Metabolic Syndrome: A Growing Epidemic

Course #91543 - $25 • 5 Hours/Credits


Self-Assessment Questions

    1 . Which of the following is included in the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III definition of metabolic syndrome?
    A) Elevated triglycerides (150 mg/dL or greater)
    B) Decreased high-density lipoprotein (HDL) (<40 mg/dL in men, <50 mg/dL in women)
    C) Abdominal obesity/central adiposity (waist circumference >102 cm [40 inches] in men, >88 cm [35 inches] in women)
    D) All of the above

    DEFINITION OF METABOLIC SYNDROME

    NCEP ATP III CLINICAL IDENTIFICATION OF METABOLIC SYNDROMEa

    Risk FactorDefining Level
    Abdominal obesity (waist circumference)
    Men: >102 cm (>40 in)
    Women: >88 cm (>35 in)
    Triglycerides ≥150 mg/dL
    High-density lipoprotein (HDL) cholesterol
    Men: <40 mg/dL
    Women: <50 mg/dL
    Blood pressure ≥130/≥85 mm Hg
    Fasting glucose ≥110 mg/dL
    aDefined by the presence of three or more of the listed components
    Click to Review



    2 . Which of the following is a criterion outlined by the American College of Endocrinology's definition of insulin resistance syndrome?
    A) HDL greater than 50 mg/dL
    B) Fasting glucose 80–100 mg/dL
    C) Triglyceride level less than 150 mg/dL
    D) Blood pressure greater than 130/85 mm Hg

    DEFINITION OF METABOLIC SYNDROME

    The American College of Endocrinology (ACE) has also described a metabolic syndrome, which they refer to as insulin resistance syndrome. The ACE emphasizes that there are no set diagnostic criteria for this syndrome but rather a constellation of abnormalities that raise the risk of adverse outcomes. Their statement describing the insulin resistance syndrome suggests that a patient with two or more of the following is probably insulin resistant and at elevated cardiovascular risk, although the possibility of increased risk should not be excluded in patients who do not fulfill these criteria [10,11]:

    • IFG and/or IGT fasting:

      • 110–125 mg/dL

      • 120-minute post-glucose challenge: 140–200 mg/dL

    • Triglyceride greater than 150 mg/dL

    • HDL cholesterol:

      • Men: less than 40 mg/dL

      • Women: less than 50 mg/dL

    • Blood pressure greater than 130/85 mm Hg

    Click to Review



    3 . Which of the following statements regarding the epidemiology of metabolic syndrome is TRUE?
    A) Metabolic syndrome is roughly the same among non-Hispanic white women and men.
    B) Metabolic syndrome is more prevalent among non-Hispanic black men than non-Hispanic black women.
    C) Metabolic syndrome is more prevalent among Mexican American men than Mexican American women.
    D) All of the above

    EPIDEMIOLOGY

    Among non-Hispanic whites, the age-adjusted prevalence for metabolic syndrome is 35% among men and 36% among women. Minority populations are disproportionately affected; however, the prevalence of metabolic syndrome varies for men and women. Prevalence in non-Hispanic black women is 34%; prevalence in non-Hispanic black men is 27%. Mexican American women have a prevalence that is slightly higher (31%) than in Mexican American men (27.5%) [14].

    Click to Review



    4 . Which of the following statements regarding the costs of metabolic syndrome is TRUE?
    A) Obesity costs an estimated $17 billion annually.
    B) Diabetes costs an estimated $327 billion annually.
    C) Metabolic syndrome costs an estimated $117 billion annually.
    D) Metabolic syndrome costs an estimated $132 billion annually.

    EPIDEMIOLOGY

    The costs of metabolic syndrome are not yet well established. However, healthcare expenses related to metabolic syndrome symptoms and/or risk factors are significant. Among participants 65 years of age and older in the large Cardiovascular Health Study, Medicare costs were 20% higher for those with metabolic syndrome compared to those without the syndrome. The increase was primarily due to costs attributed to the individual risk factors of abdominal obesity, low HDL, and elevated blood pressure [17]. Obesity costs alone are estimated to be at least $147 billion annually [16]. Total medical expenditures attributable to diabetes are estimated at $327 billion, with $237 billion in direct medical expenditures and $90 billion for indirect expenditures (e.g., disability, work loss, premature mortality) [18,19]. The health costs associated with hypertension and dyslipidemia are also significant.

