医学教育研究中的随机化对照试验

本文介绍了随机化对照试验(RCT)在医学教育研究中的应用,评论表明RCT已被用于少数教育研究项目。在医学教育领域,有人认为RCT不应当使用,因为学生无权选择自己的学习方法。但是,为了评估多种教学方法的效果,医学教育家建议必须广泛地采用RCT,并指出不对教学方法作RCT是不符合伦理准则的。

葡萄糖酸氯己定鼻咽和口咽部消毒预防心脏手术后院内感染的随机化对照研究

背景：院内感染是心脏手术后患病和死亡的重要原因。消除内源性潜在致病微生物对于院内感染的预防非常重要。目的：确定围手术期应用0．12％的葡萄糖酸氯己定进行鼻咽部和口咽部消毒减少心脏手术后院内感染的有效性。设计、地点和参与者：2003年8月1日至2005年9月1日间，在荷兰阿姆斯特丹的Onze Lieve Vrouwe Gasthuis医院进行了一项前瞻性、随机、双盲、安慰剂对照临床试验。研究期间991例年龄〉18岁、接受择期心胸外科手术的患者中，945例适合分析研究。干预措施：含有葡萄糖酸氯己定或安慰剂的口咽冲洗液和鼻软膏。主要观察指标：院内感染的发生率、金黄色葡萄球菌鼻部携带率以及住院时间。

热凝切割刀应用于剖腹术的随机化对照研究

目的 通过随机化对照研究，评价热凝切割刀应用于剖腹术的临床价值。方法 选择上腹部手术患者９０ 例，随机均分为３ 组。Ａ组为热凝切割组，Ｂ组为高频电刀切割组，Ｃ组为普通手术刀切割组。从切皮至进腹为止，采用止血效果、肌肉颤动、组织炭化、术中焦糊气味及烟雾、刀片粘结组织、切口愈合、脂肪液化等指标评价手术效果。结果 Ａ组止血和切口愈合时间与Ｂ 组相比差异无显著性（Ｐ＞０ ．０５），肌肉颤动、组织炭化、组织焦化烟雾污染、皮下脂肪液化等项指标则显著优于Ｂ 组（ Ｐ＜０．０１），且止血功能优于Ｃ组（Ｐ＜ ０．０１） ，其手术创缘较Ｂ组和Ｃ 组整齐。结论 热凝切割术能够明显提高进腹手术质量，减少手术创伤，促进腹部外科手术技术的进步。

急性心肌梗塞二级预防的大系列前瞻性随机对照临床试验

近年来国际上先后组织了数百个大规模多中心前瞻性临床试验,所获结果因其科学位和普遍性,对临床工作具有重大指导意义。现综述急性心肌梗塞(AMI)二级预防的国际性大系列前瞻性随机化对照临床试验结果如下。1 抗心律失常药物的应用 为了评价用抗心律失常药物抑制AMI后无或轻度症状性室性心律失常能否降低病死率,著名的CAST选用了经CAPS筛选出的药物:高效的恩卡胺(Encainide)、氟卡胺(Flecainide)和中效的乙吗噻嗪(Moricizine)。

出生前母体补充多种复合微量营养素对于尼泊尔新生儿出生体重和妊娠时间的影响:随机双盲对照试验

Background: Neonatal mortality is the biggest contributor to global mortality of children younger than 5 years, and low birthweight is a crucial underlying factor. We tested the hypotheses that antenatal multiple micronutrient supplementation would increase infant birthweight and gestational duration. Methods: We did a doubleblind, randomised controlled trial in Dhanusha district, Nepal. Women attending for antenatal care with singleton pregnancies at up to 20 weeks’ gestation were invited to participate. Participants were randomly allocated either routine iron and folic acid supplements (control; n=600) or a multiple micronutrient supplement providing a recommended daily allowance of 15 vitamins and minerals (intervention; n=600). Supplementation began at a minimum of 12 weeks’ gestation and continued until delivery. Primary outcome measures were birthweight and gestational duration. Analysis was by intention to treat. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN88625934. Findings: Birthweight was available for 523/600 infants in the control group and 529/600 in the intervention group. Mean birthweight was 2733 g (SD 422) in the control group and 2810 g (453) in the intervention group, representing a mean difference of 77 g (95% CI 24-130; p=0.004) and a relative fall in the proportion of low birthweight by 25% . No difference was recorded in the duration of gestation (0.2 weeks -0.1 to 0.4 ; p=0.12), infant length (0.3 cm -0.1 to 0.6 ; p=0.16), or head circumference (0.2 cm -0.1 to 0.4 ; p=0.18). Interpretation: In a poor community in Nepal, consumption of a daily supplement containing a recommended daily allowance of 15 micronutrients in the second and third trimesters of pregnancy was associated with increased birthweight when compared with a standard iron and folic acid preparation. The effects on perinatal morbidity and mortality need further comparisons between studies.

