Omega-3s & Heart Health: Strong Science Supports Broad Recommendations

Broad medical recommendations, like those now advanced by the American Heart Association (AHA) and National Cholesterol Education Program, come only after extensive research has confirmed usefulness. Multiple types of research are used. Epidemiologic studies compare the difference in disease and diet across groups of people. Experimental studies assess the role of a nutrient or medication in laboratory animals. Clinical studies assess the impact when given to a test group of people. This impact is compared to a “control” group not taking the nutrient or medicine.

Omega-3s from fish oils have been subject to all types of studies, and the benefits associated with cardiovascular health and disease prevention have been consistently shown. As a result, leading medical organizations now recommend Omega-3s from fish oil for cardiovascular health. The recommendations include:

• 500mg/day of Omega-3s from fish oil for adults that have not been diagnosed with coronary artery disease.


• 1000mg (1g)/day for adults that have been shown to have coronary artery disease.


• 3000mg-4000mg (3-4g)/ day for adults with highly elevated triglycerides.

Omega-3s are not associated with reductions in LDL (bad) cholesterol levels. Yet, cholesterol alone is only part of the cause of heart disease. A number of other factors can determine the damage that cholesterol can do. Omega-3s appear to favorably affect these factors including decreased blood pressure, reduced inflammation that leads to plaque formation, and the stabilization of existing plaque.

How significant is the impact on Omega-3s? Studies have indicated as much as a 18-20% reduction in a cardiovascular event such as a heart attack for healthy adult. For those with a history of heart disease, the impact has been shown at least as significant, and perhaps higher.

Omega-3s from fish oil represent an important component of an integrated and comprehensive nutritional approach to cardiovascular health. Other broad recommendations include the consumption of 10+ grams/day of selected soluble fibers such as those from oats, beans, barley and psyllium, 2 grams/day of plant sterols, and diet that restricts saturated fats, trans fats and dietary cholesterol. Click here for more information on nutritional and natural cholesterol management.

Link to report on Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease in Circulation Journal of the American Heart Association, 2002.

Cardiovascular Disease Prevention: Between Healthy Habits and Prescription Medications

With cardiovascular disease the largest cause of death and disability in the United States, the scientific community continues intense investigations into approaches for prevention. In the New England Journal of Medicine, Doctor Mark Hlatky of Stamford University School of Medicine, writes, "The aphorism 'prevention is better than cure' makes perfect sense when applied to healthy habits such as following a sensible diet, maintaining an ideal body weight, exercising regularly, and not smoking. But increasingly, prevention of cardiovascular disease includes drug therapy, particularly statins to lower cholesterol levels."

In this editorial, Dr. Hlatky is reponding to the growing interest in prescribing cholesterol-lowering medications to a much larger segment of the American population---including those with cholesterol levels well below the risk standards established by the National Cholesterol Education Program of the National Institutes of Health. These medications already are the single largest class of drugs sold in the U.S. today, exceeding $30 billion/year.

There is mounting evidence that lowering LDL cholesterol below the NCEP risk-adjusted standards is reducing the incidence of cardiovascular events such as heart attack and strokes. Further, recent studies, notably the JUPITER study published in the New England Journal of Medicine, reinforces the evidence that statin medications not only favorably alters cholesterol levels but also reduce the level of inflammation in the arteries. In addressing inflammation, the medication may reduce a root cause of arterial plaque development.

Yet, what remains lost in the discussions between healthy habits and drug treatment is the positive, therapeutic power of nutrition. Nutritional solutions extends beyond the restriction of saturated fats, trans fats and cholesterol to nutrients that actively improve cholesterol levels and reduce inflammation. For many, these nutritional tools can allow the individual to achieve target cholesterol levels and serve as an effective statin alternative. For others, the nutritional approach offers an opportunity for reductions in the dosages and number of medications required to achieve heart healthy targets.

The tragedy: compared with the funding for pharmaceutical studies, an incredible small amount of money is being spent to advance the nutritional science. With few major studies reporting on the benefits of nutritional cholesterol management, the news media reports on the pharmaceutical studies. The extensive and widely reviewed understanding of the nutritional solution is then overshadowed.

