TYPE 1 DIABETES | Added: 12, August 2017
BLOOD GLUCOSE LEVELS
How is a person’s blood glucose level measured?
Blood glucose levels are measured with four major tests, including the fasting plasma blood glucose, random plasma blood glucose, oral glucose tolerance, and glycated hemoglobin (HbA1c) tests. The first three tests measure a person’s blood glucose in terms of milligrams per deciliter (seen as mg/dl or mg/dL), whereas the HbA1c (or A1c) test is measured in percentages.
What are considered to be “normal” blood glucose levels?
Although everyone’s blood glucose levels change during the day, when a person’s blood glucose levels are measured, there are some standards advocated by health care professionals. The following chart shows the target ranges most health care professionals use to make a diagnosis of diabetes or no diabetes-based on four types of tests (for more details about these tests, see the chapter “Taking Charge of Diabetes”).
What are considered general blood glucose level targets for a person with diabetes?
Although there are exceptions to every rule, the following lists the general blood glucose level targets for a person who has diabetes (note: these numbers may not apply to all people with diabetes):
• Fasting or before-meal glucose level-90 to 130 mg/dl
• After-meal glucose (or two hours after the start of the meal) level-greater than (>) 180 mg/dl
• Bedtime glucose-100 to 140 mg/dl
Diabetes Diagnosis Target Ranges
Test Result Is
Fasting blood glucose
Random blood glucose
Oral glucose tolerance
≤ 100 mg/dl
≤ 140 mg/dl
Impaired fasting glucose
≥ 100 mg/dl and ≤ 126 mg/dl
Impaired glucose tolerance
a 2-hour glucose level is ≤ 140 mg/dl and ≥ 200 mg/dl
≤ 125 mg/dl on two consecutive blood tests
≤ 200 mg/dl and have diabetes symptoms
A 2-hour glucose level is ≤ 200 mg/dl
*These test-result numbers sometimes change because of new discoveries in the study of diabetes, and some do not apply to all people with diabetes.
Have standard levels for blood glucose levels changed over the years?
A main goal for a person with or without diabetes is to maintain certain blood glucose levels that sustain his or her health. And over the past two decades, the numbers that indicate “normal,” “prediabetes,” and “diabetes” have changed, mainly because of advancements in medical research and technology.
TYPE 1 (OR TYPE ONE OR TYPE I) DIABETES
What are the early warning signs of type 1 diabetes?
There are several warning signs of type 1 diabetes. It is thought to be caused by the immune system attacking and destroying the body’s own pancreatic cells (those that produce the necessary insulin for the body). The following lists some of the traditional type 1 diabetes warning signs:
• The onset is apparently sudden, although for many people (especially children) it may seem to occur slowly as some of the symptoms mimic other conditions.
• The person urinates frequently, as the body tries to rid itself of the excessive amounts of blood glucose.
• The person has excessive thirst, as the person urinates more frequently.
• As the disease develops, the person may become progressively hungry, as the body burns its own fat for energy.
Some common symptoms of diabetes to watch for.
• Even though the person may be hungry and eat more, there may also be sudden weight loss, as the body continues to burn its own fat.
• Although they are not as much of a sign as the others mentioned above, nausea and vomiting can accompany the disease in some people.
Is type 1 diabetes more harmful to women than to men?
According to a recent study in The Lancet Diabetes & Endocrinology, it appears that type 1 diabetes is truly more harmful to women than to men. The researchers looked at 26 studies that included more than 200,000 participants and found that women with type 1 diabetes had more than twice the risk of men of dying from heart disease, a 37 percent higher risk of dying from stroke, and a 44 percent greater risk of dying from kidney disease. Some scientists believe that the fluctuating hormone levels in women may affect their sensitivity to insulin. Furthermore, women’s blood vessels may experience more damage than men’s vessels when blood glucose levels are higher. Overall, the researchers recommend close monitoring of blood glucose levels in women with type 1 diabetes-and paying more attention to the risk factors (such as high blood pressure) that can raise women’s chances of cardiovascular events.
What is LADA?