甘草酸二胺治疗慢性乙型肝炎的临床评价

目的 研究甘草酸二胺对慢性乙型肝炎的治疗作用。方法 ２００ 例慢性乙型肝炎患者随机分成三组，Ⅰ组用甘草酸二胺１５０ ｍ ｇ 静滴，每日一次，肝功能正常后减量再治疗一月，改甘草酸二胺口服，１００ ｍ ｇ，每日三次；Ⅱ组用甘草酸二胺１５０ ｍ ｇ 静滴，每日一次，肝功能正常后改口服；Ⅲ组常规用一般护肝药物作为对照。结果 甘草酸二胺静滴治疗后１５天、３０天、６０天对患者ＡＬＴ、ＳＢ复常率为１６．２５％ 、６１．２５％ 和９２．２５％ ，应用常规护肝药组ＡＬＴ、ＳＢ复常率为２．５０％ ，３５．００％和６８．７５％ （Ｐ＜ ０．０５），甘草酸二胺治疗ＡＬＴ、ＳＢ下降速度和幅度也优于对照组（ Ｐ＜ ０．０５）。甘草酸二胺注射液治疗患者肝功能正常后减量再治疗一月疗效优于立即改为口服治疗组，有效率分别为９０．００％ 和６２．５０％ （Ｐ＜ ０．０５）。治疗过程中未发现甘草酸二胺严重的副反应发生。

Effectiveness of 5-flurouracil-based neoadjuvant chemotherapy in locally-advanced gastric/gastroesophageal cancer:A meta-analysis

AIM:To investigate the effectiveness of 5-flurouracilbased neoadjuvant chemotherapy(NAC) for gastroesophageal and gastric cancer by meta-analysis.METHODS:MEDLINE and manual searches were performed to identify all published randomized controlled trials(RCTs) investigating the efficacy of the flurouracilbased NAC for gastroesophageal and gastric cancer,and RCTs of NAC for advanced gastroesophageal and gastric cancer vs no therapy before surgery.Studies that included patients with metastases at enrollment were excluded.Primary endpoint was the odds ratio(OR) for improving overall survival rate of patients with gastroesophageal and gastric cancer.Secondary endpoints were the OR of efficiency for down-staging tumor and increasing R0 resection in patients with gas-troesophageal and gastric cancer.Safety analyses were also performed.The OR was the principal measurement of effect,which was calculated as the treatment group(NAC plus surgery) vs control group(surgery alone) and was presented as a point estimate with 95% confidence intervals(CI).All calculations and statistical tests were performed using RevMan 5.1 software.RESULTS:Seven RCTs were included for the analysis.A total of 1249 patients with advanced gastroesophageal and gastric cancer enrolled in the seven trials were divided into treatment group(n = 620) and control group(n = 629).The quality scores of the RCTs were assessed according to the method of Jadad.The RCT quality scores ranged from 2 to 7(5-point scale),with a mean of 3.75.The median follow-up time in these studies was over 3 years.The meta-analysis showed that NAC improved the overall survival rate(OR 1.40,95%CI 1.11-1.76;P = 0.005),which was statistically significant.The 3-year progression-free survival rate was significantly higher in treatment group than in control group(37.7% vs 27.3%)(OR 1.62,95%CI 1.21-2.15;P = 0.001).The tumor down-stage rate was higher in treatment group than in control group(55.76% vs 41.38%)(OR 1.77,95%CI 1.27-2.49;P = 0.0009) and the R0 resection rate of the gastroesophageal and gastric cancer was higher in treatment group than in control group(75.11% vs 68.56%)(OR 1.38,95%CI 1.03-1.85;P = 0.03),with significant differences.No obvious safety concerns about mortality and complications were raised in these trials.There were no statistically significant differences in perioperative mortality(5.08% vs 4.86%)(OR 1.05,95%CI 0.57-1.94;P = 0.87 fixed-effect model) and in the complication rate between the two groups(13.25% vs 9.66%)(OR 1.40,95%CI 0.91-2.14;P = 0.12 fixed-effect model).Trials showed that patients from Western countries favored NAC compared with those from Asian countries(OR 1.40,95%CI 1.07-1.83).Monotherapy was inferior tomultiple chemotherapy(OR 1.40,95%CI 1.07-1.83).Intravenous administration of NAC was more advantageous than oral route(OR 1.41,95%CI 1.09-1.81).CONCLUSION:Flurouracil-based NAC can safely improve overall survival rate of patients with gastroesophageal/gastric cancer.Additionally,NAC can down the tumor stage and improve R0 resection.

