Why Do You Get Leukocytosis In Dka?

Diabetic Ketoacidosis And Hyperglycemic Hyperosmolar Syndrome

In Brief Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS) are two acute complications of diabetes that can result in increased morbidity and mortality if not efficiently and effectively treated. Mortality rates are 2–5% for DKA and 15% for HHS, and mortality is usually a consequence of the underlying precipitating cause(s) rather than a result of the metabolic changes of hyperglycemia. Effective standardized treatment protocols, as well as prompt identification and treatment of the precipitating cause, are important factors affecting outcome. The two most common life-threatening complications of diabetes mellitus include diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS). Although there are important differences in their pathogenesis, the basic underlying mechanism for both disorders is a reduction in the net effective concentration of circulating insulin coupled with a concomitant elevation of counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). These hyperglycemic emergencies continue to be important causes of morbidity and mortality among patients with diabetes. DKA is reported to be responsible for more than 100,000 hospital admissions per year in the United States1 and accounts for 4–9% of all hospital discharge summaries among patients with diabetes.1 The incidence of HHS is lower than DKA and accounts for <1% of all primary diabetic admissions.1 Most patients with DKA have type 1 diabetes; however, patients with type 2 diabetes are also at risk during the catabolic stress of acute illness.2 Contrary to popular belief, DKA is more common in adults than in children.1 In community-based studies, more than 40% of African-American patients with DKA were >40 years of age and more than 2 Continue reading >>

Prediction And Rate Of Infections In Diabetes Mellitus Patients With Diabetes Ketoacidosis In Penang, Malaysia

Syed Wasif Gillani1*, Syed Azhar Syed Sulaiman1, Shameni Sundram2 1School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia 2Hospital Pulau Pinang, Pulau Pinang, Malaysia Email: *[email protected] Keywords: Diabetes Mellitus; Diabetes Ketoacidosis; Infections; Predictors; Rate of Infection Study aimed to determine the rate and prediction of infection in diabetes mellitus patients ≥ 18 year, with diabetic ketoacidosis (DKA). Retrospective cohort study design was adopted to achieve the objectives. Universal sampling technique was employed for data collection among Diabetes ketoacidosis patients, over a period of 3 years (Jan 2008-Dec 2010). Statistical package for social sciences used to analyze data. Over a 3-year period, total of 967 admissions were identified. Of it, 112 (11.6%) with no infection, 679 (70.2%) with bacterial infection and 176 (18.2%) with presumed viral infection. The mean WBC for all the patients was 18,177 (±9431). 721 (74.6%) had leukocytosis, as defined by a WBC ≥ 15,000/mm3. WBC, differential, leukocytosis, as well as sex, temperature were not significant predictors (p > 0.05) of bacterial infection. There was significant (p < 0.05) difference of age between the 3 groups, age above 57 years have high rate of infection as compared to age below and equal 57 years. The infection rate in elderly patients with DKA was high and majority of them had lack of clinical evidence. Major bacterial infections with potential serious sequel were particularly common (33.3%), among every third patient being presumed to have serious consequences. It is commonly believed that acute infectious illness can precipitate episodes of ketoacidosis in patients with diabetes mellitus. For this reason, a diligent search for bacterial infect Continue reading >>

Starvation Ketoacidosis: A Cause Of Severe Anion Gap Metabolic Acidosis In Pregnancy

