Evidence of the Benefits of Weight Loss

Introduction

There is a large and expanding body of evidence for the many benefits of intentional weight loss in individuals with overweight/obesity. While it is well known that there are significant improvements in patients both at risk for and who suffer from Type 2 Diabetes (T2D), the benefits of weight loss extend beyond to include improvements in hypertension, dyslipidemia, metabolic syndrome and obstructive sleep apnea (OSA), as well as improvements in both mood and functional status.

To date, the largest body of data on the benefits of intentional weight loss has come from two long-term prospective, multicenter, randomized studies that compared the effects of intensive lifestyle intervention (ILI) to usual clinical care in two different populations. The Diabetes Prevention Program (DPP) was performed in individuals with overweight/obesity who were at high risk for T2D, while the participants in the Look AHEAD (Action for Health in Diabetes) study had previously been diagnosed with T2D.

DPP AND DPPOS

Objectives and Design

The DPP study was a multicenter, prospective, randomized clinical trial in 3,234 adults in the United States who were at high risk for the development of T2D. The primary objective was to assess whether an ILI or treatment with metformin could prevent or delay the onset of diabetes compared with standard lifestyle recommendations (e.g., diabetes support and education [DSE]) in US adults at high risk for diabetes.

The primary outcome was development of T2D diagnosed on the basis of an annual oral glucose-tolerance test or a semiannual fasting plasma glucose test. Metformin treatment was initiated at a dose of 850 mg once daily in one of the treatment groups, with placebo tablets also given once a day in the control group. At 1 month in the metformin group, the dose of metformin was increased to 850 mg twice daily.

The goals for the participants randomized to the ILI were to achieve and maintain a weight reduction of at least 7% of initial body weight through a healthy low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week. A 16-lesson curriculum covering diet, exercise and behavior modification was taught by case managers on a one-to-one basis during the first 24 weeks and continued on a flexible schedule thereafter. Masked treatment was discontinued when the DPP study demonstrated that ILI reduced the incidence of diabetes by 58% and metformin by 31% compared with the DSE control group during an average duration for all participants of 2.8 years in the DPP.

The long-term persistence of the results of the DPP study is being assessed in the ongoing Diabetes Prevention Program Outcomes Study (DPPOS). All active DPP participants were eligible for continued follow-up, of whom 2,766 (88%) enrolled for a median additional follow-up of 5.7 years. After this, there was a 13-month “bridge period” before implementation of the DPPOS protocol. During this bridge period, those in the metformin and DSE groups entered into a 1- to 2-week drug washout. After treatments were unmasked, the DSE intervention was stopped. All participants, including those in the original ILI group and those who had developed diabetes, were offered a group-administered version of the 16-session lifestyle curriculum followed by lifestyle sessions every 3 months, with provision of educational materials to reinforce the original weight loss and physical activity goals. All participants are followed in their original groups with their clinical care provided by practitioners outside of the study.

Prevention/Delay of Diabetes

The primary objective of the DPP and DPPOS trials was to assess whether an ILI or treatment with metformin could prevent or delay the onset of diabetes compared with standard lifestyle recommendations. After mean follow-up of 2.8 years, the cumulative incidence of diabetes was lower in the metformin and ILI groups than in the DSE group. The crude incidences of diabetes were 11.0, 7.8 and 4.8 cases per 100 person-years in the DSE, metformin, and ILI groups, respectively (Figure 4-1), and the estimated cumulative incidences of diabetes in the DSE, metformin and ILI were 28.9%, 21.7 % and 14.4%, respectively.

These results translate into a risk reduction of 58% with ILI and by 31% with metformin compared with DSE. Given these results, the estimated numbers of persons who would need to be treated for 3 years to prevent one case of diabetes during this period were 6.9 with ILI and 13.9 with metformin. Of particular interest is that these reductions in the cumulative incidences of diabetes were accomplished with only moderate degrees of weight loss namely 0.1 kg, 2.1 kg and 5.6 kg in the DSE, metformin and ILI groups, respectively.

