联合应用甘精胰岛素和门冬胰岛素治疗儿童1型糖尿病疗效初步观察

目的:观察联合应用甘精胰岛素和门冬胰岛素治疗儿童1型糖尿病(type1diabetes mellitus,T1DM)的临床效果。方法:比较12例采用传统治疗方案(诺和灵30R,2/3量早餐前半小时皮下注射,1/3量晚餐前半小时皮下注射)的T1DM患儿,改用3+1治疗方案(3餐前0-15分钟诺和锐皮下注射,睡前来的时皮下注射)治疗后HbA1c水平、低血糖发生和胰岛素用量变化。结果:12例T1DM患儿改用3+1方案治疗时HbA1c基础值为9.51±0.71%,治疗后3个月时为9.12±0.82%,6个月时为8.61±0.87%、9个月时为8.71±0.68%、12个月时为8.65±0.79%。换用3+1方案治疗后第6、9、12个月时HbA1c值较基础值明显降低,差异有统计学意义(P<0.05)。每日胰岛素用量由1.1±0.8U/kg降至1.0±0.5U/kg,差异无统计学意义。传统方案治疗期间,6例次发生过严重低血糖,改用3+1治疗方案后,无1例发生严重低血糖。轻中度低血糖的发生次数由2.2±0.1次/周降至1.3±0.1次/周,差异有显著统计学意义(P<0.001)。结论:采用传统治疗方案治疗的T1DM患儿,改...     

双时相门冬胰岛素30联合艾塞那肽对血糖控制不佳2型糖尿病的疗效及安全性分析

目的:探讨双时相门冬胰岛素30联合艾塞那肽在口服降糖药物和基础胰岛素血糖控制不佳的2型糖尿病的疗效及安全性。方法:将在我院接受治疗的72例既往使用的口服降糖药联合基础胰岛素治疗血糖控制不佳的2型糖尿病患者随机、平行、开放平分成治疗组(BIAsp30+艾塞那肽治疗,早餐和晚餐前注射BIAsp30和艾塞那肽注射液)和对照组(睡前1次皮下注射甘精胰岛素),两组均与二甲双胍联合用药。比较两组治疗前后8点血糖谱;比较两组日胰岛素用量、BMI、HbA1c以及低血糖发生次数;比较两组不良事件。结果:治疗8周、16周后,两组8个点血糖与治疗前相比均有明显下降,差异有显著性(P0.05);治疗8周后、16周后,治疗组早餐前和早餐后2小时血糖、午餐前和午餐后2小时血糖值分别与对照组的血糖相比,有统计学差异(P0.05);两组之间的晚餐前和晚餐后2小时血糖、睡觉前血糖(晚上10点)和凌晨3点血糖相互比较无显著性差异(P0.05);治疗16周后,每天胰岛素类似物用量、BMI组间比较无统计学意义(P0.05);两组治疗后HbA1c分别与治疗前相比有统计学意义(P0.05),治疗组治疗后HbA1c与对照组治疗后HbA1c相比,差异有显著性(P0.05);两组低血糖发生次数有明显差异(P0.05);两组不良事件次数相互比较无统计学意义(P0.05)。结论:BIAsp30联合艾塞那肽可显著改善基础胰岛素联合OAD血糖控制不佳的2型糖尿病患者的血糖控制,有效控制血糖,并具有良好的安全性。     

甘精胰岛素联用瑞格列奈治疗初诊2型糖尿病的疗效研究

目的:通过甘精胰岛素联用瑞格列奈与预混人工合成胰岛素(诺和灵30R)治疗初诊2型糖尿病患者的比较,探讨其疗效与安全性.方法:将初诊2型糖尿病患者随机分为甘精胰岛素+瑞格列奈组(A组)和诺和灵30R组(B组),根据血糖情况调整用药剂量.治疗12周后,比较两组的空腹血糖、餐后2小时血糖、糖化血红蛋白(HbA1c)、体重指数(BMI)和低血糖发生率.结果:A组低血糖事件明显少于B组,在餐后2小时血糖方面也优于B组,差异有统计学意义(P<0.05);在空腹血糖、HbA1c和BMI方面差异无统计学意义(p0.05).结论:甘精胰岛素与瑞格列奈联用对于初诊2型糖尿病患者,其血糖控制满意,餐后血糖更加平稳,低血糖发生率低,是一种针对初诊2型糖尿病患者安全、有效、方便的治疗方案.     

