Abstract
INTRODUCTION:
Colonoscopy is currently considered as one of the principal techniques to diagnose the colorectal diseases. Admittedly, qualified bowel preparation before colonoscopy is a premise for high-quality examination. Lower quality bowel preparation might seriously impede visualization of the intestinal mucosa, resulting in missed and misdiagnosed intestinal lesions. Therefore, it is necessary to choose the appropriate oral laxative based on the guarantee of safety and efficacy.
METHODS:
This prospective randomized controlled study was conducted to compare lactulose oral solution and polyethylene glycol (PEG) electrolyte powder for bowel preparation using the following indicators: Boston Bowel Preparation Scale, Bowel Bubble Score, detection rate of adenoma and lesion, patients' satisfaction, and adverse effects. Our study investigated the suitability of 2 bowel preparation reagents for patients with different body mass indices mainly based on body mass index (BMI).
RESULTS:
In the lactulose group, there was a significant improvement in the quality of bowel preparation compared with those in the PEG group (P < 0.05), especially in people with normal BMI and higher BMI. Compared with the PEG group, individuals in the lactulose group had a significantly higher adenoma detection rate (50% vs 33.5%, P < 0.05) and taste scores (8.82 vs 6.69, P < 0.05), as well as significantly fewer adverse reactions (6.5% vs 32.5%, P < 0.05).
DISCUSSION:
Lactulose oral solution is superior to PEG in bowel preparation quality and taste, especially in normal BMI and higher BMI groups. It can be used clinically as a potential and promising bowel preparation agent in the future. Clinical Trial registration number: ChiCTR2100054318.
KEYWORDS: lactulose, polyethylene glycol, bowel preparation, BMI
INTRODUCTION
Colorectal cancer is one of the common malignancies of the gastrointestinal system, and its incidence is gradually on the rise. Colonoscopy is the gold standard for visualization diagnosis and treatment of intestinal diseases, and adequate intestinal preparation before colonoscopy is extremely important and can directly affect the diagnostic and therapeutic effects of gastrointestinal endoscopy (1,2). Inadequate bowel preparation can reduce the efficacy and safety of colonoscopy while also increasing the rate of missed and misdiagnosed intestinal diseases.
Despite the wide variety of bowel preparation reagents that are readily available in clinical practice, there are not many customized bowel preparation procedures. Compound polyethylene glycol (PEG) electrolyte powder has been proven to be secure and reliable for bowel preparation (3,4). When divided dosages are taken orally as opposed to one large dose given all at once, as is frequently done in clinical practice, a better quality of bowel preparation is achieved (5). Lactulose is commonly used in constipated populations, and in recent years, it has been explored for its bowel-preparing effects and further validated for its safety and efficacy (6–9). In a study that included 360 patients, 2 L of PEG was used in combination with 100 mL of lactulose for bowel preparation (7). The results showed that the combination group could improve the quality of the bowel preparation. There was also a study (6) comparing 2 L of PEG with 200 mL of lactulose alone, with higher efficacy and better tolerability of lactulose.
Previous studies have confirmed that body mass index (BMI) is associated with the quality of bowel preparation (10–13). Among them, the Washington University Medical Center proposed that BMI >25 is an independent predictor of inadequate bowel preparation at colonoscopy. Each unit increase in BMI was associated with a 2.1% increase in the likelihood of inadequate bowel preparation.
Therefore, this study stratified the patient population by BMI, compared 2 L of lactulose with 3 L of PEG, and incorporated the metrics of Boston Bowel Preparation Score (BBPS), Bowel Bubble Score (BBS), intestinal adenoma and lesion detection rate, palatability score, and adverse events, with the hope of providing individualized bowel preparation regimens for different populations.
MATERIALS AND METHODS
Study design
This study was a prospective, randomized controlled, single-center clinical study (Clinical Trial registration number: ChiCTR2100054318) comparing 2 bowel preparation reagents, lactulose and PEG. The study had been approved by the ethics committee of the Affiliated Drum Tower Hospital of Nanjing University Medical School. This study was financially supported by the Nanjing Health Science and Technology Development Project (No. YKK22255) and the 2022 Nanjing Drum Tower Hospital Special Fund for Clinical Research (2022-LCYJ-MS-40).