Management of liver cirrhosis between primary care and specialists

This article discusses a practical, evidence-based approach to the diagnosis and management of liver cirrhosis by focusing on etiology, severity, presence of complications, and potential home-managed treatments. Relevant literature from 1985 to 2010 (PubMed) was reviewed. The search criteria were peer-reviewed full papers published in English using the following MESH headings alone or in combination: "ascites", "liver fibrosis", "cirrhosis", "chronic hepatitis", "chronic liver disease", "decompensated cirrhosis", "hepatic encephalopathy", "hypertransaminasemia", "liver transplantation" and "portal hypertension". Forty-nine papers were selected based on the highest quality of evidence for each section and type (original, randomized controlled trial, guideline, and review article), with respect to specialist setting (Gastroenterology, Hepatology, and Internal Medicine) and primary care. Liver cirrhosis from any cause represents an emerging health issue due to the increasing prevalence of the disease and its complications worldwide. Primary care physicians play a key role in early identification of risk factors, in the management of patients for improving quality and length of life, and for preventing complications. Specialists, by contrast, should guide specific treatments, especially in the case of complications and for selecting patient candidates for liver transplantation. An integrated approach between specialists and primary care physicians is essential for providing better outcomes and appropriate home care for patients with liver cirrhosis.

Neoadjuvant chemoradiotherapy for resectable esophageal carcinoma:A meta-analysis

AIM:To compare neoadjuvant chemoradiotherapy and surgery with surgery alone for resectable esophageal carcinoma. METHODS:We used MEDLINE and EMBASE databases to identify eligible studies and manual searches were done to ensure no studies were missed.Trial validity assessment was performed and a trial quality score was assigned. RESULTS:Eleven randomized controlled trials(RCTs) including 1308 patients were selected.Neoadjuvant chemoradiotherapy significantly improved the overall survival compared with surgery alone.Odds ratio(OR) [95%confidence interval(CI),P value],expressed as neoadjuvant chemoradiotherapy and surgery vs surgery alone,was 1.28(1.01-1.64,P=0.05)for 1-year survival,1.78(1.20-2.66,P=0.004)for 3-year survival,and 1.46(1.07-1.99,P=0.02)for 5-year survival.Postoperative mortality increased in patients treated by neoadjuvant chemoradiotherapy(OR: 1.68,95%CI:1.03-2.73,P=0.04),but incidence of postoperative complications was similar in two groups (OR:1.14,95%CI:0.88-1.49,P=0.32).Neoadjuvant chemoradiotherapy lowered the local-regional cancer recurrence(OR:0.64,95%CI:0.41-0.99,P=0.04), but incidence of distant cancer recurrence was similar (OR:0.94,95%CI:0.68-1.31,P=0.73).Histological subgroup analysis indicated that esophageal squamous cell carcinoma did not benefit from neoadjuvantchemoradiotherapy,OR(95%CI,P value)was 1.16(0.85-1.57,P=0.34)for 1-year survival,1.34 (0.98-1.82,P=0.07)for 3-year survival and 1.41 (0.98-2.02,P=0.06)for 5-year survival. CONCLUSION:Neoadjuvant chemoradiotherapy can raise the survival rate of patients with esophageal adenocarcinoma.

