.72) 0.02 25.53 89.17 106.50 C: total cholesterol; TG: total triacylglyceride; HDL: high- ‡ ‡ ‡ ‡ ∗ ∗ ∗ ∗ value Yes ( 0.001 0.001 0.001 0.001 . ase; Cr: creatinine; eGFR: estimated glomerular filtration rate; and 𝑃 < < < < ) Yin deficiency ( ) 𝑃 < 0.001 ‡ 35.91 0.17 174.30 9.14 0.53 76.99 47.00 0.25 145.40 3.84 30.73 0.05 14.56 0.79 131.30 10.14 13.13 0.88 65.55 7.81 0.73 9.76 21.77 0.72 64.40 14.67 0.19 51.56 1.60 0.03 163.20 0.45 143.00 0.57 0.64 1.21 993.60 0.53 293.30 202.50 0.98 29.49 ± ± ± ± ± ± ± ± ± ± ± ± ± ± 𝑛 = 846 ± ± 𝑛 = 734 ,and 𝑃 < 0.01 † , )No( 4.39 25.33 15.09 131.60 43.66 174.60 43.21 143.60 13.17 63.65 11.67 88.66 34.19 105.50 13.29 52.60 1.64 7.64 9.66 77.69 23.93 68.24 91.77 33.33 8.69 8.88 122.90 147.90 1140.80 237.10 0.48 1.17 𝑃 < 0.05 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ∗ ± 𝑛 = 112 35 (31.25) 170 (23.16) 0.06 70 (30.17) 135 (21.99)35 (31.25) 0.01 301 (41.01) 0.05 69 (61.61) 297 (40.46) ‡ ∗ ∗ value Yes ( 0.001 𝑃 < Table 1: Participants’ characteristics. )Phlegmstasis( ) -test for continuous variable. ) for categorical variable. 𝑡 31.30 0.31 111.90 3.90 0.41 26.85 % 14.39 0.45 132.00 851.10 0.30 309.20 36.67 0.66 180.60 44.70 0.35 149.10 9.02 0.46 77.11 7.74 0.36 9.16 13.02 0.37 63.86 14.67 0.52 50.66 10.32 0.79 93.02 1.59 0.33 8.00 163.20 0.52 157.70 201.8 0.50 33.01 21.40 0.95 67.44 0.57 0.57 1.15 𝑛 = 846 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 𝑛 = 747 )No( Yang deficiency ( 16.32 131.80 4.33 25.49 58.52 143.70 30.92 106.00 11.47 89.27 40.05 175.20 1821.3 224.30 13.97 63.82 10.57 77.51 9.19 8.82 116.60 148.20 13.20 52.46 79.44 34.15 26.60 68.11 1.68 7.66 0.50 1.17 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 𝑛=99 Yes ( (%) 0 (0) 26 (3.48) 0.06 0 (0) 26 (3.54) 0.04 𝑛 SD for continuous variable and as number ( (%) 4 (4.04) 37 (4.95) 0.69 6 (5.36) 35 (4.77) 0.79 9 (3.88) 32 (5.21) 0.42 ± (%) 73 (73.74) 595 (79.65) 0.17 71 (63.39) 597 (81.34) 𝑛 (%) 30 (30.30) 306 (40.96) 0.04 (%) 33 (33.33) 172 (3.03) 0.02 𝑛 𝑛 𝑛 (%) 92 (92.93) 716 (95.85) 0.19 106 (94.64) 702 (95.64) 0.64 222 (95.69) 586 (95.44) 0.88 𝑛 g/mg) 415.90 )25.84 𝜇 2 (%) 67 (67.68) 299 (40.03) 𝑛 ALB/Cr ( TC (mg/dL) 176.90 Exercise habits, yes, FBS (mg/dL) 149.50 DMH (year) 9.70 TG (mg/dL) 156.60 SBP (mmHg) 130.60 Alcohol consumption, yes, Smoking history, yes, HDL (mg/dL) 51.46 HbAlc (%) 7.83 OHA use, yes, Insulin usage, yes, DBP (mmHg) 78.34 LDL (mg/dL) 109.40 Microalbumin (mg/dL) 26.77 Cr (mg/dL) 1.14 eGFR (mL/min) 68.29 values were calculated using the chi-square test for categorical variable and Age (years)Female, BMI (kg/m 62.56 Lipid profile Diabetic retinopathy, Diabetic factors Waist circumference (cm) 88.96 Blood pressure Lifestyle behaviors Kidney function density lipoprotein; LDL: low-density lipoprotein; SBP:ALB/CR: systolic microalbumin blood to pressure; creatinine DBP: ratio. diastolic blood pressure; GPT: glutamic pyruvic transamin BMI: body mass index; FBS: fasting blood sugar; HbA1c: glycosylated hemoglobin; DMH: duration of diabetes mellitus; OHA: oral hypoglycemic agent; T Data were presented as mean 𝑃 Evidence-Based Complementary and Alternative Medicine 5

Table 2: Prevalence of albuminuria in patients with T2DM according to body constitution.

Albuminuria Nonalbuminuria Total BC (𝑛 = 363)(𝑛 = 483)(𝑛 = 846) 𝑃 value 𝑛 (%) 𝑛 (%) 𝑁 (%) Yang deficiency Yes 56 (56.57) 43 (43.43) 99 (100) † <0.01 No 307 (41.10) 440 (58.90) 747 (100) Phlegm stasis Yes 63 (56.25) 49 (43.75) 112 (100) † <0.01 No 300 (40.87) 434 (59.13) 734 (100) Yin deficiency Yes 112 (48.28) 120 (51.72) 232 (100) 0.05 No 251 (40.88) 363 (59.12) 614 (100) † BC: body constitution; DM: diabetes mellitus. 𝑃 < 0.01. 𝑃 values were calculated using the two-sided chi-square test.

Table 3: Unadjusted and adjusted odds ratios and 95% CI for albuminuria in patients with T2DM according to body constitution.

Albuminuria, OR (95% CI) Yang deficiency Phlegm stasis Yin deficiency OR (95% CI) 𝑃 value OR (95% CI) 𝑃 value OR (95% CI) 𝑃 value † † Model 1 1.87 (1.22–2.85) 0.004 1.86 (1.25–2.78) 0.002 1.35 (1.00–1.83) 0.053 † ∗ Model 2 2.00 (1.29–3.11) 0.002 1.74 (1.15–2.65) 0.010 1.28 (0.93–1.74) 0.126 † ∗ Model 3 1.97 (1.26–3.08) 0.003 1.64 (1.07–2.50) 0.023 1.25 (0.91–1.71) 0.170 † ∗ Model 4 1.99 (1.26–3.14) 0.003 1.66 (1.08–2.56) 0.022 1.28 (0.93–1.76) 0.128 † ∗ Model 5 1.93 (1.21–3.08) 0.006 1.61 (1.03–2.51) 0.035 1.19 (0.86–1.65) 0.298 † ∗ Model 6 2.16 (1.31–3.58) 0.003 1.84 (1.15–2.94) 0.011 1.13 (0.80–1.60) 0.485 † † Model 7 2.26 (1.36–3.75) 0.002 1.92 (1.19–3.08) 0.007 1.13 (0.80–1.60) 0.487 Model 1 is unadjusted. Model 2 is additionally adjusted for sociodemographic characteristics. Model 3 is additionally adjusted for lifestyle behaviors. Model 4 is additionally adjusted for blood pressure and lipid profile. Model 5 is additionally adjusted for diabetic factors. Model 6 is additionally adjusted for eGFR. Model 7 is additionally adjusted for diabetic retinopathy. ∗ † Analysis by logistic regression. 𝑃 < 0.05, 𝑃 < 0.01. BC: body constitution, including Yang deficiency, Ying deficiency, and Phlegm stasis. Sociodemographic characteristics: gender, age, BMI, and waist circumference. Lifestyle behaviors: smoke and alcohol drinking history and exercise. Blood pressure: SBP and DBP. Lipid profile: TG, HDL, and LDL. Diabetic factors: FBS, HbA1c, DM duration, oral hypoglycemia agent, and insulin use.

diabetic history, lipid profile, blood pressure, kidney function, Table 3 lists the unadjusted and hierarchically adjusted and DR among the participants with and without Yang ORsforalbuminuriaassociatedwitheachBCtype.Par- deficiency, Yin deficiency, and Phlegm stasis. Participants ticipants with Yang deficiency or Phlegm stasis were more with Yin deficiency had a higher mean age. Patients with Yang likely to develop albuminuria (crude OR = 1.87, 95% CI = deficiency, Phlegm stasis, and Yin deficiency had a higher 1.22–2.85, 1.860, and 1.25–2.78, resp.). After adjustment for proportion of females than those without corresponding BC. other risk factors, including sociodemographic characteris- Patients with Phlegm stasis were less likely to have alcohol tics, lifestyle behaviors, blood pressure, lipid profile, diabetes consumption and regular exercise habits. These patients had history, eGFR, and DR, Yang deficiency and Phlegm stasis higher BMI and waist circumference. Higher percentage of remained strongly associated with albuminuria (OR = 2.26, insulin usage was noted in participants with Yang or Yin 95% CI = 1.36–3.75, 1.92, and 1.19–3.08, resp.). In addition, deficiency. Participants with Yin deficiency had lower eGFR significant joint effect of Yang deficiency and Phlegm stasis on level. Participants with Yang deficiency or Phlegm stasis were albuminuria (OR = 3.037, 95% CI = 1.57–5.87) was observed less likely to develop DR. (Table 4). Among the study participants, 363 (42.9%) showed elevated urine albumin excretion (urinary albumin/creatinine 4. Discussion ratio ≥ 30 𝜇g/mg). Table 2 shows the prevalence of albuminuria according to BC types. Participants with Yang deficiency In our study, we considered traditional risk factors for or Phlegm stasis had significantly higher prevalence of albu- albuminuria, including HbA1c, systolic blood pressure, DR, minuria (56.57% versus 41.10% and 56.25% versus 40.87%, duration of diabetes, kidney function, and smoking [11]. After resp., both 𝑃 < 0.01). multivariate adjustment, the results of this cross-sectional 6 Evidence-Based Complementary and Alternative Medicine

Table 4: Adjusted odds ratios and 95% CI for albuminuria in Health promotion and disease prevention are essential in patients with T2DM according to Yang deficiency and Phlegm stasis TCM. BC is modifiable and may transform as time passes body constitution. or when a crucial health event occurs [38]. An epidemiological study revealed that the factors influencing BC include Albuminuria 𝑃 emotions, body weight, educational level, mental work, age, OR (95% CI) value and exercise habit [39]. Chinese people have endeavored to Non-Yang deficiency and 1.00 improve their health for the past thousand years by adjusting non-Phlegm stasis their unbalanced BC status. A recent clinical study proved Yang deficiency 1.59 (0.75–3.37) 0.23 thatChinesefoodtherapy,aneffectivenonpharmacological Phlegm stasis 1.30 (0.69–2.45) 0.40 approach, can restore the Yin-Yang harmony, improve the ‡ quality of life, control blood pressure, and minimize disease Yang deficiency and Phlegm 3.04 (1.57–5.87) <0.001 stasis symptoms in hypertensive patients with Yin deficiency [40]. Non-Yang deficiency and non-Phlegm stasis as reference. From public health perspectives, screening, monitoring, Adjusted for sociodemographic factors, lifestyle, blood pressure, lipid profile, and treating patients with albuminuria are strongly recom- diabetic factors, eGFR, and diabetic retinopathy. mended for preventing chronic kidney disease and cardiovas- ‡ Analysis by logistic regression. 𝑃 < 0.001. cular disease [41]. However, an early detection of albuminuria DM: diabetes mellitus. Sociodemographic factors: gender, age, BMI, and requires a particular but expensive immunochemical test. The waist circumference. Lifestyle: smoking and alcohol drinking history and exercise. Blood pressure: SBP and DBP. Diabetic factors: FBS, HbA1c, DM questionnaire, BCQ, with favorable reliability and validity duration, oral hypoglycemia agent, and insulin use. [17, 21, 25–27], has been used to distinguish patients who had different risks of certain diseases [34, 42, 43]. Furthermore, the BCQ facilitates a noninvasive, convenient, fast, and inexpensive method that can be easily applied by health study suggest that Yang deficiency and Phlegm stasis were care professionals to assess a patient’s BC status. Our results independent risk factors for albuminuria. In addition, a can aid health care professionals in identifying patients with significant joint effect of Yang deficiency and Phlegm stasis on diabetes who are at a high risk of albuminuria. albuminuria was noted. T2DM patients who had both Yang With the rising burden of chronic illness and global aging deficiency and Phlegm stasis were three times more likely to population, public health research in integrative and com- develop albuminuria. plementary medicine has become essential [44]. People who Based on our research, this is the first clinical study to use CAM have a greater degree of health-seeking behavior to evaluate the association between albuminuria and BC in prevent disease and promote health wellness compared with patients with T2DM. People with different BC types are more those who do not; thus, CAM providers play a critical role prone to certain diseases than others [17, 20, 35]. Accord- in health promotion and disease prevention [45]. A previous ing to TCM theory, a person’s BC is formed by Yin and Yang, study revealed that general practitioners with more Chinese andanimbalancebetweenthetwomaycausePhlegmsta- medicine knowledge referred their patients to TCM practi- sis. Yang deficiency implies that an energy level responsi- tioners more frequently [46]. Hence, it is crucial to provide ble for maintaining bodily functions has diminished [17], scientific evidence in support of CAM or TCM concepts whereas Yin deficiency implies diminishing of materials (in- that can aid in disease prevention and health promotion and cluding blood, body fluid, and essence) in performing bodily to share the newly established information with health care functions [25]. Phlegm stasis is induced when the materials providers. Thus, people can integrate health service effectively transported by the energy are impeded by external or envi- and safely. Therefore, we launched the Taichung Diabetic ronmental stimuli [21]. Body Constitution Study (TDBS) to evaluate the effect of BC In TCM, diabetic nephropathy is referred to as an intrin- on patients with T2DM [34, 47] and to continue following the sically deficient but extrinsically excessive syndrome. Defi- study cohort for determining the longitudinal effect. ciency of qi and excess of phlegm stasis are believed to be the Our study has three major limitations. First, a potential main pathologic mechanism responsible for development of selection bias may exist because all the study participants diabetic nephropathy [36]. Several clinical trials have aimed were recruited from a medical center. The disease severity to discover the efficacy of TCM on diabetic proteinuria, and of patients with T2DM treated at a medical center may the results suggest that Chinese herbal medicine seems to differfromthatofpatientswithT2DMtreatedinother be an effective and safe therapy option [36]. The three most clinical settings. The participants in our study may have had commonly used herbs in different herbal preparations are more comorbidities, poorer control of blood sugar, and a Astragalus (Huang Qi), Salvia miltiorrhiza (Dan Shen), and longer duration of diabetes compared with other patients. Poria (Fuling), consecutively [36]. In TCM, the Astragalus Nevertheless, the results can be applied to other T2DM has the effect of replenishing Qi [36, 37]. Salvia miltiorrhiza patients exhibiting similar disease characteristics. Second, and Poria are used to activate blood circulation and to resolve there was a potential confounding effect caused by other phlegm [36]. By using epidemiology module, our study unmeasured variables because this was an observational results, that T2DM patients with both Yang deficiency and study. We included most of the confounding factors reported Phlegm stasis are at a threefold risk of exhibiting albuminuria, in the literature to minimize the possibility of a confounding successfully correspond with the pathology mechanism and effect. Finally, we examined a cross-sectional association, clinical usage of certain Chinese medicine herbs. which cannot make causal inference because it lacked time Evidence-Based Complementary and Alternative Medicine 7 sequence. A cohort study is necessary to determine the casual end-stage renal disease in the united states—perface,” American relationship. Journal of Kidney Diseases,vol.45,no.1,pp.A5–A7,2005. [8] W.-C. Yang, S.-J. Hwang, and Taiwan Society of Nephrology, 5. Conclusion “Incidence, prevalence and mortality trends of dialysis end- stagerenaldiseaseinTaiwanfrom1990to2001:theimpactof CAM is a public health resource for increasing the preven- national health insurance,” Nephrology Dialysis Transplantation, tion of certain disease and promoting health. Distinguish- vol. 23, no. 12, pp. 3977–3982, 2008. ing patients with T2DM who exhibit an increased risk of [9]H.H.Parving,B.Oxenbøll,P.A.Svendsen,J.S.Christiansen, and A. R. Andersen, “Early detection of patients at risk of devel- albuminuria is crucial for preventing diabetic nephropathy. oping diabetic nephropathy. A longitudinal study of urinary According to TCM theory, BC is modifiable, and different albumin excretion,” Acta Endocrinologica,vol.100,no.4,pp. BC types may affect the development and prognosis of 550–555, 1982. certain diseases differently. The results of the current study [10]R.Retnakaran,C.A.Cull,K.I.Thorne,A.I.Adler,andR.R. suggest that T2DM patients who have both Yang deficiency Holman, “Risk factors for renal dysfunction in type 2 diabetes: and Phlegm stasis are at a threefold risk of developing U.K. prospective diabetes study 74,” Diabetes,vol.55,no.6,pp. albuminuria. Using BCQ to assess BC status is noninvasive, 1832–1839, 2006. convenient, fast, and inexpensive and should be adopted in [11] H.-H. Parving, J. B. Lewis, M. Ravid, G. Remuzzi, and L. 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Research Article Characterizing Herbal Medicine Use for Noncommunicable Diseases in Urban South Africa

Gail D. Hughes,1 Oluwaseyi M. Aboyade,2 Roxanne Beauclair,3,4 Oluchi N. Mbamalu,5 and Thandi R. Puoane6

1 South African Herbal Science and Medicine Institute (SAHSMI), Faculty of Natural Sciences, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa 2South African Herbal Science and Medicine Institute, University of the Western Cape, Bellville 7535, South Africa 3The South African Centre for Epidemiological Modelling and Analysis, Stellenbosch University, Stellenbosch 7602, South Africa 4International Centre for Reproductive Health (ICRH), Ghent University, De Pintelaan 185 UZP114, 9000 Gent, Belgium 5School of Pharmacy, University of the Western Cape, Bellville 7535, South Africa 6School of Public Health, University of the Western Cape, Bellville 7535, South Africa

Correspondence should be addressed to Gail D. Hughes; [email protected]

Received 2 July 2015; Accepted 16 September 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Gail D. Hughes et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Economic challenges associated with noncommunicable diseases (NCDs) and the sociocultural outlook of many patients especially in Africa have increased dependence on traditional herbal medicines (THMs) for these diseases. A cross-sectional descriptive study designed to determine the prevalence of and reasons for THM use in the management of NCDs among South African adults was conducted in an urban, economically disadvantaged area of Cape Town, South Africa. In a cohort of 1030 participants recruited as part of the existing Prospective Urban and Rural Epidemiological (PURE) study, 456 individuals were identified. The overall prevalence of THM use was 27%, of which 61% was for NCDs. Participants used THM because of a family history (49%) and sociocultural beliefs (33%). Hypertensive medication was most commonly used concurrently with THM. Healthcare professionals need to be aware of the potential dualistic use of THM and conventional drugs by patients, as this could significantly influence health outcomes. Efforts should be made to educate patients on the potential for drug/herb interactions.

1. Introduction already under considerable pressure because of the high prevalence of tuberculosis and HIV/AIDS, has to contend with The 2014 Global Status Report on noncommunicable diseases the burden of NCDs [9]. This burden affects the individual’s (NCDs) by the World Health Organization [1] indicates that qualityoflifeandhasresultedinincreasedhealthcare thesediseasescurrentlycausemoredeathsthanallother expenses, not only financially, but also in terms of morbidity, causes combined. These deaths are projected to increase from at the individual and national levels [6, 10–12]. Recent updates 38 million in 2012 to 52 million by 2030 [1]. This report indicate that South Africa is going through an epidemiolog- also showed that four major NCDs (cardiovascular diseases, ical shift, with deaths occurring mainly as a result of NCDs cancer, chronic respiratory diseases, and diabetes) are respon- [13]. siblefor82%ofNCDdeaths[1].About75%ofallNCD Risk factors associated with the development of NCDs deaths occur in low- and middle-income countries, usually in include heredity, unhealthy diets, a generally sedentary patients younger than 70 years old, and in the age range which lifestyle and environment, and exposure to tobacco and constitutes the bulk of the work force [1–4]. This is a major alcoholic products. Such risk factors, caused by pressures health and development challenge for the 21st century [5–7]. of urbanization and modernization, have resulted in an InSouthAfrica,themajorNCDsarecardiovascular increased burden to the struggling healthcare systems of diseases, diabetes, cancers, chronic respiratory diseases, and developing countries [14]. Many of the affected citizens mentalillness[8].TheSouthAfricanhealthcaresystem, in these countries are unable to afford primary healthcare 2 Evidence-Based Complementary and Alternative Medicine treatment for NCDs; hence, they depend, even if minimally, Province, were recruited. Langa, the oldest African township on alternative therapies such as traditional herbal medicines in Cape Town, has a high population of migrant black South (THMs). Africans, who initially settled here because of lower living In certain parts of Africa, THMs still remain the most costs, proximity to the city, and available transport resources utilised form of healthcare because of their accessibility [28]. Most of the respondents were born in Langa. Like many to the community [15]. Some physicians have reportedly other townships in Cape Town, it is one of the poorest areas recommended nonorthodox healing methods, such as tradi- as determined from the City Development Index and Human tional (herbal) healing to their patients, sometimes in cases Development Index values which are below the provincial where orthodox methods and treatment have not shown average [29, 30]. Formal houses exist along with informal improvement [16, 17]. The various uses of many traditional settlements (the Joe Slovo informal settlement in Langa is herbal products have also been validated by in vitro stud- one of the largest informal settlements in the country), ies, which may have informed such recommendations. The unemployment is high, and the education level is generally World Health Organization, in recognition of the role of below matric level [31]. THMs especially in resource-constrained settings, has called for preservation and acknowledgement of THM use in cases 2.3. Sampling for THM Study. Sampling for the PURE-THM where such use has been scientifically validated [18]. The study was conducted according to methods reported by significance of this, in the face of the increasing global Teo et al. [27]. The sampling frame for the current THM practice of medical pluralism (the adoption of more than one studymadeuseofthe1030participantswhowererecruited medical system), cannot be overlooked. fromLangaintheurbanSouthAfricacohortofthePURE Surveys conducted in South Africa revealed that patients parent study. Participants’ information captured throughout admit to using THMs for conditions such as diabetes, high the PURE follow-up period was used to conveniently select blood pressure, sexually transmitted diseases, asthma, pain, 458 individuals who were originally enrolled in the PURE HIV/AIDS, gynaecological and obstetric complaints, and parent study and who had reported having at least one NCD. childhood diseases [19–25]. In their study among Indians Those recruited were subsequently interviewed to determine in Durban, South Africa, Singh et al. [26] reported that theprevalenceofTHMuse.Twoofthe458individualswere herbal/natural medicines were the most commonly used excluded from the analysis, because they did not answer the complementary and alternative medicines (CAM) to manage question, “Do you use THM?” Participants’ names, contact NCDs such as diabetes, arthritis, hypertension, and respira- details, and residential addresses were noted to facilitate the tory disorders, sometimes in conjunction with conventional process of data collection. All individuals who agreed to medicines. participate provided written informed consent. DespitethewideuseofTHMs,thereislimiteddataon the prevalence of using these for the treatment of NCDs among people living in different regions of South Africa. 2.4. Data Collection. Appointments to collect data were This is certainly of importance to all stakeholders—patients, first made with participants by means of telephone calls. physicians, and government—as there exists potential for Using the participants’ residential addresses, trained inter- prescription drug-traditional medicine interaction, which viewers visited the households/individuals on the day of may be beneficial or detrimental to patients. Therefore, this the appointment to collect data on the epidemiology of study characterized the use of THM in a selected urban THM use for NCDs. For the purpose of this study, data area of Cape Town, South Africa, and examined potential were collected between October 2013 and August 2014 using predictors of use and the relationship between diagnosed structured questionnaires which were administered through NCDs and THM use. face-to-face interviews. The interviews were conducted by five trained data collectors in the preferred language of the respondent (English or isiXhosa). Participants residing in 2. Methods Langa, with origins mainly from the Eastern Cape Province of South Africa, speak isiXhosa and preferred to be interviewed 2.1. Study Design. A cross-sectional descriptive study was and to respond in their mother tongue. This cohort is conducted,andsubjectswereconvenientlyrecruitedfromthe established, most of them having been born in Langa; how- South African arm of a larger prospective study, the Prospec- ever, participants regularly travel back to the Eastern Cape tive Urban and Rural Epidemiological (PURE) study. For the Province of origin to see family members. Data were collected PURE study, a global cohort has been developed to investigate about the respondents’ demographic characteristics (age, sex, the impact of social and environmental transition on health, education, and employment status), clinical/medical history, involving over 150,000 adults initially aged between 35 and traditional medicine use (duration of use, condition for use, 75 years from communities in 17 low-, middle-, and high- dosage, and form), and migratory status. The quality of data income countries. A detailed description of the PURE study collected was maintained through the use of standardized design has been published by Teo et al. [27]. protocols and centralized training.

2.2. Study Setting. For the THM aspect of the PURE study, 2.5. Data Analysis. Statistical analysis was performed using South Africa, urban participants residing in Langa, a black R statistical programming language, version 3.1.1 [32]. Ini- community located in Cape Town in the Western Cape tially, the frequency distributions and summary statistics for Evidence-Based Complementary and Alternative Medicine 3 participant attributes and characteristics of THM use were Table 1: Participant characteristics. computed. Participants were classified as THM users if they Overall THM use No THM use answered “Yes”to the question “Do you use traditional herbal 𝑛 =456 𝑛 =124 𝑛 =332 medicine?” THM use 𝑛 (%) Next, a bivariate analysis of eight different self-reported conditions and THM use was conducted. The conditions were Yes 124 (27.2) hypertension, diabetes, rheumatoid arthritis, cardiovascular No 332 (72.8) 𝑛 disease, heart disease, depression, hypercholesterolemia, and Gender (%) asthma. Some conditions were rare and thus had low fre- Male 100 (22.0) 25 (20.3) 75 (22.6) quencies; therefore, Fisher’s exact tests were employed to Female 355 (78.0) 98 (79.7) 257 (77.4) determine statistical significance. The proportion of THM Marital status 𝑛 (%) users who concurrently used specific classes of conven- Never married 223 (49.8) 50 (42.0) 173 (52.6) tional medicines, antihypertensives, diuretics, medicines Married or cohabiting 127 (28.3) 38 (31.9) 89 (27.1) for pain, anti-inflammatory agents, and antidiabetic and Divorced, widowed, or 98 (21.9) 31 (26.1) 67 (20.4) cholesterol-reducing agents, were also graphically present- separated ed. Education 𝑛 (%) Finally, 18 variables were explored as potential predic- None or primary 129 (28.7) 46 (37.4) 83 (25.5) tors of THM use: Gender (male/female), Marital status Secondary 283 (63.0) 67 (54.5) 216 (66.3) (never married/married or cohabiting/divorced, widowed, or Tertiary or other 37 (8.2) 10 (8.1) 27 (8.3) separated), Education (none or primary/secondary/tertiary Employed 𝑛 (%) or other), Employed (Yes/No), Income per month (R0– Yes 68 (15.6) 23 (19.7) 45 (14.2) > R1999 [0–163 USD]/R2000–R5000 [163–408 USD]/ R5000 No 367 (84.4) 94 (80.3) 273 (85.8) > [ 408 USD]), Religion (Christian/Other), Medical insurance Income 𝑛 (%) (Yes/No), Age (numeric, continuous), Number of people in R0–R1999 369 (81.6) 93 (75.0) 276 (84.1) household (numeric, discrete), Health compared to last year R2000–R5000 73 (16.2) 26 (21.0) 47 (14.3) (same as last year/better than 1 year ago/worse than 1 year R5000+ 10 (2.2) 5 (4.0) 5 (1.5) ago), Have current health condition (No/Yes), Uses conven- Religion 𝑛 (%) tional medication (No/Yes), Sees a family doctor (No/Yes), Sees a specialist doctor (No/Yes), Sees a hospital doctor (No/Yes), Other 19 (4.2) 7 (5.6) 12 (3.70) Sees a traditional healer (No/Yes), Has a noncommunicable Christian 431 (95.8) 117 (94.4) 314 (96.3) 𝑛 disease (No/Yes), and Migrant (Yes/No). Has a noncommuni- Medical insurance (%) cable disease and Migrant were constructed variables. Partici- Yes 18 (4.1) 8 (6.7) 10 (3.1) pants were classified as having a noncommunicable disease if No 426 (95.9) 111 (93.3) 315 (96.9) they reported having any of the following conditions: hyper- Smoking status 𝑛 (%) tension, diabetes, stroke, rheumatoid arthritis, cardiovascular Never smoked 275 (62.2) 78 (66.7) 197 (60.6) disease, heart disease, depression, hypercholesterolemia, and Past smoker 32 (7.2) 10 (8.5) 22 (6.8) asthma. For the Migrant variable, participants were coded as Current smoker 124 (28.1) 28 (23.9) 96 (29.5) “Yes,” if they reported living in another province different Casual smoker 11 (2.5) 1 (0.9) 10 (3.1) from their province of origin or birth (i.e., migrating between Alcohol use 𝑛 (%) provinces). These 18 variables were considered because of the Never drank 225 (50.6) 66 (55.9) 159 (48.6) study team’s apriorihypotheses that these may influence a Past drinker 40 (9.0) 13 (11.0) 27 (8.3) person’suseofTHM.Logisticregressionwasusedtocalculate Current drinker 127 (28.5) 24 (20.3) 103 (31.5) crude odds ratios (OR) and 95% confidence intervals (95% Casual drinker 53 (11.9) 15 (12.7) 38 (11.6) CI). However, none of these models were adjusted for other General health 𝑛 (%) variables as the research focus was to determine marginal Excellent 35 (7.8) 10 (8.4) 25 (7.6) associations with THM use. Very good 71 (15.9) 16 (13.4) 55 (16.8) Good 176 (39.5) 55 (46.2) 121 (37.0) 3. Results Fair 106 (23.8) 23 (19.3) 83 (25.4) A total of 456 participants were included in the analyses. Poor 58 (13.0) 15 (12.6) 43 (13.1) 𝑛 Characteristics of these participants are presented in Table 1. Migrant (%) The median age of participants was 56 years, and over one- No 170 (37.6) 58 (46.8) 112 (34.1) quarteroftheparticipants(27.2%,𝑛 = 124)reportedusing Yes 282 (62.4) 66 (53.2) 216 (65.9) THM. Most participants were female (78.0%, 𝑛 = 355), Age med (IQR) 56 (47–64) 57 (49–64) 56 (46–64) 𝑛 = 283 Number of people living in had at least a secondary education (63.0%, ), and 5 (3–6) 5 (3.8–7) 5 (3–6) were identified with the Christian religion (95.8%, 𝑛 = 431). household med (IQR) Abouthalfoftheparticipantshadneverbeenmarried(49.8%, Number of people earning 𝑛 = 223). Only 15.6% and 4.1% of the study participants were an income in household 1(1-2) 1(1-2) 1(1-2) employed and had medical insurance, respectively. med (IQR) 4 Evidence-Based Complementary and Alternative Medicine

For every year when participants’ age increases, there High blood pressure appears to be 1% increased odds of using THM (95% CI: 0.99–1.03). Table 1 reflects the median age for THM users as 57, compared to 56 among nonusers. Participants with a Pain secondary education are 44% less likely to use THM than people with no education or primary education (95% CI: Diuretics 0.36–0.88). Corroborating this, Table 1 shows that two-thirds of nonusers have a secondary education versus only 54.5% of THM users. Those who said their health was better at the time Anti-inﬂammatories ofthesurveythanthepreviousyearweremorelikelytohave used THM than those who claimed their health was the same Conventional medication Conventional Diabetes as in the year prior to the survey (OR 1.72, 95% CI: 1.04–2.91). Participants who reported a current health condition had approximately two times the odds of using THM compared Cholesterol to those without (95% CI: 1.28–3.34). Consultations with a family doctor (OR 2.26, 95% CI: 1.48–3.46), specialist 0204060 physician (OR 2.38, 95% CI: 1.40–4.00), or a traditional healer Prevalence of use (%) (OR 8.66, 95% CI: 3.50–24.52) were predictors of using THM. Figure 1: Proportion of THM users who are also using different Participants who were currently living in their province of types of conventional medicines. birth or origin had 41% reduced odds of using THM (95% CI: 0.39–0.90) compared to migrants. Of those using THM, more than half (53.2) were classified as migrants (Table 1).

Table 2 presents characteristics of THM use among the 4. Discussion 124 self-ascribed users in our study sample. The median age at first use of THM was 35 years and over half of these The aim of this study was to understand the prevalence of users had used THM for several years or were unsure of THMuseforNCDsinanurbantownshipintheWestern how long they had been using these (26.9% and 28.6%, Cape Province of South Africa. The township has been in resp.). The THMs were obtained from the markets (39.5%) existence for over 100 years and most of the respondents and traditional health practitioners (THPs) (26.6%) or were were born there. The prevalence of THM use observed in personally harvested by the participating user (21.0%). this study falls within the range, 6.1%–38.5%, documented The preferred mode of THM preparation was as a tea for in the systematic review of THM/CAM use in South Africa oral consumption (83.9%), as opposed to an extract (10.2%), conducted by Peltzer [33]. This is however lower than what powder (9.3%), decoction (6.8%), or tablet (2.5%). More hasbeenreportedinotherSouthAfricanstudies[20,26]and than half of the participants (57.8%) reported that relatives in studies conducted in different settings and countries within influenced them to use THM, and the most common reasons Africa such as in Nigeria [34], Ghana [35], and Uganda [36], for using THM were ascribed to family history (48.8%) and and further afield in Korea [37], Turkey [38], Finland [39], cultural beliefs (33.3%). The percentage of participants who and Australia [40]. The observed difference in prevalence believe in the efficacy of THM was 64.7, with such efficacy ofTHMusemightbeasaresultofvariationinsample rated by 47.5% of THM users as equal to or more than that characteristics, study setting, and population. of conventional medicines. The practice of medical pluralism Patterns of THM acquisition recorded in this study bear is evident, with 37.1% of THM users admitting to concurrent some similarity to another study conducted in Ghana [41]. use of THM with their conventional medicines. Also, 61.3% For instance, in this study, the major sources of THM for of people who use THM self-reported diagnosis of an NCD. many of the users were the market (39.5%), the traditional Figure 1 depicts the proportion of THM users who also health practitioner (26.6%), and personal harvest (21.0%) used different types of conventional medicines. Among the whilefortheGhanaianstudy,themajorsourcesofCAM THM users, the highest prevalence of medical pluralism products,mostofwhichwereherbalmedicinalproducts, (specifically, concurrent THM and conventional medicine were personal harvest (37/3%), the market (21.6%), and the use) was noted among participants who used conventional pharmacy (11.8%). The high percentage of participants in this medicines for high blood pressure and pain. study who obtain THM from the market and their personal The associations between different reported conditions harvest implies that many of the participants self-prescribed andTHMusecanbeseeninTable3.Theonlystatistically and could identify these medicines (for purchases from the significant relationship observed is that between having market and personal harvest). The percentage of participants rheumatoid arthritis and using THM (𝑝 < 0.05). Although who obtain their THM from the pharmacy with respect to not statistically significant, a greater proportion of THM this study (13.7%) and the Ghanaian study (11.8%) perhaps users were hypertensive (53.2%) compared to nonusers of implies increasing confidence in such products, seeing that THM who were hypertensive (47.3%). they can be obtained from the same place as conventional Finally, Table 4 presents the predictors of THM use as drugs. This raises concern regarding the quality and potential determined by logistic regression analysis. interactions of these products and the need for the pharmacist Evidence-Based Complementary and Alternative Medicine 5

Table 2: Characteristics of traditional herbal medicines (THMs) Table 2: Continued. use. Treating a condition is the reason for THM use 𝑛 (%) Age when participant first used THM med (IQR) 35 (20–54) Yes 40 (32.5) Obtains THM at market 𝑛 (%) 83 (67.5) Yes 49 (39.5) No No 75 (60.5) Managing a condition is the reason for THM use 𝑛 (%) Obtains THM at traditional practitioner 𝑛 (%) Yes 16 (13.0) Yes 33 (26.6) No 107 (87.0) No 91 (73.4) HowoftenisTHMusedbytheparticipant?𝑛 (%) Obtains THM from personal harvest 𝑛 (%) Yes 26 (21.0) Never 2 (1.6) No 98 (79.0) Rarely 33 (26.8) Obtains THM from the pharmacist 𝑛 (%) Sometimes 46 (37.4) Yes 17 (13.7) Often 28 (22.8) No 107 (86.3) Always 14 (11.4) Obtains THM over the counter 𝑛 (%) Participant uses THM in combination with 5 (4.0) Yes conventional medicine? 𝑛 (%) No 119 (96.0) 46 (37.1) Participant takes THM as a tea 𝑛 (%) Yes Yes 99 (83.9) No 78 (62.9) No 19 (16.1) Participant thinks THM is effective? 𝑛 (%) 𝑛 Participant takes THM as a powder (%) Yes 75 (64.7) Yes 11 (9.3) No 20 (17.2) No 107 (90.7) 21 (18.1) Participant takes THM as an extract 𝑛 (%) Sometimes Yes 12 (10.2) ParticipantthinksTHMisbetterthanCM?𝑛 (%) No 106 (89.8) Less efficacy 38 (31.1) Participant takes THM as a tablet Equal efficacy 32 (26.2) Yes 3 (2.5) More efficacy 26 (21.3) No 115 (97.5) Unknown 26 (21.3) Participant takes THM as a decoction How much is the family willing to pay for THM per Yes 8 (6.8) year? No 110 (93.2) R1000 6(5.1) Advertisement 3 (2.6) Nothing 62 (52.5) Healthcare providers 2 (1.7) Other 1 (0.9) to educate patients and customers regarding this. Since less Family history is the reason for THM use 𝑛 (%) Yes 60 (48.8) than half (26.6%) of the THM users in this study obtained theirTHMfromTHPs,itcanbeassumedthatthepracticeof No 63 (51.2) self-diagnosis and self-medication with traditional medicine Cultural beliefs are the reason for THM use 𝑛 (%) is widespread in urban areas of developing countries. Self- Yes 41 (33.3) medication with THM has also been observed among all age No 82 (66.7) groups and social categories of people [42, 43]. LowcostisthereasonforTHMuse𝑛 (%) This study observed that drinking the THM as a tea Yes 20 (16.3) was the most common mode of THM consumption, which No 103 (83.7) 𝑛 raises questions regarding the quality and stability profiles of Accessibility is the reason for THM use (%) the prepared remedy on storage. The use of THM is largely Yes 15 (12.2) influenced by family and cultural reasons. Interestingly, while No 108 (87.8) literature sources have reported that many people utilized A positive recommendation is the reason for THM use 𝑛 THMs because they were more affordable and accessible than (%) conventional treatment methods [44–47], less than 30% of Yes 28 (22.8) the present study participants utilized THMs for these two No 95 (77.2) reasons, in spite of the high percentage of unemployment and 6 Evidence-Based Complementary and Alternative Medicine

Table 3: Reported diagnosed conditions and traditional herbal Table 4: Predictors of traditional herbal medicines use. medicines (THMs) use. Crude OR (95% CI) THM use Age 1.01 (0.99–1.03) 𝑝 Gender Variable Yes No value Male 1.00 𝑛 (%) 𝑛 (%) Female 1.14 (0.70–1.93) High blood pressure/hypertension Marital status Yes Never married 1.00 66 (53.2) 157 (47.3) 0.29 No 58 (46.8) 175 (52.7) Married or cohabiting 1.48 (0.90–2.42) Divorced, widowed, or separated 1.60 (0.94–2.71) Diabetes Education Yes 20 (16.1) 62 (18.7) 0.59 None or primary 1.00 No 104 (83.9) 270 (81.3) Secondary 0.56 (0.36–0.88) Rheumatoid arthritis Tertiary or other 0.67 (0.29–1.47) Employed Yes 21 (16.9) 32 (9.6) <0.05 No 1.00 No 103 (83.1) 300 (90.4) Yes 1.48 (0.84–2.56) Cardiovascular disease Income per month R0–R1999 1.00 Yes 2 (1.6) 4 (1.2) 0.67 R2000–R5000 1.64 (0.95–2.78) No 122 (98.4) 328 (98.8) >R5000 2.97 (0.81–10.89) Heart diseases Religion Yes 3 (2.4) 6 (1.8) Other 1.00 0.71 Christian 0.64 (0.25–1.75) No 1221 (97.6) 326 (98.2) Medical insurance Depression No 1.00 Yes Yes 2.27 (0.84–5.90) 4 (3.2) 14 (4.2) 0.80 No 120 (96.8) 318 (95.8) Number of people in household 1.00 (0.93–1.07) Health compared to last year Hypercholesterolemia Same as last year 1.00 Yes 2 (1.6) 10 (3.0) 0.53 Better than 1 year ago 1.72 (1.04–2.91) No 122 (98.4) 322 (97.0) Worse than 1 year ago 1.60 (0.80–3.18) Asthma Have current health condition No 1.00 Yes 4 (3.2) 13 (3.9) 1.00 Yes 2.04 (1.28–3.34) No 120 (96.8) 319 (96.1) Uses conventional medication No 1.00 Yes 1.17 (0.76–1.81) Sees a family doctor low-income level of the participants. In the urban community No 1.00 where this study was set, THMs are used mainly because of Yes 2.26 (1.48–3.46) their sociocultural acceptance, largely influenced by family Sees a hospital doctor and the respondent’s satisfaction with THM. This is also No 1.00 reflected in the percentage of THM users who believed that Yes 0.67 (0.38–1.19) THMnotonlywaseffectivebutalsohadanefficacywhich Sees a specialist doctor wasequaltoorgreaterthanthatofconventionalmedicines No 1.00 (Table 2). The results of this study imply that THM use Yes 2.38 (1.40–4.00) mayhavemoretodowiththeparticipant’shealthbeliefs Sees a traditional healer No 1.00 and family history of use compared to sociodemographic Yes 8.66 (3.50–24.52) attributes such as income and employment. Has a noncommunicable disease More than 90% of respondents reported being Christians, No 1.00 and this applied to both users and nonusers of THM alike. Yes 1.35 (0.89–2.07) This perhaps shows that respondents still adhere to their Migrant sociocultural heritage and do not see it as opposing to their Yes 1.0 0 spiritual views. Indeed, spirituality has been documented No 0.59 (0.39–0.90) as a strong predictor of traditional or complementary and alternative medicine use [48]. Studies in countries such as Sierra Leone, India, and Malaysia also bear credence to this, allopathic and traditional or CAM practitioners believe this with many CAM and allopathic practitioners believing that improves health outcomes [49–51]. there was an increase in spiritual focus among patients when Although our study indicated no statistically significant they are ill compared to when they are healthier. Individuals difference between diagnosed conditions and THM use, with reportedly receive religious support during illness, and many the exception of rheumatoid arthritis, a high prevalence of Evidence-Based Complementary and Alternative Medicine 7

