Nutrition in Pancreatic Diseases 2

It involves a systemic immuno-inflammatory response to a localized process of autodigestion of the pancreatic gland with variable involvement of the peri-pancreatic tissue and remote organ systems

Acute Pancreatitis Clinical Patterns Range

Acute PancreatitisThe sentinel acute pancreatitis event (SAPE) hypothesis:while there is a plethora of etiologic agents or insults which may injure the pancreas, there is a final common pathway of inflammation in the disease process termed the sentinel event

Acute PancreatitisThe sentinel acute pancreatitis event (SAPE) hypothesis:while there is a plethora of etiologic agents or insults which may injure the pancreas, there is a final common pathway of inflammation in the disease process termed the sentinel event

Acute PancreatitisAn early pro-inflammatory process starts with the stimulation of chemotaxis and migration of neutrophils into and around the pancreatic acinus, with neutrophil activation, recruitment, and infiltration. This is followed by a later pro-fibrotic response that involves stimulation of stellate cells surrounding the acinar cells. It is not the initial insult, but the subsequent sentinel event and its vicious cycle of inflammation that drives the morbidity and mortality. As the sentinel event sets up around the acinar cell, two defects occur which promote further inflammation and stimulate autolysis or autodigestion the pancreatic tissue.

Acute PancreatitisThe first defect is an intra-acinar activation of pancreatic enzymes in which zymogen are co-localized with lysosomal enzymes like Cathepsin. The second defect is inhibitioof secretion, in which the zymogen enzymes are activated, but then retained within the acinar cell. This process results in inflammation, edema, an necrosis of the pancreatic tissue as well as inflammation and injury of extrapancreatic organs75-80% has mild, oedematous and about 20-25% severe necrotizing pancreatitis.

Acute PancreatitisThe first defect is an intra-acinar activation of pancreatic enzymes in which zymogen are co-localized with lysosomal enzymes like Cathepsin. The second defect is inhibitioof secretion, in which the zymogen enzymes are activated, but then retained within the acinar cell. This process results in inflammation, edema, an necrosis of the pancreatic tissue as well as inflammation and injury of extrapancreatic organs75-80% has mild, oedematous and about 20-25% severe necrotizing pancreatitis.

Acute PancreatitisIn patients with acute pancreatitis was the absolute influence of organ failure and infected pancreatic necrosis on mortality the same. Both indicate severe disease. If both are present the relative risk of mortality doubles. Nutritional support in severe necrotising pancreatitis is essential because these patients develop rapidly nutritional deficiencies. This is even more fatal if patients are already malnourished at the time of the initial attack.

Outcome predictorsTwo factors, the severity of pancreatitis and the nutritional status can be used to predict the outcome in acute pancreatitis.

Severity Of Acute Pancreatitisa score of 3 or more in the Ranson Criteria (Table 1) or a score of 8 or more in the APACHE II-Score and evidence of organ failure and intrapancreatic pathological findings (necrosis or interstitial pancreatitis) (Tab. 2). This classification is helpful because it also allows the comparison of different trials and methodologies

Severity Of Acute PancreatitisFailure of pancreatic parenchyma to enhance during the arterial phase of intravenous contrast-enhanced CT indicates necrosis, which predicts a severe attack if more than 30% of the gland is affected.

CT gradeQuantity of necrotic pancreasGrade A = 0Normal appearing pancreas 50% = 6Grade B = 1Focal or diffuse enlargement of the pancreasGrade C = 2Pancreatic gland abnormalities accompanied by mildGrade D = 3parapancreatic inflammatory changesGrade E= 4Fluid collection in a single location, usually within theTotal score = CT grade (0-4) + necrosis (0-6)

Severe acute pancreatitis

The measurement of concentrations of serum Creactive protein (CRP) is very useful in clinical practice. CRP concentration has an independent prognostic value. A peak of more than 210 mg/l on day 2 to 4, or more than 120 mg/l at the end of the first week, is as predictive as multiple-factor scoring systems (12). The blood urea nitrogen levels (BUN) were persistently higher among nonsurvivors than survivors in the first 48 hours of hospitalisation --> BUN is a new valuble marker for predicting mortality (13).