诺和锐和诺和灵R在胰岛素泵应用比较

目的比较糖尿病患者应用超短效人胰岛素类似物诺和锐和短效人胰岛素诺和灵R在胰岛素泵持续皮下注射的疗效。方法将2005年1月~2007年1月住院的100例患者随机分为2组,观察组用诺和锐治疗,对照组用诺和灵R治疗,疗程均为2周。观察两组患者三餐前后血糖、凌晨血糖控制的情况,低血糖发生率等。结果观察组的三餐前的空腹血糖、三餐后的2 h血糖优于对照组,低血糖发生率明显低于对照组,在体重增加方面无显著性差异。结论诺和锐在胰岛素泵中的应用疗效优于诺和灵R。     

门冬胰岛素与人普通胰岛素及胰岛素泵在2 型糖尿病患者围手术期 的疗效比较

目的:探讨速效胰岛素类似物(门冬胰岛素,诺和锐)与人普通胰岛素(诺和灵R)及胰岛素泵在2型糖尿病(T2DM)围手术期治疗中的有效性和安全性。方法:158例围手术期T2DM患者随机分为胰岛素泵输注门冬胰岛素治疗CSII组52例,门冬胰岛素多次皮下注射治疗MSII(A)组56例,人普通胰岛素多次皮下注射治疗MSII(B)组50例。观察各组患者治疗前后空腹和餐后2h血糖变化、血糖达标时间、胰岛素用量、低血糖发生率及术后并发症发生率。结果:3组治疗后血糖均明显低于治疗前,CSII组治疗后血糖低于MSII(A)组(P<0.05),MSII(A)组治疗后血糖低于MSII(B)组(P<0.05);术后并发症CSII组低于MSII(A)组(P<0.05),MSII(A)组低于MSII(B)组(P<0.05)。结论:门冬胰岛素对T2DM围手术期血糖控制有较好的有效性、安全性和顺应性,胰岛素泵是2型糖尿病患者围手术期胰岛素输注的最佳模式。     

持续皮下胰岛素注射对2型糖尿病合并肺部感染患者的疗效分析

目的:分析持续皮下注射胰岛素对2型糖尿病(T2DM)合并肺部感染患者的临床疗效。方法:将我院2010年6月至2013年6月收治的86例2型糖尿病合并肺部感染患者随机分为2组,分别采用胰岛素泵持续皮下注射(治疗组)和多次皮下注射胰岛素(对照组),观察患者血糖指标、血糖达标时间、低血糖发生率及肺部感染治愈率情况。结果:治疗后,两组患者的血糖均得到控制,治疗组的血糖指标变化、血糖达标时间及住院时间均优于对照组,差异均有统计学意义(均P0.05)。治疗组的低血糖发生率明显低于对照组,而肺部感染治愈率显著高于对照组,差异均有统计学意义(均P0.05)。结论:胰岛素泵持续皮下胰岛素注射在治疗2型糖尿病合并肺部感染患者中使用,血糖达标迅速,降低低血糖发生率,缩短住院时间,提高感染治愈率,临床效果好。     

地特胰岛素与NPH胰岛素治疗口服降糖药控制不佳的2型糖尿病 临床比较研究

目的:观察口服降糖药控制不佳的2型糖尿病患者分别加用地特胰岛素和NPH胰岛素治疗24周的有效性和安全性。方法:63例口服降糖药物控制不佳(HbA1c>7%)的2型糖尿病患者随机加用地特胰岛素或鱼精蛋白锌(NPH)胰岛素作为基础胰岛素,每日1次治疗24周,比较两组治疗前后糖化血红蛋白、体重、血脂的变化及低血糖的发生率。结果:两组的糖化血红蛋白、空腹血糖与基线比较均有显著下降,治疗后组间无差异。与NPH胰岛素组比较地特胰岛素组体重增加明显减少,差异有统计学意义。地特胰岛素组治疗期间全部低血糖次数较NPH胰岛素组减少54.69%(P<0.01)。结论:地特胰岛素与NPH胰岛素相比,在有效控制血糖的同时可降低低血糖发生风险,而且有减少体重增加的优势。     