During a 10-year mean follow-up in the DPPOS study, the ILI group initially lost the most weight (mean of 7 kg by 1 year) but gradually regained it, although they still weighed about 2 kg less than they did at DPP randomization. The metformin group lost a mean of 2.5 kg during DPP and maintained most of that weight loss. The mean weight loss in the DSE group was <1 kg from DPP randomization. The ILI group subsequently regained about 1 kg, whereas the metformin and DSE groups initially lost and then regained weight back to their respective levels at DPPOS baseline. Beyond 10 years following randomization, a slight weight loss trend emerged in all three groups. Fifteen years after randomization, patients from the placebo group had a mean weight loss of 2.32 kg, compared to 3.48 kg in the metformin group and 3.23 kg in the ILI group.

Diabetes incidence during DPPOS did not differ significantly between the three initial randomized groups. However, this finding was not attributable to a rebound effect in the ILI group but rather to a decrease in diabetes incidence in the placebo and metformin groups that resulted in similar rates as achieved by lifestyle intervention, which changed little throughout 10 years of follow-up (Table 4-1). Therefore, 10 years after DPP randomization, the cumulative incidence of diabetes remained lower in the ILI and metformin groups than in the diabetes support and education (DSE) group, despite changes in treatments after a mean of 3.2 years. Fifteen years after randomization, the cumulative incidence of diabetes was 28% lower in the ILI group and 18% lower in the metformin group, compared to the placebo (P<0.0001 and P = 0.001, respectively). The cumulative incidence of diabetes during DPP and DPPOS is shown in Figure 4-2.

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Reduction in Cardiovascular Risk Factors

In the original DPP cohort, 30% had hypertension, 29% had hypertriglyceridemia and 44% had hypercholesterolemia at baseline. Annual assessments showed progressive increases in the prevalence of hypertension and dyslipidemia in the DSE and metformin groups compared with a decrease in the ILI group by year 3. Triglyceride levels fell in all treatment groups but fell significantly more with ILI. Total cholesterol and LDL cholesterol levels were similar among treatment groups. ILI significantly increased the HDL cholesterol level compared with the other interventions. After 3 years of follow-up, the use of medications to achieve pre-established treatment goals in the ILI group was reduced (by 27% to 28% for antihypertensive agents and 25% for lipid-lowering medications) compared with DSE and metformin groups.

The DPPOS study is providing additional follow-up of the randomized DPP study population, thereby allowing an assessment of the durability of the beneficial effect of ILI and DSE interventions and metformin treatment on CV risk factors. After unmasking of treatment and a brief bridge period, all groups received a lifestyle intervention. Also, metformin was continued (unless terminated by the care provider) in participants who were in the original metformin arm. After 10 years of follow-up from the DPP baseline, there were reductions in SBP (-2 to -3 mm Hg) and DBP (-6 to -6.5 mm Hg), as well as in LDL cholesterol (-0.51 to -0.6 mmol/L) and triglycerides (-0.23 to -0.25 mmol/L) in all groups, with no between-group differences (Figure 4-3). In addition, HDL cholesterol levels rose significantly (0.14 to 0.15 mmol/L) in all groups. Analysis of medication use found reductions in the overall use of lipid-lowering (P = 0.01) and antihypertensive (P = 0.09) medications throughout the follow-up period, however, their use was lower in the original ILI group during DPPOS. At 15-years of follow-up, there was no difference between the three treatment groups as a whole in the prevalence of the aggregate microvascular outcome (nephropathy, neuropathy and retinopathy; 11-13%). Interestingly, among women, ILI did result in a lower prevalence of the aggregate microvascular outcome (8.7%) than either metformin treatment (11.2%; P = 0.02) or placebo (11%; P = 0.03), but the mechanistic basis of this difference is not understood. 

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Incidence and Resolution of Metabolic Syndrome

The metabolic syndrome is “a complex cluster of interrelated risk factors for CV disease and diabetes which occur together more often than by chance alone.” Three abnormal findings out of the five listed in Table 4-2 would support a diagnosis of metabolic syndrome. The presence of the metabolic syndrome is a clinically useful indicator of high morbidity and mortality risk. Patients with the metabolic syndrome are at twice the risk of developing CVD over the subsequent 5 to 10 years as those without the syndrome. In addition, the metabolic syndrome confers a 5-fold increase in the risk of developing T2D.