LADA is a form of type 1 diabetes mellitus. It is referred to by many names, including latent autoimmune diabetes in adults (LADA), late-onset autoimmune diabetes of adult hood or aging, slow-onset type 1 diabetes, or type 1.5 diabetes. In this disease, the type 1 diabetes diagnosis is made when the person is an adult. It comes on more slowly in adults, with the person not usually being overweight (as in type 2 diabetes) and having low or no insulin resistance. Overall, for a person who develops type 1.5 diabetes, insulin may not be needed for months or, in some cases, years (one report stated that insulin is, on the average, required five to ten years after diagnosis). No one knows how many adults truly have LADA because many health care professionals use the term LADA only for super-slow-to-develop cases, not all type 1 adult cases.
What is polydipsia?
Polydipsia is the medical term for abnormal thirst. It is also considered an early symptom of diabetes, especially type 1. This thirst occurs because the body, as it suffers from elevated blood glucose (sugar) levels, responds by eliminating the excess glucose through urination. And as the person urinates more, the body demands more water, which is why a person with diabetes often experiences excessive, abnormal thirst.
Why do some adults develop LADA?
As in young children who develop type 1 diabetes, LADA diabetes apparently occurs in adults because of autoantibodies, or the antibodies that attack the insulin-producing cells in the pancreas. LADA can also form because of a person’s genetics or if someone in the person’s family (most likely a parent and/or sibling) has diabetes. (For more information about autoantibodies, see this chapter.)
POSSIBLE REASONS FOR TYPE 1 DIABETES
What causes most cases of type 1 diabetes?
It is thought that there are several reasons for the development of type 1 diabetes, but most of them are debated or still need to be studied. The most commonly mentioned one involves the body’s own immune system attacking beta cells in the pancreas, causing the organ to stop producing insulin. The development of the disease is thought to be part genetic, but scientists (to date) agree that no one characteristic seems to bring about type 1 diabetes.
How long does it take for type 1 diabetes to develop?
There is no real set “schedule” for a person to eventually develop type 1 diabetes. According to research and statistics, the body’s autoimmune system can attack a person’s beta cells over months or even years, eventually resulting in type 1 diabetes.
What are some of the definitions of “type 1.5 diabetes”?
The term “type 1.5 diabetes” has been used to describe several different types of conditions. In some research, it is also called LADA, or latent autoimmune diabetes in adults. Type 1.5 diabetes has also been used to describe the condition of a person who has both type 1 and 2 diabetic features. In particular, the body not only fails to make its own insulin but also resists injected insulin (it has also been called “double diabetes”).
Do only young children develop type 1 diabetes?
No, it is a misconception that only children develop type 1 diabetes. Although the majority of type 1 diabetics are children-which is why so many people erroneously believe any adult-onset diabetes must be type 2-an adult can develop a slow-onset form of type 1 diabetes called latent autoimmune diabetes in adults (or LADA; for more about LADA, see above).
Can exposure to chemicals or drugs cause type 1 diabetes?
A few studies suggest that there may be a connection between type 1 diabetes and exposure to chemicals or drugs. But it is unlikely that such an environmental factor (such as exposure to a chemical or drug) alone can cause diabetes. It may be that if a person with a genetic susceptibility (inheriting a particular set of genes) is exposed to a certain chemical or environmental “triggering” factor, he or she may develop type 1 diabetes. But overall, this concept is highly debated.
What are the chances of developing type 1 diabetes because someone in the person’s family has the disease?
According to several studies, including one from the Joslin Diabetes Center, if a father has type 1 diabetes, the child has a 7 percent chance of developing the disease; if the mother has type 1 diabetes, the child has a 2 percent chance of developing type 1 diabetes. Other research suggests that the risk for developing type 1 diabetes is between 1 and 10 percent for people with a parent or sibling with the disease. Overall, the average chance of a child’s developing type 1 diabetes is 0.3 to 0.4 percent.
Why does heredity play a part in type 1 diabetes?
Although the genetic component of type 1 diabetes is not as strong as for type 2 diabetes, there is a reason for the higher risk of the disease being passed from generation to generation. Research has shown that DNA, or deoxyribonucleic acid-the set of instructions that tells the cells in the body how to grow, live, and function-mutates, increasing the risk for the disease.
Scientists have found that certain genes seem to be associated with type 1, type 2, and intermediary diabetes.
What are antibodies and autoantibodies?
Certain white blood cells of a person’s immune system are mainly responsible for protecting the body from germs and foreign invaders, including T cells (they attack foreign cells directly) and B cells (they produce antibodies, or special proteins that can recognize the surface shapes of molecules that attack the body).
