clinical randomized single-blind placebo-controlled study.

Transcription

1 Online Submissions: J Tradit Chin Med 06 April 5; 6(): 5-59 info@journaltcm.com ISSN JTCM. All rights reserved. CLINICAL STUDY TOPIC Curative effect of acupuncture on quality of life in patient with depression: a clinical randomized single-blind placebo-controlled study Fan Ling, Fu Wenbin, Chen Zhao, Xu Nenggui, Liu Jianhua, Lǚ Aiping, Li Ziping, Su Shengyong, Wu Taixiang, Ou Aihua aa Fan Ling, Department of Acupuncture and Moxibustion, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 500, China; Post-doctoral Research Station of Guangzhou University of Chinese Medicine, Guangzhou 50405, China Fu Wenbin, Liu Jianhua, Li Ziping, Department of Acupuncture and Moxibustion, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 500, China Chen Zhao, Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson 8574, USA Xu Nenggui, College of Acupuncture and Moxibustion, Guangzhou University of Chinese Medicine, Guangzhou 50007, China Lǚ Aiping, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong , China Su Shengyong, Department of Acupuncture and Moxibustion, The First Affiliated Hospital of Gunagxi University of Chinese Medicine, Nanning 500, China Wu Taixiang, Primary Registry of World Health Organization International Clinical Trials Registry Platform, Chinese Clinical Trial Registry, Chinese Evidence-Based Medicine Center, Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu 6004, China Ou Aihua, Epidemiology Center, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 500, China Supported by the Youth Fund Project of Natural Science Foundation of China (Antidepressant Mechanism of Acupuncture Based on Snare Proteins Modulating the Release of Glutamic Acid in Presynaptic Neurons,. 8004); the China Postdoctoral Science Foundation (Mechanism Research of Acupuncture on Hippocampal Tripartite Glutamatergic Synapses of Depressive Disorder Rats,. 0M5784); the Outstanding Young Innovation Foundation of Guangdong Provincial Department of Education (Clinical Research of Acupuncture in the Treatment of Mild to Moderate Depression,. 0LYM004); Special Research Foundation of New Teacher Category for the Doctoral Program of Higher School of National Ministry of Education (the Moderating Effects of Acupuncture for Hippocampal Tripartite Glutamatergic Synapses of Depressive Disorder rats, ); the Special Financial Grant from the China Postdoctoral Science Foundation (the Modulating Effects of Acupuncture for Glutamic Acid in Hippocampal Presynaptic Neurons of Depressive Disorder Rats,. 0T6079 ); the Science Foundation of the Postdoctoral Researchers in Guangzhou University of Chinese Medicine from Guangdong Provincial Department of Human Resources and Social Security (Clinical Study on Acupuncture and Moxibustion for Treatment of Depression Based on Patient Reported Outcome Indicators,. BBK49K9) Correspondence to: Fu Wenbin, Department of Acupuncture and Moxibustion, Guangdong Provincial Hospital of TCM, Guangzhou 500, China; Chen Zhao, Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson AZ 8574, USA. tcm866@6.com Telephone: Accepted: June 8, 05 Abstract OBJECTIVE: To evaluate the effect of acupuncture on the quality of life in patients with depression by clinical randomized single-blind placebo-controlled study. METHODS: one hundred and sixty-three cases of depression according with the inclusion criteria were randomly divided into a group of acupuncture dredging liver and regulating flow of theosophy (group ), a group of acupoint shallow stab (group ) and a group of non-acupoint shallow stab (group ) at ratio, and treated with acu- JTCM www. journaltcm. com 5 April 5, 06 Volume 6 Issue

2 puncture, moxibustion, and intradermal embedding of needle, twice a week, for a total of weeks. Scale of Quality of Life (SF-6) was used to measure the scores at four different time points and evaluate the effect of acupuncture on the quality of life of the patients with depression. RESULTS: At each time point after treatment, in scores of the 8 items, physical function, physical role, bodily pain, general physical condition, energy, social function, emotional function and mental health there were statistically significant differences among the groups (P < 0.05). CONCLUSION: Acupuncture can effectively improve the quality of life of patients with depression. 