At baseline in the DPP study, 53% of randomized patents had the metabolic syndrome defined as having three or more characteristics (increased waist circumference; elevated BP; low HDL, elevated triglycerides and elevated fasting plasma glucose) that met criteria from the National Cholesterol Education Program Adult Treatment Panel III.

By year 3, the prevalence of metabolic syndrome among all study participants increased from 55% at baseline to 61% after 3 years in the DES group (P = 0.003) and from 54% to 55% in the metformin group (P >0.2). In the ILI group, overall prevalence decreased from 51% to 43% (P <0.001). Among individuals without metabolic syndrome at baseline, 53% of those in the DSE group had acquired the metabolic syndrome by year 3 compared with 47% in the metformin group and 38% in the ILI group. Thus, the ILI results in reduction of 41% in incidence of the metabolic syndrome compared with DSE and a significant 29% reduction compared with metformin (P <0.001), which itself yielded a 17% lower incidence than DSE (P = 0.03).

Among the individuals with the metabolic syndrome at baseline, the differences by treatment group were less striking; however, the prevalence at 3 years did vary significantly by treatment group (P <0.001): 18% of the DSE group, 23% of the metformin group, and 38% of the ILI group no longer had the syndrome.

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Look AHEAD

Objectives and Design

The Look AHEAD study was a prospective, multicenter, randomized, controlled trial designed to determine whether intentional weight loss reduces CV morbidity and mortality in individuals with overweight and T2D. The primary objective was to assess the long-term effects (up to 11.5 years) of an intensive weight loss program delivered over 4 years in individuals with overweight or obesity and T2D. The primary study outcome was time to incidence of a major CV event. Other outcomes included components of CVD risk, cost and cost-effectiveness, diabetes control and complications, hospitalizations, intervention processes and quality of life.

Participants were randomly assigned to one of two intervention groups: an ILI designed to achieve and maintain weight loss through decreased caloric intake and increased physical activity, or to enhanced usual care (ie, DSE). The two principal goals of the ILIs were to induce a mean loss ≥7% of initial weight and to increase participants’ moderately-intense physical activity to ≥175 minutes a week. A total of 5145 US individuals with overweight/obesity and with T2D were randomized to ILIs (n = 2570) or DSE (n = 2575). Overall, 59% of the participants were women; 37% were from racial or ethnic minorities; 14% reported a history of CVD at baseline, their average age was 58.7 and their average BMI was 36.

Reduction in Cardiovascular Events and Risk Factors

Although Look AHEAD did not achieve its primary efficacy outcome, i.e., improvement in the time to incidence of a major CV event, it did demonstrate benefits in components of CVD risk.

After 1 year, patients in the ILI group lost an average 8.6% of their initial weight compared with 0.7% in the DSE group (P <0.001). Fitness, assessed by submaximal exercise test to determine ≥80% of age-predicted maximal heart rate, increased by 20.9% in the ILI group compared with 5.8% in the DSE group (P <0.001). A greater proportion of ILI patients experienced reductions in the incidence of diabetes, hypertension and the use of lipid-lowering drugs. Mean A1C decreased from 7.3% to 6.6% with ILI (P <0.001) vs from 7.3% to 7.2% with DES. In addition, there were significantly greater improvements in SBP and DBP, triglycerides and HDL cholesterol among ILI-treated patients than among DSE-treated patients (all P <0.01).

Averaged over 4 years, patients in the ILI group had significantly greater improvements in weight, fitness, glycemic control, SBP and levels of HDL cholesterol and triglycerides than those in the DSE group (Table 4-3). There was no significant difference in DBP. Although the DSE group experienced greater overall reductions in LDL cholesterol levels, changes in LDL cholesterol levels did not differ between the groups after adjusting for use of lipid-lowering medications.