Study participants
Patients who were chosen to prepare for colonoscopy at the Endoscopy Center of the Gastroenterology Department, Affiliated Hospital of Nanjing University Medical School, aged between 18 and 75 years who voluntarily participated in this study and signed an informed consent form were eligible for inclusion criteria. Exclusion criteria included (1) patients with severe primary diseases, such as heart failure and liver and kidney failure; (2) patients with intestinal obstruction, bowel resection, intractable constipation, massive ascites, and diabetes mellitus; and (3) women preparing for pregnancy or those who were pregnant and lactating. Calculating the sample size based on the work by Hu et al (7), 180 participants would be required in each group to detect a 2-sided difference in treatment success between the 2 groups, with α = 0 01, 1 − β = 0 95, and an equal size (1:1 ratio) for each group. Assuming 10% missing data, the final sample size included at least 200 participants in each category. Each patient was randomized into the lactulose group and PEG group, with 200 patients included in each group for comparison of bowel preparation, resulting in a total of 400 patients enrolled in this clinical trial.
Randomization and grouping
All patients enrolled were randomized by drawing envelopes in a 1:1 ratio to determine the bowel preparation. One group was required to take 2 L of lactulose, and the other group was required to take 3 L of PEG solution. The investigator who made the envelopes was not involved in the subsequent trials.
Procedure
Each 100 mL of the lactulose oral solution (H20171057; Abbott Biologicals B.V., Netherlands) contains 67 g of lactulose, no more than 10 g of galactose, and no more than 6 g of lactose.
The PEG electrolyte powder (H20020031; Jiangxi Hengkang Pharmaceutical Co. Ltd, P.R. China) was divided into 3 packs A, B, and C. Pack A contains 0.74 g of potassium chloride and 1.68 g of sodium bicarbonate, pack B contains 1.46 g of sodium chloride and 5.68 g of sodium sulfate, and pack C contains 60 g of PEG-4000.
As demonstrated in Figure 1, there were 3 main steps of bowel preparation for both the groups. The first stage should be started the night before the colonoscopy if the procedure is scheduled for the morning. If the colonoscopy is scheduled for the afternoon, the first stage can begin early on the day of the colonoscopy.
Figure 1.
The specific method of administration. PEG, polyethylene glycol.
All enrolled patients were given instructions to eat a lower fiber diet the day before the colonoscopy and to take an oral defoamer such as dimethicone after taking the final. All of these steps are intended to improve colonoscopy visualization of the intestinal mucosa and lower the incidence of misdiagnosis and underdiagnosis of colorectal lesions.
Endoscopic evaluation
BBPS and BBS (14,15) were used to evaluate the quality of bowel preparation. The lower intestinal tract was separated into 3 segments: right-side colon, transverse colon, and left-side colon, and the overall score and each segmental score were completely recorded. BBPS ranged from 0 to 3 points per segment, and the total score was 0–9. Each bowel portion should receive no less than 2 points, with the overall average for bowel preparation quality being no less than 6 points. Similarly, each section receives a BBS between 0 and 3. All colonoscopies were performed by 2 senior chief doctors with at least 5 years of clinical practice experience, who had independently performed 2,000 colonoscopies, and were blinded to the bowel preparation assignments of the participants. The quality of the bowel examination was then evaluated by 2 experienced medical experts to guarantee uniform grading after each patient's colonoscopy assessment was completed (Tables 1 and 2).
Table 1.
Boston Bowel Preparation Score
| Points | Specific description |
| 0 | Presence of a large amount of solid residue; the mucosa is not visible |
| 1 | Presence of solid and liquid residues; the mucosa is partially visible |
| 2 | Presence of brown fluid and mobile semisolid residues; the mucosa can be seen well |
| 3 | All the mucosa was visible |
Table 2.
Bowel Bubble Score
| Points | Specific description |
| 0 | Complete absence of bubbles and clear vision |
| 1 | A sparse concentration of bubbles, taking up less than 25% of the endoscopic visual field |
| 2 | A moderate number of bubbles, which take up between 25% and 50% of the visual field |
| 3 | A significant number of bubbles that take up most of the endoscopic field of view |
Questionnaire record
Patients in this study were given follow-up questionnaires after their colonoscopies, which included the gathering of basic data including height and weight, taste ratings for laxatives, and any associated negative effects (e.g., nausea, vomiting, abdominal pain, bloating, dry mouth, and fatigue).