Copyright © 2014 Nupur Sinha et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pregnancy is a diabetogenic state characterized by relative insulin resistance, enhanced lipolysis, elevated free fatty acids and increased ketogenesis. In this setting, short period of starvation can precipitate ketoacidosis. This sequence of events is recognized as “accelerated starvation.” Metabolic acidosis during pregnancy may have adverse impact on fetal neural development including impaired intelligence and fetal demise. Short periods of starvation during pregnancy may present as severe anion gap metabolic acidosis (AGMA). We present a 41-year-old female in her 32nd week of pregnancy, admitted with severe AGMA with pH 7.16, anion gap 31, and bicarbonate of 5 mg/dL with normal lactate levels. She was intubated and accepted to medical intensive care unit. Urine and serum acetone were positive. Evaluation for all causes of AGMA was negative. The diagnosis of starvation ketoacidosis was established in absence of other causes of AGMA. Intravenous fluids, dextrose, thiamine, and folic acid were administered with resolution of acidosis, early extubation, and subsequent normal delivery of a healthy baby at full term. Rapid reversal of acidosis and favorable outcome are achieved with early administration of dextrose containing fluids. 1. Introduction A relative insulin deficient state has been well described in pregnancy. This is due to placentally derived hormones including glucagon, cortisol, and human placental lactogen which are increased in periods of stress [1]. The insulin resistance increases with gestational age Continue reading >>

Emergent Treatment Of Alcoholic Ketoacidosis

Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON BCise causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined BYDUREON BCise is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with the use of BYDUREON BCise and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for detection of MTC in patients treated with BYDUREON BCise Acute Pancreatitis including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been reported. After initiation, observe patients carefully for symptoms of pancreatitis. If suspected, discontinue promptly and do not restart if confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis Acute Kidney Injury and Impairment of Renal Function Altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation have been reported. Not recommended in patients with severe renal impairment or end-stage renal disease. Use caution in patients with renal transplantation or moderate renal impairment Gastrointestinal Disease Because exenatide is commonly associated with gastrointestinal adverse reactions, not recommended in patients with sev Continue reading >>

Management Of Diabetic Ketoacidosis In Children And Adolescents

Objectives After completing this article, readers should be able to: Describe the typical presentation of diabetic ketoacidosis in children. Discuss the treatment of diabetic ketoacidosis. Explain the potential complications of diabetic ketoacidosis that can occur during treatment. Introduction Diabetic ketoacidosis (DKA) represents a profound insulin-deficient state characterized by hyperglycemia (>200 mg/dL [11.1 mmol/L]) and acidosis (serum pH <7.3, bicarbonate <15 mEq/L [15 mmol/L]), along with evidence of an accumulation of ketoacids in the blood (measurable serum or urine ketones, increased anion gap). Dehydration, electrolyte loss, and hyperosmolarity contribute to the presentation and potential complications. DKA is the most common cause of death in children who have type 1 diabetes. Therefore, the best treatment of DKA is prevention through early recognition and diagnosis of diabetes in a child who has polydipsia and polyuria and through careful attention to the treatment of children who have known diabetes, particularly during illnesses. Presentation Patients who have DKA generally present with nausea and vomiting. In individuals who have no previous diagnosis of diabetes mellitus, a preceding history of polyuria, polydipsia, and weight loss usually can be elicited. With significant ketosis, patients may have a fruity breath. As the DKA becomes more severe, patients develop lethargy due to the acidosis and hyperosmolarity; in severe DKA, they may present with coma. Acidosis and ketosis cause an ileus that can lead to abdominal pain severe enough to raise concern for an acutely inflamed abdomen, and the elevation of the stress hormones epinephrine and cortisol in DKA can lead to an elevation in the white blood cell count, suggesting infection. Thus, leukocytosi Continue reading >>