Nutritional statusUndernutrition and obesity are often seen in patients with acute pancreatitis. Both are well-known risk factors for more complications and higher mortality. Undernutrition is known to occur in 50-80% of chronic alcoholics and alcohol is a major etiological factor in acute pancreatitis patients (30-40%).Patients with biliary pancreatitis have a high tendency to be overweight. For nutritional support it is therefore necessary to assess the severity of acute pancreatitis and the nutritional status at the time of admission and during the course of the disease. Both factors are necessary to plan nutrition interventions in patients with acute pancreatitis.

Energy and substrate metabolism during acute pancreatitisSpecific and non-specific metabolic changes occur during acute pancreatitis. A variety of proinflammatory cytokines increase the basal metabolic rate. This can result in increased energy consumption. The resting energy expenditure varies according to the severity and the duration of disease. If patients develop sepsis, 80% of them show an elevation in protein catabolism and an increased nutrient requirement. A prolonged negative nitrogen balance determines negative clinical outcome. Whether negative nitrogen balance is the principle factor for outcome is not clear. The relationship between nitrogen balance and outcome may only reflect the relationship between nitrogen balance and severity of disease. There is no study available in which patients were stratified according to the disease severity.

Metabolism of carbohydratesGlucose metabolism in acute pancreatitis is determined by the SIRS response, oxidative stress, and insulin resistance. The resultant futile fluid cycling and milieu of inflammatory cytokines may cause an increase in energy demand. Endogenous gluconeogenesis is increased as a consequence of the metabolic response to the severe inflammatory process. Glucose is an important source of energy and can partially counteract the intrinsic gluconeogenesis from protein degradation. This can counteract, to a certain degree, the deleterious and unwanted effect of protein catabolism.

Metabolism of carbohydratesThe maximum rate of glucose oxidation is approximately 4 mg/kg/min. The administration of glucose in excess can be harmful, and even wasteful, because of lipogenesis and glucose recycling. Furthermore, hyperglycemia and hyperkapnia can occur. Hyperglycemia is a major risk factor for infections and metabolic complications. Monitoring and blood glucose control is therefore essential. Evidence glucose intolerance occurs in the majority of cases (incidence 85%).

Protein metabolism

A negative nitrogen balance is often seen in severe acute pancreatitis. The protein losses must be minimized and the increased protein turnover must be compensated. If acute pancreatitis is complicated by sepsis, up to 80% of the patients are in a hypermetabolic state with an increase of the resting energy expenditure. A negative nitrogen balance is associated with adverse clinical outcome.Nitrogen losses are as much as 20-40 g/day in some patients with acute pancreatitis.

Lipid metabolism

Hyperlipidemia is a common finding in acute pancreatitis. The mechanism of altered lipid metabolism is not entirely clear. After an acute attack, serum lipid concentration returns to normal ranges. It is also known that in some patients with severe hyperlipidemia an acute pancreatitis can develop.Evidence of fat intolerance occurs only in 12-15% of cases

Exocrine pancreatic stimulation by macronutrientsIn general all forms of enteral nutrition can stimulate the exocrine pancreatic secretion to some extent. Only with parenteral nutrition this is not the case. For nutritional intervention the administration of glucose, protein and fat are necessary, but for long time enteral applications were considered to be harmful because of the potential stimulation of the exocrine pancreatic enzyme secretion.Enteral glucose perfusion into the jejunum is a very weak stimulus for exocrine pancreatic secretory response. Jejunal perfusion of elemental diets containing defined amounts of protein or amino acids are well tolerated and do not stimulate exocrine pancreatic secretion.

Exocrine pancreatic stimulation by macronutrients

The only concern of potentially exacerbating acute pancreatitis with intravenous PN is through the development of hypercalcemia or hypertriglyceridemia. Compared to delivery of the same nutrients intravenously, an enteral infusion results in a greater insulin response, less insulin resistance, and less hypertriglyceridemia due to the enteroinsular pathway. All this findings have changed the nutritional concept in acute pancreatitis. Nowadays, enteral feeding in the jejunum 20-120cm after the ligamentum of Treitz is regarded to be safe without major stimulating of autodigestive processes in the pancreas and maintaining the gut integrity by modulating the GI-tract systemic immunity.