Here at Kardea, we are working to provide you with both the knowledge and the natural products that advance heart health. We are only one source. For others, discuss with your medical providers. Also, check out our the resource page on the Kardea Nutrition website or for great recipes for cholesterol management, click over to Kardea Gourmet .

Another good source of information: http://cholesterol.about.com/od/treatments/u/Treatments.htm

Kardea Nutrition, Heart Healthy & Inspired.

Cholesterol Management: Beyond Disease Prevention

The guidelines of the National Cholesterol Education Program define LDL cholesterol below 100mg/dl as optimal for otherwise healthy people. Yet, as a matter of disease prevention, these same guidelines suggest that substantially higher levels of LDL cholesterol may be acceptable. These standards are used as a baseline for determining the appropriateness of cholesterol-lowering medications.


Many doctors also are well aware that the non-optimal LDL standards are only a baseline. These doctors are apt to prescribe a cholesterol-lowering medication to achieve the more optimal level.

Here at Kardea, we look to natural cholesterol management to achieve the more optimal levels. Yes, medications may be needed by some, but a nutritional approach has proven as potent as many pharmaceutical therapies. And we recognize that cholesterol management extends well beyond simply lowering LDLs. Our prior blog posts and the numerous links and articles found on our resources page explore this more comprehensive approach.

The important point: cholesterol management is consistent with good health, not simply disease prevention. Whatever your currents levels ---- even if you believe that your cholesterol is not at risky levels ---- consider the benefits of pursuing a more integrated and comprehensive approach.

Intermediate Dose Niacin and Natural Cholesterol Management

Niacin, also known as Vitamin B3, is vital for good health. Niacin helps convert food into energy, build red blood cell counts, and synthesize hormones.

For basic good health, a relatively small amount of niacin, about 20mg/day, is needed. Americans typically obtain this level from a balanced, healthy diet. Our bodies also can manufacture niacin.

At substantially higher levels—1000-2500mg/day--- a specific type of niacin significantly improves cholesterol levels. Niacin as nicotinic acid can lower LDL cholesterol by up to 25%, raise HDL cholesterol by as much as 35%, and lower triglyceride levels by 20% to 50%.[i] The medical community[ii] generally defines these high dosages as a drug that should be taken under a physician’s care. The primary concerns relate to potential liver complications. A doctor will monitor liver function as part of a routine blood test. As a practical matter, the very real and sometimes intense flushing side-effects associated with nicotinic acid at these levels may make a “buffered” prescription nicotinic acid the only viable option.

Nonetheless, nicotinic acid supplements are approved for sale by the Food and Drug Administration. Further, the intake of niacin at intermediate dosage levels --- 100-1000mg/day---has been shown to significantly improve the levels of both HDLs and triglycerides. Coupled with other elements of natural cholesterol management, intermediate dosage of niacin in the form of supplements may provide a meaningful contribution in long term cardiovascular health.

Cholesterols Management: Beyond LDL Reduction

LDL cholesterol reduction has been the primary focus of the medical and pharmaceutical community. This focus is supported by the significant and extensive research confirming the positive health effects of lowered LDL, including reduced heart attacks, strokes and other cardiovascular diseases.

Increasingly, medical science recognizes that LDL reduction alone is only part of cholesterol management and cardiovascular health and wellness.

Researchers are assessing the composition of cholesterol and triglycerides in our blood. For instance, the NIHs’ National Cholesterol Education Program (NCEP) reports that “strong epidemiological evidence links low levels of serum HDL cholesterol to increased CHD (coronary heart disease). High HDL-cholesterol conversely conveys reduced risk.”[iii] The NCEP identifies having HDLs less than 40mg/dl as a risk factor for heart disease. Levels above 60mg/dl are associated with a reduced risk of heart disease.

Statins, the leading medication for LDL reduction, have been associated with some HDL increases. Yet, under the NCEP guidelines, statins are typically recommended only when LDL levels are elevated.

