Expand Document  |  Expand Chapter  |  Full TOC  |  Printable HTML version
SARS: Clinical Trials on Treatment Using a Combination of Traditional Chinese Medicine and Western Medicine
(2004; 194 pages) View the PDF document
Table of Contents
View the documentAcknowledgements
View the documentIntroduction
View the documentReport of the International Expert Meeting to review and analyse clinical reports on combination treatment for SARS
View the documentReport 1: Clinical research on treatment of SARS with integrated Traditional Chinese medicine and Western Medicine
View the documentReport 2: Clinical efficacy of the treatment of SARS with integrated Traditional Chinese medicine and Western medicine: an analysis of 524 cases
View the documentReport 3: Manifestation of symptoms in patients with SARS and analysis of the curative effect of treatment with integrated Traditional Chinese medicine and Western medicine
View the documentReport 4: Clinical study on 103 inpatients undergoing therapy with integrated Traditional Chinese medicine and Western medicine
View the documentReport 5: Clinical observations of 11 patients with SARS treated with Traditional Chinese medicine
View the documentReport 6: Effects of applying integrated therapy with Traditional Chinese medicine and Western medicine on liver and kidney functions in patients with SARS
View the documentReport 7: Clinical research on 63 patients with SARS treated with integrated Traditional Chinese medicine and Western medicine
View the documentReport 8: Influence of integrated therapy with Traditional Chinese medicine and Western medicine on lymphocytes and T-lymphocyte subpopulations of patients with SARS
View the documentReport 9: Analysis of the clinical curative effects on patients with SARS of treatment with Traditional Chinese medicine and Western medicine
View the documentReport 10: Evaluation of clinical curative effects of Traditional Chinese medicine in treatment of patients convalescing from SARS
View the documentReport A: A herbal formula for the prevention of transmission of SARS during the SARS epidemic in Hong Kong Special Administrative Region - a prospective cohort study
View the documentReport B: Effects of Chinese medicine on patients convalescing from SARS in Hong Kong special administrative region - a prospective non-randomized controlled trial
View the documentReport C: Traditional Chinese medicine in the management of patients with SARS in Hong Kong Special Administrative Region - a case-control study of 24 patients
View the documentAnnex
 

Report 6: Effects of applying integrated therapy with Traditional Chinese medicine and Western medicine on liver and kidney functions in patients with SARS

Li Jun24, Li Shaodan24, Du Ning24, Dong Yi24, Xiao Xiaohe24, Yang Yongping24 and Li Li24

24 No. 302 Hospital of PLA Beijing 100039, People's Republic of China


Abstract The objective was to investigate the effectiveness and safety of treatment for severe acute respiratory syndrome (SARS) applying an integrated therapeutic regimen of Traditional Chinese medicine (TCM) and Western medicine. Forty-seven patients with confirmed SARS were randomly allocated to either the integrated treatment group or the Western medicine-treated group for a treatment course of 3 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbil) and creatinine (CRE) and blood urea nitrogen (BUN) were measured every week throughout the treatment period. Hepatic dysfunction occurred in all patients. The total numbers of patients with hepatic dysfunction were 23 in the integrated treatment group and 21 in the group treated with Western medicine, and the numbers had decreased to 13 and 20 after treatment (p = 0.00441). The effect of TCM on ALT was the most marked: before treatment there were 20 and 8 patients with abnormal ALT in the integrated treatment group and the group treated with Western medicine, respectively, whereas the numbers were 13 and 19 after treatment. The highest level of ALT in the integrated treatment group was 81.54 ± 49.25 IU/l reached on day 7, and after treatment, it had decreased to 46.92 ± 29.25 IU/l (p < 0.05). In the group treated with Western medicine, the value before treatment was 53.96 ± 48.59 IU/l, and it had risen to 80.80 ± 56.26 IU/l after treatment (p < 0.05). There were nine and six patients with abnormal AST before treatment in the integrated treatment group and the group treated with Western medicine, respectively; the numbers had decreased to one and three cases, respectively after treatment. Fifteen patients in the integrated treatment group and 10 in the group treated with Western medicine had renal dysfunction. After treatment there were still six and four cases in the two groups, respectively. Dysfunction in liver and kidney appeared in SARS patients during the onset and later stages of the disease (particularly in ALT). It was shown that the integrated therapy with TCM and Western medicine was effective in alleviating damage to liver and kidneys, promoting improvement of hepatic function, protecting renal function and accelerating patients’ recovery from illness, and the TCM regimen proved safe when applied in the treatment of SARS.

