牙周基础治疗对2型糖尿病相关性牙周炎患者血糖控制的Meta分析

目的系统评价牙周基础治疗对2型糖尿病相关性牙周炎患者血糖控制的影响,探讨牙周基础治疗在糖尿病治疗中的具体作用。方法计算机检索Cochrane图书馆对照试验注册中心、Medline、EMbase、SIGLE、GreyNet、NTIS、中国生物医学文献数据库、中文科技期刊全文数据库、中国期刊全文数据库和万方数据库,查找有关牙周基础治疗对糖尿病血糖控制影响的研究。检索时限均为1991-2011年4月31日。均由2名评价者独立选择试验、提取资料和评估方法学质量,然后采用RevMan 5．1软件对资料进行Meta分析。纳入7个研究,共计471例受试患者。结果牙周基础治疗能明显降低2型糖尿病相关性牙周炎患者糖化血红蛋白的水平,组间差异有统计学意义（95％CI：-0．94—0．22,P=0．001）。治疗组牙周袋探诊深度低于对照组,组间差异也有统计学意义（95％CI：-2．26～0．69,P=0．0002）。结论牙周基础治疗有利于2型糖尿病相关性牙周炎患者总体血糖水平的控制。     

The effect of improved periodontal health on metabolic control in type 2 diabetes mellitus

OBJECTIVES: The aim of the present study was to investigate the effect of improved periodontal health on metabolic control in type 2 diabetes mellitus (DM) patients. MATERIAL AND METHODS: Fourty-four patients with type 2 DM were selected. Subjects were randomly assigned into two groups. Data collection: Plaque index (PI), gingival index (GI), probing pocket depth (PPD), clinical attachment levels (CALs), gingival recession (GR) and bleeding on probing (BOP) were recorded at baseline at 1st and 3rd months. Fasting plasma glucose (FPG), 2-h post-prandial glucose (PPG), glycated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), HDL-cholesterol, LDL-cholesterol and microalbuminure were analysed at baseline, 3 months following the periodontal therapy. The treatment group received full-mouth scaling and root planing whereas the control group received no periodontal treatment. RESULTS: A statistically significant effect could be demonstrated for PI, GI, PPD, CAL and BOP for the treatment group. HbA1c levels in the treatment group decreased significantly whereas the control group showed a slight but insignificant increase for this parameter. CONCLUSIONS: The results of our study showed that non-surgical periodontal treatment is associated with improved glycaemic control in type 2 patients and could be undertaken along with the standard measures for the diabetic patient care.     

牙周基础治疗对2型糖尿病患者糖脂代谢的影响

目的:观察伴发2型糖尿病的慢性牙周炎患者的牙周状况,探讨牙周基础治疗对牙周状况及糖脂代谢的影响.方法:选择伴发2型糖尿病的慢性牙周炎患者30例,非糖尿病慢性牙周炎患者30例,分析治疗前及治疗后1、3个月的牙龈指数、牙周探诊深度、附着丧失水平以及糖化血红蛋白、甘油三酯、总胆同醇水平.研究数据采集完成后,以SAS 6.12软件包对结果进行双因素方差分析.结果:牙周治疗后,患者的牙周状况均有改善,差异有显著性(P＜0.05).血糖控制欠佳的患者,治疗后糖化血红蛋白有所改善,差异有显著性(P＜0.05);而血糖控制较好者,其糖化血红蛋白治疗后下降不明显.基础治疗对患者的血脂水平无显著影响.结论:伴发2型糖尿病的慢性牙周炎患者接受基础治疗后,短期效果良好;血糖控制欠佳的患者,基础治疗有助其糖代谢水平的改善,但血糖控制良好者,基础治疗对其糖代谢水平无显著影响.     

Prevalence of periodontal pathogens with varying metabolic control of diabetes mellitus

Abstract. The purpose of this study was to determine the prevalence of 5 periodontal pathogens in individuals with diabetes mellitus. Subjects ( n = 107) 20–70 years of age with type 1 ( n = 60) or 2 ( n = 47) diabetes mellitus were studied for the occurrence of the periodontal pathogens A. actinomycetemcomitans, F. nude-alum, E. corrodens, P. gingivalis and P. intermedia. Subgingival plaque was sampled in each subject from a single site exhibiting the greatest inflammation. The evaluation of selected periodontal bacterial pathogens was based on an immunoassay utilizing bacterial specific monoclonal antibodies. 35% of the sites harbored P. gingivalis , 28% F. nucleatum and 21% E. corrodens. A. actinomycetemcomitans and P. intermedia were found in less than 10% of the sites. Subjects for whom the probing depth at the sampled site was 4 mm were more often found to have detectable pathogens than those with a probing depth 3 mm. Diabetic factors such as duration, type and metabolic control of the disease had no statistically significant effect on the prevalence of these bacteria.     