血糖水平对缺氧缺血新生大鼠体重和脑重的影响观察

目的　观察不同血糖水平及缺氧缺血 (hypoxicischemia ,HI)前后血糖对缺氧缺血新生大鼠体重和脑重的影响。方法　通过制备缺氧缺血新生大鼠合并高低血糖模型 ,分别在脑HI后 2、2 4、48、72h和 7d共 5个时段 ,分别在断头前测体重和断头后取脑称脑重 ,并辅以免疫组化分析HI后 2 4h时段各组脑内葡萄糖转运蛋白 1(GLUT1)及葡萄糖转运蛋白 3 (GLUT3 )合成量的变化。结果　 2 4h时段HI组、HI前低血糖组、HI后低血糖组体重呈显著意义 ,低于正常组 ;2 4h时段缺氧缺血前后低血糖脑重均呈显著意义 ,低于其他各组 ,7d时段I前重高血糖组脑重高于HI组及HI前低血糖组。HI前重高血糖组HI后 2 4h在皮质部位GLUT1的合成量显著高于其他各组。HI前低血糖组HI后 2 4h在皮质部位GLUT3的合成量显著低于其他各组。结论　HI前低血糖对新生大鼠体重、脑重增长不利 ,HI前重高血糖有可能缓解HI引起的体重、脑重的减轻而显示一定的保护作用     

老年糖尿病患者肠道菌群与糖化血红蛋白的关系CSCD

目的 研究老年2型糖尿病患者肠道菌群的变化,分析肠道菌群与糖化血红蛋白(HbA1c)的关系,为老年2型糖尿病患者血糖控制提供指导。方法 选择2019年1月至2020年1月我院169例老年2型糖尿病患者为研究对象,分为血糖控制良好组(67例,HbA1c<7.0%)及血糖控制不良组(102例,HbA1c≥7.0%),并选择同期83例健康老年志愿者为对照组,采用光冈法检测3组研究对象肠道菌群,分析肠道菌群变化与HbA1c关系。结果 对照组、血糖控制良好组以及血糖控制不良组对象肠道双歧杆菌、乳杆菌、拟杆菌数量依次降低,肠杆菌数量依次升高,任意组间差异均有统计学意义(均P<0.05);但肠球菌数量在3组间差异无统计学意义(均P>0.05)。2型糖尿病患者肠道双歧杆菌、乳杆菌数量与HbA1c水平呈负相关,相关系数分别为-0.431、-0.356,均有统计学意义(均P<0.05)。结论 2型糖尿病与肠道菌群紊乱相互影响,纠正肠道菌群紊乱对于2型糖尿病患者血糖控制有重要意义。     

GLP-1 受体激动剂联合门冬胰岛素30 对2 型糖尿病患者控糖效果及体重的影响

目的:探讨胰高血糖素样肽-1(GLP-1)受体激动剂联合门冬胰岛素30对2型糖尿病患者控糖效果及体重的影响。方法:选取116例2型糖尿病患者为研究对象,随机数字表法分成研究组(A组,n=58)和对照组(B组,n=58)两组。B组予以门冬胰岛素30治疗方案,A组则采用门冬胰岛素30联合利拉鲁肽治疗方案,均持续治疗24周后观察疗效。比对两组患者治疗前后控糖指标、脂质生化指标及体重指数(BMI)等变化情况,记录其甲级血糖控制率、血糖总控制率及低血糖发生率差异。结果:1治疗6个月后,两组患者除HDL-C水平较治疗前对比无统计学意义(P0.05)外,FBG、2 h PG、Hb A1c等控糖指标,TG、TC、LDL-C等脂质生化指标及BMI水平均较治疗前显著降低,其中A组降幅大于B组,差异具有统计学意义(P0.05);2A组甲级控制率及血糖总控制率分别为70.7%和100.0%,均显著高于B组的37.9%和93.1%(P0.05);3两组患者治疗期间均无严重不良反应及严重低血糖事件发生,其中A组轻微低血糖发生率为6.9%(4/58),显著低于B组的24.1%(14/58),差异具有统计学意义(P0.05)。结论:将门冬胰岛素30联合GLP-1受体激动剂方案应用于2型糖尿病患者的临床治疗中,疗效确切,血糖控制效果良好,能有效改善其血脂水平、抑制体重发展,于患者预后提升有利。     

Improvement of glucose tolerance in type 2 diabetic patients: traditional vs. modern insulin regimens (results from the Austrian Biaspart Study).