Statistical analysis
Microsoft Excel software (Microsoft Inc) was used to collect the data, which were then statistically analyzed using IBM SPSS version 25.0 (IBM, Armonk, NY) for Windows. The software used for drawing was GraphPad Prism 9 (GraphPad Software Inc). Quantitative data were expressed as mean ± SD and compared using the independent-sample t-test. Categorical data are presented as absolute values and percentages, and they were checked using the χ2 test or Fisher exact probability test. At the 95% confidence level, a P-value of less than 0.05 was regarded significant.
RESULTS
Patient characteristics
A total of 400 patients were included in this study, including the lactulose group (n = 200) and PEG group (n = 200). The average age was 48.01 ± 14.03 years. BMI is one of the World Health Organization standards for measuring the degree of body fat and thinness, and a population with a BMI <18.5 kg/m2 is defined as lower BMI, 18.5 <BMI<24.0 kg/m2 as normal BMI, and BMI ≥24.0 kg/m2 as higher BMI. This study analyzed the total population and patients in each group according to BMI. There were no statistically significant differences in age, sex, height, and weight (Table 3).
Table 3.
Patient characteristics (n=400)
| Lactulose (n = 200) | PEG electrolytes power(n = 200) | P | |
| Age (mean ± SD), (yr) | 48.01 ± 14.03 | 49.67 ± 14.00 | 0.243 |
| Male, n (%) | 97(48.5) | 100(50) | 0.764 |
| Height (mean ± SD), (m) | 1.67 ± 0.08 | 1.67 ± 0.08 | 0.480 |
| Body weight (mean ± SD), (kg) | 65.52 ± 12.19 | 66.06 ± 14.00 | 0.912 |
| BMI (mean ± SD), (kg/m2) | 23.41 ± 3.25 | 23.76 ± 4.48 | 0.820 |
BMI, body mass index; PEG, polyethylene glycol.
Bowel preparation quality
In this study, the BBPS and BBS were used to evaluate the quality of bowel preparation. Among them, a BBPS of less than 6 was identified as inadequate bowel preparation quality. The unqualified rate was 4.5% in the lactulose group and 3.5% in the PEG group. According to Tables 4 and 5, the BBPSs of the total population over the entire colon, right colon, and transverse colon in the lactulose group were better than those in the PEG group, and the BBSs of the total population over the entire colon and right semicolon were also better in the lactulose group. In the population with normal BMI and higher BMI, the lactulose group also was better than the PEG group in the quality of bowel preparation of some intestinal segments, which was similar to the conclusion obtained in the total population. There was no significant difference between the 2 schemes in the intestinal preparation quality score of the people with lower BMI, but the average BBPS of the lactulose group was higher than that of the PEG group.
Table 4.
Boston Bowel Preparation Scores were compared between the lactulose group and the PEG group
| Lactulose (mean ± SD) (n = 200) | PEG (mean ± SD) (n = 200) | P | |
| Entire colon | |||
| Total population | 7.19 ± 1.19 | 6.73 ± 0.93 | <0.001 |
| Lower BMI | 7.33 ± 1.21 | 6.67 ± 0.78 | 0.291 |
| Normal BMI | 7.21 ± 1.28 | 6.73 ± 0.96 | <0.001 |
| Higher BMI | 7.15 ± 1.07 | 6.72 ± 0.92 | 0.010 |
| Right colon | |||
| Total population | 2.34 ± 0.56 | 2.10 ± 0.40 | <0.001 |
| Lower BMI | 2.50 ± 0.55 | 2.00 ± 0.00 | 0.102 |
| Normal BMI | 2.33 ± 0.59 | 2.15 ± 0.43 | 0.004 |
| Higher BMI | 2.33 ± 0.52 | 2.05 ± 0.38 | <0.001 |
| Transverse colon | |||
| Total population | 2.50 ± 0.57 | 2.36 ± 0.49 | <0.001 |
| Lower BMI | 2.50 ± 0.55 | 2.42 ± 0.52 | 0.820 |
| Normal BMI | 2.56 ± 0.58 | 2.32 ± 0.49 | <0.001 |
| Higher BMI | 2.46 ± 0.55 | 2.39 ± 0.49 | 0.270 |
| Left colon | |||
| Total population | 2.34 ± 0.53 | 2.27 ± 0.47 | 0.144 |
| Lower BMI | 2.33 ± 0.52 | 2.25 ± 0.45 | 0.820 |
| Normal BMI | 2.32 ± 0.54 | 2.26 ± 0.46 | 0.314 |
| Higher BMI | 2.36 ± 0.53 | 2.29 ± 0.48 | 0.315 |
BMI, body mass index.
