Effect Of Continuous Glucose Monitoring Research Articles

Real-Time Continuous Glucose Monitoring Significantly Reduces Severe Hypoglycemia in Hypoglycemia-Unaware Patients With Type 1 Diabetes

OBJECTIVETo evaluate the effect of continuous glucose monitoring (CGM) on the frequency of severe hypoglycemia (SH) in patients with established hypoglycemia unawareness.RESEARCH DESIGN AND METHODSWe conducted a retrospective audit of 35 patients with type 1 diabetes and problematic hypoglycemia unawareness, despite optimized medical therapy (continuous subcutaneous insulin infusion/multiple daily insulin injections), who used CGM for >1 year.RESULTSOver a 1-year follow-up period, the median rates of SH were reduced from 4.0 (interquartile range [IQR] 0.75–7.25) episodes/patient-year to 0.0 (0.0–1.25) episodes/patient-year (P < 0.001), and the mean (±SD) rates were reduced from 8.1 ± 13 to 0.6 ± 1.2 episodes/year (P = 0.005). HbA1c was reduced from 8.1 ± 1.2% to 7.6 ± 1.0% over the year (P = 0.005). The mean Gold score, measured in 19 patients, did not change: 5.1 ± 1.5 vs. 5.2 ± 1.9 (P = 0.67).CONCLUSIONSIn a specialist experienced insulin pump center, in carefully selected patients, CGM reduced SH while improving HbA1c but failed to restore hypoglycemia awareness.

Systematic Review of the Effects of Continuous Glucose Monitoring on Metabolic Control in Children and Adolescents with Type 1 Diabetes

Rigorous metabolic control helps delay long-term health complications in children with type 1 diabetes (T1D). Continuous subcutaneous insulin infusion (CSII) with continuous glucose monitoring (CGM) provides valuable information regarding blood glucose levels that is not available with self-monitoring of blood glucose (SMBG) alone. To critically appraise the research evidence on metabolic control in children diagnosed with T1D using CGM. Published studies evaluating metabolic control in children with T1D where CGM was used were evaluated. Electronic searches were conducted in MEDLINE, EMBASE, Health and Psychosocial Instruments, and Ovid Healthstar. The articles were reviewed and assessed for methodological quality. Of the 1427 published articles on CGM, only 18 met the inclusion criteria and were included in the analysis. The review yielded 9 randomized controlled trials (RCTs) and 9 non-randomized controlled trials. The studies included 1424 children and adolescents with T1D ranging in age from 1 to 19 years with a diabetes duration ranging from 0.2 to 15 years, with 75% of children using CSII for diabetes management. Improvements in HbA1c were found in only 6 studies, of which only 3 were significant improvements. The remaining 15 studies did not reveal significant improvements in HbA1c between groups (n=8) or between the first and second time point (n=7). There are the beginnings of an evidence base indicating that CGM may lead to improved metabolic control compared to SMBG alone in children with T1D. However, future studies using a more rigorous study design (RCT) are required to build on this evidence base.

5.2. Effectiveness of Continuous Glucose Monitoring and Fingerstick Blood Glucose Monitoring in Pregnancy Outcome of Gestational Diabetes (2692-PO)

The purpose of this study is to evaluate the blood glucose management effectiveness through glucose variability evaluation with two different glucose monitoring methods (Continuous Glucose Monitoring (CGM) and Fingerstick Blood Glucose Monitoring) on pregnancy outcomes of the Gestational Diabetes Mellitus (GDM) patients.