Introduction

SARS is a respiratory system disease with strong infectivity and a high case fatality rate caused by a corona virus subtype (SARS virus) (1). The illness progresses very fast; acute respiratory distress syndrome (ARDS) may occur in some patients and many will suffer from impairment of liver and kidney functions (2-4). Because there is as yet no specific treatment for SARS, the present study used the general clinical characteristics of SARS patients and a prospective case-control study design to investigate the effects of therapy with integrated traditional and Western medicine on liver and kidney functions. The investigation considered the effectiveness and safety of TCM when used in the treatment of patients with SARS.

Methods

Study subjects

Source of case history

Medical histories were obtained from 47 patients with confirmed SARS admitted to our hospital. The histories of the patients were in compliance with the inclusion criteria for this study. The study subjects were randomly allocated to either the integrated treatment group (the experiment group) (24 cases) or the group treated with Western medicine (the control group) (23 cases). General information on the 47 cases is given in Table 1 and the distribution of symptoms is shown in Fig. 1.

The steroid, methylprednisolone, was used to treat patients in both groups, and the average accumulated dose was 5278.33 ± 4032.20 mg in the integrated treatment group and 6266.70 ± 4137.25 mg in the group treated with Western medicine (t-test; p = 0.4113) and there was no significant difference between the two groups with respect to sex, age, stage of illness, clinical classification and use of hormone (p > 0.05).


Fig. 1. Main symptoms of 47 cases at time of admission to hospital

Table 1. Case distribution of patients at the time of their inclusion into the treatment groups

 

Control group

Experiment group

Total

Number of subjects

23

24

47

Sex

     
 

Male

18

14

32

 

Female

5

10

15

Age (years)

     
 

18-20

2

3

5

 

21-30

7

11

18

 

31-40

9

6

15

 

41-50

2

3

5

 

51-60

2

1

3

 

61-65

1

0

1

Profession

     
 

Health care workers

10

9

19

 

Others

13

15

28

Days after onset when patient was included in treatment group

     
 

< 7 days

5

8

13

 

8-14 days

6

5

11

 

> 15 days

12

11

23

Body temperature (°C)

     
 

38.1-39.0

12

13

25

 

39.1-40.0

6

5

11

 

37.1-38.0

3

6

9

 

> 40.0

2

0

2

Diagnostic criteria

Diagnoses were made according to the criteria in Clinical diagnosis criteria for infectious SARS (proposed) promulgated by the State Ministry of Health on 3 May 2003. Forty-seven patients were clinically classified as follows: 44 common cases (23 cases in the integrated treatment group); three serious cases (one case in the integrated treatment group); no very serious cases were included.

Case inclusion criteria

Patients were included if they met the diagnostic criteria for SARS and were aged between 18 and 65 years. Patients were classified as normal cases, serious cases and very serious cases according to the Guide to clinical work in respect of infectious SARS issued by the Beijing SARS Treatment and Command Centre on 27 April 2003.

Case exclusion criteria

Patients were excluded if they had severe cardiovascular or cerebrovascular diseases, liver and kidney diseases, blood diseases, endocrine diseases, pulmonary diseases, neuropsychosis or serious diseases such as tumours or acquired immunodeficiency syndrome that affected their quality of life before contracting SARS.

Allocation to treatment group

The SAS 6.12 software kit was used to allocate the patients randomly to one or other of the treatment groups.

Therapeutic regimens

Therapeutic regimen for Western medicine

The treatment regimen for Western medicine recommended by the Ministry of Health on 3 May 2003 was adopted. The basic components of this treatment are: antiviral agent, antibiotics, immunopotentiator and hormone.

Therapeutic regimens for integrated treatment

The therapeutic regimens for integrated traditional and Western medicine were based on the above regimen for Western medicine treatment together with a combination of the treatment regimens appropriate to the types and stages of diseases in accordance with the theories of TCM.

Normal cases

Mixture of honeysuckle flower and isatis leaf including Flos Lonicerae (20 g), Folium Isalipis (20 g), Radix Purariae (15 g) and Folium Perilla (12 g) used to remove heat and ventilate the lung, relieve exterior syndrome and regulate channels, and to remove dampness heat and expel pathogens.