Neoadjuvant chemoradiotherapy for resectable esophageal cancer:an in-depth study of randomized controlled trials and literature review

Surgery following neoadjuvant chemoradiotherapy(NCRT) is a common multidisciplinary treatment for resectable esophageal cancer(EC). After analyzing 12 randomized controlled trials(RCTs), we discuss the key issues of surgery in the management of resectable EC. Along with chemoradiotherapy, NCRT is recommended for patients with squamous cell carcinoma(SCC) and adenocarcinoma(AC), and most chemotherapy regimens are based on cisplatin, fluorouracil(FU), or both(CF). However, taxane-based schedules or additional studies, together with newer chemotherapies, are warranted. In nine clinical trials, post-operative complications were similar without significant differences between two treatment groups. In-hospital mortality was significantly different in only 1 out of 10 trials. Half of the randomized trials that compare NCRT with surgery in EC demonstrate an increase in overall survival or disease-free survival. NCRT offers a great opportunity for margin negative resection, decreased disease stage, and improved loco-regional control. However, NCRT does not affect the quality of life when combined with esophagectomy. Future trials should focus on the identification of optimum regimens and selection of patients who are most likely to benefit from specific treatment options.

The effect of Supplementing Qi and Nourishing Yin combined with chemotherapy for lung cancer： a meta-analysis

Objective： To evaluate whether herbs of supplementing Qi and nourishing Yin combined with chemotherapy （versus chemotherapy alone） improve survival, increase tumor response, improve performance status or reduce chemotherapy toxicity in patients with lung cancer. Methods： Searching the randomized controlled trials （RCT） studies from the databases （China HowNet database, Wan Fang database, VIP database, Master Thesis and Pubmed） between January 2013 and January 2017. RevMan 5.3 software was used to evaluate the quality of these collected papers. Results： Of 48 potentially relevant publications, 10 randomized studies representing 691 patients met inclusion criteria with 369 cases in the supplementing Qi and nourishing Yin plus Chemotherapy group （Herbs ＋ Chem group） and 322 cases in Chemotherapy group （Chem only group）. There were significant differences between Herbs ＋ Chem group and Chem only group in improving the treatment efficacy and reducing the side effects of chemotherapy （P 〈 0.001 for all）. There were also significant differences between the two groups in tumor response and quality of life （P 〈 0.001 for all）. Conclusion： Herbs of supplementing Qi and nourishing Yin may increase chemotherapy effectiveness, reduce chemotherapy toxicity and improve the quality of life of patients with lung cancer when combined with chemotherapy.

Andropause and the development of cardiovascular disease presentationmore than an epi-phenomenon

Andropause refers to a generalized decline of male hormones, including testosterone and dehydroepiandrosterone in middle-aged and aging men. This decline in hormones has been associated with changes such as depression, loss of libido, sexual dysfunction, and changes in body composition. Aging has been associated with an abundance of concomitant diseases, in particular cardiovascular diseases, and although andropause is correlated to aging, a causal relationship between reduction of androgens and the development of chronic diseases such as atherosclerosis and heart failure has not been convincingly established yet. On the other hand, increasing data has emerged that revealed the effects of low levels of androgens on cardiovascular disease progression. As an example, low levels of testosterone have been linked to a higher incidence of coronary artery disease. Whether hormone replacement therapy that is used for andropausal men to alleviate symptoms of ＂male menopause＂ can halt progression of cardiovascular disease, remains controversially discussed, primarily due to the lack of well-designed, randomized controlled trials. At least for symptom improvement, the use of androgen replacement therapy in andropausal men may be clinically indicated, and with the appropriate supervision and follow up may prove to be beneficial with regard to preservation of the integrity of cardiovascular health at higher ages.

前列腺癌筛查

前列腺癌是美国男性最常见的癌症之一，估计2011年将有24万人被诊断为患前列腺癌，约3．4万人死于该病。前列腺特异性抗原（prostate—specific antigen，PSA）被广泛应用于前列腺癌的早期诊断。但是，Hoffman博士列举了早期的两个大型随机化对照筛查试验结果并不一致，欧洲的一项研究表明筛查会使前列腺发病率有所下降，

Effect of Sancaijiangtang on plasma nitric oxide and endothelin-1 levels in patients with type 2 diabetes mellitus and vascular dementia:a single-blind randomized controlled trial