Systematic review and meta-analysis of the effectiveness of continuous glucose monitoring (CGM) on glucose control in diabetes

Diabetes mellitus is a chronic disease that necessitates continuing treatment and patient self-care education. Monitoring of blood glucose to near normal level without hypoglycemia becomes a challenge in the management of diabetes. Although self monitoring of blood glucose (SMBG) can provide daily monitoring of blood glucose level and help to adjust therapy, it cannot detect hypoglycemic unawareness and nocturnal hypoglycemia which occurred mostly in T1DM pediatrics. Continuous glucose monitoring (CGM) offers continuous glucose data every 5 minutes to adjust insulin therapy especially for T1DM patients and to monitor lifestyle intervention especially for T2DM patients by care providers or even patients themselves. The main objective of this study was to assess the effects of continuous glucose monitoring (CGM) on glycemic control in Type 1 diabetic pediatrics and Type 2 diabetic adults by collecting randomized controlled trials from MEDLINE (pubmed), SCOPUS, CINAHL, Web of Science and The Cochrane Library up to May 2013 and historical search through the reference lists of relevant articles. There are two types of CGM device: real-time CGM and retrospective CGM and both types of the device were included in the analysis. In T1DM pediatrics, CGM use was no more effective than SMBG in reducing HbA1c [mean difference – 0.13% (95% CI -0.38% to 0.11%,]. This effect was independent of HbA1c level at baseline. Subgroup analysis indicated that retrospective CGM was not superior to SMBG [mean difference -0.05% (95% CI -0.46% to 0.35%)]. In contrast, real-time CGM revealed better effect in lowering HbA1c level compared with SMBG [mean difference -0.18% (95% CI -0.35% to -0.02%, p = 0.02)]. In T2DM adults, significant reduction in HbA1c level was detected with CGM compared with SMBG [mean difference – 0.31% (95% CI -0.6% to -0.02%, p = 0.04)].This systematic review and meta-analysis suggested that real-time CGM can be more effective than SMBG in T1DM pediatrics, though retrospective CGM was not. CGM provided better glycemic control in T2DM adults compared with SMBG.

The role of continuous glucose monitoring in the care of children with type 1 diabetes

Continuous glucose monitoring (CGM), while a relatively new technology, has the potential to transform care for children with type 1 diabetes. Some, but not all studies, have shown that CGM can significantly improve hemoglobin A1c levels and reduce time spent in the hypoglycemic range in children, particularly when used as part of sensor-augmented pump (SAP) therapy. Despite the publication of recent clinical practice guidelines suggesting CGM be offered to all children 8 years of age or older who are likely to benefit, and studies showing that younger children can also benefit, this technology is not yet commonly used by children with type 1 diabetes. Effects of CGM are enhanced when used on a near-daily basis (a use-dependent effect) and with insulin pump therapy. Therefore, coordinated strategies are needed to help children and their families initiate and continue to use this resource for diabetes care. This review introduces CGM to pediatric endocrinologists who are not yet familiar with the finer details of this technology, summarizes current data showing the benefits and limitations of CGM use in children, reviews specific case examples demonstrating when CGM can be helpful, and shows the value of both retrospective and real-time CGM. It is hoped that this information leads to discussion of this technology in pediatric endocrinology clinics as an important next step in improving the care of children with type 1 diabetes.

Effectiveness of continuous glucose monitoring during diabetic pregnancy (GlucoMOMS trial); a randomised controlled trial

BackgroundHyperglycemia in pregnancy is associated with poor perinatal outcome. Even if pregnant women with diabetes are monitored according to current guidelines, they do much worse than their normoglycaemic counterparts, marked by increased risks of pre-eclampsia, macrosomia, and caesarean section amongst others. Continuous Glucose Monitoring (CGM) is a new method providing detailed information on daily fluctuations, used to optimize glucose control. Whether this tool improves pregnancy outcome remains unclear. In the present protocol, we aim to assess the effect of CGM use in diabetic pregnancies on pregnancy outcome.Methods/designThe GlucoMOMS trial is a multicenter open label randomized clinical trial with a decision and cost-effectiveness study alongside. Pregnant women aged 18 and over with either diabetes mellitus type 1 or 2 on insulin therapy or with gestational diabetes requiring insulin therapy before 30 weeks of gestation will be asked to participate. Consenting women will be randomly allocated to either usual care or complementary CGM. All women will determine their glycaemic control by self-monitoring of blood glucose levels and HbA1c. In addition, women allocated to CGM will use it for 5–7 days every six weeks. Based on their CGM profiles they receive dietary advice and insulin therapy adjustments if necessary. The primary outcome measure is rate of macrosomia, defined as a birth weight above the 90th centile. Secondary outcome measures will be birth weight, composite neonatal morbidity, maternal outcome and costs. The analyses will be according to the intention to treat principle.DiscussionWith this trial we aim at clarifying whether the CGM improves pregnancy outcome when used during diabetic pregnancies.Trial registrationNederlands Trial Register: NTR2996