Energy requirements

Patients with severe acute pancreatitis are hypermetabolic. The more severe acute pancreatitis is the more excessive is hypermetabolism. Resting energy expenditure can be variable in these patients. 77- 158% of the predicted energy expenditure was reported. If the disease is complicated by sepsis or multiorgan failure, the resting energy expenditure is significantly increased.It was shown that in severe acute pancreatitis, the Harris-Benedict equation is not sensitive enough to estimate the caloric expenditure. In these cases, indirect calorimetry is recommended to avoid over- or underfeeding.

For enteral or parenteral nutrition, 25-35kcal/kgBW/d is recommended. Overfeeding and hyperglycemia should be avoided. Blood glucose concentration should not exceed 10 mmol/l. Insulin treatment is recommended, but the doses should not be higher than 4 to 6 units/h. The impaired glucose oxidation rate can not be normalized by insulin administration. Normally, 3-6g/kgBW/d of carbohydrates can be recommended. The optimal goal of protein supply is between 1.2 to 1.5g/kgBW/d. Lower protein intake should only be given to patients with renal or severe hepatic failure. Fat can be given up to 1g/kgBW/d, but blood triglyceride levels must be monitored carefully. Triglycerides are tolerated up to 12 mmol/l.

Enteral or parenteral nutritionIn mild to moderate acute pancreatitis these studies showed no effect on outcome in these patients.TPN did not change the course of the disease but TPN was more expensive or accompanied with an increase in catheterrelated infections and a longer hospital stay. In the last years it became clear, that these complications were often the consequence of overfeeding. Recently, the nutritional management shifted from parenteral to enteral feeding.Enteral eeding in acute pancreatitis may reduce catabolism and loss of lean body mass and may modulate the acute phase response with the potential to down regulate splanchnic cytokine response

Nutritional support in mild to moderate pancreatitis

There is no evidence that a nutritional support (enteral or parenteral) has a beneficial effect on clinical outcome in patients with mild acute pancreatitis. Enteral nutrition is unnecessary, if the patients can consume normal food after 5 to 7 days (ESPEN Guidelines: Grade B).Enteral or parenteral nutrition within 5 to 7 days has no positive effect on the course of the disease and is therefore not recommended (ESPEN Guidelines: Grade A). Early enteral nutrition support can be of importance in patients with pre-existing severe malnutrition or in patients when early refeeding in 5 to 7 days is not possible.

Nutritional support in severe acute pancreatitisIn patients with severe pancreatitis, who have complications or need for surgery, early nutritional support is needed to take advantage of window of opportunity by which EN can favorably alter patient outcome. In severe necrotizing pancreatitis, enteral nutrition is indicated first if possible (ESPEN Guidelines: Grade A, ASPEN/SCCM Guidelines: Grade C). In the last decade, the nutritional strategy in acute pancreatitis has changed. The nutritional management has shifted from parenteral to enteral nutrition. Enteral feeding in acute pancreatitis have shown to reduce catabolism and loss of lean body mass, modulation of the acute phase response, with the potential to down regulate the splanchnic cytokine response. Furthermore, enteral nutrition has been shown in many studies to be safe and well tolerated.

Nutritional support in severe acute pancreatitisSevere Acute pancreatitisEarly continuous enteral nutrition(naso-jejunal tube) elemental diet or polymeric diet orimmune-enhancing dietEnteral nutrition is not possiblePN after 5 daysif EN is unable to use, add supplemental PN to hypocaloric EN after 7 days if it is unable to reach the goal calories by EN aloneand continuous small amount of anenteral diet (10-30 ml/h) perfused to thejejunumnutritional goal not reachedAdd parenteral nutritionall in one or single componentsolutions?(CH, protein (AS), fat)

Route of feedingThe route of nutrient delivery (parenteral/enteral) should be determined by patients tolerance. Tube feeding is possible in the majority of patients, but some patients need a combination with parenteral nutrition (ESPEN Guideline: Grade A). Placing a jejunal feeding tube distally to the ligament of Treitz can easily be performed. The tubes are placed either with fluoroscopic help or more and more with the endoscope. Another way is also to use self-propelling nasojejunal feeding tubes. Normally, jejunal tubes are well tolerated. Early initiation of distal jejunal feeding was associated with reduced mortality in patients with severe acute pancreatitis. The early achievement of the feeding goals was also associated with a shorter length in the ICU. Rarely, proximal migration of the feeding tube and subsequent pancreatic stimulation can aggravate acute pancreatitis. Partial ileus is not a contraindication for enteral feeding because these patients frequently tolerate continuous low-volume jejunal nutrients.