OBJECTIVE: Major advantages of modern insulin regimens containing premixed insulin analogues in comparison to traditional insulin regimens have not been evaluated yet. The aim of the present study was to investigate whether meal-related (breakfast, lunch, dinner) application of biphasic insulin aspart 30 (BIAsp 30) provides better glycaemic control than administration of biphasic human insulin 30 (BHI 30) twice per day. RESEARCH DESIGN AND METHODS: In a multi-centre, randomized, open-label parallel trial, a total of 177 patients with type 2 diabetes mellitus were exposed to the two different insulin regimens described above over a study period of 24 weeks. HbA1c and glycemic exposure parameters were measured at predefined intervals. RESULTS: The mean difference between treatment groups in HbA1c after 24 weeks of treatment was 0.08% (p = 0.6419). Analysing the 7-point blood-glucose (BG) profiles, significant differences in BG levels were observed after lunch (156 vs. 176 mg/dl, p = 0.0289), before dinner (142 vs. 166 mg/dl p = 0.006) and after dinner (154 vs. 182 mg/dl p = 0.002) in favour of BIAsp 30 insulin. Prandial BG increment was lower in the BIAsp 30 group at breakfast (p = 0.057) and lunch (p < 0.0005). No difference was found regarding safety parameters in the two treatment groups. CONCLUSIONS: This study demonstrates that meal-related BIAsp 30-insulin maintains postprandial BG control more effectively than traditional BHI 30 insulin twice per day in type 2 diabetic patients.     

Calibration of a subcutaneous amperometric glucose sensor implanted for 7 days in diabetic patients. Part 2. Superiority of the one-point calibration method

Calibration, i.e. the transformation in real time of the signal I(t) generated by the glucose sensor at time t into an estimation of glucose concentration G(t), represents a key issue for the development of a continuous glucose monitoring system. OBJECTIVE: To compare two calibration procedures. In the one-point calibration, which assumes that I(o) is negligible, S is simply determined as the ratio I/G, and G(t) = I(t)/S. The two-point calibration consists in the determination of a sensor sensitivity S and of a background current I(o) by plotting two values of the sensor signal versus the concomitant blood glucose concentrations. The subsequent estimation of G(t) is given by G(t) = (I(t)-I(o))/S. RESEARCH DESIGN AND METHODS: A glucose sensor was implanted in the abdominal subcutaneous tissue of nine type 1 diabetic patients during 3 (n = 2) and 7 days (n = 7). The one-point calibration was performed a posteriori either once per day before breakfast, or twice per day before breakfast and dinner, or three times per day before each meal. The two-point calibration was performed each morning during breakfast. RESULTS: The percentages of points present in zones A and B of the Clarke Error Grid were significantly higher when the system was calibrated using the one-point calibration. Use of two one-point calibrations per day before meals was virtually as accurate as three one-point calibrations. CONCLUSION: This study demonstrates the feasibility of a simple method for calibrating a continuous glucose monitoring system.     

Evaluation of the new software program DegifXL4 in the determination of the glycaemic indices of foodstuffs

Aims: There is no standardized protocol for measuring glycemic index (GI) that takes time-of-day effects into account. The software DegifXL2 and Medtronic-Minimed's CGMS and Solutions, makes the GI calculation at breakfast and dinner time possible. The aim of this study was to assess the enhanced data processing software (DegifXL4) enabling the GI calculation at breakfast, lunch, afternoon snack and dinner times. Methods: The glucose levels of 20 healthy volunteers were monitored after they consumed either 50 g of glucose or one of ten alternative foodstuffs either for breakfast and dinner or for lunch or snack. Within the 9-day test period, 10 such meals were monitored in 3 replicates for each volunteer. Specifically, CGMS was used to monitor plasma glucose levels at 5-minute intervals for a period of 120 min following the foodstuff ingestion. Results: Using the enhanced spreadsheed DegifXL 4, a total of 640 profiles were obtained and 491 (77 %) accomplished the criteria for further processing. The percentage of successful tests in each foodstuff varied from 57 to 87 %. Conclusions: The use of the new software DegifXL4 offers accurate GI estimates for foodstuffs eaten for breakfast, lunch, snacks and dinners in three replicates. In combination with the CGMS Solutions Software is DegifXL4 an enhanced efficient and comfortable way to routinely measure GI values.     