Systematic Review of the Effects of Continuous Glucose Monitoring on Metabolic Control in Children with Type 1 Diabetes

Systematic Review of the Effects of Continuous Glucose Monitoring on Metabolic Control in Children with Type 1 Diabetes

Psychosocial Factors and Adherence to Continuous Glucose Monitoring in Type 1 Diabetes

Several studies have demonstrated beneficial effects of continuous glucose monitoring (CGM) in patients with type 1 diabetes mellitus (T1DM).1–3 In most of the studies, however, a subgroup of patients uses CGM less than recommended or discontinues use. To facilitate treatment adherence in this patient group, thorough understanding of motives for CGM termination is a prerequisite, but only little is known about mechanisms underlying patient adherence to CGM.4–6 Psychosocial factors may affect CGM use because of the constant efforts required of the user to benefit from CGM. To pursue this hypothesis, we invited 24 adults with T1DM from our clinic to take part in a focus group study. Twenty-five ± four months previously, patients had participated in the multicenter Eurythmics Trial2 and started using sensor-augmented pumps (SAPs) during (intervention group) or immediately after completion of the trial (control group). Sensor-augmented pump costs were covered by the Danish health care system. Sixteen patients agreed to participate in the focus group study (Table 1). Twelve were still using SAPs, while four had chosen to cease CGM and continue insulin pump treatment only. Three focus groups were formed based on self-reported CGM use: two groups of current CGM users (six persons in each) and one group of former CGM users (four persons). “CGM use” was defined as sensor use >60% of the time in the past three months. Table 1 Patient Characteristicsa The most notable observation during the focus group sessions was that personal ambitions for metabolic control clearly differed between former and current CGM users. Patients who had discontinued CGM utilization were aware that they could have better metabolic control using CGM; nevertheless, they chose not to. A former user stated: “I know that the sensor improves my hemoglobin A1c (HbA1c)… Intellectually I know that I should wear it. Why don’t I? Now that’s a good question.” Conversely, none of the current users were willing to stop CGM at the expense of a rise in HbA1c. “I want to live a little longer, and I want to be free of all the late complications, so in that respect I don’t think that I have much to negotiate with,” a current CGM user said. All participants praised the glucose curve on the pump display and the arrows indicating rises and falls, but a major complaint coming from both current and former SAP users was CGM inaccuracy. The expression “false security” was used, and two SAP users stated: “I don’t trust it 100% any longer.” “Neither do I. I use it mostly as a guideline.” Continuous glucose monitoring alarms were also vigorously discussed. In particular, alarms caused by inaccurate sensor readings were considered irrelevant interruptions, but also hypo- and hyperalarms that continued after the blood glucose had been corrected due to the inherent time lag of the sensor. Interestingly, former and current users reported different ways of coping with CGM alarms, and the current users seemed less disturbed by alarms. A SAP user explained: “I mute it. You can still follow [the glucose curve] on the display.” In contrast, a former user said: “These nightly alarms…I think you can turn them off, but I never figured out how.” A third important point was that body image played a crucial role for patients in all groups, and to some, it was the most limiting factor of CGM use. Based on this focus group study, we propose that pre-CGM counseling focusing on patient motivation, alarm coping strategies, and body image may increase CGM adherence.