Diabetic Ketoacidosis Causes, Symptoms, Treatment, And Complications

Diabetic ketoacidosis definition and facts Diabetic ketoacidosis is a life-threatening complication of type 1 diabetes (though rare, it can occur in people with type 2 diabetes) that occurs when the body produces high levels of ketones due to lack of insulin. Diabetic ketoacidosis occurs when the body cannot produce enough insulin. The signs and symptoms of diabetic ketoacidosis include Risk factors for diabetic ketoacidosis are type 1 diabetes, and missing insulin doses frequently, or being exposed to a stressor requiring higher insulin doses (infection, etc). Diabetic ketoacidosis is diagnosed by an elevated blood sugar (glucose) level, elevated blood ketones and acidity of the blood (acidosis). The treatment for diabetic ketoacidosis is insulin, fluids and electrolyte therapy. Diabetic ketoacidosis can be prevented by taking insulin as prescribed and monitoring glucose and ketone levels. The prognosis for a person with diabetic ketoacidosis depends on the severity of the disease and the other underlying medical conditions. Diabetic ketoacidosis (DKA) is a severe and life-threatening complication of diabetes. Diabetic ketoacidosis occurs when the cells in our body do not receive the sugar (glucose) they need for energy. This happens while there is plenty of glucose in the bloodstream, but not enough insulin to help convert glucose for use in the cells. The body recognizes this and starts breaking down muscle and fat for energy. This breakdown produces ketones (also called fatty acids), which cause an imbalance in our electrolyte system leading to the ketoacidosis (a metabolic acidosis). The sugar that cannot be used because of the lack of insulin stays in the bloodstream (rather than going into the cell and provide energy). The kidneys filter some of the glucose (suga Continue reading >>

Diabetic Ketoacidosis (dka)

Snap Shot A 12 year old boy, previously healthy, is admitted to the hospital after 2 days of polyuria, polyphagia, nausea, vomiting and abdominal pain. Vital signs are: Temp 37C, BP 103/63 mmHg, HR 112, RR 30. Physical exam shows a lethargic boy. Labs are notable for WBC 16,000, Glucose 534, K 5.9, pH 7.13, PCO2 is 20 mmHg, PO2 is 90 mmHg. Introduction Complication of type I diabetes result of ↓ insulin, ↑ glucagon, growth hormone, catecholamine Precipitated by infections drugs (steroids, thiazide diuretics) noncompliance pancreatitis undiagnosed DM Presentation Symptoms abdominal pain vomiting Physical exam Kussmaul respiration increased tidal volume and rate as a result of metabolic acidosis fruity, acetone odor severe hypovolemia coma Evaluation Serology blood glucose levels > 250 mg/dL due to ↑ gluconeogenesis and glycogenolysis arterial pH < 7.3 ↑ anion gap due to ketoacidosis, lactic acidosis ↓ HCO3- consumed in an attempt to buffer the increased acid hyponatremia dilutional hyponatremia glucose acts as an osmotic agent and draws water from ICF to ECF hyperkalemia acidosis results in ICF/ECF exchange of H+ for K+ moderate ketonuria and ketonemia due to ↑ lipolysis β-hydroxybutyrate > acetoacetate β-hydroxybutyrate not detected with normal ketone body tests hypertriglyceridemia due to ↓ in capillary lipoprotein lipase activity activated by insulin leukocytosis due to stress-induced cortisol release H2PO4- is increased in urine, as it is titratable acid used to buffer the excess H+ that is being excreted Treatment Fluids Insulin with glucose must prevent resultant hypokalemia and hypophosphatemia labs may show pseudo-hyperkalemia prior to administartion of fluid and insulin due to transcellular shift of potassium out of the cells to balance the H+ be Continue reading >>