THM use was observed among patients who had hyper- previous year were more likely to use THM. Participants who tension. Previous studies have also documented evidence of see a family doctor or a specialist doctor also have a greater common use of CAM such as THM among hypertensive likelihood of THM use than those who see hospital doctors. patients [41, 52]. Rheumatoid arthritis is perhaps viewed, Possibly, these participants might have a patient-physician and perhaps wrongly too, as one of the least threatening relationship which increases such odds, unlike participants NCDs without an urgent need for treatment/management who see a hospital doctor. Could the pressures that hospital as required for NCDs like hypertension and diabetes. Many doctors work under in public settings be an obstacle to the patients do not receive timely and appropriate therapy for development of such relationship? No evidence was however the management of this condition. This has been attributed found in the literature to support these views. A professional to difficulty in making a diagnosis among physicians who diagnosis possibly empowers these patients to know without arenotspecializedinrheumatology,unlikethediagnosis question what their health problems are. This may enable of other NCDs like hypertension and diabetes which can them to access and assess THM practices for NCDs as easily be made and managed even by nonspecialist physicians opposed to patients who see a doctor, who may not be a [53]. This perhaps leads to participants’ exploration of CAM specialist, at the local community clinic or hospital. and significantly increases the likelihood of THM use by Postapartheid South Africa is undergoing urban migra- patients with rheumatoid arthritis, compared to those with tion. Although urban areas within the country are known to other NCDs such as hypertension and diabetes, which can have better health infrastructures than the rural areas, excep- be easily diagnosed. Patients with rheumatoid arthritis were tions to this fact are the urban areas with high concentration also more likely than patients with hypertension or diabetes of slums and squatter settlements [65]. Migrant populations to underutilize their prescription medications as part of cost- in this study were more likely to use THM compared to cutting measures [54], which may predispose them to use of the nonmigrants. This is consistent with many other studies nonprescription alternative medicines such as THM. which document a higher prevalence of CAM measures such Moreover, participants did not use THMs to treat or as THM among migrant and immigrant populations [42, 66– manage a condition. This lends support to findings from pre- 70]. vious studies where individuals are documented to use CAM In consultations with patients, physicians generally do not treatment measures, such as THM to improve immunity and make enquiries regarding their patients’ use of CAM, such promote general well-being [22, 55]. While some participants as THM [40, 41]. There is a need to improve communication indicated the frequent use of THM, majority utilized THM flow between physician and patient, especially patients with rarely. This may perhaps be explained by the premise that NCDs. This would make the physician aware of THM preva- THMs are not used exclusively, but in combination with and lence, as well as understand patients’ health-seeking patterns. as a supplement to conventional medicines, a view which is Data presented identifies four major factors—basic or no supported by Cook [56] and Singh et al. [26]. education, individual view of health status, relationship with Medical pluralism was evident among hypertensive family/specialist doctor, and migratory history—that may patients. Given that diuretics are a major class of drugs predict a patient’s likelihood of using THM. These predictors utilized to control hypertension, the prevalence of use among may serve as indicators (of THM use) to physicians during hypertensive patients may be higher than presented in the consultations with patients, thus enabling them to introduce figure. The same interpretation may also be made forthe appropriate education and intervention programmes to assist prevalence of medical pluralism among patients who use patients in making informed decisions regarding their use of conventional medicines for pain and inflammation. Previous THM. studies have also hinted that patients with NCDs may use THM for the treatment of their condition and its related side 5. Study Strengths and Limitations effects as well as for other unrelated self-limiting ailments [22, 52, 57]. The use of complementary treatment methods This study represents a timely investigation of THM use such as THMs is also quite common among individuals with in black African participants with NCDs living in a South NCDs in other parts of the world [58–60]. African urban setting. A strong case is made with its Unlike our previous study which found age and marital multidisciplinary approach which focuses on THM use and and employment status as predictors of THM use [22], the its public health implications. Being a cross-sectional study, same relationship could not be established in the present it has indicated associations between some of the assessed study. This could be as a result of differences in the popu- predictors and THM use. This is the first analysis of THM lations assessed as well as differences in the study locations. prevalence and predictors of use among patients in this In the study population, participants with a secondary edu- community, the results of which may be used as baseline data cation are less likely to use THM than those with primary for future studies. or postsecondary education. A similar study in Ghana also We acknowledge that this study had some limitations. reported that respondents with a secondary education uti- The cross-sectional nature of the study means that causality lized THM less than those with basic or no education but less may not be developed between the exposure and outcome. than those with a tertiary education [35]. Although people In addition, while face-to-face interviews along with trained with poor health are generally more likely to seek alternative data capturers and the employment of a centralized training treatment methods such as THM [61–64], our study showed system may serve to improve quality of data collected, it that participants who reported a better health status than the may also suffer from social desirability and self-report bias 8 Evidence-Based Complementary and Alternative Medicine

on the part of the participant. Therefore, the fact that the [3]J.J.Miranda,S.Kinra,J.P.Casas,G.DaveySmith,andS. validity of our findings may be subjective, depending as it Ebrahim, “Non-communicable diseases in low- and middle- was on the participants’ ability to recall as well as present income countries: context, determinants and health policy,” accurate information with respect to their THM use, cannot Tropical Medicine and International Health,vol.13,no.10,pp. be dismissed. In addition, the study population was from 1225–1234, 2008. a township in an urban area and so results many not be [4] T. A. Gaziano, “Cardiovascular disease in the developing world generalized to other townships or rural areas. and its cost-effective management,” Circulation,vol.112,no.23, pp. 3547–3553, 2005. [5]U.E.Bauer,P.A.Briss,R.A.Goodman,andB.A.Bowman, 6. Conclusions “Prevention of chronic disease in the 21st century: elimination of the leading preventable causes of premature death and The results of this study highlight the prevalence of and pat- disability in the USA,” The Lancet,vol.384,no.9937,pp.45–52, terns of use of THMs in an urban South African community. 2014. Generally, THM use is unsupervised via the South African [6]D.O.Abegunde,C.D.Mathers,T.Adam,M.Ortegon,and health system. Information on THM is largely sourced from K. Strong, “The burden and costs of chronic diseases in low- family, and the practice of self-medication is common. Of income and middle-income countries,” The Lancet,vol.370,no. concern from the results of this study is the prevalence of 9603, pp. 1929–1938, 2007. THM coutilization with conventional medicines. Records of [7] J. E. Epping-Jordan, R. Bengoa, and D. Yach, “Chronic potential drug interactions and contraindications for the use conditions—the new health challenge,” South African Medical of THMs are not yet available. Nevertheless, it is of important Journal,vol.93,no.8,pp.585–590,2003. public health interest to make health workers aware of [8]B.M.Mayosi,A.J.Flisher,U.G.Lalloo,F.Sitas,S.M.Tollman, patients’ THM use and the potential for prescription drug- and D. Bradshaw, “The burden of non-communicable diseases THM interaction and its clinical significance. Such awareness in South Africa,” The Lancet,vol.374,no.9693,pp.934–947, will enable them to offer appropriate advice regarding the use 2009. of these products. [9]V.P.Wyk,W.Msemburi,R.Laubscheretal.,“SecondNational Given the diverse multicultural and multiethnic orienta- Burden of Disease Study South Africa: national and subnational tion of the South African population, it would be of great mortality trends, 1997–2009,” The Lancet,vol.381,p.S113,2013. public and health interest to conduct similar studies among [10] L. Chaker, A. Falla, S. V.van der Lee et al., “The global impact of other cultural and ethnic groups. non-communicable diseases on macro-economic productivity: a systematic review,” European Journal of Epidemiology,vol.30, no.5,pp.357–395,2015. Ethical Approval [11] D. A. Watkins, Z. D. Olson, S. Verguet, R. A. Nugent, and D. T. Jamison, “Cardiovascular disease and impoverishment averted The study protocol was approved by the Senate Research due to a salt reduction policy in South Africa: an extended cost- Committee of the University of the Western Cape, South effectiveness analysis,” Health Policy and Planning,2015. Africa. [12]R.Pradeepa,D.Prabhakaran,andV.Mohan,“Emerging economies and diabetes and cardiovascular disease,” Diabetes Conflict of Interests Technology & Therapeutics, vol. 14, supplement 1, pp. S-59–S-67, 2012. The authors declare that there is no conflict of interests. [13] SSA Statistics South Africa, “Mortality and causes of death in South Africa, 2013: findings from death notification,” Statistical Release P0309.3, Statistics South Africa, Pretoria, South Africa, Acknowledgments 2014. The authors wish to express their appreciation to the field [14] R. Nugent, “Chronic diseases in developing countries: health and economic burdens,” Annals of the New York Academy of workers, for their assistance in data collection. The PURE Sciences, vol. 1136, pp. 70–79, 2008. study participants are sincerely appreciated for their time [15] J. W. Kiringe, “A survey of traditional health remedies used by and willingness to participate in this study. Authors want to the Maasai of Southern Kaijiado District, Kenya,” Ethnobotany thank Jean Fourie for her editorial assistance. Funding for Research and Applications,vol.4,pp.61–73,2006. the study was provided by the National Research Foundation [16] V. Roy, M. Gupta, and R. K. Ghosh, “Perception, attitude SouthAfricaandtheUniversityoftheWesternCapeOfficeof and usage of complementary and alternative medicine among Research.TheClaudeLeonFoundationisalsoacknowledged doctors and patients in a tertiary care hospital in India,” Indian for support. Journal of Pharmacology,vol.47,no.2,pp.137–142,2015. [17] D. Jean and C. Cyr, “Use of complementary and alternative References medicine in a general pediatric clinic,” Pediatrics,vol.120,no. 1, pp. e138–e141, 2007. 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Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 976123, 10 pages http://dx.doi.org/10.1155/2015/976123

Research Article Effects of Tai Chi and Walking Exercises on Weight Loss, Metabolic Syndrome Parameters, and Bone Mineral Density: A Cluster Randomized Controlled Trial

Stanley Sai-Chuen Hui,1 Yao Jie Xie,1 Jean Woo,2 and Timothy Chi-Yui Kwok2

1 Department of Sports Science and Physical Education, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong 2Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

Correspondence should be addressed to Stanley Sai-Chuen Hui; [email protected]

Received 13 May 2015; Accepted 28 June 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Stanley Sai-Chuen Hui et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Tai Chi and walking are both moderate-intensity physical activity (PA) that can be easily practiced in daily life. The objective of the study was to determine the effects of these two PAs on weight loss, metabolic syndrome parameters, and bone mineral density (BMD) in Chinese adults. We randomized 374 middle-aged subjects (45.8 ± 5.3 years) into 12-week training (45 minutes per day, 5daysperweek)ofTaiChi(𝑛 = 124) or self-paced walking (𝑛 = 121) or control group (𝑛 = 129). On average, Tai Chi and walking groups lost 0.50 and 0.76 kg of body weight and 0.47 and 0.59 kg of fat mass after intervention, respectively. The between- group difference of waist circumference (WC) and fasting blood glucose (FBG) was −3.7 cm and −0.18mmol/LforTaiChiversus control and −4.1 cm and −0.22 mmol/L for walking versus control. No significant differences were observed regarding lean mass, blood pressure, triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol, and BMD compared to control. Change in lean mass, not fat mass or total weight loss, was significantly correlated to the change in BMD. Our results suggest that both of these two PAs can produce moderate weight loss and significantly improve the WC and FBG in Hong Kong Chinese adults, with no additional effects on BMD.

1. Introduction through exercise leads to weight loss and produces metabolic benefits12 [ ]. A study conducted in America showed that Along with the increasing prevalence of obesity and seden- moderate-intensity PA programs had significant effectiveness tary lifestyles worldwide, the metabolic syndrome (MetSyn) on reducing body fat and controlling for risk factors of Met- has become a global public health problem [1–3]. The com- Syn [11]. However, concern exists in the weight loss-related ponents of MetSyn are risk factors for many chronic con- decline in bone mineral density (BMD) [12, 13]. Although ditions, including cardiovascular diseases, stroke, diabetes, there are many studies showing that exercise improved bone and kidney disease, and result in the increased all-cause health in older adults [14], the contrary finding that exercise- mortality [4–7]. More attention to lifestyle modifications for induced weight loss caused a reduction in BMD has been reducing obesity and promoting physical activity (PA) is reported [13],andsomeotherstudiesdemonstratedlittleor thereby suggested [2]. In the Asia-Pacific region particularly no effect on BMD [15–17]. The exercise type, intensity, and greater China, rapid economic development coexists with the duration,aswellasthetargetpopulation,mayleadtothe population aging [8]; the scientific and effective prevention of discordance in study results. In addition, evidence has shown obesity and MetSyn in middle-aged people is thereby critical that lean mass exerts a greater effect on BMD than fat mass for healthy aging and health policy-making. [18], thus investigating the changes of lean mass and fat mass Evidences have shown that exercise is beneficial for during exercise which can help to better understand the effect preventing MetSyn [9–11]. The increased energy expenditure of exercise-induced weight loss on BMD. 2 Evidence-Based Complementary and Alternative Medicine

Tai Chi (also called Tai Chi Chuan or Taiji), a tradi- 0.05 ± 0.09 mmol/L in HDL-C, 0.02 ± 0.035mmol/LinLDL- tional Chinese mind-body exercise, is popular in Chinese C, and 0.05 ± 0.09 mmol/L in triglycerides between the group population, particularly middle-aged and elderly people. Its means. physiological and psychosocial benefits on health outcomes have been well addressed [19, 20]. However, limited studies 2.3. Randomization and Intervention. Participants recruited reported the effect of Tai Chi on all MetSyn parameters from one geographical area were considered as one cluster. [21, 22]. We analyzed the data from a cluster randomized The randomization was carried out at geographic area level controlled trial (C-RCT) among generally healthy, inactive for avoiding contamination. Nine clusters were then random- Hong Kong middle-aged people who practiced Tai Chi or ized to either Tai Chi, walking, or control arms, with the self-paced brisk walking under the same frequency and allocation ratio of 1 : 1. An independent statistician conducted duration for 12 weeks and kept the stable dietary intake in this the randomization using Excel to generate the allocation period, with the purpose to see how much body weight would sequence. Another independent researcher critically carried be reduced and to what extent would the MetSyn parameters out the allocation according to the sequence, to shield be improved; if a significant weight loss was observed, relevant investigators who might admit participants to the what were the changes in fat and lean mass, whether this trial from knowing the upcoming assignments. exercise-induced body mass loss had additional effect on A modified 32-short form Yang-style Tai Chi Chuan was BMD. adopted in the Tai Chi group. Tai Chi integrates physical and spiritual elements to slowly and gently move qi (vital energy) 2. Method throughout the body. Those rich with this qi feel wonderfully alive and strong. The Yang-style Tai Chi is the most popular 2.1. Design and Participants. A 3-arm parallel-group C-RCT and widely practiced Tai Chi style in the world. Its short form was designed. The whole research project has been briefly is typically done with slow, steady movements, which is a reported elsewhere [23] under the contractual obligation as practical entry point for many beginners. Participants were a condition of funding approval. The experimental methods required to practice 30 min per day, 5 days per week for 12 were carried out in accordance with relevant guidelines weeks. Within 1 week, the qualified Tai Chi Chuan instructors and regulations. All participants provided written informed led 3 days of practices, and 2 other days were alloted for consent. And all experimental protocols were approved by self-practice. Before and after the normal pratice, 10 min of the Joint Chinese University of Hong Kong-New Territories warm-up stretching and 5 min of cool-down stretching were East Cluster Clinical Research Ethics Committee. The study implemented, respectively. For the walking group, firstly, the was registered at http://clinicaltrials.gov with the unique qualified instructors gave a briefing session to the partici- identifier number: NCT02163798. pants, to clarify the types of walking and demonstrated how Subjects were recruited from some large housing estates topracticethestandardself-pacedbriskwalking.Participants in the Shatin district of Hong Kong. These recruitment sites were advised to walk 30 min per day. They were encouraged were classified as 9 geographic areas. Advertisements in flyers, to walk with their friends or families; the route of the walk surface mails, and bulletin boards were used for recruitment. could be a circle line or straight line depending on their The target subjects were aged 36 to 60. To screen eligible par- preference. The warm-up and cool-down stretching, as well ticipants, all preliminary registered subjects were evaluated as the practice frequency, were similar as Tai Chi exercise. by health consultants using professional assessment form. The actual implementations of practicing Tai Chi and walking Only inactive (no lifestyle physical activity or structured were recorded by an exercise log. For those allocated to exercise experiences for at least 6 months [24]) persons were control group, they were told that they would be provided two included. Those with cardiovascular and pulmonary diseases, sessions of free health and fitness assessment with an interval neurological disorder, asthma, hearing and visual disabilities, of three months (12 weeks). No additional exercise traning communicable diseases, and musculoskeletal disorder were was provided. excluded. 2.4. Data Collection. Individual information indluding 2.2. Sample Size and Study Power. Basedonthecluster sociodemographic characteristics (age, sex, residential randomized trial design, fixed three clusters per arm (9 area, and housing estate), medical history, and medication geographic areas/3 arms) were determined in advance. The were obtained at baseline by face-to-face interviews. planned number of participants was 360, 120 in each arm, Participants were also required to provide a 1-week diet food 40 in each cluster. Based on the conventional assumptions of frequency data, which were collected by the Food Frequency two-sided 5% significance level and assuming the intracluster Questionnaire (FFQ). Dietary nutrients (energy, protein, correlation was 0.01, according to the formula for fixed and total fat) were then calculated. The MetSyn parameters number of clusters each of fixed size by Donner and Klar include waist circumference, blood pressure (BP), FBG, total [25, 26], we would have 80% power to detect a difference of cholesterol, HDL-C, LDL-C, and triglycerides [2]. These 2 0.6 ± 1.1 kg in body weight, 11.4 ± 20.0 mg/cm in BMD, data, together with the dietary intake information and BMD, 3.5 ± 5.0 cm in waist circumference, 1.2 ± 2.0 mm Hg in were collected twice: at baseline and upon completion of the systolic blood pressure (SBP), 0.20 ± 0.35 mmol/L in fasting 12-week program. The independent assessors who collected blood glucose (FBG), 0.10 ± 0.17 mmol/L in total cholesterol, outcome data were unaware of the assigned intervention Evidence-Based Complementary and Alternative Medicine 3 until the end of the trial. An external private clinic was a modified hexokinase enzymatic method (7020 clinical delegated to analyze the blood samples. All staffs in this analyzer, Hitachi, Tokyo, Japan). clinic did not know the assigned intervention. 2.5. Statistical Analysis. Statistical analysis was performed 2.4.1. Measurement of Anthropometrics and BP. Weight, by SPSS 20.0 (SPSS Institute) software. Data were analyzed height, and waist circumference were measured to the nearest according to an intention-to-treat (ITT) principle. All par- 0.1kilogramorcentimeterbasedonastandardprotocol.BMI ticipants who attended baseline assessment were involved 2 was then calculated (BMI = weight (kg)/height (m )). All in the ITT. Baseline differences between three groups were measurements were conducted twice by the trained research compared by one-way ANOVA and Pearson chi-square test assistant; the average value was used. Waist circumference for continuous and categorical variables, respectively. Post was measured by a standardized Gulick tape. To avoid the hoc procedures were further conducted for the pairwise contraction of abdominal muscles, the measurement was comparison. One-way analysis of covariance (ANCOVA)was recorded after the participant exhaled gently in normal used to compare the mean changes of outcomes from baseline breathing. The measurement position was at a level midway to after intervention (12-week) between three groups. To between the lower rib margin and the iliac crest. Obesity compare the between-group differences in mean change from 2 and central obesity were defined as BMI ≥ 25 kg/m and baseline to 12-week, repeated measures of ANCOVA were waist circumference ≥ 80 cm for women and ≥ 90 cm for implemented. The time × group interaction effects between men, respectively [27]. BP was measured to the nearest intervention group and control group, as well as between 0.1 millimeter of mercury (mm Hg). A corrected mercury the two intervention groups, were examined. The variables sphygmomanometer and an appropriately sized cuff were that were significantly different between groups at baseline used. Measurements were taken after at least ten minutes were adjusted as covariates in the ANCOVAmodels. Bivariate ofseatedrest.Themeanoftwotimesmeasurementswas correlations between main outcomes at baseline, as well as computed. Participants who were currently taking antihyper- theintentionalweight(andbodymass)loss,andchangesin tensionmedicinewereaskedtonottakeitbeforecoming BMD and MetSyn parameters at 12 weeks were examined by to the laboratory for body measurements. Hypertension was Spearman’s correlation test. 𝑃 value < 0.05 was considered as defined as either a SBP of ≥ 140 mm Hg or a diastolic blood statistically significant. pressure (DBP) of ≥ 90 mm Hg [28]. 3. Results 2.4.2. Measurement of Body Mass and Bone Mineral Density. Body mass and BMD were measured by Hologic QDR-2000 A total of 398 subjects from 9 locations were successfully dual-energy X-ray densitometer (Hologic, Bedford, MA, US) enrolled in the study. 24 subjects (3 in the Tai Chi group, at baseline and 12 weeks. The machine provides values for 2 in the walking group, and 19 in the control group) lean mass, fat mass, BMD, and total body water assuming quit after randomization because they were unwilling to that water constitutes 73.2% of lean mass. The BMD were participate in the allocated group. Finally 374 subjects measured at the hip (femoral neck, intertrochanteric area, attended baseline assessment. Detailed study flow and inter- and the total hip), the spine (L1–L4), and the total body. vention allocating were indicated in the Supplementary Thevaluesfromtotalbodywereusedincurrentanalysis. Figure 1 (see Supplementary Material available online at The stability of the machine and the long-term precision http://dx.doi.org/10.1155/2015/976123). The number of valid of the measurement have been identified acceptable where participants was 129, 121, and 124 in Tai Chi, walking, and the coefficient of variance (CV%) was less than 0.42% ina control group, respectively. After 12 weeks follow-up, 21 previous study using the same machine [29]. (5.6%) participants withdrew with eight in the Tai Chi group, ten in the walking group, and three in the control group. The retention rates in the three groups were all higher 2.4.3. Blood Samples and Biochemical Parameters. Overnight than 90%. No significant differences were observed in the fasting (10–12 h) venous blood samples were obtained at 8–10 baseline characteristics between participants who completed am for the measurement of glucose and lipid concentrations. theentirestudyandthosewhowerelosttofollow-up(all Blood withdrawal was conducted by professional nurses. 𝑃 > 0.05). Participants who had acute inflammation or taking anti- inflammation drugs (i.e., aspirin or antibiotics) at the time of completing 12-week program were required to postpone 3.1. Baseline Characteristics. The mean age of participants 1 week for blood withdrawal. The blood samples were cen- inTaiChi,walking,andcotrolgroupswas45.9 ± 5.2, ∘ trifuged at 3000 ×g for 15 min under condition of 4 C. The 46.6 ± 4.9,and44.9 ± 5.6 years, respectively. The difference serum was isolated within 2 h after collection and divided was statistically significant𝑃 ( = 0.034). Other baseline ∘ into several aliquots and stored at −85 Cuntilanalysis. characteristics are shown in Table 1. No significant differences Serum was measured by enzymatic methods and serum ACE were observed among the three groups in terms of age and (Gcell, Beijing Strong Biotechnologies, Inc.) by colorimetric gender proportions, dietary intake, proportions of obesity, assay. The FBG, total cholesterol, high-density lipoprotein andhypertension(all𝑃 > 0.05). Nevertheless, the proportion cholesterol (HDL-C), and triglycerides were measured with of central adiposity was higher in Tai Chi and walking groups 4 Evidence-Based Complementary and Alternative Medicine

Table 1: Baseline characteristics of participants and comparisons among groups.

Tai Chi group Walking group Control group 𝑃 valuea Geographic areas (𝑛)333 Participants (𝑛)129121124 Age group, 𝑛 (%) 0.068 36–40 18 (14.0) 14 (11.6) 30 (24.2) 41–50 89 (69.0) 82 (67.8) 71 (57.3) 51–60 22 (17.1) 25 (20.7) 23 (18.5) Gender, 𝑛 (%) 0.863 Female 77 (59.4) 75 (62.0) 78 (62.9) Male 52 (40.3) 46 (38.0) 46 (37.1) Dietary intake Energy, kCal/day, mean (SD) 2094.9 (838.8) 2159.4 (1135.1) 2216.2 (898.6) 0.608 Protein, g/day, mean (SD) 93.7 (20.4) 100.4 (28.1) 88.1 (38.7) 0.494 Fat, g/day, mean (SD) 88.5 (25.5) 84.6 (29.1) 85.9 (25.1) 0.909 Obesity, BMI ≥ 25 kg/m2, 𝑛 (%) 0.446 Yes 41 (31.8) 32 (26.4) 31 (25.0) No 88 (68.2) 89 (73.6) 93 (75.0) Central adiposity, waist circumference ≥ 80 cm, 𝑛 (%) 0.004 Yes 44 (34.1) 42 (34.7) 22 (17.7) No 85 (65.9) 79 (65.3) 102 (82.3) Hypertension, 𝑛 (%) 0.180 Yes 13 (10.1) 20 (16.5) 12 (9.7) No 116 (89.9) 101 (83.5) 112 (90.3) Metabolic syndrome, 𝑛 (%)b 0.662 Yes 16 (12.4) 13 (10.7) 11 (8.9) No 113 (87.6) 108 (89.3) 113 (91.1) Presence of any 1 of 5 risk factors of metabolic syndrome, 𝑛 (%) 0.064 Yes 83 (64.3) 72 (59.5) 62 (50.0) No 46 (35.7) 49 (40.5) 62 (50.0) Presence of any 2 of 5 risk factors of metabolic syndrome, 𝑛 (%) 0.142 Yes 44 (34.1) 30 (24.8) 30 (24.2) No 85 (65.9) 91 (75.2) 94 (75.8) a𝑃 values generated from one-way ANOVA or Pearson chi-square test where appropriate. bThe presence of any 3 of 5 risk factors constitutes a diagnosis of metabolic syndrome: (1) central adiposity; (2) triglycerides ≥ 1.7 mmol/L; (3) high-density lipoprotein cholesterol < 1.0 mmol/L in males; <1.3 mmol/L in females; (4) systolic BP ≥ 130 and/or diastolic BP ≥ 85 mm Hg; (5) blood fasting glucose ≥ 100 mg/dL.

than in the control group (34.1%, 34.7%, and 17.7%, 𝑃= From baseline to 12 weeks, on average, Tai Chi and 0.004). walking groups significantly lost 0.50 and 0.76 kg of body weight and 0.47 and 0.59 kg of fat mass, respectively (all 3.2. Intervention Effects on Weight Loss, MetSyn Parameters, 𝑃 < 0.01, Table 2). The between-group difference of weight and BMD. Table 2 shows the values of all outcomes from loss was −0.60 kg for Tai Chi versus control (95% confidence baslineto12weeks,aswellasthemeanchangesbetween interval (CI): −0.94 to −0.25) and −0.85 kg for walking versus the two time meaures; Table 3 shows the pairwise compar- control (95% CI: −1.20 to −0.50) (both 𝑃 < 0.001, Table 3). isons of between-group difference at 12 weeks. At baseline, NosignificantchangesofleanmassandBMDinboth participants in the Tai Chi and walking groups were more intervention groups and control group were observed (all likely to have larger waist circumferences and higher FBG 𝑃 > 0.05). than those in the control group (all 𝑃 < 0.01, Table 2). Participants in two intervention groups also had signifi- Age, baseline waist circumference, baseline fasting glucose, cantly greater decreases in waist circumference and FBG than and HDL-C were adjusted as covariates in corresponding those in the control group (Table 2). The mean decrease of ANCOVA models because of their imbalance among groups waist circumference was 3.3 cm in both intervention groups at baseline. The dietary intake was not significantly different (95% CI: −3.9 to −2.6 for Tai Chi group and −4.5 to −2.9 for between three groups at 12 weeks (𝑃 > 0.05,datanotshown). walking group). The between-group difference was −3.7 cm Evidence-Based Complementary and Alternative Medicine 5

Table 2: Changes of weight, body mass, bone mineral density, and metabolic syndrome parameters from baseline to 12 weeks in each group.

Measurea TaiChigroup(𝑛 = 129)Walkinggroup(𝑛 = 121)Controlgroup(𝑛 = 124) 𝑃 valueb Weight (kg) Baseline 61.1 (11.2) 61.1 (11.0) 59.9 (11.0) 0.661 12-week 60.6 (11.0) 60.3 (10.8) 60.0 (11.0) 0.933 Mean change from baseline −0.50 (−0.80 to −0.21) −0.76 (−0.97 to −0.55) 0.1 (−0.12 to 0.31) <0.001 Total body fat mass (kg) Baseline 18.6 (49.8) 18.8 (52.8) 18.1 (60.9) 0.580 12-week 18.1 (51.9) 18.2 (49.7) 18.2 (60.7) 0.980 Mean change from baseline −0.47 (−0.79 to −0.15) −0.59 (−0.92 to −0.26) 0.09 (−0.07 to 0.26) 0.002 Total body lean mass (kg) Baseline 39.4 (90.9) 39.5 (92.1) 39.2 (85.3) 0.968 12-week 39.4 (92.4) 39.3 (92.5) 39.1 (86.1) 0.987 Mean change from baseline −0.03 (−1.01 to 0.96) −0.11 (−0.64 to 0.42) −0.10 (−0.24 to 0.04) 0.714 Waist circumference (cm) ∗∗ ∗∗ Baseline 80.9 (8.8) 81.1 (9.4) 76.1 (9.8) <0.001 12-week 77.7 (9.1) 77.4 (9.6) 76.5 (9.8) 0.585 Mean change from baseline −3.3 (−3.9 to −2.6) −3.3 (−4.5 to −2.9) 0.4 (−0.0 to 0.8) <0.001 Systolic blood pressure (mm Hg) Baseline 114.8 (15.4) 112.9 (16.0) 113.3 (14.3) 0.561 12-week 112.3 (14.6) 110.4 (14.3) 112.0 (13.9) 0.560 Mean change from baseline −2.6 (−4.3 to −0.8) −2.4 (−4.2 to −0.7) −1.4 (−3.0 to 0.2) 0.509 Diastolic blood pressure (mm Hg) Baseline 74.4 (11.7) 74.9 (13.2) 75.3 (11.0) 0.929 12-week 72.9 (11.5) 71.7 (12.9) 72.3 (11.9) 0.704 Mean change from baseline −1.8 (−3.2 to −0.3) −3.2 (−4.7 to −1.7) −2.9 (−4.4 to −1.5) 0.397 Fasting blood glucose (mmol/L) ∗∗ ∗∗ Baseline 4.8 (0.5) 4.8 (0.4) 4.5 (0.4) <0.001 12-week 4.6 (0.5) 4.6 (0.5) 4.5 (0.5) 0.355 Mean change from baseline −0.17 (−0.22 to −0.11) −0.21 (−0.28 to −0.14) 0.01 (−0.06 to 0.09) <0.001 Total cholesterol (mmol/L) Baseline 5.1 (0.9) 5.1 (0.9) 5.0 (0.9) 0.363 12-week 5.1 (1.0) 4.9 (0.9) 4.8 (0.8) 0.064 Mean change from baseline −0.07 (−0.16 to 0.03) −0.13 (−0.23 to −0.03) −0.18 (−0.27 to −0.09) 0.235 HDL-C (mmol/L) ∗ Baseline 1.5 (0.4) 1.7 (0.5) 1.5 (0.4) 0.035 12-week 1.5 (0.4) 1.6 (0.5) 1.4 (0.4) 0.033 Mean change from baseline −0.03 (−0.08 to 0.03) −0.09 (−0.14 to −0.05) −0.10 (−0.15 to −0.06) 0.087 LDL-C (mmol/L) Baseline 3.0 (0.8) 2.9 (0.8) 2.9 (0.8) 0.645 12-week 3.0 (0.9) 2.9 (0.8) 2.9 (0.7) 0.528 Mean change from baseline −0.01 (−0.11 to 0.09) −0.03 (−0.11 to 0.06) −0.03 (−0.12 to 0.06) 0.932 Triglycerides (mmol/L) Baseline 1.4 (1.0) 1.2 (0.7) 1.3 (1.0) 0.121 12-week 1.4 (0.9) 1.1 (0.6) 1.2 (0.9) 0.017 Mean change from baseline 0.01 (−0.08 to 0.09) −0.05 (−0.13 to 0.03) −0.10 (−0.20 to 0.00) 0.204 Bone mineral density (mg/cm2) Baseline 1037.3 (79.6) 1039.3 (85.0) 1034.1 (82.3) 0.887 12-week 1036.9 (79.1) 1037.6 (85.0) 1033.8 (83.5) 0.930 Mean change from baseline −0.39 (−6.57 to 5.80) −1.65 (−5.16 to 1.85) −0.33 (−2.43 to 1.78) 0.480 HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol. aValues were presented as mean (SD) for 12-week measurement and mean (95% CI) for mean change from baseline; mean change from baseline = 12-week evaluation − baseline evaluation. bOne-way ANOVA was used to compare the mean difference at baseline and at 12 weeks between groups; univariate ANCOVA was used to compare the mean change difference between groups; variables with significant different between groups at baseline were adjusted as covariates. ∗ Post hoc comparison was used; differences are significant (𝑃 < 0.05) between intervention and control group. ∗∗ Post hoc comparison was used; differences are significant (𝑃 < 0.01) between intervention and control group. 6 Evidence-Based Complementary and Alternative Medicine

Table 3: Between-group differences of body weight, body mass, metabolic syndrome parameters, and bone mineral density after intervention.

Tai Chi versus controla Walking versus control a Tai Chi versus walkinga Measure Between-group 𝑃 value Between-group 𝑃 value Between-group 𝑃 value difference (95% CI) difference (95% CI) difference (95% CI) Weight (kg) −0.60 (−0.94 to −0.25) 0.008 −0.85 (−1.20 to −0.50) <0.001 0.26 (−0.09 to 0.60) 0.164 Total body fat mass (kg) −0.56 (−0.96 to −0.17) 0.004 −0.68 (−1.08 to −0.28) <0.001 0.12 (−0.28 to 0.51) 0.353 Total body lean mass (kg) 0.08 (−0.86 to 1.01) 0.926 −0.01 (−0.96 to 0.94) 0.858 0.08 (−0.85 to 1.02) 0.878 Waist circumference (cm) −3.7 (−4.4 to −2.9) <0.001 −4.1 (−5.0 to −3.2) <0.001 0.5 (−0.6 to 1.5) 0.489 Systolic blood pressure (mm Hg) −1.2 (−3.6to1.1) 0.311 −1.1 (−3.5 to 1.3) 0.283 0.4 (−0.5 to 1.3) 0.824 Diastolic blood pressure (mm Hg) 1.2 (−0.9 to 3.2) 0.568 −0.3 (−2.4to1.8) 0.340 1.4 (−0.7 to 3.5) 0.201 Fasting blood glucose (mmol/L) −0.18 (−0.27 to −0.09) <0.001 −0.22 (−0.31 to −0.13) <0.001 0.04 (−0.05 to 0.13) 0.366 Total cholesterol (mmol/L) 0.11 (−0.02 to 0.24) 0.095 0.05 (−0.09 to 0.18) 0.269 0.06 (−0.07 to 0.20) 0.453 HDL-C (mmol/L) 0.07 (0.01 to 0.14) 0.330 0.01 (−0.06 to 0.08) 0.705 0.06 (−0.004 to 0.13) 0.060 LDL-C (mmol/L) 0.02 (−0.11 to 0.15) 0.850 0.002 (−0.13 to 0.14) 0.882 0.02 (−0.11 to 0.15) 0.708 Triglycerides (mmol/L) 0.10 (−0.02 to 0.23) 0.085 0.05 (−0.17 to 0.08) 0.693 0.06 (−0.06 to 0.18) 0.265 Bone mineral density (mg/cm2) −0.06 (−6.16 to 6.03) 0.477 1.33 (−7.52 to 4.86) 0.295 1.27 (−4.85 to 7.39) 0.573 HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol. a𝑃 values were calculated for the time × group interaction effects from baseline to 3 months between groups by repeated ANCOVA; variables with significantly different between groups at baseline were adjusted as covariates.

Table 4: Correlation coefficients of weight loss, fat mass, lean mass, waist circumference with BMD, and metabolic syndrome parametersa.

Δ BMD Δ waist circumference Δ SBP Δ DBP Δ FBG Δ TC Δ HDL-C Δ LDL-C Δ triglycerides ∗∗ ∗ ∗∗ Weight loss (Δ body weight) −0.05 0.38 0.13 0.04 0.03 0.09 −0.01 0.05 0.20 ∗∗ ∗ ∗ Δ fat mass 0.05 0.19 0.03 0.06 0.07 0.12 0.05 0.11 0.04 ∗∗ Δ lean mass 0.41 0.09 −0.08 −0.06 −0.01 −0.02 −0.05 −0.04 0.05 ∗∗ ∗∗ Δ waist circumference 0.01 1.00 0.15 0.03 0.23 0.00 0.00 0.00 0.01 BMD: bone mineral density; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting blood glucose; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol. aCorrelation analyses were conducted between pre-post differencesΔ ( ) of body weight, fat mass, lean mass, waist circumference and pre-post differencesΔ ( ) of bone mineral density (BMD) and other metabolic syndrome parameters. Analysis only included cases in Tai Chi and walking groups. Pre-Post difference (Δ) = post value − pre value. ∗∗ Correlation is significant at the 0.01 level (2-tailed). ∗ Correlation is significant at the 0.05 level (2-tailed). for Tai Chi versus control (95% CI: −4.4 to −2.9) and −4.1 cm we compared the effects between two intervention groups, all for walking versus control (95% CI: −5.0 to −3.2) (both outcomes showed no significant differences at 12 weeks (all 𝑃 < 0.001, Table 3). For FBG, participants in the Tai Chi 𝑃 > 0.05, Table 3). Figure 1 showsthechangesinbodyweight, and walking groups had a mean decrease of 0.17 mmol/L fat mass, waist circumference, and FBG in three groups by (95% CI: −0.22 to −0.11) and 0.21 mmol/L (95% CI: −0.28 to male and female seperately. Females had significantly higher −0.14), respectively (Table 2). It showed significant reductions reductioninwaistcircumferncethanmalesafterintervention than the control group (0.01 mmol/L, 95% CI: −0.06 to (𝑃 < 0.05). 0.09, 𝑃 < 0.001). The mean between-group difference was −0.18 mmol/L for Tai Chi versus control (95% CI: −0.27 to 3.3. Relationships of Weight Loss with BMD and MetSyn −0.09) and −0.22 mmol/L for walking versus control (95% CI: Parameters. The correlation coefficients between changes −0.31 to −0.13) (both 𝑃 < 0.001, Table 3). The BP also showed in body weight, fat mass, lean mass, waist circumference, notablereductionsinbothinterventiongroups.ForSBP, BMD, and other MetSyn parameters at 12 weeks in the two mean change was −2.6 mm Hg and −2.4 mm Hg for Tai Chi intervention groups were shown in Table 4.Lossinbody and walking groups, respectively. However, the changes were weight and fat mass both positively correlated with the not significantly different when compared with control (both decrease in waist circumference (𝑟 = 0.38 and 0.19, resp., 𝑃 > 0.05, Table 2). The mean between-group differences both 𝑃 < 0.01); the changes in waist circumference also were also small and not significant (all 𝑃 > 0.05). Similar correlated with the changes in SBP and FBG (𝑟 = 0.15 and situation was found in DBP.For all other outcomes, including 0.23, both 𝑃 < 0.05). For the BMD, however, only the changes total cholesterol, HDL-C, LDL-C, and triglycerides, both Tai in lean mass showed significant correlation with it𝑟 ( = 0.41, Chi and walking training showed no significant effects when 𝑃 < 0.01). Correlation analysis of these outcomes at baseline compared with control (all 𝑃 > 0.05,Tables2 and 3). When showed similar results (in all participants, data not shown). Evidence-Based Complementary and Alternative Medicine 7

0.60 0.60

0.40 0.40

% CI 0.20 0.20 % CI 95 95 0.00 0.00

−0.20 −0.20

−0.40 −0.40

−0.60 −0.60

−0.80 −0.80

−1.00 −1.00

−1.20 mass (kg) with of fat difference Mean

Mean difference of body weight (kg) with of weight body difference Mean −1.20

−1.40 −1.40

Tai Chi Walking Control Tai Chi Walking Control Groups Groups

2.00 0.20 % CI 95

% CI 1.00 95 0.10

0.00 0.00 −1.00

−0.10 −2.00

−3.00 −0.20

−4.00 −0.30 −5.00 −0.40 Mean difference of waist circumference (cm) with circumference of waist difference Mean

−6.00 blood of fasting with (mmol/L) glucose difference Mean Tai Chi Walking Control Tai Chi Walking Control Groups Groups

Gender Gender Female Female Male Male

Figure 1: Mean differences of body weight, total fat mass, waist circumference, and fasting blood glucose from baseline to 12 weeks bymale and female in three groups.