Which enteral and parenteral formula should be used in acute pancreatitis

Most studies have been done using peptide-based formulae. The use of peptide-based formulae showed beneficial effects (ESPEN Guidelines: Grade A). Nowadays in most institutions polymeric formula are used although only few data are concluded that a polymeric formula compared to a (semi)elemental formula show no significant higher risk of feeding intolerance, infectious complication or mortality in acute pancreatitis patients. In addition the polymeric formulas are less expensive

They found a significant benefit for the early supplementation of glutamine. They showed a reduction of the presence and duration of organ failure, the incidence of infection, the need for surgery, and mortality. The supplementation of n-3 fatty acids alone in moderately severe acute pancreatitis significantly lowered the length of hospital stay, and the need of nutritional therapy. The overall complication rate was not different

Gastral versus jejunal feedingWheather the jejunal feeding is absolutely necessary is not completely clear. Minimizing stimulation of the exocrine pancreatic secretion would support the jejunal feeding route. It is, however, controversial whether stimulation of pancreatic secretion is important for the outcome in this disease. Four randomized studies comparing naso-gastric versus naso-jeunal feeding or naso-gastric versus TPN in severe acute pancreatitis were published. In these studies, naso-gastric feeding was as safe as naso-jejunal feeding; little difference were documented between the two methods with respect to pain, analgesic requirements, nutritional intolerances, serum CRP concentration, or mortalityCompared to parenteral nutrition there were significantly more complications in the first 3 days in the naso-gastric group, but there was a better control of blood glucose levels.

The advantage of gastric feeding is to facilitate delivery of EN, reduce time to initiation of feeding, and minimize chances for ileus and intolerance. The limitations of jejunal feeding are the need for expertise in tube placement below the ligament of Treitz. There is little harm and no real downside from this strategy of gastric feeding, as evidence of intolerance can be ameliorated by adjustments in level of infusion and content of formula.

Oral refeeding

There are only few data available on oral refeeding. Oral feeding with normal food and/or oral supplements can be progressively attempted once gastric outlet obstruction has resolved, provided it does not result in pain, and if complications are under control. Tube feeding can be gradually withdrawn as intake improves with several meals given during the day.

Nutritional support in patients after pancreatic surgery

Postoperative feeding with a needle catheter jejunostomy was successful in several small studies. Hernandez-Aranda et al found no difference between groups of patients who received postoperative parenteral nutrition or enteral nutrition via jejunostomy.Furthermore, in patientsundergoing surgery for severe acute pancreatitis, needle catheter jejunostomy for longterm enteral nutrition was safely applied with no nutritional risk. In general, in these patients, nutritional support has to be planned before the operation according to the clinical situation and the course of the disease

Summary

75-80% of patients with acute pancreatitis have mild to moderate disease and do not need specific nutritional support. Early oral refeeding can be started within a few days if the patients have no pain and GI-disturbances. The best time and the best composition of the diet are not clear. There is no evidence that a specific enteral or parenteral nutrition is of benefit in patients with mild to moderate pancreatitis. There are no data available to give a nutritional recommendation in patients with severe pre-existing malnutrition or overweight. Patients with severe disease, complications or the need for surgery require early nutritional support.

In patients with severe pancreatitis, an enteral jejunal approach should be established, but parenteral nutrition is an alternative method, when enteral nutrition is insufficient. For the future, more aggressive use of pharmaconutrition may be employed to modulate epigenetics and activate the bodys own antioxidant response elements to reduce oxidative stress.

Several factors have to be clarified: The optimal timing of nutritional therapy, the optimal feeding side (oral, gastric, jejunal or TPN), the optimal nutrient formulation, semi-elemental diet, polymeric diet, immune-enhancing diet, pre- and probiotics). Furthermore, in new studies a clear stratification of the patients according to their nutritional status on admission should be performed.

