- Research article
- Open Access
- Open Peer Review
Clinical effects of a standardized Chinese herbal remedy, Qili Qiangxin, as an adjuvant treatment in heart failure: systematic review and meta-analysis
BMC Complementary and Alternative Medicine volume 16, Article number: 201 (2016)
Qili Qiangxin capsule is a standardized Chinese herbal treatment that is commonly used in China for heart failure (HF) alongside conventional medical care. In 2014, Chinese guidelines for the treatment of chronic HF highlighted Qili Qiangxin capsules as a potentially effective medicine. However, there is at present no high quality review to evaluate the effects and safety of Qili Qiangxin for patients with HF.
We conducted a systematic review and meta-analysis and followed methods described in our registered protocol [PROSPERO registration: CRD42013006106]. We searched 6 electronic databases to identify randomized clinical trials (RCTs) irrespective of blinding or placebo control of Qili Qiangxin used as an adjuvant treatment for HF.
We included a total of 129 RCTs published between 2005 and 2015, involving 11,547 patients, aged 18 to 98 years. Meta-analysis showed no significant difference between Qili Qiangxin plus conventional treatment and conventional treatment alone for mortality (RR 0.53, 95 % CI 0.27 to 1.07). However, compared with conventional treatment alone, Qili Qiangxin plus conventional treatment demonstrated a significant reduction in major cardiovascular events (RR 0.46, 95 % CI 0.34 to 0.64) and a significant reduction in re-hospitalization rate due to HF (RR 0.49, 95 % CI 0.38 to 0.64). Qili Qiangxin also showed significant improvement in cardiac function measured by the New York Heart Association scale (RR 1.38, 95 % CI 1.29 to 1.48) and quality of life as measured by Minnesota Living with Heart Failure Questionnaire (MD −8.48 scores, 95 % CI −9.56 to −7.39). There were no reports of serious adverse events relating to Qili Qiangxin administration. The majority of included trials were of poor methodological quality.
When compared with conventional treatment alone, Qili Qiangxin combined with conventional treatment demonstrated a significant effect in reducing cardiovascular events and re-hospitalization rate, though not in mortality. It appeared to significantly improve quality of life in patients with HF and data from RCTs suggested that Qili Qiangxin is likely safe. This data was drawn from low quality trials and the results of this review must therefore be interpreted with caution. Further research is warranted, ideally involving large, prospective, rigorous trials, in order to confirm these findings.
Heart failure (HF) is a serious and increasingly prevalent worldwide public health problem and has become a major cause of mortality and morbidity . HF is the most common cause of hospitalization in people aged 65 and older  and survival rates are reportedly worse than in cancer . According to the European Society of Cardiology (ESC), approximately 26 million people worldwide suffer from HF and which affects 10 % of people over the age of 70, a prevalence which is expected to rise in coming years.
HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood from the heart. Cardinal manifestations include dyspnea and fatigue, which can limit exercise tolerance as well as create fluid retention, and which may lead to pulmonary and peripheral edema . Furthermore, quality of life (QOL) for patients can be adversely impacted owing to sleep-disordered breathing, cognitive dysfunction and neuropsychological disturbances. Conventional medical care for HR typically involves oxygen therapy, diet, diuretics, angiotensin-converting enzyme inhibitors (ACEI) or beta-blockers . Previous research has estimated that the total estimated direct and indirect cost of HF in the US in 2005 was approximately $27.9 billion, with approximately $2.9 billion alone being spent annually on drugs . Despite this significant annual spend, HF continues to be associated with poor prognosis, with absolute mortality rate remaining approximately 50 % within 5 years of initial diagnosis . It is clear that the effectiveness of available care is limited and which warrants further research into optimizing current treatments.