Serious and very serious cases

Compound mixture of cordate houttuynia including Herba Houttuyniae (45 g), Radix Scutellariae (15 g), Semen Armeniacae Amarum (15 g), Radix Bupleuri (15 g), Fossilia Chitonis (30 g) and Radix Pseudostellariae (20 g). This preparation is used to ventilate the lung and subdue adversity, regulate shaoyang, replenish qi and nourish yin.

Patients at the stage of recovery from disease (reduced dose of hormone)

Mixture of licorice and astragalus root consisting of Radix Astragali seu hey sar (45 g), Radix Glycyrrhizae (30 g), Semen Persicae (30 g). This preparation is used to replenish qi and nourish yin, tonify lung and promote digestion, remove dampness and regulate channels. Changes in the ingredients based on the above three prescriptions may be made during clinical treatment in response to a patient’s actual symptoms. All regimens were administered as one dose per day to be decocted and taken orally.

No. 1 SARS granules: consist of Rhizome Cyrtomium (20 g), Radix Bupleuri (10 g), fibrous root of American Ginseng (5 g) and Fructus Schisandrae (10 g). They were used to remove heat and toxin, replenish qi and nourish yin; they were also used against dominance of pathogenic heat and deficiency of both qi and yin.

No. 2 SARS granules: consist of Chinese globeflower (10 g), Rhizome Cyrtomium (10 g) and Folium Isalidis (10 g), used to remove heat, toxin and pathogens in patients with excess pathogenic heat.

One or other of the above prescriptions were administered for a 3-week course of treatment.

Outcome indicators and evaluation criteria

Outcome indicators were indices of hepatic function and renal function, including ALT, AST, Tbil, CRE and BUN. The range of normal values is as follows: ALT, 0-40 IU/l; AST, 0-40 IU/l; Tbil, 0-17.1 µmol/l; CRE, 44-106 µmol/l; BUN, 2.9-8.2 µmol/l.

Observations

Changes in the clinical conditions of patients were noted and ALT, AST, Tbil, CRE and BUN were measured before treatment and on days 7, 14 and 21 after commencement of treatment in all patients. A fully automatic biochemical analyser was adopted for testing and analysing functions of liver and kidney. An observation cycle lasted 3 weeks.

Quality control

To ensure the quality of this research and avoid errors in gathering case information, the following quality control measures were taken during research. The head of the subject group and the coordinator were appointed to coordinate matters relevant to data gathering in the hospital under the leadership of the chief official of the Centre. Centralized training was provided to physicians participating in the clinical research so that each understood and had mastered the treatment proposals, the requirements and precautions for filling out case report forms. Standardization of data gathering, data management and counterchecking of original documents were also strengthened by the training programme.

Data management and statistical treatment

The responsible physician filled in the required details on the state of illness and on the treatment measures in the case report form without delay. The details were entered into the database after they had been examined and certified to be true and correct by higher-ranking physicians. The data were then examined, errors in the database were corrected and the database made read-only for statistical analysis. The database was established using ACCESS, the Wilcoxon rank-sum test and Fisher’s exact test were also used for the statistical analysis. Measurements were expressed as mean value ± standard deviation.

Research results

Serum hepatic function tests - overall findings

The classification of abnormality in ALT, AST and Tbil conformed to that given in Preventive and curative regimens for virus hepatitis (2000) (5). Hepatic dysfunction occurred in all patients after admission to hospital. The total numbers of patients with hepatic dysfunction (abnormal levels of any one of ALT, AST or TBil) in the integrated treatment group and the group treated with Western medicine were 23 and 21, respectively, and, after treatment, the numbers of patients with abnormal results were 13 and 20, respectively. The result of Fisher’s exact test (p = 0.00441) showed that the differences were statistically significant, especially that for ALT. The numbers of patients with abnormal ALT in the two treatment groups are shown in Table 2.