    Click to Review



    5 . Irrespective of whether a person is overweight or not, a contributor to insulin resistance is
    A) younger age.
    B) intra-abdominal fat.
    C) persistent xerostomia.
    D) None of the above

    RISK FACTORS

    Of note, accumulation of intra-abdominal fat, irrespective of whether a person is overweight, may result in insulin resistance and contribute to metabolic syndrome [26]. Individuals in the upper-normal weight and slightly overweight BMI range have a relatively high prevalence of insulin resistance and are at increased risk of having metabolic syndrome, thus increasing the risk of diabetes and cardiovascular disease.

    Click to Review



    6 . In the Kuopio Ischemic Heart Disease Risk Factor study, patients with metabolic syndrome showed what increase in relative risk for mortality from coronary heart disease?
    A) 1.95
    B) 2.52
    C) 3.77
    D) 4.53

    RISK FACTORS

    In the Kuopio Ischemic Heart Disease Risk Factor Study, data from more than 1,200 men without cardiovascular disease at baseline showed that the presence of metabolic syndrome was associated with a relative risk of 3.77 for mortality from coronary heart disease [39]. It also showed a relative risk of 2.43 for all-cause mortality compared with the absence of the syndrome. In an analysis of the West of Scotland Coronary Prevention Study, hazard ratios for coronary events increased with an increasing number of metabolic syndrome factors, from 1.79 for one factor, 2.25 for two factors, 3.19 for three factors, and 3.65 for four or more factors [40].

    Click to Review



    7 . Evaluation of patients for metabolic syndrome should include
    A) lipid profile.
    B) measurement of vital signs.
    C) measurement of waist circumference.
    D) All of the above

    DIAGNOSIS/SCREENING

    Evaluation of patients for metabolic syndrome should include measurement of [6]:

    • Vital signs

    • Height

    • Body weight

    • BMI

    • Waist circumference

    Click to Review



    8 . The first step in the treatment of metabolic syndrome is
    A) pharmacotherapy.
    B) strict calorie restriction.
    C) insulin and immunotherapy.
    D) effective lifestyle interventions, focusing on nutrition and exercise.

    GENERAL TREATMENT

    Treatment consists of the correction of the individual components, with weight loss as a major goal. Weight loss improves all aspects of metabolic syndrome. Weight loss of 5% to 10% can lead to significant reductions in morbidity and mortality. The goal of treatment is to prevent or ameliorate diabetes, hypertension, and cardiovascular disease. Therefore, the first step in treatment is effective lifestyle interventions, focusing on nutrition and exercise.

    Click to Review



    9 . According to the Dietary Reference Intake by IOM, what percent of daily calories should be from fat?
    A) 10% to 15%
    B) 15% to 25%
    C) 20% to 35%
    D) 25% to 40%

    GENERAL TREATMENT

    Since the 1990s, the Institute of Medicine (IOM) has issued a series of reports that suggests dietary reference values for intake of nutrients. One of these reports, updated in 2005, establishes the Dietary Reference Intakes (DRI) for energy, carbohydrates, fiber, fat, fatty acids, cholesterol, protein, and amino acids. The following ranges are recommended in the 2005 report for percentage of daily caloric intake [73]:

    • Carbohydrates: 45% to 65%

    • Sugars: No more than 25%

    • Fats: 20% to 35%

    • Protein: 10% to 35%

    • Fiber: Men younger than 50 years of age should receive 38 g of fiber; women younger than 50 years of age need 25 g. Men older than 50 years of age should receive 30 g of fiber; women older than 50 years require 21 g.

    Click to Review



    10 . According to the Dietary Guidelines for Americans, intake of added sugars should be limited to no more than what percent of overall calorie intake?
    A) 1%
    B) 5%
    C) 10%
    D) 15%

    GENERAL TREATMENT

    The following quantitative recommendations were made for components of the diet that should be limited as they are of particular public health concern in the United States [78]:

    • Consume less than 10% of calories per day from added sugars.

    • Consume less than 10% of calories per day from saturated fats.

    • Consume less than 2,300 mg of sodium (approximately one teaspoon of salt) daily.