In the recent 2014 Chinese guidelines for treatment of chronic HR, a Chinese herbal remedy, Qili Qiangxin capsules, was mentioned as a potentially effective treatment . Qili Qiangxin capsule is a standardized Chinese herbal treatment that is widely used in China for HF patients and which is frequently administered alongside conventional medical care. It is prepared from 11 Chinese herbs including astragali radix, ginseng radix et rhizoma, aconite lateralis radix preparata, salvia miltiorrbiza radix et rhizoma, semen descurainiae lepidii, alismatis rhizoma, polygonati odorati rhizoma, cinnamomi ramulus, carthami flos, periploca cortex, and citri reticulatae pericarpium. Previous research has suggested that Qili Qiangxin may have a role in the treatment of HF through a number of different mechanisms, for example reducing N-terminal pro-brain natriuretic peptide (NT-proBNP), high levels of which are associated with cardiac ventricular volume and pressure overload . In a study on rats with myocardial infarction (MI), Qili Qiangxin induced heart muscle regeneration and improved cardiac function through regulating the balance between tumor necrosis factor (TNF)-α and interleukin (IL)-10, factors closely associated with inflammatory processes in HF . This suggests promise in this area of research which may be of significant interest to the international medical community and which warrants a robust review of the current evidence to date. A number of systematic reviews have been published in this area. However, all have been published in Chinese and have various shortcomings such as insufficient searches, inappropriate outcome selection and lack of quality assessment, leading us to question the scientific rigor of the results and subsequent recommendations [11–16]. The aim of this study was to evaluate the effects and safety of Qili Qiangxin for patients with HF by conducting a systematic review and meta-analysis.
The method used to conduct this systematic review has been previously published in a registered protocol [PROSPERO registration: CRD42013006106]. This review was constructed using the PRISMA guidelines (Additional file 1).
The following electronic databases were searched from date of inception to March 2015: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Issue January, 2015), China National Knowledge Infrastructure (CNKI), VIP Database, Sino-Med Database, and Wanfang Database. We used the following search terms: (“Qili Qiangxin” OR “qiliqiangxin” OR “qiangxinli”) and (“heart failure” OR “cardiac failure” OR “heart decompensation”). We searched for trials from mainstream registries including Current Controlled Trials (http://www.controlled-trials.com), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; http://apps.who.int/trialsearch/), ClinicalTrials.gov trials registry (http://www.clinicaltrials.gov), the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au), and Centre Watch (http://www.centerwatch.com). We also hand-searched the reference lists of all full text papers for additional relevant reports. No language restrictions were imposed.
We accepted RCTs regardless of blinding procedures and included only parallel design studies. Only human studies were included in this review and we required the use of internationally-accepted criteria for diagnosis of HF. We placed no other requirements of the participant population in terms of gender, age, etiology, ethnic group, severity or course of disease. Only Qili Qiangxin capsules, composed of the aforementioned 11 Chinese herbs, were accepted as the intervention. This could be used alone or alongside appropriate control treatments such as placebo, conventional treatment or no treatment, and trials with any other Chinese herbal medicine in control group will be excluded. Our primary outcome measures were all-cause mortality or cardiovascular mortality due to HF, major cardiovascular events such as MI, outpatient visits, hospitalizations or re-admission for HF. Secondary outcomes measures were quality of life (QOL) measured by Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association (NYHA) functional classification, echocardiography measurements, six-minutes walking distance (6MWD), plasma amino-terminal pro-brain natriuretic peptide (NT-pro-BNP). We also collected safety and adverse events data. We included only RCTs reporting one or more of these outcomes.
Data extraction and quality assessment
Two authors (from J Sun, K Zhang, WJ Xiong, and YJ Zhang) independently identified articles for eligibility with any disagreements resolved through discussion with a third party (JP Liu). Two authors independently extracted data and which included patient characteristics, details of the intervention and control groups, outcome measures and main results. The same process was used to assess the methodological quality of included RCTs using the risk of bias tool as described in the Cochrane Handbook for Systematic Reviews of Interventions . This process requires seven criteria to be assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, free of selective reporting, and other bias.
Strategy for data synthesis
Statistical analyses were performed by using RevMan 5.2 software (The Cochrane Collaboration). Pooled risk ratio (RR) with 95 % confidence interval (CI) of dichotomous outcomes was used to estimate report effect. Continuous data was presented as mean difference (MD) with 95 % CI. We used a fixed effect model unless there was evidence of heterogeneity. Heterogeneity was assessed using both the Chi-squared test and the I-squared statistic, and we considered an I-squared value greater than 50 % to be indicative of substantial heterogeneity. If missing data from the original trials are available, intention-to-treat analysis will be applied for primary outcome.