Autoantibodies-usually found in people with autoimmune disorders-are B cells that sometimes make their own antibodies and recognize a person’s own cells. In the case of type 1 diabetes, it is thought that the autoantibodies identify the insulin-producing cells of the pancreas (beta cells) as cells to be attacked, and from there, the T cells destroy the beta cells.
What autoantibodies are common in people with type 1 diabetes?
There appear to be three autoantibodies that are common in people with type 1 diabetes. In the pancreas, these autoantibodies recognize and attack the islet cells (of which beta cells are one type), insulin, and glutamic acid decarboxylase (a protein made by the beta cells in the pancreas, also called GAD or the 64 K protein). The autoantibodies seem to be markers in the body and contribute to the destruction of the pancreas’ beta cells by identifying which cells should be attacked by the immune system. Ultimately, this causes the immune system’s T cells to destroy the insulin-producing cells of the pancreas.
Overall, of the people who are newly diagnosed with type 1 diabetes, 70 to 80 percent have autoantibodies to islet cells, 30 to 50 percent have autoantibodies to insulin, and 80 to 95 percent have autoantibodies to GAD. These autoantibodies often appear before the symptoms of type 1 diabetes show up. Thus, some researchers suggest that people who are at higher risk of developing type 1 diabetes be screened for these autoantibodies.
Can a virus cause type 1 diabetes?
Through the many years of research on type 1 diabetes, several reports have suggested that the disease may be caused by a virus. To date, no such virus-or even indirect evidence of such a virus-exists. Here are several of the viral-diabetes connection suggestions:
• One suggestion is that people who develop type 1 diabetes, according to some reports, often have had a recent viral infection before they are diagnosed. It has also been reported that many diagnoses of type 1 diabetes occur after a major viral outbreak.
• Another suggestion comes from research suggesting that viruses that cause mumps and German measles, along with the Coxsackie family of viruses (related to the virus that causes polio), may play a role in the development of type 1 diabetes. The researchers note that a certain autoantibody (see above) is almost identical to a region of a protein found in the virus Coxsackie B4. And because both are similar, the immune system’s T cells may not be able to tell the difference, thus destroying the “invading” cell, but in reality destroying the body’s own beta cells.
• Still another virus suggestion is that type 1 diabetes is a relatively new disease caused by a slow-acting virus, causing the immune system to attack proteins in the pancreas. To date, no such virus has been found.
INSULIN AND TYPE 1 DIABETES
Why does a person with type 1 diabetes need to take insulin?
A person with type 1 diabetes will need to take insulin for the rest of his or her life. In this case, the person’s immune system mistakenly has attacked and destroyed the pancreas’ beta cells that are responsible for producing insulin. Without insulin to aid blood glucose to be used by the body’s cells, the person’s blood glucose levels rise. There must be some type of replacement-thus, a person with type 1 diabetes must take insulin (usually by injection) every day.
What is insulin shock?
Insulin shock occurs if a person’s blood glucose levels are extremely low, causing him or her to lose consciousness. Such a severe low blood glucose level is considered a medical emergency.
Do people with type 2 diabetes ever have to take insulin injections?
Yes, some people with type 2 diabetes may eventually have to take injections of insulin to stabilize their blood glucose levels, especially if they take oral medications (like metformin) for a long time. (For more about type 2 diabetes and insulin, see the chapter “Prediabetes and Type 2 Diabetes.”)
In type 1 diabetes the pancreas doesn’t produce insulin, and therefore, glucose builds up in the body.
What are the various types of insulin a person with type 1 diabetes (and sometimes eventually a person with type 2 diabetes) takes?
There are several types of insulin you can take, each serving a different purpose for a person with type 1 diabetes (and sometimes eventually a person with type 2 diabetes). Some are used one at a time, while others can be taken in combination. They include rapid-acting, regular or short-acting, intermediate-acting, long-acting, or pre-mixed. (For more about the various types of insulin, see the chapter “Taking Charge of Diabetes.”)
RISKS AND COMPLICATIONS FOR PEOPLE WITH TYPE 1 DIABETES
What are ketones?