4. Discussion interventions showed no apparent effect on BMD. Further- more, we found that BMD only correlated with the lean mass; Results from this exploratory study provide novel informa- the exercise-induced weight loss, particular loss in fat mass, tion about the effects of 12-week Tai Chi and brisk walking had no significant associations with the changes in BMD. trainings on weight loss, BMD, and MetSyn parameters in TheeffectofTaiChionweightlossisinconsistentin middle-aged Hong Kong adults. We found that these two the literature. A study [30] conducted in postmenopausal moderate-intensity, short-term PA programs both slightly women showed that the body weight and fat mass in reducedthebodyweightandfatmassandhadsignificant dynapenic women reduced 1.5 kg and 1.1 kg, respectively, improvements on waist circumference and FBG. These two whereasnochangewasfoundinnondynapenicwomen. 8 Evidence-Based Complementary and Alternative Medicine

Another study among transitionally frail older adults showed cluster RCT led to imbalance in some variables. Participants ameandecreaseof1.49kginbodyweightafter48weeks inthecontrolgroupseemedtohavebetterwaistcircumfer- training of Tai Chi [31]. Compared with these studies, our 12- ence and FGB than those in intervention groups at baseline. week trial obtained a smaller but still significant reduction in However, we suggest that the improvement effects in these body weight and fat mass. However, some previous studies two variables are unlikely due to worse shape in intervention conducted in elderly Chinese subjects [32]andinoldwomen groups, because the significant within-group improvement with osteoarthritis [33]showednosignificantchangeinbody was also observed. Nevertheless, the effect sizes might be weight/BMI. These heterogeneous findings indicate that the slightly overestimated. Second, double-blind study design training time, the frequency, and duration of exercise, as was not available due to the difficulty of administration and well as the target population, are all important in detecting operation. Participants in the intervention groups might have significant clinically relevant effect. higher expectations of the treatment results. This awareness Exercise is a well-known lifestyle description for manag- of intervention assignments might introduce some bias into ing type 2 diabetes or impaired glucose tolerance. However, the results. Third, 12 weeks of intervention may not be long whether Tai Chi has any benefit on glucose control is enough to observe significant improvement on certain health conflicted in the literature [34]. Some studies have shown outcomes; thus, a longer-term follow-up study is suggested. their benefits on blood glucose in diabetic patients35 [ , 36], In summary, our study was the first to comprehensively whereas other studies demonstrated limited effect or no effect examine the effects of a type of mind-body exercise and a [22, 32, 37]. Of note, all these studies had relatively small simple physical exercise on the MetSyn parameters, weight sample size or non-RCT design. Our study provides evidence loss, and BMD with a certain large sample size and using that Tai Chi and walking can both significantly decrease a cluster RCT design. We found that these two exercise FBG in adults. Regarding total cholesterol, HDL-C, LDL- interventions moderately reduced the body weight and fat C, and triglycerides, no significant changes were observed mass and improved the waist circumference and FBG, and in the study. For the BP, an apparent within-group pre- theexercise-inducedweightlossdidnotimpacttheBMD.We postchange was found in Tai Chi and walking participants, suggestthatTaiChiandwalkingarebothfeasibleandpromis- but this effect was limited because no significant difference ing daily moderate PA for middle-aged adults. Findings from was observed compared to control. Evidence has shown this study provide referable information for current public that reductions in BP appear to be more pronounced in health initiatives to health aging and future community- hypertensive subjects [38–40]. Smaller effect size observed in based moderate PA and lifestyle intervention programs. ourstudymaybeduetothefactthatmostparticipantswere normotensive subjects. Whether Tai Chi or walking can serve Ethics Approval as the nonpharmacologic adjuncts to prevent hypertension may need long-term observation. The study protocol was approved by the Joint Chinese No significant change in BMD was observed in our University of Hong Kong-New Territories East Cluster Clin- study. A study in Hong Kong elderly people indicated that ical Research Ethics Committee. All participants returned a short-term Tai Chi exercise (e.g., 12 weeks) may not provide signed statement of informed consent. sufficient training stimulation in improving bone health [41]. Other studies concluded that Tai Chi can act as a protective factor for bone loss in old women [42, 43]. Similar debates Conflict of Interests exist in walking [14, 15, 44, 45]. It may need a more definitive, Alltheauthorshavedeclarednocompetinginterests. long-term trial to examine whether Tai Chi or walking have protective effect on bone loss. In our study, we further identified that the moderate exercise-induced weight loss Authors’ Contribution had no significant association with reductions in BMD; it is comparable to a previous study [16]. This study also found no Stanley Sai-Chuen Hui, Jean Woo, and Timothy Chi-Yui impact of exercise-induced weight loss on BMD when simi- Kwok designed the study. Stanley Sai-Chuen Hui carried larly the caloric intake was kept stable for the exercise group. out the experiments. Yao Jie Xie and Stanley Sai-Chuen Hui Furthermore, we found that only the change in lean mass analyzedthedataandwrotethepaper.Allauthorsreviewed was associated with the change in BMD; the reduction in fat the paper. mass did not influence the BMD. The finding was consistent with previous studies [18]. On the other hand, we found a Acknowledgment significant decrease in waist circumference; it was positively correlated with the reductions in body weight and fat mass. This study was entirely supported by the Health and Health All these findings imply that Tai Chi and walking exercises Service Research Fund (HHSRF) from the Food and Health maybothbesuitablefordesigningweightlosstherapypro- Bureau, Hong Kong (HHSRF 02030511). gram or obesity management program in middle-aged adults, becausetheyhavenoadditionaladverseeffectonBMDand References canreducefatmassandimprovewaistcircumference. Our study presents several limitations. First, predeter- [1] M. Ng, T. Fleming, M. Robinson et al., “Global, regional, and mined number of clusters per arm (9 clusters/3 arms) in our national prevalence of overweight and obesity in children and Evidence-Based Complementary and Alternative Medicine 9

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Whitworth, “2003 World Health Organization andW.M.Kohrt,“Protectionofbonemassbyestrogensand (WHO)/International Society of Hypertension (ISH) statement raloxifene during exercise-induced weight loss,” The Journal of on management of hypertension,” Journal of Hypertension,vol. Clinical Endocrinology and Metabolism,vol.90,no.1,pp.52–59, 21, no. 11, pp. 1983–1992, 2003. 2005. [29]M.Li,E.M.C.Lau,andJ.Woo,“Methylenetetrahydrofolate [14] A. Gomez-Cabello,´ I. Ara, A. Gonzalez-Ag´ uero,J.A.Casaj¨ us,´ reductase polymorphism (MTHFR C677T) and bone mineral and G. Vicente-Rodr´ıguez, “Effects of training on bone mass in density in Chinese men and women,” Bone,vol.35,no.6,pp. older adults: a systematic review,” Sports Medicine,vol.42,no. 1369–1374, 2004. 4, pp. 301–325, 2012. [30] S. Barbat-Artigas, M.-E. Filion, S. Dupontgand, A. D. Karelis, [15]A.Guadalupe-Grau,T.Fuentes,B.Guerra,andJ.A.L.Calbet, and M. Aubertin-Leheudre, “Effects of tai chi training in “Exercise and bone mass in adults,” Sports Medicine,vol.39,no. dynapenic and nondynapenic postmenopausal women,” 6, pp. 439–468, 2009. Menopause, vol. 18, no. 9, pp. 974–979, 2011. [16] D. T. Villareal, L. Fontana, E. P. Weiss et al., “Bone mineral [31] S. L. Wolf, M. O’Grady, K. A. Easley, Y. Guo, R. W. Kressig, density response to caloric restriction-induced weight loss or and M. Kutner, “The influence of intense Tai Chi training on 10 Evidence-Based Complementary and Alternative Medicine

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Review Article A Systematic and Narrative Review of Acupuncture Point Application Therapies in the Treatment of Allergic Rhinitis and Asthma during Dog Days

Cai-Yu-Zhu Wen,1 Ya-Fei Liu,2 Li Zhou,3 Hong-Xing Zhang,3 and Sheng-Hao Tu4

1 Hubei University of Chinese Medicine, No. 1 Huangjiahu West Road, Wuhan, Hubei 430065, China 2Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, Henan 450052, China 3Department of Acupuncture and Moxibustion, Wuhan Integrated TCM and Western Medicine Hospital, Hubei University of Chinese Medicine, No. 215 Zhongshan Avenue, Wuhan, Hubei 430022, China 4Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China

Correspondence should be addressed to Hong-Xing Zhang; [email protected] and Sheng-Hao Tu; [email protected]

Received 2 July 2015; Revised 25 August 2015; Accepted 26 August 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Cai-Yu-Zhu Wen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acupuncture point application therapies, including San-Fu-Tie and San-Fu-Jiu, have been widely employed to treat diseases with attacks in winter during dog days in China. The therapies combine Chinese herbal medicine and acupuncture points with the nature. However, the previous studies were reported to be unsystematic and incomplete. To develop a more comprehensive understanding of the effects of acupuncture point application therapies on allergic rhinitis and asthma, a systematic review of the literature up to 2015 was conducted. After filtering, eighteen randomizedntrolled co trials (RCTs) involving 1,785 subjects were included. This systematic and narrative review shows that acupuncture point application therapies have been extensively applied inthe treatment of allergic rhinitis and asthma with advantages of favorable treatment effect, convenient operation, receiving patients’ good acceptability and compliance, and few side effects. Meanwhile, the study elaborated the operating process of San-Fu-Tie and San-Fu-Jiu in detail. The review may provide a reference for clinical application in future. However, the efficacy, safety, and mechanisms of San-Fu-Tie and San-Fu-Jiu in treating the above diseases need to be validated by more well-designed and fully powered RCTs in a larger population of patients.

1. Introduction The therapies are predominantly comprised of San-Fu- Tie and San-Fu-Jiu. The former applies special Chinese herbal Acupuncture point application therapies, combining Chinese medicine paste to the acupuncture points [2]. The basic herbal medicine and acupuncture points during dog days, herbal prescription of San-Fu-Tie is usually composed of Bai have been extensively applied for a long time in the treatment Jie Zi (Semen Sinapis Albae), Xi Xin (Herba Asari), Gan Sui of allergic rhinitis (AR) and asthma [1]. Dog days are usually (Radix Kansui), and Yan Hu Suo (Rhizowa Corydalis)[1]. the three ten-day periods of the hottest season. They are Based on the theory of syndrome differentiation of traditional divided into “1st dog day,” “2nd dog day,” and “3rd dog day.” Chinese medicine (TCM), other herbal medicines of similar According to the lunar calendar, the period of adjacent Geng effects are allowed to be applied according to different day is ten days. The 3rd Geng day after the summer solstice diseases. The herbal medicine is processed as follows: ground is “1st dog day.” The 4th Geng day after the summer solstice into powder, mixed with ginger juice or honey, divided into and the 1st Geng day after the beginning of autumn are “2nd small cubes of 3–5 g each, and laid on the applications (Fig- dog day” and “3rd dog day,” respectively. ure 1) [3–5]. The latter is the combination of ginger-separated 2 Evidence-Based Complementary and Alternative Medicine

Figure 1: Chinese herb medicine pastes for San-Fu-Tie. Figure 3: San-Fu-Tie was applied on Dazhui (GV14), Fengmen (BL12), and Feishu (BL13).

Figure4:TheleftscarafterSan-Fu-TieorSan-Fu-Jiu.

on the herb potency and skin tolerability. There is a little warm feeling, burning sensation, or distending pain in the vicinity of acupoints during the therapy [7]. The paste should be removed immediately when patients cannot stand pain. Figure 2: San-Fu-Tie was applied on Shenshu (BL23), Yaoyangguan Moreover,trynottoscratchtheskinoftheselectedacupoints. (GV3), Mingmen (GV4), and Pishu (BL20). Theskincouldhaveleftscarsifpastedtoolong(Figure4). San-Fu-Jiu is another important therapy on the dog days. Moxa wool and fresh ginger are the main materials of San- moxibustion and acupoint application [6]. However, there is Fu-Jiu. Firstly, fresh ginger is cut into about 1.5–2.5 cm in no clear distinction between San-Fu-Tie and San-Fu-Jiu in diameter, about 0.2–0.3 cm thick slices. Secondly, ginger some hospitals, which is universally called San-Fu-Tie San- slices are pierced by acupuncture needle to form small holes Fu-Jiu. On the contrary, they are considered different in some to facilitate heat transfer. Lastly, moxa wool is molded into other hospitals. In this review, we consider that they are two moxa cones. A moxa cone of half an olive size with a diameter different therapies. of 1–1.5 cm, weighing about 2 g, is placed on the ginger The San-Fu-Tie is operated conforming to the following slice which is put on the selected acupoint and burned for steps: firstly, the acupoints are selected according to different moxibustion stimulation (Figure 5). Five to seven consecutive diseases; secondly, the prepared herbal medicine is placed moxa cones are needed to be burned on every acupuncture onto the selected acupoints; thirdly, in order to prevent paste point. Generally, the treatment lasts half an hour each time. falling off, medical adhesive tapes are needed to reinforce Warm feeling, skin redness, and local blisters are normal theapplications(Figures2and3).Adultsarealwayspasted phenomena (Figure 6) [7]. for 4–6 hours in principle. Considering the delicate skin of AR, a common chronic respiratory disorder, is charac- children, they are often pasted for less than 2 hours to avoid terized by sneezing, rhinorrhea, nasal congestion, and nasal local blisters. The duration of treatment should be dependent pruritus [8]. Although it is not life-threatening, symptoms Evidence-Based Complementary and Alternative Medicine 3

acutefebrilepatientsarebannedfromacupuncturepoint application therapies. Patients had better not take spicy or irritant foods, cold drinks, and alcohol during treatment [7]. In addition, try to keep body warm and avoid catching cold on dog days. While the effects of acupuncture point application therapies have been frequently reported in treating AR and asthma, there exist several issues. In this regard, the processes of San-Fu-Tie and San-Fu-Jiu had not been elucidated in detail. The majority of the clinical information derives from uncontrolled clinical trials or from retrospective reports, Figure 5: Moxa cones for San-Fu-Jiu. and few multicenter clinical trials have been conducted to confirm the effects of acupuncture point application therapies inthetreatmentofARandasthma.Inaddition,thescien- tific evidence validating that acupuncture point application therapies are as effective as other conventional treatments in treating AR and asthma remains to be further validated. Given these issues, it is essential to assess the pertinent studies to systematically review the potential effects and safety of acupuncture point application therapies in the treatment of AR and asthma.

2. Materials and Methods To ensure the accuracy of the systematic review, the results Figure 6: San-Fu-Jiu was being applied. were designed and reported by employing a checklist of items that was as consistent as possible with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement are bothersome and unbearable. In addition, it has a sig- [18]. nificantimpactonworkandqualityoflife,imposinga significant burden on both the families and society [9–12]. The antihistamine drugs or glucocorticoid was the common 2.1. Search Strategy. We conducted a systematic search of the agents for patients of AR [13]. The short-term effect was following databases to identify trials: PubMed, the Cochrane satisfied. However, the long-term effect was unsatisfactory Library, and Clinical Trials.gov. In addition, the literatures and recurrence rate was high [13]. Furthermore, those drugs were also collected from the Chinese databases: the CNKI may lead to medicamentous rhinitis over a long period of Database, CBM Database, Wanfang Database, and Chinese time. The studies showed that San-Fu-Tie and San-Fu-Jiu Clinical Trial Register. All of the databases were searched could reduce the rate of recurrence compared with western from their available dates of inception to the latest issue (May medicine [2]. San-Fu-Tie is applied onto the acupoints which 2015). For the English databases, free text terms were used, areassociatedwithAR.Meanwhile,San-Fu-Jiucouldbe such as “Sanfutie,” “Sanfujiu,” or “Acupuncture point appli- applied in AR patients. With the patient in the prone position, cation therapies” and “Allergic rhinitis” or “Asthma.” For the some acupuncture points on the back are chosen to put ginger Chinesedatabases,weusedfreetextterms,suchas“Sanfutie,” slices for moxibustion therapy. “Sanfujiu,” “Dong bing xia zhi,” or “Xue wei fu tie” (which are all alternative names for San-Fu-Tie or San-Fu-Jiu in Chi- Asthma is another chronic respiratory disorder in the nese) and “Guo min xing bi yan” or “Xiao chuan” (which world. It approximately affects 300 million people worldwide means allergic rhinitis and asthma in Chinese, resp.). and will influence more in the next decades [14]. Being an extensive global health issue, uncontrolled asthma is associated with work productivity loss and poor quality of life. 2.2. Inclusion and Exclusion Criteria. The focus of the review Moreover, a serious economic burden of asthma soars up in was on studies of acupuncture point application therapies recent years [15]. Despite advances in the understanding and regardless of gender and publication status. All studies were management of asthma, many patients were not available to required to fulfill the following inclusion criteria: (1) regard- antiallergic agents due to adverse effects [16]. As a comple- less of blinding or language, randomized controlled trials mentary therapy, San-Fu-Tie or San-Fu-Jiu could strengthen (RCTs) were included; (2) for the types of interventions, physique with the purpose of preventing or reducing asthma treatment with San-Fu-Tie or San-Fu-Jiu alone in RCTs was attacks and had few side effects [17]. considered; (3) acupuncture points were the same every time Despite the favorable therapeutic effect, patients with duringdogdays;(4)thesubjectsonlyreceivedtreatment damaged skin or skin allergies should be treated with cau- three times a year (treatment could be four times when dog tion. Pregnant women, active pulmonary tuberculosis, and days are four ten-day periods in some years). 4 Evidence-Based Complementary and Alternative Medicine

Records identified through database searching (n=3278)

Identification

Records screened (n=3278)

Screening

Records excluded based on title or abstract and duplication (n = 2987)

Full-text articles assessed for eligibility (n = 291)

Eligibility Not RCT (n = 119) Experimental group combined other therapies (n=73) Not during dog days (n=25) Not only three times treatments (n=19) Acupoints changed during the treatments (n=20) Review records (n=15) Not relevant (n=2) Studies included in the review (n=18)

Included

Figure 7: Process of searching for and screening studies.

Case reports, reviews, retrospective studies, open-label criterion of Schulz et al. [22]. Studies with Jadad scores of extension study, and studies without a control group were more than 3 were regarded as being of high quality. excluded. 3. Results 2.3. Data Collection and Management. The search strategy, data collection, and management were executed by two inde- 3.1. Study Selection. The process of study selection was shown pendent reviewers and when divergences existed, a third in Figure 7. According to the selection criteria defined in reviewer was encouraged to achieve consensus. In the study Materials and Methods, eighteen RCTs [17, 19, 20, 23–37] publishedbyLinetal.[19],thesubjectsofthreeTCMsyn- involving 1,785 subjects were included. Three of them [19, drome patterns were pooled. For the trials that applied a 23,24]wereaboutARandacupuncturepointapplication three-armed group design [17, 20], only two groups were therapies. Together, those studies included a total of 333 extracted while blank group was excluded. Information on participants. Fifteen RCTs [17, 20, 25–37] involving 1,452 par- population, interventions (including medicine, acupuncture ticipants were included with acupuncture point application points, and duration), outcomes, and adverse events was therapiesasinterventiontotreatasthma. indicated in the tables (Tables 1 and 2). We adopted the validated Jadad instrument to evaluate the included studies’ 3.2. Study Descriptions. The included studies were published methodological quality [21]. The items of Jadad score are as as full texts between 2008 and 2014. All of the RCTs originated follows: randomization (0–2 points); double-blinding (0–2 in China and were performed as single-center trials, while points); and description of withdrawals and dropouts (0-1 three studies were in English and excluded as one [1] was a point). Allocation concealment (0–2 points) referred to the review article and two [3, 5] were not controlled trials. Evidence-Based Complementary and Alternative Medicine 5 ;Xin 2 2 4 Jadad score Herba Ephedrae Adverse events (experimental) Not mentioned Not mentioned Not mentioned ;MaHuang, Outcomes Efficacy evaluation Efficacy evaluation, symptom rating scale Efficacy evaluation Rhizoma Pinelliae guan;LI4,Hegu;ST36,Zusanli. ;BanXia, Rhizome Zingiberis Recens dipropionate aqueous nasal spray, for ten consecutive days nasal spray, for four weeks and dexamethasone, withdrawal when symptomatic relief occurs ;ShengJiang, Rhizoma Corydalis ;YanHuSuo, Table 1: AR and acupuncture point application therapies. Radix Kansui Experimental Control San-Fu-Tie, for one yearSan-Fu-Tie, four times a year (dogten-day days periods are in four 2013), for oneBai year Jie Zi, Xi Xin, MaSuo, Huang, Ding Cetirizine Gan Xiang, and Sui, beclometasone Sheng Yan Hu Jiang BL13, BL20, GV14, BL23, BL12, LI4,ST36, EX-B1, EX-HN15 Beclometasone dipropionate aqueous Bai Jie Zi, Xi Xin, GanGV14, Sui, BL20, Yan CV17, Hu BL12, Suo, BL13, Ban BL23 Xia San-Fu-Tie, for two-three consecutive years Oxymetazoline hydrochloride spray Bai Jie Zi, Xi Xin, MaGV14, Huang, BL13, Xin BL43, Yi, Sheng PC6 Jiang ;GanSui, . Herba Asari Flos Caryophylli ;XiXin, 40/4–7 34/4–7 47/5–55 44/8–50 84/5–82 84/5–82 Number and range of age Intervention (herbal medicine and acupoints) and duration Experimental Control ;DingXiang, Semen Sinapis Albae Flos Magnoliae Author Zhu 2010 [23] ChenandGu2011[24] Lin et al. 2014 [19] BL13, Feishu; BL43, Gaohuang; EX-HN15, Bailao; CV17, Danzhong; EX-B1, Dingchuan; GV14, Dazhui; BL20, Pishu; BL12, Fengmen; BL23, Shenshu; PC6, Nei Yi, AR, allergic rhinitis; cAMP, cyclic Adenosine Monophosphate; cGMP, cyclic Guanosine Monophosphate. Bai Jie Zi, 6 Evidence-Based Complementary and Alternative Medicine 1 2 2 2 2 2 4 4 4 4 Jadad score No No No No blisters allergies had local One patient swelling and Two patients hadmildskin Not mentioned Not mentioned Not mentioned Not mentioned Adverse events (experimental) 𝛾 Outcomes Efficacy evaluation, symptom rating scale Efficacy evaluation, the average number of cold, IgA, IgG, IgM Symptom rating scale, IL-4, IFN- Symptom rating scale, safety assessment Efficacy evaluation Symptom rating scale Symptom rating scale, IgA, IgE, IgG, IgM Symptom rating scale, safety assessment Efficacy evaluation Efficacy evaluation Oral preparation of traditional Chinese medicine, three months in one year,three for consecutive years BCG Polysaccharide and nucleic acid injection, once every other day, formonth one PBO, three times a year, forEX-B1, one BL20, year BL23, GV14, BL13 PBO, three times a year, forBL23, one GV14, year BL13, EX-B1, BL20 PBO, three times a year, forBL23, one GV14, year BL13, EX-B1, BL20 BCG polysaccharide and nucleic acid injection, twice a week, for three months Ketotifen, July to September eachthree year, consecutive for years Pulmicort, for one year Salbutamol, withdrawal when symptomatic relief occurs Yupingfeng granules, thirty days duringdays dog every year, for three consecutive years Table 2: Asthma and acupuncture point application therapies. San-Fu-Tie, for three consecutive years Bai Jie Zi, Xi Xin, GanSheng Sui, Jiang, Yan Hu Rou Suo, Gui, HuangShen, Qi, Shan Dang Yao, Gan Cao, BingBL13,EX-B1,CV17,CV22,LU1 Pian San-Fu-Tie, for one year Bai Jie Zi, Ma Huang, XiJiang Xin, Can, Sheng Feng Jiang, Mi BL13,CV17,CV22,BL17 San-Fu-Tie, for one year Bai Jie Zi, Ma Huang,EX-B1, Tan Xiang BL20, BL23, GV14, BL13 San-Fu-Tie, for one year Bai Jie Zi, Ma Huang,BL23, Tan Xiang GV14, BL13, EX-B1, BL20 San-Fu-Tie, for one year Bai Jie Zi, Ma Huang,BL23, Tan Xiang GV14, BL13, EX-B1, BL20 ExperimentalSan-Fu-Tie, for one year Bai Jie Zi, Ma Huang,EX-B1, Tan Xiang BL20, BL23, GV14, BL13 Control San-Fu-Tie, for three consecutive years Bai Jie Zi, Xi Xin, YanBL13, Hu EX-B1, Suo BL20, CV4 San-Fu-Tie, for one year Bai Jie Zi, Xi Xin, GanSheng Sui, Jiang, Wu Su Zhu Zi, Yu, SheBL13, Xiang BL12, BL43 San-Fu-Tie, for one year Bai Jie Zi, Xi Xin, GanSheng Sui, Jiang, Yan Ma Hu Huang, Suo, Ban Xia BL13,CV17,CV22,LU1,GV14,BL17, EX-HN15, BL12 San-Fu-Tie, for three consecutive years Bai Jie Zi, Xi Xin, GanHuang Sui, Qi Sheng Jiang, BL12, BL13, EX-B1, BL20, CV4, BL23 28/2–14 28/2–14 60/3–14 60/3–14 60/3–14 60/3–14 60/3–14 60/3–14 40/2–12 40/2–12 50/3–80 30/5–81 91/18–65 55/18–65 30/3–8.2 30/3.2–8.5 36/18–65 36/19–63 30/18–70 30/18–70 Number and range of age Intervention (herbal medicine and acupoints) and duration Experimental Control Author Cai 2008 [17] Mou et al. 2009 [25] Cai et al. 2010 [26] Li and Yuan 2010 [27] Zhang 2010 [28] Tao 2012 [29] Cui 2012 [20] Li 2012 [30] Zhu and Chen 2012 [31] You et al.[32] 2012 Evidence-Based Complementary and Alternative Medicine 7 ; ;Tan 5 2 2 2 2 Jadad score Herba Ephedrae Borneolum Syntheticum Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Adverse events (experimental) ;MaHuang, ;BingPian, 𝛾 ,FVC, ,PEF, /FVC, 1 1 1 Rhizoma Pinelliae guan;LI4,Hegu;ST36,Zusanli;CV22,Tiantu;LU1, Outcomes Symptom rating scale, IL-4, IFN- Efficacy evaluation, IgA, IgE, IgG, IgM Efficacy evaluation Attack frequency, FEV Efficacy evaluation, FEV PEFR FVC, FEV EOS PLT, blood platelet. Radix Glycyrrhizae . ;BanXia, ;GanCao, Radix Saposhnikoviae Rhizoma Dioscoreae Rhizome Zingiberis Recens ;FangFeng, ;ShanYao, Moschus ;ShengJiang, BCG polysaccharide and nucleic acid injection, twice a week, for three months PBO, three times a year, forBL13, one BL15, year BL17 Yupingfeng granules, for thirty daysdog during days, for one year Acupuncture therapy, thirty days during dog days every year, for three consecutiveBL13, years BL20, GV14, BL23, CV22, BL12 Salmeterol xinafoate and fluticasone propionate powder for inhalation, for one year ;SheXiang, Radix Codonopsis Table 2: Continued. , Forced Expiratory Volume in One Second; FVC, Forced Vital Capacity; PEFR, Peak Expiratory Flow Rate; PEF, Peak 1 Rhizoma Corydalis ;DangShen, Fructus Perillae ;YanHuSuo, ;SuZi, ;PBO,placebo;FEV 𝛾 Radix Astragali Radix Kansui Fructus Evodiae ,interferon- 𝛾 ;HuangQi, San-Fu-Tie, for one year Bai Jie Zi, Ma Huang,BL13, Tan Xiang BL20, GV14, BL23, EX-B1 San-Fu-Tie, for one year Bai Jie Zi, Xi Xin, GanSheng Sui, Jiang, Yan Fang Hu Feng, Suo, Bing Pian BL13, BL15, BL17 ExperimentalSan-Fu-Tie, for one year Bai Jie Zi, Xi Xin, GanSheng Sui, Jiang, Yan Su Hu Suo, Zi BL13, BL15, BL17 San-Fu-Tie, for three consecutive years Bai Jie Zi, Xi Xin, GanBL13, Sui, BL20, Wu GV14, Zhu BL23, Yu CV22, BL12 San-Fu-Tie, for one year Bai Jie Zi, Xi Xin, GanBL13, Sui, BL20, Yan GV14, Hu BL11 Suo Control ;GanSui, ;WuZhuYu, Mel Herba Asari Cortex Cinnamomi ;FengMi, ;XiXin, ´ erin; IL-4, interleukin-4; IFN- ;RouGui, 50/5–12 50/5–12 56/3–14 30/2.8–14 70/4–12 70/4–12 46/3–14 46/2.8–14 60/18–65 60/18–65 Number and range of age Intervention (herbal medicine and acupoints) and duration Experimental Control Bombyx Batryticatus Semen Sinapis Albae Lignum Santali Albi Author Chen et al. 2013 [33] Z. P. Zhang and H. Y. Zhang 2013 [34] Hu 2014 [35] Shi and Zhao 2014 [36] Chen 2014 [37] BCG, Bacillus Calmette-Gu Xiang, Jiang Can, Expiratory Flow; EOS, eosinophils; WBC, white bloodBL13, cell; NEUT, Feishu; neutrophil; LYM, BL43, lymphocyte; MONO, Gaohuang; monocyte; RBC, EX-HN15, red Bailao; blood CV17, cell; Danzhong; HGB, EX-B1, hemoglobin; Dingchuan; GV14, Dazhui; BL20, Pishu; BL12, Fengmen; BL23, Shenshu; PC6, Nei Zhongfu; BL17, Geshu; CV4, Guanyuan; BL15, Xinshu; BL11, Dazhu. Bai Jie Zi, 8 Evidence-Based Complementary and Alternative Medicine

3.3. Interventions and Controls. Four studies [26, 29, 30, 36] Yin and Yang [1, 39]. Consequently, the body’s Yang could compared San-Fu-Tie with a placebo. Eleven studies [17, 19, be improved to defense against the diseases which occur 20,23–25,27,28,31,35,37]randomizedtheparticipants in the cold days and to rebalance the Yin and Yang. With to receive San-Fu-Tie alone versus a control of western the assistance of external environment, herbs and acupoints medicine. Three trials [32–34] compared San-Fu-Tie with stimulation play a paramount role at a specific time. a control of Chinese herbal medicine or acupuncture. All San-Fu-Tie and San-Fu-Jiu are two different patterns of included studies were about San-Fu-Tie. As showed in Table 1, acupuncture point application therapies during dog days. Feishu (BL13) was frequently applied to treat AR. As indicated San-Fu-Tie is more simple and convenient to operate than inTable2,theacupuncturepointsfrequentlyselectedtotreat San-Fu-Jiu. Therefore, the former is more widespread used asthma were Feishu (BL13), Dazhui (GV14), Dingchuan (EX- for both clinical practice and clinical research. As shown B1), Shenshu (BL23), and Pishu (BL20). in Tables 1 and 2, all included studies were concerning the application of San-Fu-Tie. Two studies applying San-Fu-Jiu 3.4. Outcomes and Adverse Effects. The majority of the out- were excluded as one was applied for cervical spondylosis comes were efficacy evaluation and symptom rating scale. [40] and the other one was a review article [41]. Twelve studies [19, 23–25, 28, 31–37] did not mention adverse According to the theory of treating different diseases with effects. Four studies [17, 26, 29, 30] had no adverse effects. thesamemethodinTCM,theseacupuncturepointsapplied Two studies [20, 27] reported mild skin allergies or local forasthmaweresimilarwiththoseforAR.Infact,therelevant swelling and blisters. acupuncture points are not limited to those shown in the tables. Yingxiang (LI20), located beside the midpoint of the nasalalaandamongthenasolabialgroove,wasanimportant 3.5. Quality of the Included Studies. Compared with the six acupoint which is able to rapidly relieve the symptoms of trials [19, 26, 27, 29, 30, 36] that were of high quality, most AR. However, the majority of studies did not select Yingxiang oftheincludedtrialswereoflowquality(Jadadscore< 3) (LI20). They may take the aesthetic judgments into account. because of unclear randomization, deficient allocation con- The data of the included studies was not pooled owing cealment, inadequate blinding, and undescribed withdrawals to their different interventions (including acupuncture points and dropouts. and Chinese herb medicine), comparisons, and outcomes. Acupuncture point application therapies could be superior to 3.6. Effects of Interventions. All the included studies indicated other therapies in the treatment of AR and asthma based on that acupuncture point application therapies were more all included studies. effective and superior than various control groups regarding However,therearestillsomelimits.Firstly,allthe clinical symptoms or objective outcomes. They displayed sig- participants were recruited from Chinese populations, which nificant differences between experimental group and control implied a high risk of selection bias. Secondly, the majority of group. the studies were of poor quality. Only four studies [26, 29, 30, 36] applied an adequate blinding and three studies [19, 27, 36] 4. Discussion performed allocation concealment. Therefore, potential bias, such as that in the selection of patients, the administration Acting on the recommendation of China Association for of interventions, and assessment of outcomes, could have Acupuncture and Moxibustion and China Academy of TCM, resulted in the overestimation of the therapeutic efficacy of acupuncture point application therapies are suitable for San-Fu-Tie. Thirdly, the herbal formula, acupuncture points, chronic and refractory respiratory diseases including AR and and outcomes are too incongruous to pool them. Therefore, asthma [7]. Meanwhile, San-Fu-Tie and San-Fu-Jiu belong it is necessary for all conclusions to be carefully explained. to the transdermal drug delivery. The transdermal drug deliverycanbeabsorbedintocirculatorysystemfromthe 5. Conclusion localcapillary[38].Comparedwithoralroute,theroute of drug administration offers pharmacological advantages In summary, the narrative review elaborates the operating in decreasing the irritation of digestive tract and liver [16]. process and contraindications of San-Fu-Tie and San-Fu-Jiu Asshownintheresults,theminorityofstudiesreported indetail.ThissystematicreviewsuggeststhatSan-Fu-Tieand mild adverse effects. Consequently, San-Fu-Tie and San-Fu- San-Fu-Jiu have been widely employed in the treatment of Jiu could improve patients’ acceptability and compliance. AR and asthma characterized by favorable treatment effect, AccordingtotheTCM,YinandYangareubiquitousinthe convenient operation, and few side effects. Consequently, body and the environment. When deficiency of Yang fails to it is worth spreading and utilizing in clinic. However, the controlYin,somediseasesalwaysrecurinwinter,suchasAR outcomes of the included studies were not pooled due to their andasthma.InTCMtheory,dogdaysarethehottestperiods inconsistency. Given the low methodological quality of the which are characterized by abundant Yang, skin and muscles randomized trials, large and well-designed RCTs are needed being loose. Therefore, it is easy for body to absorb drugs to confirm our conclusions. [3, 5]. Applying herbal medicine, pungent in the taste and hot or warm in the nature onto the special acupoints, could Conflict of Interests help body absorb Yang from the environment, strengthen Yang inside the body, and maintain the functional status of The authors declare no conflict of interests. Evidence-Based Complementary and Alternative Medicine 9

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Research Article Development and Preliminary Validation of the Questionnaire (the First Edition) Based on TCM for Detecting Health Status in China

Xuan Zhou,1 Fang Xu,2 Jian Gao,3 Shan Cao,1 Ziwei Zhao,1 Mingli Heng,2 Huaien Bu,2 Liqun Yin,4 and Hongwu Wang2

1 Chinese Internal Medicine, Graduate School, Tianjin University of Traditional Chinese Medicine, Anshan West Road 312, Nankai District, Tianjin 300193, China 2Department of Public Health, Tianjin University of Traditional Chinese Medicine, Anshan West Road 312, Nankai District, Tianjin 300193, China 3School of Humanistic Management, Tianjin University of Traditional Chinese Medicine, Tianjin 300073, China 4Department of Mathematics, Tianjin University of Traditional Chinese Medicine, Anshan West Road 312, Nankai District, Tianjin 300193, China

Correspondence should be addressed to Hongwu Wang; [email protected]

Received 4 February 2015; Revised 16 June 2015; Accepted 17 June 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Xuan Zhou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. More and more people come to realize the importance of healthcare and early detecting of health status before becoming much more serious. Self-perceived health is an easy, economic, and effective indicator of health, which has been widely applied in measuring health. In this paper, the development and preliminary validation of the questionnaire (the First Edition) based on TCM theory were described and combined with Manual Mental Health Pattern for detecting health status in community of Tianjin, China. Methods. Questionnaire validity and reliability were evaluated in a small sample as a pilot study. Analyses included tests for reliability and internal consistency, exploratory factor analysis, and tests for discriminative ability and convergent validity. Results. Overall, 294 of 303 participants completed the questionnaire (97.3%). The questionnaire included 49 items. Cronbach’s 𝛼 was 0.83. Factor analysis established 10 distinct domains. The Pearson’s rho correlation between the total scores and MHP (SCL) was statistically significant (𝑟 = 0.43, 𝑃 < 0.001). t-test revealed significant differences (𝑃 < 0.05) in total scores between the healthy and unhealthy results distinguished by physical examination. Conclusions. Questionnaire reliability and validity were acceptable. Further work and larger sample would be warranted to refine items that measure the health status, to improve the reliability and discriminated validity of the questionnaire.

1. Introduction andpeople-centeredhealthcareandpromotingthesafeand effective use of T&CM through the regulation of products, With China entering the aging society, it is increasingly rec- practices, and practitioners. One of the Strategic objectives is ognized that wellness and health promotion are important, promoting universal health coverage by integrating T&CM as well as detecting health status to carry out early diagnosis and early treatment. Based on countries’ progress and current services and self-health care into national health systems [1]. new challenges in the field of traditional medicine, WHO Chinese medicine theory has its special characteristic; Traditional Medicine Strategy 2014–2023 recently set out the many researchers paid attention to explore deep-seated course for TM and CM (T&CM) in the next decade. The key theories and took it into practice, but more studies were goals of the strategy are supporting Member States in harness- concentrated in clinical treatment and drug development. ing the potential contribution of T&CM to health, wellness, The notion that prevention is better than cure was quite clear 2 Evidence-Based Complementary and Alternative Medicine in Huangdi Neijing: Yellow Emperor’s Canon of Medicine, Four mental health patterns, Relaxed (standard stress the most important ancient Chinese medicine book. It is adaptation), Energetic (stress adaptation), Fatigued (malad- more valuable that monitoring and evaluating health status justment) and Exhausted (stress disorder), were classified by beforehewasill.MoreoverWHOdefineshealthasastate usingtheStressCheckList(SCL)andQOLscores[9–11]. of complete physical, mental, and social well-being and not The Chinese version of MHP had been translated, revised, merely the absence of disease or infirmity [2, 3]. Therefore we and standardized by professor Gaojian before the test that have attempted measuring health status by Chinese medicine has been performed in more than 3000 people in Tianjin. theory [4–7]. In TCM theory, there are four diagnostic The result was satisfactory, which was also consistent with approaches that refer to inquiring, inspection, auscultation- psychometrics method [12]. The Chinese version scores of olfaction, and palpation diagnosis and are regarded as basic each item were added 4 (mostly matched), and 5 (totally in Chinese medicine. All these approaches are aimed at matched). providing objective basis for differentiation of syndromes by The figure of score divided method and classification was collecting symptoms and signs from the patient. It is believed attached in Appendix C. that by inspecting the exterior we can examine the interior viscera inside the body that can manifest themselves exter- 2.2. Study Participants. The participants were selected from nally. Exterior means symptoms and signs that the disease communities undergoing a regular physical examination in reflects, while the interior means the fundamental pathology health examination center of Hospital in Tianjin. Participants of the internal organs. According to this, theory of Chinese hadtomeetthefollowinginclusioncriteria. diagnosis, such as skin, complexion, smells, sounds, body (1)Theyhadtosigntheinformedconsentbeforethe build,andbones,canreflectthestateoftheinternalorgans. interview, (2) their age was from 18 through 60 years, and (3) A practitioner of TCM can derive detailed information about they lived in Tianjin city more than three year. the state of the whole organism, from examination of a small Participants were asked separately to complete the ques- part of it [8]. tionnaire. All participants underwent a standardized examination, including medical history, physical examination, 2. Methods blood hematology and biochemistry analysis, rest electrocardiography, and abdominal ultrasonography. A blinded 2.1. Item Generation. Items were generated based on a assessor objectively measured the health status by the physical reviewoftheliteratureandthroughcounselingwithsubject examination center. matter experts, including clinicians of TCM, mental health researchers, and scholars of TCM theory from provinces 2.3. Data Collection. After the questionnaire was completed, of Shandong and Jilin and cities of Tianjin and Shanghai each participant was scheduled for physical examination in and universities of Chinese Medicine and affiliated hospitals. medical examination center. The completed questionnaire Further discussions and modification of the items would be was checked by researchers to make sure all questions had done after the pilot study and provided analysis results. been answered.

