The earliest oral diabetes drugs were the sulfonylureas. These work by stimulating the pancreas to produce more insulin. The oldest of these drugs still on the market is chlorpropamide (Diabinese), which has been used for more than 50 years. The second-generation sulfonylureas are taken once or twice a day. They include glipizide (Glucotrol, Glucotrol XL), glyburide (Micronase, DiaBeta, Glynase), and glimepiride (Amaryl).
There are many drugs available to treat type 2 diabetes. Your diabetes care team can help you understand the differences among the types of medication on this long list, and will explain how you take them, what they do, and what side effects they may cause. Your doctor will discuss your specific situation and your options for adding one or more types of medication to your treatment.
Other drugs are on the horizon as well, as scientists work to improve the variety of medications to treat type 2 diabetes. Frequently physicians will prescribe one type of oral medication and discover it isn't really helping to control blood glucose that much. In the past, this would have meant that the patient would likely be put on insulin. Now, physicians can try another type of medication to see if it helps correct problems. Physicians often notice that a particular medication works well for a period of time and then begins to work less well for a patient. Now they can mix and match medications that work on different aspects of the diabetes problem to see if that will improve blood glucose control.
Peripheral neuropathy, one of the most common complications of type 2 diabetes, occurs most often in the distal extremities and typically affects the sensory, motor, and autonomic systems. Acupuncture has been demonstrated to exert a beneficial effect on neuropathic pain.2 The effects of acupuncture, particularly on pain, are mediated in part by the release of endogenous opioids from the spinal cord, brainstem, and hypothalamus. In addition, it has been demonstrated that neurotransmitters, such as serotonin and substance P, are released during acupuncture treatments. Increases in local blood flow and vasodilation and increased levels of cortisol have also been demonstrated.10 A 300% increase in plethysmographic recordings of blood flow has been demonstrated in the digits of limbs stimulated with electroacupuncture.10
In addition to walking and stretching exercises, try interval training cardio, like burst training, or weight training three to five days a week for 20–40 minutes. Burst training can help you burn up to three times more body fat than traditional cardio and can naturally increase insulin sensitivity. You can do this on a spin bike with intervals, or you can try burst training at home.
Many people have heard about type 2 diabetes, but its common precursor, prediabetes, doesn’t get as much attention. Prediabetes is estimated by CDC to affect 86 million Americans (51% of whom are 65 years and older), and an estimated 90% of people with prediabetes don’t even know it. According to the CDC, 15-30% of these individuals will develop type 2 diabetes within five years. In other words, as many as 26 million people that currently have prediabetes could develop type 2 diabetes by 2020, effectively doubling the number of people with type 2 diabetes in the US.
The accepted view has been that the β-cell dysfunction of established diabetes progresses inexorably (79,82,83), whereas insulin resistance can be modified at least to some extent. However, it is now clear that the β-cell defect, not solely hepatic insulin resistance, may be reversible by weight loss at least early in the course of type 2 diabetes (21,84). The low insulin sensitivity of muscle tissue does not change materially either during the onset of diabetes or during subsequent reversal. Overall, the information on the inhibitory effects of excess fat on β-cell function and apoptosis permits a new understanding of the etiology and time course of type 2 diabetes.
High blood sugar (hyperglycemia). Your blood sugar level can rise for many reasons, including eating too much, being sick or not taking enough glucose-lowering medication. Check your blood sugar level often, and watch for signs and symptoms of high blood sugar — frequent urination, increased thirst, dry mouth, blurred vision, fatigue and nausea. If you have hyperglycemia, you'll need to adjust your meal plan, medications or both.
Magnesium is a mineral found naturally in foods such as green leafy vegetables, nuts, seeds, and whole grains and in nutritional supplements. Magnesium is needed for more than 300 biochemical reactions. It helps regulate blood sugar levels and is needed for normal muscle and nerve function, heart rhythm, immune function, blood pressure, and for bone health.
Type 2 diabetes mellitus is a condition in which the body cells develop resistance to insulin and fail to use it properly. Type 2 diabetes mellitus is more common amongst overweight and obese adults over 40 years of age. The disorder can also be referred to as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes mellitus. Mostly, these patients need to manage their blood sugar levels through regular exercise, weight control, balanced diet, and anti-diabetes medications.