    • If alcohol is consumed, limit it to no more than one drink per day for women and up to two drinks per day for men, and only by adults of legal drinking age.

    Click to Review



    11 . The Institute of Medicine (IOM) recommends setting a long-term goal of how many minutes of exercise, at least five days per week?
    A) 20 minutes
    B) 30 minutes
    C) 45 minutes
    D) 60 minutes

    GENERAL TREATMENT

    According to the IOM, adults should set a long-term goal of at least 60 minutes of moderate-intensity physical activity on at least five days of the week [73]. This is an increase from 30 minutes recommended by the U.S. Surgeon General. Recommendations described in the U.S. Dietary Guidelines suggest the following [78]:

    • 60 minutes or more of physical activity daily for children 6 to 17 years of age. Most should be moderate- or vigorous-intensity aerobic activity and should include vigorous-intensity, muscle-strengthening, and bone-strengthening activity at least three days of the week.

    • At least 150 minutes per week of moderate-intensity activity or 75 minutes per week of vigorous-intensity aerobic physical activity, or an equivalent combination for adults 18 to 64 years of age. Aerobic activity should be performed in episodes of at least 10 minutes and, if possible, spread throughout the week. Adults should also include muscle-strengthening activities two or more days/week.

    • Adults 65 years of age and older should follow the adult guidelines whenever possible with an emphasis on maintaining/improving balance if at risk of falling.

    Click to Review



    12 . Which of the following statements regarding exercise is TRUE?
    A) Moderate exercise should noticeably raise the heart rate.
    B) Some data suggest that one can be overweight and fit if they exercise regularly.
    C) Patients should alternate between flexibility, aerobic, and resistance training.
    D) All of the above

    GENERAL TREATMENT

    Patients often want to know how intense their activity should be. Physiologically, intensity refers to relative load or resistance against which a muscle works. One important point is for patients to elevate their heart rate. AHA recommendations provide a simple way to gauge intensity. Moderate activity, such as a brisk walk, will noticeably elevate the heart rate. Vigorous activity, for example jogging, causes rapid breathing and substantially raises the heart rate. Moderate exercise can be accumulated in increments of 10 minutes or more. Moderate and vigorous activity can be combined to meet the weekly recommendations; the AHA offers a chart with examples of different types of exercise and details about how to judge the total amount of exercise per week [89].

    The following advice regarding exercise may be given to patients:

    • Plan to exercise a minimum of three days per week. Patients can slowly add days as they become more comfortable. The goal should be to exercise five days per week or more.

    • Start off with 10 to 15 minutes of exercise on the days you exercise and increase the time to 60 minutes daily over a few months. Everyone can find 10 to 15 minutes a few days per week. Encourage patients to make it a part of their schedule. The key is to help them find activities that they enjoy. Exercise should not be viewed as a burden or a chore.

    • Alternate between flexibility, aerobic, and resistance training. By doing this, patients will target all the major muscle groups.

    Clinicians should consider writing these recommendations on a prescription pad or a special form. Patients are more likely to follow this advice when it is written down. In addition, consider asking patients to keep a journal or log when they begin an exercise program, which can be reviewed on the next visit. There should be regular discussion about physical activity at each office visit. Continuous long-term care is essential.

    It is important to stress to patients that physical activity, even without weight loss, can reduce the risks of developing heart disease and type 2 diabetes. Some studies indicate that one may be overweight and "fit" if they exercise regularly. Researchers studied 906 women who were being evaluated for coronary artery disease [90]. They found that women with low fitness levels were 46% more likely to have a coronary event than those with high fitness levels. Overweight women who were fit had better outcomes than unfit thin women. More and more data point to the notion that low cardiorespiratory fitness is an established risk factor for cardiovascular and total mortality. A 15-year study was conducted of 4,400 patients who were given a treadmill test between the ages of 18 and 30 years as part of the Coronary Artery Risk Development in Young Adults (CARDIA) study [91]. Researchers found that 60% of the women and 50% of the men who had low fitness levels in their twenties had double the risk of developing diabetes, metabolic syndrome, and high blood pressure by the end of the study.