Relationship between diurnal glucose levels and HbA1c in type 2 diabetes.

AIMS AND METHODS: Study results still conflict on the contribution of diurnal blood glucose (BG) values to Hb (A1c) in type 2 diabetes. We investigated the relationship between Hb (A1c) and diurnal BG obtained under standardized conditions - before breakfast, two hours after breakfast, before lunch, two hours after lunch, before dinner, two hours after dinner, and at 10 PM, 12 midnight and 3 AM in 68 type 2 diabetic patients before and after optimizing glycemic control. The areas under the curve above fasting BG (AUC1) and above 5.6 mmol/l (AUC2) were calculated for further evaluation. Hb (A1c) was measured at baseline and after a mean of 89 (74 to 108) days. RESULTS: Each BG value at baseline and after treatment optimization significantly correlated with baseline and follow-up Hb (A1c), respectively. The pre-breakfast BG showed the closest correlation with Hb (A1c). The relative contribution of postprandial BG concentrations (AUC1) to overall hyperglycemia (AUC2) decreased with poorer glycemic control. However, treatment optimization mainly resulted in improved blood glucose values in patients with the poorest glycemic control at baseline. Multiple regression analysis demonstrated that fasting (AUC2-AUC1) and postprandial (AUC1) hyperglycemia independently determined Hb (A1c) or the change in Hb (A1c) after treatment optimization. CONCLUSIONS: Our findings indicate that intensive blood glucose monitoring during fasting and postprandial states is important for glycemic control, and is therefore an essential part of good clinical practice.     

24-Hour Glycemic Variations in Drug-Na?ve Patients with Type 2 Diabetes: A Continuous Glucose Monitoring (CGM)-Based Study

Objective

To investigate a 24-hour glycemic variation in drug-naïve, type 2 diabetic patients by using CGM.

Methods

A total of 30 inpatients with type 2 diabetes were included in the study to analyze the 24-hour CGM data.

Results

The patients’ median age was 58 years old (interquartile range: 42–66 years), and their median HbA1c value was 7.6 (6.7–8.8)%. The median time to postprandial peak glucose levels(Peak Time) for each meal was 70–85 minutes, with the range of postprandial glucose increases(Increase Range) for each meal being 83–109 mg/dL. There was a significant positive correlation between the HbA1c values and Increases Range, Peak Time observed after breakfast and dinner, respectively. When the patients were stratified by a median HbA1c value of 7.6% into 2 groups, Increases Range and Peak Time, after breakfast, were shown to be significantly higher in the high-HbA1c group (H) than in the low-HbA1c (L) group. When the subjects were divided into four groups according to HbA1c levels:1 (<7.0%, n = 8), 2 (7.0–7.9%, n = 8), 3 (8.0–8.9%, n = 8), and 4 (≥9%, n = 6), the average glucose level, pre-meal glucose level and postprandial peak glucose level increased steadily from group 1 to 4 in a stepwise manner.

Conclusions

In drug-naïve, Japanese type 2 diabetic patients, the Peak Time and the Increase Range were maximal after dinner. It was shown that the greater the HbA1c values, the longer Peak time and the higher Increase Range after breakfast and dinner. The average glucose level, pre meal glucose level and postprandial peak glucose level increased steadily as HbA1c level increased.     

Meal energy content is related to features of meal-related ghrelin profiles across a typical day of eating in non-obese premenopausal women.

Some features of the meal-related profile of ghrelin correspond to acute energy intake, suggesting a role in short-term energy homeostasis. Yet, no studies have examined this relationship across a typical day of eating when effects of time of day and or cumulative energy intake may also exist. AIM OF STUDY: To examine the relation between ghrelin and acute energy intake by quantifying changes in ghrelin over 24 hours in response to three typical meals and a snack occurring throughout the day. METHODS: Fourteen non-obese women consumed three meals and a snack at specific times; total ghrelin was measured repeatedly over 24 hours. RESULTS: Significant correlations existed between: 1) meal calories and the post-meal trough (r = - 0.36; p < 0.05), and 2) the sum of breakfast and lunch calories and subsequent dinner rise (r = - 0.45; p < 0.02) and 3) the sum of breakfast and lunch calories and dinner peak (r = - 0.54; p < 0.003). Thus, as energy intake increased across the day, pre-meal rises of subsequent meals were reduced. CONCLUSION: Meal-related profiles of ghrelin are not only associated with the energy content of specific meals, but also with the accumulated calories prior to a subsequent meal, suggesting a role in the modulation of acute energy homeostasis.     