Low HDL levels without elevated LDL levels are nonetheless fairly common. Up to 50% of patients not typically candidates for LDL-lowering medications have low levels of HDLs. In patients with premature coronary artery disease, low HDL levels are the most common abnormality in blood lipids.[iv]

A number of recent studies indicate that small increases in HDLs can significantly reduce the incidence of cardiovascular-related death. A 1mg/dl increase in HDL has been associated with a 2%-3% reduction in coronary artery disease.[v] Another extensive study concluded that increasing HDLs by 6% in patients with low HDL cholesterol decreased heart-related deaths and non-fatal heart attacks by 22%.[vi]

Intermediate Daily Dosages of Niacin as Nicotinic Acid

Between the 20mg recommended for basic health and the 100x greater levels used to manage at-risk patients lies a potential role for niacin for promoting cardiovascular health. In one study, patients took 50mg of niacin as nicotinic acid twice per day for 3 months. The patients on the niacin experienced an average 5% increase in HDLs, or an average of 2.1mg/dl.[vii] In another study, 500mg/day of niacin as nicotinic acid raised HDLs by 10% (close to 5mg/dl) and lowered LDLs by 5% and Triglycerides by 5%.[viii] At 1000mg/day, improvements were 15%, 7% and 11% for HDL, LDL and triglycerides respectively.

The medical community has refrained from endorsing the use of nicotinic acid supplements at these dosage levels as part of a more natural, statin-free solution to blood lipid management. The medical community’s reticence flows, in part, from doctors’ distrust of nutritional supplements. Supplements are subject to fewer regulations than pharmaceuticals, but the industry also is not without regulatory requirements, and many high quality and reliable supplement manufacturers and retailers exist.

Another issue surrounding niacin relates to the potential for consumer confusion. There are three types of niacin available---nicotinic acid, niacinamide, inositol hexanicotinate. Only nicotinic acid has been shown to be effective for cholesterol management.

Further, there are three forms of nicotinic acid—immediate release, sustained release and extended release.

Immediate release nicotinic acid often causes a very uncomfortable flushing of the skin accompanied by an intense feeling of heat, tingling and itching---even at relatively low levels of niacin. The flushing can start a few minutes or a few hours after taking niacin. Flushing typically subsides within 30 minutes, often much sooner.

At the intermediate dosage levels, flushing can be managed by gradually increasing the levels of nicotinic acid. You can start by trying 50mg with lunch and dinner. As your body grows accustomed to these levels, you can try raising your niacin intake with these meals. You might also try taking nicotinic acid before bed.

For individuals who cannot overcome the flush or for those looking to move to higher a dosage level, nicotinic acid is sold as a supplement in a sustained release version. The sustained releases version reduces the intensity of flushing, but at higher levels, it has been associated with liver damage.

The third form of nicotinic acid, extended release niacin, is available as a prescription. This form has typically been used at high level and only to treat harmful cholesterol levels that cannot be remedied through nutrition, certain lifestyle changes and statins.

Integrating Niacin into Natural Cholesterol Management

Intermediate doses of niacin as nicotinic acid may be meaningful for raising HDL cholesterol for cardiovascular health promotion, since the corresponding 5-10% increase in HDLs can significantly lower the risk of heart attack. The impact at these dosage levels alone may fall short of achieving more optimal cholesterol and triglyceride levels. When coupled with other nutrients, however, these niacin dosages may enable an individual to achieve optimal targets. Substantial LDL reductions can be further achieved through the restricted intakes of saturated and trans fats, higher intakes of monounsaturated fats, and therapeutic levels of plant sterols and selected types of fibers (including soluble fiber from oats, barley, psyllium, beans and certain fruits) .[ix] While Omega-3s have not been proven to lower LDL cholesterol, they lower triglycerides and may positively alter other factors leading to the build-up of arterial plaque. Modest weight loss and increased physical activity can further raise HDLs.

With many Americans suffering from the side-effects of statins and others preferring to minimize a lifetime of prescription drugs, it seems appropriate for the medical community to take a greater interest in the role of intermediate dosages of niacin, particularly as a component of broader therapeutic nutrition efforts.
_________________________
[i] Anne Goldberg, M.D. et al, Multiple-Dose Efficacy and Safety of an Extended-Release Form of Niacin in the Management of Hyperlipidemia. The American Journal of Cardiology, Vol. 85, pp 1100-1105 May 1, 2000.

[ii] Detection, Evaluation & Treatment of High Blood Cholesterol in Adults, Third Report of the National Cholesterol Education Program Expert Panel National Institute of Heart, Lung and Blood Institute, National Institutes of Health, September 2002. www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf

[iii] Ibid ”II Rational for Intervention”.

[iv] Ibid.