2.1.1. Questionnaire of TCM and MHP. The questionnaire 2.4. Statistical Analyses. Before analysis, all questionnaires of TCM (the First Edition) included 49 items, which was were reread and checked for accuracy. All data were double designed for detecting the physical health status of the entered with EPI DATA 3.1 (EpiData Association Odense, participants. 35 items were given indicative guidelines for Denmark). The final dataset was converted into SPSS format. frequency scores ranging from 0 (absent) to 1 (never), 2 All statistical analyses were performed using the SPSS version (occasionally), 3 (sometimes), 4 (often), and 5 (always). 14 19.0 (SPSS, USA). Data were presented as percentages or items included in the second part, scores were stand for 1 (no), means ± standard deviations (SD). Comparison between two 2(yes). groups was done with independent sample 𝑡-test. WetookMHP(ManualforMentalHealthPattern, Chinese version) in this study to measure the mental health state of the participants. 2.5. Examination of Reliability and Validity Test. Internal MHP, a scale that includes 40 items, classifies state of consistency is a measure of reliability that assesses the degree mental health as it pertains to stress and Quality of Life to which the items were related to each other, it measures (QOL); the original version was developed by Japanese aunifiedconstruct[13]. Internal consistency was measured psychology professor Hashimoto Kimio in 1999, designed with Cronbach’s alpha (𝛼). with six subscales to measure stress: Persistence, Lack of Exploratory Factor Analysis (EFA) was used to determine Concentration, Antisocial Behavior, Nervous Tension to thescaleoftheitemsmainlyduetotheTCMtheory Others,Fatigue,andSleep/WakeupDisorder.Twosubscales aspects; principal component exploratory factor analysis with tomeasureQOLareasfollows:LifeSatisfactionandLife varimax rotation with Kaiser normalization was carried out Passion. Each subscale consists of five items. There were 40 to assess the underlying structure of questionnaire items items and scores of each item were from 1 (not matched), 2 [14]. The criterion applied to retain scales was an eigen (notmatchedpartly),and3(basicallymatched)to4(totally value ≥ 1.0 for that scale [15]. The critical threshold for matched). each item to meet this condition has been preset at 0.30. Evidence-Based Complementary and Alternative Medicine 3

Table 1: MHP scores of participants and two genders in study.

Participants (𝑛 = 294)Male(𝑛 = 165)Female(𝑛 = 129) MHP subscales 𝑡 value 𝑃 Mean SD Mean SD Mean SD Psychological Stress Persistence 7.11 2.89 7.01 2.94 7.23 2.82 −0.65 0.516 ∗ Lack of Concentration 7.28 2.81 6.88 2.22 7.77 3.35 −2.70 0.007 Social Stress ∗ Antisocial Behavior 6.82 2.79 6.54 2.40 7.19 3.19 −1.97 0.049 ∗ Nervous Tension to Others 7.78 2.80 7.36 2.27 8.31 3.29 −2.89 0.004 Somatic Stress ∗ Fatigue 7.79 3.29 7.38 3.14 8.32 3.42 −2.44 0.015 Sleep/Wake up Disorder 7.89 3.71 7.56 3.65 8.29 3.76 −1.66 0.098 QOL Life Satisfaction 19.28 5.75 19.36 5.84 19.18 5.65 0.26 0.796 Life Passion 16.79 4.34 16.98 4.45 16.55 4.22 0.83 0.406 Psychological Stress 14.29 5.17 13.77 4.59 14.95 5.78 −1.94 0.054 ∗ Social Stress 14.49 4.99 13.76 4.21 15.43 5.72 −2.87 0.004 ∗ Somatic Stress 15.57 6.18 14.80 6.03 16.55 6.25 −2.41 0.017 ∗ SCL 44.35 13.60 42.33 12.11 46.92 14.94 −2.90 0.004 QOL 35.84 9.67 36.02 9.99 35.60 9.26 0.37 0.712 ∗ 𝑃 < 0.05.

After determining scales, internal consistency was retested by Table 2: Cronbach’s 𝛼 coefficient of questionnaire and 10 subscales. 𝛼 calculating Cronbach’s coefficient for subscales. 𝛼 Criterion-related validity of the questionnaire was Subscale Number of items Cronbach’s assessed with Pearson’s rho correlation coefficients between Questionnaire 49 0.83 the scores of the questionnaire and somatic stress dimension I 11 0.77 of the MHP [16]. It hypothesized that the scores would II 5 0.75 significantly correlate with the scores for stress. 𝑡-tests III 5 0.73 used to determine whether the questionnaire was able IV 4 0.65 to distinguish between healthy and unhealthy status as V 4 0.68 measured by the physical examination results in hospital VI 5 0.63 and psychological measurement by MHP. The differences VII 4 0.40 between group comparisons were determined using analysis VIII 4 0.52 of 𝑡-test, when 𝑃 value lower than 0.05 was considered as statistically significant. IX 4 0.47 X 3 0.44 3. Results 3.1. Characteristics of Participants. 294 of 303 participants genders in scales: Lack of Concentration, Nervous Tension to completed the questionnaire (97.03%). The data of 294 people Others, Fatigue, Social Stress, and Somatic Stress. It indicated were collected, female were 129 (43.88%), and male were thatwomenweremoreliabletofeelstressthanmen. 165 (56.12%). Mean age of participants was 41.35 (standard deviation 8.57). 3.3. Internal Consistency. Internal consistency results using the Cronbach’s 𝛼 coefficient, 49 items were 0.83 for the whole 𝛼 3.2. Mental Health State of Participants: MHP Scores. The questionnaire (see Table 2); Cronbach’s higher than 0.6 was 𝛼 mental health state of participants and two genders were acceptable [17]andCronbach’s coefficient of scale VII to shown in Table 1. The mean scores of QOL (36.43) and SCL X was below our desired value; although we decided to retain (45.07) of study participants located the point in the number this scale, further modification would be made of these scales 2 area of Cartesian coordinates. It showed that participants and items. were in the state of Relaxed, Standard stress adaptation, which indicated that their mental health states were in a good 3.4. Factor Analysis. The Kaiser-Meyer-Olkin measure of condition. There was significant difference between scores of sampling adequacy (KMO) was 0.64, and the Bartlett test of 4 Evidence-Based Complementary and Alternative Medicine

2 sphericity was significant𝜒 ( (1176) = 4888.12, 𝑃 < 0.001), to 0.52). This could be due to the small number of items for indicating that the data were suitable for factor analysis. 16 eachsubscaleandmostoftheitemsaretwo-graded.Further factors had eigen values > 1, explaining 65.17% of the total modifications should be made to refine the items number variance. By scree test and TCM theory conclusion, 10-factor and contents, some items probably are to be removed in the solution was more interpretable. 10 factors explained 50.15% formal investigation, and make the questionnaire much more of the total variance. Each factor and loadings of the items are succinct. provided in Table 3.Asshowninthetable,thetenfactorswere In health care, many of the variables are abstract concepts (1) heart system (11 items), (2) spleen and stomach system known as theoretical constructs. Using tests or instruments is (5 items), (3) lung system (5 items), (4) urine and stool (4 valid and reliable to measure such constructs [20]. Through items), (5) metabolic systems (4 systems), (6) liver system the factor analysis, the underlying dimensions could be (5 items), (7) head (4 items), (8) body (4 items), (9) kidney extracted to support this conceptual model. The analysis system (4 items), and (10) skin (3 items). Cronbach’s 𝛼 and resulted in 10 distinct factors, as conceptualized in this model. intercorrelation of Subscales were showed in Tables 2 and 4. However, the first factor consisted of 11 items that seemed to describe 2 dimensions, including symptoms of kidney 𝛼 3.5. Discriminative Ability. 𝑡-test revealed significant differ- and skin. Cronbach’s of the scales was 0.40 and 0.44, ences (𝑡 = −4.21, 𝑃 = 0.000) in total scores, between respectively, lower than that for the domain of heart system the healthy (57.23 ± 6.00) and unhealthy (62.65 ± 11.03) (0.77). Therefore, the study did not regroup these items into 2 results distinguished by physical examination. As presented groups. In the light of the traditional Chinese medical theory in Table 5, the score of the questionnaire did not differ regarding the human body as a whole, themes of holism are significant𝑡 ( = −0.43, 𝑃 = 0.67) between males (60.93 ± deeply embedded in the doctrine of TCM [21, 22]. 10.89) and females (61.59 ± 9.66).Scoreoffemaleinhealthy ± ± (56.31 5.20) and unhealthy status (63.60 10.22) showed 5. Limitations significant differences𝑡 ( = −4.55, 𝑃 = 0.000), but male did not indicate significant differences (𝑡 = −1.23, 𝑃 = 0.22). Some symptoms may appear in different dimensions, taking the symptom of edema as example, which may occur both in 3.6. Convergent Validity. The correlation between the score of heart and kidney system. As a result, it leads to collinearity, questionnaire (60.63 ± 9.55) and that for SCL of MHP (44.35 which has influence on stability of the dimension. That ± 13.60, Cronbach’s 𝛼 = 0.74)wasstatisticallysignificant may cause factor analysis of the overall result that is not (Pearson’s 𝑟 = 0.43, 𝑃 < 0.001). Scores of somatic stress ideal, though it can still reflect the basic structure of the subscale of MHP and the questionnaire showed significant questionnaire in accordance with the theory of TCM. In differences (Pearson’s 𝑟 = 0.53, 𝑃 < 0.001). other examples, the morbidity of the organs can be revealed by the human facial complexion [23–27], and symptom of fatigue may occur not only in heart disease but also 4. Discussion in liver or endocrine problems such as diabetes [28–30]. These give guidance for the follow-up study to structure 294 of 303 participants completed the questionnaire (97.3%), optimization and adjusting; future research could explore indicating that it is user-friendly and easily understand for performing a confirmatory factor analysis of these results. participants, and they responded to the questions carefully. Many complementary medicine researchers confront the In this pilot study, Cronbach’s alpha is 0.83, which shows a same research design problems such as the spectrum of good level of internal consistency for the questionnaire, as interventions, holistic concepts, and individual practices [31– reliability coefficients were evaluated according to Nunnally 34], but more and more studies try to explore the right points and Bernstein [18](𝛼>0.70 = acceptable, 𝛼>0.80 = good, of combining the ancient TCM theories with constantly and 𝛼>0.90 = excellent). changing environment, social-demographic, reproductive, The traditional Chinese medicine considers that various lifestyle, systemic health, emotional status, and so on [35–37]. factors can affect health, from physical, psychological, nature, The participants were selected from communities that andsociety,andthesefactorsinfluenceeachother[19]. attended the physical examination in health examination Becausehealthystateshouldbeofcompletephysical, center of Hospital, by convenience sampling which is widely mental, and social well-being, the study utilized the MHP used in health-related scales [38, 39]. Nevertheless, the Scale to measure the mental health state of the participants. imperfection of the sample is less representative than a The results showed that the questionnaire was able to discrim- random sample and may limit the generalizability of this inate between groups. As expected, the correlation between study. Therefore, it would be valuable to test the questionnaire the score of questionnaire scores of the questionnaire and on a representative larger sample in more places of Tianjin at SCL of MHP and somatic stress subscale scores were statis- next stage of studies. tically significant differences. The higher scores represent a less healthy mental, social, and physical state of human body. They have a good consistency. 6. Conclusion When individual internal consistency was analyzed further within each domain, Cronbach’s 𝛼 for VII to X subscales The questionnaire of TCM (first version) was established (head, body, skin, and kidney system) was relatively low (0.40 for detecting physical health status; it is easy to complete, Evidence-Based Complementary and Alternative Medicine 5 Communalities 0.18 0.49 0.14 0.39 0.01 0.51 0.01 0.58 0.02 0.61 0.02 0.59 0.05 0.48 0.05 0.61 0.07 0.54 0.07 0.69 0.08 0.58 0.09 0.66 − − − − − − − − − − − − 0.13 0.10 0.03 0.58 0.10 0.01 0.01 0.08 0.47 0.23 0.07 0.58 0.07 0.16 0.38 0.07 0.07 0.12 0.53 0.06 0.03 0.44 − − − − − − − − − − 0.11 0.13 0.22 0.07 0.50 0.12 0.34 0.10 0.01 0.21 0.03 0.09 0.33 0.33 0.05 0.19 0.18 0.39 0.05 0.16 0.05 0.07 0.07 0.07 0.04 0.06 − − − − − − − − − − − − 0.12 0.04 0.16 0.05 0.07 0.22 0.09 0.04 0.06 0.01 0.00 0.04 0.13 0.11 0.03 0.69 − − − − − − − 0.15 0.00 0.01 0.02 0.09 0.21 0.00 0.63 0.23 0.35 0.05 0.05 0.23 0.05 0.01 0.07 0.06 0.07 0.16 0.07 0.04 − − − − − − − − − 0.11 0.13 0.00 0.12 0.01 0.05 0.39 0.10 0.04 0.05 0.08 0.12 0.06 0.16 0.06 0.13 0.10 0.00 0.27 0.03 0.40 0.06 0.04 0.24 0.04 0.14 0.07 0.13 0.08 EFA factor loadings − − − − − − − − − 0.14 0.07 0.13 0.07 0.06 0.11 0.01 0.38 0.01 0.01 0.03 0.00 0.08 0.28 0.05 0.23 0.13 0.57 0.02 0.02 0.05 0.07 0.08 0.19 0.04 0.19 0.08 0.11 0.00 0.81 0.22 0.14 0.63 0.67 0.64 − − − − − − − − − − Table 3: Exploratory factor analysis of questionnaire. 0.11 0.19 0.12 0.14 0.01 0.00 0.15 0.03 0.11 0.05 0.04 0.01 0.03 0.11 0.02 0.07 0.20 0.00 0.06 0.72 0.62 0.63 0.70 0.70 − − − − − − 0.11 0.11 0.13 0.33 0.12 0.14 0.01 0.06 0.07 0.04 0.12 0.11 0.18 0.02 0.00 0.10 0.16 0.11 0.14 0.03 0.14 0.04 0.04 0.22 0.34 0.02 0.14 0.10 0.16 0.01 0.05 0.12 0.17 0.25 0.10 0.81 0.05 0.01 0.30 0.11 0.11 0.01 0.10 0.55 0.75 0.74 0.62 − − − − − − − − 0.01 0.02 0.02 0.02 0.19 0.06 0.05 0.02 0.52 0.55 0.74 0.57 0.39 0.62 0.36 0.40 0.60 0.48 0.46 − − − − − Factor1 Factor2 Factor3 Factor4 Factor5 Factor6 Factor7 Factor8 Factor9 Factor10 Soreness of the waist Throat itching 0.02 0.10 Skin swelling Fatigue Expectoration 0.04 0.12 Vexation Dizziness Memory deterioration Edema Lassitude in the knees Acid regurgitation 0.07 Frequency of micturition 0.15 Shortness of breath Chest distress Abdominal distensionCough 0.22 Running noseUrgency of urination 0.01 0.11 0.27 0.10 Diarrheas Items, subscales, and total (I) Heart system Palpitation (II) Spleen and stomach system Vomit (III) Lung system Nasal obstruction (IV) Urine and stool Dysuria BelchingNausea 0.14 6 Evidence-Based Complementary and Alternative Medicine 0.59 0.34 0.64 Communalities 0.11 0.34 0.17 0.42 0.21 0.35 0.14 0.60 0.01 0.45 0.03 0.45 0.08 0.36 0.09 0.54 0.06 0.60 0.15 0.24 0.03 0.42 0.02 0.50 0.75 0.79 0.38 − − − − − − − − − 0.13 0.17 0.08 0.35 0.21 0.10 0.05 0.24 0.10 0.14 0.53 0.01 0.05 0.06 0.11 0.37 0.12 0.10 0.56 0.09 0.02 0.83 0.43 0.42 0.56 0.49 − − − − − − − − 0.01 0.10 0.01 0.02 0.05 0.06 0.05 0.05 0.05 0.08 0.08 0.29 0.14 0.66 0.06 0.34 0.14 0.72 0.04 0.19 0.13 0.03 0.14 0.25 0.01 0.17 0.03 0.70 0.45 0.90 0.40 − − − − − − − − − − 0.19 0.01 0.07 0.02 0.12 0.08 0.09 0.06 0.34 0.06 0.11 0.19 0.20 0.06 0.53 0.40 0.48 0.64 − − − − − − − 0.02 0.05 0.29 0.04 0.05 0.07 0.07 0.27 0.08 0.09 0.11 0.05 0.09 0.09 0.71 0.07 0.02 0.06 0.00 0.08 0.49 0.44 0.40 0.64 − − − − − − − 0.13 0.01 0.10 0.01 0.11 0.01 0.02 0.21 0.17 0.24 0.05 0.12 0.04 0.00 0.09 0.09 0.15 0.21 0.04 0.65 0.70 0.69 0.69 EFA factor loadings − − − − − − − − − Table 3: Continued. 0.14 0.05 0.30 0.10 0.100.10 0.09 0.05 0.16 0.09 0.01 0.05 0.01 0.00 0.03 0.02 0.02 0.05 0.05 0.05 0.08 0.07 0.09 0.10 0.04 − − − − − − − − − − − − − 0.15 0.01 0.01 0.02 0.19 0.02 0.00 0.02 0.05 0.07 0.08 0.21 0.12 0.04 0.15 0.12 − − − − − − − − − − 0.13 0.01 0.05 0.07 0.09 0.09 0.00 0.02 0.06 0.14 0.05 0.04 0.04 − − − − − − − 0.14 0.05 0.15 0.01 0.01 0.02 0.02 0.08 0.09 0.07 0.08 − − − − − − Factor1 Factor2 Factor3 Factor4 Factor5 Factor6 Factor7 Factor8 Factor9 Factor10 Simultaneous sweat and night sweat 0.19 0.38 0.12 PolyuriaMouth (bad breath) Teeth and gums 0.01 Tinnitus 0.11 0.03 Skin color and luster 0.06 0.01 0.06 0.11 Symptoms of bleeding Skin diseases Arms and legs 0.19 0.04 0.01 0.08 PolydipsiaThroat 0.07 0.19 0.08 0.10 0.17 0.14 Pain 0.30 0.14 0.11 Items, subscales, and total (V) Endocrine & Metabolic system Overdrinking(VI) Liver system Insomnia, dream disturbed sleep 0.05 0.03 (VII) Head Five sense organs(VIII) Body Waist and back 0.12(IX) Kidney system Hypoacusis 0.05(X) Skin 0.05Complexion 0.00 Eigen values% of varianceCumulative 0.04 % 0.28 0.03 0.04 0.03 3.72 7.60 7.60 3.16 6.45 14.05 2.64 5.39 19.44 2.45 24.45 5.00 2.40 29.35 4.91 33.73 2.15 4.38 38.06 2.12 4.33 42.33 2.09 4.27 46.31 1.95 3.98 50.15 1.88 3.85 Chest and abdomen PruritusNeck symptoms 0.18 0.29 0.10 0.03 Dryness of mouth 0.21 0.11 0.09Hoarse voice or aphonia 0.21 Renal percussive pain 0.06 0.25 0.20 0.09 0.05 Extraction method: principal componentBold analysis. font Varimax for rotation the with EFA factor Kaiser loadings normalization, indicates the sorted scale by on size. which the items load. Evidence-Based Complementary and Alternative Medicine 7

Table 4: Intercorrelation of subscales (Pearson’s 𝑟).

Subscale Factor1 Factor2 Factor3 Factor4 Factor5 Factor6 Factor7 Factor8 Factor9 Factor10 I1 ∗∗ II 0.25 1 ∗ ∗ III 0.16 0.13 1 ∗∗ ∗ IV 0.24 0.05 0.13 1 ∗∗ ∗ ∗ V0.32 0.14 0.08 0.19 1 ∗∗ ∗ ∗ ∗ ∗ VI 0.41 0.11 0.13 0.18 0.15 1 ∗∗ ∗∗ ∗∗ VII 0.27 0.23 0.10 0.05 0.08 0.25 1 ∗ ∗ ∗ ∗ VIII 0.13 0.19 0.14 −0.02 0.05 0.02 0.13 1 ∗∗ ∗∗ ∗ ∗∗ ∗ IX 0.33 0.26 0.17 0.06 0.12 0.28 0.17 0.10 1 ∗ X 0.00 0.06 0.07 −0.03 −0.03 0.11 0.16 0.03 0.10 1 ∗ ∗∗ 𝑃<0.05, 𝑃<0.001.

Table 5: Scores of questionnaire in different physical exam results and genders.

Gender Physical exam result Female Male Total 𝑡 value 𝑃 𝑛 Scores mean ± SD 𝑛 Scores mean ± SD Healthy 26 56.31 ± 5.20 21 58.38 ± 6.83 47 1.18 0.24 Unhealthy 68 63.60 ± 10.22 69 61.71 ± 11.78 137 −1.00 0.32 ∗ Total 94 61.59 ± 9.66 90 60.93 ± 10.89 184 −0.43 0.67 ∗ There were 110 of 294 participants that were excluded, because their physical examination results were subhealth status. forapplyingincommunityhealthcare.The49-itemques- Low QOL High Relaxed (standard tionnaire encompasses the domains of heart, spleen and SCL Energetic (stress adaptation) stress adaptation) stomach, lung, endocrine and metabolic syndrome, liver, 30 Low kidney system, head, body, skin, urine, and stool feces. 7535 31 Although more work is needed in further refinement of 40 thestructure,itwillbeusefulinmovingtowardsdeveloping 45 the integrating T&CM services and self-health care into 8650 42 57 national health systems. 10 12 14 18 20 23 24 26 28 31 32 34 36 40 58 QOL SCL 14 13 70 10 9 Appendices 81 90 100 A. Questionnaire: 49 Items 16 15 110 12 11 120 High The questions in Table 6 inquire about health events during Exhausted (stress disorder) Fatigued (maladjustment) the last 2 weeks. Answer every question by marking the Classification of four mental health patterns ✓ appropriate box with a “ .” You may choose from one of the Figure 1 following answers:

1: never or almost never 2: occasionally C. MHP Scale: Construction and 3: often Classification Method 4: very often See Table 8 and Figure 1. 5: always Conflict of Interests B. Items Analysis Results The authors declare that there is no conflict of interests See Table 7. regarding the publication of this paper. 8 Evidence-Based Complementary and Alternative Medicine

Table 6 Do you have the symptoms of the following? How often? 12 3 4 5 1 Nasal obstruction ◻◻ ◻ ◻ ◻ 2 Running nose ◻◻ ◻ ◻ ◻ 3 Throat itching ◻◻ ◻ ◻ ◻ 4Cough ◻◻ ◻ ◻ ◻ 5Expectoration ◻◻ ◻ ◻ ◻ 6 Chest distress ◻◻ ◻ ◻ ◻ 7 Palpitation ◻◻ ◻ ◻ ◻ 8 Vexation ◻◻ ◻ ◻ ◻ 9 Dryness of mouth ◻◻ ◻ ◻ ◻ 10 Polydipsia ◻◻ ◻ ◻ ◻ 11 Acid regurgitation ◻◻ ◻ ◻ ◻ 12 Belching ◻◻ ◻ ◻ ◻ 13 Nausea ◻◻ ◻ ◻ ◻ 14 Vomit ◻◻ ◻ ◻ ◻ 15 Abdominal distension ◻◻ ◻ ◻ ◻ 16 Diarrhea ◻◻ ◻ ◻ ◻ 17 Soreness of the waist ◻◻ ◻ ◻ ◻ 18 Lassitude in the knees ◻◻ ◻ ◻ ◻ 19 Frequency of micturition ◻◻ ◻ ◻ ◻ 20 Urgency of urination ◻◻ ◻ ◻ ◻ 21 Dysuria ◻◻ ◻ ◻ ◻ 22 Polyuria ◻◻ ◻ ◻ ◻ 23 Edema ◻◻ ◻ ◻ ◻ 24 Fatigue ◻◻ ◻ ◻ ◻ 25 Shortness of breath ◻◻ ◻ ◻ ◻ 26 Simultaneous sweat and night sweat ◻◻ ◻ ◻ ◻ 27 Overdrinking ◻◻ ◻ ◻ ◻ 28 Dizziness ◻◻ ◻ ◻ ◻ 29 Memory deterioration ◻◻ ◻ ◻ ◻ 30 Insomnia, dream disturbed sleep ◻◻ ◻ ◻ ◻ 31 Hypoacusis ◻◻ ◻ ◻ ◻ 32 Tinnitus ◻◻ ◻ ◻ ◻ 33 Pain ◻◻ ◻ ◻ ◻ 34 Symptoms of bleeding ◻◻ ◻ ◻ ◻ 35 Pruritus ◻◻ ◻ ◻ ◻ Physical examination: Is there something wrong with the part of body as following? YES NO Comments 36 Complexion ◻◻ 37 Skin color and luster ◻◻ 38 Skin diseases ◻◻ 39 Skin swelling ◻◻ 40 Five sense organs: eyes, ears, nose, and lips ◻◻ 41 Teeth and gums ◻◻ 42 Mouth(badbreath) ◻◻ 43 Hoarse voice or aphonia ◻◻ 44 Throat ◻◻ 45 Neck ◻◻ 46 Chest and abdomen ◻◻ 47 Waist and back ◻◻ 48 Arms and legs ◻◻ 49 Renal percussive pain ◻◻ Evidence-Based Complementary and Alternative Medicine 9 value 𝑡 −5.59 ∗∗∗ −2.59 ∗∗ −4.33 ∗ ∗ ∗ −4.30 ∗ ∗ ∗ −1.98 −6.94 ∗ ∗ ∗ −6.57 ∗ ∗ ∗ −5.32 ∗ ∗ ∗ −5.85 ∗ ∗ ∗ −6.66 ∗ ∗ ∗ −3.67 ∗∗∗ −8.15−8.66 ∗ ∗ ∗ ∗ ∗ ∗ −7.94 ∗∗∗ −8.74−3.68 ∗∗∗ ∗ ∗ ∗ −6.02 ∗ ∗ ∗ −3.09−2.49 ∗∗ ∗ −4.90 ∗ ∗ ∗ −2.53−1.82 −1.75 ∗ −4.11−2.48 ∗ ∗ ∗ ∗ −2.38 ∗ −1.75 −3.96 ∗ ∗ ∗ −7.15 ∗ ∗ ∗ −4.36 ∗ ∗ ∗ −1.52 −2.38 ∗ −3.09−2.81 ∗∗ −5.78 ∗∗ ∗∗∗ −5.78 ∗∗∗ −5.62 ∗ ∗ ∗ −11.52 ∗ ∗ ∗ −11.62 ∗ ∗ ∗ ) 𝑛=81 𝜒𝑠 )Highscoregroup( 𝑛=82 𝜒𝑠 Low score group ( Table 7 𝛼 0.83 1.12 0.46 1.38 0.78 0.83 1.04 0.19 1.46 0.85 0.83 1.12 0.43 1.69 1.11 0.83 1.00 0.00 1.15 0.67 0.83 1.01 0.11 1.37 0.87 0.83 1.00 0.00 1.60 0.58 0.83 1.17 0.41 1.78 1.04 0.83 1.00 0.00 1.04 0.19 0.83 1.01 0.11 1.16 0.56 0.830.83 1.00 1.00 0.00 0.00 1.06 1.20 0.37 0.75 0.82 1.12 0.48 1.85 1.07 0.82 1.07 0.31 1.85 0.96 0.82 1.04 0.25 1.81 1.04 0.82 1.09 0.32 1.73 0.94 0.82 1.05 0.27 1.78 0.95 0.82 1.01 0.11 1.57 0.94 0.820.82 1.01 1.02 0.11 0.22 1.89 1.91 0.96 0.90 0.82 1.05 0.22 2.32 1.29 0.820.82 1.01 1.40 0.11 0.72 1.28 3.05 0.66 1.07 0.82 1.02 0.16 1.93 1.01 0.82 1.00 0.00 1.63 0.94 0.82 1.23 0.53 2.84 1.12 0.820.820.82 1.00 1.00 1.01 0.00 0.00 0.11 1.46 1.19 1.23 1.00 0.67 0.64 0.82 1.01 0.11 1.42 0.92 0.82 1.12 0.46 2.12 1.18 0.82 1.01 0.11 1.48 0.96 0.820.820.82 1.00 1.02 1.04 0.00 0.22 0.25 1.26 1.26 1.73 0.76 0.72 1.05 0.82 1.06 0.36 1.73 0.98 0.82 1.01 0.11 1.53 0.82 Cronbach’s ) ∗ ∗ ∗ ∗∗ ∗∗ ∗∗ 𝑟 ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ Correlation (Pearson’s Items Nasal obstruction 0.13 Running nose 0.24 Throat itching 0.33 CoughExpectoration 0.44 0.44 Overdrinking 0.15 Dizziness 0.48 Memory deterioration 0.43 Chest distress 0.49 Insomnia, dream disturbed sleep 0.44 Palpitation 0.61 Hypoacusis 0.34 VexationDryness of mouth 0.46 0.55 Polydipsia 0.40 TinnitusPain 0.25 0.53 Acid regurgitation 0.34 Symptoms of bleeding 0.25 Pruritus 0.56 BelchingNauseaVomitAbdominal distension 0.38 0.31 0.31 0.30 ComplexionSkin color and lusterSkin diseasesSkin swelling 0.08 0.11 0.09 0.12 0.83 0.83 0.83 1.00 1.00 1.04 0.00 0.00 0.19 1.04 1.07 1.11 0.19 0.26 0.32 DiarrheaSoreness of the waist 0.47 0.17 Lassitude in the knees 0.44 Frequency of micturitionUrgency of urination 0.31 0.33 DysuriaPolyuriaEdema 0.19 0.20 0.35 Fatigue 0.42 Shortness of breath 0.42 Simultaneous sweat and night sweat 0.41 10 Evidence-Based Complementary and Alternative Medicine value 𝑡 −1.95 −1.42 −4.88−3.27 ∗ ∗ ∗ ∗∗ −3.54 ∗∗∗ −1.00 −1.00 −4.09 ∗ ∗ ∗ −3.99 ∗ ∗ ∗ −2.20 ∗ who got the low scores entered the ) % 𝑛=81 𝜒𝑠 ) Highscoregroup( 𝑛=82 𝜒𝑠 Low score group ( of the participants in high score sorted into the high score group, and 27 𝛼 % Table 7: Continued. 0.830.83 1.00 1.04 0.00 0.19 1.02 1.20 0.16 0.40 0.83 1.01 0.11 1.07 0.26 0.83 1.45 0.50 1.72 0.45 0.83 1.00 0.00 1.17 0.38 0.83 1.01 0.11 1.09 0.28 0.83 1.02 0.16 1.22 0.42 0.82 1.02 0.16 1.28 0.45 Cronbach’s ) ∗ 𝑟 ∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ Correlation . (Pearson’s 𝑃 < 0.05 : ∗ , 𝑃 < 0.01 : ∗∗ : the correlation coefficient item of and total the score. , 𝑟 𝑃 < 0.001 : ∗∗∗ value: independent-sample test. Hoarse voice or aphoniaThroat 0.12 0.33 Teeth and gumsMouth (bad breath) 0.17 0.21 Items Five sense organs: eyes, ears, nose, and lips 0.29 NeckChest and abdomenWaist and backArms and legsRenal percussive pain 0.01 0.22 0.09 0.20 0.24 0.83 0.83 1.00 1.00 0.00 0.00 1.00 1.01 0.00 0.11 𝑡 It is divided into two groups according to the scores: a high mark group and a low mark group. 27 low score group. Evidence-Based Complementary and Alternative Medicine 11

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Review Article Resistance to Antibiotics and Antifungal Medicinal Products: Can Complementary and Alternative Medicine Help Solve the Problem in Common Infection Diseases? The Introduction of a Dutch Research Consortium

Esther T. Kok,1,2 Miek C. Jong,3,4,5 Barbara Gravendeel,1,6 Willem B. Van Leeuwen,1 and Erik W. Baars1,3

1 University of Applied Sciences, 2333 CK Leiden, Netherlands 2Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK 3Department of Healthcare and Nutrition, Louis Bolk Institute, 2972 LA Driebergen, Netherlands 4Department of Health Sciences, Mid Sweden University, 871 31 Sundsvall, Sweden 5National Information and Knowledge Centre on Integrative Medicine (NIKIM), Amsterdam, Netherlands 6Naturalis Biodiversity Center, 2333 CR Leiden, Netherlands

Correspondence should be addressed to Esther T. Kok; [email protected]

Received 29 June 2015; Accepted 25 August 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Esther T. Kok et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The increase of antibiotic resistance worldwide, rising numbers of deaths and costs associated with this, and the fact that hardly any new antimicrobial drugs have been developed during the last decade have increased the interest in Complementary and Alternative Medicine (CAM) therapeutic interventions, if proven safe and effective. Observational studies on clinical CAM practices demonstrate positive effects of treatment of infections with CAM therapies (clinical effects, patient satisfaction) in combination with small percentages of antibiotics prescription. However, Cochrane reviews and other studies demonstrate that in most instances the quality of clinical trials on CAM treatment of infections is currently too low to provide sufficient evidence. Therefore a Dutch consortium on (in vitro and clinical) scientific research on CAM and antibiotic resistance has been formed. The aim and objective of the consortium is to establish an enduring partnership and to develop expertise to further develop and investigate safe and effective CAM treatments for infectious diseases of humans (and animals). A first ongoing project on the development of safe and effective biobased CAM antimycotics in women with (recurrent) vaginal candidiasis infection is introduced.

1. Introduction The development of generations of antibiotic-resistant microbes and their distribution are the result of many years The discovery of antibiotics was one of the most significant of underuse, overuse, and misuse of antibiotics by human events in medical history and is said to have added a decade to applications (weak or no antibiotic policy and poor infection the life expectancy of humans [1]. Together with vaccination control). For more than five decades the problem of how to and public health measures (e.g., clean water, invention, and contain antimicrobial resistance (AMR) persists and due to introduction of drainage systems and the fridge), antibiotics thelowchanceofsuccesswearenow,intheearlydecades were responsible for a dramatic reduction of the mortality of the 21st century, facing a global issue of concern with rate from infectious diseases. Regrettably, it seems that the serious consequences: “Drug-resistant infections already kill successful use of any therapeutic agent is compromised by hundreds of thousands a year globally, and by 2050 that the potential development of tolerance or resistance to that figure could be more than 10 million. The economic cost compound from the time it is first employed. will also be significant, with the world economy being hit 2 Evidence-Based Complementary and Alternative Medicine by up to $100 trillion by 2050 if we do not take action [2].” new antimicrobial agents are listed [13, 14]. One of these Therefore, worldwide actions are established to disprove the recommendations is to increase the cooperation between hypothesis of Felix Marti-Ibanezin, already stated in 1955: academia and industry for identifying potential targets. “Antibiotic therapy, if indiscriminately used, may turn out to Potential targets might be vaccination, surgical interventions, be a medicinal flood that temporarily cleans and heals, but awareness, and control of environmental risk factors, as well ultimately destroy life itself” [3]. as complementary and alternative medicine (CAM) [15]. The fact that hardly any new antimicrobial drugs have been developed during the last decade has increased the 3. Complementary and Alternative Medicine interest in Complementary and Alternative Medicine (CAM) therapeutic interventions, if proven safe and effective. CAM Consumer interest in CAM has increased over the past interventions can contribute to a reduction in antibiotic use decade. Recent data indicate that a large proportion of the by (1) strengthening the self-healing capacities of the individ- population of developed countries, including Australia (52– ual and/or (2) providing an alternative treatment which has 69% of those surveyed), Canada (59-60%), the United States its own antimicrobial effect [4, 5]. (62%), Singapore (76%), and Japan (50%), has used CAM at In this paper the introduction of CAM in the future least once over a twelve-month period [16]. Between 20% and control of AMR and examples of the evidence on CAM 80% of citizens in different EU countries have used CAM in alternatives are presented. A Dutch consortium of research their healthcare [17]. In the Netherlands 15 percent of the total partners is initiated to (further) develop safe and effective population visits a CAM therapist yearly [18]. CAM alternatives to antibiotics. There are several explanations for the increasing use of CAM services across the world. Earlier studies have suggested 2. Future Control of AMR that consumer dissatisfaction with conventional medication maybealeadingreasonforCAMuse[16]; however, more The environmental and policy factors that contribute to recent reports indicate that an aspiration for active health- resistance require regulatory and governmental intervention. care participation, greater disease chronicity and severity, Therefore actions for future control are being taken to deter- holistic healthcare beliefs, and increase in health awareness mine (research) and promote (education) appropriate use of behaviour are more likely to be associated with CAM use [19– antimicrobial drugs on national and international basis. 21]. This suggests that complementary medicine is addressing Ongoing research is being performed to obtain evidence unmet needs in healthcare. for sophisticated molecular, immunologic, and microbial Due to the worldwide increasing use of CAM services, techniques that will change the way infectious diseases are the attention for safety, effectiveness, and cost-effectiveness of diagnosedinthehopetoreducediagnosticuncertaintyin CAMgrows.Apreviousreview[22] reported that some CAM the next 2 decades [6]. Furthermore the development of new therapies are cost-effective compared with usual care for vaccines might contribute to a decreased transmission and various conditions. More recent results of two Dutch studies impact of antimicrobial-resistant bacteria in the near future demonstrated that patients whose general practitioner (GP) as these vaccines might have the potential to effectively con- practices CAM tend to have lower costs (10.1%) [23, 24]. trol infectious agents [7]. However, vaccine escape mecha- The effectiveness of many CAM therapies has not been nisms for bacteria have already been reported [8]. Variability proven in clinical trials yet [25]. Randomized controlled trials in parts of the genome coding for antigenic determinants, (RCTs) are still considered and applied as the golden standard such as in Bordetella pertussis (whooping cough), may lead to forevaluationofeffectiveness.However,RCTsmaynot a vaccine escape. In this way, despite vaccination, this DNA always be suitable for the evaluation of CAM, in particular, variability contributed to reemergence of whooping cough in to investigate the individual response treatment. The descrip- the Netherlands. tion of individual cases is probably the most important tool National and international antimicrobial drug policies for teaching in medicine, especially in CAM. However, most and guidelines on infection control have been developed and of the times the information provided in single case reports implemented resulting in a decrease of the volume of anti- is not sufficient to provide sufficient evidence for effective- microbials over the past 10 years [9, 10]. Besides, national ness [26]. Development of other methods for evaluation of campaigns to educate physicians and patients about the individual response instead of RCTs or adapted in RCTs is appropriate use of antibiotics have been launched resulting in necessary as it is essential that scientific evidence for CAM promising changes in attitude among the public and health- will be established. In the best case, once scientific evidence care professionals [11]. is there to prove a CAM therapy safe and effective and when Whether the current epidemic of AMR is sustainable there is a clear working mechanism, the status can change or will succumb to the current efforts will also depend on from CAM into conventional medicine. the worldwide healthcare regulation, as antimicrobial use is Between January 2010 and December 2012, the CAM- affected by reimbursement policies, financial incentives, and brella consortium has been looking into the current status of healthcare regulation [12]. CAM in Europe from different angles. Their findings stated However, even if the use of antibiotics was entirely appro- that future research methods must reflect the real-world priate resistance would still occur. Hence, the develop- settings of healthcare in Europe and that everyone needs to ment of new pharmaceuticals and antimicrobial agents is know in what situation CAM is a reasonable choice [27]. essential and recommendations to facilitate development of Therefore they recommend a clear emphasis on concurrent Evidence-Based Complementary and Alternative Medicine 3 evaluation of CAM as an additional or alternative treatment effects, patient satisfaction) in combination with small per- strategy in real-world settings. The strategy for the investiga- centages of antibiotics prescription [28]. tion of CAM should include a broad range of mixed-method With regard to positive reviews, Echinacea is one of the research strategies including comparative effectiveness most widely used botanical supplements in North America research and qualitative and quantitative designs. Stakehold- in the treatment of upper respiratory tract infections. One ers such as citizens, patients, and providers should be closely review of 34 studies using Echinacea for the prevention of involved to ensure real-world relevance for the research [27]. upper respiratory tract infections showed that 22 had positive outcomes [33]. Another review of nine RCTs showed that 8 4. CAM Alternatives to Antibiotics reported some benefit of Echinacea in the early treatment of upper respiratory infections [34]. CAM can contribute to a reduction in antibiotic use. On The good antimicrobial properties of Abrus precatorius, the one hand, CAM therapies, which are proven safe, can be Terminalia phanerophlebia, Indigofera arrecta,andPentanisia used to strengthen the self-healing capacities of the organism prunelloides authenticate their traditional use in treatment of (preventive and curative health promotion) [4]. Here CAM is respiratory diseases [35]. an alternative for antibiotics but is not directly based on the The increasing prevalence of isolates of Escherichia coli antimicrobialpropertiesoftheproductitself.Forexample, (the most prevalent uropathogen) that are resistant to antimi- compared to conventional treatment, anthroposophic treat- crobial agents has stimulated interest in novel nonantibiotic ment of primary care patients with acute respiratory and ear methods for prevention of urinary tract infections (UTIs). symptoms had more favourable outcomes, lower antibiotic Cranberries have been used in the prevention of UTIs for prescription rates, less adverse drug reactions, and higher many years. A meta-analysis of the results of two well- patient satisfaction [28]. Moreover, the introduction of CAM performed RCTsshowed that, in women with recurrent UTIs, medicinal products might overcome the related side effects of cranberry products reduced the incidence of recurrences at 12 antibioticuseinchildhoodasseveralstudiesshowthatboth months by 39% compared with placebo or control interven- maternal and child’s use of antibiotics were associated with an tions [36]. Beerepoot et al. reported that in premenopausal increased risk of eczema or asthma [29–31]. women the use of antibiotics (TMP-SMX) is more effective On the other hand, several (natural) medicinal products than cranberry capsules to prevent recurrent UTIs. However, as used in CAM can act as an alternative (fighting disease the use of TMP-SMX resulted in a considerable increase in strategies) to control infectious diseases based on their own antibiotic resistance [37]. (bactericide or bacteriostatic) antimicrobial properties [5]. Another example is found in tackling antibiotic-resistant The development of conventional medicinal products and strains of pathogens as Candida albicans. Candidiasis is a CAM medicinal products such as those used in anthro- benign mycosis resulting from a yeast infection caused by posophic medicine, homeopathy, and traditional Chinese Candida albicans. Candida albicans develops resistance to medicine follow different pathways. Conventional medicinal regularly applied, standard antimycotic drugs such as clotri- products are developed in the laboratory and subsequently mazole, nystatin, fluconazole, and ketoconazole38 [ ], and, as tested in preclinical studies, phases 1–3 clinical studies, and a consequence, demand for prevention is high. Worldwide finally in clinical practice. They are mostly used according several plant extracts have traditionally been used to prevent to a fixed schedule and for one indication. Conversely, CAM Candidiasis [39]. The drawback with these treatments is that medicinal products are developed in clinical practice with they might interact with other medications if taken together regard to the principles of the respective medical system, through changes in drug solubility and uptake, metabolism, mostly have a long tradition of use, are often selected indi- and physiology of the gastrointestinal tract [40]. This results vidually to address the needs of each patient on the basis in adverse drug reactions such as allergic reactions, reduced of trained judgment skills of the health practitioner, and effects of contraceptives, and stomach damage41 [ ]. Therefore are often used in combination with other (conventional) research to profile, detect, and screen alternatives among, for medicinal products or nonpharmacological therapies. As a example, plant compounds, which are effective in preventing result, CAM usually has multiple therapy options for each Candidiasis without these shortcomings, is needed. indication [32]. Overall, there is much expert knowledge on CAM treat- 5. Scientific Evidence as Key ment of infectious diseases but little scientific evidence based on clinical trials. Currently there are 61 Cochrane reviews on WorldwideresearchinCAMisseriouslyhamperedbya CAM treatments of specific infections (e.g., 29 on respiratory lack of research infrastructure and funding, lack of research tract infections). However, in most instances the quality of expertise among CAM practitioners, lack of appropriate clinical trials on CAM treatment of infections reviewed is research models and strategies, and the scepticism of the currently too low to provide sufficient evidence. Nevertheless, conventional scientific community. In the USA, the national some reviews and observational studies do demonstrate authorities have taken the growing demand for CAM seri- positive and promising results. ously. The established National Centre for Complementary For example, an observational study on anthroposophic and Alternative Medicine (NCCAM) in 1998 has already clinical practice demonstrates positive effects of treatment of funded 57 university based centres for research on CAM, acute middle ear and upper respiratory infections (clinical in contrast to Europe where only some western countries 4 Evidence-Based Complementary and Alternative Medicine