Resolution of periodontal inflammation does not guarantee improved glycemic control in type 1 diabetic subjects

Objective: The aim of this study was to find out if periodontal therapy has any effect on glycemic control of type 1 diabetes mellitus (DM).
Subjects and Methods: The periodontal health status of 65 type 1 diabetic subjects was assessed at the baseline and 8 weeks after completion of periodontal therapy. Glycemic control was assessed on both visits by measuring the percentage of glycosylated haemoglobin (GHbA1c). The change in HbA1c (ΔHbA1c) was assessed by using both a positive or negative change 0.5% and any change in HbA1c.
Results: The mean HbA1c level (±SD) of the whole study group was 8.6% (±1.5) at the baseline and 8.5% (±1.5) after treatment. Glycemic control improved during the study period in 23 subjects (35%) and worsened in 18 subjects (28%). Approximately 78% of the bleeding sites and 87% of the sites with probing depth 4 mm presented healing. ΔHbA1c associated significantly with baseline HbA1c but not with baseline periodontal health status or periodontal healing.
Conclusion: Regardless of a significant resolution of periodontal infection, a great majority of the subjects did not present any improvement in their glycemic control.     

The effect of non-surgical periodontal therapy on peroxidase activity in diabetic patients: a case-control pilot study

Objective: To evaluate the effect of periodontal therapy on clinical parameters as well as on total salivary peroxidase (TSP) activity and myeloperoxidase (MPO) activity in the gingival crevicular fluid (GCF) of patients with type 2 diabetes mellitus (DM2) and of systemically healthy individuals.
Material and Methods: Twenty DM2 subjects with inadequate metabolic control (test group) and 20 systemically healthy individuals (control group), both groups with chronic periodontitis, were enrolled. Periodontal clinical parameters, namely periodontal probing depth (PD), clinical attachment level (CAL), visible plaque index (VPI), bleeding on probing (BOP), gingival bleeding index (GBI) and presence of suppuration (SUP), as well as TSP activity and GCF MPO activity, were assessed before and 3 months after non-surgical periodontal therapy.
Results: At baseline and 3 months post-treatment, the test group presented a higher percentage of sites with VPI and BOP ( p <0.01). MPO activity in the GCF presented lower values ( p <0.05) for the test group at both baseline and the post-treatment period. The periodontal treatment resulted in a significant improvement of most clinical and enzymatic parameters for both groups ( p <0.05).
Conclusions: In both groups, the periodontal therapy was effective in improving most clinical parameters and in reducing salivary and GCF enzymatic activity. The diabetic individuals presented lower MPO activity in the GCF.     

Relationship between markers of metabolic control and inflammation on severity of periodontal disease in patients with diabetes mellitus

AIM: The aim of this study was to investigate the relationship between markers of metabolic control and inflammation and periodontal disease parameters in patients with diabetes. MATERIAL & METHODS: One hundred and eighty one adult patients with diabetes attending treatment at two diabetes centres were invited to participate in the study. Periodontal examination included full-mouth assessment for probing depths and bleeding on probing (BOP). Blood analyses were carried out for glycated haemoglobin, (HbA1c), high-sensitivity C reactive protein, (hsCRP) and lipid profile comprising total cholesterol, low-density lipoprotein cholesterol (LDL chol), high-density lipoprotein cholesterol (HDL chol) and triglycerides. RESULTS: Upon multivariate analysis, periodontal disease severity in terms of increased percentage of BOP and mean percentage of sites with probing depths > or = 5 mm were found to be associated with inadequate glycaemic control as measured by HbA1c (p<0.01). HsCRP was also found to be a significant predictor for mean percentage of sites with probing depths > or = 5 mm (p<0.05). After controlling for age, gender, smoking habits and number of teeth, positive correlations were found between HbA1c and percentage sites with probing depths > or = 5 mm, percentage sites BOP, total cholesterol, LDL chol and triglycerides (p<0.05). Using the adjusted differences, subjects with acceptable glycaemic control (HbA1c < 8%) showed a lower percentage of sites with BOP and probing depths > or = 5 mm (p<0.05) when compared with those having inadequate glycaemic control. There was also a trend towards lower blood cholesterol in the well-controlled group. CONCLUSION: The level of glycaemic control as measured by HbA1c emerged as the most consistent risk factor associated with the extent and severity of periodontal disease in this study cohort.     