Chronic Pancreatitis

Pancreatic physiologyThe exocrine response of the exocrine pancreas is time dependent (Fig. 2) and related to several factors (Fig.3). The exocrine pancreas consists mostly of acinar, but additionally of centroacinar and duct cells. Whereas the acinar cells synthesize > 10 digestive enzymes, the duct cells are responsible for generation of bicarbonate, which is necessary to neutralize gastric acid and to raise the pH in the duodenum to obtain an optimal alkaline milieu for the pancreatic enzymes as well as for the jejunal digestive brush border enzymes.The vagus nerve and the hormones secretin and cholecystokinin (CCK) are responsible for stimulation of the exocrine pancreas. The pancreatic enzymes digest starch (amylase), lipids (lipase), and protein (trypsin and other proteolytic enzymes). The most important stimulus for pancreatic secretion is the presence of nutrients in the duodenal lumen.

Pancreatic physiology

Pancreatic physiologyThe quantity and the composition of nutrients in the duodenal lumen influencesthe pancreatic secretory response

Pathophysiology of chronic pancreatitisDue to the loss of acinar and duct cells (Fig. 4) the secretory capacity of the exocrine pancreas decreases. The large physiological reserve of the pancreas is the reason why clinical signs of fat maldigestion occur late in the course of CP, typically when 80 % of the secretory capacity of the pancreas has been lost. Fat maldigestion (steatorrhoea; > 10 g of stool fat per 24 hours) is the major problem in these patients. Steatorrhoea is caused by (i) reduced pancreatic bicarbonate secretion leading to more rapid and complete inactivation of lipase in the acidic duodenum; (ii) further impairment of lipid absorption by bile acid denaturation within the acidic duodenum; (iii) rapid degradation of lipase in the small intestine lumen due to its greater vulnerability to proteolysis thereby reducing the period of lipase activity;(iv) limited capacity of extrapancreatic lipase (gastric); (v) no compensating triglyceride-digesting enzymes in the intestinal brush border. Because fat is the major source of energy, fat maldigestion creates a high risk of protein-energy malnutrition, but also causes micronutrient and vitamin deficiency

Creatorrhoea (excess nitrogen losses in the stool: >2.5 g of stool nitrogen per 24 hours) only occurs when trypsin output is less than 10% of normal. The problem with nitrogen balance studies is the difficulty of separating the contribution to stool nitrogen loss of ingested protein, compared with that from proteins secreted into the GI tract and that derived from bacteria.

The effect of enzyme supplementation on protein maldigestion has therefore not been well characterized. As well as the increased risk of malnutrition, the increased stool volume and fat content cause abdominal symptoms such as pain, fullness, distension, diarrhoea, meteorism, and flatulence. Twenty to 25 % of cases with exocrine pancreatic insufficiency may also have the complication of bacterial overgrowth, which can further contribute to diarrhoea and other GI symptoms.

Clinical features of chronic pancreatitis

The cardinal symptom of CP is pain, which can present either as repeated mild or moderate attacks or as persistent and intractable abdominal and back pain. The median latency between onset of first symptoms and signs of maldigestion is about 89 years in alcoholic chronic pancreatitis and more than 15 years in idiopathic non-alcoholic pancreatitis. In a minority of patients the clinical signs of exocrine pancreatic precede the other features of the condition.

Nutritional status in CPBody weight and body composition Weight loss occurs in those patients with maldigestion and in those with reduced food intake due to pancreatic pain. Although, weight loss is a frequent symptom in CP, only limited data on nutritional status in CP patients are available. Patients with symptomatic CP have a lower body mass index, reduced lean body mass and fat mass compared to healthy controls.Malnutrition is associated with higher morbidity (e.g. higher incidence of postoperative complications after surgery for chronic pancreatitis). Therefore, those patients with malnutrition should be identified and treated.Nutritional assessment is easy to perform. Weight loss over time, body mass index, anthropometry and some laboratory values are useful parameters. Furthermore, nutritional screening scores, e.g. subjective global assessment (SGA), the ESPEN nutritional risk score (ESPEN-NRS; see www.espen.org/) are available for detecting those patients with nutritional deficiencies who are at risk of developing complications.