    Click to Review



    13 . According to NHLBI guidelines, which of the following patients would be considered for drug therapy?
    A) BMI greater than 25
    B) BMI greater than or equal to 30
    C) BMI greater than or equal to 27 with comorbidities
    D) Both B and C

    TREATMENT OF SPECIFIC CONDITIONS

    According to NHLBI guidelines, obese patients with a BMI ≥30, or overweight patients with a BMI ≥27 and concomitant obesity-related risk factors or diseases, such as hypertension, diabetes, or dyslipidemia, are candidates for drug therapy [69]. Although a useful tool, it is important to remember that drug therapy is only one part of the treatment. Given that discontinuation of drug therapy often leads to rapid weight regain, the pharmacologic treatment of obesity should only be used as part of a program that includes lifestyle modification interventions, such as intensive diet and/or exercise counseling and behavioral interventions [69]. In addition, patients should have realistic expectations of drug therapy and not have contraindications to the drugs.

    Click to Review



    14 . Which of the following statements regarding the weight-loss medication orlistat is TRUE?
    A) Typical dosage of orlistat is 120 mg with each meal.
    B) Orlistat is a gastric and pancreatic lipase inhibitor.
    C) Orlistat is a norepinephrine, dopamine, and serotonin reuptake inhibitor.
    D) Both A and B

    TREATMENT OF SPECIFIC CONDITIONS

    Orlistat is a gastric and pancreatic lipase inhibitor. It reduces the absorption of 30% of a patient's dietary fat intake [106]. Orlistat acts by reversibly inhibiting pancreatic, gastric, and carboxyl ester lipases and phospholipase A2—all of which are required for the hydrolysis of dietary fat in the gastrointestinal tract. A meta-analysis of orlistat versus placebo trials demonstrated that patients treated with orlistat lost 2.5 kg at 6 months and 2.75 kg at 12 months [107]. These data are statistically significant. Like most medications, orlistat does have side effects, including fecal urgency, oily spotting, and flatulence [106,108]. The drug may not be suitable for patients with bowel conditions, such as ulcerative colitis and Crohn disease, or irritable bowel syndrome. Typical dosage is 120 mg with each meal [106,108].

    Click to Review



    15 . A patient with which of the following is considered a good candidate for bariatric weight-loss surgery?
    A) BMI less than 30
    B) BMI between 30 and 35
    C) BMI between 27 and 30 with comorbidities
    D) BMI greater than 35 with comorbidities

    TREATMENT OF SPECIFIC CONDITIONS

    For some patients who do not achieve weight loss with diet, physical activity, and drug therapy (typically patients with a BMI greater than 40, or greater than 35 with comorbid conditions), surgical intervention may be a consideration [69]. Other selection criteria include a good social support system, no active substance abuse, no clinically significant or unstable psychopathology, and previously demonstrated adherence to medical recommendations [69,115].

    Click to Review



    16 . In a meta-analysis of bariatric surgery studies conducted between 1990 and 2003, what percentage of patients who underwent surgery were cured of diabetes?
    A) 55%
    B) 66%
    C) 77%
    D) 88%

    TREATMENT OF SPECIFIC CONDITIONS

    It is important that both healthcare providers and patients recognize that bariatric surgery is not a cure, but rather a tool. A meta-analysis of 136 studies of bariatric surgery (conducted between 1990 and 2003) involved a total of 22,094 weight loss patients [119]. Of these patients, 19% were men and 72% were women. The mean age was 39 years (range: 16 to 64 years), and the mean BMI was 46.9 (range: 32.3 to 68.8). The objective of the analysis was to determine the impact of bariatric surgery on weight loss, operative mortality (at 30 days), and four obesity co-morbidities: diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea. Seventy-seven percent of the patients who underwent surgery were "cured" of diabetes (as defined by discontinuation of all diabetes-related medications and maintenance of blood glucose levels within normal range), 62% had blood pressure return to normal levels, 70% saw improvements in cholesterol levels, and 86% of those suffering from sleep apnea saw the condition improve [119].

    Click to Review



    17 . One characteristic lipid problem associated with metabolic syndrome is a(n)
    A) low LDL level.
    B) low HDL level.
    C) elevated HDL level.
    D) low triglyceride level.