Table 5.
Bowel Bubble Scores were compared between the lactulose group and the PEG group
| Lactulose (mean ± SD) (n = 200) | PEG (mean ± SD) (n = 200) | P | |
| Entire colon | |||
| Total population | 0.77 ± 1.02 | 1.02 ± 1.13 | 0.032 |
| Lower BMI | 0.83 ± 0.98 | 1.25 ± 1.22 | 0.553 |
| Normal BMI | 0.75 ± 1.04 | 0.99 ± 1.15 | 0.120 |
| Higher BMI | 0.80 ± 1.01 | 1.01 ± 1.11 | 0.224 |
| Right colon | |||
| Total population | 0.24 ± 0.44 | 0.50 ± 0.50 | <0.001 |
| Lower BMI | 0.00 ± 0.00 | 0.58 ± 0.52 | 0.053 |
| Normal BMI | 0.24 ± 0.43 | 0.49 ± 0.50 | <0.001 |
| Higher BMI | 0.25 ± 0.46 | 0.47 ± 0.50 | 0.003 |
| Transverse colon | |||
| Total population | 0.21 ± 0.41 | 0.29 ± 0.45 | 0.083 |
| Lower BMI | 0.33 ± 0.52 | 0.42 ± 0.52 | 0.820 |
| Normal BMI | 0.19 ± 0.40 | 0.28 ± 0.45 | 0.146 |
| Higher BMI | 0.23 ± 0.42 | 0.28 ± 0.47 | 0.445 |
| Left colon | |||
| Total population | 0.33 ± 0.47 | 0.25 ± 0.43 | 0.077 |
| Lower BMI | 0.50 ± 0.55 | 0.25 ± 0.45 | 0.437 |
| Normal BMI | 0.32 ± 0.47 | 0.23 ± 0.42 | 0.149 |
| Higher BMI | 0.33 ± 0.47 | 0.27 ± 0.44 | 0.403 |
BMI, body mass index; PEG, polyethylene glycol electrolyte powder.
Detection rate of adenomas and intestinal lesions
Lesions were detected including adenomas, polyps, diverticulum, submucosal eminence, inflammatory bowel disease, hemorrhoids, and colon cancer. In the total population, the detection rate of adenoma and lesion in the lactulose group was higher than that in the PEG group (P＜0.05). The same conclusion can be obtained in the normal BMI group, but not in the lower BMI group and higher BMI group (Table 6).
Table 6.
Number of patients with adenomas and intestinal lesions detected on colonoscopy
| Lactulose (n = 200) | PEG (n = 200) | P | |
| Adenoma, n (%) | |||
| Total population | 100 (50.0) | 67 (33.5) | 0.001 |
| Lower BMI | 2 (1.0) | 4 (2.0) | 1.000 |
| Normal BMI | 55 (27.5) | 27 (13.5) | 0.001 |
| Higher BMI | 43 (21.5) | 36 (18.0) | 0.185 |
| Intestinal lesionsa, n (%) | |||
| Total population | 116 (58.0) | 75 (47.5) | <0.001 |
| Lower BMI | 2 (1.0) | 4 (2.0) | 1.000 |
| Normal BMI | 66 (33.0) | 32 (16.0) | <0.001 |
| Higher BMI | 48 (24.0) | 45 (22.5) | 0.456 |
BMI, body mass index; PEG; polyethylene glycol electrolyte powder.
Includes adenomas, polyps, diverticulum, submucosal eminence, inflammatory bowel disease, hemorrhoids, and colon cancer.
Palatability
After ingesting the reagent for bowel preparation, individuals were graded on a scale of 0–10 for their palate. Probably because many patients had mild discomfort from ingesting PEG, such as nausea and vomiting, lactulose scored higher on the taste scale than PEG in all groups (P < 0.05; Figure 2).
Figure 2.
Comparison of palatability score between the 2 groups. PEG, polyethylene glycol electrolyte powder.