Table 2 Patients with abnormal serum ALT in the two treatment groups

Treatment group

Abnormality of ALT

 

Number of cases

   

Day 1

Day 7

Day 14

Day 21

Integrated treatment
(n = 24)

Minor

17

13

10

11

 

Above moderate

3

6

5

2

Total

 

20

19

15

13

Western medicine
(n = 23)

Minor

6

12

11

11

 

Above moderate

2

2

6

8

Total

 

8

14

17

19

There were 12 patients more with abnormal ALT before treatment in the integrated treatment group than in the group treated with Western medicine (20 cases and eight cases, respectively). After treatment, the numbers were 13 and 19 cases, respectively (i.e. six fewer abnormal cases in the integrated treatment group than in the group treated with Western medicine). Fig. 2 is a trend chart showing the percentages of patients with abnormal ALT tests in patients of both groups at four time points. The percentage of patients with abnormal ALT levels in the group treated with Western medicine increased over time, while that of the patients in the integrated treatment group gradually decreased. AST was measured before and during the treatment. Nine patients in the integrated treatment group showed minor abnormality (40-120 IU/l) and none had moderate abnormality or above (>120 IU/l). In the group treated with Western medicine alone, six patients had minor abnormality of AST levels and none had any moderate or severe abnormality. After treatment, only one patient in the integrated treatment group showed abnormal AST, whereas in the group treated with Western medicine there were still three patients with abnormal AST.


Fig. 2. Changes in abnormal serum alanine aminotransferase (ALT) in patients of both groups

TBil was measured before and during the treatment, and eight patients in the integrated treatment group showed slight abnormality (17.1-34.2 µmol/l) and three patients had moderate abnormality or above (>34.2 µmol/l). The corresponding figures for the group treated with Western medicine alone were five and one, respectively. TBil was also measured at the end of the course of treatment, and both the treatment groups had one patient with minor abnormality. From the test results of ALT, AST and TBil of patients in both groups and the trend of abnormality in ALT, it is apparent that the therapeutic regimen of integrated treatment with TCM and Western medicine has certain advantages over the treatment with Western medicine alone in facilitating the restoration of liver function.

Change in serum ALT of patients in the two treatment groups

All the 47 SARS patients experienced hepatic dysfunction in the course of their treatment, and the abnormality of ALT was especially obvious. ALT was measured four times during the course of treatment, and the mean values in the integrated treatment group and the group treated with Western medicine alone were not significantly different (p > 0.05). In patients in the integrated treatment group ALT reached its highest level on day 7 and gradually decreased to reach the lowest level at the time of the last test; comparison of the value on day 7 with that on day 21 showed a significant difference (p = 0.0465). In the group treated with Western medicine, ALT continued to increase throughout the treatment and peaked at the end of treatment. The ALT values before and after treatment showed a statistically significant difference (p = 0.0394). From the trend of the mean values of ALT in both treatment groups, it was apparent that the integrated treatment was superior to treatment with Western medicine alone in alleviating lung inflammation and facilitating the restoration of hepatic function (Table 3, Fig. 3), which indicated that integrated therapy with TCM and Western medicine not only had better curative effects, but also greater clinical safety.

Table 3 Changes in the results of testing serum alanine aminotransferase (ALT) in patients in the two treatment groups ( ± SD IU/l)

Treatment group

ALT (IU/I)

 

Day 1
Mean ± SD

Day 7
Mean ± SD

Day 14
Mean ± SD

Day 21
Mean ± SD

Traditional Chinese plus Western medicine (n = 24)

61.54 ± 46.02

81.54 ± 49.25

77.13 ± 63.99

49.91 ± 29.00*

Western medicine only (n = 23)

53.33 ± 48.95

62.78 ± 47.34

72.85 ± 44.42

82.68 ± 57.15**

P

0.5023

0.1799

0.5876

0.1106

 

Note: Results on day 21 compared with the results on day 7 in the same treatment group, *p < 0.05; when results on day 21 were compared with the results of the same group obtained on the first day, **p < 0.05.


Fig. 3 Change trend of mean serum alanine aminotransferase (ALT) of patients in both groups

Note: Results compared with the results on day 7 in the same treatment group, *p < 0.05; when compared with the results from the same group obtained on the first day. (p < 0.05).


Change of hepatic dysfunction ratio in patients with normal hepatic function in the two treatment groups

For patients in both treatment groups with normal hepatic function indices before treatment or tested at the end of the treatment period, an analysis was conducted of the percentage change of any one parameter with an abnormal index (ALT, AST or Tbil) measured on the subsequent test day (Table 4).