Description of studies
Our search in March 2015 from six databases and other sources identified 1,390 potentially eligible articles. After removing duplicates and reviewing full text articles, we eventually included 129 randomized clinical trials published as 131 articles (Fig. 1). All 129 studies were included in our qualitative synthesis and of these, 117 studies were eligible for our meta-analysis.
Included trials were published between 2005 and 2015 with a larger proportion of trials published in 2013 (n = 41 trials, 31.78 %) and 2012 (n = 23 trials, 17.83 %). The 129 trials involved 11,547 patients diagnosed with HF with an age range of 18 to 98 years. Sixteen trials enrolled only elderly patients over the age of 60 (n = 16, 12.40 %). The majority of trials included both male and female patients (n = 127 trials, 98.45 %). Two trials included only male patients (Wei XB 2013, Miao S 2013); two trials provided gender details only for participants who completed the trial (Li XL 2013, Kuang JB 2008). 58.23 % of total populations were male except one trial failed to provide gender detail (Tao X 2011).
Included trials used the following diagnostic criteria: American College of Cardiology/American Heart Association (ACC/AHA) guidelines, European Society of Cardiology (ESC) guidelines, World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) guidelines, World Health Organization/International Society of Hypertension (WHO/ISH) guidelines, Chinese Medical Association (CMA) guidelines, guidelines issued by Ministry of Health (MoH) in China, Framingham criteria, or textbook criteria which were consistent with internationally-used diagnostic criteria .
One hundred seventeen trials (s1-s118, Additional file 2) involving 10,170 patients compared Qili Qiangxin capsules plus conventional treatment to conventional treatment alone. Three trials (s119-s121, Additional file 2) involving 702 patients compared Qili Qiangxin capsule plus conventional treatment to placebo plus conventional treatment. Nine trials (s122-s131, Additional file 2) included 675 patients comparing Qili Qiangxin capsules plus conventional treatment to recommended pharmaceuticals (including thiazide diuretics, benazepril, captopril, metoprolol, irbesartan, hydrochlorothiazide and digoxin plus conventional treatment). Almost all patients in the included trials presented with comorbidities such as hypertension, hypotension, valvular heart disease, pulmonary heart disease, cardiomyopathy, diabetes mellitus, chronic renal insufficiency, coronary heart disease, acute MI and sinus bradycardia. The duration of treatment ranged from 1 to 12 months, and the most commonly adopted was 1 month (n = 54 trials). Nineteen trials had 6 or more months of treatment.
The main outcome in the majority of trials was reported to be left ventricular ejection fraction (LVEF) (n = 91 trials). Other primary outcomes adopted included mortality (n = 6 trials), major cardiovascular events (n = 3 trials) or re-hospitalization (n = 9 trials). Details of each study are listed in Table 1.
Methodological quality of included trials
The methodological quality of included trials was generally low as most failed to provide protocols (Additional file 3). Nineteen trials (n = 2388 participants, 20.68 %) were judged as low risk on random sequence generation. Of these twenty, 17 trials used random number tables (n = 1774 participants, 72.29 %), one trial used statistical software (n = 512 participants, 21.44 %) and one trial used drawing lots. Only one (Li XL 2013) trial reported allocation concealment was judged as low risk; one trial (Yang F 2007) described using an envelope but failed to provide further details and was subsequently judged as presenting with unclear risk of bias.
We judged five trials on the use of blinding methods. Of these, three double-blind placebo controlled trials (Yu JH 2008, Li XL 2013, Yu JH 2008) were judged as low risk (n = 702 participants, 6.08 %). For the remaining two trials, one single-blind trial (Guo WB 2013) and one double-blind trial (Wei XB 2013) did not mention who was blinded and were judged as unclear risk. Besides, only one trial (Li XL 2013) reported the blinding of outcome assessment (n = 512 participants, 4.43 %).