Effect on Glycemic Control by Short- and Long-Term Use of Continuous Glucose Monitoring in Clinical Practice

In Sweden, patients with diabetes mellitus frequently receive short-term (<3 months) continuous glucose monitoring (CGM) to study glucose patterns or long-term CGM to treat poor glycemic control or severe hypoglycemia. The effects of CGM on glycemic control in clinical practice in relation to indication and duration of use has not been completely studied. Patients with diabetes, among which 99% were diagnosed as type 1, receiving CGM at 10 outpatient clinics in Sweden were studied retrospectively. Long-term use of CGM was defined as ≥ 3 months use of CGM and short-term as <3 months. A control group matched on start date and date of latest value 3 months after the start was selected for both long- and short-term groups. In 34 long-term users of CGM, over a mean follow-up of 1.1 years, the adjusted mean difference of hemoglobin A1c (HbA1c) compared with controls (n = 408) was -0.76 (95% confidence interval -1.17; -0.33, p < .001). Long-term users with indications for high HbA1c (n = 15) had a reduction of 1.2% in HbA1c from 10.1 to 8.9% (p = .003), whereas patients with hypoglycemia as their indication (n = 16) decreased by 0.3% (p = .17). Nonsevere hypoglycemic events decreased in long-term users within the same follow-up period (p = .004). Short-term users showed no statistically significant improvement in HbA1c compared with controls at 1.1 years (n = 41), p = .85 or at 2.6 years (n = 43), p = .19. Long-term CGM use was associated with improved glycemic control in clinical practice and a reduction in nonsevere hypoglycemic events, whereas short-term use had no effect on HbA1c. The effect on glycemic control varied by indication.

Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data

Objective To determine the clinical effectiveness of real time continuous glucose monitoring compared with self monitoring of blood glucose in type 1 diabetes.Design Meta-analysis of randomised controlled trials.Data sources Cochrane...

Effect of Continuous Glucose Monitoring on Hypoglycemia in Type 1 Diabetes

OBJECTIVETo assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes.RESEARCH DESIGN AND METHODSIn this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A1c (HbA1c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients.RESULTSThe time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference −0.27%; 95% CI −0.47 to −0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009).CONCLUSIONSContinuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA1c in children and adults with type 1 diabetes.

Continuous glucose monitoring reduces both hypoglycaemia and HbA 1c in hypoglycaemia-prone type 1 diabetic patients treated with a portable pump

Aim This study aimed to assess the effectiveness of continuous glucose monitoring (CGM) for glucose control in type 1 diabetic patients treated by continuous subcutaneous insulin infusion (CSII) and presenting with frequent hypoglycaemic episodes. Methods Thirteen patients with type 1 diabetes (diabetes duration: 25 ± 15 years; CSII duration: 5.5 ± 7.0 years), with more than six recorded capillary blood glucose (CBG) values < 60 mg/dL, according to their metres for the past 14 days, were offered the permanent use of a CGM device (Guardian RT ®, Medtronic) plus ongoing self-monitoring of blood glucose (SMBG) for 12 weeks, followed by a 12-week crossover period of SMBG only, or vice versa. Glucose control, determined by recorded 14-day CBG values < 60 mg/dL and HbA 1c levels, and quality of life according to the Diabetes Quality of Life (DQOL) questionnaire, were assessed at baseline, and after 12- and 24-week follow-ups. Results Four patients withdrew from the study during the first period (of whom three were using CGM). In the nine study completers, the number of low CBG values decreased significantly from 13.9 ± 9.2 to 7.6 ± 6.8 ( P = 0.011) when patients used CGM, in either the initial or final trial period, while a decrease in HbA 1c from 8.3 ± 0.7 to 7.7 ± 0.6% ( P = 0.049) was also observed, in contrast to the absence of any significant differences during the SMBG-only period. DQOL scores were also essentially unaffected. Conclusion This pilot observational study supports the hypothesis that CGM use can significantly improve overall glucose control while reducing hypoglycaemic episodes in hypoglycaemia-prone type 1 diabetic patients treated by CSII.