A comparison of the effectiveness, tolerability and safety of high and low carbohydrate diets in women with gestational diabetes

INTRODUCTION: Nutrition therapy is an integral part of the management of gestational diabetes mellitus (GDM). Most women with GDM are treated by nutritional management alone. The goal of our study was to compare low and high carbohydrate diets in their effectiveness, safety and tolerability in women with GDM. MATERIAL AND METHODS: The study group consisted of 30 Caucasian women newly diagnosed with GDM, with a mean age of 28.7 +/- 3.7 years and pregnancy duration of 29.2 +/- 5.4 weeks. The patients were randomised into two groups: those on a low and those on a high carbohydrate diet (45% vs. 65% respectively of energy supply coming from carbohydrates). The presence of urine ketones was controlled every day. After two weeks daily glucose profiles and compliance with the recommended diets were analysed. RESULTS: Glucose concentration before implementation of the diet regimen did not differ between groups. No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet, although a significant decrease in glucose concentration was observed after breakfast (102 +/- 16 vs. 94 +/- 11 mg/dl), lunch (105 +/- 12 vs. 99 +/- 9 mg/dl) and dinner (112 +/- 16 vs. 103 +/- 13 mg/dl) (p < 0.05). In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change. A significant decrease in glycaemia was noticed after lunch (106 +/- 15 vs. 96 +/- 7 mg/dl) and dinner (107 +/- 12 vs. 97 +/- 7 mg/dl) (p < 0.05). Ketonuria was not observed in either group. Obstetrical outcomes did not differ between groups. CONCLUSIONS: Both high and low carbohydrate diets are effective and safe. A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast.     

Effects of Dinner Composition on Postprandial Macronutrient Oxidation in Prepubertal Girls

Objective: To see whether a fat‐rich (50%) evening meal promoted fat oxidation and a different spontaneous food intake on the following day at breakfast than a meal with a lower fat content (20%) in 10 prepubertal obese girls. Research Methods and Procedures: The postabsorptive and postprandial (10.5 hours) energy expenditure after a low‐fat (LF) (20% fat, 68% carbohydrate, 12% protein) and an isocaloric (2.1 MJ) and isoproteic high‐fat (HF; 50% fat, 38% carbohydrate, 12% protein) meal were measured by in direct calorimetry. Results: Fat oxidation was not significantly different after the two meals [LF, 31 ± 9 vs. HF, 35 ± 9 g/10.5 hours, p = not significant (NS)]. The girls oxidized 1.8 ± 0.9 times more fat than that ingested (11.1 grams) with the LF meal vs. 0.3 ± 0.3 times more fat than that ingested (27.1 grams) with the HF meal (p < 0.001). Carbohydrate oxidation was significantly higher after an LF than an HF meal (39 ± 12 vs. 29 ± 9 g/10.5 hours, p < 0, 05). At breakfast, the girls spontaneously ingested a similar amount of energy (1.5 ± 0.7 vs. 1.5 ± 0.6 MJ, p = NS) and macronutrient proportions (fat, 23% vs. 26%, p = NS; protein, 9% vs. 10%; carbohydrate, 68% vs. 64%,) independently of their having eaten an HF or an LF dinner. Discussion: An HF dinner did not stimulate fat oxidation, and no compensatory effect in spontaneous food intake was observed during breakfast the following morning. Cumulated total fat oxidation after dinner was higher than total fat ingested at dinner, but a much larger negative fat balance was observed after the LF meal. Spontaneous energy and nutrient intakes at breakfast were similar after LF and HF isocaloric, isoproteic dinners. This study points out the lack of sensitivity of short‐term fat balance to subsequently readjust fat intake and emphasizes the importance of an LF meal to avoid transient positive fat imbalance.