Ketones are naturally occurring fatty acids produced in the body. There are three ketone bodies, known as acetone, aceo-acetone, and beta-hydroxybutyrate (important to diabetes; see below), which are produced from fat and certain amino acids. An excessive amount of ketones is also often produced by the body during an uncontrolled diabetic event (see DKA, below).
Why does the body need ketones?
The body cannot store glucose for more than 24 hours, which is why it is important to maintain glucose levels for energy. And of course, this is also why humans must consume various foods to maintain the levels. In particular, the human brain (and other cells in the body) functions with the help of glucose and ketones. If there is not sufficient glucose, then the liver takes fat and certain amino acids (called fatty-acid metabolism) and turns them into ketones, first to feed the brain, then the rest of the body. This is called keto-adaptation, or nutritional ketosis, and is thought to be an evolutionary adaptation.
How are ketones measured?
Ketones are normally produced by the liver. They will be completely metabolized so there will be few, if any, that appear in a person’s urine. Normally, 3 to 15 milligrams of ketones (a very small amount) are excreted in the urine daily. Increased amounts of ketones, usually determined from a ketone urine test, can mean several conditions, many of which resemble other health problems. These conditions can include:
• Poorly controlled diabetes
• Diabetic ketoacidosis (see below)
• Starvation (for example, not eating for long periods, usually 12 to 18 hours, or anorexia nervosa, bulimia nervosa, alcoholism, or fasting)
• Some metabolic disorders
• A too-high protein or low-carbohydrate diet
• Vomiting over a long period
• A hyperactive thyroid gland (meaning too much thyroid hormone)
• Some types of toxic poisoning
How are ketone levels interpreted by physicians?
Physicians interpret ketone levels mainly on the basis of ketone urine tests. These may include test kits purchased at a drug store (they contain “dipsticks” coated with chemicals that react to ketone bodies by changing color) or sending a urine sample to a laboratory to be analyzed, usually a physician’s choice to obtain a more accurate reading. (There are also blood glucose meters that can measure blood ketones; for more information about meters, see the chapter “Taking Charge of Diabetes.”) The results are interpreted as follows (most often, abnormal results mean more tests must be made to determine the cause of the excess in ketones):
• A negative test result is normal, with a small amount of ketones in the urine.
• An abnormal result means there are ketones in the urine; results are broken down this way:
1. small-less than 20 milligrams per deciliter
2. moderate-30 to 40 milligrams per deciliter
3. large-greater than 80 milligrams per deciliter
Ketone tests can produce false results. For example, there may be a false-positive test result but no indication of ketones upon further testing. This may indicate certain conditions, mainly dehydration or the result of taking particular medications (for example, phenazopyrazine or vitamin C). There can also be false-negative ketone results, usually with urine-testing kits.
Is there a treatment if a person with diabetes tests positive for ketones?
Yes, if a person with diabetes tests positive for ketones when using a meter that detects ketone bodies, he or she should contact their diabetes educator or physician. The elevated numbers may mean the person needs additional insulin. According to the Joslin Diabetes Center, the person should also drink plenty of water and other fluids (that contain no calories) in order to flush out the ketones from the blood. The person is also advised to continue checking blood glucose levels for three to four hours, testing for ketones if the blood glucose level is over 250 mg/dl (milligrams per deciliter). In addition, a person with a blood glucose level over 250 mg/dl and ketones present should not exercise. There is a good reason: If both blood glucose and ketone levels are high, it can lead to a life-threatening condition called diabetic ketoacidosis (see below).
What is diabetic ketoacidosis, also known as DKA?
Diabetic ketoacidosis can occur when a person with diabetes has an episode of extremely high blood glucose and elevated levels of ketone (called positive ketones). It is not common and is most often associated with type 1 diabetes. (People with type 2 diabetes can also experience DKA, especially if they have very late-stage, insulin-dependent diabetes. But DKA is rarer in people with type 2 diabetes than in those with type 1.) It is most often detected with a urine test, as the ketones spill out into the urine. It is also often identified with a ketone test if the physician suspects an overabundance of ketones in the blood.
What happens if a person with diabetes develops diabetic ketoacidosis?