    TREATMENT OF SPECIFIC CONDITIONS

    As noted, the dyslipidemia in metabolic syndrome is characterized by elevated triglyceride (greater than 150 mg/dL), low HDL (less than 40 mg/dL in men; less than 50 mg/dL in women), and small, dense LDL cholesterol. The diagnosis of dyslipidemia is best made when a patient does not have any acute illness. HDL and LDL levels are not significantly altered by food, but triglyceride levels can rise substantially after food intake. The recommendation for testing requires a 9- to 12-hour fast prior to laboratory measurements [163,164]. There are some conditions that can cause similar dyslipidemia, particularly low HDL, characteristic of metabolic syndrome. These include glucocorticoid excess as well as hypothyroidism; although relatively uncommon, healthcare providers should be aware of them.

    Click to Review



    18 . The ATP III suggests treating which of the following first in dyslipidemia management for patients with metabolic syndrome?
    A) LDL
    B) HDL
    C) Triglycerides
    D) Total cholesterol

    TREATMENT OF SPECIFIC CONDITIONS

    When addressing dyslipidemia in the absence of other cardiovascular risk factors, physicians should first target LDL levels that are greater than 190 mg/dL [165,166]. Lowering LDL is critical as it is primarily elevated LDL cholesterol that is associated with coronary artery disease. In high-risk patients, an LDL cholesterol level goal of less than 70 mg/dL is a therapeutic option [166]. Ideally, HDL for men should be at least 40 mg/dL and at least 50 mg/dL for women [167,168].

    Click to Review



    19 . The report from members of the Eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) recommends antihypertensive drugs in patients younger than 60 years of age with blood pressures greater than
    A) 130/80 mm Hg.
    B) 130/90 mm Hg.
    C) 140/90 mm Hg.
    D) 150/80 mm Hg.

    TREATMENT OF SPECIFIC CONDITIONS

    The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) introduced a category of "prehypertension" to recognize that underlying risk factors raise blood pressure to ranges that increase a patient's risk for cardiovascular disease (Table 2) [185]. Prehypertension includes people with a systolic blood pressure of 120–139 mm Hg or a diastolic blood pressure of 80–89 mm Hg. Though a report from the JNC 8 panel was released in 2014, it does not include information related to the categorization of blood pressure levels [186]. Keep in mind that ATP III includes a blood pressure of 130/85 mm Hg or greater as a risk factor for metabolic syndrome. The JNC 8 Committee recommends antihypertensive drugs in patients, including those with diabetes, with blood pressures greater than 140/90 mm Hg. The threshold levels are slightly higher (i.e., ≥150/90 mm Hg) for adults 60 years of age or older [186].

    Click to Review



    20 . Which of the following statements regarding blood pressure management is TRUE?
    A) The DASH diet has been shown to reduce blood pressure.
    B) Thiazide diuretics should not be used in people with metabolic syndrome.
    C) Lifestyle intervention has not been shown to be effective in lowering blood pressure.
    D) All of the above

    TREATMENT OF SPECIFIC CONDITIONS

    Patients with either prehypertension or stage 1 hypertension should initially be treated with lifestyle modifications, including weight reduction, dietary modifications (i.e., adopting the Dietary Approach to Stop Hypertension [DASH] eating plan), dietary sodium reduction, physical activity, and moderation of alcohol consumption [185]. Exercise has been demonstrated to reduce hyperinsulinemic responses to glucose challenges in patients with metabolic syndrome [187]. Researchers evaluated the effects of a six-month intervention involving either aerobic exercise training alone or exercise combined with a structured weight-loss program on cardiovascular risk factors associated with metabolic syndrome. A total of 53 men and women who showed the hyperinsulinemia, dyslipidemia, and high blood pressure characteristic of metabolic syndrome were randomly assigned to an exercise-only group, an exercise and weight loss group, or a control group. Before and following treatment, participants underwent measurement of glucose tolerance, lipid levels, and clinical blood pressure. At the end of the study, hyperinsulinemic responses to the glucose challenge test were significantly reduced in both exercise groups. Participants who showed the largest amount of weight loss showed the most robust improvements in abnormal insulin responses. Diastolic blood pressure was significantly reduced in the exercise and weight loss group but not in the exercise-only group. Lipid profile was not significantly improved by either intervention [187]. These results suggest that exercise is an effective treatment for hyperinsulinemia and lowering of diastolic blood pressure in patients with metabolic syndrome.