Adverse reactions
The adverse reactions recorded in this study included nausea, vomiting, abdominal pain, and abdominal distension. According to Table 7, among the two groups, the total adverse reactions, nausea, vomiting and abdominal distension in the lactulose group were less than those in the PEG group, especially in the people with normal BMI and higher BMI. In the lactulose group, 4 patients had symptoms of abdominal pain, which were not found in the PEG group, but no statistically significant conclusions were drawn (P = 0.132).
Table 7.
Adverse reactions
| Lactulose (n = 200) | PEG (n = 200) | P | |
| Total adverse reaction, n (%) | |||
| Total population | 13 (6.5) | 65 (32.5) | <0.001 |
| Lower BMI | 0 | 7 (3.5) | 0.038 |
| Normal BMI | 8 (4.0) | 39 (19.5) | <0.001 |
| Higher BMI | 5 (2.5) | 19 (9.5) | 0.003 |
| Nausea, n (%) | |||
| Total population | 8 (4.0) | 48 (24.0) | <0.001 |
| Lower BMI | 0 | 5 (2.5) | 0.114 |
| Normal BMI | 6 (3.0) | 29 (14.5) | <0.001 |
| Higher BMI | 2 (2.5) | 14 (7.0) | 0.002 |
| Vomiting, n (%) | |||
| Total population | 7 (3.5) | 26 (13.0) | 0.001 |
| Lower BMI | 0 | 2 (1.0) | 0.529 |
| Normal BMI | 5 (2.5) | 19 (9.5) | 0.001 |
| Higher BMI | 2 (1.0) | 5 (2.5) | 0.470 |
| Abdominal pain, n (%) | |||
| Total population | 4 (2.0) | 0 (0) | 0.132 |
| Lower BMI | 0 | 0 | — |
| Normal BMI | 2 (1.0) | 0 | 0.270 |
| Higher BMI | 2 (1.0) | 0 | 0.239 |
| Bloating, n (%) | |||
| Total population | 0 (0) | 10 (5.0) | 0.001 |
| Lower BMI | 0 | 0 | — |
| Normal BMI | 0 | 4 (2.0) | 0.110 |
| Higher BMI | 0 | 6 (3.0) | 0.042 |
BMI, body mass index; PEG, polyethylene glycol.
DISCUSSION
Colonoscopy is a crucial procedure for diagnosing, treating, and screening for the intestinal diseases. The standard of intestinal preparation has a direct impact on the precision of the diagnosis and the safety of the course of therapy. Inadequate bowel preparation has been reported in up to 30% of patients undergoing colonoscopy (3). The ideal intestinal preparation reagent should be able to almost completely empty the intestines and clearly display the intestinal mucosa while causing minimal irritation to the colonic mucosa and lesions, having little effect on physiological function, producing few side effects, and performing at a lower cost (8,16,17). However, few bowel preparation reagents can meet the above requirements.
The most commonly used reagent in clinical bowel preparation is PEG electrolyte powder. The European Society of Gastrointestinal Endoscopy recommends a split regimen of 4 L of PEG for routine bowel preparation (3). The 3 L PEG divided-dose regimen is the preferred bowel cleansing regimen for Chinese population (18). PEG is a kind of volumetric laxative drug, which is a long chain polymer. It can lock water through hydrogen bonds in the molecular formula, increase the osmotic pressure in the intestine, soften the stool, and promote intestinal peristalsis so as to empty the feces and fecal water in the intestine, and it does not affect the absorption and secretion function of the intestinal mucosa (19) and will not cause water and electrolyte disorders in the patients. Nevertheless, most of the patients complained that the laxative had a bad taste and that they needed to drink extra fluids to prepare their bowels because of how salty it tasted.
Lactulose is a disaccharide, which can be decomposed into monosaccharides by normal bacteria, and monosaccharides are further decomposed into organic acids such as lactic acid and acetic acid. These acids form an acidic environment in the intestinal tract (20), which is conducive to the establishment and growth of normal flora and inhibits the growth of intestinal pathogenic bacteria. Lactulose also has osmotic activity, is not absorbed by the small intestine, increases intestinal osmotic pressure, and prevents water absorption while the acidic environment can accelerate intestinal peristalsis and fecal softening and ultimately achieve the role of promoting defecation (19,21).