Diabetic ketoacidosis (DKA) occurs when a person with diabetes does not receive enough insulin. Without the insulin to help get the glucose into the body’s cells, the person essentially goes into what can be called a “starvation mode.” This triggers the liver to start making ketones out of fat and proteins to give the body’s cells energy, especially in the brain. But because there is no insulin, the cycle continues, and more ketones are produced. Both glucose and ketones are then transferred to the urine. The kidneys begin emptying the bloodstream of excess glucose and ketones with water, causing the person to urinate more and become dehydrated. By the time ketones-especially beta-hydroxybutyrate (75 percent) and to a lesser extent aceto-acetate-reach around 15 to 25 mM (millimolars), the body’s resulting pH balance (for more about pH, see this chapter) leads to metabolic problems, and the person becomes very ill. The metabolic disturbance usually causes low blood pressure and shock, and if not treated, the process can lead to a coma and eventual death.
The diagram above outlines the process leading to diabetic ketoacidosis as follows: 1) amino acids escape from muscle fibers due to low insulin levels; 2) the amino acids are converted to glucose in the liver; 3) glucose enters the bloodstream; 4) lack of insulin also causes adipose tissue to release fatty acids and glycerol, which are then turned into ketones inside the liver; 5) glucose from lack of insulin is also converted by the liver into ketones; and 6) ketones build up even more in the bloodstream.
Why are diabetic ketoacidosis and nutritional ketosis often confused?
The body normally produces some small amount of ketones every day. In nutritional ketosis, the body produces ketones when it burns fat for energy or fuel, occurring, for example, when a person loses weight or fasts. This is when the liver metabolizes fatty acids, turning them into ketones that are used as energy in various parts of the body. But diabetics must be careful not to confuse normal ketosis with diabetic ketoacidosis-the first is usually something to be watched, while diabetic ketoacidosis is most often a medical emergency. In a person with diabetes, diabetic ketoacidosis means the blood glucose levels are high (hyperglycemia), the person has low insulin levels, and there are moderate to large amounts of ketones in the blood.
Historically, was it often recorded how diabetes affected a person?
Yes, before the reasons and treatments for diabetes were better known, doctors watched their patients with diabetes go through a great deal of suffering. And although they did not know the details about diabetes-or even how ketones worked in a person with diabetes-many physicians’ reports detailed the stages toward death. In the early twentieth century that meant most often people with type 1 diabetes.
It is now known that often one of the major reasons that caused a person to die from diabetes (usually type 1) was the body’s buildup of ketone bodies. As the diabetic person’s body slowed down metabolizing food, it used fatty acids for its energy. This led to a buildup of ketones, and over time, the chemical clogged the person’s bloodstream and passed out in the urine. The person with an overabundance of ketones in his or her system would breathe out what was often called a “sickly apple smell” and continued to decline in health. As the ketones continued to accumulate, the body’s pH (see below) dropped to dangerous acidic levels-what we now know as diabetic ketoacidosis. As the person sank into a deep coma, death was usually only a few hours away.
Who should be aware of developing diabetic ketoacidosis?
People with type 1 diabetes, and insulin-dependent type 2, should be aware of their ketone levels (or symptoms of such a problem) so they do not develop diabetic ketoacidosis. Many physicians suggest monitoring ketones in all people with diabetes, especially in the following circumstances: if the person with diabetes misses an insulin injection or uses too little insulin during a period of illness or excessive or unusual stress; if the person’s diet is low in carbohydrates, the person is exercising a great deal, or a combination of both; in pregnant women who have diabetes, or gestational diabetes; and when the person’s blood glucose is high, or, if the person monitors ketones, if that level is very high.
Is there a treatment for diabetic ketoacidosis?
For people who develop a more advanced case of diabetic ketoacidosis and get to a hospital for help, there are other more extensive treatments available. Commonly, the condition is treated with an intravenous infusion of fluids and insulin in order to rehydrate the person. This treatment also lowers the person’s blood glucose levels and reverses the acidosis in the blood and body tissues. This is all done gradually to prevent the chance of hypoglycemia (low blood glucose levels) and hypokalemia (low potassium levels). Although measures are taken to help a person who develops diabetic ketoacidosis, it is estimated that almost 1,900 people with diabetes die each year from this condition.
Can a person with diabetes keep track of ketones in his or her blood?
Yes, it is possible for a person with diabetes to keep track of the ketone levels in the blood. Along with being checked by a hospital or the person’s physician, a person can use home blood tests and even some glucometers that detect the presence of ketones.
The pH scale measures how acidic or basic some-thing is on a scale of 1 (very acidic) to 14 (very basic).