Overall six trials reported patient attrition (n = 948 participants, 8.21 %). Of these, three trials (Chen WQ 2012, Fu JZ 2012, Sun LP 2007) reported no drop-out. Three trials (Guo P 2014, Li XL 2013, Kuang JB 2008) described the occurrence of attrition, one (Li XL 2013) used a flow chart to describe patient attrition in the two parallel groups throughout the whole study and adopted intention to treat (ITT) analysis, and one (Kuang JB 2008) was judged as high risk as the authors failed to provide drop-out reasons in text. The remaining trials reported the same number of participants between the baseline and data analyzed, except one study (Guo WB 2013) which reported six cases less than the number at baseline without providing further explanation.
Twenty-four trials failed to report all outcomes listed in the methods. The remaining trials reported all outcomes as specified in methods, although only one provided a study protocol. Insufficient information was available for us to conduct a risk of bias assessment in terms of selective reporting. In terms of other biases, only 122 trials reported comparability of baseline data and only one study (Li XL 2013) reported conducting a sample size calculation (Fig. 2).
Effects of interventions
Qili Qiangxin capsule plus conventional treatment versus conventional treatment
Our meta-analysis (Additional file 4) showed that in comparison to conventional treatment alone, Qili Qiangxin plus conventional treatment did not have a statistically significant effect on reducing mortality (RR 0.53, 95 % CI 0.27 to 1.07, I2 = 0 %). Qili Qiangxin plus conventional treatment led to a significant reduction in major cardiovascular events (RR 0.46, 95 % CI 0.34 to 0.64, I2 = 0 %; defined as outpatient visits or re-admission for HF and cardiogenic or all-cause mortality), when separately analyzed, it significantly reduced the outpatient visits (n = 1 trial, 60 participants, RR 0.22, 95 % CI 0.05 to 0.94), but did not have a statistically significant effect on reducing cardiogenic mortality (n = 1 trial, 56 participants, RR 0.67, 95 % CI 0.21 to 2.11). Meta-analysis showed a statistically significant reduction in hospitalizations due to HF (RR 0.49, 95 % CI 0.38 to 0.64, I2 = 0 %), and in addition, sensitivity analysis based on consideration of ‘worst-case’ scenarios revealed that missing data did not change the result of this meta-analysis (RR 0.50, 95 % CI 0.39 to 0.65, I2 = 0 %). Besides, due to the limited quantity of trials reported major outcomes, we did not carry out subgroup analyses on different types of heart failure or different durations of treatment.
In addition, when compared with conventional treatment alone, Qili Qiangxin plus conventional treatment significantly improved cardiac function (RR 1.38, 95 % CI 1.29 to 1.48, I2 = 0 %; defined as an increase of two or more functional classes using NYHA) and QOL (MD −8.48 scores, 95 % CI −9.56 to −7.39, I2 = 24 %). Used as an adjunctive treatment, Qili Qiangxin was associated with a lower incidence of adverse events (RR = 0.56, 95 % CI 0.40 to 0.78, I2 = 19 %). Details are displayed in Table 2.
A total of 84 trials evaluated LVEF and were pooled with a random model. Pooled comparisons demonstrated that Qili Qiangxin plus conventional treatment had a statistically significant beneficial effect compared to conventional treatment alone in terms of LVEF (MD 5.87, 95 % CI 5.28 to 6.47). However, a significant degree of heterogeneity was detected (I2 = 91 %), and when take subgroup analysis on duration of treatment, large heterogeneity still existed. Tests for subgroup differences showed no significant difference in effect between the trials with different treatment duration. Meta-analysis of 24 trials demonstrated that Qili Qiangxin plus conventional treatment significantly reduced levels of NT-proBNP (MD −214.43 pg/ml, 95 % CI −269.42 to −159.45). The high level of heterogeneity (I2 = 96 %) in these trials however should be noted. Similarly, pooled comparison of 42 trials indicated that Qili Qiangxin plus conventional medicine significantly improved the 6MWD (MD 47.21 meters, 95 % CI 44.53 to 49.90) when compared with conventional medicine alone. Again, a considerable level of heterogeneity (I2 = 96 %) was observed.
Considering general low quality of included trials, we did not take sensitivity analyses based on study quality according to protocol.