Changes in weight and risk factors at each of the 4 years are shown in Figure 4-4. The ILI group experienced significantly greater weight losses than the DSE group at each year. The maximal weight loss (8.6%) in the ILI group occurred at year 1 and the mean weight loss by year 4 was 4.7% compared with 1.1% in the DSE group (P <0.001). For several risk factors, the between group differences were most apparent at year 1. At each of the 4 years, the ILI group continued to have greater improvements in SBP and in A1C and HDL cholesterol levels. Among patients who were using antihypertensive to antihyperglycemic medications at baseline, a greater proportion of patients in the ILI group than the DSE group discontinued use of these medications.

Conversely, among those not using these medications at baseline, fewer patients in the ILI group initiated the use of these agents. However, the percentage of patients using lipid-lowering medications almost doubled during the 4 years, with greater initiation in the DSE than in the ILI group. The ADA goals for A1C and BP were met by a significantly greater proportion of patients in the ILI group compared with the DSE group at years 1, 2 and 3. The percentage of patients achieving the ADA goals for LDL cholesterol level did not differ until year 4, when 64.5% of DSE patients compared with 61.0% of ILI patients (P = 0.01) met this goal.

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Remission of Diabetes

An ancillary analysis of the 4-year Look AHEAD study results examined the association of long-term ILI with the frequency of remissions from T2D defined as transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (fasting plasma glucose <126 mg/dL and A1C <6.5% with no antihyperglycemic medication).

The results showed that the ILI group was significantly more likely to experience a partial or complete remission with prevalences of 11.5% during the first year and 7.3% at year 4 compared with 2.0% for the DSE group at both time points (P <0.001 for each) (Figure 4-5). In the ILI group, 9.2%, 6.4% and 3.5% of participants experienced continuous, sustained remission for at least 2, at least 3 and 4 years, respectively, compared with <2% of patients in the DSE group at the same time points.

Although the prevalence of complete remission was more common in the ILI group than in the DSE group across all years of the study (prevalence ratio, 6.6; P <0.001), the absolute prevalence of complete remission was low, ranging from 1.3% with or ILI vs 0.1% with DSE (P <0.001) in year 1 to 0.7% with ILI vs 0.2% with DSE at year 4.

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Magnitude of Weight Loss and Clinical Benefits

Individuals with overweight and obesity are frequently encouraged to lose 5% to 10% of their weight and are told that weight losses of that magnitude will help improve their CVD risk factors. The Look AHEAD study provided the opportunity to assess the effects of various magnitudes of weight loss on improvements in CVD risk factors.

An observational analysis of data from the Look AHEAD study examined the association between the magnitude of weight loss and changes in CVD risk factors at 1 year and the odds of meeting predefined criteria for clinically significant improvements in risk factors in individuals with T2D.

After 1 year, patients were divided into the following categories based on their weight changes from baseline to 1 year: gained >2%; remained weight stable (±2%); lost ≥2% to 5%; lost ≥5% to 10%; lost ≥10% to 15%; or lost ≥15%. There was a strong graded association for changes in glucose, A1C, SBP, DBP, triglycerides and HDL cholesterol (all P values <0.0001) (Figure 4-6). Each higher increment of weight loss was associated with greater improvements in the risk factor. In contrast, the magnitude of improvement in LDL cholesterol did not differ across the weight categories. Furthermore, the odds of having a clinically meaningful improvement in risk were strongly related to the magnitude of weight loss achieved such that the odds of a clinically meaningful improvement also increased with each weight loss increment.

Individuals who lost 2% to 5% of their body weight had increased odds of having significant improvements in SBP (OR 1.24), glucose (OR 1.75), A1C (OR 1.80) and triglycerides (OR 1.46), while those who lost 5% to <10% of their body weight had increased odds of significant improvement in all risk factors. These results support for the assertion that modest weight losses of 5% to 10% (and even 2% to 5%) of initial weight are sufficient to produce significant, clinically relevant improvements in CVD risk factors in patients with overweight or obesity and T2D.

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Weight Loss in Patients with Class III Obesity

There has been a long-held belief that dietary and lifestyle interventions are less effective in individuals with class III obesity than in those with less excessive body weight. A sub study from the Look AHEAD trial compared the effect of ILI on weight loss and CVD risk in patients with T2D who had class III obesity (BMI ≥40) to those who had overweight (BMI 25 to <30), class I obesity (BMI 30 to <35) and class II obesity (BMI 35 to <40). At 1 year, the weight loss in patients with class III obesity in the ILI group was -9.04% of initial body weight, which was significantly greater (P <0.05) than patients with overweight (-7.43%) and comparable to those with class I (-8.72%) or class II obesity (-8.64%).