(Denmark, Germany, Norway, the UK, and the Netherlands) (2) Extracts of living accessions from the profiled species have granted some money for research projects in CAM [42]. are being tested in antifungal and cellular assays. CAM research might contribute to controlling AMR and (3) The most promising extract will be added to a regis- in broader context to improving health, reducing disease, tered medical device (using good manufacturing and reducing healthcare related costs. However, the CAM practice guidelines) and will after ethics approval be industry alone cannot be expected to support all research tested on safety and efficacy using a double blind- activities in these areas. At the moment there is huge disparity placebo controlled trial design in clinical practice. between public funding for conventional drug research and that for CAM research. Nowadays, national health authorities are asking for 8. Conclusion effective actions to control AMR, and therefore the need for The increasing incidence of drug-resistant pathogens has soundclinicalresearch(methods)totesttheefficacyforCAM drawn the attention of the pharmaceutical and scientific com- strategies becomes more important. Clinicians using CAM in munities towards studies on the potential antimicrobial activ- daily routine practice, often resulting in nonuse or extended ity of CAM products and therapies. The aim of the introduced useofantibiotics,areconvincedabouttheeffectiveness Dutch CAM consortium is to provide evidence of safety, effi- of their services. However, before general acceptation and cacy, cost (effects), and modes of actions of CAM therapies, introduction of these specific CAM alternatives first scientific which are useful as alternative strategies to control infectious evidence is needed. Clearly, scientific evidence of CAM based diseases and can become useful therapeutic tools in clinical on sound clinical research methodology is the key to action. practice. The Dutch consortium will serve as a starting point for further international collaboration with stakeholders 6. The Introduction of a Consortium involved and/or interested in the study of CAM contributions The Professorships of Anthroposophic Healthcare, Biodiver- to the treatment of infections and the reduction of AMR. sity, and Innovative Molecular Diagnostics of the University of Applied Services of Leiden and the Louis Bolk Institute in Appendix the Netherlands have taken the initiative to form a consortium on scientific research on CAM and antibiotic resistance Composition of the Consortium (see Appendix). The aim and objective of the consortium isto establish an enduring partnership and to develop expertise The consortium consists of the following parties: to further develop and investigate safe and effective CAM (1) University of Applied Sciences Leiden (Hogeschool Lei- treatments for infectious diseases of humans (and animals). den) participates with three professorships as follows: The knowledge generated will lead to (1) evidence-based CAM alternatives to antibiotics that can be used in clinical (i) Anthroposophic Healthcare (ProfessorDr.E.W. practice and (2) guidelines for CAM treatments for infectious Baars and Dr. E. T. Kok): it is able to cooperate diseases in human and veterinary clinical practice. with the Louis Bolk Institute to perform clinical studies to the safety and effects of (new) CAM 7. Description of First Project treatments in patients with infectious diseases. The research group also has a large network A first project to find close relatives of species traditionally with anthroposophic care professionals includ- used to prevent Candidiasis that could serve as safe biobased ing doctors and nurses. antimycotics to be applied in registered medical sprays has (ii) Biodiversity (Professor Dr. B. Gravendeel) and started (granted by the Naturalis tender application-oriented Innovative Molecular Diagnostics (Professor Dr. research 2013). In short the study exists out of the following W. van Leeuwen): both research groups are able activities: to investigate the in vitro effects and safety of (1) Instead of using random screening, a multistep tar- (new) CAM treatments for infectious diseases. geted approach is used that incorporates information retrieved from museum collection labels to optimize (2) Louis Bolk Institute (Dr. M. C. Jong): it is able to efficient species selection. collaborate with the professorship of Anthroposophic Healthcare to perform clinical studies to the safety (a)Speciesacrosstheangiospermsthathave and effects of CAM treatments in patients with infec- uncomplicated European Medicines Agency tious diseases. The institute also has a large network (EMA) regulations will be selected. with CAM practitioners in the Netherlands. (b) Phylogenetic prospecting will be applied to identify closely related species of interest. Abbreviations (c) Crucial information of commercial interest, that is, cultivation requirements and traditional use, AHI: Animal Health Institute will be retrieved from metadata attached to AMR: Antimicrobial resistance specimens, screened for legal constraints, and CAHCIM: Consortium of Academic Health Centres for applied in the prospecting. Integrative Medicine Evidence-Based Complementary and Alternative Medicine 5

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Research Article Postmarketing Safety Surveillance and Reevaluation of Danhong Injection: Clinical Study of 30888 Cases

Xue-Lin Li,1 Jin-Fa Tang,1 Wei-Xia Li,1 Chun-Xiao Li,1 Tao Zhao,2 Bu-Chang Zhao,2 Yong Wang,2 Hui Zhang,1 Xiao-Fei Chen,1 Tao Xu,1 and Ming-Jun Zhu1

1 The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China 2Shandong Buchang Pharmaceutical Co., Ltd., Heze 274000, China

Correspondence should be addressed to Ming-Jun Zhu; [email protected]

Received 12 November 2014; Revised 24 February 2015; Accepted 10 March 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Xue-Lin Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Traditional Chinese medicine injections (TCMIs) have played an irreplaceable role for treating some clinical emergency, severe illness, and infectious diseases in China. In recent years, the incidence rates of adverse drug reactions (ADRs) of TCMIs have increased year by year. Danhong injection (DHI) is one representative TCMI comprised of Danshen and Honghua for treating cardiovascular and cerebrovascular diseases in clinic. In present study, the postmarketing safety surveillance and reevaluation of DHI were reported. Total 30888 patients in 37 hospitals from 6 provinces participated in the study. The results showed that the ADR incidence rate of DHI was 3.50‰. Seventeen kinds of new adverse reactions of DHI were found. The main type of ADRs of DHI was type A (including sweating, dizziness, headache, flushing, vasodilation, eye hemorrhage, faintness, chest pain, palpitations, breathlessness, anxious, nausea, flatulence, vomiting, hypotension, hypertension, local numbness, dyspnea, joint disease, and tinnitus) accounting for 57.75%. The severities of most ADRs of DHI were mild and moderate reactions accounting for 25.93% and 66.67%, respectively. The main disposition of ADRs of DHI was drug withdrawal and without any treatments. The results can provide basis for amendment and improvement of the instructions of DHI, as well as demonstration and reference for the postmarketing safety surveillance and reevaluation of other TCMIs. And the rationality, scientificity, and safety of clinical applications of TCMIs could be improved.

1. Introduction ADRs/ADEs caused by TCMIs are particularly prominent [7]. ADRs/ADEs are a worldwide problem and are one of Traditional Chinese medicine injection (TCMI) is prepared the leading causes of mortality and morbidity in health care by extracting and purifying effective substances from herbs facilities worldwide [8, 9]. They can significantly impede a (or decoction pieces) with modern scientific techniques patient’s adherence to treatment and in turn diminish the and methods. Compared with orally administrated herb therapeutic benefit, potentially reducing health and quality medicines, the injection is a new form of TCM preparations of life. Therefore, understanding ADRs/ADEs of TCMIs is including solutions, emulsions, powder, or concentrated essential for managing unintended outcomes and achieving solutions [1, 2]. It has played an irreplaceable role in the successful treatment. When one kind of TCMIs comes into treatment of some clinical emergency, severe illness, and the market, its safety profile is always little known. Thus, infectious diseases [3–6]. it is very necessary to carry out the postmarketing safety In recent years, the incidence rates of adverse drug surveillance and reevaluation of TCMIs. reactions (ADRs)/adverse drug events (ADEs) of TCMs A representative injection is Danhong injection (DHI), have increased gradually along with the wider application which was awarded the first Chinese medicine patent gold and increasing varieties of TCMs. It is worth noticing that medal in the year of 2010. DHI showed 3 consecutive annual 2 Evidence-Based Complementary and Alternative Medicine sales of more than 1 billion yuan RMB, reaching 3 billion and was carried out by total research group (The First Affil- in 2011, and had become the top Chinese medicine for car- iated Hospital of Henan University of TCM and Shandong diovascular and cerebrovascular diseases in China [10]. DHI Buchang Pharmaceutical Co., Ltd.). Director of pharmacy, is a standardized water-soluble product manufactured from quality control personnel, and monitoring staff of each the root and rhizome of Salvia miltiorrhiza Bge. (Danshen, monitoring hospital all should participate in the training. officially recognized in the Chinese Pharmacopoeia as Salviae Most of the quality control personnel and monitoring staff Miltiorrhizae Radix et Rhizoma) and the flower of Carthamus were clinical pharmacists; some of them were pharmacists- tinctorius L. (Honghua, officially recognized in the Chinese in-charge. The training content included monitoring pro- Pharmacopoeia as Carthami Flos). It is a famous Chinese cess and filling requirements of “Monitoring Information medicinal formula which is used extensively for treating Form.” After training, all trainers should participate in the cardiovascular and cerebrovascular diseases in clinic (such examination, and the trainers whose scores are less than 80 as coronary heart disease, angina, myocardial infarction, points should participate in the training again or cancel their ischemic encephalopathy, and cerebral thrombosis) due to participation. All examination papers were saved by the total its traditional Chinese medical effects of activating blood research group. circulation, dissipating blood stasis, and dredging meridians and collaterals [11]. 2.4.2. The Filling Requirements of “Monitoring Information However, the postmarketing safety of DHI is relatively Form”. The filling requirements of “Monitoring Information little known [12–14]. In our previous studies, four assessment Form” mainly included the following. (1) Please use black methods of postmarketing safety on DHI were compared, ink or ball-point pen to fill out the “Monitoring Information and the results showed that centralized hospital monitoring Form”. In order to prevent Carbonless printing to the next was an appropriate method to carry out postmarketing safety page,pleaseputthepadsontopofthatpagewhichwillbe evaluation of TCMIs [15]. Therefore, the postmarketing safety filled out. (2) Items in the “Monitoring Information Form” (including the incidence rate, types, severities, and other should be carefully and truthfully filled out. Those contents information of ADRs/ADEs) of DHI with 30888 cases was should be filled in or written neatly and clearly, which also further investigated by a trained physician and pharmacist should be legible and accurate. If an error occurred, please team by using the centralized hospital monitoring method, draw a single line above the errors, write the correct answer which could objectively reflect the real world of clinical above or next to those errors, and write the modifier’s name applications. andmodifieddateontheupperrightcornerofthecorrect answer. (3) All items should be filled out. Choice questions 2. Subjects and Methods thatwerenotmarkedasmultiplechoicewereallsinglechoice. Please fill the correct answer code in the ◻. And all horizontal 2.1. Ethical Approval. The experimental protocol was lines should be answered with words. (4) The items reviewed and approved by the Ethical Committee of The which were “not done” should be filled with “ND”; “do not First Affiliated Hospital of Henan University of TCM and know” should be filled with “UK.” (5) The “start time of drug was conducted according to the principles expressed in the administration”shouldbeaccuratetominute.(6)Namesof Declaration of Helsinki. all drugs should be filled with their generic names, rather than their trade names. The dosage form of drugs should be shown in parentheses following the name of drugs. Dosage unites 2.2. Subjects. Total 30888 patients administrated of DHI should be written clearly, such as “mg, mL, tablets, pills.” (7) from37hospitalsin6provincesparticipatedinthestudy The “Monitoring Information Form” was in duplicate. The between April 1, 2009, and August 30, 2013. first form associated with cover should be retained by the manufacturer. The second copy form should be retained by 2.3. Drug. DHI was manufactured by Shandong Buchang each monitoring hospital. Pharmaceutical Co., Ltd. (Heze, Shandong, China), which The basic information (including name, gender, age, was one of the exclusive varieties. nationality,bodyweight,badhabits,drugallergyandwhether it was the first time of administration of DHI), syndrome, dose regimen, adverse reactions, efficacy, laboratory test- 2.4. Methods ing, and rationality evaluation of drug administration of 30888 patients were mainly observed and recorded. Then, all 2.4.1. The Training of Safety Monitoring. Centralized hospital information was entered into the HIS (hospital information monitoring method was used to reevaluate the postmarketing system) database, which was used for the further statistical safety of DHI. Pharmacists as a third party who did not analysis. All analyses were performed by using the SPSS interfere with the normal clinical treatment of doctors went statisticalsoftwarepackage(version16.0). to ward every day to carry out the safety monitoring of each in-patient administered DHI during the therapeutic period. At the beginning of research, all clinical pharmacists who 2.4.3. The Process of Postmarketing Safety Reevaluation of participated in the study must accept the unified training DHI. In order to guarantee the objectivity and accuracy of of safety monitoring. The training of safety monitoring was ADR results, 3 grades evaluation of ADRs and ADEs were organized by Shandong Buchang Pharmaceutical Co., Ltd. conductedinthepresentstudy.Primaryevaluation:ADRs Evidence-Based Complementary and Alternative Medicine 3

ADRs/ADEs of DHI Centralized hospital monitoring method

Draw up research plan; researchers accept the unified training

HIS system retrieves new cases

Clinical observation by pharmacists

Follow-up observation until the end Pharmacists of medication Clinical pharmacists Clinical observation by pharmacists

1 ADRs/ADEs occurred? Yes Quality control (QC) Copy medical reports and fill out by each monitoring No the ADR/ADE report form hospital

Fill out the monitoring form

Collect and check monitoring forms

No Comply with filling 3 requirements? Correlation Yes reevaluation Data entry in pairs by experts 2 group on ADR/ADE QC by total research Data error correction team Centralized monitoring database of DHI

Standardization of database Data management Statistical analysis Statistical analysis

∙ Report on ADRs/ADEs of DHI by centralized hospital monitoring method ∙ Technical specification on postmarketing safety reevaluation of TCMIs by centralized hospital monitoring

Figure 1: The overall experimental flow chart of postmarketing safety surveillance and reevaluation of DHI.

and ADEs were preliminarily determined by the evaluation the results of the primary and intermediate evaluations. The team (including the director of pharmacy, quality control overall experimental flow chart is shown in Figure 1. personnel, and monitoring staffs) of each monitoring hospital, respectively. Intermediate evaluation: ADRs and ADEs determined by each monitoring hospital were reevaluated by 2.4.4. The Correlation Evaluation between ADRs and ADEs. ADRs/ADEs experts of total research team (The First Affil- During the process of postmarketing safety reevaluation of iated Hospital of Henan University of TCM and Shandong DHI, the correlation evaluation between ADRs and ADEs Buchang Pharmaceutical Co., Ltd.). Ultimate evaluation: all was the focal point. All ADRs/ADEs should be preliminar- ADRs/ADEs were evaluated by authoritative clinical and ily differentiated on basis of their definitions, respectively. pharmaceutical experts (Chief Pharmacists, Chief Physicians, An ADR is a response to a drug which is noxious and Deputy Chief Pharmacists, and Deputy Chief Physicians). unintended and which occurs at dose normally used in Final results were comprehensively given by combining with man for prophylaxis, diagnosis, or therapy of disease, or for 4 Evidence-Based Complementary and Alternative Medicine

Collect medical records and reports

Medical record number, name of ADR/ADE, basic information of patients, medications, manifestations of ADR/ADE, and relevant physicochemical indexes

Attribute the names of ADRs to their systems

Terminology standardization of ADRs/ADEs according to MedDRA

Database of 30888 patients on ADRs/ADEs of DHI was standardized and established by centralized hospital monitoring method

ADRs and ADEs of DHI were analyzed and differentiated

ADRs Correlation evaluation ADEs

General New Severe Certain Drug quality Medication errors

Probable Type A Type B Type C Doctors’ factor Possible Side effect Specific genetic Pharmacists’ factor qualities reaction Unlikely Toxic effect Nurses’ factor Sequelae effect Drug allergies Conditional

Secondary effect Others Unassessable Patients’ factor

Others

Figure 2: The detail flow chart of correlation evaluation between ADRs and ADEs.

the modification of physiologic function. ADRs may occur increase significantly when drug was readministered. It could following a single dose or prolonged administration of a drug be supported by literatures. The primary disease and other or result from the combination of two or more drugs. It factors had been ruled out. (2) Probable: there was no history does not include the reactions caused by accidental or of repeat medication; others were same as “Certain.” If the intentional drug overdoses and improper medications. The investigational drug was administrated by combination with meaning of ADR differs from the meaning of “side effect,” other drugs, the probability of ADR occurrence produced as the last expression might also imply that the effects can by the combination drugs could be excluded. (3) Possible: be beneficial. The study of ADRs is the concern of the field there was close relationship between medication and ADEs’ known as pharmacovigilance. An ADE refers to any injury occurrence. It could be supported by literatures. But more occurring at the time of drug administration, whether or than one drug could cause the ADRs/ADEs, or the factors of notitisidentifiedasacauseoftheinjury.AnADRisa primarydiseasecouldnotberuledout.(4)Unlikely:there special type of ADE in which a causative relationship can be was no close relationship between medication and ADEs’ shown. The causal relationship with the administration of the occurrence. The performances of reactions did not match the investigational drug or a study procedure was assessed knownADRs/ADEsoftheinvestigationaldrug.Thereactions according to the categories as described by the Uppsala during the development of primary disease might have Monitoring Centre and recommended by the World Health similar clinical manifestations. (5) Conditional: the contents Organization (WHO) (certain, probable, possible, unlikely, of “Monitoring Information Form” were not complete, which conditional, and unassessable) [16–18]. The detail flow of could be evaluated after the supplementary specification. It correlation evaluation between ADRs and ADEs is shown in was difficult to determine the relationship between cause Figure 2. and effect, which was scant in documentation. (6) Unassess- The explanations of the terms were as follows. (1) Certain: able: many items in the “Monitoring Information Form” the sequence between medication and ADRs’ occurrence were missed. It was difficult to determine the relationship was reasonable. ADRs could stop or quickly reduce or turn between cause and effect. And the missing items could not better after drug withdrawal. ADRs could occur again or be supplemented. Evidence-Based Complementary and Alternative Medicine 5

3. Results All adverse reactions in Table 3 could be classified into typesA,B,andC.TypeAreactionincludedsweating, 3.1.PrimaryEvaluationofADRsofDHIinEachMonitoring dizziness, headache, flushing, vasodilation, eye hemorrhage, Hospital. When the monitoring hospitals were selected, the faintness, chest pain, palpitations, breathlessness, anxious- monitoring hospitals should include general hospitals and ness, nausea, flatulence, vomiting, hypotension, hyperten- Chinese medicinal hospitals. The proportion of general hos- sion, local numbness, dyspnea, joint disease, and tinnitus. pitals in all hospitals should be greater than 0.5. Of the 37 Type B reaction included pruritus, rash, allergic purpura, monitoring hospitals, there were 31 general hospitals and 6 and periorbital edema. Type C reaction included clammy Chinese medicinal hospitals in the postmarketing safety skin, tics, superficial phlebitis, chills, high fever, fever, and surveillance and reevaluation of DHI. As shown in Table 1, cyanosis. there were total 132 ADE cases in 30888 patients. Several adverse reactions might occur in one patient, which belonged to different types of ADRs. For example, if 3.2. Intermediate Evaluation of ADRs/ADEs. Among the 132 dizziness and superficial phlebitis occurred in one patient, ADE cases, 115 cases (the cases of grades I, II, and III) were this patient would have both types A and C, because dizziness determined as the ADRs/ADEs of DHI (Table 2). belongedtotypeA,whilesuperficialphlebitisbelongedto type C. Among the 108 cases, 55, 31, and 14 cases were classified into types A, B, and C, respectively; 4 cases had both 3.3. Ultimate Evaluation of ADRs/ADEs. Among the 115 typesAandB;andanother4caseshadbothtypesAandC. ADR/ADE cases of DHI, 108 cases were identified as ADRs Therefore, patients with types A, B, and C reactions were 63, of DHI, and 7 cases were identified as ADEs of DHI. Of the 7 35, and 18 cases, respectively. ADEs, 2 cases were caused by nurses because of the DHI injection speed; 5 cases were caused by doctors including the improper medications (2 cases), solvents (2 cases), and 3.6. Occurrence Time of ADRs. The ADRs of 41, 14, 20, and compatibility (1 cases). 33 cases were observed within half an hour, from half an hour to 1 hour, from 1 hour to 24 hours, and over 24 hours, respectively.Theshortestofthatcouldbeobservedin1 3.4. Incidence Rate and Manifestations of ADR. The ADR minute after administration of DHI, while the longest of that incidence rate of DHI was 3.50‰. ADRs of DHI involved the was found in the 11th day. damage of several systems. Among them, the damages of skin and its appendages, central and peripheral nervous system, and extracardiac vascular system were more common, which 3.7. Severity Classification of ADRs. The severities of ADRs totally accounted for 68.35% (Table 3). There were 17 kinds of were divided into three grades, including mild (temporary new adverse reactions of DHI which were found in the discomfort and tolerable), moderate (significant discomfort), present study, manifesting as sweating, clammy skin, superfi- andsevere(potentiallylifethreateningorcausingperma- cial phlebitis, allergic purpura, vasodilation, eye hemorrhage, nent disability or death) reactions [18]. Mild reactions are periorbital edema, faintness, chest pain, anxious, flatulence, perceptible symptoms or signs without stopping medication cyanosis, hypotension, hypertension, local numbness, joint and special treatment, which do not affect the daily life. The disease, and tinnitus. symptoms or signs of moderate reactions can be tolerated but need special treatment, which also do not affect the daily life. The symptoms or signs of severe reactions cannot 3.5. Classification of ADRs. On basis of pathogenesis of be tolerated, which need to stop medication and special ADRs, ADRs are divided into three types (types A, B, and C) treatment. And the severe reactions can affect the daily life. by WHO [16, 17]. Type A are predictable adverse reactions Of 108 ADRs, 28, 72, and 8 cases were classified as which are a consequence of the drug’s normal pharmaco- mild, moderate, and severe reactions, respectively; which logical effects and dose-related with a low mortality. Such accounted for 25.93%, 66.67%, and 7.41%.Among the 8 severe reactions are usually due to incorrect dosage (too much or cases, the symptoms of 4 cases had more severe reactions, too long) or disordered pharmacokinetics and failure of drug manifesting as chills, fever, cyanosis, and convulsions. elimination. Type A usually include side effects, toxic effects, aftermath effects, and sequelae effect. Type B reactions are not predictable from the drug’s main pharmacological actions. 3.8. Disposition of ADRs. Treatment measures against the They are not dose-related and they have a considerable ADRs of DHI included drug withdrawal, symptomatic treat- mortality. Type B reactions occur infrequently, which usually ment for the ADRs, combination method between reducing include allergies and specific genetic qualities reactions. Type thedosageofdrugsanddrugwithdrawal,andcombination C reactions refer to the abnormal reactions other than types method between drug withdrawal and symptomatic treat- A and B, which usually occur after long-term treatment and ment for the ADRs. Among 108 cases, 28 cases recovered have long incubation period. It is difficult to predict type C withoutanytreatmentmeasures(25.93%);57,4,1,and18cases reactions, which do not have ambiguous relationship with recovered after drug withdrawal, symptomatic treatment, time. The pathogenesis of some type C reactions correlated combination method between reducing the dosage of drugs with carcinogenic, teratogenic, and cardiovascular disease and drug withdrawal, and combination method between and fibrinolytic system changes after long-term medication. drug withdrawal and symptomatic treatment for the ADRs, 6 Evidence-Based Complementary and Alternative Medicine 30888 100.00 132 100.00 Table 1: The general information and numberthe of ADE cases monitoring 37 in hospitals. HospitalsThe First Affiliated Hospitalof Henan University Henan Provincial People’s HospitalThe First Affiliated Hospitalof Zhengzhou The University Second Affiliated Hospital Zhengzhou of The University Second Affiliated Hospital Henan of Zhengzhou University Municipal People’s HospitalShanxi Province Hospital of TCM (Xi’an)General Hospital of TISCOTaiyuan City Centre HospitalWuhan Union HospitalChongqing Third People’s HospitalThe Second TCM Hospital of of ShanxiThe Medical First College Hospital (Taiyuan) Shanxi of MedicalChongqing University (Taiyuan) First People’s HospitalZhongshan Hospital of Chongqing of TCMThe Second Affiliated Hospital Xi’an of MedicalXi’an 521University HospitalXi’an Aerospace General HospitalXi’an Liberation People’s Army 451 HospitalXi’an TCM9468 141 Hospital 600Gaoling County Hospital 149Xi’an Central Hospital 2002Chang’an District3580 Hospital 1050 501People’s Liberation Army 789 153 Number Hospital of casesZhengzhou First People’s HospitalShanxi Province Hospital of TCM (Taiyuan)Taiyuan People’s Hospital Constituent ratio (%)Shanxi Hospital 1.94 of Integrated Traditional and WesternThe Medicine Second (Taiyuan) 199 Hospital 398 149 0.48 of Hebei MedicalShijiazhuang University 6.48 Hospital of TCM Number of ADEThe cases First Hospital 1.62 Hebei of MedicalShanxi University Provincial2.55 942 People’s Hospital (Taiyuan) 239299People’s Liberation Army 323 Hospital 420 331 Constituent ratioShanxi (%) Coal Central 999 Hospital (Taiyuan) 902Chongqing Cancer HospitalWuhan Fifth People’s Hospital 506Wuhan 0.64 General Hospital 1.29 0.48 3 of the 30.65 71 53.79 Yangtze RiverTotal Shipping 5 3.05 0.77 0 11.59 16 12.12 518 1002 1.36 300 1.07 3.40 3 2.27 0.97 1 0.76 3.23 299 503 300 200 100 500 1.64 0 2 2.27 300 1.52 2 500 3.79 3.24 1.68 389 0 0.97 4 1006 0.00 200 0.97 3 2.27 1 0 496 1.63 2 0.97 0.65 0.32 1.62 2.92 0 0.00 1.63 503 0 0.97 0.00 3 2.27 149 1.52 100 1.62 1.26 3.26 0.65 0 0 0.00 0 1.61 3.03 0 0.00 0.76 1.52 1 0 0 4 0.00 0.48 2 0.32 0 7 0 0 0.00 0.00 0.00 0 0.00 0 0.00 0.76 0.00 0.00 3.03 0 0.00 1 1.52 0.00 5.30 0.00 0.00 0.00 0.76 0.76 1 Evidence-Based Complementary and Alternative Medicine 7

Table 2: Results of correlation evaluation between ADRs and ADEs of DHI. Grade Results of correlation evaluation Number of cases Constituent ratio (%) I Certain 21 15.91 II Probable 61 46.21 III Possible 33 25.00 IV Unlikely 13 9.85 V Conditional 1 0.76 VI Unassessable 3 2.27 Total 132 100.00

Table 3: ADR manifestations of DHI. Systems/organs Frequency Constituent ratio (%) Manifestations (number of cases) Skin and its appendages 47 30.13 Pruritus (23), rash (19), sweating (3), and clammy skin (2) The central and peripheral nervous system damage 34 21.79 Dizziness (17), headache (16), and tics (1) Superficial phlebitis (12), flushing (9), allergic Extracardiac vascular damage 25 16.03 purpura (1), vasodilation (2), and eye hemorrhage (1) Systemic damage 12 7.69 Chills (6), high fever (2), fever (1), periorbital edema (1), faintness (1), and chest pain (1) Heart rate and rhythm disorders 10 6.41 Palpitations (10) Neurological disorders 10 6.41 Breathlessness (7), anxiousness (3) Gastrointestinal system damage 9 5.77 Nausea (6), flatulence (2), and vomiting (1) General damages to the cardiovascular system 4 2.56 Cyanosis (2), hypotension (1), and hypertension (1) Medication site damage 2 1.28 Local numbness (2) Respiratory system damage 1 0.64 Dyspnea (1) Musculoskeletal system damage 1 0.64 Joint disease (1) Auditory and vestibular dysfunction 1 0.64 Tinnitus (1) Total 156 100.00

respectively, which accounted for 52.78%, 3.70%, 0.93%, and Several methods of surveillance are used in the clin- 16.67%. ical setting to detect ADRs/ADEs. In our previous study, centralizedhospitalmonitoringmethodwastheappropriate method to carry out postmarketing safety evaluation of 3.9. Recovery of ADRs. Among 108 ADRs, 64 cases were TCMIs [15].Thismethodisonekindoftheinternational completelycuredand46casestookaturnforthebetter.There advanced research methods of drug epidemiology. It is an werenosequelaeordeaths.Ofthem,11,26,12,and59cases observational research method, which can make intensive improved within 1 hour (10.19%), 1∼6hours(24.07%),6∼24 study of clinic without intervention of clinical applications. hours (11.11%), and over 24 hours (54.63%). This method can timely, comprehensively, and accurately observe the adverse reactions, which is called “the research of real world.” Additionally, the correlation evaluation between 4. Discussion ADRs and ADEs could be carried out according to the collected clinical materials, and the accurate incidence rate WHO,theFoodandDrugAdministration(FDA),andthe and types and severity of ADRs/ADEs can be obtained. Joint Commission on Accreditation of Healthcare Organi- It is a fast and scientific method of postmarketing safety zations (JCAHO) have recognized the importance of estab- reevaluation. This method is suitable for monitoring the lishing mechanisms for ADRs/ADEs surveillance in health varieties which have a certain market time and stable amount care organizations [19–21]. Hospitals are mandated to have of applications. Otherwise, the number of cases is too low to ongoing drug surveillance programs in place in order to achieve the purpose of the evaluation. Due to the restrictions detect and evaluate the effects of drugs and to propagate safe, of observation time and funding, it is not easy to find appropriate, and effective drug therapies [21]. the rare adverse reactions. Therefore, accurate conclusions 8 Evidence-Based Complementary and Alternative Medicine could be comprehensively obtained by the conjunction with in 6 provinces. The incidence rate, types, severities, and other assessment methods such as the spontaneous reporting other information of ADRs/ADEs of DHI were obtained. method. Voluntary spontaneous reporting systems can be The research system and mode of postmarketing safety used as a necessary complement of centralized hospital surveillance and reevaluation of TCMIs were established, monitoring method. The rare ADRs/ADEs can be found by which can provide demonstration and reference for other voluntary spontaneous reporting systems. TCMIs and improve the rationality, scientificity, and safety of There are postmarketing safety surveillance and reeval- clinical applications of TCMIs. uations for the western medicine and TCMIs. For example, the postmarketing safety surveillance of Shenmai Injection Conflict of Interests was reported [22]. The results showed that were 5 ADRs in 699 cases, and the ADR incidence rate of Shenmai injec- The authors declare that there is no conflict of interests tion was 0.72%. Guangdong Pharmacological Society was regarding the publication of this paper. entrusted with postmarketing intensive monitoring study of Shenqifuzheng injection in 2007 [23]. Their results showed that, among 20100 cases observed, the incidence of ADR Acknowledgments was 1.85‰, 27 cases had “mild” ADRs/ADEs, and 10 cases This work was supported by the Task of Subproject of displayed “moderate” ADRs/ADEs. There were no severe the 12th Five-Year “the Creation of Significant New Drugs” ADRs/ADEs. Additionally, the postmarketing safety surveil- Major Special Project “Research Technology Platform for lance data of AS03-adjuvated A (H1N1) pandemic vaccine in IV Phase Clinical Trials of Great Variety of Drugs and Ontario, Canada, was reviewed [24]. Clinical Trial Review of New Drugs”, Post-Marketing Clin- Clinical pharmacists play an important role in ADE ical Study of Danhong Injection (no. 2011ZX09304-07), the surveillance activities. Pharmacists’ training in therapeutics Subproject of “the 11th Five-Year” Scientific and Technolog- and comprehensive drug knowledge makes them an obvious ical Support Projects “Standard and Specification Research choice for ADE surveillance. Pharmacists’ knowledge of of Postmarketing safety surveillance and reevaluation of drugs and clinical therapeutics may give them an advantage Chinese Medicines/Demonstration Research of Emphasis over other clinicians for the purpose of inpatient ADRs/ADEs Monitoring and Assessment of Traditional Chinese Medicine detection. As awareness of patient safety issues increases, Injections” (no. 2006038086056), and Henan Province Scien- pharmacists find themselves more engaged in ADRs/ADEs tific and Technological Projects—Standardized Application surveillance activities. It is important to note that, in the Research of Traditional Chinese Medicine Injections (no. studies, pharmacists not only were limited to medication 102102310077). orders or laboratory values but also took into account any textual signals that existed in the medical record, such as progress notes, shift assessments, and pharmacist’s notes. 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Zhang, Clinical Application Guide of TCM guidance of previous monitoring results, the quality of DHI Injections, People’s Health Publishing House, Beijing, China, had been improved after the quality control of original 2011. ingredients and the optimization of processing technique; (3) [4] W.-T. Song, F.-F.Cheng, L. Xu, C.-R. Lin, and J.-X. Liu, “Chinese the analysis of results was more standardized and accurate; medicine shenfu injection for heart failure: a systematic review (4) the administration of DHI by doctors and nurses was and meta-analysis,” Evidence-Based Complementary and Alter- more standardized and reasonable. native Medicine,vol.2012,ArticleID713149,25pages,2012. The postmarketing surveillance of TCMIs was a good [5] M. Sun, J.-J. Zhang, J.-Z. Shan et al., “Clinical observation of method to solve information lag of drug instructions. It Danhong Injection (herbal TCM product from Radix Salviae could supplement the drug instructions, keep up with the miltiorrhizae and Flos Carthami tinctorii) in the treatment of latest research progress of related drugs, guide the clinical traumatic intracranial hematoma,” Phytomedicine,vol.16,no. application of drugs, and improve the safety and effectiveness 8, pp. 683–689, 2009. of drugs in clinical applications. [6] Z. Zhao, H. Fan, T. Higgins et al., “Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via 5. Conclusions TRPV1 signaling pathways,” Cancer Letters,vol.355,no.2,pp. 232–241, 2014. The postmarketing safety surveillance and reevaluation of [7] X.-J. Niu, “The situation, causes, and prevention of adverse DHI was carried out with 30888 cases from 37 hospitals reactions of traditional Chinese medicine injections,” Chinese Evidence-Based Complementary and Alternative Medicine 9

JournalofClinicalRationalDrugUse,vol.7,no.7,pp.93–94, [23] Q.-H. Ai, W. Zhang, Y.-M. Xie, W.-H. Huang, H. Liang, and 2014. H. Cao, “Post-marketing safety monitoring of Shenqifuzheng [8] A. Miguel, L. F. Azevedo, M. Araujo,´ and A.-C. Pereira, injection: a solution made of Dangshen (Radix Codonopsis) “Frequency of adverse drug reactions in hospitalized patients: and Huangqi (Radix Astragali Mongolici),” Journal of Tradi- asystematicreviewandmeta-analysis,”Pharmacoepidemiology tional Chinese Medicine, vol. 34, no. 4, pp. 498–503, 2014. and Drug Safety, vol. 21, no. 11, pp. 1139–1154, 2012. [24]T.Harris,K.Wong,L.Stanford,J.Fediurek,N.Crowcroft,and [9]K.J.Patel,M.S.Kedia,D.Bajpai,S.S.Mehta,N.A.Kshirsagar, S.-L. Deeks, “Did narcolepsy occur following administration and N. J. Gogtay, “Evaluation of the prevalence and economic of AS03-adjuvanted A(H1N1) pandemic vaccine in Ontario, burden of adverse drug reactions presenting to the medical Canada? A review of post-marketing safety surveillance data,” emergency department of a tertiary referral centre: a prospec- Eurosurveillance,vol.19,no.36,2014. tive study,” BMC Clinical Pharmacology,vol.7,article8,2007. [10] Y. Guan, Y. Yin, Y.-R. Zhu et al., “Dissection of mechanisms of a Chinese medicinal formula: danhong injection therapy for myocardial ischemia/reperfusion injury in vivo and in vitro,” Evidence-Based Complementary and Alternative Medicine,vol. 2013, Article ID 972370, 12 pages, 2013. [11] S.-J. Li, Y.-P. Tang, J. Shen, J.-P. Li, J.-M. Guo, and J.-A. Duan, “Research of Chinese medicine pairs (VIII)-salviae miltiorrhizae radix et rhizoma-carthami Flos,” Chian Journal of Chinese Materia Medica, vol. 38, no. 24, pp. 4227–4231, 2013. [12] C. Shi, Y. Zhao, S.-W. Zheng, and P. Huang, “Analysis of clinical use of the post-marketing Danhong injection based on hospital central monitoring method information system,” Chinese Journal of Hospital Pharmacy,vol.34,no.2,pp.119–122, 2014. [13] L.-M. Huang, J.-Q. Ma, X. Zhang, -L. Kang, S.-C. Zhang, and S.-H. Zhang, “Use situation of Danhong injection: centralized monitoring of 987 cases,” China Pharmaceuticals,vol.22,no.17, pp.49–50,2013. [14] S. Yu and Y.-X. Liu, “The clinical efficacy of Danhong injection in treating angina pectoris,” Guide of China Medicine,vol.10,no. 11, pp. 47–48, 2012. [15]X.Li,J.Tang,F.Meng,C.Li,andY.Xie,“Comparativestudyon four kinds of assessment methods of post-marketing safety of Danhong injection,” China Journal of Chinese Materials Medica, vol.36,no.20,pp.2786–2788,2011. [16] D.-Q. Ren and B.-L. Zhang, Guide for Clinical Application of Traditional Chinese Medicine Injections, People’s Medical Publishing House, Beijing, China, 2011. [17] Y.-Y. Wang, A.-P. Lv, and Y.-M. Xie, The Key Technologies of Clinical Re-evaluation of Post-Marketing Traditional Chinese Medicine, People’s Medical Publishing House, Beijing, China, 2011. [18] E.-W.Baars, M. Jong, A.-F.Nierop, I. Boers, and H.-F.Savelkoul, “Citrus/cydonia compositum subcutaneous injections versus nasal spray for seasonal allergic rhinitis: a randomized con- trolledtrialonefficacyandsafety,”ISRN Allergy, vol. 2011, Article ID 836051, 11 pages, 2011. [19] International Drug Monitoring, The Role of the Hospital,vol. 425 of World Health Organization Technical Report Series,1969. [20] K.-C. Pearson and D.-L. Kennedy, “Adverse drug reactions and the food and drug administration,” Journal of Pharmacy Practice,vol.2,no.4,pp.209–213,1989. [21] Joint Commission on Accreditation of Healthcare Organiza- tions, Accreditation Manual for Hospitals, Joint Commission on Accreditation of Healthcare Organizations, Chicago, Ill, USA, 1991. [22]W.Lu,P.Jiang,andS.-H.Zhang,“Post-marketingsafetyre- evaluation of Shenmai injection,” China Journal of Hospital Pharmacy,vol.33,no.6,pp.491–492,2013. Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 217494, 8 pages http://dx.doi.org/10.1155/2015/217494

Research Article Antitumor Efficacy and Mechanism in Hepatoma H22-Bearing Mice of Brucea javanica Oil

Wen-Rong Shi, Yan Liu, Xiao-Ting Wang, Qiong-Ying Huang, Xue-Rong Cai, and Shao-Rong Wu College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China Correspondence should be addressed to Yan Liu; liu [email protected]

Received 9 April 2015; Accepted 3 June 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Wen-Rong Shi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Brucea javanica is a traditional herbal medicine in China, and its antitumor activities are of research interest. Brucea javanica oil, extracted with ether and refined with 10% ethyl alcohol from Brucea javanica seed, was used to treat hepatoma H22-bearing mice in this study. The antitumor effect and probable mechanisms of the extracted Brucea javanica oil were studied in H22-bearing mice by WBCcount,GOT,GPTlevels,andwesternblotting.TheH22tumorinhibitionratioof0.5,1,and1.5g/kgbwBrucea javanica oil were 15.64%, 23.87%, and 38.27%. Brucea javanica oil could inhibit the involution of thymus induced by H22 tumor-bearing, but it could not inhibit the augmentation of spleen and liver. Brucea javanica oil could decrease the levels of WBC count and GOT and GPT in H22-bearing mice. The protein levels of GAPDH, Akt, TGF-𝛽1, and 𝛼-SMA in tumor tissues decreased after being treated with Brucea javanica oil. Disturbing energy metabolism and neoplastic hyperplasia controlled by Akt and immunoregulation activity were its probable antitumor mechanisms in hepatoma H22-bearing mice.