Healing response to non-surgical periodontal therapy in patients with diabetes mellitus: clinical, microbiological, and immunologic results

Abstract. The aim of the present study was to monitor clinical, microbiological, medical, and immunological effects of non-surgical periodontal therapy in diabetics Lind healthy controls. 20 IDDM (insulin dependent. n = l) or NIDDM (non-insulin dependent. n = 13) diabetic patients (median duration 11.5 years, range of HbA_1C: 4.4–10.6%) with moderate to advanced periodontal disease and 20 matched healthy control patients, were subjected to supragingival pretreatment and subsequent subgingival therapy Periodontal examinations (API. PBI, BOP. PPD, PAL), microbiological examinations (culture), medical routine examinations, and immunological examinations (oxidative burst response of PMNs to TNF-α and FMLP) were performed at baseline, 2 weeks after supragingival, and 4 months after subgingival therapy. 4 months after completion of non-surgical therapy, the following compared to baseline significant ( p ≤0.05) changes (Δ) of clinical parameters (median) were found in diabetic patients versus control patients: JAPI (30.4% versus 36.3%), ΔPBI (22.9% versus 24.2%), ΔBOP (39.5% versus 46.9%). The median % per patient of pockets with PPD≥4 mm decreased from 41.9% to 28.3% in diabetics, and from 41.6% to 31.8% in controls. Microbiologically. similar reductions of periopathogenic bacteria were found in diabetics and controls. Neither periodontal data nor the oxidative burst response of PMNs showed any significant difference ( p >0.05) between diabetics and control patients. In this study, periodontal therapy had no significant influence on medical data of diabetics. In conclusion, this study indicates that metabolically well-controlled diabetics might respond to non-surgical periodontal therapy as well as healthy control patients.     

The effect of periodontal therapy on uncontrolled type 2 diabetes mellitus in older subjects

OBJECTIVE: The purpose of this study was to examine the effect of periodontal therapy on glycemic control in older type 2 diabetic patients. METHODS: Fifty-two diabetic patients, age 55-80 years (mean age = 61 years), with glycated hemoglobin (HbA1c) 7.5-11.0% (mean +/- s.d. = 8.98 +/- 0.88) and severe periodontitis were included in the present study. The treatment group received mechanical periodontal treatment combined with systemic doxycycline, 100 mg day(-1) for 14 days. The control group received neither periodontal treatment nor systemic doxycycline. Clinical periodontal parameters, fasting plasma glucose (FPG), and HbA1c levels were measures at baseline and 3 months. RESULTS: Periodontal treatment significantly improved periodontal status of the treatment group (P < 0.05), however the reduction in the level of FPG and HbA1c did not reach significance. In the control group, no significant changes in clinical periodontal parameters, FPG and HbA1c levels were observed, except for significant increase in attachment loss (P < 0.05). Comparing the two groups, although the 3-month level of HbA1c of the treatment group was lower than that of the control group, the difference did not reach significance. CONCLUSIONS: The results of the present study indicate that the periodontal condition of older Thais with uncontrolled diabetes is: (a) significantly improved 3 months after mechanical periodontal therapy with adjunctive systemic antimicrobial treatment, and (b) rapidly deteriorating without periodontal treatment. The effect of periodontal therapy on the glycemic control of older uncontrolled diabetics will require further studies that will have to include much larger sample sizes.     