06 JTCM. All rights reserved. Key words: Acupuncture; Moxibustion; Intradermal needle therapy; Depression; Quality of life; Randomized controlled trial INTRODUCTION Depression is characterized by mental retardation, interest blank, hypoactivity, accompanied by anxiety, loss of appetite, sexual dysfunction, sleep disorders and other symptoms. "World Health Report 00" published by the World Health Organization points out that the global depression incidence rate is about %, being the world's fourth largest disorder, and till 00 it will be second, only next to ischemic heart disease., For treating depression, antidepressant drugs are commonly used in modern medicine, but they have the side effect of drug resistance. Acupuncture treatment for depression has a definite effect with few side effects, so the World Health Organization (WHO) recognizes that acupuncture treatment has advantages for depression. Acupuncture treatment can dredge meridians and activate collaterals by stimulating some specific acupoints. The heat effect of moxibustion can directly enhance the immunity of human body and the sustained stimulation of intradermal embedding needle in acupoints can consolidate the curative effect. In this trial, these three treatment methods were combined together to treat the disease, so as to improve the life quality of the patient, with the long-term curative effect. MATERIALS AND METHODS Subjects From January 00 to December 00, adult patients of depression receiving acupuncture treatment in the Guangdong Provincial Hospital were included in this study. All participants gave a signed informed consent. Diagnostic criteria Diagnostic criteria of Western Medicine for depression were stipulated in reference to the Chinese Classification and Diagnostic Criteria of Mental Disorders issued by the China Society of Psychiatrics, the third edition (CCMD-), 4 and Traditional Chinese Medicine (TCM) syndrome differentiation was adopted in reference to the Criteria of TCM Syndrome Differentiation and Therapeutic Effects issued by the State Administration of TCM in 995. Inclusion criteria The patients who met the following criteria were included: (a) mild to moderate depression (0 points < HAMD 4-item version score < 5 points) according to Western diagnostic criteria of depression; (b) melancholia with liver Qi stagnation according to the diagnostic standards of Chinese medicine; (c) consciousness with no aphasia and mental retardation, and able to understand the Scale of Quality of Life (SF-6) and the treatment; (d) aged over 8 years and less 70 years; (e) had not used antidepressants for two weeks; (f) signed the written informed consent form. Exclusion criteria The following patients were excluded: (a) the patient had schizophrenia, affective psychosis, reactive depression, neurasthenia, somatic diseases, etc; (b) the patient of severe depression (HAMD 4-item version score > 5 points); (c) the patient was diagnosed as melancholia with heart and spleen deficiency; (d) the patient aged less than 8 years and more than 70 years; (e) the patient had epilepsy, and serious diseases of cardio-cerebral blood vessels, liver, kidney, hematopoietic system and gastrointestinal tract; (f) the patient was pregnant women; (g) the patient took antidepressants in last weeks; or (h) the patient had more than once clinical trials for depression. Criteria of dropout The patients were removed from the trial if they: (a) had poor compliance without treatment according to medical advice; (b) refused to continue treatment due to poor efficacy; (c) could not be contacted due to changes of address and telephone number during follow-up; (d) refused to follow-up study for personal reasons; or (e) had acupuncture and acupuncture-related adverse reactions and refused the treatment. Estimation of required size of samplesaccording to the sample size estimation formulas: n =, 4 cases each group were estimated and considering the maximum allowable drop-off rate of 5% in the observation process, ultimately the sample size of 65 cases was estimated. Randomization and blinding methods The subjects were divided into groups at ratio: a group of acupuncture dredging the liver and regulating the flow of theosophy (group ), a group of acu- JTCM www. journaltcm. com 5 April 5, 06 Volume 6 Issue