There also were comparable improvements in fitness, physical activity, LDL cholesterol, triglycerides, BP, fasting glucose and A1C at 1 year across all BMI groups. Finally, treatment adherence (e.g., treatment session attendance) among individuals with class III obesity was excellent and did not differ among weight categories (patients with class III obesity 80% vs others 83%; P = 0.43). These results demonstrate that dietary and lifestyle interventions can be considered in individuals with class III obesity.

Depression

Some evidence suggests there are bidirectional associations among depression, obesity and diabetes. Since the Look AHEAD study population consisted of individuals with overweight/obesity and T2D, a separate analysis of the Look AHEAD cohort was performed to determine whether moderate weight loss would be associated with incident symptoms of depression and suicidal ideation, and whether symptoms of depression at baseline would limit weight loss at 1 year. Virtually all (n = 5129) trial participants completed the Beck Depression Inventory (BDI) and had their weight measured at baseline and 1 year. A BDI score of ≥10 indicated potentially significant symptoms of depression.

During this 1-year study, there was a significantly lower number of incident cases of symptoms of depression in the ILI group at 1 year than in the DSE group (6.3% vs 9.6%; P <0.001), which remained significant after controlling for use of antidepressant medications. The overall change from baseline weight at 1 year (regardless of a depression status) was -8.6% in the ILI group and -0.7% in the DSE group (P <0.001) (Figure 4-7). ILI group participants who reported mild or symptoms of depression at baseline showed a decrease of 5.3 points on the BDI at 1 year compared with a decrease of 0.6 points in those individuals reporting no symptoms of depression. In the DSE group, there was a decrease of 3.7 points among individuals with symptoms of depression at baseline compared with an increase of 0.2 points in participants without depressive symptoms at baseline.

Although participants in both intervention groups with mild or greater symptoms of depression at baseline lost significantly less weight than individuals with no symptoms of depression (4.3% vs 4.8%), this difference cannot be considered as clinically meaningful. Similarly, the difference in weight loss between participants with and without symptoms of depression in the ILI group (7.8% vs 8.7%) is not clinically meaningful. According to the authors, these findings indicate that individuals with overweight/obesity and T2D individuals with mild or greater symptoms of depression are able to achieve similar degrees of weight loss as people with overweight/obesity without T2D.

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Obstructive Sleep Apnea

OSA is strongly associated with obesity and untreated OSA is associated with significant CVD morbidity and mortality, debilitating daytime symptoms and increased risk of work and motor vehicle accidents.

The Sleep AHEAD ancillary study of Look AHEAD assessed the prevalence of OSA among 305 individuals with overweight/obesity and T2D. Almost all (86.6%) of these individuals had OSA of various levels of severity. The mean apnea-hypopnea index (AHI) was 20.5; 33.4% had mild OSA, 30.5% moderate OSA and 22.6% severe OSA. Independent of other variables, a 1-cm increase in waist circumference was associated with a 10% increase in the predicted odds of the presence of OSA (AHI ≥5). In participants with AHI ≥5, BMI was the only significant predictor of severe OSA.

A total of 264 of the above individuals were assigned to either ILI or DSE intervention. Their mean baseline weight was 102.4 kg, their mean BMI was of 36.7, and their mean AHI was 23.2 (16.5 events/hour). At 1 year, more than three times as many patients in the ILI group than in the DSE group had total remission of their OSA, and the prevalence of severe OSA among ILI participants was half that of the DSE group.