The reason they need it: Their own insulin-producing islet cells, located in the pancreas, aren’t working. Now, scientists across the US are racing to develop effective ways to transplant new islet cells in people with diabetes—an alternative that could make daily life easier and lower risk for insulin side effects like dangerous low blood sugar episodes.
Herbal products are not well controlled by government. They may not be what the bottle says they are. According to Rodale Press, research by the U.S. Food and Drug Administration and the Canadian government both found that many combination herbal capsules contained NONE of the herbs listed on the label. That’s why I mainly recommend plants you can buy and use in their whole form, such as ginger, cinnamon, bitter melon, and okra.
Another study published in the same journal, however, examined the effect of chromium on glycemic control in insulin-dependent people with type 2 diabetes. People were given either 500 or 1,000 mcg a day of chromium or a placebo for six months. There was no significant difference in glycosylated hemoglobin, body mass index, blood pressure, or insulin requirements across the three groups.
Initial clinical trial results, published in a 2012 PLOS One paper, reported that two doses of BCG spaced four weeks apart led to reductions in autoreactive T cells, an increase in Tregs and what turned out to be a transient increase in insulin production. But by the end of that short, 20-week trial, there was no reduction in HbA1c, the established measure of blood sugar levels over time. An extension and expansion of that trial with long term follow-up, the current results are based on data from 282 human study participants – 52 with type 1 diabetes who participated in the BCG clinical trials and 230 who contributed blood samples for mechanistic studies.
A recent study of 46 patients with painful peripheral neuropathy evaluated acupuncture analgesia to determine its short- and long-term efficacy. Using TCM acupuncture points, 34 patients (77%) experienced significant improvement in their symptoms. After a follow-up period of 18–52 weeks, 67% were able to stop or significantly reduce their pain medications. Only 8 (24%) required additional acupuncture treatment; 7 (21%) stated that their symptoms had cleared completely.11
Gymnema Sylvestre is a vine native to Central & South India. Used in traditional Indian medicine since the 6th century BC, the leaves of this plant contain ‘gymnemic acids’ that have the amazing ability to slow down the transport of glucose from the intestines to the bloodstream. Some scientists even believe that Gymnema Sylvestre extract can help repair and regenerate pancreatic beta cells that produce insulin!
Recent advances and research in management of Diabetes with traditionally used natural therapies have resulted in development of products from that facilitate production and proper utilization of insulin in the body. These preparations (Biogetica) are natural and work in conjugation with conventional therapies as supportive treatment protocols, they are absolutely safe and the patients are never at risk of developing hypoglycemic attacks due to the therapies.
At Diabetes Daily, we prefer using the word remission over cure because far too often the state of diabetes returns even with people’s best efforts. Regardless of the definition of a cure, finding a way to live with little to know highs or lows is a worthwhile endeavor. Long-term studies show that even a few years of great blood sugars significantly reduces your long-term risk of complications.
In type 2 diabetes, even though insulin resistance is what leads to the condition, injections of insulin are not the first resort. Instead, other drugs are used to help boost insulin production and the body’s regulation of it. Insulin resistance occurs when the body’s cells don’t respond properly to insulin, which is a hormone made in the pancreas that’s responsible for ferrying glucose to cells for energy.
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Regular monitoring of clinical trial participants found that HbA1c levels of those receiving BCG had dropped by more than 10 percent at three years after treatment and by more than 18 percent at four years. That reduction was maintained over the next four years, with treated participants having an average HbA1c of 6.65, close to the 6.5 considered the threshold for diabetes diagnosis, and with no reports of severe hypoglycemia. Participants in the placebo group and in a comparison group of patients receiving no treatment experienced consistent HbA1c elevations over the same eight-year time period.
The review affirmed how effective surgery is at treating diabetes (possibly even type 1 diabetes). Around two-thirds of patients with diabetes experience a full remission soon after surgery, while the rest are often better able to control their blood sugar through diet, exercise and medication. Other studies have shown that diabetics who have surgery outlive those who haven’t. Some longer-term research has suggested that one-third of these successes slide back into having active diabetes after five years, but to a lesser degree than they might have without surgery. By contrast, a 2014 study found that fewer than 2 percent of diabetes patients given standard care experienced any remission within a seven-year span.