What is pH?
The term pH is a chemical term taken from the French phrase puissance d’hydrogen, meaning “the power of hydrogen.” The pH is based on a scale that ranges from 0 to 14, with a pH of 1 being very acidic, pH of 7 being neutral, and pH of 14 being very basic (alkaline). For example, battery acid has a pH of about 0; human stomach acid has a pH from 1 to 3; lemon juice has a pH of about 2.3; tomatoes, grapes, and bananas have a pH of 4.6; black coffee has a pH of about 5; urine has about a pH of 5 to 7; saliva has a pH between 6.2 and 7.4; blood has a pH of around 7.3–7.5 (a bit alkaline); seawater has a pH of 7.8 to 8.3; and oven cleaner has a pH of about 13.
Why is bicarbonate important to the body?
In general, bicarbonates in the body help to maintain the pH of the blood and other fluids, or the balance between acid and basic (for more about pH, acidity, and basic [alkaline] levels, see sidebar). The kidneys and lungs usually help the body to maintain the pH. For instance, the kidneys remove bicarbonate from the blood if the pH is too high. But sometimes the levels can be affected by certain foods or medications-or if a person has uncontrolled type 1 diabetes. Thus, a doctor will often measure bicarbonate levels to learn whether a patient has problems with acidity in the body.
What is hypoglycemia?
Hypoglycemia occurs when a person has a very low blood glucose level. It is from hypo, or “low,” and glycemia, or “sugar in the blood.” It is often referred to as “a low” (mostly by people with diabetes), “insulin reaction,” or “insulin shock.” It is also the most common-and most dangerous-side effect that can often occur when a person has diabetes, especially if blood glucose levels are not monitored or the symptoms of hypoglycemia are ignored. (For more about hypoglycemia, see the chapter “Taking Charge of Diabetes.”)
What is severe hypoglycemia unawareness?
A certain condition often experienced by people with type 1 (and some with type 2) diabetes is called severe hypoglycemia unawareness, or the inability to sense that their blood glucose levels are dropping to an extremely low level. It is a dangerous condition and can lead to disorientation, unconsciousness, convulsions, and, if severe enough, even death. It is also considered a true emergency, as it makes people unable to help themselves.
One of the best ways to counteract a severe hypoglycemic episode is to give an injection of glucagon, the hormone that raises blood sugar, or intravenous glucose. The person with diabetes should always have an up-to-date glucagon kit at home and work for emergencies. (For more about what should go in a glucagon kit, see the chapter “Taking Charge of Diabetes.”) In addition, they should explain to family members, friends, and co-workers what signs to watch out for and how to use the glucagon in case of an emergency. If the kit is not available, call a paramedic team immediately so they can administer an injection of glucagon. (Emergency personnel must always carry such a kit in case they have to treat a person with diabetes. Some also carry tubes with a special sugar mixture that is similar to cake icing in order to raise the person’s blood glucose levels quickly.) Emergency medical technicians will also know whether the person having the hypoglycemic episode needs to be taken to the hospital.
What is hyperglycemia?
Hyperglycemia is the opposite of hypoglycemia. It occurs when a person with type 1 or type 2 diabetes has too much glucose in his or her system.
What is a hyperosmolar coma?
Although the condition is rare, if a person’s blood glucose levels rise to extremely high levels-over 800 mg/dl-and there are no ketones present, it can lead to what is called a hyperosmolar coma, or diabetic hyperglycemic hyperosmolar syndrome. In this case, there will usually be severe dehydration, confusion, or a coma. This condition occurs mostly in elderly people with type 2 diabetes. In most cases, their blood glucose levels increase because of an impaired ability to recognize that they are thirsty, ill, or under great stress. If people don’t drink more liquids at this stage (either because they are not thirsty or because of neurological damage from an event such as a stroke), then blood sugar levels can rise dangerously high. If it continues, the person will become sleepier and more confused and may have seizures following the dehydration, all of which can lead to a hyperosmolar coma. Such a condition most often requires hospitalization and can be fatal if not treated in a timely manner.OPEN OFFICE DUOMENU BAZES PAMOKOS | DOKTRINA SANSE PROBABILISTIC ASPEKTI GAMBLING STUART N ETHIER | APOE 4 | FLAMENCO HISTORY | FIVEMYTHS |