<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Beta blocker and can you explain it in depth? [/INST] Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack (secondary prevention). They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.Beta blockers are competitive antagonists that block the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block activation of all types of β-adrenergic receptors and others are selective for one of the three known types of beta receptors, designated β1, β2 and β3 receptors. β1-adrenergic receptors are located mainly in the heart and in the kidneys. β2-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3-adrenergic receptors are located in fat cells.Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stimulated by epinephrine (adrenaline). Beta blockers interfere with the binding to the receptor of epinephrine and other stress hormones and weaken the effects of stress hormones.
In 1964, James Black synthesized the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.For the treatment of primary hypertension, meta-analyses of studies which mostly used atenolol have shown that although beta blockers are more effective than placebo in preventing stroke and total cardiovascular events, they are not as effective as diuretics, medications inhibiting the renin–angiotensin system (e.g., ACE inhibitors), or calcium channel blockers.

Medical uses
Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below.
Indications for beta blockers include:

Angina pectoris (contraindicated for Prinzmetals angina)
Atrial fibrillation
Cardiac arrhythmia
Congestive heart failure
Essential tremor
Glaucoma (as eye drops, they decrease intraocular pressure by lowering aqueous humor secretion)
Hypertension, although they are generally not preferred as an initial treatment
Hyperthyroidism
Migraine prophylaxis
Mitral valve prolapse
Myocardial infarction
Phaeochromocytoma, in conjunction with α-blocker
Postural orthostatic tachycardia syndrome
Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
Theophylline overdoseBeta blockers have also been used for:
Acute aortic dissection
Hypertrophic obstructive cardiomyopathy
Long QT syndrome
Marfan syndrome (treatment with propranolol slows progression of aortic dilation and its complications)
Prevention of variceal bleeding in portal hypertension
Possible mitigation of hyperhidrosis
Social and other anxiety disorders
Controversially, for reduction of perioperative mortality in non-cardiac surgery, but the best evidence suggests that they increase mortality when used this way

Congestive heart failure
Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition due to their effect of decreasing cardiac contractility, studies in the late 1990s showed their efficacy at reducing morbidity and mortality.Bisoprolol, carvedilol, and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure, although at doses typically much lower than those indicated for other conditions. Beta blockers are only indicated in cases of compensated, stable congestive heart failure; in cases of acute decompensated heart failure, beta blockers will cause a further decrease in ejection fraction, worsening the patients current symptoms.
Beta blockers are known primarily for their reductive effect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure. Beta blockers, in addition to their sympatholytic β1 activity in the heart, influence the renin–angiotensin system at the kidneys. Beta blockers cause a decrease in renin secretion, which in turn reduces the heart oxygen demand by lowering the extracellular volume and increasing the oxygen-carrying capacity of the blood. Heart failure characteristically involves increased catecholamine activity on the heart, which is responsible for several deleterious effects, including increased oxygen demand, propagation of inflammatory mediators, and abnormal cardiac tissue remodeling, all of which decrease the efficiency of cardiac contraction and contribute to the low ejection fraction. Beta blockers counter this inappropriately high sympathetic activity, eventually leading to an improved ejection fraction, despite an initial reduction in ejection fraction.
Trials have shown beta blockers reduce the absolute risk of death by 4.5% over a 13-month period. In addition to reducing the risk of mortality, the numbers of hospital visits and hospitalizations were also reduced in the trials.Therapeutic administration of beta blockers for congestive heart failure ought to begin at very low doses (1/8 of target) with a gradual escalation of the dose. The heart of the patient must adjust to decreasing stimulation by catecholamines and find a new equilibrium at a lower adrenergic drive.