Other studies have found that people with pre-diabetes or type 2 diabetes can go into remission through changes to their dietary and exercise habits. People who manage to achieve this with food alone will often express their excitement publicly by claiming they “cured” their diabetes with their diet. In reality, the likely put it into remission, though that remission can last a very long time.
Qigong (pronounced “chi gong”) is literally translated as “function of Qi.” It emphasizes the connection between the mind and body. It is a meditative method that consists of breathing techniques that can be combined with body movements in order to regulate, harness, and enhance Qi. Qigong is used as a means of promoting health, healing, spiritual growth, and overall well-being. While Qigong is not typically used as a major treatment modality for diabetes, it has been found to be a valuable adjunctive therapy for this condition. There are specific Qigong exercises for diabetes.15
However, the observation that normalization of glucose in type 2 diabetes occurred within days after bariatric surgery, before substantial weight loss (15), led to the widespread belief that surgery itself brought about specific changes mediated through incretin hormone secretion (16,17). This reasoning overlooked the major change that follows bariatric surgery: an acute, profound decrease in calorie intake. Typically, those undergoing bariatric surgery have a mean body weight of ∼150 kg (15) and would therefore require a daily calorie intake of ∼13.4 MJ/day (3,200 kcal/day) for weight maintenance (18). This intake decreases precipitously at the time of surgery. The sudden reversal of traffic into fat stores brings about a profound change in intracellular concentration of fat metabolites. It is known that under hypocaloric conditions, fat is mobilized first from the liver and other ectopic sites rather than from visceral or subcutaneous fat stores (19). This process has been studied in detail during more moderate calorie restriction in type 2 diabetes over 8 weeks (20). Fasting plasma glucose was shown to be improved because of an 81% decrease in liver fat content and normalization of hepatic insulin sensitivity with no change in the insulin resistance of muscle.
For over a decade, Cummings and others have tried to reframe the very concept of bariatric surgery (they prefer “metabolic surgery”). Their work has shown these procedures just don’t change how much food the stomach can fit; they trigger a cascade of metabolic and bodily changes, many of which help people with type 2 diabetes naturally get their blood sugar under control. Some changes even start happening before a patient loses weight, such as higher levels of peptide production in the gut that seem to restore a patient’s sensitivity to insulin.
If you are someone who has struggled with the roller coaster of blood sugar management, I have some good news! Research shows that there are common herbs and spices, likely ones that you already have in your kitchen, that have some potential positive effects on improving blood sugar. Today, I’m breaking down some of the superstar herbs and spices that data has indicated may help with blood sugar management.
Jambul fruit is an effective anti-diabetes agent considering its effect on the pancreas. The fruit, its seed, and juice, all are helpful in treatment of diabetes. Jambul fruit seeds contain a glucoside compound called "jamboline", which, supposedly, has the power to check the pathological conversion of starch into sugar in cases of increased production of glucose. Regular intake of jambul fruit can trigger pancreas to release insulin. Also, it can bring down blood sugar levels considerably. Therefore, jambul is an excellent anti-diabetes agent. It is one of the best home remedies for diabetes.
Meanwhile, other scientists are studying fenugreek seeds, a folk remedy for diabetes. Several studies, including one published in 1990 in the European Journal of Clinical Nutrition suggest that this herb can lower blood sugar. Researchers found that type 1 diabetics who took 50 grams of fenugreek seed powder twice daily had significantly lower blood sugar levels than those who took a placebo.
In medical world, diabetes is known more commonly by the name of diabetes mellitus. In simpler and day-to-day language, it is referred as diabetes. It is a group of metabolic diseases in which a person has high blood sugar, either because cells do not respond to the insulin that is produced, or the body does not produce enough insulin. In both the conditions, the body is not able to get enough amount of insulin to function properly.
According to the 2017 National Diabetes Statistics Report, over 30 million people living in the United States have diabetes. That’s almost 10 percent of the U.S. population. And diabetes is the seventh leading cause of death in the United States, causing, at least in part, over 250,000 deaths in 2015. That’s why it’s so important to take steps to reverse diabetes and the diabetes epidemic in America.