1. Introduction terpenoids, alkaloid glycosides, quassinoid glycosides, and quassinoids [4–8]. In addition, a complex mixture of fatty Cancer is a generic term for a large group of diseases that can acids and fatty acid derivatives (Brucea javanica oil), whose affect any part of the body. One defining feature of cancer main activity components are oleic acid and linoleic acid, is the rapid creation of abnormal cells that grow beyond has been extracted from the seed of Brucea javanica. Oleic their usual boundaries and which can then invade adjoining acid, linoleic acid, and quassinoids are known to be the major partsofthebodyandspreadtootherorgans.Thisprocess antitumor activity compounds [9]. It has been reported that is referred to as metastasis. Metastases are the major cause Brucea javanica oil inhibited tumor cell growth via inhibition of death from cancer. Cancer is a leading cause of death worldwide, accounting for 8.2 million deaths in 2012. The of DNA polymerase, overcoming tumor multidrug resistance, most common causes of cancer death are cancers of lung and the damage of tumor cell membrane system [10]. and liver [1]. Chinese medicine, one of the most popular Brucea javanica oilisanaturalplantproductthatpos- complementary and alternative medicines, is an available sesses antitumor properties, but more molecular mechanisms option in many cancer centres in Asia, North America, and of the antitumor effects of it are still unrevealed. Here we Europe [2]. investigate the antitumor efficacy of Brucea javanica oil Brucea javanica (B. javanica (L.) Merr.) is a shrub extracted with ether and refined with 10% ethyl alcohol in mostly originated in India, Southeast Asia, and Northern hepatoma H22-bearing mice. Furthermore, the protein levels Australia [3]. Brucea javanica seed is used for oncotherapy of 𝛽-catenin, PI3K, Akt, TGF-𝛽1, 𝛼-SMA, GAPDH, and 𝛽- in Chinese medicine. A series of chemical compounds have actin (as internal control) in H22 tumor tissues treated in vivo been isolated from this plant, such as alkaloids, lignans, with Brucea javanica oil were detected. 2 Evidence-Based Complementary and Alternative Medicine

2. Materials and Methods (%) = [(𝐴 − 𝐵)/𝐴]00%, ×1 where 𝐴 is the average tumor weight of the negative control and 𝐵 is the tumor weight of 2.1. Mice and Cell Lines. Female Chinese Kunming mice the treated group or positive control. (weight 18∼20 g) were purchased from Fujian medical university laboratory animal center (Fuzhou, China). The mice were 2.5. Antibodies for Western Blotting. Antibodies against 𝛽- housed under normal condition and with free access to food catenin, Akt, and PI3K were from Cell Signaling Technology and water. Animal experiments and animal care were carried (Beverly, MA, USA). Antibodies against TGF-𝛽1and𝛼-SMA out according to protocols approved by the institutional com- were from Abcam (UK). The antibody against GAPDH was mittee for animal care and also in accordance with the policy from Hangzhou Xianzhi Biological Technology (Zhejiang, of the National Ministry of Health. Murine hepatoma cell CN). Anti-𝛽-actin antibody was from Sigma. Anti-mouse line H22 was purchased from China Centre for Type Culture IgG peroxidase-linked whole antibody and anti-rabbit IgG Collection (CCTCC, Wuhan, China), subcultured, and main- peroxidase-linked species-specific whole antibody were from tained in our laboratory according to the guidelines given. Beyotime Institute of Biotechnology (Jiangsu, CN).

2.2. Extraction and Refining of Brucea javanica Oil. Brucea 2.6. Tumor Harvesting and Western Blotting. The H22 tumors javanica fruits (Chinese medicinal materials, place of origin: were excised from the mice of negative control group and Xiamen, China) were purchased from Suzhou Hengfeng 1.5 g/kg Brucea javanica oil groups and snap frozen in Ginseng & Deer Antler Commercial Firm, Jiangsu, China. ∘ liquid nitrogen. Lysates were prepared in RIPA lysis buffer Brucea javanica fruits were dried to constant weight at 80 C (Beyotime Institute of Biotechnology, Jiangsu, CN) using a and shelled to get the seeds. Brucea javanica seeds were milled dounce homogenizer. Protein concentrations were quantified andsoakedwithethertoextracttheseedoil.Thecrude using BCA Protein Assay Reagent (Beyotime Institute of seed oil was refined with 10% ethyl alcohol according to the Biotechnology, Jiangsu, CN). Lysates were run at 40 𝜇gper patented method [11]. lane on 8% to 10% Bis-Tris gels and transferred to PVDF membranes (Invitrogen). Western blot band intensity quan- 2.3. Acute Toxicity in Mice. Kunming mice were randomly tification was done using Gel-Pro Analyzer software v4.0 divided into 8 groups according to the dose (𝑛=12each (Media Cybernetics, Inc., USA). To account for differences group). The refined Brucea javanica oil was injected subcuta- in protein loading, all band intensities were corrected for 𝛽- neously in the back with doses of 1.25, 2.5, 5, 6.25, 7.5,8.75, 10, actin. and 11.25 g/kg bw. After 24 h of injection, the number of mice surviving was recorded and the value of LD50 of Brucea javan- 2.7. Statistical Analysis. Student’s 𝑡-test and ANOVA were ica oil was calculated using the Bliss method with BL-420E used to analyze mean differences between groups of mice. 𝑃 software (Chengdu TME Technology Co., Ltd., China) [12]. values of <0.05 were considered significant.

2.4. Antitumor Efficacy on Mice Hepatoma. H22-Bearing 3. Results Mice models were generated by subcutaneous injection of 6 2 × 10 H22 cells (mice hepatoma) in the armpit of left 3.1. Acute Toxicity in Mice. The LD50 was used to deter- forelimb of each mouse. After injection, the mice models mine the acute toxicity, the changes in behavior, breathing, were randomly divided into 5 groups (𝑛=10each group): cutaneous effect, and sensory nervous system responses, soybean oil for injection (negative control), 0.5, 1, and and gastrointestinal effects were observed. The subcutaneous 1.5 g/kg bw Brucea javanica oil (groups A, B, and C), and injection of Brucea javanica oil in doses ranging from 25 mg/kg bw 5-Fu (positive control). And 10 other normal 1.25 g/kg bw to 5 g/kg bw did not produce significant toxicity mice were set as normal control with injection of equal symptoms. Accompanying the increase of dose, towering volume of soybean oil. The Brucea javanica oil was diluted to hair, reduction in locomotor activity, and dull reactions corresponding concentration with soybean oil for injection. were produced and the mortality was 100% in the dose of The mice were injected subcutaneously in the back with cor- 11.25 g/kg bw. The LD50 of Brucea javanica oil and its 95% responding medicines and the body weights before and after confidence limits were 8.36 and 7.07–10.05 g/kg bw. the experiment were measured. Seven days of continuous infusion later, all the mice were sacrificed, the tumor weights 3.2. Effect of Brucea javanica Oil on Body Weight of H22- were recorded, and the whole blood, serum, thymus, spleen, Bearing Mice. The changes in body weights of mice before heart, liver, kidney, and lung were collected. The blood white and after the experiment were as shown in Table 1; body blood cells (WBC) were counted manually and the levels weights increased markedly in all of the experimental groups. of GOT and GPT in serum were measured with automated After experiment, the average body weights of mice did not biochemical analyzer (Hitachi, Japan). The organ coefficients have significant differences between six groups, although the (mg/g) of thymus, spleen, liver, kidney, and lung were calcu- average body weight of mice in positive control group was a lated using the following formula: organ coefficient = organ little lower compared with normal control or negative control weight/(body weight – tumor weight). Antitumor effects are group. The subcutaneous injection of Brucea javanica oil for 7 expressed with inhibition ratio (%). The inhibition ratio (%) days in dose no more than 1.5 g/kg bw did not affect the body was calculated by the following formula: inhibition ratio weight growth. Evidence-Based Complementary and Alternative Medicine 3

Table 1: Effect of Brucea Javanica oil on body weight of H22-bearing mice before and after experiment (𝑋±𝑆, 𝑛=10).

Group Dose Number of Average body weight of mice Average body weight of mice (g/kg bw) animals before the experiment (g) after the experiment (g) Normal control 10 19.32 ± 1.86 23.67 ± 2.08 Negative control 10 19.31 ± 1.63 22.35 ± 2.29 5-Fu 0.25 10 19.15 ± 1.49 21.14 ± 1.92 A 0.5 10 19.30 ± 1.73 23.49 ± 1.94 B 11019.06± 1.67 22.35 ± 2.34 C 1.5 10 19.34 ± 1.79 22.39 ± 1.68 The average body weight of mice after the experiment excluding the tumor weight.

Table 2: Effect of Brucea Javanica oil on tumor weight and tumor significantly. Compared with the negative control group, low inhibition ratio (𝑋±𝑆, 𝑛=10). dose Brucea javanica oil can increase the thymus index, but the high dose Brucea javanica oil decreased the thymus index Dose Number Average tumor Inhibition Group 𝑃 = 0.08 (g/kg bw) of animals weight (g) ratio (%) instead ( ). The spleen index of tumor-bearing mice can be more or less increased by 0.5, 1, and 1.5 g/kg bw Negative 10 2.43 ± 1.08 — Brucea javanica oil. There were no significant differences in control ∗∗ the indices of kidney, heart, and lung between all groups. 5-Fu 0.025 10 1.40 ± 0.62 42.39 A 0.5 10 2.05 ± 0.78 15.64 3.5.EffectofBruceajavanicaOilonWBCCountofMice. The B1101.85± 0.73 23.87 ∗∗ changes of average WBC count of mice were as shown in C1.5101.50± 0.39 38.27 Table 5. It can be seen from the result H22 tumor-bearing ∗∗ Comparison with the negative control group, 𝑃 < 0.01. increased WBC count of mice obviously and the WBC counts in 5-Fu treated or in Brucea javanica oil treated tumor- bearing mice decreased to the normal level.

3.6. Changes in GOT and GPT of Mice. The changes in the levels of GOT and GPT in serum of mice were as shown in Table 6. The results showed that Hepatoma H22-bearing increased the levels of GOT and GPT significantly and the levels of GOT and GPT decreased after being treated with 5- Fu or Brucea javanica oil compared with the negative control group.

Figure 1: The tumors excised from the mice in the different groups. 3.7.Changes in Protein Levels of 𝛽-catenin, PI3K, Akt, GAPDH, A Negative group, B 0.5 g/kg bw Brucea javanica oil, C 1g/kgbw 𝛼-SMA, and TGF-𝛽1. The protein levels of 𝛽-catenin, PI3K, D E Brucea javanica oil, 1.5 g/kg bw Brucea javanica oil, and Akt, GAPDH, 𝛼-SMA, and TGF-𝛽1innegativecontrolgroup positive group (25 mg/kg bw 5-Fu). and 1.5 g/kg bw Brucea javanica oil group were as shown in Figure 2.

3.3. Effect of Brucea javanica Oil on Tumor Weight and Tumor 4. Discussion Inhibition Ratio. The results for the effect of Brucea javanica oil on tumor weight and tumor inhibition ratio were as shown Brucea javanica fruit is a kind of Chinese herb with toxicity. in Figure 1 and Table 2. There was a mouse in the negative In China, the emulsion formulation of Brucea javanica oil control group that died in the sixth day, and only the body hasbeenusedclinicallywidelyincombinationwithcon- weight and tumor weight were recorded. The tumor excised ventional therapy to treat carcinoma, demonstrating efficacy from this mouse was not photographed. enhancing, toxicity reducing effects, and immunoregulation activity [13–16], but the exact antitumor active components 3.4. Changes in Main Organ Coefficients of Mice. The main and corresponding molecular mechanisms have not been organ coefficients of mice, including thymus, spleen, liver, fully clarified [17]. kidney, heart, and lung index, were as shown in Tables 3 and Brucea javanica oil has been found to exhibit lethal tox- 4. Compared with the normal control group, H22 tumor- icity to human or experimental animals, which has brought bearing decreased the thymus index and increased the spleen many difficulties to clinical application. The water-soluble and liver indices significantly. Treated with 25 mg/kg bw quassinoid compounds were considered as the major material 5-Fu, the thymus index of tumor-bearing mice decreased basis of its toxicity such as brucenol, bruceoside, brusatol and 4 Evidence-Based Complementary and Alternative Medicine

Table 3: Changes in thymus index, spleen index, and liver index of mice (𝑋±𝑆).

Group Dose Number of Thymus index Spleen index Liver index (g/kg bw) animals (mg/g) (mg/g) (mg/g) Normal control 10 5.01 ± 0.79 5.11 ± 1.35 46.79 ± 5.27 ∗∗ ∗∗ ∗∗ Negative control 92.72± 1.06 8.76 ± 2.11 66.01 ± 6.29 ∗∗,△△ ∗ ∗∗ 5-Fu 0.025 10 1.22 ± 0.32 7. 6 4 ± 1.77 62.33 ± 6.89 ∗∗,△ ∗∗,△ ∗∗ A 0.5 10 3.72 ± 1.28 10.83 ± 1.09 68.56 ± 6.76 ∗∗ ∗∗,△△ ∗∗ B 1103.17± 0.95 11.80 ± 3.09 64.80 ± 6.72 ∗∗ ∗∗ ∗∗ C 1.5 10 2.00 ± 0.75 10.37 ± 3.08 64.28 ± 8.36 ∗ ∗∗ △ △△ Comparison with the normal control group, 𝑃 < 0.05, 𝑃 < 0.01.Comparisonwiththenegativecontrolgroup, 𝑃 < 0.05, 𝑃 < 0.01.

Table 4: Changes in kidney index, heart index, and lung index of mice (𝑋±𝑆).

Group Dose Number of Kidney index Heart index Lung index (g/kg bw) animals (mg/g) (mg/g) (mg/g) Normal control 10 12.17 ± 0.84 5.29 ± 0.82 7.74 ± 2.46 Negative control 9 12.07 ± 0.49 5.26 ± 0.47 6.01 ± 0.48 5-Fu 0.025 10 12.88 ± 1.57 5.48 ± 0.69 6.41 ± 0.69 A 0.5 10 13.49 ± 2.52 5.87 ± 0.87 7.16 ± 1.26 B 11013.08± 1.58 5.44 ± 0.87 7.20 ± 1.47 C 1.5 10 12.21 ± 1.99 4.83 ± 0.70 7.25 ± 2.34

Table 5: Changes of WBC count of mice (𝑋±𝑆). javanica oil induces apoptotic death of cancer cells via both the death receptors and the mitochondrial-related pathways. Dose Number of WBC count (109 Group Brucea javanica oil also could inhibit the invasion and migra- (g/kg bw) animals cells/L) tion of tumor cells targeting at MRP-1/CD9 and integrin Normal control 10 4.79 ± 1.36 alpha-5. In addition, the autophagic process contributed to ∗∗ Negative control 9 13.88 ± 7. 4 3 an increasing rate of cell death induced by Brucea javanica △△ 5-Fu 0.025 10 3.97 ± 1.22 oil. In this study, we concluded immunoregulation activity △△ A 0.5 10 5.25 ± 1.53 and neoplastic hyperplasia controlled by Akt were probable ± △△ antitumor mechanisms of Brucea javanica oil in H22-bearing B 1 10 5.98 2.36 mice. ± △△ C1.5105.582.33 The thymus is the major site of T cell differentiation and ∗∗ Comparison with the normal control group, 𝑃 < 0.01;comparisonwith a key organ of the immune system. Many studies proved △△ the negative control group, 𝑃 < 0.01. that tumor-bearing in mice could induce thymic atrophy due to the abnormal T cell development and apoptosis. In tumor-bearing mice, T cell recruitment from the thymus bruceine [18, 19]. In our past study, the LD50 of Brucea javan- to the spleen and splenic excess augmentation could be ica oil extracted with ether directly was 2.26 g/kg bw in mice. observed. The splenic excess augmentation in H22-bearing We used the 10% ethyl alcohol to extract and refine the Brucea mice was associated with the export of cells which was javanica oil. After the removal of residual water-soluble toxic restrained after the cells entered the spleen, especially the components, the LD50 of refined Brucea javanica oil increased CD8+T cell being detected. CD8+T cell was bound up with to 8.36 g/kg bw in mice. Oleic acid and linoleic acid were immunosuppression of spleen in H22-bearing mice [27–30]. considered as the major antitumor activity compounds in Our results showed that low and medium dose of Brucea Brucea javanica oil [9]. In addition, three terpene alcohols, javanica oilcouldpreventthethymicatrophyofmiceinduced lupeol, and taraxerol also had antitumor activity [20–22]. Our with H22 tumor-bearing in different extent, but the high results clearly indicated that the refined Brucea javanica oil dose of Brucea javanica oil could not. Treated with high dose caninhibitthegrowthofimplantedhepatomaH22inmice of Brucea javanica oil, the splenic excess augmentation in in a dose-dependent manner. The antitumor efficacy of high H22 tumor-bearing mice became serious. Whether the more dose Brucea javanica oil (1.5 g/kg bw) was slightly lower than serious splenic excess augmentation could cause more serious 25 mg/kg bw 5-Fu. immunosuppression of spleen in H22-bearing mice or not ThenweinvestigateprobablemechanismsofBrucea needs further study. javanica oil in hepatoma H22-bearing mice. The multiple According to the result of effect of Brucea javanica oil pathways involved in the action of Brucea javanica oil were on WBC count of mice, it was showed that H22 tumor- further identified [17, 23–26]. It could be proposed Brucea bearing induced the increase of WBC count and 5-Fu as Evidence-Based Complementary and Alternative Medicine 5

Table 6: Changes in the levels of GOT and GPT in serum of mice (𝑋±𝑆).

Group Dose Number of GOT (U/L) GPT (U/L) (g/kg bw) animals Normal control 10 146.00 ± 33.93 70.04 ± 14.47 ∗∗ ∗∗ Negative control 9 780.16 ± 225.02 384.16 ± 70.41 ∗∗,△△ ∗∗,△△ 5-Fu 0.025 10 395.00 ± 116.43 172.67 ± 41.59 ∗∗,△ ∗∗,△△ A 0.5 10 589.60 ± 147.56 286.17 ± 71.84 ∗∗,△ ∗∗,△△ B 110568.40 ± 248.91 276.60 ± 90.91 ∗∗ ∗∗ C 1.5 10 665.66 ± 183.02 331.67 ± 91.01 ∗∗ △ △△ Comparison with the normal control group, 𝑃 < 0.01;comparisonwiththenegativecontrolgroup, 𝑃 < 0.05, 𝑃 < 0.01.

2 𝛽-catenin 1.8

PI3K 1.6

1.4 Akt 1.2

GAPDH 1 ∗∗ ∗∗ 0.8 ∗ 𝛼-SMA ∗ 0.6 Protein levels (fold changes) (fold levels Protein 𝛽1 TGF- 0.4

0.2 𝛽-actin 0

Negative control 1.5 g/kg bw K 𝛽1 3 Brucea Javanica Akt oil PI -SMA 𝛼 TGF- -catenin GAPDH 𝛽 Negative control 1.5 g/kg bw Brucea Javanica oil

Figure 2: The protein levels of 𝛽-catenin, PI3K, Akt, GAPDH, 𝛼-SMA, and TGF-𝛽1innegativecontrolgroupand1.5g/kgbwBrucea javanica oil group. The 𝛽-actin was as internal control. There were 8 samples detected randomly per group and the error bars correspond to mean ± ∗ ∗∗ standard deviations. Comparison with the negative control group, 𝑃 < 0.05, 𝑃 < 0.01. a myelosuppressive agent could decrease the WBC count of tumor-bearing mice [34]. Our results indicated that both 5- tumor-bearing mice. Brucea javanica oil could also decrease Fu and Brucea javanica oil could decrease the levels of GOT the WBC count of tumor-bearing mice to the normal level. and GPT in H22 tumor-bearing mice in different extent and The effect of Brucea javanica oil on inhibiting the increase of Brucea javanica oilindosenomorethan1.5g/kgbwdidnot WBCcountisnotrelevanttomyelosuppressiveeffectperhaps have obvious toxicity to the liver. due to its anti-inflammatory property [31]. Disturbing energy metabolism and neoplastic hyperpla- Hepatocellular carcinoma cell line H22 can express hep- sia controlled by Akt could be another probable antitu- atocyte growth factor (HGF), which is a potent stimulator mor mechanisms in hepatoma H22-bearing mice. Akt is of DNA synthesis in a variety of epithelial cells, including a serine/threonine protein kinase that plays an important hepatocytes, and has been implicated in liver regeneration role in cell growth, proliferation, and survival. Numerous [32, 33]. This study showed that the liver index of mice studieshaverevealedtheblockageofAktsignalingto increased significantly after hepatoma H22 was implanted in result in apoptosis and growth inhibition of tumor cells mice. Neither 5-Fu nor Brucea javanica oil could inhibit the [35]. Akt counteracts apoptosis through a block of caspase- liver augmentation induced with H22 tumor-bearing. It was 9, phosphorylation of proapoptotic members of the Bcl2- reported that the levels of GOT and GPT in serum would family of mitochondria-targeting proteins such as BAD, and increase significantly when H22 cells were implanted into stimulating signaling pathway of NF-kB and is also involved mice, and cytoxan (CTX) could decrease the levels in H22 in the regulation of autophagy [36], DNA damage response 6 Evidence-Based Complementary and Alternative Medicine and repair induced by commonly used genotoxic agents [37], mice. The work on Brucea javanica oil’s antitumor compo- and normal vascularization and pathological angiogenesis. nents and compatibility with other herbs to reduce acute Therefore, this signaling pathway of downstream of Akt toxicity and enhance its antitumor activity is underway now has been considered to be a new target for effective cancer in our laboratory and will be communicated in due course. therapeutic strategies. In this study, treated with Brucea javanica oil the level of Akt in tumor tissue decreased, Conflict of Interests suggesting the potential of triggering apoptosis of Brucea javanica oil in hepatoma H22 cells. The authors declare that there is no conflict of interests In contrast to normal differentiated cells, which rely pri- regarding the publication of this paper. marily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Authors’ Contribution Warburg effect.” GAPDH is an important enzyme for energy Wen-RongShiandYanLiusupervisedanddirectedtheover- metabolism and the production of ATP and pyruvate through all project. Yan Liu conceived and designed the experiments. anaerobic glycolysis in the cytoplasm. Additionally, it partic- Wen-Rong Shi, Xiao-Ting Wang, Xue-Rong Cai, Qiong-Ying ipates in apoptosis, membrane trafficking, iron metabolism, Huang, and Shao-Rong Wu contributed to the antitumor nuclear activities, and receptor mediated cell signaling. It was experiments and data interpretation. Wen-Rong Shi and Yan reported that overexpressed GAPDH in tumor could bind to Liu contributed to the western blot experiments. Wen-Rong active Akt and limit its dephosphorylation. This would lead to Shi and Yan Liu discussed the results and analyzed the data Bcl-xL overexpression and escape from caspase-independent and wrote the paper. All the authors were involved in the cell death [38]. Recent reports indicate that GAPDH has discussions. the ability to interact with Akt in many settings [39, 40]. Since most cancers have evolved multiple strategies such as hypoxia to evade programmed cell death, it is suggested that Acknowledgment GAPDH-dependent Akt expression is protecting cancer cells from hypoxia. In this study, treated with Brucea javanica oil The authors gratefully acknowledge the financial support the level of GAPDH and Akt in tumor tissue decreased. It is from the third round of foundation for colleges and uni- indicated that Brucea javanica oil could inhibit the growth versities in the construction of key subjects of Fujian of implanted hepatoma H22 in mice by disturbing energy Province, funds for integrated traditional Chinese and west- metabolism and neoplastic hyperplasia controlled by Akt. ern medicine (no. 3003-905011010). The TGF-𝛽 and PI3K/Akt signaling pathways are used in cells to control numerous responses, including prolifer- References ation, apoptosis, and metastasis. 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Research Article Traditional Chinese Medicine Decreases the Stroke Risk of Systemic Corticosteroid Treatment in Dermatitis: A Nationwide Population-Based Study

Kao-Sung Tsai,1,2,3 Chia-Sung Yen,3 Po-Yuan Wu,1,2 Jen-Huai Chiang,1,2 Jui-Lung Shen,4,5 Chung-Hsien Yang,1 Huey-Yi Chen,1,2 Yung-Hsiang Chen,1,2,6 and Wen-Chi Chen1,2

1 Institute of Chinese Medicine, School of Chinese Medicine, Graduate Institute of Integrated Medicine, School of Post-Baccalaureate Chinese Medicine, Research Center for Chinese Medicine & Acupuncture, Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung 40402, Taiwan 2Departments of Dermatology, Medical Research, Obstetrics and Gynecology, and Urology, Management Office for Health Data, China Medical University Hospital, Taichung 40447, Taiwan 3Department of Applied Cosmetology, Master Program of Cosmetic Science, and Department of Cultural and Creative Industries, Hungkuang University, Taichung 43302, Taiwan 4Center for General Education, Feng Chia University, Taichung 40724, Taiwan 5Department of Dermatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan 6Department of Psychology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan

Correspondence should be addressed to Yung-Hsiang Chen; [email protected] and Wen-Chi Chen; [email protected]

Received 4 March 2015; Accepted 15 June 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Kao-Sung Tsai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Epidemiological studies have shown a strong association between dermatitis and stroke. Systemic corticosteroid, the mainstay treatment for dermatitis, could enhance the atherosclerotic process. Traditional Chinese Medicine (TCM) has been used for dermatitis to decrease the side effects of corticosteroid. However, the different stroke risk in dermatitis patients treated with systemic corticosteroid or TCM remains unclear. This study identified 235,220 dermatitis patients and same comorbidity matched subjects between 2000 and 2009 from database of NHRI in Taiwan. The two cohorts were followed until December 31, 2011. The primary outcome of interest was new diagnosis of stroke. The crude hazard ratio (HR) for future stroke among dermatitis patients treated with systemic corticosteroid was 1.40 (95% CI, 1.34–1.45; 𝑃 < 0.0001) and TCM was 1.09 (95% CI, 1.05–1.13; 𝑃 < 0.0001). The log-rank test showed a higher cumulative incidence of ischemic stroke in the patient treated with only systemic corticosteroid group than that treated with systemic corticosteroid and TCM, only TCM, and neither systemic corticosteroid nor TCM in the matched cohort during the follow-up period (𝑃 < 0.0001). We demonstrated that patients treated with systemic corticosteroid had an increased risk of stroke and that the risk probably decreased by TCM treatment.

1. Introduction proportion of all skin disease. Some studies have suggested that dermatitis is an allergic disease in which systemic Many complementary and alternative medicine (CAM) prac- inflammation involves more than just the skin3 [ –5]. More tices have emphasized health promotion; however, this has evidences have shown that systemic inflammation can accel- not been the focus of the bulk of CAM research. CAM erate the progression of atherosclerosis and thrombosis with practitioners could be seen as a public health resource to resulting ischemic stroke [6]. Epidemiological studies have increase the population’s access to certain clinical preventive shown a strong association between systemic inflammatory services [1, 2]. Eczematous dermatoses account for a large disease, particularly dermatoses, and cardiovascular diseases 2 Evidence-Based Complementary and Alternative Medicine

[7]. Furthermore, Su et al. demonstrated that atopic dermati- obtained these data sets of NHRI from 2000 to 2011 for use tis, a chronically relapsing and constitutive skin disease, may as our research database. This study was approved by the be an independent risk factor for ischemic stroke [8]. Institutional Review Board of CMU-REC-101-012 from Insti- Contemporary medicines often used combinations of tutional Review Board approval of Public Health, Social and topical steroid agents, systemic antihistamine, corticos- Behavioral Science Committee Research Ethics Committee, teroids, and immune-modulating agents to control this China Medical University and Hospital. frustrating disease. The treatment of dermatitis, especially systemic corticosteroid therapy, can influence the atheroscle- 2.2. Study Design and Population. This population-based rotic process. It is believed that this treatment is atherogenic cohort study utilizing a nationwide database was conducted for the long-term used, partially due to effects on plasma of two groups. The population with dermatitis (aged ≥ 20 lipoproteins, elevation of total cholesterol and triglycerides years) were identified by codes 690.X, 691.X, and 692.X in and for promoting an abnormal distribution of high-density the ICD-9-CM and newly dermatitis diagnosis (at least two lipoprotein subclasses [9]. The systemic corticosteroid can medicalvisits)between1January2000and31December also indirectly accelerate the process by augmenting other 2009andfollowedupuntilDecember31,2011.Subjectswho traditional risk factors, including hypertension and obesity have a past history of stroke before the enrollment date were [10]. On the other hand, inflammation is associated with excluded from the study group. Systemic corticosteroid or atherosclerosis, and therefore corticosteroid therapy could TCM coding was obtained for medication variant control in have a protective effect. Previous studies published in the advanced step of analysis. We included the most common literature about this issue were contradictory. The role of prescribed systemic corticosteroids: dexamethasone, methyl- treatment with systemic corticosteroid or alterative treatment prednisolone, and prednisolone. Treatment was divided into in the evolution of stroke in dermatitis need to be further non-TCM and nonsystemic steroid user, only TCM user, only investigated. systemic steroid user, and TCM and systemic steroid user. The decision to use CAM is multifactorial, including The primary outcome of interest was new diagnosis of stroke dissatisfaction with conventional treatment and frustration (ICD-9-CM codes: 430–438). For stroke type analysis, we with the chronic nature course of eczema. For avoiding the separated hemorrhagic stroke (ICD-9-CM codes 430, 431, potential adverse effects of systemic conventional dermatitis and 432) and compared the ischemic stroke (ICD-9-CM treatments and also to attain better clinical outcomes, many codes 433–438) in further adjusted hazard ratio analysis. The patients and practitioners have tried to seek alternative date for dermatitis diagnosis was defined as index date. All the treatment [11]. Regarding the benefits, there is a raising subjects were followed from the index date to occurrence of trend of CAM treatment and the use of CAM is actually endpoint or until December 31, 2011, whichever was first, and associated with eczema prevalence [12]. Traditional Chinese the observations on the last dates were considered as censored Medicine (TCM) is one of the popular alternative treatments observations. for dermatitis in Asia and the world [13, 14]. The aim of this study was to determine the different risk of stroke in 2.3. Comparison Group. Subjects without dermatitis were dermatitis patients treated with systemic corticosteroid or randomly selected from the same data set. Each patient with TCM by using a nationwide database and proved a part newly diagnosed dermatitis in the NHRI database was pair- of a structured initiative to established evidenced-based matched with one subject of the same age, sex, and index year. clinical recommendation for management of comorbidities TCM or systemic corticosteroid medications and comorbidi- in dermatitis. ties (allergic rhinitis, asthma, urticarial, diabetes mellitus, hypertension, hyperlipidemia, and atrial fibrillation) were not 2. Materials and Methods matched. We selected comparison subjects using incidence density sampling by computer programming [17]. In the 2.1. Data Sources. Taiwan’s National Health Insurance (NHI) comparison group, subjects who have past history of stroke program, implemented by the government in March 1995, before enrollment were also excluded as the study group. provides comprehensive health care to almost all Taiwanese To determine stroke and survival analyses adjusting for citizens, with a coverage rate of more than 99% of Taiwan’s age, sex, comorbidities, and medications were carried out entire population, and contracted with 97% of hospitals with Cox’s proportional hazards model. All enrollees were and 92% of clinics. The National Health Research Institute followed from the date of enrollment until the first diagnosis (NHRI) of Taiwan manages and publicly releases for research of stroke or censored date of death, or date of withdrawal from purposes multiple NHI databases that include information the insurance, or until 31 December 2011. about basic patient characteristics, date of visit, diagnoses codes for the International Classification of Diseases, Ninth 2.4. Potential Confounders. In the analysis of the effect of dif- Revision, Clinical Modification (ICD-9-CM) codes, detailed ferent treatment, systemic corticosteroid or TCM, in patients claims data for examinations, disease management, and with dermatitis on the outcome of stroke, we controlled the drug prescriptions for all admitted patients and outpatients age and sex and identified the following comorbidities as [15, 16]. The NHRI created research data sets including a potential confounders: diabetes mellitus (ICD-9-CM code: random sample of 1,000,000 subjects from the registry of 250), hypertension (ICD-9-CM codes: 401–405), hyperlipi- all NHI enrollees in 2000, with the encryption of personal demia (ICD-9-CM codes: 272.0, 272.1, 272.2, 272.3, and information that could identify any individual patient. We 272.4), and atrial fibrillation (ICD-9-CM code: 427.31). Evidence-Based Complementary and Alternative Medicine 3

2.5. Statistical Analysis. Person-years of two populations were calculated from baseline to the occurrence of stroke or 0.15 closing date (December 31, 2011). All statistical analyses were performed using SAS version 9.4 software (SAS Institute, Inc., Cary, NC). All data are expressed as mean standard deviation or 𝑛 (%) 0.10 unless otherwise stated. Comparisons between groups were performed using Student’s 𝑡-test for continuous variables and Pearson’s chi-square test, as appropriate, for categorical variables. The Cox’s proportional hazards model was used to 0.05 estimate the hazards ratio for the progression of outcome. The incidence Cumulative probability of survival difference between each group with dermatitis user and nondermatitis users was tested with the log-rank test. The Kaplan-Meier method was used to plot 0.00 Log-rank test, P < 0.0001 the cumulative incidence. Cox proportional hazard model wasusedtocalculatethehazardratiosand95%confidence 0 246810 interval of stroke for patients with dermatitis compared with Time (years) nondermatitis user. All analyses were carried out with SAS Nondermatitis statistical software. All statistical tests were performed at the Dermatitis 𝑃 < two-tailed significance level of 0.05. A value 0.05 was Figure 1: The estimated cumulative incidence of stroke between the considered statistically significant. dermatitis cohort and the nondermatitis cohort by Kaplan-Meier analysis. 3. Results

Clinical characteristics of this study population identified Cox’s proportional hazard regression demonstrated that the patients newly diagnosed with dermatitis between 1 January crude hazard ratio (HR) for future stroke among patients 2000 and 31 December 2009. After excluding patients aged with dermatitis was 1.13 (95% confidence interval, (95% CI, under 20 years or with antecedent stroke, 235,220 patients 1.1–1.16; 𝑃 < 0.0001) and ischemic stroke among patients with dermatitis were included in the analyses. Other 235,220 with dermatitis was 1.16 (95% CI, 1.12–1.19; 𝑃 < 0.0001). patients without dermatitis were selected by 1 : 1 matching Furthermore, compared with non-TCM and nonsystemic by age, sex, and index year. The study subjects were pre- steroiduser,theadjustedhazardratio(HR)forfuturestroke dominantly female (58.13%), and the median age was 41.9 ± among patients treated with only TCM was 1.22 (95% CI, 15.5 years for dermatitis cohort group and 41.5 ± 15.9 1.13–1.32; 𝑃 < 0.0001), only systemic steroid was 1.55 (95% years for nondermatitis cohort group. Table 1 shows that CI, 1.43–1.67; 𝑃 < 0.0001) and TCM and systemic steroid basic characteristics and selected comorbidities were similar user was 1.64 (95% CI, 1.53–1.76) (Tables 2 and 3). These between groups. HR results suggested that dermatitis and patient treated with Predictors of difference stroke risk between systemic systemic corticosteroid or TCM may be an independent corticosteroid and TCM treatment in patients with dermatitis risk factor for stroke. The log-rank test showed a higher were conducted in this study. During the follow-up period, cumulative incidence of ischemic stroke in the patient with 206,402 (87.75%) patients with dermatitis were treated with dermatitis and treated with systemic corticosteroid group systemic corticosteroid and 160,541 (68.25%) were com- than treated with systemic corticosteroid and TCM, only parison subjects. 207,890 (88.38%) patients with dermatitis TCM, and neither systemic corticosteroid nor TCM in the treated with TCM and 183,949 (78.20%) were comparison matched cohort during the follow-up period (𝑃 < 0.0001, subjects. Also, subject with and without dermatitis had Figure 2). 78.47and57.22percentagewhohadusedbothTCMand We also identified the following independent factors systemic steroid. We also found that 13,079 (5.65%) patients determining the risk of future stroke. The adjusted HRs of with dermatitis and 10,006 (4.25%) comparison subjects strokeweresignificantlylowerinfemalethanmale(HR:0.81; experienced stroke attack. Analyzing different stroke type, 95% CI, 0.78–0.83; 𝑃 < 0.0001) and increased with increasing 12,450 (5.29%) patients with dermatitis and 9,277 (3.94%) age. Significant adjusted HRs of stroke in Cox proportional comparisonsubjectshadIschemicstrokeattack.However, hazard models were asthma (HR: 1.07; 95% CI, 1.02–1.12; there was no statistically difference in patients with dermati- 𝑃 = 0.0073), diabetes mellitus (HR: 1.37; 95% CI, 1.32–1.41; tis and comparison subjects that experienced hemorrhagic 𝑃 < 0.0001), hypertension (HR: 1.87; 95% CI, 1.81–1.93; 𝑃< stroke attack. The log-rank test showed a higher cumulative 0.0001), and atrial fibrillation (HR: 1.70; 95% CI, 1.51–1.91; incidence of stroke in the dermatitis group than in the 𝑃 < 0.0001). matched cohort during the follow-up period (𝑃 < 0.0001, Figure 1), suggesting that patients with dermatitis had an 4. Discussion increasedriskofstrokeinthelongterm. After adjusting for age, gender, comorbidities, and medi- In this large population-based cohort study, we demon- cations, we compared with comparison subjects and stratified strated that the patient with dermatitis treated with systemic 4 Evidence-Based Complementary and Alternative Medicine

Table 1: Demographic characteristics and comorbidity in patients with and without dermatitis.