Table 4. Change of hepatic dysfunction ratio in patients who started with normal hepatic function in both treatment groups

Treatment group

Abnormal cases/normal cases

 

Day 1

Day 7

Day 14

Day 21

Integrated (Chinese traditional plus Western medicine)

0/4

3/4

1/2

3/9

Western medicine alone

0/13

7/1

5/9

3/6

p

 

0.6030

1.0000

0.6220

Changes of serum creatinine (CRE) and blood urea nitrogen (BUN) of patients in both treatment groups

Renal dysfunction occurred in some of the 47 SARS patients, including 15 cases in the integrated treatment group and 10 in the group treated with Western medicine alone. After treatment there were six cases and four cases in the integrated treatment group and the group treated with Western medicine, respectively. However, no significant difference was found between the mean values for the two treatment groups when CRE and BUN were measured at four different times during the course of treatment (p > 0.05) (Table 5), the change trend in the mean values is shown in Figs 4 and 5. No significant differences were seen in CRE and BUN between patients at the same stage of illness in the two groups or between different stages in the same group (p > 0.05).

Table 5. Change of serum creatinine (CRE) and blood urea nitrogen (BUN) ( ± SD IU/l)

Item measured

Treatment group

Day 1

Day 7

Day 14

Day 21

CRE (µmol/l)

Integrated (TCM plus Western medicine)
(n = 24)

84.58 ± 16.49

85.38 ± 15.96

82.90 ± 18.76

85.22 ± 15.77

 

Western medicine alone (n = 23)

82.65 ± 11.11

82.35 ± 16.65

80.45 ± 19.47

82.74 ± 11.58

BUN(mmol/l)

Integrated (TCM plus Western medicine)
(n = 24)

6.48 ± 2.18

6.80 ± 1.72

6.89 ± 1.73

6.74 ± 2.19

 

Western medicine alone (n = 23)

6.15 ± 1.50

7.16 ± 1.82

7.50 ± 1.86

7.58 ± 1.82

 

TCM, Traditional Chinese medicine; SD, standard deviation.


Fig. 4. Change trend of mean serum creatinine in patients in the two treatment groups


Fig. 5. Change trend of mean serum blood urea nitrogen in patients in the two treatment groups

Change of renal dysfunction ratio in patients with normal renal function in the two treatment groups

For patients with normal renal function indices in both groups before treatment or when previously measured, an analysis was made of the percentage change in CRE and BUN tested at the end of the treatment period (Table 6 and Fig. 6).

Table 6. Change of renal dysfunction ratio in patients with normal renal function in the two treatment groups

Treatment group

Percentage (abnormal cases/normal cases)

 

Day 1

Day 7

Day 14

Day 21

Integrated treatment (Chinese plus Western medicine)

0 (0/16)

18.75 (3/16)

15.00 (3/20)

10.53 (2/19)

Western medicine only

0 (0/22)

22.73 (5/22)

16.67 (3/18)

17.65 (3/17)

p

 

1.0000

1.0000

0.6500


Fig. 6. Change trend of renal dysfunction ratio in patients with normal renal function in the two treatment groups

Discussion and conclusion

The present treatment for SARS includes antiviral agents such as ribavirin and oseltamivir; hormone to suppress immune reaction, avoid damage to the lung and allay fever; and antibiotics to prevent potential bacterial infections. Treatment with TCM is based on an overall analysis of symptoms and signs, the cause, nature and location of the illness, and the patient’s physical condition according to the basic theories of TCM, and the provision of appropriate treatment based on the specific symptoms.

It has been reported that the SARS virus may cause serious infection of the lower respiratory tract and damage to several systems in the body. Clinical workers from mainland China, Hong Kong SAR and other countries have noted impairment of the functions of liver and kidney in many patients. This dysfunction is mainly demonstrated as an abnormality of ALT, AST, Tbil, CRE and BUN; changes in ALT were especially significant (2-4). These findings suggest that damage to the parenchyma cells of the liver and kidney probably occur in SARS patients during the onset and progression of the disease. The results of the present study support this suggestion.