What is prediabetes? Prediabetes is a condition where blood sugar levels are higher than normal, but not high enough to be diagnosed as type 2 diabetes. This occurs when the body has problems in processing glucose properly, and sugar starts to build up in the bloodstream instead of fueling cells in muscles and tissues. Insulin is the hormone that tells cells to take up glucose, and in prediabetes, people typically initially develop insulin resistance (where the body’s cells can’t respond to insulin as well), and over time (if no actions are taken to reverse the situation) the ability to produce sufficient insulin is reduced. People with prediabetes also commonly have high blood pressure as well as abnormal blood lipids (e.g. cholesterol). These often occur prior to the rise of blood glucose levels.
Magnesium is high in green leafy vegetables, nuts, beans, and grains, but we remove most beans and all grains from the diet of patients, which is why using magnesium as part of a natural remedy for diabetes can be beneficial. Low intracellular magnesium can cause insulin resistance. Dosing of up to 500 mg a day is fine, but higher than that may result in diarrhea in patients.
Data from the Swedish randomized study of gastric banding showed that a loss of 20% body weight was associated with long-term remission in 73% of a bariatric surgery group, with weight change itself being the principal determinant of glucose control (13). Dietary weight loss of 15 kg allowed for reversal of diabetes in a small group of individuals recently receiving a diagnosis (21). In individuals strongly motivated to regain normal health, substantial weight loss is entirely possible by decreasing food consumption (88). This information should be made available to all people with type 2 diabetes, even though with present methods of changing eating habits, it is unlikely that weight loss can be achieved in those not strongly motivated to escape from diabetes. Some genetic predictors, especially the Ala12 allele at PPARG, of successful long-term weight loss have been identified (89), and use of such markers could guide future therapy. It must be noted that involuntary food shortage, such as a result of war, results in a sharp fall in type 2 diabetes prevalence (90,91).
After every hospitalisation she used to come back with blood sugar under reasonable limits. Within 30 days or so, her blood sugar levels will start increasing. With the rising blood sugar level, she used to get severe tooth ache. To manage her tooth ache she used to take pain killers. After few days of use of pain killers her blood sugar will become very high. Almost 450 to 550.
If diagnosed at an early stage, diabetes can be controlled with some minor lifestyle changes. A person can straightaway keep a check on his/her diet and start exercising on a regular basis. At any stage of diabetes, however, lifestyle changes are required. Therefore, it is better to imbibe these changes in one's life as soon as one comes to know about this disease.
Researchers are working on vaccines to prevent someone with type 1 diabetes from losing their insulin producing cells. In type 1 diabetes, the body’s immune system turns on its own insulin producing cells and periodically kills them off. A successful vaccine would prevent this from happening. The vaccine has been successful in rodents but vaccines have yet to demonstrate the same success in human trials.
If you are interested in trying a natural treatment in addition to standard treatment, be sure do so only under the close supervision of your physician. If diabetes is not properly controlled, the consequences can be life-threatening. Also, inform your physician about any herbs, supplements, or natural treatments you are using, because some may interact with the medications you are taking and result in hypoglycemia unless properly coordinated.
There is a risk that those who attempt it and fail could end up worse off, speculates Annie Hoang, a registered dietitian at Sunnybrook. An individual’s metabolism might switch into “starvation mode,” reducing the amount of energy needed at rest, she explains. That means some patients could regain all the weight they lost – and more – if they stop doing intermittent fasting.
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Diabetes is nearly 100% preventable. You won't hear this from mainstream medicine -- which ridiculously claims there is no cure for diabetes -- because treating diabetics is just too darned profitable. Big Pharma is drooling over the profit potential of seeing one-third of Americans becoming diabetic by 2050. It will mean hundred of billions of dollars in annual profits.
Now the question is, "what is the medicine that cures Diabetes?" The answer is, "Food is the medicine." Sounds interesting? Here in India, in the last 10 years we have seen a few thousands of them completely cured of Diabetes. All they have done is, they reversed the situation. To understand this, we first have to understand the bio-chemistry of Type-2 Diabetes. Type-2 Diabetes is caused either because our Pancreas not producing enough Insulin and/or our cells are not able to take the Insulin. Without the insulin accepted by the insulin receptors, the Glucose channel is not activated to take the Glucose. In most patients, even if Pancreas does not work well, Insulin units are given and then the insulin is slowly accepted by the Insulin receptors. But any food rich in Sugars, releases lot of Glucose instantly into the blood stream which cannot be absorbed by the cell at the same pace as the Insulin receptors are not capable/ready to accept the Insulin.