Pseudohyponatremia Definition And Causes

Pseudohyponatremia is not true hyponatremia but a false result of the measurement of blood sodium levels usually caused by 1: Hyperlipidemia (hypertriglyceridemia, hypercholesterolemia 7) Hyperproteinemia (for example, in multiple myeloma 8 or intravenous infusion of immunoglobulins) Radiocontrast used in chronic renal insufficient patients. Pseudohyponatremia is not a medical condition, has no symptoms and requires no treatment. Explanation: True hyponatremia means the decrease of sodium levels in the aqueous phase of the blood serum. Pseudohyponatremia is a false result of certain older tests (flame-emission spectrophotometry and indirect potentiometry I-ISE) that measure sodium levels in the whole serum (aqueous and nonaqueous phase). When the volume of the nonaqueous phase of the serum increases due to severely increased lipid or protein levels or radiocontrast substances or dextran, these tests show hyponatremia, but this is only pseudohyponatremia, because the sodium levels in the aqueous phase of the serum remain unchanged 1,3. Newer tests that use direct potentiometry with ion-specific Na+ electrodes (D-ISE), which measure sodium only in the aqueous part of the serum are not affected by hyperlipidemia or hyperproteinemia 1,3. Correction Formula for Pseudohyponatremia in Hypertriglyceridemia and Hyperlipidemia Plasma triglycerides (g/L) x 0.002 = mEq/L decrease in Na+ Plasma proteins – 8 (g/L) x 0.025 = mEq/L decrease in Na+ Reference: 2 Other Typical Changes Associated With Pseudohyponatremia Increased blood lipids or proteins result not only in pseudohyponatremia but also in false low levels of potassium (pseudohypokalemia), uric acid and blood urea nitrogen (BUN). The proliferation of the blood cells: leukocytosis, thrombocytosis, polycythemia vera is not as Continue reading >>

Diabetic Emergencies-diagnosis And Clinical Management: Diabetic Ketoacidosis In Adults, Part 2

Hyperglycemia Hyperglycemia in DKA is the result of reduced glucose uptake and utilization from the liver, muscle, and fat tissue and increased gluconeogenesis as well as glycogenolysis. The lack of insulin results in an increase in gluconeogenesis, primarily in the liver but also in the kidney, and increased glycogenolysis in liver and muscle.8,9 In addition, the inhibitory effect of insulin on glucagon secretion is abolished and plasma glucagon levels increase. The increase of glucagon aggravates hyperglycemia by enhancing gluconeogenesis and glycogenolysis. In parallel, the increased concentrations of the other counter-regulatory hormones enhance further gluconeogenesis. In addition to increased gluconeogenesis, in DKA there is excess production of substances which are used as a substrate for endogenous glucose production. Thus, the amino acids glutamine and alanine increase because of enhanced proteolysis and reduced protein synthesis.8,9 Hyperglycemia-induced osmotic diuresis leads to dehydration, hyperosmolality, electrolyte loss (Na+, K +, Mg 2 +, PO 4 3+, Cl−, and Ca+), and eventually decline in glomerular filtration rate. With decline in renal function, glucosuria diminishes and hyperglycemia worsens. Dehydration results in augmentation of plasma osmolality, which results in water movement out of the cells to the extracellular space. Osmotic diuresis caused by hyperglycemia results in loss of sodium in urine; in addition, the excess of glucagon aggravates hyponatremia because it inhibits reabsorption of sodium in the kidneys. With impaired insulin action and hyperosmolality, utilization of potassium by skeletal muscles is markedly decreased leading to intracellular potassium deficiency. Potassium is also lost due to osmotic diuresis. In addition, metabolic ac Continue reading >>

Original Article Acute Activation Of Peripheral Lymphocytes During Treatment Of Diabetic Ketoacidosis

Abstract Activated peripheral T-lymphocytes are increased in both pre-insulin-dependent diabetes mellitus (IDDM) patients and in recently diagnosed IDDM patients, as well as in various forms of acute stress. We studied the in vivo T-lymphocyte activation in six patients in severe diabetic ketoacidosis (DKA) prior to treatment, after 24 h of treatment and ≥5 days after admission. Five of the six patients showed an increased percentage of activated T-lymphocytes based on the expression of HLA-DR at 24 h of treatment when compared to the admission percentage of activation (P<.05). There was no correlation to the admission serum glucose, osmolality, or electrolytes. Serum pH showed a trend toward an inverse correlation, but was not statistically significant. We speculate that T-lymphocyte activation plays a role in the progression of the acute complications of subclinical brain edema and interstitial pulmonary edema of DKA. This process could also be another factor in the progression of the chronic complications of IDDM in addition to the well-established effects of hyperglycemia and hypertension. Continue reading >>