[v] DJ Gordon et al., High Density Lipoprotein Cholesterol and Disease: Four Prospective American Studies, Circulation 1989

[vi] HB Robins et al., Gemfibrozil for the Prevention of Coronary Heart Disease in Men with Low Levels of High-Density Lipoprotein Cholesterol, The New England Journal of Medicine 1999.

[vii] Jennifer Wink, MD et al., Effect of Very-Low-dose Niacin on High-Density Lipoprotein in Patients Undergoing Long-Term Statin Therapy, American Heart Journal, Volume 143, Number 3, March 2002.

[viii] Goldberg Op Cite, p1102

[ix] Ibid

Father's Day Gourmet & Cholesterol Management

The science is clear and convincing. Therapeutic nutrition---that incorporates 2g of plant sterols, over 10g of soluble fiber, monounsaturated fats replacing saturated and trans fats, and reduced animal sources of protein-- can achieve cholesterol reductions comparable to many of the widely prescribed medications.

With my daughter, we have created a delicious, natural, cholesterol-lowering Father’s Day menu.

We recommend recipes for lunch, a snack and dinner. With a single serving of each dish, you will enjoy:

• 2g of natural plant sterols from foods and taken through the course of the day.
• 30g of total fiber
• 7 grams of heart healthy soluble fiber.
• 1g Omega-3 fatty acids (EPA/DHA)
• Only 150mg of dietary cholesterol (from the chicken and salmon)
• Saturated fat is below 7 percent of total calories.
• Monounsaturated fats equal about 23% of total calories.

Overall, we are nearly in-line with the recommendations of the National Cholesterol Education Program, but we fall a bit short on the heart healthy soluble fiber.

So look to breakfast to finish your therapy. Here are some simple guidelines. A good morning start would be an oat cereal and fruit. If you are looking for something a bit more interesting, there are a number of oat pancake recipes that can be found online. Stay away from the ones with butter and lots of eggs in the ingredients. Either way, you should get you to the 10g minimum recommendations for soluble fiber.

In my life, I actually shoot for the higher, 20-25g recommendation. The only way I have been able to achieve this goal is with psyllium husk or concentrated oat bran. I dissolve a tablespoon of one of these fibers into my morning juice. A heaping tablespoon of the psyllium husk, for instance, delivers 9g of heart health soluble fiber. Most people can tolerate such a dosage, but it is probably something you need to work up to.

The Menu

Luncheon
Mediterranean Salmon Salad
Chick Peas with Oregano
Roasted Asparagus
Whole Grain Bread or Whole Wheat Roll

Snack
Kardea Gourmet Nutrition Bar with 1g plant sterols, 7g fiber, and 7g protein.

Dinner
1st Course
Gazpacho: Quick, Bold & Delicious

2nd Course
Chicken Balsamic Reduction
Steamed Broccoli
Barley Pilaf

Dessert
Sorbet of Your Choosing
Fresh Berries or Sliced Ripe Peaches.

Carbohydrates & Cholesterol: Recommendations from the National Cholesterol Education Program

NCEP Evidence Statement: When carbohydrate is substituted for saturated fatty acids, LDL cholesterol levels fall (Strength of Evidence: A2, B2). However, very high intakes of carbohydrates (greater than 60 percent of total calories) are accompanied by a reduction in HDL cholesterol and a rise in triglyceride (B1, C1). The latter responses are sometimes reduced when carbohydrate is consumed with viscous fiber (C2); however, it has not been demonstrated convincingly that viscous fiber can fully negate the triglyceride-raising or HDL-lowering actions of very high intakes of carbohydrates.

NCEP Recommendations: Carbohydrate intakes should be limited to 60 percent of total calories. Lower intakes (e.g. 50% of calories) should be considered for persons with the metabolic syndrome who have elevated triglyceride or low HDL cholesterol. Regardless of intakes, most of the carbohydrate intake should come from grain products, especially whole grains, vegetables, fruits, and fat-free or low-fat dairy products.

Macronutrient NCEP Dietary Recommendations

Carbohydrate: 50-60% of Total Calories* **

Protein: 15% of Total Calories

Total Fat: 25-35% of Total Calories*

Monunsaturated Fat: Up to 20% of Total Calories

Polyunsaturated Fat: Up to 10% of Total Calories

Saturated Fat: Less than 7% of Total Calories

Dietary Cholesterol: Less than 200mg/day.