At his first visit, the naturopathic doctor told John he’d be “off medication and free of diabetes in three months.” John left the doctor’s office with instructions to eat a low-carb diet. He’d been on a low-fat diet for years because of heart problems, but while he’d cut the fat, his meals included many highly processed foods. His new diet included “a lot of salads and healthful, organic foods.” He was given several whole food supplements that he says were “simple to mix and tasted good.”
In 2017 the results of the DIRECT study were published, where obese type 2 diabetic were put on a 830 Cal diet for 6 month by their GPs (the two former studies were led by medical specialists), mean weight loss 15% ≈ 15 kg Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The more weight one lost, the higher the success rates
The prevalence of prediabetes is also on the rise, as it’s estimated that almost 34 million U.S. adults were prediabetic in 2015. People with prediabetes have blood glucose levels that are above normal but below the defined threshold of diabetes. Without proper intervention, people with prediabetes are very likely to become type 2 diabetics within a decade.
Currently, people with diabetes who receive a transplanted pancreas (typically not possible unless you are also having a kidney transplant) or who receive islet-cell transplants as part of a research study in the US must take these drugs so that their own body won’t attack the new cells. The drugs work, but raise risk for bacterial and viral infections as well as for mouth sores, nausea, diarrhea, high cholesterol, high blood pressure, fatigue and even some cancers.
Scientists are trying to figure out how to transplant islet cells and then protect them from the patient’s immune system so that long-term immunosuppressive medications aren’t required. Micro encapsulation is an approach scientists are testing to find out if a special coating to the transplanted islets can help the patient avoid rejection of those islets. These coatings let in nutrients to nourish the cells but prevent your body’s immune system from attacking them.
Keep your immunizations up to date. High blood sugar can weaken your immune system. Get a flu shot every year, and your doctor will likely recommend the pneumonia vaccine, as well. The Centers for Disease Control and Prevention (CDC) also recommends the hepatitis B vaccination if you haven't previously received this vaccine and you're an adult age 19 to 59 with type 1 or type 2 diabetes. The CDC advises vaccination as soon as possible after diagnosis with type 1 or type 2 diabetes. If you are age 60 or older, have diabetes and haven't previously received the vaccine, talk to your doctor about whether it's right for you.
You’re probably referring to Salacia oblonga (or S. oblonga) an herb traditionally used in Indian medicine to help control the increase in blood sugar that follows a meal. A study published in the January 2005 issue of the Journal of the American Dietetic Association found that a drink made with the herb blunts this effect and also reduces insulin levels. S. oblonga grows in India and Sri Lanka, but is not well known in the United States, and has not been widely researched.
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The extent of weight loss required to reverse type 2 diabetes is much greater than conventionally advised. A clear distinction must be made between weight loss that improves glucose control but leaves blood glucose levels abnormal and weight loss of sufficient degree to normalize pancreatic function. The Belfast diet study provides an example of moderate weight loss leading to reasonably controlled, yet persistent diabetes. This study showed that a mean weight loss of 11 kg decreased fasting blood glucose levels from 10.4 to 7.0 mmol/L but that this abnormal level presaged the all-too-familiar deterioration of control (87).
The twin cycle hypothesis of the etiology of type 2 diabetes. During long-term intake of more calories than are expended each day, any excess carbohydrate must undergo de novo lipogenesis, which particularly promotes fat accumulation in the liver. Because insulin stimulates de novo lipogenesis, individuals with a degree of insulin resistance (determined by family or lifestyle factors) will accumulate liver fat more readily than others because of higher plasma insulin levels. In turn, the increased liver fat will cause relative resistance to insulin suppression of hepatic glucose production. Over many years, a modest increase in fasting plasma glucose level will stimulate increased basal insulin secretion rates to maintain euglycemia. The consequent hyperinsulinemia will further increase the conversion of excess calories to liver fat. A cycle of hyperinsulinemia and blunted suppression of hepatic glucose production becomes established. Fatty liver leads to increased export of VLDL triacylglycerol (85), which will increase fat delivery to all tissues, including the islets. This process is further stimulated by elevated plasma glucose levels (85). Excess fatty acid availability in the pancreatic islet would be expected to impair the acute insulin secretion in response to ingested food, and at a certain level of fatty acid exposure, postprandial hyperglycemia will supervene. The hyperglycemia will further increase insulin secretion rates, with consequent enhancement of hepatic lipogenesis, spinning the liver cycle faster and driving the pancreas cycle. Eventually, the fatty acid and glucose inhibitory effects on the islets reach a trigger level that leads to a relatively sudden onset of clinical diabetes. Figure adapted with permission from Taylor (98).