3 point shallow stab (group ) and a group of non-acupoint shallow stab (group ). For the randomized controlled trial design, the 65 samples were numbered and inputted PEMS. (West China Center of Medical Sciences, Sichuan) package to produce the sequence number and grouping. The computer output produced a random card, which was placed into opaque sealed envelopes, and random sequences were written on the envelope. Acupuncturists knew grouping of the subjects, but the subjects were unable to distinguish the difference of the groups. The persons for efficacy evaluation did not participate in the course of treatment and did not know the grouping of the subjects. Treatments The acupuncture points were located in reference to the Color Atlas of Acupuncture Points edited by Traditional Chinese Medicine Press in All the treatments were carried by acupuncturists with clinical physician certificates and more than three years work experience, at room temperature of 8. : for acupuncture treatment, 0.5 mm 5 mm filiform needles were used. After disinfection, acupuncture was given at Hegu (LI 4) and Taichong (LR ) into a depth of 0- mm, with a lifting-thrusting and twisting method to get needing sensation (De Qi). Then the needle was inserted into Baihui (GV 0) at a 0- degree angle with the scalp to a depth of 4-5 mm, and for needling Yintang (EX-HN ) the needle was inserted into a depth of 4-5 mm at a 0-degree angle with the forehead. The needles were retained for 0 min and the patients took a deep breath with the nose. The treatment was given more than times a week with an interval > h between treatments, for a total of weeks. After acupuncture treatment, moxabustion with a conical moxa cone of cm in diameter and cm in highness was given on the selected points applied flower oil, Geshu (BL 7), Danshu (BL 9). When the moxa cone was burned out / and the patient had warm or mild burning sensation, it was removed, five cones for each acupoint, twice a week with an interval > h between treatments, for a total of weeks. Then, intradermal embedding of needle was applied to Xinshu (BL 5), Ganshu (BL 8), with the needle body embedded into 5 mm, twice a week with an interval > h between treatments, for a total of weeks. : acupuncture was applied to Hegu (LI 4), Taichong (LR ), Baihui (GV 0), Yintang (EX-HN) with the same method as the group, but the depth of the needle inserting into Hegu (LI 4), Taichong (LR ), Yintang (EX-HN ) were - mm, with no twisting-lifting and thrusting. Then, moxibustion was given on Geshu (BL 7), Danshu (BL 9) with the same method as the group, but moxa cone was burn nearly / and when the patient did not have warm feeling, the moxa cone was removed. Finally, intradermal embedding of needle was applied to Xinshu (BL 5), Ganshu (BL 8), with the same methods as the group, but the needle body only was inserted into a deep of - mm. : acupuncture was given at radial side 0 mm of Hegu (LI 4) and 0 mm lateral to Taichong (LR ) on both sides, left 0 mm from Baihui (GV 0), left 0 mm from Yintang (EX-HN ), with the same operation method as the group. Then, moxibustion was applied on 0 mm lateral to Geshu (BL 7) and 0 mm lateral to Danshu (BL 9) on both sides, with the same operation method as the group. Finally, the intradermal needle was embedded into 0 mm lateral to Xinshu (BL 5) and 0 mm lateral to Geshu (BL 7) on both sides with the same operation method as the group. Outcome measures Demographic data included date of birth, age, gender, height, weight, family history, education level, occupation, healthy care, living habits, sleep habits, medical history characteristics and treatment history. SF-6 Quality of Life Scale Short Form Health Questionnaire developed by the Boston Institute of Health in the United States, is widely used in the measurement of quality of life for the general population, evaluation of clinical trial results and health policy assessment. 