OBJECTIVE: To observe the effect of Sancaijiangtang powders on plasma nitric oxide and endothelin-1 levels. We sought to identify the common pathological link and mechanism of action for Traditional Chinese medicine in type 2 diabetes mellitus and vascular dementia,and to explicate the material basis for treating the different diseases with the same method in Traditional Chinese Medicine.METHODS: In total,168 patients with type 2 diabetes mellitus and vascular dementia were enrolled in the study,and randomly divided into two groups by simple randomization. Patients in the treatment group received oral Sancaijiangtang powders with pioglitazone hydrochloride three times daily,while patients in the control group received pioglitazone hydrochloride alone. The treatment course was for12 weeks. Mini-mental state examinations(Chinese version) and Montreal Cognitive Assessments(Beijing version) were performed,and fasting plasma glucose,fasting insulin,hemoglobin A1 c,homeostasis model assessment of insulin resistance,plasma nitric oxide and endothelin-1 levels were measured before and after the treatment.RESULTS: The post-treatment levels for all measurements in both groups were better than pre-treatment levels(P < 0.05). The post-treatment levels for all measurements in the treatment group were better than the levels measured in the control group(P < 0.05).CONCLUSION: Type 2 diabetes mellitus and vascular dementia have common pathological mechanisms for insulin resistance and endothelium dysfunction. Sancaijiangtang powders could improve the release of nitric oxide and inhibit the secretion of endothelin-1. Therefore,the material basis exists for treating the different diseases with the same method in Traditional Chinese Medicine.

Effect of Shoushen granule on arterial elasticity in patients with carotid atherosclerosis:a clinical randomized controlled trial

OBJECTIVE: To investigate the effectiveness of Shoushen granule,Chinese herbal preparation,on carotid artery elasticity in patients with carotid atherosclerosis.METHODS: The total of 156 carotid atherosclerosis patients were randomly divided into the intervention group(83 cases,treated with Shoushen granule) and the control group(73 cases,treated with pravastatin). Brachial-ankle pulse wave velocity(ba PWV) and Ankle-Brachial Pressure Index(ABI)were measured by automated arteriosclerosis detector. The changes of common carotid artery intima-media thickness(IMT) and parameters of the carotid artery elasticity in patients,including stiffness parameter(β),pressure-strain elastic modulus(Ep),arterial compliance(Ac),augmentation index(AI),and pulse wave velocity β(PWVβ) were detected by Echo-Tracking(ET) technique before and after 24 week treatment. In the meantime,levels of blood lipid,and liver and renal function were measured respectively.RESULTS: After 24 weeks,ba PWV,IMT and parameters of the carotid artery elasticity(β,Ep,AI and PWVβ) were markedly decreased in intervention group compared with those of before treatment(P < 0.01),but the level of Ac was increased significantly(P < 0.01). And there were no significant differences compared with control group on the same period(P > 0.05).CONCLUSION: In this pilot study,it was demonstrated ET technology and automated arteriosclerosis detector could be used to evaluate carotid artery elasticity effectively,and the action of Shoushen granule on carotid atherosclerosis might be related to the regulation of carotid artery elasticity.

Acupuncture therapy with point selection based on syndrome differentiation along the meridians for functional dyspepsia:a randomized controlled trial

Objective:To observe the difference in clinical efficacy between acupuncture with point selection based on syndrome differentiation along the meridians and acupuncture at non-meridian and non-acupoint points for functional dyspepsia(FD).Methods:A total of 74 FD patients were randomized into an observation group and a control group,with 37 cases in each group.Both groups received acupuncture treatment.Zusanli(ST 36)and Neiguan(PC 6)were selected in the observation group,with Taichong(LR 3)and Neiting(ST 44)added for excess syndrome,and Gongsun(SP 4)and Yinlingquan(SP 9)added for deficiency syndrome.Four non-meridian and non-acupoint points were selected in the control group.The treatments in both groups were performed once a day with a 2-day break after 5 consecutive treatments,which constituted one treatment course.A total of 4 courses were performed.The scores of Nepean dyspepsia index(NDI)and Leeds dyspepsia questionnaire(LDQ)were recorded before and after treatment,and during follow-up(8,12,16,20 and 24 weeks after recruitment)to assess the clinical efficacy.Results:The NDI scores in the two groups after treatment and at each time point during follow-up were higher than those before treatment(all P<0.05),and the LDQ scores were lower than those before treatment(all P<0.05).The NDI scores after treatment and at each time point during follow-up in the observation group were higher than those in the control group(all P<0.01);the total LDQ score and scores of upper abdominal pain,postprandial satiety and upper abdominal burning sensation after treatment and at each time point during follow-up in the observation group were significantly lower than those in the control group(P<0.01 or P<0.05)..Conclusion:Acupuncture with point selection based on syndrome differentiation along the meridians has a better curative effect than acupuncture at non meridian and non-acupoint points in the treatment of FD.