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a life-threatening condition when the body has practically no insulin. This insulin deficiency results in extremely high blood sugar levels. Consequently, the muscle, fat and liver cells cannot use glucose for fuel. These cells are converted into glucose by hormones such as glucagon and adrenalin and turned into ketones through oxidation. As a result, the body uses fat for fuel. The increased levels of blood sugar are not flushed through urination. DKA is usually noticed in patients suffering from Insulin-dependent diabetes. A person can suffer from diabetic ketoacidosis if there has been severe dehydration and consequently the blood chemistry has been affected. There is accumulation of organic acids and ketones in the blood. Elevated ketone levels in the body upset its blood pH and make the blood acidic thereby triggering a toxic condition for the body's cells. Diabetic ketoacidosis is noticed when hyperglycemia exceeds 300 mg/dL. If diabetes ketoacidosis is not addressed in time, it can lead to coma and death. Surgery, infection, trauma, stroke or heart attack can also trigger diabetes ketoacidosis. Insufficient fluid intake, pancreatitis and alcohol abuse can trigger diabetes ketoacidosis. Symptoms of diabetes ketoacidosis include excessive thirst and general weakness. There is frequent urination, loss of appetite and vomiting. Other symptoms of diabetes ketoacidosis are weight loss and abdominal pain. A person suffering from DKA tends to experience low blood pressure and increased heart rate. High ketone levels can give rise to a fruity-scent on the breath and vomiting. The patient will be restless and agitated. The skin will be hot and dry and appear flushed. Patients suffering from diabetes must check their blood glucose levels if th Continue reading >>

Infection As A Trigger Of Diabetic Ketoacidosis In Intensive Care—unit Patients

Together with hyperglycemic coma, diabetic ketoacidosis (DKA) is the most severe acute metabolic complication of diabetes mellitus [ 1 ]. Defined by the triad hyperglycemia, acidosis, and ketonuria, DKA can be inaugural or complicate known diabetes [ 2 ]. Although DKA is evidence of poor metabolic control and usually indicates an absolute or relative imbalance between the patient's requirements and the treatment, DKA-related mortality is low among patients who receive standardized treatment, which includes administration of insulin, correction of hydroelectrolytic disorders, and management of the triggering factor (which is often cessation of insulin therapy, an infection, or a myocardial infarction) [ 3–8 ]. Although there is no proof that diabetics are more susceptible to infection, they seem to have more difficulty handling infection once it occurs [ 9 , 10 ]. Indeed, several aspects of immunity are altered in diabetic patients: polymorphonuclear leukocyte function is depressed, particularly when acidosis is present, and leukocyte adherence, chemotaxis, phagocytosis, and bactericidal activity may also be impaired [ 11–15 ]. Joshi et al. [ 10 ] reported recently on the lack of clinical evidence that diabetics are more susceptible to infection than nondiabetic patients. Nevertheless, infection is a well-recognized trigger of DKA. Earlier studies have investigated the prevalence of infection as a trigger of DKA and the impact of antimicrobial treatment [ 2 , 15–18 ]. However, none of these studies were of intensive care unit (ICU) patients only. Furthermore, most were descriptive, included small numbers of patients, used univariate analysis only, and did not designate infection as the sole outcome variable of interest. Efforts to identify correlates of infection h Continue reading >>