6 The Chinese version translated by Sun Yat-sen University is used in this study. The higher score of each item indicates the better therapeutic effect of the quality of life. Adverse reactions were in detail recorded to determine its relationship with the treatment. Follow-up for one month and three months, they were followed up times to observe the efficacy indexes, respectively. Statistical analysis SPSS 8.0 statistical software package (IBM, SPSS Data Collection, Guangzhou, China) was used for statistical analysis of all the data. Descriptive statistics was used for calculation of the data, min, max and M. The paired t-test was used for the comparison between groups. When the variance was homogeneous, analysis of variance was used for the comparison between the two groups after treatment and at the observation time points. Wilcoxon rank sum test was used for non-normal distribution and heterogeneity of variance, and χ test was used for enumeration data. The baseline test level α = 0.; the significance level α = 0.05; rate α = RESULTS Selection of subjects In this study, 6 subjects were included and ultimately 0 cases were dropped, the dropout rate being. %. Among them, 6 cases were dropped in the group ( cases could not be treated on time due to work and other personal events; cases took unauthorized antidepressants during the trial; cases due to JTCM www. journaltcm. com 5 April 5, 06 Volume 6 Issue

4 fainting after treatment); 8 cases in the group (4 cases could not be treated on time due to work; cases took unauthorized antidepressants, cases lost contact due to changes of address or telephone number); and 6 cases in the group (5 cases did not take the authorized antidepressant medicine during the trial, one case lost contact) (Figure ). Treated patients (n = 9) Comparison of baseline data among the groups Among the three groups of patients in age, height, weight, duration of illness, gender, education level, occupation, habits, treatment of Western Medicine, and acupuncture treatment there were not statistically significant differences (P > 0.05). In the health care, family history and psychological treatment (less than 5 in the theoretical number of Fisher's exact test) among the three groups there were not statistically significant differences (P > 0.05) (Tables, ). Comparison of SF-6 scores before treatment among the groups of patients Before treatment among the three groups of depression Excluded (n = 76) Meeting the inclusion criteria (n = 6) Randomization (n = 5) (n = 56) (n = 54) Off (n = 6) Off (n = 8) Off (n = 6) (n = ) (n = ) (n = ) Analysied (n = 4) Figure Flow chart of subject selection In this study, 6 subjects were included and ultimately 0 cases were dropped, the dropout rate being.%. Among them, 6 cases were dropped in the group ( cases could not be treated on time due to work and other personal events; cases took unauthorized antidepressants during the trial; cases due to fainting after treatment); 8 cases in the group (4 cases could not be treated on time due to work; cases took unauthorized antidepressants, cases lost contact due to changes of address or telephone number); and 6 cases in the group (5 cases did not take the authorized antidepressant medicine during the trial, one case lost contact). Table Baseline data of the three groups of patients with depression ( xˉ ± s) Age (year) Height (centimeter) Body weight (kilogram) Duration of illness (month) n Score 9± 4± 4± 64±7 6±7 65±8 58±8 55±0 59±0 5±5 5±6 4± Lower limit 95% CI JTCM www. journaltcm. com 54 April 5, 06 Volume 6 Issue Upper limit Min Max F value tes: group : a group of acupuncture dredging the liver and regulating the flow of theosophy; group : a group of acupoint shallow stab; group : a group of non-acupoint shallow stab

5 patients in the scores of the SF-6 Scale there were no significant differences (P > 0.05), suggesting that the three groups were comparable (Table ). Comparison of SF-6 Scale scores at each time point after treatment among the three groups of patients, the scores of the eight items in the SF-6 Scale at each time point increased significantly in the groups (all P < 0.05), with statistically significant differences as the group compared with the group and the group, respectively (all P < 0.05). While one and three months after treatment, except the social function score (Z =.5, P = 0.), in the other item scores, there were no statistically significant differences between the group and the group (P < 0.05), as shown in Table 4. It is indicated that the group at each time point after treatment in improvements of physical function, physical role, bodily pain, general health condition, energy, social function, emotional function and mental health were better than the group and. DISCUSSION To set the placebo control has an important meaning for evaluation of acupuncture curative effect, and still faces a lot of difficulties in the randomized controlled research of acupuncture and moxibustion. 