In type 1 diabetes, patients sometimes experience what physicians have come to call a "honeymoon period" shortly after the disease is diagnosed. During the "honeymoon period" diabetes may appear to go away for a period of a few months to a year. The patient's insulin needs are minimal and some patients may actually find they can maintain normal or near normal blood glucose taking little or no insulin.
Type 1 diabetes is commonly called “juvenile diabetes” because it tends to develop at a younger age, typically before a person turns 20 years old. Type 1 diabetes is an autoimmune disease where the immune system attacks the insulin-producing beta cells in the pancreas. The damage to the pancreatic cells leads to a reduced ability or complete inability to create insulin. Some of the common causes that trigger this autoimmune response may include a virus, genetically modified organisms, heavy metals, vaccines, or foods like wheat, cow’s milk and soy. (4)
Some of the above drugs are available in compound form, and there are many patients taking three to four of them to control their blood sugar. But again, "the most common duo is metformin and a sulfonylurea,” says Arti Bhan, MD, division head of endocrinology at Henry Ford Health System in Detroit. “Metformin makes the body utilize insulin more effectively, and the sulfonylurea works on the pancreas to make more insulin in response to food consumption. Another common combination is metformin and insulin.”
Researchers from Newcastle and Glasgow Universities believe they have found a way to effectively reverse type 2 diabetes, without requiring a new kind of drug or invasive surgery. Type 2 diabetes is a chronic condition that affects how a person’s body metabolizes sugar, either because they’ve developed resistance to the hormone insulin, or their pancreas fails to produce enough insulin.
Panax ginseng (Korean ginseng), which has a long history of use as a hypoglycemic agent. At least five constituents of this herb have been shown to exert hypoglycemic effects. In one study, treatment with ginseng lowered blood glucose levels and improved mood and psychological performance as compared with placebo. Recommended dosage is 100–200 mg/day.14
It's unclear whether this rare side effect poses a risk for otherwise healthy kids with diabetes taking the drug, but until this is known, the precautions recommended for adults should be followed. Because in adults lactic acidosis is more likely to happen when a person is ill, diabetes pills should be stopped when your child is sick or has the flu.
Several types of plants are referred to as ginseng, but most studies have used American ginseng. They've shown some sugar-lowering effects in fasting and after-meal blood sugar levels, as well as in A1c results (average blood sugar levels over a 3-month period). But we need larger and more long-term studies. Researchers also found that the amount of sugar-lowering compound in ginseng plants varies widely.
According to TCM, Xiao-ke is attributed to three main factors: improper diet (consuming large quantities of sweets, fatty or greasy foods, alcohol, and hot drinks such as hot coffee or tea), emotional disturbances (stress, anxiety, depression,) and a constitutional Yin deficiency (fatigue, weakness, lethargy, pale complexion).7 To the Western ear, TCM diagnoses sound esoteric, even poetic. In the case of a person with diabetes presenting with symptoms of excessive thirst, the diagnosis can be described as kidney Yin deficiency along with lung Yin deficiency and “internal heat that consumes fluids, thus bringing on wasting and thirsting.”7
In order to reverse diabetes naturally, remove foods like refined sugar, grains, conventional cow’s milk, alcohol, GMO foods and hydrogenated oils from your diet; incorporate healthy foods like foods high in fiber, chromium, magnesium, healthy fats and clean protein, along with foods with low glycemic loads; take supplements for diabetes; follow my diabetic eating plan; and exercise to balance blood sugar.
It was the same endorsement the first Diabetes Surgery Summit, also organized by Cummings in 2007, had made, but the landscape had changed since then. In addition to more accumulated research, this time, their stance was backed by over 50 international professional organizations, including the American Diabetes Association. And while other medical societies and organizations had long backed surgery as an option for diabetes, the DSS-II guidelines are the first meant to guide clinical practice.