Hyperglycemic Crises In Adult Patients With Diabetes

Go to: PATHOGENESIS The events leading to hyperglycemia and ketoacidosis are depicted in Fig. 1 (13). In DKA, reduced effective insulin concentrations and increased concentrations of counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone) lead to hyperglycemia and ketosis. Hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues (12–17). This is magnified by transient insulin resistance due to the hormone imbalance itself as well as the elevated free fatty acid concentrations (4,18). The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to the release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation in the liver to ketone bodies (β-hydroxybutyrate and acetoacetate) (19), with resulting ketonemia and metabolic acidosis. Increasing evidence indicates that the hyperglycemia in patients with hyperglycemic crises is associated with a severe inflammatory state characterized by an elevation of proinflammatory cytokines (tumor necrosis factor-α and interleukin-β, -6, and -8), C-reactive protein, reactive oxygen species, and lipid peroxidation, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of obvious infection or cardiovascular pathology (20). All of these parameters return to near-normal values with insulin therapy and hydration within 24 h. The procoagulant and inflammatory states may be due to nonspecific phenomena of stress and may partially explain the association of hyperglycemic crises with a hypercoagulable state (21). The pathogenesis of HHS is not as wel Continue reading >>

Tropical Journal Of Pharmaceutical Research October 2012; 11 (5): 815-821 Â© Pharmacotherapy Group,

Ezzeldi & Nahhas Trop J Pharm Res, October2012;11 (5): 815 Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved. Available online at Research Article Serological Prediction of infections in Diabetic Patients with Diabetes Ketoacidosis in Penang, Malaysia Syed Wasif Gillani1*, Syed Azhar Syed Sulaiman1, Shameni Sundram2, Yelly Oktavia Sari3,4, Mirza Baig5 and Mian Muhammad Shahid Iqbal6 1School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia, 2Doctor, Hospital Pulau Pinang, 10990, Residential Street, Penang, 3Faculty of Pharmacy, Andalas University, Padang 25163, Indonesia, 4Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, 5Department of Clinical Pharmacy, Aimst University, Kedah, 6School of Pharmacy and Health Sciences, International Medical University, Malaysia. Abstract Purpose: To determine the prevalence and predictors of infection in diabetic patients with diabetic ketoacidosis (DKA) who were â‰¥18 years. Methods: A retrospective cohort design was adopted for this study. A total of 967 diabetes ketoacidosis patients from Hospital Pulau Pinang for the 3-year period, Jan 2008 - Dec 2010, were identified and enrolled. The data were analysed, as appropriate, by Student t-test and ANOVA for the normally distributed data, Mann-Whitney U rank sum and Kruskall-Wallis tests for continuous, non-nominal data and Chi-square for dichotomous variables. Odd Ratios with 95% confidence interval (CI) were also presented where applicable. Results: Of the total diabetes ketoacidosis patients, 112 (11.6 %) were cases without infection, 679 (70.2 %) bacterial infection cases and 176 (18.2 %) presumed viral infection cases. The mean white blood count (WBC) fo Continue reading >>

Thyroid Storm Presenting As Psychosis: Masked By Diabetic Ketoacidosis

While extremely uncommon, diabetic ketoacidosis (DKA) and thyroid storm (TS) are endocrine emergencies that can coexist. We describe a case with a confounding clinical presentation that identifies these two emergencies within the setting of sepsis and influenza. Case A 69-year-old diabetic female was found by the paramedic staff to be disoriented. She demonstrated tachycardia and had a foul-smelling abdominal wound. Laboratory evaluation revealed DKA, leukocytosis, influenza B, and urinary tract infection. After appropriate management in the intensive care unit, the DKA resolved the following morning. However, the patient developed a fever, and her psychosis became more pronounced. Extensive analysis was performed but did not explain her mental status. The patient was found to have thyroid stimulating hormone of 0.06 mIU/mL, free T4 (thyroxine) of 2.38 ng/dL, and total T3 (triiodothyronine) of 72 ng/dL. Based on the Burch and Wartofsky criteria (score of 65), TS was diagnosed. Based on more recent diagnostic criteria suggested by Akamizu et al., the patient met criteria for TS grade 1. Within several hours of initiating treatment, the patient's mental state and tachycardia improved, and her psychosis resolved by the third day. This case highlights the importance of recognizing the clinical diagnosis of TS, as the magnitude of thyroid hormone derangements may not correlate with clinical severity. While rare, DKA and TS can simultaneously occur and are associated with increased morbidity and mortality if not promptly recognized and treated. Continue reading >>