7,8 All subjects were told that this study aimed at comparison of two effective acupuncture methods. The patients in the group knew that they were treated by needling the skin, and the patients in the group were unable to determine whether the needled acupoint is accurate, so all the patients considered that they were treated with acupuncture. The results indicated that the placebo acupuncture also had a certain effect, which is considered to be related to the patient's psychological hint. 9 The curative effect of the group was better than the placebo groups, indicating the importance of the needling response (De Qi), 9 which includes sensation of soreness, distension, pressure and numbness, electric shock or pain, and can be induced through different acupuncture manipulations. 0 According to WHO's definition about quality of life, individual physical, psychological and social function gradually are used as important indicators to assess the clinical efficacy and disease prognoses. At present, the quality of life, especially health-related quality of life has been widely used for health assessment of the gener- Table Baseline data of the three groups of patients with depression [n (%)] Gender Man 6 (6.) 4 (9.) (4.4) χ value Woman (7.8) 4 (9.) 7 (.9) Education Elementary education 9 (7.9) (0.9) 8 (4.) Secondary education 9 (9.6) 5 (.) 4 (9.) University and above 9 (.) (44.4) 6 (.) Occupation Manual workers 9 (40.4) (7.7) 5 (.9) Mental workers (4.4) (.8) (.8) Unemployed 6 (8.8) 4 (4.8) (7.5) Medical insurance (7.) (8.) 6 (54.5) (.) 46 (4.8) 4 (.8) Habits and customs 7 (7.0) 5 (4.) (8.8) (8.6) (.9) 7 (8.6) Family history 4 (.) (5.6) 44 (.) (54.5) (9.) 4 (6.4) Western Medicine treatment (9.5) 40 (5.7) 9 (4.8) (45.) 8 (5.8) 9 (9.0) Acupuncture treatment 9 (.5) 4 (5.8) 8 (.7) (4.8) 5 (.7) 0 (4.5) Psychological treatment 46 (4.) (4.8) 4 (.) (.5) (.5) 6 (75.0) tes: group : a group of acupuncture dredging the liver and regulating the flow of theosophy; group : a group of acupoint shallow stab; group : a group of non-acupoint shallow stab. JTCM www. journaltcm. com 55 April 5, 06 Volume 6 Issue

6 Table Scores of SF-6 scale in the three groups of patients before treatment ( xˉ ± s) Physical function Physical role Bodily pain General physical condition Energy Social function Emotional function Mental health al population and special populations, assessment of quality of life of patients of cancer and chronic disease, evaluation and selection of clinical treatment programs and preventive interventions, and clinical medicine, preventive medicine, pharmacy, health management and other fields. Application of the quality of life as main indicators to evaluation of the acupuncture efficacy on depression is still at its infancy in China. The high-quality clinical research reports based on evaluation of the quality of life are very few. The assessment method of quality of life is used for the evaluation of the efficacy of acupuncture treatment on depression, which can more scientifically reflect the actual efficacy of acupuncture, and help to establish a unified evaluation standard, so as to enhance comparability and reproducibility of clinical efficacy studies, with an important clinical significance. 4 With popularity of social medical model, the current treatment is no longer simply for pain in the patients, n Score 9.5±.5 9.9±.4 9.6±.7 5.5±.6 5.5±.6 6.±.6 4.7±.5 4.5±. 5.±.9 5.±.8 5.4±.8 5.±. 7.8±.6 7.5±.0 7.7±.8 40.±.7 40.± ±. 0.±.0 0.±.9 0.0±.8.±.4.5±..4±.6 Lower limit % CI Upper limit but rather focuses on the overall improvement of patients' physical and mental function and subjective health status, and the improvement of life satisfaction. The concept of the balance of Yin and Yang in Chinese medicine theory covers the physical, nutritional, psychological, environmental (social environment and natural environment), and other many factors, as well as the body physically and mentally maintains a balance, which are basically the same as the latest interpretation of the WHO's definition about health or even have a wider range. 5 Thus, the theory of traditional Chinese culture and Chinese medicine has rich connotation of quality of life. The concept of quality of life adapts to changes in the modern medical disease spectrum and interlinks thinking of Traditional Chinese Medicine syndromes in many ways. 6 Therefore, evaluation of the quality of life for clinical efficacy of Traditional Chinese Medicine can provide a more consistent evaluation standard for TCM clinical trials and increase their JTCM www. journaltcm. com 56 April 5, 06 Volume 6 Issue Min Max F value tes: group : a group of acupuncture dredging the liver and regulating the flow of theosophy; group : a group of acupoint shallow stab; group : a group of non-acupoint shallow stab