Dermatitis No Yes † Variables 𝑃 value (𝑁 = 235220)(𝑁 = 235220) 𝑛 % 𝑛 % Sex Female 136734 58.13 136734 58.13 0.99 Male 98486 41.87 98486 41.87 Age, years 20–39 118623 50.43 118623 50.43 0.99 40–49 51025 21.69 51025 21.69 50–59 31596 13.43 31596 13.43 ≥60 33976 14.44 33976 14.44 † Mean (SD) 41.47 ± 15.92 41.93 ± 15.52 <0.0001 Comorbidity Asthma 9394 3.99 14123 6.00 <0.0001 Allergic rhinitis 21178 9.00 33243 14.13 <0.0001 Urticaria 11167 4.75 26983 11.47 <0.0001 Diabetes mellitus, DM 14864 6.32 20171 8.58 <0.0001 Hypertension 32216 13.70 40360 17.16 <0.0001 Hyperlipidemia 14819 6.30 21579 9.17 <0.0001 Atrial fibrillation, AF 625 0.27 700 0.30 0.0391 Treatment TCM (excluded acupuncture) 183949 78.20 207890 88.38 <0.0001 Systemic corticosteroid 160541 68.25 206402 87.75 <0.0001 Dexamethasone 103693 44.08 146470 62.27 <0.0001 Methyl prednisolone 35995 15.30 62122 26.41 <0.0001 Prednisolone 128167 54.49 182906 77.76 <0.0001 Treatment (new) Non-TCM and nonsystemic steroid 25312 10.76 5507 2.34 <0.0001 Only TCM 49367 20.99 23311 9.91 Only systemic steroid 25959 11.04 21823 9.28 TCM and systemic steroid 134582 57.22 184579 78.47 Outcome Stroke 10006 4.25 13079 5.56 <0.0001 Hemorrhagic stroke 1543 0.66 1463 0.62 0.1432 Ischemic stroke 9277 3.94 12450 5.29 <0.0001 † Chi-square test; two-sample 𝑡-test. corticosteroid is a risk factor for stroke and the patients with development of stroke [18]. Obesity, diabetes mellitus, treated with TCM may decrease incidence of this risk. hypertension, atrial fibrillation, and hyperlipidemia may be Patients with dermatitis treated with TCM had decreased worse as corticosteroid treated; furthermore, these adverse incidence of ischemic stroke compared with the corticos- effects may contribute to the later development of atheroscle- teroid group. These findings support the concept that der- rosis and ischemic stroke [19–21]. matitis may exert a systemic effect contributing to stroke and The atherosclerotic changes or stroke are associated with different treatments are important confounders. inflammatory processes resulting from several dermatoses, Corticosteroid is the mainstay treatment for dermati- such as atopic dermatitis [8], dermatitis herpetiformis [22], tis,withtherouteofadministrationanddosageschedule systemic lupus erythematosus [23], bullous pemphigoid [24], dependent primarily on the severity, while complications drug rash eosinophilia and systemic symptoms (DRESS) range in severity and frequency, which are generally con- [25], and psoriasis [26]. Possible explanations for the high sidered to be depend on the dosage and/or duration of risk of stroke in patients with dermatitis are atherosclerotic corticosteroid. However, the adverse effects result from not changes [4, 14, 23], oxidative stress [27], and activation of the only the cumulative corticosteroid dose but also high-dose coagulation system related to chronic inflammation [28, 29]. corticosteroid treatment which was significantly associated Increasing evidence has shown that systemic inflammation Evidence-Based Complementary and Alternative Medicine 5

Table 2: Cox model measured hazard ratio and 95% confidence intervals of stroke associated with dermatitis and covariates. Crude Adjusted Characteristics HR (95% CI) 𝑃 value HR (95% CI) 𝑃 value Dermatitis (ref = no) Yes 1.27 (1.23–1.3) <0.0001 1.13 (1.10–1.16) <0.0001 Gender (ref = male) Female 0.67 (0.66–0.69) <0.0001 0.79 (0.77–0.81) <0.0001 Age, years (ref = 20–39) 40–49 4.18 (3.97–4.41) <0.0001 3.75 (3.56–3.96) <0.0001 50–59 9.58 (9.1–10.08) <0.0001 7.27 (6.90–7.67) <0.0001 ≥60 25.70 (24.54–26.92) <0.0001 16.17 (15.37–17.00) <0.0001 Comorbidity Asthma (ref = no) Yes 2.42 (2.32–2.53) <0.0001 1.07 (1.03–1.12) 0.0019 Allergic rhinitis (ref = no) Yes 1.02 (0.97–1.06) 0.4694 0.95 (0.91–0.99) 0.0158 Urticaria (ref = no) Yes 1.12 (1.07–1.17) <0.0001 0.99 (0.94–1.04) 0.6715 DM (ref = no) Yes 4.20 (4.07–4.33) <0.0001 1.35 (1.30–1.39) <0.0001 Hypertension (ref = no) Yes 6.26 (6.1–6.43) <0.0001 1.87 (1.82–1.93) <0.0001 Hyperlipidemia (ref = no) Yes 3.08 (2.97–3.18) <0.0001 1.00 (0.96–1.04) 0.9719 AF (ref = no) Yes 7.04 (6.28–7.9) <0.0001 1.68 (1.50–1.89) <0.0001 Treatment (ref = non-TCM and nonsystemic steroid) Only TCM 0.98 (0.90–1.06) 0.5871 1.22 (1.13–1.32) <0.0001 Only systemic steroid 2.19 (2.03–2.36) <0.0001 1.55 (1.43–1.67) <0.0001 TCM and systemic steroid 1.66 (1.55–1.77) <0.0001 1.64 (1.53–1.76) <0.0001 HR: hazard ratio; CI: confidence interval. Adjusted HR: adjusted for age, gender, treatment, and comorbidity in Cox proportional hazards regression. can promote the progression of atherosclerosis and throm- A number of studies on TCM have been performed, with bosistoischemicstroke[6]. There are several possible mech- a collective result of symptom improvement and decreased anisms of dermatitis resulting in stroke. First, the elevation of levels of inflammatory cytokines. Since standard TCM pre- platelet activation and reducing fibrinolysis were founded in scribed of many herbs combined in different forms and dosed patients with chronic inflammatory allergic diseases such as differently depending on each individual patient, randomized atopic dermatitis [30, 31]. Second, mast cell may participate control trials in this area have been difficult to perform. in atherosclerosis by releasing proinflammatory cytokines, It has been postulated that Zemaphyte might work as an chemokines, and proteases to induced inflammatory cell efficient antioxidant, capable of scavenging both superoxide recruitment, cell apoptosis, and angiogenesis [32, 33]. Third, and hydroxyl and preventing peroxidation of biological increased serum IgE levels in myocardial infarction patients membranes. Pentaherbs formulation, another TCM prescrip- and mast cell accumulated in atherosclerotic lesions [34]. tion formula, postulated that suppression of the low-affinity Fourth, hypereosinophilia may play an import role in some of receptors for IgE on antigen-presenting cell, modulated mast these dermatoses, included dermatitis, bullous pemphigoid, cells and inhibited the inflammatory mediators from mast and DRESS. Thrombosis may be related to eosinophilic cells [37], and possessed immunomodulatory effects and hypothiocyanous acid productions, which lead to a proinflammatory mediators [38]. Methodological advantages of thrombotic state [35]. Furthermore, encephalopathy may the interdisciplinary secondary database utilized include a arise from small cerebral stroke or direct eosinophil toxicity high degree of generalizability, completeness and absence [36]. Dermatitis is an allergic disease, like asthma; it probably of recall bias due to prospective input of diagnoses and exerts systemic inflammatory effect in a similar fashion, researchquestionsandlargesamplesize[39]. In this study, we thereby contributing to cardiovascular or cerebrovascular replicated the previous reported positive association between consequences. However, allergic rhinitis and urticarial seem the major stroke risk factors and found that atrial fibrillation, to be of milder and less systemic inflammation than other hypertension, diabetes, and hyperlipidemia seem to be very atopic diseases. sensitive to change to multivariate models (Table 2). This may 6 Evidence-Based Complementary and Alternative Medicine

Table 3: Cox model measured hazard ratio and 95% confidence intervals of ischemic stroke associated with dermatitis and covariates. Crude Adjusted Characteristics HR (95% CI) 𝑃 value HR (95% CI) 𝑃 value Dermatitis (ref = no) Yes 1.30 (1.27–1.34) <0.0001 1.16 (1.12–1.19) <0.0001 Gender (ref = male) Female 0.69 (0.67–0.71) <0.0001 0.81 (0.78–0.83) <0.0001 Age, years (ref = 20–39) 40–49 4.60 (4.34–4.87) <0.0001 4.12 (3.89–4.37) <0.0001 50–59 10.88 (10.3–11.5) <0.0001 8.25 (7.8–8.73) <0.0001 ≥60 29.39 (27.95–30.89) <0.0001 18.48 (17.5–19.5) <0.0001 Comorbidity Asthma (ref = no) Yes 2.45 (2.35–2.57) <0.0001 1.07 (1.02–1.12) 0.0073 Allergic rhinitis (ref = no) Yes 1.04 (1–1.09) 0.0829 0.97 (0.92–1.01) 0.1195 Urticaria (ref = no) Yes 1.12 (1.07–1.18) <0.0001 0.98 (0.94–1.03) 0.5232 DM (ref = no) Yes 4.35 (4.22–4.49) <0.0001 1.37 (1.32–1.41) <0.0001 Hypertension (ref = no) Yes 6.48 (6.31–6.65) <0.0001 1.87 (1.81–1.93) <0.0001 Hyperlipidemia (ref = no) Yes 3.18 (3.07–3.3) <0.0001 1.01 (0.97–1.05) 0.6112 AF (ref = no) Yes 7.24 (6.44–8.14) <0.0001 1.70 (1.51–1.91) <0.0001 Treatment (ref = non-TCM and nonsystemic steroid) Only TCM 1.01 (0.93–1.09) 0.8967 1.25 (1.15–1.36) <0.0001 Only systemic steroid 2.23 (2.06–2.42) <0.0001 1.56 (1.44–1.69) <0.0001 TCM and systemic steroid 1.72 (1.60–1.85) <0.0001 1.68 (1.57–1.81) <0.0001 HR: hazard ratio; CI: confidence interval. Adjusted HR: adjusted for age, gender, treatment, and comorbidity in Cox proportional hazards regression. be due to the low prevalence of those traditional risk factors of death but was not recorded as an endpoint. The role for stroke in the dermatitis group. We demonstrated that of inflammation biomarkers, ingredients of TCM, and the dermatitis may be an independent risk factor for ischemic relationship between TCM, dermatitis, and stroke are not stroke. In light of our limited understanding of the exact clear. Further research is needed to determine the possible mechanisms explaining the adverse stroke risk factors in pathogenic mechanisms of TCM prescribed in dermatitis and dermatitis patients, it has been speculated that the established stroke which is necessary. association between stroke and different treatments might explain these findings. 5. Conclusions Our study has several limitations. First, patients with dermatitis and stroke were identified using a diagnostic code This large population-based study demonstrated that patients in a database, introducing the possibility of misclassification treated with systemic corticosteroid had an increased risk because of coding errors or misdiagnosis. Second, some ofstrokeandthattheriskprobablydecreasedbyTCM potential risk factors, including obesity, smoking, alcohol treatment. use, and family history of cardiovascular disease, were not included in our analyses because these data were not Conflict of Interests available. Third, the follow-up period may not have been sufficiently long to detect stroke development because atopic The authors declare that they have no conflict of interests. dermatitis always course in child to teenager but stroke often attacks Middle-aged to elderly patients. Fourth, we could Acknowledgments not directly evaluate the severity of dermatitis stroke, the accumulated dosage of systemic corticosteroid, ingredients ThisstudyissupportedinpartbyChinaMedicalUniversity of TCM, and each comorbidity. Finally, because we did not (CMU103-S-47), CMU under the Aim for Top University have the information of causes of death, stroke may be a cause Plan of the Taiwan Ministry of Education, Taiwan Ministry Evidence-Based Complementary and Alternative Medicine 7

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Research Article From Body to Mind and Spirit: Qigong Exercise for Bereaved Persons with Chronic Fatigue Syndrome-Like Illness

Jie Li,1 Jessie S. M. Chan,2,3 Amy Y. M. Chow,2 Lai Ping Yuen,4 and Cecilia L. W. Chan2,3

1 Renmin University of China, 59 Zhongguancun Street, 1007 Block D, Huixian Building, Haidian, Beijing 100872, China 2Department of Social Work and Social Administration, The University of Hong Kong, Pokfulam, Hong Kong 3Centre on Behavioral Health, The University of Hong Kong, Pokfulam, Hong Kong 4International Association for Health and Yangsheng, Happy Valley, Hong Kong

Correspondence should be addressed to Jessie S. M. Chan; [email protected] and Cecilia L. W. Chan; [email protected]

Received 3 June 2015; Accepted 18 June 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Jie Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Bereavement may bring negative impacts on the mind, body, and spiritual well-being of grieving persons. Some bereaved persons with chronic fatigue syndrome- (CFS-) illness experience a dual burden of distress. This study investigated the effects of bereavement on CFS-like illness by comparing bereaved and nonbereaved participants. It also adopted a random group design to investigate the effectiveness of Qigong on improving the well-being of bereaved participants. The Qigong intervention comprised 10 group sessions delivered twice a week for 5 weeks and home-practice for at least three times a week lasting 15–30 minutes each. The participants’ fatigue, anxiety, and depression, quality of life (QoL), and spiritual well-being were measured at baseline and 3 months after treatment. The bereaved participants experienced significantly greater mental fatigue (16.09 versus 14.44, 𝑝 = 0.017)andlower physical QoL (34.02 versus 37.17, 𝑝 = 0.011) than their nonbereaved counterparts. After 3 months, the mental fatigue− ( 8versus −4, 𝑝 = 0.010) and physical fatigue (−10 versus −5, 𝑝 = 0.007) experienced by intervention group had declined significantly, and improvements on their spirituality (14 versus −2, 𝑝 = 0.013) and psychological QoL (8.91 versus 0.69, 𝑝 = 0.002) scores exceeded those of the control group.

1. Introduction or longing for the return of the deceased [6]. Moreover, bereavement may induce spiritual change: as a life crisis The death of a loved one is considered to be one of the it can challenge one’s assumptions about human existence most distressing life experiences. Bereavement can pro- [7]. Although the death of a loved one may incur great foundly affect various aspects of a person’s well-being. First, distress and impair one’s spirituality [8], it may also trigger it impairs bodily functions: it is associated with abnormal psychospiritual transformation and facilitate spiritual growth neuroendocrine changes [1],reducedimmuneresponse[2], [9]. Therefore, researchers should pay more attention to ways and sleep disturbance [3, 4]. Stroebe et al. carried out an of improving the spiritual well-being of the bereaved. extensive review of the consequences of bereavement for Given the wide scope of negative influences of bereave- health [5]. Most alarmingly, bereaved spouses face a higher ment, it is justifiable to hypothesize that grieving people are risk of mortality, probably due to a higher morbidity rate also at risk of chronic fatigue syndrome (CFS), which is among those with physical illnesses [5]. Second, various associated with negative life events prior to the onset of illness mental symptoms are associated with grief, the primary [10]. Grieving persons share certain physiological/somatic reaction to bereavement. Grieving individuals may not only symptoms with CFS patients, such as fatigue, sleep distur- be afflicted with anxiety, sadness, guilt, anger, and shame, bance, exhaustion, somatic complaints, loss of appetite, and but also experience a sense of disbelief, a preoccupation social withdrawal [5]. CFS is a condition characterized by with memories of the deceased, the circumstances of his or a constellation of somatic and neurocognitive symptoms. her death, and the dying process, and an intense yearning It is defined as “clinically unexplained” fatigue lasting for 2 Evidence-Based Complementary and Alternative Medicine at least six months and is considered to have no definite reactions of bereavement. Second, most current bereavement effective treatment11 [ ]. CFS is associated with a constellation interventions are provided by mental health professionals of physical and neurocognitive symptoms that may interfere and accessibility may become a problem as professional with the patient’s daily activities in family, work, and social resources are often limited. As a result, some people may not life.However,duetotheunknownetiologyandlackof obtain sufficient or timely help5 [ ]. Third, although current effective treatment for the condition, a large proportion of interventions may have positive short-term effects, they may persons with it remain unrecognized and undertreated in be difficult to sustain in the long term if treatment ends the community. CFS-like illness is defined using criteria [19]. Self-help methods such as Qigong exercises can be used similartothoseforCFS,butwithoutconfirmationbymed- to supplement and sustain these positive outcomes through ical examination. Most persons with CFS-like illness have continuous practice. psychiatric disorders, for which they are often undertreated. The aims of this study were to investigate the effects of CFS patients usually experience poor quality of life [12, 13] bereavement on individuals with CFS-like illnesses and to and report greater psychological distress and lower functional explore the potential of Qigong exercises to assist bereaved well-being than their healthy peers [13, 14]. persons with CFS-like illness. To the best of our knowledge, As bereaved persons with CFS bear the double bur- no previous study has applied Qigong to treat this group of den of grief and chronic fatigue, researchers and clinicians people or evaluated the effectiveness of Qigong as an alter- should aim to identify techniques to help them adjust and native approach to assisting bereaved persons. The data were improve their well-being. To date, several methods have been drawn from a larger research program on CFS-like illness implemented to assist bereaved persons, such as pharma- with a random controlled group design, which investigated cotherapy [15], psychotherapy [16], and various combinations the effects of Qigong on multiple aspects of well-being, such of pharmacotherapy, psychotherapy, and psychoeducation as physical symptoms, mental health, spirituality, and quality [17]. However, researchers have shown that these types of of life. intervention have only minor positive effects on the bereaved [16, 18–21]. Thus, it is necessary to develop alternative forms 2. Methods of bereavement intervention. In a recent review, a novel body-mind intervention was found to outperform two major 2.1. Study Design. The study was part of a larger prospective traditional forms of bereavement intervention: emotional randomized waiting-list controlled study. More details of the expression and education [22]. In accordance with this trend, recruitment and randomization processes can be found in Qigong, a Chinese body-mind exercise, may provide new apreviousreport[27]. After providing informed consent, insight into the situation. the participants in both groups completed the questionnaires Qigong is an ancient Eastern self-healing technique. Qi first at baseline and again 3 months after intervention. The means“vitalinternalenergy”;gong denotes “practice or skill.” intervention comprised a 10-session Qigong course plus 15– According to Qigong practitioners, the body, mind, and spirit 30-minute self-practice sessions at least three times per week. are sufficiently intertwined that physical adjustments can The ten Qigong sessions (wu xing ping heng gong)lastedfor2 result in mental, emotional, and spiritual changes. Qigong hours each and were delivered twice a week for 5 weeks by an can facilitate the regulation of the mind, body, and breathing. experienced Daoist Qigong master. Each session comprised a It focuses on the balance between yin and yang, as well as brief introduction of the basic theories of traditional Chinese regulating the circulation of Qi within the meridian system medicine (the concepts of Qi, yin-yang, five elements, and (Qi vital energy channel) to foster a sense of somatic harmony meridian system), precautions on practicing Qigong exercise, that consequently helps in bringing about changes in mood and answering any questions or concerns raised by the and spiritual well-being. Qigong can be used as a self-care participants (45 minutes), followed by warm-up movements technique to buffer stress and improve one’s quality of life and including gentle movements or body stretching (15 minutes) spiritual state [23]. A systematic review showed that Qigong and a one-hour session of Qigong exercise training. More reduces stress and anxiety [24]. Recently, Qigong has been details of the description of Qigong exercise can be found found to have beneficial effects on persons with CFS-like in the intervention section in a previous report [27]. The illness, who have shown limited clinical reaction to pharma- participants in the control group were advised to maintain ceutical treatments. It can reduce patients’ fatigue, anxiety, their usual lifestyles and refrain from joining Qigong classes depressive symptoms, and sleep disturbance, improve their for the duration of the study. The same intervention was mental functioning, and even alter their telomerase activity delivered to the participants in the control group after the [25–27]. final outcome measurements had been collected. Given the promising effects of Qigong exercise on CFS- like illness, it is postulated that Qigong should have positive 2.2. Study Participants. Between October 5 and October effect on bereaved persons with CFS-like illness. More- 14, 2010, the study was publicized in the media and 1441 over, there are several advantages of using Qigong to assist Chinese adults who claimed to experience fatigue symptoms bereaved persons. First, current popular interventions with were recruited as potential participants. The volunteers were bereaved persons are mainly psychotherapies that address the screened using an online questionnaire based on the CFS emotional and psychosocial aspects of bereavement. Qigong, diagnostic criteria established by the US Center for Disease based on the integrated body-mind-spirit framework, is Control and Prevention [11], but without further medical likely to have a holistic effect on the multidimensional examination. Volunteers were considered to suffer from Evidence-Based Complementary and Alternative Medicine 3 a CFS-like illness if they met the following two inclusion Spiritual well-being was assessed using the “spiritual- criteria: (1) unexplained, persistent fatigue that could not be ity” subscale of the Body-Mind-Spirit Well-being Inventory relieved by rest and that resulted in a significant reduction in (BMSWBI-S) [34], a 13-item questionnaire with three dis- previous activity levels and (2) having four or more of the fol- tinct components: tranquility, disorientation, and resilience. lowing symptoms for 6 or more months: (a) impaired mem- Spirituality is measured by evaluating the patient’s core values ory or concentration, (b) postexertional malaise (extreme and and philosophy and the extent to which he or she regards life prolonged exhaustion following physical or mental activity), as having meaning. The measure has proven to bear sound (c) unrefreshing sleep, (d) muscle pain, (e) multijoint pain, validity, high internal consistency, and test-retest reliability (f) headaches of a new type, (g) sore throat, and (h) tender when used with Chinese respondents [34]. lymph nodes. Based on a medical history checklist in the online questionnaire, the persons with any history of cancer, 2.4. Statistical Analysis. First, bereaved and nonbereaved sleep apnea, hypothyroidism, narcolepsy, hepatitis B or C participants were compared in terms of fatigue severity, virus infection, severe obesity, mental disorders, including mental health, spirituality, and health-related quality of life schizophrenia, major depressive disorder, and bipolar disor- using chi-square test for the categorical data and a t-test for der, and alcohol or other substances’ abuse were excluded. As the continuous data. To confirm that the intervention group CFSmainlyaffectsyoungadults,patientsover60werealso and control group were comparable, demographic data and excluded, to minimize the possibility that CF was experienced outcome variables at baseline for the intervention and control due to ageing and/or other comorbid chronic conditions. groups were compared using a chi-square test and the Mann- Only 154 participants with CFS-like illness were recruited Whitney test, due to the small sample size. The effects of into the study. Eighteen participants dropped out. Of the practicing Qigong were examined by comparing the outcome remaining 136 participants, 46 had been bereaved within the variables at baseline with those observed 3 months after inter- previous 2 years. They were randomly assigned to the Qigong vention. Qigong group and control group were compared in group (𝑛=22)andthecontrolgroup(𝑛=24). terms of their preintervention score, postintervention score, and the changes between before and 3 months after treatment 2.3. Measures. Demographic data including age, gender, (T1–T0). All data analysis was conducted using the Statistical employment status, education level, marital status, religion, Package for the Social Sciences 18.0. and bereavement experience within 2 years were collected through a questionnaire. 3. Results The severity of fatigue was assessed using the Chalder Fatigue (CF) scale, which is a 14-item self-rating scale. It has As shown in Table 1, the bereaved persons with CFS-like illness exhibited significantly greater mental fatigue (16.09 been shown to be reliable and valid. Respondents score the 𝑝 = 0.017 items using a Likert-type response scale where 0 is none, versus 14.44, ) and received significantly lower scores for the physical-health component of the SF-12 (34.02 1isbetterthanusual,2isnomorethanusual,3isworse 𝑝 = 0.011 thanusual,and4ismuchworsethanusual.TheCFscale versus 37.17, ) than their nonbereaved counterparts. shows a high degree of internal consistency, with a principal The Qigong group and the control group were compara- components analysis supporting the notion of a two-factor ble in terms of both their demographic characteristics and solution (physical and mental fatigue). Items 1–8 measure their scores for the baseline outcome variables of fatigue, physical fatigue, and items 9–14 measure mental fatigue. A mental health, and health-related quality of life (see Tables total score is obtained by summing all of the item scores [28]. 2 and 3). The Chinese version of CF scale has been validated and found After 3 months of Qigong intervention, the Qigong group − − to be reliable among Chinese adults in the general population reported a significant decrease in total fatigue ( 17 versus 9, 𝑝 = 0.007 − − 𝑝 = 0.010 [29]. ) and mental fatigue ( 8versus 4, )and significant improvements in their psychological quality of life Mental health was assessed using the Hospital Anxiety 𝑝 = 0.002 and Depression Scale (HADS), which comprises two sub- (8.91 versus 0.69, ) compared to the control group. scales: HADS-A (7 items) and HADS-D (7 items). HADS-A Compared with the control group, the Qigong group and HADS-D measure the respondents’ anxiety and depres- experienced a significant reduction in physical fatigue after − − 𝑝 = 0.007 sion, respectively, in the previous week [30]. HADS has a high the Qigong intervention ( 10 versus 5, ). internal consistency for both anxiety (Cronbach’s 𝛼 = 0.93) However, no significant difference in physical quality of life 𝑝= and depression (Cronbach’s 𝛼 = 0.90). In addition, both the was observed between the two groups (2.66 versus 3.79, 0.451 anxiety subscale and the depression subscale have a high test- ). retest reliability (𝑟 = 0.89 and 𝑟 = 0.92, resp.). The Chinese The improvement in spirituality score from baseline to version of HADS has also been validated with good internal 3 months after intervention (T1–T0) was also found to be consistency and test-retest reliability [31]. significant (14 versus −2, 𝑝 = 0.013). However, the spirituality Quality of life was assessed using the Short Form Health score of the Qigong group at T1 did not improve significantly, Survey (SF-12), a 12-item questionnaire with separate sub- compared with that of the control group (72 versus 68, 𝑝= scales for physical health and mental health. Higher scores 0.183). No significant changes were observed in anxiety, and signify higher functioning [32]. The SF-12 has been translated the change in depression was only marginally significant. No intoChineseandvalidatedforuseinHongKong[33]. adverse events were observed. 4 Evidence-Based Complementary and Alternative Medicine

Table 1: Comparison of bereaved and nonbereaved participants with CFS-like illness at baseline (𝑛 = 136). 𝑛=46 𝑛=90 Bereaved ( )Nonbereaved() 𝑝∗ Mean (SD) Mean (SD) CF total score 40.87 (6.26) 38.94 (6.25) 0.092 CF: physical score 24.78 (4.16) 24.50 (3.65) 0.684 CF: mental score 16.09 (3.33) 14.44 (3.93) 0.017 HADS Anxiety 10.96 (2.17) 10.93 (2.25) 0.954 Depression 9.13 (2.23) 9.27 (2.06) 0.718 SF-12 SF-PSC 34.02 (6.00) 37.17 (7.11) 0.011 SF-MSC 33.22 (9.50) 32.80 (9.64) 0.807 Spirituality Total score 68.74 (25.11) 67.52 (25.10) 0.790 Tranquility 25.39 (10.64) 24.40 (10.37) 0.602 Disorientation 24.76 (11.66) 24.81 (12.08) 0.982 Resilience 18.11 (6.73) 17.93 (6.19) 0.880 ∗ CF: Chalder Fatigue; 𝑡-test. HADS: Hospital Anxiety and Depression Scale (score interpretation for each subscale: 0–7: normal; 8–10: mild; 11–14: moderate; 15–21: severe). PCS: physical-component summary; MCS: mental-component summary.

Table 2: Demographic characteristics for bereaved participants with CFS-like illness (𝑛=46).

Intervention (𝑛=22)Control(𝑛=24) ∗ Demographics 𝑝 Median (range) 𝑁 (%) Median (range) 𝑁 (%) Age (years) 46 (23–52) 45 (32–51) 0.508 Gender Female 19 (86.4%) 21 (87.5%) Employment 0.670 Full-time 16 (72.7%) 20 (83.3%) Part-time 2 (9.1%) 0 Housewife 2 (9.1%) 2 (8.3%) Unemployed 1 (4.5%) 1 (4.2%) Other 1 (4.5%) 1 (4.2%) Education 0.594 Forms 1 to 5 10 (45.5%) 12 (50.0%) Forms 6 to 7 2 (9.1%) 3 (12.5%) Tertiary/university 9 (40.9%) 6 (25.0%) Master’s level or above 1 (4.5%) 3 (12.5%) Marital status 0.336 Single 3 (13.6%) 7 (29.2%) Married/cohabiting 15 (68.2%) 15 (62.5%) Divorced/separated 4 (18.2%) 2 (8.3%) Religion Yes 6 (27.3%) 9 (37.5%) 0.460 Bereavement within 2 yrs 0.559 Spouse 1 (4.5%) 0 Sibling 2 (9.1%) 3 (12.5%) Parents 10 (45.5%) 8 (33.3%) Others 9 (40.9%) 13 (54.2%) ∗ Chi-square test of categorical variable and Mann-Whitney test of continuous variable. Evidence-Based Complementary and Alternative Medicine 5

Table 3: Comparison of bereaved participants with CFS-like illness in Qigong group and control group (𝑛=46). 𝑛=22 𝑛=24 Qigong group ( )Controlgroup() 𝑝∗ Median (range) Median (range) CF total score Before (T0) 41.5 (28–53) 40 (31–53) 0.956 After (T1) 21 (8–34) 37 (11–50) 0.003 T1–T0 −17 (−35–−6) −9(−22–8) 0.007 CF: physical score Before (T0) 24 (15–32) 24.5 (19–32) 0.791 After (T1) 16 (4–22) 21 (9–32) 0.002 T1–T0 −10 (−23–0) −5(−14–6) 0.007 CF: mental score Before (T0) 17 (12–21) 16 (7–22) 0.903 After (T1) 6 (2–17) 13 (2–21) 0.011 T1–T0 −8(−16–0) −4(−9–5) 0.010 HADS Anxiety Before(T0) 11(8–14) 11(6–16) 0.929 After (T1) 8 (2–12) 9 (2–18) 0.259 T1–T0 −3(−10–1) −2(−12–11) 0.376 Depression Before (T0) 8 (5–12) 10 (5–15) 0.051 After (T1) 7 (3–12) 11 (2–17) 0.016 T1–T0 −1(−5–4) 0 (−7–8) 0.072 Spirituality Total score Before (T0) 63 (8–116) 78.5 (16–118) 0.169 After (T1) 72 (61–116) 68 (29–118) 0.183 T1–T0 14 (−37–62) −2(−37–36) 0.013 SF-12 SF-PCS Before (T0) 34.83 (25.55–45.01) 31.60 (21.47–46.57) 0.141 After (T1) 40.00 (22.79–53.15) 35.82 (24.84–49.70) 0.511 T1–T0 2.66 (−12.67–17.97) 3.79 (−1.76–22.19) 0.451 SF-MCS Before (T0) 31.49 (12.20–49.65) 35.63 (11.09–49.14) 0.582 After (T1) 45.54 (28.88–57.16) 36.59 (16.43–54.25) 0.002 T1–T0 8.91 (−2.14–30.94) 0.69 (−23.07–16.34) 0.002 ∗ CF: Chalder Fatigue; HADS: Hospital Anxiety and Depression Scale; PCS: physical-component summary; MCS: mental-component summary; Mann- Whitney test.

4. Discussion practiced Qigong for a period, the participants reported a significant decrease in negative physical symptoms. This Bereaved participants with CFS-like illness in this study had finding is consistent with the results of previous studies, significantly higher mental fatigue scores and lower physical which have found similar effects of Qigong on physical health functioning than did the nonbereaved participants. This among patients with chronic illnesses [36]andwithCFS- result underlines the negative influence of bereavement on like illnesses [25–27]. This study extends these findings to well-being. It is also consistent with an early assumption that bereaved persons. It should be noted that the change in the stressful events such as bereavement are a potential cause of participants’ average score for the physical component of the CFS [10, 35]. SF-12 was not significant. Long-term Qigong practice may be The study’s findings suggest that Qigong is an effective necessary to improve physical functioning [25]. aid for bereaved persons with CFS-like illness. Comparing The data also indicated that Qigong reduced the patients’ the Qigong group with the control group confirmed that mental fatigue and improved mental functioning, although Qigong improves the health of bereaved persons. Having no significant changes were observed in their depression 6 Evidence-Based Complementary and Alternative Medicine or anxiety. Similarly, the authors of an earlier study with Conflict of Interests asmallsample(𝑛=50) found that Qigong improved psychological health but did not significantly decrease the The authors declare that they have no conflict of interests. depression score [36]. However, another large scale study 𝑛 = 137 ( ) showed that Qigong had an antidepressive effect Authors’ Contribution but did not significantly reduce anxiety symptoms for persons with CFS-like illness compared with a control group [27]. In Jie Li and Jessie S. M. Chan contributed equally to this work. alaterstudy(𝑛 = 150) with a longer intervention (16 Qigong sessions and daily self-practice sessions lasting at least 30 minutes each), Qigong was found to significantly reduce the Acknowledgments anxiety and depressive symptoms reported by patients with ThisstudywassupportedbytheCenterofBehavioralHealth CFS-like illness [26]. The marginally significant improvement Research Fund of the University of Hong Kong. The authors in depressive symptoms (𝑝 = 0.072)inthecurrentstudywas thank colleagues in the Centre on Behavioral Health, Dr. LP probably due to small sample size (𝑛=46). Whether Qigong Yuen’s group, the volunteers of International Association for is effective in alleviating depression and anxiety symptoms in Health and Yangsheng, and all participants who made this bereaved persons deserves further examination using a larger study possible. sample size. Although the spiritual well-being of bereaved persons is an area of interest for both researchers and clinicians, References few related interventions have been proposed or tested. The results of this study indicate that Qigong not only improves [1] K. Kim and S. Jacobs, “Neuroendocrine changes following the physical fatigue, mental fatigue, and mental functioning bereavement,” in Handbook of Bereavement: Theory, Research of bereaved persons but also enhances their spiritual well- and Intervention, M. S. Stroebe, W.Stroebe, and R. O. Hansson, being. 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Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 564648, 6 pages http://dx.doi.org/10.1155/2015/564648

Research Article Using the Theory of Planned Behaviour to Explain Use of Traditional Chinese Medicine among Hong Kong Chinese in Britain

Tina L. Rochelle,1 Steven M. Shardlow,2,3 and Sik Hung Ng1,4

1 City University of Hong Kong, Kowloon Tong, Hong Kong 2The University of Salford, Salford M5 4WT, UK 3The University of Keele, Staffordshire ST5 5TB, UK 4Renmin University of China, Beijing 100872, China

Correspondence should be addressed to Tina L. Rochelle; [email protected]

Received 3 June 2015; Accepted 22 July 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Tina L. Rochelle et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The UK Chinese are known for their underutilisation of western healthcare services. Reasons for this underutilisation are complex. The Theory of Planned Behaviour (TPB) is a widely used modelial ofsoc cognition, which in the present study is being applied to traditional Chinese medicine (TCM) utilisation and satisfaction with TCM services. Two hundred and seventy-two UK Chinese aged between 15 and 91 years (M = 46.55; SD = 18.53) enrolled in the study. TCM utilisation was associated with gender, age, cultural attachment, and subjective norms. TCM users were more likely to be female and older and have a strong attachment to Chinese culture, and be influenced by the views of important others. Findings highlight the potential of the TPB in exploring TCM utilisation, whilst also throwing light on other factors influential in the use of TCM and satisfaction with TCM service provision among Chinese in the UK.

1. Introduction the NHS. However, these services are generally provided by health professionals trained in WM, rather than TCM The United Kingdom (UK) Chinese community has grown practitioners [4]. TCM provides a holistic approach to health- substantially in recent decades. Ethnic Chinese currently con- care where the object is to achieve mind-body balance [5]. stitutearound0.7%ofthetotalUKpopulationandaround TCM has a preventative approach to illness, which is in 7% of the total nonwhite population, with a population of contrast to the western biomedical model of illness, which around 451,500 [1]. The UK Chinese may be at different levels focuses on dealing with illness only when symptoms of ill of acculturation as a result of the various influxes of migration health have presented themselves [5–7]. Illness in TCM is to the UK [2, 3]. Many migrants may hold on to their cultural commonlytreatedwithherbalremediesincontrasttoWM’s beliefsandpracticesuponarrivalintheUK. useofwhattheChineseperceivetobestrongmedication The National Health Service (NHS) is the public face of [8]. The Chinese model of health and illness emphasises not British healthcare and is the main provider of healthcare in only the importance of balance, but also the significance of the UK. NHS services are largely free at the point of delivery food. The use of various dietary prescriptions as a means and are paid for by the British taxpayer [4]. Healthcare in of self-medication is both common and widespread [5]. the NHS is provided through the western biomedical disease- Research indicates dual utilisation of TCM and WM among centred model. Despite the dominance of western medicine the Chinese, both at home [6]andoverseas[9]. Recent (WM) within the NHS, a very limited range of tradi- research points to this medical pluralism as an explanation tional Chinese medicine (TCM) services is available through for the low use of WM, implying that use of TCM may 2 Evidence-Based Complementary and Alternative Medicine lower use of WM services [8, 9]. Despite limited availability and“IwoulddescribemyselfasaHongKonger”(strongly of TCM services on the NHS, Chinese migrants tend to disagree to strongly agree). utilise those TCM services available from private Chinese Measures of TPB constructs were used to measure beliefs herbalists commonly based around local Chinatowns, such about TCM. Each of the TPB measures was based on standard as in London and Manchester, as well as herbal packages sent wording recommended for measuring components of the from migrants’ relatives [8, 9]. TPB [10]. Attitude towards TCM utilisation was measured The Theory of Planned Behaviour (TPB) is a social cog- using five semantic differentials: “For me to use TCM nitive model that predicts behavioural intention as a proxy is...‘harmful-beneficial,’ ‘unpleasant-pleasant,’ etc.” Subjec- of actual behaviour [10]. According to the model, the most tive norms were measured using four items, including “Peo- important predictor of whether people will perform a given ple who are important to me think I should use....” Perceived behaviour is the behavioural intention concerning the perfor- behavioural control was measured by four items, including mance of the behaviour. An individual’s intention to perform “How much control do you have in using TCM?” (no control- any given behaviour is determined by three global constructs: complete control). All items were measured on a 5-point attitudes (perceptions of the advantages and disadvantages scale. Cronbach’s alphas for the domains ranged from 𝛼=0.6 of performing a behaviour), subjective norms (perceptions to 𝛼 = 0.88. of the approval of significant others of performing the The Chinese SF-12 [15] was used to measure health status. behaviour), and perceived behavioural control (perceptions The SF-12 yields both a physical health composite scale about how much control a person feels they have to per- (PCS) and mental health composite scale (MCS). One item form the behaviour). The TPB has been used to examine a measured current health status on a 5-point scale (very bad- number of different behaviours and has been shown to pre- very good). One item measured experience of using TCM in dict a variety of health behaviours, including dietary supple- the UK on a 2-point scale (yes-no). Four items measuring ment behaviour [11], physical activity [12], and breast self- engagement with healthcare in the past six months with examinations among women [13]. Thus, the validity of the a general practitioner (GP), traditional Chinese medicine TPB is well established. However, use of the TPB to explore practitioner (TCMP), hospital outpatient consultation, and determinants of utilisation of different types of healthcare, hospital inpatient stay were adopted from census questions specifically among migrants, remains unchartered. [16]. These items were measured on a 5-point scale (never, > Using a quantitative approach, the present study exam- once, 2–4 times, 5–7 times, and 8 times). Another item ines predictors of TCM utilisation and satisfaction with TCM measured frequency of engagement with different types of services among Hong Kong Chinese migrants in Britain. UK healthcare services or providers on a 5-point scale Specifically, the following was hypothesised: (always-never). A further 18 items measured satisfaction with UK TCM healthcare on a 5-point scale (strongly disagree- (1) TCM users will have greater attachment to Chinese strongly agree) and were adapted from a previously validated culture than nonusers. Nonusers will have a greater scale originally designed to measure satisfaction with social attachment to British culture. services in the UK [17]. (2) There will be significant differences between users and nonusers of TCM regarding TPB components, 2.2. Procedure. The measure was available for respondents in particularly with regard to attitude. two languages: Traditional Chinese or English (Traditional ChineseandSimplifiedChinesearetwostandardsetsof (3) Stronger Chinese cultural attachment and favourable Chinese characters of the contemporary written form of attitude towards TCM will be predictive of greater the Chinese language; while Traditional Chinese is used satisfaction with utilisation of TCM services in the in Taiwan, Hong Kong, and Macau, Simplified Chinese is UK. officially used in Mainland China, Singapore, and Malaysia). All items in the measure were translated into Chinese from 2. Methodology English (SHN) and then backtranslated by another member of the research team (TKN) to ensure accuracy. The measure 2.1. Questionnaire. The questionnaire consisted of three sec- was piloted among 30 British Chinese across the UK prior tions: cultural attachment, engagement with the healthcare to the full implementation in order to improve wording and system, and beliefs about healthcare services, as well as a comprehensibility of the measure. Pilot participants were number of items relating to personal characteristics, such as recruitedfromaChineseorganisationinManchester,which age, marital status, educational attainment, monthly income, also served as one of the main recruitment sites for the and length of residency. study. Minor amendments to the Chinese wording of the Items measuring cultural attachment were adopted from measure were made following the pilot. Pilot participants apreviousvalidatedmeasure[14]. Attachment to British and wereexcludedfromthemainstudy.Thestudyreceivedethical Chinese culture was measured using 23 items on a 5-point approval from The University of Salford Ethical Review scale. Items included “Follow Chinese/English traditions and Committee (ref.: REP09/025). Participants were recruited via festivals” and “Eat Chinese/Western food” (never to always). local Chinese organisations in the UK, predominantly in Respondents were also asked to describe their identification Manchester and London, two large British cities containing of British/Chinese identity and culture using items such as “I a significant concentration (around 10% and one-third, resp.) feel the Chinese/British identity in me is...”(weaktostrong) of the UK Chinese population. The organisations, comprising Evidence-Based Complementary and Alternative Medicine 3

Chinese community centres, health centres, and advice cen- Table 1: Sociodemographic details of respondents. tres, were invited to be involved in the study by serving as a Percent recruitment site for participants. All organisations were con- tacted directly by a member of the research team (TLR). Only Gender those service users identified by the organisation as being Male 44% Hong Kong Chinese were approached to participate in the Female 56% study. Respondents received a participant information sheet Age with detailed information about the study before providing ≤15 yrs 0.4% informed consent. The questionnaire was administered by a 16–24 yrs 14% member of the research team (SHN and TLR). 25–44 yrs 30% 45–64 yrs 40% 2.3. Analysis. Descriptive analysis was initially performed. 𝑡 65–74 yrs 6% Independent samples -tests were used to compare mean ≥75 yrs 8.6% scores for the TPB components and cultural attachment Marital status variables between users and nonusers of TCM. The influence of age, gender, cultural attachment, TPB components, and Single 34% recent utilisation behaviour on TCM utilisation and satis- Married 53% faction with UK TCM services among users of TCM in the Separated/divorced 6% UK (including services available on the NHS, private TCM Widowed 7% services, and self-prescription) was examined using linear Educational attainment regression. All analyses were carried out using IBM SPSS m3,000 22% a bachelor degree or above. More than half of respondents Length of HK residency (prior to living in UK) (53%) were married (see Table 1). <10 yrs 7% 10–19 yrs 37% 3.2. Descriptive Statistics. Forty percent of respondents rated 20–29 yrs 34% their health as acceptable, relative to their age, while a 30–39 yrs 13% further 36% rated their health as good. Seventy-six percent 40–49 yrs 7% of respondents reported experience of using WM, and 24% of > respondents had no experience of using WM in the UK. Fifty- 50 yrs 2% nine percent of respondents reported consulting a general Length of UK residency practitioner (GP) within the previous six months. Twenty- <10 yrs 26% eight percent of respondents reported having a hospital 10–19 yrs 26% outpatient appointment in the last six months, and 5% 20–29 yrs 12% had been a hospital inpatient in the previous six months. 30–39 yrs 20% One quarter (25%) of respondents reported experience of 40–49 yrs 12% TCM utilisation in the UK, with 14% having consulted a >50 yrs 4% traditional Chinese medicine practitioner (TCMP) in the last ∗ Note: GCSE: General Certificate of Secondary Education; m:BritishPound six months. Sterling.