牙周治疗对2型糖尿病患者血清白细胞介素6及糖化白蛋白的影响

目的 探讨牙周非手术治疗对伴牙周炎2型糖尿病患者血清白细胞介素-6及糖化白蛋白的影响.方法 选择2型糖尿病伴重度慢性牙周炎患者32例,于牙周治疗前、后一个月分别检测血清白细胞介素-6(IL-6)和糖化白蛋白(FA)、甘油三酯(TG)水平、牙周指数.结果 经牙周治疗后,伴重度牙周炎的2型糖尿病患者除TG水平外,血清IL-6阳性百分率(P＜0.05)、FA水平(P＜0.001)有明显下降;探诊深度(PD)、附着丧失(AL)治疗后均较基线明显下降(P＜0.001).结论 非手术牙周治疗可能降低糖尿病牙周炎患者外周血循环IL-6水平,糖化白蛋白水平、牙周状况也有明显改善.     

Improved metabolic control, clinical periodontal status and subgingival microbiology in insulin-dependent diabetes mellitus

The effect of improved metabolic control on the clinical periodontal condition and the subgingival microflora of diseased and healthy periodontal pockets in 6 ambulatory insulin-dependent diabetes mellitus (IDDM) patients was prospectively studied. Duplicate measurements with a time-interval of 3 days were made every 4 moths for assessment of the metabolic status, the clinical periodontal condition and the subgingival microflora. During the study, patients maintained personal oral hygiene measures as they usually did before the study. Neither supplementary dental prophylaxis nor oral hygiene measures were applied during the investigation. Long-term metabolic control (HbAlc) improved significantly with intensive conventional insulin treatment. Gingival redness decreased significantly whereas gingival swelling showed a not significant trend to decrease. It is suggested that microvascular changes associated with improved metabolic control in diabetes mellitus may mediate the observed change in gingival redness. No effect could be demonstrated for probing pocket depth, probing attachment level, bleeding on probing and the plaque index. Statistical analysis of the effect of improved metabolic control on the subgingival microflora revealed that only the % of streptococci increased significantly in diseased periodontal pockets. In general, no significant changes were found in either healthy or diseased pockets with regard to the bacterial flora associated with periodontal disease. The results of the present study indicate that improved metabolic control in IDDM patients may have no potential impetus for an improved clinical periodontal condition nor on the subgingival bacterial flora. It is concluded that the periodontal condition in IDDM patients may only ameliorate when local oral hygiene measures are applied.     

Effect of antimicrobial periodontal treatment and maintenance on serum adiponectin in type 2 diabetes mellitus

Aims: The aims of this study were to evaluate the effect of mechanical periodontal treatment with local application of minocycline (APT) on serum adiponectin as a marker of insulin resistance improvement in type 2 diabetes mellitus (T2DM) patients and to investigate if effect of APT on serum adiponectin level was sustained by periodontal maintenance (PM).
Material and Methods: Twenty-seven T2DM patients were randomly assigned into test or control groups. Test received scaling with ultrasonic devices at baseline and APT biweekly for 2 months while control received scaling at baseline and mechanical tooth cleaning (MPT) at the same interval. At 6 months, all patients received mechanical tooth cleaning as PM. Periodontal examination and blood measurements were performed at baseline, 4 and 9 months.
Results: Adiponectin concentrations in test had significantly increased by 31.4% after APT ( p =0.024) and by 30.4% after PM ( p =0.002) compared with baseline. The percentage of 4 mm probing depths (PD) had shown 8.3% and 9.3% reduction after APT and PM ( p =0.046, 0.02) in test while 5.0% reduction after MPT in control group ( p =0.031).
Conclusions: Our results suggested that APT and PM not only improve periodontal disease but also increase serum adiponectin in T2DM patients.     

Periodontal condition and microbiology of healthy and diseased periodontal pockets in type 1 diabetes mellitus patients