Effectiveness of Continuous Glucose Monitoring in a Clinical Care Environment

OBJECTIVETo determine whether continuous glucose monitoring (CGM) is effective in the management of type 1 diabetes when implemented in a manner that more closely approximates clinical practice.RESEARCH DESIGN AND METHODSAfter completion of a 6-month randomized controlled trial (RCT) evaluating CGM in children, adolescents, and adults with type 1 diabetes, CGM was initiated in the trial's control group with less intensive training and follow-up than was included in the RCT. Subjects had an outpatient training session, two follow-up phone calls, and outpatient visits at 1, 4, 13, and 26 weeks. For subjects with baseline A1C ≥7.0%, the primary outcome was change in A1C at 6 months.RESULTSCGM use decreased from a median of 7.0 days/week in the first month in the ≥25-year-old group, 6.3 days/week in the 15–24 year olds, and 6.8 days/week in the 8–14 year olds to 6.5, 3.3, and 3.7 days/week in the 6th month, respectively (P < 0.001 for each age-group). Among subjects with baseline A1C ≥7.0%, CGM use was associated with A1C reduction after 6 months (P = 0.02 adjusted for age-group). Severe hypoglycemia decreased from 27.7 events per 100 person-years in the 6-month control phase of the RCT to 15.0 events per 100 person-years in the 6-month follow-up CGM phase (P = 0.08).CONCLUSIONSFrequent use of CGM in a clinical care setting may improve A1C and reduce episodes of hypoglycemia. However, sustained frequent use of CGM is less likely in children and adolescents than in adults.

Sustained Benefit of Continuous Glucose Monitoring on A1C, Glucose Profiles, and Hypoglycemia in Adults With Type 1 Diabetes

OBJECTIVETo evaluate long-term effects of continuous glucose monitoring (CGM) in intensively treated adults with type 1 diabetes.RESEARCH DESIGN AND METHODSWe studied 83 of 86 individuals ≥25 years of age with type 1 diabetes who used CGM as part of a 6-month randomized clinical trial in a subsequent 6-month extension study.RESULTSAfter 12 months, median CGM use was 6.8 days per week. Mean change in A1C level from baseline to 12 months was −0.4 ± 0.6% (P < 0.001) in subjects with baseline A1C ≥7.0%. A1C remained stable at 6.4% in those with baseline A1C <7.0%. The incidence rate of severe hypoglycemia was 21.8 and 7.1 events per 100 person-years in the first and last 6 months, respectively. Time per day with glucose levels in the range of 71–180 mg/dl increased significantly (P = 0.02) from baseline to 12 months.CONCLUSIONSIn intensively treated adults with type 1 diabetes, CGM use and benefit can be sustained for 12 months.

The Effect of Continuous Glucose Monitoring in Well-Controlled Type 1 Diabetes

OBJECTIVEThe potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined.RESEARCH DESIGN AND METHODSA total of 129 adults and children with intensively treated type 1 diabetes (age range 8–69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level ≤70 mg/dl, A1C level, and severe hypoglycemic events.RESULTSAt 26 weeks, biochemical hypoglycemia (≤70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant (P = 0.16). Median time with a glucose level ≤60 mg/dl was 18 versus 35 min/day, respectively (P = 0.05). Time out of range (≤70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline (P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively (P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group (P < 0.001, 0.007, 0.005, and 0.003).CONCLUSIONSMost outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%.