In the past, lactulose and PEG were used to treat hepatic encephalopathy and constipation (2,22–27). As early as 2008, a French study (19) used isotope labeling to prove that lactulose significantly accelerated ascending colon emptying compared with PEG and supported the additional stimulating effect of bacterial fermentation on proximal colonic transit. This is consistent with our findings that lactulose was superior to PEG in bowel preparation in the ascending colon. In recent years, lactulose and PEG have been used in several bowel preparation studies in clinical practice (6–8,28,29). The findings demonstrate that, in comparison with the PEG-alone control group, the combination can decrease patients’ pain and water intake while also improving the quality of bowel preparation. In an another study conducted by Jagdeep et al (30) in 2021, lactulose is a significantly more palatable form of bowel preparation with good bowel cleansing comparable with PEG, causing minor discomforts without causing any hemodynamic changes; Li et al (6) also reached the same conclusion, and the detection rate of intestinal lesions in the lactulose group was higher than that in the PEG group (P < 0.05).
This study presents a modified lactulose bowel preparation regimen with better BBPSs and BBSs in the 2 L lactulose regimen compared with 3 L PEG, especially in patients with normal BMI and higher BMI, which may be due to the acidification of the intestinal lumen to promote intestinal peristalsis by lactulose being more pronounced than PEG and also because lactulose induced fewer reactions of vomiting in patients, whereas it did not demonstrate a significance in the group with a lower BMI, which may be due to the smaller sample size of this group. The taste score of lactulose was significantly higher than that of PEG, which may be due to the obvious nausea and discomforts caused by the taste of PEG. In addition, 4 patients in the lactulose group reported abdominal pain, whereas no such cases were reported in the PEG group, probably because of the significant osmotic activity of lactulose, which induced significant intestinal peristalsis.
However, there are certain restrictions on this clinical investigation. First, the study lacked information on the patients' customary bowel movement frequency, dietary habits, and the interval between the last oral intake of a reagent for stool preparation and the colonoscopy, all of which can affect the quality of bowel preparation. Second, variations in electrolyte and glucose levels before and after colonoscopy were not taken into account in the study, which could serve in the assessment of the adverse effects. Third, this study was a single-center investigation; further multicenter large-sample research should be performed to create a more effective bowel preparation protocol.
In conclusion, bowel preparation reagents are frequently used in large institutions because of the growing acceptance of colonoscopy examination. Based on safety and effectiveness, our investigation has shown that lactulose has better intestinal preparation quality than PEG, especially in those with normal or higher BMI, and that it also tastes pleasant and causes less side effects. It is a clinically viable option for bowel preparation.
CONFLICTS OF INTEREST
Guarantor of the article: Chen Min, PhD.
Specific author contributions: S.W. and C.M.: wrote the first paper draft. All authors further contributed to the writing and approval of the manuscript.
Financial support: The study is financially supported by the Nanjing Health Science and Technology Development Project (No. YKK22255) and the 2022 Nanjing Drum Tower Hospital Special Fund for Clinical Research (2022-LCYJ-MS-40).
Potential competing interests: None to report.
Study Highlights.
WHAT IS KNOWN
✓ Recent studies had shown the safety and efficacy of lactulose as an intestinal preparation agent.
WHAT IS NEW HERE
✓ Our prospective randomized controlled clinical study was designed to explore individualized bowel preparation modalities. In the population with normal and higher BMI, the quality of intestinal preparation was better with lactulose than with polyethylene glycol. In the lower BMI population, there was no significant difference in the quality of intestinal preparation between the two groups. Compared to polyethylene glycol (PEG), the patients using lactulose had a higher rate of adenoma and lesion detection, fewer adverse effects, and higher taste scores.
ACKNOWLEDGMENT
Our clinical study was supported by the Abbott laboratories Trading (Shanghai) Co., Ltd. We are grateful for the contribution of Abbott company.
Contributor Information
Sun Wenqi, Email: swq980715@163.com.
Zhao Bei, Email: 1730678147@qq.com.
Wu Xinrong, Email: wyr2018521@163.com.
Li Yifan, Email: liyifanc2019@163.com.
Ni Muhan, Email: nimuhan@foxmail.com.
Yan Peng, Email: yp12233@163.com.
Dou Xiaotan, Email: dxtzt@126.com.
Li Wen, Email: 1472118368@qq.com.
Yang Hua, Email: nissan3600@163.com.
Wang Lei, Email: leiwang9631@nju.edu.cn.
Chen Min, Email: croweminchan@nju.edu.cn.
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