Abstract On the basis of glycosylated hemoglobin (HbA_IC)values, 22 type I (insulin-dependent) diabetic adults were grouped into patients with near normal (HbAt_1c≤7.7%) and Poor (HbA_tc≥9.9%) metabolic control. A total of 44 subgingival sites were examined for Actinobacillus actinomycetemcomitans, black-pigmented Bacteroides species and Capnocytophaga species. No significant difference could be demonstrated between patients in the 2 test groups with regard to periodontal condition. Neither age of diabetic patients nor duration of diabetes mellitus influenced the periodontal parameters. In both test groups, pocket depth of 4 mm or more (≥4 mm) was found to be significantly associated with increased swelling, bleeding after probing and amount of marginal plaque. Proportionally high %s of cultivable A. actinomycetemcomitans (mean 4.3%; range 2.8–5.8%), Bacteroides gingival (33.2% and 34.6%) and Bacteroides intermedius (mean 4.2%; range 0.001–13.5%) were isolated from diseased periodontal pockets. In diabetic patients with poor metabolic control, B. intermedius was isolated from diseased periodontal pockets with a mean % of 7.2%, range 0.3–12.5%. Independent of the degree of metabolic control, low %s of Capnocytophaga species were isolated from diseased and healthy periodontal pockets, mean 0.9% (range 0.003–3.9%) and mean 1.4% (range 0.04–4.9%), respectively. It was concluded from this study that metabolic control seems to have no direct effect on the periodontium. Furthermore, the role of Capnocytophaga species in the pathogenesis of infectious periodontal disease in type I diabetic patients seems to be overestimated. However, A. actinomycetemcomitans and blackpigmented Bacteroides species may be important pathogens in periodontal disease in type I diabetic patients, as they are known to be in non–diabetic periodontal patients.     

Effects of non-surgical periodontal treatment on clinical response, serum inflammatory parameters, and metabolic control in patients with type 2 diabetes: a randomized study

Background: Scientific evidence on the effects of chronic periodontitis on diabetes mellitus remains inadequate and inconclusive. This intervention study is designed to evaluate the effects of periodontal treatment on clinical response, systemic inflammatory parameters, and metabolic control in patients with Type 2 diabetes. Methods: A total of 134 patients were randomly allocated into two treatment groups and one control group. Treatment group 1 underwent non‐surgical periodontal treatment at baseline and additional subgingival debridement at the 3‐month follow‐up. Patients in treatment group 2 received non‐surgical periodontal treatment and supragingival prophylaxis at the 3‐month follow‐up, and those in the control group received no intervention throughout the study. All participants were reexamined at 1.5, 3, and 6 months after initial treatment. At each visit, clinical periodontal examinations were conducted and blood samples were taken to evaluate high‐sensitivity C‐reactive protein (hsCRP), tumor necrosis factor‐α (TNF‐α), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and lipid profiles. Results: Both treatment groups had a significantly lower hsCRP level after periodontal therapy (P <0.05). Although HbA1c declined significantly in treatment group 2 (P <0.05), the intergroup difference for HbA1c, FPG, TNF‐α, and lipid profiles was not statistically significant after therapy (P >0.05). Conclusions: Non‐surgical periodontal treatment can effectively improve periodontal and circulating inflammatory status. Despite a lack of strong evidence, trends in some results support improved glycemic control after periodontal treatment in patients with diabetes.     

Effect of non-surgical periodontal treatment with or without doxycycline on the periodontium of type 1 diabetic patients

AIM: The present investigation was performed to study how type 1 diabetics responded to non-surgical periodontal treatment with and without adjunctive doxycycline. METHOD: Sixty diabetic type 1 patients (mean age 35.3+/-9 years) with moderate-to-severe periodontal disease were selected and divided into two groups of 30 patients each. Both groups were sex and age matched and had similar amounts of periodontal destruction. Plaque index (PI), bleeding on probing (BOP), probing depth (PD) and clinical attachment levels (CAL) were recorded. Group 1 (30 patients) was treated with oral hygiene instruction, scaling and root planing, chlorhexidine rinses twice a day and doxycycline (100 mg/day for 15 days). Group 2 (30 patients) had the same treatment but without doxycycline. After 12 weeks their periodontal condition was reevaluated. RESULTS: After treatment, both groups had a significant improvement in all periodontal parameters, since PI, BOP, probing pocket depth (PPD) and CAL were significantly reduced. However, the reduction in PD in pockets > or =6 mm and in BOP were more evident when doxycycline was used (group 1). Differences between groups for these parameters were statistically significant (p=0.03). CONCLUSION: Although both periodontal treatment regimens are effective in type 1 diabetics, the use of doxycycline as an adjunct, provided more significant results when good plaque control was achieved.     