As a relatively sensitive index, ALT might reflect the scale of liver inflammation in SARS patients, and the status of liver function could be determined directly through measurement of ALT. Hepatic dysfunction probably occurs at the early stage in most patients, as indicated by the autopsy results of one patient who died from SARS in our hospital. Hepatic damage was mainly due to secondary anoxia caused by infection and other factors, which could be related to SARS itself. It is also possible that the use of antivirals, hormone and other drugs caused impairment of liver function during the treatment. Because the liver is the central organ for metabolizing medicine to enable it to perform its curative function, a knowledge of how to alleviate liver inflammation and protect the parenchyma cells of the liver from damage so as to facilitate the restoration of liver function would also be a critical step in the successful treatment of SARS.

From the changes of the mean values of ALT in both groups, the integrated treatment was shown to be better than the treatment with Western medicine alone, demonstrating that integrated therapy was effective in treating SARS.

The kidney is a target organ in SARS virus infection. Although renal dysfunction was seen in some patients, the rate of abnormality was lower than that for hepatic function, and no significant differences between the mean values of CRE and BUN between the two treatment groups were found. As seen in the change trend of the ratio of hepatic dysfunction and renal dysfunction in patients in both groups who had normal hepatic and renal function at the start of treatment, the integrated treatment was superior to the treatment with Western medicine alone. This finding suggests that treatment with integrated TCM and Western medicine was safe.

It has been reported that treatment of SARS patients with integrated traditional and Western medicine can significantly enhance the overall recovery of patients from illness (6). We also found that this treatment could significantly shorten the duration of clinical symptoms, speed up the usage of hormone, promote absorption of lung inflammation and accelerate recovery of patients from illness. Based on the integrative concept, theory and principles of overall analysis of symptoms and signs, the cause, nature and location of the illness and the patient’s physical condition in TCM together with the general law regarding the progress of epidemic febrile diseases, we chose appropriate herbal remedies. These included Flos Lonicerae, Folium Isalidis, Herba Houttuynia and Radix Isatidis for clearing away heat and toxin, Radix Astragali and Radix Panalis Quinquefolii for replenishing qi and nourishing yin, also large Fructus Scutellariae, Radix Bupleuri and Carapax Trionycis for clearing, regulating, nourishing the liver and replenishing the kidney. The TCM curative regimens, recognized the integrative concept of TCM, i.e. to regulate yin and yang in order to achieve an equilibrium and to strengthen body resistance and expel pathogens so as to reach the goal of overcoming pathogens and promoting recovery.

As was shown from the results of this study, the adoption of the therapeutic regimen of integrated traditional and Western medicine had significant advantages over Western medicine in promoting hepatic function, protecting renal function and further accelerating recovery of patients from illness. The results also indicate that the therapeutic regimen of integrated traditional and Western medicine is safe for the treatment of SARS. These findings should be taken into consideration in choosing appropriate treatment for SARS patients.

Acknowledgements

The State Ministry of Science and Technology and State Administration of Traditional Chinese Medicine offered great support in terms of funding during the campaign against SARS and our research work. The China Institute of Traditional Chinese Medicine provided us with training and guidance so as to ensure the quality of this research, and the leaders in our hospital and the Institute of Infectious Diseases were also most helpful. We herewith express our thanks to them.

References

1. Coronavirus never before seen in humans is the cause of SARS. 2003. Available at http://www.who.int/csr/sarsarchive/2003-04-16/en/

2. Dong Yuwei, et al. Changes in liver function of patients of infectious atypical pulmonary disease. China Liver Diseases Magazine, 2003, 11:418- 420.

3. Acute respiratory syndrome in China update 3: disease outbreak reported. Geneva, World Health Organization, 2003.

4. Booth CM, et al. Clinical features and short-term outcomes of 144 patients with SARS in the Greater Toronto Area. Journal of the American Medical Association, 2003, 289:1-9.

5. Branch of Contagion and Verminosis and Branch of Liver Diseases of China Medical Institute. Preventive and curative regimen for virus hepatitis. China Liver Diseases Magazine, 2000, 8:324-329.

6. Zou Jinpan, et al. Clinical characteristics of 42 cases of SARS patients and integrated therapeutics of traditional and Western Medicine. China Integrated Therapeutics of Traditional and Western Medicine Magazine. 2003, 23:486-488.

 

to previous section
to next section
 
 
The WHO Essential Medicines and Health Products Information Portal was designed and is maintained by Human Info NGO. Last updated: June 25, 2014