Short-Term Effects on Patient Satisfaction of Continuous Glucose Monitoring with the GlucoDay with Real-Time and Retrospective Access to Glucose Values: A Crossover Study

This randomized crossover trial examines the effect of continuous glucose monitoring (CGM) with real-time access (RTA) to glucose data versus CGM with a retrospective analysis (RA) of glucose data regarding satisfaction with CGM and other patient-reported outcomes. Participants used the CGM device (GlucoDay, Menarini Diagnostics, Florence, Italy) twice. In one study phase, patients were allowed RTA to, and in the other phase RA of, current glucose values. The order of these two conditions was randomized. At baseline and after the first and second trials, subjects completed questionnaires (Continuous Glucose Monitoring Satisfaction Scale) about perceived satisfaction with CGM. They also completed the Problem Areas in Diabetes Questionnaire, a state anxiety scale (State-Trait Anxiety Inventory), and a depression scale (Center of Epidemiological Studies-Depression Scale). Fifty patients with type 1 diabetes (41.7 +/- 12.3 years old, diabetes duration of 14.75 +/- 11.9 years, 48% female, hemoglobin A1c 8.1 +/- 1.5%, years of education 10.3 +/- 2.1 years) participated in this study. At baseline patients perceived CGM as rather advantageous, but after RA and RTA the perceived benefits were reduced (baseline, 101.0 +/- 16.0; RA, 95.7 +/- 20.2; RTA, 93.6 +/- 22.8; P < 0.01). However, there was no significant difference between RA and RTA. Also, there was no significant effect on diabetes-related distress or state anxiety, but a positive effect on depression scores. There was no specific, significant, negative or positive effect of RA versus RTA on satisfaction with CGM. Exposing patients with type 1 diabetes to their current glucose values does not seem to have a specific negative impact on the appraisal of CGM or more generic patient-reported outcomes.

Effectiveness of Continuous Glucose Monitoring in Pregnant Women With Diabetes: Randomized Clinical Trial

Near optimal control of glucose levels during early pregnancy has not reduced the risk of macrosomia among infants of women with type 1 or 2 diabetes. Observational data suggest a strong correlation in the third trimester between maternal postprandial glucose levels and increased risk of macrosomia. The effectiveness of long-term glycemic control in reducing diabetes related morbidity in pregnant women is unclear. This prospective, open label randomized controlled trial evaluated the effectiveness of antenatal continuous glucose monitoring on maternal glycemic control and risk of macrosomia in patients with type 1 and 2 diabetes at 2 diabetic antenatal clinics between 2003 and 2006. A total of 71 pregnant women aged 16 to 45 with type 1 (n = 46) or type 2 diabetes (n = 25) were allocated to either antenatal care using intermittent monitoring of capillary blood glucose supplemented with continuous glucose monitoring (n = 38) or to standard antenatal care using intermittent self monitoring of glucose levels (n = 33). Continuous glucose monitoring was provided for up to 7 days at intervals of 4 to 6 weeks from 8 to 32 weeks of gestation. There were no other differences in antenatal care of the 2 study groups. Compared with women randomized to standard antenatal care (control group), women randomized to continuous glucose monitoring (intervention group) had lower mean HbAlc levels at 32 to 36 weeks' gestation: 6.4% (SD, 0.7) versus 5.8% (SD, 0.6), respectively, P = 0.007. The mean birth weight standard deviation scores of singletons of women in the intervention group were lower than those of healthy singletons of women in the control group (0.9 vs. 1.6; effect size 0.7 SD, 95% confidence interval [CI], 0.0-1.3; P = 0.05). The median birth weight centiles were significantly lower: 69% in the intervention group compared with 93% in the control group (P = 0.02). Thirty-five percent of the infants in the intervention group were macrosomic compared to 60% in the control group (odds ratio, 0.36; 95% CI, 0.13-0.98; P = 0.05). These findings suggest that supplementary continuous glucose monitoring during routine antenatal care can improve glycemic control in pregnant women with diabetes and reduce the risk of macrosomia among their infants.

Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial

Objective To evaluate the effectiveness of continuous glucose monitoring during pregnancy on maternal glycaemic control, infant birth weight, and risk of macrosomia in women with type 1 and type 2...