Qili Qiangxin capsule plus conventional treatment versus placebo plus conventional treatment
Three trials were identified for this comparison. One multicenter double-blind trial (Li XL 2013) evaluated the composite cardiac events (CCEs) for 491 patients, and reported that CCE rate was 4.51 % in the Qili Qiangxin plus conventional treatment group, compared with 10.93 % in the placebo plus conventional treatment group (p < 0.05) . This study also reported a favorable effect of Qili Qiangxin plus conventional treatment on the plasma NT-proBNP level, the NYHA functional classification and QOL by MLHFQ at 12 weeks (p < 0.001 for above outcomes). Meta-analysis of three trials (Fig. 3) showed statistically significant improvement of 6MWD in the Qili Qiangxin plus conventional medicine group compared to placebo plus conventional medicine (MD = 49.55 meters, 95 % CI 38.79 to 60.32, I2 = 0 %).
Qili Qiangxin capsule plus conventional treatment versus medications recommended in guidelines plus conventional treatment
Nine trials compared Qili Qiangxin capsule plus conventional treatment to supplementary medications recommended in clinical guidelines. The supplementary medications included thiazide diuretics, benazepril, captopril, metoprolol, irbesartan, trimetazidine, hydrochlorothiazide and digoxin.
Meta-analysis with a fixed model of four trials indicated no significant effect on cardiac function (RR = 1.26, 95 % CI 0.94 to 1.70, I2 = 4 %) for Qili Qiangxin plus conventional treatment when compared with supplementary medications plus conventional treatment. Further subgroup analyses on cardiac function according to medications found that Qili Qiangxin had no statistically significant differences compared to captopril (n = 2 trials, RR = 1.27, 95 % CI 0.89 to 1.82, I2 = 0 %), irbesartan plus trimetazidine (n = 1 trial, RR = 2.50, 95 % CI 0.83 to 7.49), or digoxin (n = 1 trial, RR = 0.85, 95 % CI 0.45 to 1.59).. Meta-analysis with a random model of four trials showed that Qili Qiangxin plus conventional treatment had significantly lower risk of adverse events (RR = 0.21, 95 % CI 0.06 to 0.74, I2 = 49 %). Two trials reported 6MWD and meta-analysis showed that Qili Qiangxin plus conventional treatment significantly improved 6MWD compared with supplementary medications (MD = 43.29 meters; 95 % CI =14.91 to 71.67, I2 = 58 %).
A funnel plot analysis was generated for 50 trials comparing Qili Qiangxin plus conventional treatment to conventional treatment alone for the outcome of NYHA levels. No asymmetry was observed, suggesting no publication bias (Fig. 4).
Summary of findings
The findings of this review suggest that in patients with HF, Qili Qiangxin used as an adjunct to conventional treatment leads to a statistically significant reduction in major cardiovascular events and re-hospitalization due to HF when compared with conventional treatment alone. However, there appeared to be no additional effects of Qili Qiangxin in terms of mortality rate. Qili Qiangxin plus conventional treatment also appears to significant improvements in cardiac function measured by levels of NHYA and showed significant beneficial effects on NT-proBNP levels, QOL, LVEF and 6MWD. Pooled data indicated that Qili Qiangxin as an adjuvant treatment have clinical significance in improving exercise capacity as well as symptomatic status. Preliminary data suggests that Qili Qiangxin appears to be safe. However, it should be noted that the majority of included trials had low methodological quality and a high risk of bias. Any conclusions drawn from this review should therefore be interpreted with caution.
Strength and limitations
This study presents the first comprehensive and rigorous review of Qili Qiangxin as a supplementary treatment for patients with HF. Previous criticisms have been made regarding the use of different terms to describe types of HF potentially being confusing . It is strength of this review that we included all types of HF with different comorbidities in order to maximize the impact and clinical relevance of our findings.
There are a number of limitations to this review which need to be acknowledged. The majority of included studies were assessed as unclear risk of bias. This was largely owing to the lack of details, particularly in terms of random sequence generation, allocation concealment, blinding methods and availability of a protocol. Due to limited resources and time constraints we were not able to contact trial authors to request missing data and other information preventing us from being able to make a complete assessment regarding risk of bias. However, the sensitivity analysis indicated that the missing data not change the results in this review. Furthermore, the follow-up period in the included studies was no longer than six months, with the majority reporting a follow-up of three months or less. This makes it difficult to interpret the present evidence on mortality as an outcome, and in assessing the long-term effects and safety of administering Qili Qiangxin. We excluded 40 articles on the basis of no relevant outcomes reported. These articles did not report the outcomes we listed in protocol, instead, they chose composite outcome indicator. We excluded these articles as they failed to provide data of separate components. Considering all studies excluded for this reason reported positive results for the composite outcome, we believed the exclusion was unlikely to affect the results of our review.