3.3. Independent Samples 𝑡-Test. Table 2 summarises the differences between users and nonusers of TCM based on perceived behavioural control over TCM utilisation than reportedpastbehaviouroneachofthecomponentsofthe nonusers, supporting Hypothesis 2. TPB. Hypothesis 1 was concerned with differences between users and nonusers of TCM regarding cultural attachment. 3.4. Predictors of Utilisation of TCM. A four-block hierar- Utilizers of UK TCM reported stronger Chinese cultural chical regression model was conducted to test the sequential attachment, supporting Hypothesis 1, and although nonusers effects of gender and age, cultural attachment, TPB compo- reported stronger attachment to British culture than TCM nents, and recent TCM utilisation behaviour on predictors of users, this difference was not significant. TCM users held TCM utilisation among HK Chinese in the UK (see Table 3). more positive attitudes towards use of TCM and greater The purpose of the blocking procedure was to examine 4 Evidence-Based Complementary and Alternative Medicine

Table 2: Comparison between users and nonusers of TCM in the UK [mean (SD)].

Users Nonusers Significance of difference 95% CI for difference (𝑛=65) (𝑛 = 196) ∗∗∗ Chinese cultural attachmenta 4.35 (0.39) 4.07 (0.61) <0.001 0.15 to 0.41 Britishculturalattachmenta 3.54 (0.89) 3.57 (0.84) 0.875 −0.26 to 0.22 ∗∗ Attitudesa 3.83 (0.78) 3.50 (0.82) <0.01 0.10 to 0.58 Subjective norms 0.51 (0.47) 0.43 (0.46) 0.23 −0.05 to 0.22 ∗∗ Perceived behavioural controla 2.75 (0.61) 2.51 (0.50) <0.01 0.08 to 0.39 Self-reported healtha 3.71 (0.81) 3.59 (0.88) 0.32 −0.12 to 0.37 ∗∗ ∗∗∗ 𝑝 < 0.01; 𝑝 < 0.001. aScores are from 1 to 5. Higher scores indicate stronger attachment and so forth.

Table 3: Predictors of TCM utilisation among Chinese in the UK. Table 4: Predictors of satisfaction with UK TCM services among Chinese in the UK. Variables Step 1 𝛽 Step 2 𝛽 Step 3 𝛽 Step 4 𝛽 ∗∗ ∗∗∗ ∗∗ ∗∗∗ 𝛽 𝛽 𝛽 𝛽 Female 0.21 0.23 0.22 0.22 Variables Step 1 Step 2 Step 3 Step 4 ∗∗ ∗∗ ∗∗ ∗∗ ∗ ∗∗ ∗ ∗ Age 0.20 0.20 0.22 0.20 Female 0.27 0.32 0.25 0.25 ∗∗ ∗ ∗ Chinese cultural attachment 0.19 0.14 0.16 Age −0.04 −0.10 −0.05 −0.07 ∗∗∗ ∗∗ ∗∗ British cultural attachment 0.10 0.10 0.10 Chinese cultural attachment 0.49 0.33 0.34 Attitudes 0.01 −0.04 ∗ ∗ British cultural attachment 0.10 0.10 0.09 Subjective norms 0.14 0.14 ∗ ∗ Attitudes 0.28 0.24 Perceived behavioural control 0.13 0.12 ∗∗∗ Subjective norms 0.20 0.20 Recent utilisation behaviour 0.26 Δ𝑅2 Perceived behavioural control 0.18 0.17 0.10 0.04 0.04 0.07 ∗ df. 2/199 2/197 3/194 1/193 Recent utilisation behaviour 0.20 ∗∗∗ ∗∗ ∗ ∗∗∗ 2 Δ𝐹 10.45 4.95 3.36 16.73 Δ𝑅 0.07 0.24 0.19 0.03 ∗ ∗∗ ∗∗∗ 𝑝<0.05; 𝑝<0.01; 𝑝<0.001. df. 2/52 2/50 3/47 1/46 ∗∗∗ ∗∗∗ ∗ Δ𝐹 2.00 8.92 6.17 3.74 ∗ ∗∗ ∗∗∗ 𝑝<0.05; 𝑝<0.01; 𝑝<0.001. whether the addition of subsequent cultural attachment variables, TPB components, and recent utilisation behaviour would add predictive power to the preceding demographic variables. Age and gender entered into block one of the model theUK(seeTable4). The purpose of the blocking procedure explained 10% of the variance in TCM utilisation. The entry was to examine whether the addition of subsequent cultural of cultural attachment variables to block two explained 4% attachment variables, TPB components, and recent utilisation of the variance. The addition of TPB components to the behaviour would add predictive power to the preceding third block explained another 4% of the variance. After the demographic variables. Age and gender entered into block entry of recent utilisation to the fourth and final block, the one of the model explained 7% of the variance in TCM total variance explained by the model as a whole was 25.3%, utilisation. The entry of cultural attachment variables to 𝐹(1/193) = 8.17,(𝑝 < 0.001). Recent TCM utilisation block two explained 24% of the variance. The addition of explained an additional 7% of the variance after controlling TPB components to the third block explained 19% of the for age, gender, cultural attachment and the TPB components variance. After the entry of recent utilisation to the final of attitude, subjective norm, and perceived behavioural con- 2 block, the total variance explained by the model as a whole trol, Δ𝑅 = 0.07, Δ𝐹(1/193) = 16.73,(𝑝 < 0.001). In the final was 54.6%, 𝐹(1/46) = 6.91,(𝑝 < 0.001). Recent TCM model, gender, age, Chinese cultural attachment, subjective utilisation explained an additional 3% of the variance after norms, and recent TCM utilisation were all statistically controlling for age, gender, cultural attachment and the significant in their prediction of TCM utilisation. Recent TPB components of attitude, subjective norm, and perceived 2 TCM utilisation recorded the highest beta value in the final behavioural control, Δ𝑅 = 0.03, Δ𝐹(1/46) = 3.74,(𝑝< model (𝛽 = 0.26, 𝑝 < 0.001). 0.05). In the final model, gender, age, Chinese cultural attachment,subjectivenorms,andrecentTCMutilisationwere 3.5. Predictors of Satisfaction with UK TCM Services. Hypo- all statistically significant in their prediction of satisfaction thesis 3 was concerned with predictors of satisfaction with with UK TCM. Hypothesis 4 posited that Chinese cultural TCM in the UK. A second four-block hierarchical regression attachment and attitude towards TCM would be predictive of model was conducted to test the sequential effects of gender greater satisfaction with UK TCM; this was fully supported by and age, cultural attachment, TPB components, and recent the model. Chinese cultural attachment recorded the highest TCM utilisation behaviour on satisfaction with TCM in beta value in the final model𝛽 ( = 0.34, 𝑝 < 0.01). Evidence-Based Complementary and Alternative Medicine 5

4. Discussion Chinese migrants when it comes to health service utilisation. While migrants may demonstrate more support for the TCM The present study has identified a range of factors that may approach,theymayuseWMregardlessofstrongbeliefsand influence utilisation of TCM by UK Chinese. Greater utilisa- attitudes towards TCM as WM is available free of charge on tion of TCM was associated with being female, being older, the NHS. This may explain the low levels of TCM utilisation having a strong attachment to Chinese culture, subjective among the UK Chinese. Perhaps if TCM was regulated in the norms, and recent TCM utilisation. The findings concur to samewayasWMintheUKandwasfreelyavailableonthe some extent with the theoretical underpinnings of the TPB. NHS, more migrants would utilise UK TCM services. Subjective norms were predictive of TCM utilisation among The present findings carry practice implications to physi- UK Chinese. However, attitude and perceived behavioural cians and professionals working within the NHS. Despite the control were not. This does not demonstrate lack of support fact that most participants reported using WM, a quarter for the TPB in terms of TCM utilisation among Chinese in the of respondents reported using TCM. It is likely that WM UK per se; rather this leads to other explanations in terms of and TCM are used simultaneously, as has been previously therelativelackofutilisationofTCMbyChinesemigrants. reported [8, 9]. Health professionals need to take this into One reason why attitudes were not predictive of TCM account, bearing in mind that a common use of TCM is utilisation could be that, regardless of whether individuals with herbal remedies. Health professionals should also take have a favourable or unfavourable attitude towards TCM and into account cultural factors when providing treatment and its uses, TCM services are not freely and widely available on services. The common practice of utilising both TCM and the NHS. Individuals need to pay for these services. Previous WM should remind policy makers to consider the regulation research demonstrates that the utilisation of TCM services ofTCMtoprotectserviceusers. in the UK is costly [8], particularly when compared to Limitations of the present study must be acknowledged. Hong Kong or China. This may deter some individuals from The utilisation of convenience sampling, such as the one used utilising these services in the UK, regardless of attitude. The inthepresentstudy,meansthatthefindingsdonotreadily significanceofsubjectivenormsistobeexpected,giventhat allow for a generalisation of effects. Whether differences theChineseareknowntobeacollectivisticculture,taking identified in the present patterns of medicinal utilisation into the account that the views and opinions of important wouldbefoundinarepresentativesampleofBritishChinese others are particularly important [18]. The importance of migrants remains to be tested. The present study used a subjective norms may have a greater influence than individual convenience sample of British Chinese individuals recruited attitudes as a result of this collectivistic ideology. via British Chinese organisations in large cities in the UK, Findings indicate that identity, in the form of cultural like Manchester and London. It could be argued that these attachment, is influential in TCM utilisation. Respondents individuals may be more predisposed to utilise TCM, as with strong attachment to Chinese culture were more likely evidenced by their strong attachment to Chinese culture by to use TCM and express satisfaction with TCM services. This virtue of their association with British Chinese organisations. reinforces previous literature identifying the maintenance of However, this proved not to be the case in the present study strong cultural links by migrants [19]. Females were more with findings demonstrating relatively low utilisation of UK likely to use TCM than their male counterparts. To some TCM services. extent this is not surprising, given that, with use of medicine and health services in general, women are more likely to use Conflict of Interests services than men [20]. More so, perhaps with TCM, in that The authors declare that there is no conflict of interests herbal medicine needs to be prepared, the herbs need to be regarding the publication of this paper. boiled. Thus, it could be argued that females may be more likely to take on the role of preparing TCM, than males, which Acknowledgments maygosomewaytoexplaintheassociationbetweenhigher rates of TCM utilisation among females. Another explanation The work described in this paper was fully supported bya couldbethataccesstomainstreamWMservicesmaybemore grant from the ESRC/RGC Joint Research Scheme sponsored limitedasaresultoflanguagebarriers.Studieshaveshown by the Research Grants Council of Hong Kong and the that, despite the provision and availability of translators for Economic & Social Research Council (Project no. RES-000- medical appointments, some British Chinese, particularly 22-3656). women, do not like to use a translator, feeling uncomfortable with the idea of telling a stranger personal health information References [8]. As a result, women may avoid using WM in some cases. Only a small proportion of respondents reported using [1] Office for National Statistics, Ethnicity and National Identity in TCM exclusively. One reason for this could be that WM is the England and Wales, 2011, Office for National Statistics, London, UK, 2012, http://www.ons.gov.uk/ons/dcp171776 290558.pdf. major face of healthcare provision in the UK. A very small [2] A. Nandi and L. Platt, “Britishness and identity assimilation number of TCM services are provided by the NHS, which among the UK’s minority and majority ethnic groups,” Under- are generally accompanied by long waiting lists; all other standing Society Working Paper Series 2013-08, Economic TCMservicesareruninprivatepracticeandthusinvolve Social Research Council, 2013, https://www.understanding- costs which are not applicable if one chooses to use WM. society.ac.uk/research/publications/working-paper/understand- Previous research has pointed to the pragmatic nature of ing-society/2013-08.pdf. 6 Evidence-Based Complementary and Alternative Medicine

[3] G. Wong and R. Cochrane, “Generation and assimilation as predictors of psychological well-being in British Chinese,” Social Behaviour,vol.4,no.1,pp.1–14,1989. [4] Department of Health, The Handbook to the NHS Constitution for England, Department of Health, London, UK, 2012. [5]L.C.Koo,“TheuseoffoodtotreatandpreventdiseaseinChi- nese culture,” Social Science and Medicine,vol.18,no.9,pp.757– 766, 1984. [6] M. F. Chan, E. Mok, Y. S. Wong et al., “Attitudes of Hong Kong Chinese to traditional Chinese medicine and Western medicine: survey and cluster analysis,” Complementary Therapies in Medicine, vol. 11, no. 2, pp. 103–109, 2003. [7]V.C.Chung,C.H.Lau,E.K.Yeoh,andS.M.Griffiths,“Age, chronic non-communicable disease and choice of traditional Chinese and western medicine outpatient services in a Chinese population,” BMC Health Services Research,vol.9,article207, 2009. [8] T. L. Rochelle and D. F. Marks, “Medical pluralism of the Chi- nese in London: an exploratory study,” British Journal of Health Psychology,vol.15,no.4,pp.715–728,2010. [9]G.Green,H.Bradby,A.Chan,andM.Lee,“‘Wearenotcom- pletely Westernised’: dual medical systems and pathways to health care among Chinese migrant women in England,” Social Science and Medicine,vol.62,no.6,pp.1498–1509,2006. [10] I. Ajzen, “The theory of planned behavior,” Organizational Behavior and Human Decision Processes,vol.50,no.2,pp.179– 211, 1991. [11] M. Conner, S. F. L. Kirk, J. E. Cade, and J. H. Barrett, “Why do women use dietary supplements? The use of the theory of planned behaviour to explore beliefs about their use,” Social Science and Medicine,vol.52,no.4,pp.621–633,2001. [12] N. Hobbs, D. Dixon, M. Johnston, and K. Howie, “Can the theory of planned behaviour predict the physical activity behaviour of individuals?” Psychology & Health,vol.28,no.3, pp. 234–249, 2013. [13] P. Norman and Y. Cooper, “The theory of planned behaviour and breast self-examination: assessing the impact of past behaviour, context stability and habit strength,” Psychology and Health, vol. 26, no. 9, pp. 1156–1172, 2011. [14] S. H. Ng, N. Yam, and J. Lai, “The bicultural self of Chinese in Hong Kong,” in Casting the Individual in Societal and Cultural Contexts: Social and Societal Psychology in Asia and the Pacific, J.H.Liu,C.Ward,A.B.I.Bernardo,M.Karasawa,andR. Fischer, Eds., pp. 105–122, Kyoyook-Kwahak-Sa, Seoul, Republic of Korea, 2007. [15]C.L.K.Lam,E.Y.Y.Tse,andB.Gandek,“IsthestandardSF-12 Health Survey valid and equivalent for a Chinese population?” Quality of Life Research, vol. 14, no. 2, pp. 539–547, 2005. [16] Census & Statistics Department, Thematic Household Survey Report No. 12, Census & Statistics Department of the Hong Kong Government, 2003. [17] Social Services Inspectorate for Wales, Questionnaire for People Who Use Social Services, Wales Audit Office, Cardiff, Wales, 2006. [18] M. H. Bond, The Oxford Handbook of Chinese Psychology, Oxford University Press, Oxford, UK, 2010. [19] D. Lai and N. Chappell, “Use of traditional Chinese medicine by older Chinese immigrants in Canada,” Family Practice,vol.24, no. 1, pp. 56–64, 2007. [20] R. O’Brien, K. Hunt, and G. Hart, “‘It’s caveman stuff, but that is to a certain extent how guys still operate’: men’s accounts of masculinityandhelpseeking,”Social Science & Medicine,vol. 61,no.3,pp.503–516,2005. Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 840742, 8 pages http://dx.doi.org/10.1155/2015/840742

Review Article Efficacy of Compound Kushen Injection in Relieving Cancer-Related Pain: A Systematic Review and Meta-Analysis

Yu-ming Guo,1 Yi-xue Huang,1 Hong-hui Shen,1 Xiu-xiu Sang,1 Xiao Ma,1 Yan-ling Zhao,1 and Xiao-he Xiao1,2

1 China Military Institute of Chinese Materia Medica, 302 Military Hospital, Beijing 100039, China 2Integrative Medicine Center, 302 Military Hospital, Beijing 100039, China

Correspondence should be addressed to Xiao-he Xiao; [email protected]

Received 14 May 2015; Accepted 11 June 2015

Academic Editor: Cheryl Hawk

Copyright © 2015 Yu-ming Guo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Despite widespread popular use of complementary and alternative medicine (CAM) therapies, a rigorous evidence based on the efficacy of compound kushen injection (CKI) for cancer-related pain is lacking. In this study, we evaluated the efficacy andsafety of compound kushen injection and provided information for current or future research and clinical application. Sixteen trials were identified with a total of 1564 patients. The total pain relief rate of CKI plus chemotherapy is better than chemotherapy except for colorectal cancer. The treatment groups achieved a reduction in the incidences of leukopenia and gastrointestinal, hepatic, and renal functional lesion. However, there is paucity of multi-institutional RCTs evaluating compound kushen injection for cancer pain with adequate power, duration, and sham control. The quantity and quality of RCTs are lower so that we still have to boost the research level through scientific design and normative report.

1. Introduction smilacis glabrae). The primary components are oxymatrine and matrine [6]. CKI limited cancer pain both directly Pain is the major clinical symptom of cancer patients [1–3]. by blocking TRPV1 signaling and indirectly by reducing The management of cancer-related pain is the widespread tumor growth [7]. Nowadays, it has been used extensively measure for the patients’ quality of life. However, little throughout China for pain treatment in combination with management of western medicine can be effective. Analgesics conventional analgesics, chemotherapy, or radiotherapy. In are a mainstay of pain management, but they may cause this paper, clinical studies were reviewed to evaluate the undesired effects such as sedation, nausea, constipation, efficacy and safety of compound kushen injection for cancer- and renal or liver toxicity. Complementary and alternative related pain and provide information for current or future medicine therapies are used widely instead among cancer research and clinical application. patients to improve cancer-related pain [4, 5]. However, few studies have been published in English written journals that 2. Methods report the effectiveness and safety of many commonly used traditional Chinese medicine (TCM) therapies. 2.1. Literature Search. Two independent reviewers, includ- Compound kushen injection (CKI) was approved for the ing a librarian, conducted a systematic literature search treatment of cancer by the State Food and Drug Adminis- using databases (MEDLINE, Chinese Biomedical Litera- tration of China more than 20 years ago. It was also known ture Database, China National Knowledge Infrastructure as Yanshu injection, which contains extracts from two herbs, Database, VIP Database for Chinese Technical Periodicals, kushen (Radix sophorae flavescentis) and baituling (Rhizoma Wan-Fang Database, and the Cochrane Library), all from 2 Evidence-Based Complementary and Alternative Medicine time of inception up to December 2014. A text word search excluded (36 were not RCTs, 16 did not address the complete was done in the title and abstract for each concept and data, 5 were associated with other Chinese medicine therapies combined with the subject heading searches (cancer or neo- in experimental group or in control group or with different plasm$ [$ indicates truncation], pain, and kushen injection), dosage, 73 did not meet our inclusion criteria for treatment and then the search was limited to clinical trials. A similar measures, and 21 were with inconsistent criteria), yielding 16 search was done by another investigator independently using relevant articles for the systematic review and meta-analysis PubMed with the search term “cancer pain” and the limits of (Figure 1). “clinical trials” and “kushen injection.” Both reviewers also visually scanned the results to manually remove any citations 3.2. Study Characteristics. Atotalof1564studyparticipants that were obviously irrelevant and also scanned reference lists were identified from the 16 trials [8–23](768wereinthe of the identified articles to identify any additional articles. control group, 796 were in the treatment group, and the ages ranged from 18 to 85 years). All studies were conducted in 2.2. Inclusion and Exclusion Criteria. The inclusion criteria China, published between 2006 and 2014. Fifteen trials [8– were as follows. (1) Randomized controlled trials (RCTs) of 17, 19–23]werefromsingleinstitutionsandonly1trial[18] patients with cancer-related pain were selected: the exper- was multicenter RCT. There were different pain scales used imental group received compound kushen injection and amongthe16trials,withtheNumericalRatingScalebeing chemotherapy while control group received chemotherapy the most common. All of the included studies mentioned only. (2) Outcome assessment included pain-related mea- randomization, but only 4 trials [16, 18–20]reportedthe surements. (3) No language or blinding restriction was used. method of random sequences generation. No study men- The exclusion criteria were (1) reviews, nonclinical stud- tioned allocation concealment. One [19] report recorded the ies, and case observations; (2) no RCTs; (3) controlled loss to follow-up, and 2 [15, 18] conducted intention-to- interventions with TCM therapies as other Chinese herbs or treat analysis. Quality assessment of included randomized acupuncture; and (4) inability to find the outcome measure- controlled trials is shown in Table 1. ments or duplicated citations. Six trials [11, 13, 19–21, 23] compared CKI plus FOLFOX to FOLFOX individually. Four trials [12, 15–17]comparedCKI 2.3. Types of Outcome Measures. The primary outcome was plus NP with NP individually. Four trials [8–10, 18]compared totalpainreliefrate.Thereductioninpainintensitywasmea- sured using a numerical rating scale (NRS), visual analogue CKI plus TACE with TACE individually. Two trials [14, 22] scale (VAS), or verbal rating scale. The secondary outcomes comparedCKIplusGCwithGCindividually.Theduration were quality of life and adverse events at the end of treatment of studies lasted from 10 days to 18 weeks. All studies used course. the total pain relief rate as primary outcome. The quality of life was reported in 11 studies [8–10, 12, 15–18, 20–23]. Eight trials [8, 11, 12, 14, 16–18, 22] reported adverse effect. Detailed 2.4. Data Abstraction. The articles that met the inclusion characteristics of included studies are listed in Table 2. criteria were reviewed by two independent investigators (Yu-ming Guo, and Yi-xue Huang), and relevant data were extracted. Disagreements were resolved by a third reviewer 3.3. Efficacy Assessment (Xiu-xiu Sang). The methodological quality of RCTs was 3.3.1. Total Pain Relief Rate. All studies adopted the total pain assessed independently using seven-item criteria according to the Cochrane Collaboration-Cochrane Tool of Risk of Bias. relief rate to assess the improvement for cancer-related pain. This scale reports adequate sequence generation, allocation The random effect model was used for statistical analysis 𝑝 < 0.00001 𝐼2 concealment, blinding, incomplete outcome data addressed, because heterogeneity was significant ( , = selective reporting, other biases, and blinding of outcome 77%). The combined effects of 16 independent trial results assessment. showedthatCKIcouldrelievepaininpatientswhencom- pared with chemotherapy (𝑛 = 1265,RR=1.69,95%CI,1.36 𝑝 < 0.00001 2.5. Data Synthesis and Analysis. Data analyses were per- to 2.10, ). The subgroup analysis indicated that no formed using the statistical package RevMan 5.0 (Cochrane better improvements were observed after CKI treatment for Collaboration). Dichotomous data were presented as risk colorectal cancer (Figure 2). ratio (RR) with 95% confidence intervals (CI). Heterogeneity 2 among trials was tested using 𝐼 test and considered signif- 3.3.2. Quality of Life. Karnofsky performance status (KPS) 2 icant when 𝐼 was over 50% or 𝑝 < 0.1. The random effect increase rate data extracted from 6 studies [15–17, 20–22] model was used for the meta-analysis if there was significant showed heterogeneity among trials (heterogeneity: 𝑝 = 0.50, 2 heterogeneity while the fixed effect model was used when the 𝐼 = 54%). The random effect model was used for statistical heterogeneity was not significant. analysis. The combined effects of 6 independent trial results showed that CKI had improved the KPS increase rate in 𝑛 = 420 3. Results patients when compared with chemotherapy alone ( , RR = 1.23, 95% CI, 1.09 to 1.40, 𝑝 = 0.001)(Figure 3(a)). 3.1. Search Results. A total of 167 references were identi- KPS scores extracted from 3 studies [9, 10, 18]showed fied through database searches, of which 151 articles were no heterogeneity among trials (heterogeneity: 𝑝 = 0.68, Evidence-Based Complementary and Alternative Medicine 3

Table 1: Quality assessment of included randomized controlled trials.

Included Random sequence Allocation Blinding of outcome Incomplete Selective Blinding Other biases trials generation concealment assessment outcome data reporting CL2014 Unclear Unclear Unclear Unclear Yes No Unclear DL2008 Unclear Unclear Unclear Unclear No No Yes DL2010 Unclear Unclear Unclear Unclear No No Yes FJW2011 Unclear Unclear Unclear Unclear No No Unclear GJL2007 Unclear Unclear Unclear Unclear No No Yes LYH2011 Unclear Unclear Unclear Unclear No No Unclear LYR2013 Unclear Unclear Unclear Unclear No No Unclear SJ2012 Unclear Unclear Unclear Unclear No No Yes SXW2012 Yes Unclear Unclear Unclear No No Unclear WHJ2006 Unclear Unclear Unclear Unclear No No Unclear WS2014 Yes Unclear No Unclear No No Unclear XJX2013 Yes Unclear Unclear Unclear Yes No Unclear XXD2006 Yes Unclear Unclear Unclear No No Yes YJ2007 Unclear Unclear Unclear Unclear No No Unclear YZG2012 Unclear Unclear Unclear Unclear No No Yes ZJC2012 Unclear Unclear Unclear Unclear No No Unclear

CBM (n = 176) CNKI (n = 96) Wan-Fang (n = 61) VIP (n = 102) PubMed (n = 0) Cochrane Library (n = 0) Total: 435 records for initial

Records after duplicates removed Exclusion (n = 435) 204 duplicated citations

Records screen on the title and abstract Exclusion (n = 231) 64 records irrelevant to the study

Exclusion 36 nonrandomized controlled studies Full-text articles for further 16 incomplete data assessment 5 Chinese medicine or with different (n = 167) dosage in control 73 not meeting criteria for treatment 21 inconsistent criteria

Eligible studies included for meta-analysis (n = 16)

Figure 1: Flow diagram showing the trial selection process for the systematic review and meta-analysis. 4 Evidence-Based Complementary and Alternative Medicine

Table 2: Summary of included studies.

Included Subject Age Intervention Type of cancer pain Outcomes trials (experimental/control) (years; experimental/control) Experimental Control CL2014 42/38 Unclear Liver cancer CKI + TACE TACE Total pain relief rate Total pain relief rate; DL2008 20/20 51 (28–65)/53 (26–66) Liver cancer CKI + TACE TACE quality of life; adverse events Total pain relief rate; DL2010 30/30 51 (37–66)/50 (36–66) Liver cancer CKI + TACE TACE quality of life Total pain relief rate; FLW2011 40/40 66/65 Gastric cancer CKI + FOLFOX FOLFOX adverse events Total pain relief rate; GJL2007 32/31 60 (43,71) Lung cancer CKI + NP NP quality of life; adverse events LYH2011 83/83 71.4 (60–83)/72.7 (61–85) Gastric cancer CKI + FOLFOX FOLFOX Total pain relief rate Total pain relief rate; LYR2013 44/44 52.8 ± 14.5 Lung cancer CKI + GC GC adverse events Total pain relief rate; SJ2012 18/14 62.65 (33,81) Lung cancer CKI + NP NP quality of life Total pain relief rate; SXW2012 54/52 52.5 (32–73)/53.1 (31–72) Lung cancer CKI + NP NP quality of life; adverse events Total pain relief rate; WHJ2006 44/43 54 (33,76) Lung cancer CKI + NP NP quality of life; adverse events Total pain relief rate; WS2014 107/104 55.6/54.5 Liver cancer CKI + TACE TACE quality of life; adverse events XJX2013 60/60 18–75 Gastric cancer CKI + FOLFOX FOLFOX Total pain relief rate Total pain relief rate; XXD2006 45/44 54 (32,71) Colorectal cancer CKI + FOLFOX FOLFOX quality of life Total pain relief rate; YJ2007 64/62 56 (30–78)/60 (33–75) Colorectal cancer CKI + FOLFOX FOLFOX quality of life Total pain relief rate; YZG2012 50/40 56 (40,78)/58 (43,76) Lung cancer CKI + GC GC quality of life; adverse events Total pain relief rate; ZJC2012 33/33 52.3 ± 6.7 Colorectal cancer CKI + FOLFOX FOLFOX quality of life CKI: compound kushen injection; TACE: Transhepatic Arterial Chemotherapy and Embolization; FOLFOX: oxaliplatin + calcium folinate + fluorouracil;NP: Navelbine + cisplatin; GC: gemcitabine + carboplatin.

2 𝐼 =0%).Thefixedeffectmodelwasusedforstatistical adverse reactions (𝑛 = 238,RR=0.39,95%CI,0.21to0.72, analysis. The combined effects of 3 independent trial results 𝑝 = 0.003)(Figure 4(b)), and hepatic and renal functional showed that CKI had improved the KPS scores in patients lesion (𝑛 = 258,RR=0.44,95%CI,0.28to0.68,𝑝 = 0.0002) when compared with chemotherapy (𝑛 = 311,RR=10.07, (Figure 4(c)). No severe adverse events were found in the 95% CI, 8.57 to 11.57, 𝑝 < 0.00001)(Figure 3(b)). treatment groups.

3.3.3. Adverse Events. Specific adverse effects included 4. Discussion leukopenia, gastrointestinal adverse reactions, alopecia, hepatic and renal functional lesion, and bone marrow depres- Cancer-related pain is the perception of the effect of therapy, sions. Of the 16 trials, 8 trials reported adverse effects. The disease status, quality of services, and even survival [24]. treatment groups achieved a statistically significant reduction Intractable cancer pain resistant to World Health Organi- in the incidences of leukopenia (𝑛 = 346,RR=0.76,95% zation (WHO) analgesic ladder afflicts 10∼15% of cancer CI, 0.64 to 0.90, 𝑝 = 0.001)(Figure 4(a)), gastrointestinal pain patients [25]. Patients used to accept analgesics as per Evidence-Based Complementary and Alternative Medicine 5

Experimental Control Risk ratio Risk ratio Study or subgroup Weight Events Total Events Total M-H, random, 95% CI M-H, random, 95% CI 1.1.1 CKI + FOLFOX versus FOLFOX for gastric cancer FJW2011 30 40 12 40 6.3% 2.50 [1.51, 4.15] LYH2011 73 83 46 83 8.9% 1.59 [1.29, 1.96] XJX2013 26 35 7 31 4.9% 3.29 [1.67, 6.50] Subtotal (95% CI) 158 154 20.1% 2.19[1.35, 3.54] Total events 129 65 2 2 2 Heterogeneity: 𝜏 = 0.13; 𝜒 = 6.91, df =2(p = 0.03); I = 71% Test for overall effect: Z = 3.19 (p = 0.001)

1.1.2 CKI + FOLFOX versus FOLFOX for colorectal cancer XXD2006 7 9 1 7 1.2% 5.44 [0.86, 34.55] YJ2007 17 26 20 25 7.8% 0.82 [0.58, 1.15] ZJC2012 7 13 9 12 5.5% 0.72 [0.39, 1.31] Subtotal (95% CI) 48 44 14.5% 0.94 [0.50, 1.76] Total events 31 30 2 2 2 Heterogeneity: 𝜏 = 0.17; 𝜒 = 5.09, df =2(p = 0.08); I = 61% Test for overall effect: Z = 0.21 (p = 0.84)

1.1.3 CKI + NP versus NP for lung cancer GJL2007 25 32 15 31 7.2% 1.61 [1.07, 2.43] SJ2012 16 19 7 17 5.5% 2.05 [1.12, 3.73] SXW2012 32 54 20 52 7.2% 1.54 [1.02, 2.32] WHJ2006 23 43 13 44 6.1% 1.81 [1.06, 3.09] Subtotal (95% CI) 148 144 26.0% 1.68 [1.33, 2.13] Total events 96 55 2 2 2 Heterogeneity: 𝜏 = 0.00; 𝜒 = 0.70, df =3(p = 0.87); I =0% Test for overall effect: Z=4.37(p < 0.0001)

1.1.4 CKI + TACE versus TACE for liver cancer CL2014 28 42 3 38 2.7% 8.44 [2.79, 25.54] DL2008 15 20 8 20 5.6% 1.88 [1.04, 3.39] DL2010 24 30 16 30 7.4% 1.50 [1.03, 2.19] WS2014 45 107 13 104 5.9% 3.36 [1.93, 5.86] Subtotal (95% CI) 199 192 21.7% 2.67 [1.36, 5.26] Total events 112 40 2 2 2 Heterogeneity: 𝜏 = 0.37; 𝜒 =15.61, df =3(p = 0.001); I =81% Test for overall effect: Z = 2.84 (p = 0.005)

1.1.5 CKI + GC versus GC for lung cancer LYR2013 38 44 30 44 8.7% 1.27 [1.00, 1.60] YZG2012 49 50 30 40 9.0% 1.31 [1.09, 1.57] Subtotal (95% CI) 94 84 17.7% 1.29[1.12, 1.49] Total events 87 60 2 2 2 Heterogeneity: 𝜏 = 0.00; 𝜒 = 0.04, df =1(p = 0.83); I =0% Test for overall effect: Z=3.48(p = 0.0005)

Total (95% CI) 647 618 100.0% 1.69 [1.36, 2.10] Total events 455 250 2 2 2 Heterogeneity: 𝜏 = 0.12; 𝜒 = 65.07, df =15(p < 0.00001); I = 77% Test for overall effect: Z=4.77(p < 0.00001) 0.01 0.1 1 10 100 2 2 Test for subgroup differences: 𝜒 = 11.80, df =4(p = 0.02); I = 66.1% Favours control Favours experimental

Figure 2: Forest plot of comparison: CKI plus chemotherapy versus chemotherapy alone: total pain relief rate.

WHO analgesic ladder but were found to be recalcitrant more and more published RCTs of CKI on cancer-related or developed intolerable side effects limiting their use or pain,itisnecessarytousethemethodsofsystematicreview dose. CAM is used as an adjunct therapy with standard pain and meta-analysis to summarize the available evidence and management techniques as it is noninvasive and generally give suggestions to future research and practice. The existing considered to be relatively free of toxicity [26]. CKI is a systematic review and meta-analysis assessed the efficacy of mixture of natural compounds extracted from kushen and CKI only for bone cancer pain or hepatocellular carcinoma baituling. It exhibits a variety of pharmacological activities, [28, 29]. In our study, we used subgroup meta-analysis to including anti-inflammatory, antiallergic, antiviral, antifi- evaluate the improvement for cancer-related pain of different brotic, and especially anticancer activities [27]. Now with the organs and assessed the adverse events. 6 Evidence-Based Complementary and Alternative Medicine

Experimental Control Risk ratio Risk ratio Study or subgroup Weight Events Total Events Total M-H, random, 95% CI M-H, random, 95% CI SJ2012 26 30 16 30 9.0% 1.63 [1.13, 2.34] SXW2012 50 54 44 52 24.2% 1.09 [0.95, 1.26] WHJ2006 41 43 38 44 24.5% 1.10 [0.96, 1.26] XXD2006 36 42 25 40 13.4% 1.37 [1.05, 1.80] YJ2007 41 64 27 62 10.0% 1.47 [1.05, 2.06] YZG2012 46 50 30 40 18.7% 1.23 [1.01, 1.49]

Total (95% CI) 283 268 100.0% 1.23[1.09, 1.40]

Total events 240 180 2 2 2 Heterogeneity: 𝜏 = 0.01; 𝜒 = 10.87, df =5(p = 0.05); I = 54% 0.01 0.1 1 10 100 Test for overall effect: Z = 3.22 (p = 0.001) Favours control Favours experimental

(a)

Experimental Control Mean difference Mean difference Study or subgroup Weight Mean SD Total Mean SD Total IV, fixed, 95% CI IV, fixed, 95% CI DL2008 87.26 6.4820 76.43 7.35 20 12.2% 10.83 [6.54, 15.12] DL2010 88.39 5.6230 77.35 6.67 30 23.1% 11.04 [7.92, 14.16] WS2014 93.33 6.15107 83.75 7.57 104 64.7% 9.58 [7.72, 11.44]

Total (95% CI) 157 154 100.0% 10.07 [8.57, 11.57]

2 2 Heterogeneity: 𝜒 = 0.76, df =2(p = 0.68); I =0% −100 −50 0 50 100 Test for overall effect: Z = 13.16 (p < 0.00001) Favours control Favours experimental

(b)

Figure 3: Forest plot of comparison: CKI plus chemotherapy versus chemotherapy alone. (a) KPS increase rate; (b) KPS scores.

One hundred and sixty-seven studies reviewed were CKI However, the evidence is limited to make a conclusion on plus chemotherapy in treating cancer-related pain. Sixteen the issue of safety because only 50% of studies mentioned the trials were identified as eligible studies for systematic review adverse effects. andmeta-analysis.Themainfindingsofthepresentstudy were that CKI could improve the total pain relief rate and Limitation. The primary outcome in this review was total quality of life of patients with cancer-related pain. Despite the pain relief rate. However, the measure through subjective apparent positive findings reported, there is insufficient evi- qualitative scores such as “markedly effective,” “effective,” dencetosupportroutineuseofCKIforcancer-relatedpain and “ineffective” is not internationally recognized. In addi- due to the poor methodological quality and the small number tion, the reduction in pain intensity was measured using of trials of the included studies. Interestingly, the meta- different scales such as NRS, VAS,and other measures. So itis analysis of total pain relief rate about CKI plus chemotherapy uncertain in assessing the outcome. No study of the included for colorectal cancer found no consistent effects with other trials reported whether any adverse events relevant to CKI types of cancer (RR = 0.94, 95% CI, 0.50 to 1.76, 𝑝 = 0.84). were apparent in patients. Thus, all adverse events must be There is a clear need for further qualitative and quantitative reported by the researchers participating in a clinical trial of research to identify the efficacy of CKI for colorectal cancer. CKIinthefuture. It was of special interest that CKI with chemotherapy This systematic review and meta-analysis provides mod- couldreducetheadverseevents.Nopatientsdroppedout erate evidence for the effectiveness and safety of CKI as of their test trial due to the adverse events of CKI, which adjuvant therapy for cancer-related pain, and a clinical rec- indicated that CKI is safe for clinical use. As we all know, ommendation cannot be warranted because of the generally leukopenia, gastrointestinal adverse reactions, alopecia, and low methodological quality of the included studies (Table 1). bone marrow depressions are the common side effects of CKI may have beneficial effects in the improvement of total chemotherapy. CKI plus chemotherapy achieved a statisti- pain relief rate and quality of life and reduction of side effects. cally significant reduction in the incidences of leukopenia, However, current evidence is insufficient to support the gastrointestinal adverse reactions, and hepatic and renal efficacy of CKI for cancer-related pain because the included functional lesion (Figure 4). It indicated directly that CKI studies were of generally poor quality and had small sample could reduce the toxicity of chemotherapy drugs. That was in sizes. Future research should focus on methodologically conformity with the superiority of TCM in toxicity reduction strong RCTs to determine the potential efficacy of CKI. The and efficacy enhancement. None of the 16 studies reported CONSORT statement [30]shouldbeusedasaguideline whether there were any adverse events relevant to CKI. when designing and reporting RCTs for TCM in the future. Evidence-Based Complementary and Alternative Medicine 7

Experimental Control Risk ratio Risk ratio Study or subgroup Weight Events Total Events Total M-H, fixed, 95% CI M-H, fixed, 95% CI GJL2007 24 32 25 31 21.2% 0.93 [0.71, 1.21] SXW2012 22 54 26 52 22.1% 0.81 [0.53, 1.24] WHJ2006 24 43 35 44 28.9% 0.70 [0.52, 0.95] YZG2012 24 50 30 40 27.8% 0.64 [0.46, 0.90]

Total (95% CI) 179 167 100.0% 0.76 [0.64, 0.90]

Total events 94 116 2 2 Heterogeneity: 𝜒 = 3.62, df =3(p = 0.31); I =17% 0.01 0.1 1 10 100 Test for overall effect: Z = 3.25 (p = 0.001) Favours experimental Favours control

(a)

Experimental Control Odds ratio Odds ratio Study or subgroup Weight Events Total Events Total M-H, fixed, 95% CI M-H, fixed, 95% CI GJL2007 26 32 28 31 16.2% 0.46 [0.11, 2.05] LYR2013 8 44 18 44 44.7% 0.32 [0.12, 0.85] WHJ2006 27 43 35 44 39.1% 0.43 [0.17, 1.13]

Total (95% CI) 119 119 100.0% 0.39 [0.21, 0.72]

Total events 61 81 2 2 Heterogeneity: 𝜒 = 0.25, df =2(p = 0.88); I =0% 0.01 0.1 1 10 100 Test for overall effect: Z = 2.99 (p = 0.003) Favours experimental Favours control (b)

Experimental Control Risk ratio Risk ratio Study or subgroup Weight Events Total Events Total M-H, fixed, 95% CI M-H, fixed, 95% CI CL2014 4 42 16 38 36.4% 0.23 [0.08, 0.62] LYR2013 3 44 6 44 13.0% 0.50 [0.13, 1.87] YZG2012 15 50 21 40 50.6% 0.57 [0.34, 0.96]

Total (95% CI) 136 122 100.0% 0.44 [0.28, 0.68]

Total events 22 43 2 2 Heterogeneity: 𝜒 = 2.74, df =2(p = 0.25); I =27% 0.01 0.1 1 10 100 Test for overall effect: Z=3.71(p = 0.0002) Favours experimental Favours control (c)

Figure 4: Forest plot of comparison: CKI plus chemotherapy versus chemotherapy alone. (a) Incidences of leukopenia; (b) incidences of gastrointestinal adverse reactions; (c) incidences of hepatic and renal functional lesion.

5. Conclusions Acknowledgment CKI appears to be able to improve total pain relief and quality The current work was partially supported by Key Project of life and seems to have beneficial effects on reduction of side of the National Natural Science Foundation of China (no. effects in patients compared with chemotherapy alone. 81330090).

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