Subsequently, these patients were followed to assess whether the initial benefit of weight loss on OSA severity at 1 year is maintained at 4 years. Mean weight loss in the ILI group was 10.7, 7.4 and 5.2 kg at 1, 2 and 4 years, respectively, compared with a <1-kg weight loss in the DSE group at each time (P <0.001). The between-group differences in AHI were 9.7, 8.0 and 7.7 events/hour at 1, 2 and 4 years respectively (P <0.001) (Figure 4-8). Remission of OSA at 4 years was five times more common with the ILI (20.7%) than DSE (3.6%). Furthermore, these beneficial effects on the AHI group at 1 year persisted at 4 years, despite an almost 50% weight regain. However, it is important to note that while weight loss of 5% to 10% can result in significant benefits in many comorbidities, an ~10 kg average weight loss may be required to achieve a significant decrease in the AHI index.

There is considerable evidence that bariatric surgery has a beneficial effect on the risk of diabetes, blood pressure, dyslipidemia, and mortality in individuals with class III obesity. Bariatric surgery also has been shown to result in significant weight loss and risk factor reduction in individuals with class III obesity. A few studies have compared the effect of surgical and conservative weight loss strategies on OSA.

One 1-year study treated 133 subjects (mean BMI of 45.1, mean AHI 17.1), 63% of whom had OSA, with either a 1-year ILI-program (n = 59) or Roux-en-Y gastric bypass (RYGB) (n = 74) and repeated polysomnography. The average weight loss was 8% in the ILI-group and 30% in the RYGB-group (P <0.001). Mean AHI scores decreased in both treatment groups, although significantly more in the RYGB-group than in the ILI group (-13.1 vs -6.0, respectively). Twenty-nine RYGB-patients (66%) had remission of OSA compared with 16 ILI-patients (40%). However, after further adjustment for BMI change, the treatment group difference was no longer statistically significant (P = 0.709). As a result, the authors concluded that while the study demonstrated that RYGB was more effective than ILI at reducing the prevalence and severity of OSA, further analysis also suggests that weight loss, rather than the surgical procedure per se, explains the beneficial effects.

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Look AHEAD-E

The Look AHEAD study received a 5-year extension in 2016 called Look AHEAD-Extension or Look AHEAD-E, with the aim of assessing the effects of lifestyle changes on healthy aging in older adults with T2D (including, among others, increased lifespan and lower healthcare costs). No data from Look AHEAD-E have been published to date.

ADAPT

Osteoarthritis

Obesity has been identified as an independent modifiable risk factor for the development of OA, particularly in knees. Several studies have demonstrated the benefits of weight loss in individuals with overweight/obesity and OA of the knee.

The 18-month, randomized, single-blind Arthritis, Diet and Activity Promotion Trial (ADAPT) in 316 community-dwelling adults (ages 60 years and older) with overweight and obesity (BMI >28) and with knee pain, radiographic evidence of knee OA, and self-reported physical disability assessed whether long-term exercise and dietary weight loss are more effective, either separately or in combination, than usual care in improving physical function, pain and mobility. The primary outcome measure was self-reported physical function as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included weight loss, 6-minute walk distance, stair-climb time, WOMAC pain and stiffness scores, and joint space width.

Both weight loss intervention groups (diet only, diet plus exercise) lost significantly (P <0.05) more weight compared with the healthy lifestyle group. Individuals in the diet-only group lost an average of 4.9% of their body weight and those in the diet plus exercise group lost 5.7% of their body weight. Mean weight losses in the exercise-only and healthy lifestyle groups were 3.7% and 1.2%, respectively. After 18 months, WOMAC physical function revealed that individuals in the diet plus exercise group significantly improved their physical function (P <0.05) relative to the healthy lifestyle control group. There were no significant differences between the exercise-only or diet-only groups and the healthy lifestyle group.

Summary

Data from both the DPP and LOOK AHEAD trials clearly demonstrate that modest weight loss can have significant improvements on obesity-related comorbidities. Modest weight loss can reduce the incidence of diabetes by up to 58% and provide remission rates of up to 11% for those undergoing intensive lifestyle treatment. In addition, patients can achieve improvements in LDL, HDL, SBP as well as reduce the incidence of metabolic syndrome by 41%. Other obesity-related complications, including OSA, depression and declining functional status may also be improved. Furthermore, this benefit is not limited to patients who have mild/moderate obesity but is actually achieved in those with class III obesity (BMI >40) and therefore all patients should be considered for treatment.