*Allows an increase of total fat to 35% of total calories and reduction in carbohydrate to 50% for persons with the metabolic syndrome. Any increase in fat intake should be in the form of either polyunsaturated or monounsaturated fat.
**Carbohydrate should derive perdominantly from foods rich in complex carbohydrates including grains--especially whole grains---fruits, and vegetables.

Trans Fatty Acids: Recommendations of the National Cholesterol Education Program

NCEP Evidence Statement: Trans fatty acids raise serum LDL cholesterol levels (Strength of Evidence: A2). Through this mechanism, higher intakes of trans fatty acids should increase risk for CHD (coronary heart diseases). Prospective studies support an association between higher intakes of trans fatty acids and CHD incidence (C2). However, trans fatty acids are not classified as saturated fatty acids, nor are they included in the quantititative recommendation for saturated fatty acid intake of less than 7 percent of calories in the TLC (therapeutic lifestyle changes) Diet.

NCEP Recommendation: Intakes of trans fatty acids should be kept low. The use of liquid vegetable oil, soft margarine, and trans fatty acid-free margarine are encouraged instead of butter, stick margarine and shortening.

NCEP Discussion: Substantial evidence from randomized clinical trials indicates that trans fatty acids raise LDL cholesterol levels, compared with unsaturated fatty acids. These stuides also show that when trans fatty acids are substituted for saturated fatty acids, HDL (good) cholesterol levels are lower.

Click recommendations on unsaturated fats, both monounsaturated and polyunsatured.

Viscous Soluble Fiber: Recommendations from the National Cholesterol Education Program

NCEP Discussion (excerpt): Because of the favorable effects of viscous fiber (soluble fiber from oats, fruit pectins, guar, beans and psyllium) on LDL cholesterol levels, the NCEP recommends that the therapeutic diet be enriched by foods that provide at least 5-10 grams of viscous fiber daily (Source of Soluble Fiber Chart). Even higher intakes of 10-25 grams per day can be beneficial.

NCEP Evidence Statement: 5-10 grams of viscous fiber per day reduces LDL cholesterol levels by approximately 5 percent (Strength of Evidence: A2, B1).

NCEP Recommendation: The use of dietary sources of viscous fiber (soluble fiber from certain sources) is a therapeutic option to enhance LDL lowering.

Plant Sterols: Recommendations from the National Cholesterol Education Program

NCEP Evidence Statement: Daily intakes of 2-3 grams per day of plant stanol/sterol esters will reduce cholesterol by 6-15 percent Strength of Evidence (A2, B1)

NCEP Recommendation: Plant stanol/sterol esters (2g/day) are a therapeutic option to enhance LDL cholesterol lowering.

National Cholesterol Education Program: Assessing the Science

The National Cholesterol Education Program brings together the wisdom of many individuals and organizations* in the medical community to undertake an assessment of the available scientific evidence related to cholesterol management. The NCEP has developed a methodology to rate the strength of the available evidence and has issued an extensive set of recommendations. The evidence is defined in terms of two categories:

Type of Evidence
A Major randomized controlled clinical trials (RCTs)
B Smaller RCTs and meta-analyses of other clinical trials
C Observational and metabolic studies
D Clinical Experience

Strength of Evidence
1 Very Strong
2 Moderately strong evidence
3 Strong trend

I have posted this blog as a reference for future posts.

*Member organizations of the NCEP include National Heart, Lung & Blood Institute (NIH), American Academy of Family Physicians, American College of Cadiology, American College of Preventive Medicine, American Diabetes Association, American Dietetics Association, American Hospital Association, American Medication Association, American Red Cross, Association of Black Cardiologists, Food and Drug Administration, Centers for Disease Control, American Nurses Association.