    In 2002, a meta-analysis of 54 controlled trials examined the effects of aerobic exercise on systolic and diastolic blood pressure [188]. Aerobic exercise was associated with a significant reduction in mean systolic and diastolic blood pressure. A reduction in blood pressure was associated with aerobic exercise in hypertensive and normotensive participants and in overweight and normal-weight participants. The authors concluded that aerobic exercise reduces blood pressure in both hypertensive and normotensive persons. A meta-analysis of trials between 1998 and 2006 found statistically significant reductions in systolic blood pressure with each of several lifestyle interventions, including improved diet (5 mm Hg), aerobic exercise (4.6 mm Hg), alcohol restriction (3.8 mm Hg), sodium restriction (3.6 mm Hg), and fish oil supplements (2.3 mm Hg) [189].

    Along with exercise and the previous advice given about nutrition, healthcare providers may wish to consider the DASH diet. The DASH diet is rich in fruits, vegetables, nuts, and low-fat dairy products and low in saturated fat, sugar, cholesterol, and refined carbohydrates. The first DASH study involved 459 adults; approximately 27% of the participants had high blood pressure. The study compared three eating plans: the first was similar to what Americans regularly eat; the second was similar to what Americans regularly eat plus more fruits/vegetables; and the third was the DASH eating plan. All three plans included about 3,000 mg of sodium per day. Participants who followed both the second and DASH plans had reduced blood pressure, but the DASH plan produced the greatest effect. The second DASH study involved 412 participants and examined the effect on blood pressure of a reduced dietary sodium intake. Participants were randomly assigned to one of two plans—either a typical American diet or the DASH eating plan—and to one of three sodium levels: 3,300 mg/day, 2,300 mg/day, or 1,500 mg/day. Results showed that reduced dietary sodium produced lowered blood pressure for both eating plans, with the greatest blood pressure reductions for the DASH plan at 1,500 mg of sodium daily [190]. Numerous studies have shown the DASH diet to lower blood pressure [191,192,193]. In addition, increasing the intake of fiber in the typical Western diet and combining exercise and weight loss with the DASH diet may contribute to the prevention of hypertension [194,195]. The JNC 7 additionally recommended a public health strategy to complement the treatment of hypertension, particularly among individuals with prehypertension. A population approach that decreases the blood pressure level in the general population by even modest amounts has the potential to substantially reduce morbidity and mortality or at least delay the onset of hypertension [185].

    If blood pressure remains high, pharmacotherapy should be considered. More than two-thirds of individuals with hypertension cannot be controlled on one drug and will require two or more antihypertensive agents selected from different drug classes [185]. Because endothelial dysfunction appears to be present in many patients with metabolic syndrome, ACE inhibitors and ARBs are useful in improving hypertension as well as mitigating the endothelial damage. Furthermore, ACE inhibitors may be particularly useful in patients with diabetes, as they protect against renal disease [196,197,198]. ARBs may have similar effects. The Losartan Intervention for Endpoint (LIFE) trial demonstrated lower rates of nonfatal and fatal cardiovascular disease in patients with diabetes, hypertension, and left ventricular hypertrophy who took the ARB losartan compared to those that took atenolol, a beta-blocker [199]. Losartan was also more effective than atenolol in reducing all-cause mortality. However, authors of a 2017 Cochrane Review concluded that initiating treatment of hypertension with ARBs leads to modest reductions in cardiovascular risk and little or no effects on mortality. They also found that ARB effects are inferior to those of other antihypertensive drugs [200].

    For most cases of hypertension in the general nonblack population, the JNC 8 recommends the use of a thiazide-type diuretic, calcium channel blocker, ACE inhibitor, or ARB as initial antihypertensive therapy due to their propensity to prevent cardiovascular complications associated with hypertension [186]. Results of a 2014 Cochrane Review indicate that thiazides also are more effective at lowering systolic blood pressure than ACE inhibitors, ARBs, and renin inhibitors [201]. In the black population, the preferred first-line agents are thiazide diuretics or calcium channel blockers. Healthcare professionals treating patients with metabolic syndrome should be aware that thiazides have been associated with insulin resistance and other metabolic changes [106]. However, at lower doses, changes in glucose levels appear to be small [202].

    Click to Review