7 Table 4 Scores of each item in SF-6 Scale in the three groups of depression patients at each time point after treatment ( xˉ ± s) Time point n Score M χ value Physical function 5.0±.0 ab ±.0 ab ±.0 a ±.0 ab ±.0 ab ±.0 a ±.0 ab ±4.0 ab ± Physical role 55.0±.0 ab ±4.0 ab ±.0 a ±.0 ab ±5.0 ab ±.0 a ±.0 ab ±6.0 ab ±.0 a Bodily pain 64.0±.0 ab ±.0 ab ±5.0 a ±.0 ab ±.0 ab ±5.0 a ±6.0 ab ±6.0 ab ±5.0 a General health condition 55.0±.0 ab 49.0±4.0 ab ±.0 a ±.0 ab ±4.0 ab ±.0 a ±.0 ab ±4.0 ab ±.0 a Energy 57.0±4.0 ab ±4.0 ab ±4.0 a ±.0 ab ±4.0 ab ±4.0 a ±5.0 ab ±5.0 ab ±4.0 a JTCM www. journaltcm. com 57 April 5, 06 Volume 6 Issue

8 Table 4 Scores of each item in SF-6 Scale in the three groups of depression patients at each time point after treatment ( xˉ ± s) (Continuted) Time point Social function 60.0±.0 ab ±4.0 ab ±.0 a ±.0 ab ±5.0 ab ±.0 a ±4.0 ab ±5.0 a ±.0 a Emotional 55.0±.0 ab function 7.0±5.0 ab ±4.0 a ±.0 ab ±5.0 ab ±.0 a ±5.0 ab ±4.0 ab ±.0 a Mental Health.0±.0 ab ±.0 ab ±5.0 a ±.0 ab ±4.0 ab ±4.0 a ±.0 ab ±4.0 ab ±4.0 a tes: group : a group of acupuncture dredging the liver and regulating the flow of theosophy; group : a group of acupoint shallow stab; group : a group of non-acupoint shallow stab. Comparison of the score of quality of life before and after treatment in the groups, a P < 0.05; compared with the group, b P < N Score M χ value homogeneity and reproducibility, with broad application prospects. ACKNOWLEDGEMENTS Thanks for the staff of Scientific Research Department of Guangdong Hospital of Traditional Chinese Medicine for technical support. Thanks for the staff of the Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona for data analysis. REFERENCES Shen YT. Psychiatry. Beijing: Beijing People's Health Publishing House, 009: -49. Liu YZ. Clinical and mechanism studies of acupuncture treatment of depression. Shanghai Zhen Jiu Za Zhi 008; 7(): -49. Wang LH, Lu LX. Clinical Psychopharmacology. Beijing: People's Health Publishing, 009: Society of Mental Science, Chinese Medical Association. CCMD Classification and Diagnostic Criteria for Mental Disorder. rd ed. Jinan: Shandong Science and Technology Publishing House, 00: 8. 5 Cheng K, Wang YP. Color Atlas of Acupuncture Acupoints. Beijing: China Press of Traditional Chinese Medicine, 00: Ji S, Long Q, Newport DJ, et al. Validity of depression rating scales during pregnancy and the postpartum period: impact of trimester and parity. J Psychiatr Res 0; 45 (): Park J, White A, Ernst E. New sham method in auricular acupuncture. Arch Intern Med 00; 6(): Zhou W, Benharash P. Significance of ''De Qi'" response in acupuncture treatment: myth or reality. J Acupunct Meridian Stud 04; 7(4): Du YH, Li GP. Theoretical basis of regulating mind and relieving the depressed liver needling method for treatment of depression. Zhong Guo Zhen Jiu 005; 5(): JTCM www. journaltcm. com 58 April 5, 06 Volume 6 Issue

9 0 Liu FB, Zhao L, Liang GH, et al. Chinese medicine theory and structure of the health status scale model. Xin Zhong Yi 007; 9(9): 0-. Du YH. Acupuncture disease spectrum. Beijing: People's Health Press, 009: 4-6. Smith CA, Hay PP, Macpherson H. Acupuncture for depression. Cochrane Database of Syst Rev 00; (): CD Quah-Smith I, Smith C, Crawford JD, Russell J. Laser acupuncture for depression: a randomized double blind controlled trial using low intensity laser intervention. J Affect Disord 0; (): Burkey Dell R. Regional anesthesia and pain management: anesthesia pocket consult for ipod. Philadelphia: PA Saunders/Elsevier, 009: MacPherson H, Newbronner L, Chamberlain R, et al. Practitioner perspectives on strategies to promote longerterm benefits of acupuncture or counselling for depression: a qualitative study. PLoS One 04; 9(9): e Fava GA, Ruini C, Belaise C. The concept of recovery in major depression. Psychol Med 007; 7(): JTCM www. journaltcm. com 59 April 5, 06 Volume 6 Issue