Traditional Chinese Medicine for the treatment of influenza: a systematic review and Meta-analysis of randomized controlled trials

OBJECTIVE: To justify the clinical use of Traditional Chinese Medicine(TCM) in the treatment of influenza.METHODS: MEDLINE, EMBASE, Chinese Biomedical Literature Database, China National Knowledge Infrastructure Database, China Science and Technology Journal Database, Wanfang Database and the Cochrane Database of Systematic Reviews were searched from thedate of inception until January 1,2013, for the literature on treatment of influenza with TCM.RESULTS: A total of 7 randomized controlled trials were identified and reviewed. Of these trials, 2 compared a(modified) prescription of TCM with oseltamivir and 5 compared a patent traditional Chinese drug with oseltamivir. Based on the Meta-analysis,compared to oseltamivir, the(modified) prescription had similar effect in defervescence [WMD=5.66, 95% CI(﹣32.02, 43.35), P=0.77] and viral shedding [WMD=﹣ 6.21, 95% CI(﹣84.19, 71.76), P=0.88], and the patent traditional Chinese drug also had similar effect in viral shedding [WMD=﹣ 0.24,95% CI(﹣4.79, 4.31), P=0.92] but more effective in defervescence [WMD=﹣4.65, 95%CI(﹣8.91, ﹣0.38),P=0.03].CONCLUSION: TCM has potential positive effects in the treatment of influenza.

Effect of Banxiaxiexin Tang on treatment of functional dyspepsia: a Meta-analysis of randomized controlled trials

OBJECTIVE: To evaluate the efficacy of Banxiaxiexin Tang compared with Western Medicine in the treatment of functional dyspepsia(FD) through Meta-analysis.METHODS: Literature was searched in the following databases: MEDLINE, Excerpta Medica Database, Chinese Medical Current Contents, China Science and Technology Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. Randomized controlled trials evaluating the efficacy of Banxiaxiexin Tang for the treatment of FD were selected according to certain standards including clear general situation of patients, specific diagnostic criteria, definite clinical outcomes, etc. Articles were evaluated with quality assessment standards in the Cochrane Handbook for Systematic Reviews of Interventions. Meta-analysis was conducted with RevMan 5.0.23 software.RESULTS: Ten articles with a total of 972 patients were included. The comparison of efficacy between Banxiaxiexin Tang and Western Medicine showed a combined effect size [OR=2.75, 95% CI(1.86-4.07)]andcombinedeffectofvalueofZ=5.07(P<0.000 01),suggesting a significant difference between the groups.CONCLUSION: Banxiaxiexin Tang was more effective thanWestern Medicine in treating FD.

Landmark learning by the Ozark zigzag salamander Plethodon angusticlavius

Although salamanders have been shown to respond to classical conditioning, spatial learning has been largely unstudied. We tested whether salamanders could learn to locate foraging areas by using landmarks. We trained 10 salamanders Plethodon angusticlavius to use landmarks （small rocks） to locate patches within the arena containing food （blackworms Lumbriculus variegatus）. At the comers of each square testing arena were four plastic dishes, one containing blackworms and the other three empty. A rock was placed in front of the dish containing blackworms, and the location of the food-dish was randomly chosen for each training trial. A control group was also trained to feed on blackworms in the presence of a rock, but the rock was positioned randomly among the four dish locations so that the rock was not a reliable landmark for the worms. Although the length of the training period for individual salamanders varied （22-38 trainings per individual）, the mean number of trainings for salamanders in the control and experimental groups was equal （30 training trials）. During testing, no blackworms were present to eliminate any visual or chemical cues emanating directly from the prey. Individuals trained with the rock landmarks spent sig- nificantly more time in the area of the landmark than did control salamanders [Current Zoology 57 （4）： 485-490, 2011].