A recent editorial has suggested that Qili Qiangxin showed promising results. If Qili Qiangxin is shown to be safe and effective from further rigorous clinical trials research, this presents an interesting area of further work that may fundamentally challenge our current need to precisely understand the pharmacodynamics of all drug therapies . Herbal medicines appear to operate through a variety of often poorly defined synergistic mechanisms involving multiple chemical components. In our study we found that Qili Qiangxin capsules have a positive effect on NT-proBNP levels. Previous studies showed that NT-proBNP level can be used as a prognostic marker for congestive heart failure as decreased NT-proBNP levels predicted reducing mortality in 10 years [20–22]. Levels of NT-proBNP clearly differ among various congenital heart lesions, and a higher level of NT-proBNP correlates with diastolic dysfunction parameters. NT-proBNP levels are related to exercise capacity and also increase with the more dysfunctional HF stages . In our study, we included patients regardless of gender, age, etiology, ethnic group, severity, and course of diseases. Consequently the patients’ in different trials had different underlying diseases. All of these factors might explain the high heterogeneity in the meta-analysis of NT-proBNP. The high heterogeneity of LVEF and 6MWD might separately due to the different population baseline of LVEF and 6MWD in the included trials.
Implications for future research
The results from this review suggest that further research is warranted in order to provide further evidence assessing the effects and safety of Qili Xiangxin as an adjuvant to conventional treatments for HF. We have a number of recommendations for future research. Various diagnostic criteria are used internationally for HF and future research should ideally use internationally recognized diagnostic criteria such as the ACC/AHA guidelines or ESC guidelines as part of their inclusion criteria. Further studies of Qili Qiangxin should also incorporate a minimum one year follow-up period in order that clinically important data on outcomes such as mortality and cardiac events can be provided. These were rarely reported amongst the RCTs we found in this review and further data in this area would be clinically meaningful to patients and providers. Furthermore, we found the reporting of clinical trial methods such as random sequence generation and allocation concealment inadequate and we recommend researchers report in full their trial methodology in future publications. Linked to this, none of the RCTs we included in this review provided trial protocols, and some did not provide all outcomes that had been described in the methods section. For transparency, we recommend that researchers prospectively register trials, publish trial protocols and cite the protocol or registration number in subsequent publications. This will enable future researchers and guideline developers to consider the evidence presented in light of what had been planned by the research team prior to trial commencement. Finally, we found few RCTs using placebo-control design in this review. Studies in future should adopt a double-blinded placebo-controlled design in order that further information regarding specific effects of Qili Qiangxin in HF can be provided.
When compared with conventional treatment alone, Qili Qiangxin combined with conventional treatment demonstrated a significant effect in reducing cardiovascular events and re-hospitalization rate, though not in mortality. Qili Qiangxin appeared to be associated with an increased QOL and preliminary data suggested that it is safe. This data was drawn from low quality trials and the results of this review must therefore be interpreted with caution. Further rigorous research is warranted through large, prospective clinical trials in order to confirm these findings.
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We would like to thank Dr. Jin Luo for her professional advice.
This study was supported by the Program for Innovative Research Team (2011-CXTD-09) of Beijing University of Chinese Medicine, the grant of Research Capacity Building (No. 201207007) from the State Administration of Traditional Chinese Medicine of China. GY Yang and JP Liu was were partially funded by grant number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM) of the US National Institutes of Health (www.nccam.nih.gov).
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.
JS designed the study, performed the study and drafted the manuscript: KZ extracted and analyzed the data, and participated in the revise of the manuscripts. WJX extracted the data and prepared graphs, GYY helped to analyze the data and revised of the manuscript. YJZ extracted the data, CCW participated in extracting data. LL helped to revise the manuscript and corrected language problems. MH helped to revise the manuscripts. GL helped to correct language problems. JPL conceived of and designed the study and helped to draft the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interest.
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