Monounsaturated Fats: Recommendations from National Cholesterol Education Program

NCEP Evidence Statement: Monounsaturated fatty acids lower LDL cholesterol relative to saturated fatty acids. Monunsaturated fatty acids do not lower HDL cholesterol nor raise triglycerides. Strength of Evidence: A1, B2

NCEP Evidence Statement: Dietary patterns that are rich in monounsaturated fatty acids provided by plant sources and rich in fruits, vegetables, and whole grains and low in saturated fatty acids are associated with decreased CHD (cardiac heart disease). However, the benefits of replacement of saturated fatty acids with monounsaturated fatty acids has not been adequately tested in controlled clinical trials. Strength of Evidence C1

NCEP Recommendations: Monounsaturated fatty acids are one form of unsaturated fatty acid that can replace saturated fatty acids. Intake of monounsaturated fatty acids can range up to 20 percent of total calories. Most monounsaturated fatty acids should be derived from vegetable sources, including plant oils and nuts.

Lowering Cholesterol: A Piece of the Heart Health Puzzle

The relationship between LDL cholesterol and cardiovascular diseases has been well-documented and summarized by the NIH's National Cholesterol Education Program.

Epidemiologic studies (i.e. research that associates the lifestyles of different populations or groups to a disease), laboratory studies (i.e. research into the effects of certain nutrients or medication on cells outside the body) and clinical studies (research on the effects of certain nutrients or medications on a living person) all show that cholesterol is a critical factor in the development of atherosclerosis.

Atherosclerosis occurs when plaque builds up on the walls of your arteries. This plaque leads to a narrowing and ultimate closing of an artery. Plaque also can break free of the arterial wall. It then can lodge further down your artery, causing a blockage that can lead to a stroke, heart attack, or a blood clot in your arms, legs or other parts of your body.

National Cholesterol Education Program Summary of Research

• Studies across different populations reveal that those with higher cholesterol levels have more arterial plaque and heart disease than those with lower levels. People who migrate from regions where average serum cholesterol in the general population is low to areas with high cholesterol levels show increases in their cholesterol levels as they acculturate. These higher levels in turn are accompanied by higher levels of heart disease.
• Atherosclerosis often can be identified in adolescence or early adulthood. The cholesterol level in young adulthood predicts development of heart disease later in life. In three prospective studies with long-term follow-up, detection of elevated serum cholesterol in early adulthood predicted an increased incidence of heart disease in middle-age.
• The power of elevated LDL to cause heart disease has been shown most clearly in persons with genetic forms of very high cholesterol. In these persons, advanced coronary atherosclerosis and premature heart disease occur commonly even in the complete absence of other risk factors. These disorders provide stronge evidence that LDL is a powerful cause.
• Since LDL-cholesterol levels of less than 100 mg/dL throughout life are associated with a very low risk for heart disease in populations, they can be called optimal. Even when LDL-cholesterol concentrations are near optimal (100–129 mg/dL), plaque formation occurs; hence, such levels must also be called above optimal. At levels that are borderline high (130–159 mg/dL), plaque formation proceeds at a significant rate, whereas at levels that are high (160–189 mg/dL) and very high (above 189 mg/dL) it accelerates further.
• A large number of clinical trials on cholesterol-lowering therapy have been carried out over the past four decades. The initial encouraging findings of earlier trials have recently been reinforced by the robust findings of a large number of studies.
  

The Research in Context: Only A Piece of the Puzzle

Lowering LDL cholesterol is not a guarantee of cardiovascular health. Many people on cholesterol-lowering medications still suffer heart attacks, strokes and other cardiovascular challenges. Similarly, LDL cholesterol levels above the "optimal" levels should not necessarily require an individual to proceed to a lifetime of cholesterol-lowering medications. Each of us should discuss this carefully with our medical providers.

In these conversations, however, you should recognize that cholesterol-lowering is only one piece of the puzzle. Some things to consider:

• Once built-up in your arteries, plaque is difficult to remove. Cholesterol-lowering therapies may only serve to reduce further development, but not fully remedy arterial health.
• The medical community also is investigating the role that different types of LDLs might play in the development of both plaque itself and the ability for plaque to remain “stable” and not break free from the arterial wall. This may be a factor even if LDL levels are low.
• Low levels (below 40mg/dl) of HDL cholesterol have been shown to be a risk factor for heart diseases and high levels (above 60mg/dl) have been associated with reducing the risk of heart disease and plaque development.

Beyond cholesterol management, cardiovascular health flows from different hereditary, environmental and lifestyle factors. It is a complex equation.

The important point: cholesterol management should be thought of as a lifetime approach, starting in your teens, to maintain cardiovascular health. Like weight-management and physical fitness, cholesterol management and its nutritional tools can promote long term health.