The effect of periodontal treatment on metabolic control of type 1 diabetes mellitus

The objective of this investigation was to study the effect of nonsurgical periodontal treatment, with or without systemic administration of doxycycline, on the metabolic control of patients with type 1 diabetes. Sixty type 1 diabetic subjects with moderate to severe periodontitis were recruited. Periodontal parameters were measured, and blood samples were obtained to evaluate glycosylated hemoglobin (HbA1c). Group 1 (30 patients) was treated with scaling, root planning, and chlorhexidine rinses for 3 months in conjunction with systemic administration of doxycycline (100 mg once a day for 15 days). Group 2 (30 patients) received the same periodontal treatment but without the use of doxycycline. The paired Student t-test was used to detect differences between glycosylated hemoglobin means before and 3 months after periodontal treatment in group 1 and group 2 separately. Changes in mean HbA1c after treatment were 0.07% in group 1 and –0.06% in group 2, which were not statistically significant after 3 months. Significant changes were not found even in patients with the best response to periodontal treatment. Periodontal treatment in type 1 diabetic patients after 3 months follow-up did not improve metabolic control of diabetes as measured by glycosylated hemoglobin.

The effect of periodontal treatment on glycemic control in patients with type 2 diabetes mellitus

BACKGROUND, AIMS: This study was designed to explore the effect of periodontal therapy on glycemic control in persons with type 2 diabetes mellitus (DM). METHODS: 36 patients with type 2 DM (treatment group) received therapy for adult periodontitis during an 18-month period. A 36-person control group was randomly selected from the same population of persons with type 2 DM who did not receive periodontal treatment. RESULTS: These groups were well matched for most of the parameters investigated. During the nine-month observation period, there was a 6.7% improvement in glycemic control in the control group when compared to a 17.1% improvement in the treatment group, a statistically significant difference. Several parameters that could confound or moderate this glycemic control were explored. These included the treatment of non-dental infections, weight and medication changes. No moderating effect was associated with any of these variables. However, there were too few subjects in the study to have the statistical power necessary to assess these possible moderators of glycemic control. CONCLUSIONS: We interpret the data in the study to suggest that periodontal therapy was associated with improved glycemic control in persons with type 2 DM.     

牙周基础治疗对Ⅱ型糖尿病伴牙周炎病人糖基化终产物的影响

目的:观察牙周基础治疗对Ⅱ型糖尿病伴慢性牙周炎病人牙周组织和血清中糖基化终产物(advanced glycation end of products,AGEs)变化的长期影响。方法:诊断为Ⅱ型糖尿病并伴有中等程度以上牙周炎的病人30例,分为进行牙周基础治疗的干预组15例(DM1组),未进行牙周基础治疗的未干预组15例(DM2组);分别在初诊和每次复诊治疗前记录2组的探诊深度(probing depth,PD)、附着丧失(attachment loss,AL)、空腹血精、AGEs指标。结果:经牙周基础治疗后,DM1组牙周临床指标均有明显改善;2组AGEs水平有不同程度升高(P<0.05);DM1组第21个月AGFs水平显著低于DM2组,有统计学意义(P<0.05)。结论:牙周基础治疗对Ⅱ型糖尿病伴慢性牙周炎病人的PD、AL、血糖水平、AGEs水平有显著的改善(P<0.05),并且有助于长期稳定。     

Effects of diabetes mellitus on periodontal and peri-implant conditions: update on associations and risks

Objectives: To review the evidence for the association between diabetes and periodontal and peri-implant conditions and the impact of periodontal therapy in subjects with diabetes.
Material and Methods: A search of MEDLINE-PubMed was performed up to and including December 2007. The search was limited to clinical studies published in English. Publications on animal studies were excluded. The selection criteria included all levels of available evidence.
Results: Evidence on the association between diabetes and periodontitis supports the concept of increased severity but not extent of periodontitis in subjects with poorly controlled diabetes. Subjects with controlled diabetes do not show an increase in extent and severity of periodontitis. Periodontitis is associated with poor glycaemic control and diabetes-related complications. It is inconclusive that periodontal therapy with or without the use of antibiotics results in improvements of glycaemic control and of markers of systemic inflammation. Evidence is lacking to indicate that implant therapy in subjects with diabetes yields long-term outcomes comparable with those of non-diabetic subjects.
Conclusions: Poorly controlled diabetes may be considered a risk factor for increased severity of periodontitis. The effects of periodontal therapy on glycaemic control and systemic inflammation is not proven beyond doubt and need to be confirmed in large-scale randomized-controlled clinical trials.