Metabolic situationIn patients with chronic pancreatitis, resting energy expenditure is increased by 3050%. The loss of endocrine function in the late state of the disease also leads to glucose intolerance and eventually to frank diabetes. Glucose intolerance occurs in 4090% of all cases with severe chronic pancreatitis during the course of disease. In 2030% of all patients insulin-dependent diabetes develops. This is also associated with impaired glucagon release and reduced counter-regulatory capacity in the event of insulin induced hypoglycaemia.Minerals, Micronutrients and VitaminsCirculating levels of minerals, micronutrients and vitamins are reduced in CP patients with fat maldigestion: this includes magnesium, calcium, essential fatty acids, and vitamin A, D, E, and K. In particular, vitamin D and calcium deficiencies are associated with an increased risk of osteomalacia and osteoporosis.

Pain treatmentAnalgesics. Anti-inflammatory, non-narcotic (and therefore non-addicting) pain medicines are tried first. If these provide no relief, narcotics or morphine may be given in addition to relieve sudden episodes of inflammation. The risk of becoming depended is low in chronic pain. Note also that non-steroidal anti-inflammatory drugs may themselves cause pancreatitis.Tricyclic antidepressants. These medications are synergistic with other pain medication, particularly in those patients in whom pain and depression co-exist. .Pancreatic enzyme supplements. A time limited trial of pancreatic enzyme supplementation can be tried, but if no pain relief has been observed after 4 weeks, the enzymes should be stopped, unless exocrine deficiency is also present.Acid reducers. H2-receptor-blocking medicines and proton pump inhibitors may be given along with enzymes to reduce the production of stomach acid, which can stimulate the pancreas. But again, if this is not successful after 4 weeks, the acid reducer can be stopped.

ERCP. Patients with an obstructed pancreatic duct or pancreatic stones may profit from an endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction or placement of a stent in a narrowed pancreatic duct.Coeliac plexus nerve block. An injection of alcohol or corticosteroids into the retroperitoneal nerves (plexus) may provide temporary relief.Surgery. Pancreatic surgery (Whipple procedure or duodenum preserving pancreatic head resection) is the last treatment option for pain in CP patients. Those patients, in particular, who have had benefit from endoscopic procedures or have a pseudo-inflammatory mass of the pancreas, seem to benefit from surgery. It has to be noted, however that surgery also has some peri- and postoperative side effects.

Diet recommendationsA normal diet should be the target goal in CP patients. In general, patients should maintain a diet with high energy (35 kcal/kg/24 hours), high protein (1.0 to 1.5 g/kg/24 hours), rich in carbohydrates, and with moderate amounts of fat (0.7 to 1.0 g/kg/24 hours). A reduction in oral fat intake or the replacement of dietary fat with medium chain triglycerides (MCT) risks a reduction in energy intake and therefore, a negative energy balance. This treatment option should, therefore, only be considered if adequate enzyme supplementation and exclusion of bacterial overgrowth has not led to relief of maldigestion and its accompanying symptom

Fat soluble vitamins (A, D, E, K), and vitamin B12, as well as other micronutrients and minerals should be replaced as clinically indicated. This means that those patients with signs of persistent maldigestion should automatically receive multivitamin and trace element supplements, although neither this nor the effect of MCTs have been proved in clinical trials. In CP, antioxidant capacity is decreased and oxidative stress seems to be a factor promoting CP. This has been considered as a rationale for interventions with antioxidants like selenium or vitamin C or E.

Enteral feedingFrom clinical experience, enteral feeding via a gastric or jejunal tube is seldom necessary except during acute episodes of pancreatitis. As in acute pancreatitis, experience suggests that the optimal method of feeding may be via the jejunal route. But enteral sip feeding has the potential, in patients with severe malnutrition, to improve energy and protein intakeIn long-term enteral support, this can be maintained either by a percutaneous endoscopic gastrostomy with jejunal extension or by a direct percutaneous endoscopic jejunostomy. Parenteral nutrition (PN) is only indicated if enteral nutrition is not possible. There are no specific considerations with regard to PN in patients with CP.

Summary

Malnutrition is a frequent feature in patients with CP, with maldigestion and pain being the two major risk factors for its development. Nutritional therapy should always be considered as an integral part of the overall multimodal medical and surgical therapy of chronic pancreatitis. A low fat diet is often prescribed, but carries the risk of reduced total energy intake, thereby worsening the degree of malnutrition. This approach can, therefore, only be recommended in those patients in whom pain control and enzyme supplementation fail to resolve the gastrointestinal symptoms. Sip or enteral tube feeding are options for patients not responding to medical therapy or for those undergoing surgery.

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