Anxiety
Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration. However, many controlled trials in the past 25 years indicate beta blockers are effective in anxiety disorders, though the mechanism of action is not known. The physiological symptoms of the fight-or-flight response (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.
Musicians, public speakers, actors, and professional dancers have been known to use beta blockers to avoid performance anxiety, stage fright, and tremor during both auditions and public performances. The application to stage fright was first recognized in The Lancet in 1976, and by 1987, a survey conducted by the International Conference of Symphony Orchestra Musicians, representing the 51 largest orchestras in the United States, revealed 27% of its musicians had used beta blockers and 70% obtained them from friends, not physicians. Beta blockers are inexpensive, said to be relatively safe, and on one hand, seem to improve musicians performances on a technical level, while some, such as Barry Green, the author of "The Inner Game of Music" and Don Greene, a former Olympic diving coach who teaches Juilliard students to overcome their stage fright naturally, say the performances may be perceived as "soulless and inauthentic".

Surgery
Low certainty evidence indicates that the use of beta blockers around the time of cardiac surgery may decrease the risk of heart dysrhythmias and atrial fibrillation. Starting them around the time of other types of surgery, however, may worsen outcomes. For non-cardiac surgery, the use of beta blockers to prevent adverse effects may reduce the risk of atrial fibrillation and myocardial infarctions (very low certainty evidence), however, there is moderate certainty evidence that this approach may increase the risk of hypotension. Low-certainty evidence suggests that beta blockers used perioperatively in non-cardiac surgeries may increase the risk of bradycardia.

Performance-enhancing use
Because they promote lower heart rates and reduce tremors, beta blockers have been used in professional sports where high accuracy is required, including archery, shooting, golf and snooker. Beta blockers are banned in some sports by the International Olympic Committee. In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.For similar reasons, beta blockers have also been used by surgeons.Classical musicians have commonly used beta blockers since the 1970s to reduce stage fright.

Adverse effects
Adverse drug reactions  associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynauds syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, alopecia (hair loss), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema. Due to the high penetration across the blood–brain barrier, lipophilic beta blockers, such as propranolol and metoprolol, are more likely than other less lipophilic beta blockers to cause sleep disturbances, such as insomnia, vivid dreams and nightmares.Adverse effects associated with β2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β1-selective (often termed "cardioselective") agents, but receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa, inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia.
Hypoglycemia can occur with beta blockade because β2-adrenoceptors normally stimulate glycogen breakdown (glycogenolysis) in the liver and pancreatic release of the hormone glucagon, which work together to increase plasma glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the fast heart rate that serves as a warning sign for insulin-induced low blood sugar may be masked, resulting in hypoglycemia unawareness. This is termed beta blocker-induced hypoglycemia unawareness. Therefore, beta blockers are to be used cautiously in diabetics.A 2007 study revealed diuretics and beta blockers used for hypertension increase a patients risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes. Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes.Beta blockers must not be used in the treatment of selective alpha-adrenergic agonist overdose. The blockade of only beta receptors increases blood pressure, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha-adrenergic system stimulation unopposed. Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity from a methamphetamine overdose. The mixed alpha- and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine. The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta blockers for treatment of methamphetamine toxicity. Other appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant overdose are vasodilators such as nitroglycerin, diuretics such as furosemide, and alpha blockers such as phentolamine.

Contraindications
Contraindications for beta blockers include:

Asthma
The 2007 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines recommend against the use of non-selective beta blockers in asthmatics, while allowing for the use of cardio selective beta blockers.: 182 Cardio selective beta blocker (β1 blockers), if really required, can be prescribed at the least possible dose to those with mild to moderate respiratory symptoms. β2-agonists can somewhat mitigate β-Blocker-induced bronchospasm where it exerts greater efficacy on reversing selective β-blocker-induced bronchospasm than the nonselective β-blocker-induced worsening asthma and/or COPD.

Diabetes mellitus
Epinephrine signals early warning of the upcoming hypoglycemia.Beta blockers inhibition on epinephrines effect can somewhat exacerbate hypoglycemia by interfering with glycogenolysis and mask signs of hypoglycemia such as tachycardia, palpitations, diaphoresis, and tremors. Diligent blood glucose level monitoring is necessary for a patient with diabetes mellitus on beta blocker.

Hyperthyroidism
Abrupt withdrawal can result in a thyroid storm.

Bradycardia or AV block
Unless a pacemaker is present, beta blockers can severely depress conduction in the AV node, resulting in a reduction of heart rate and cardiac output. One should be very cautious with the use of beta blockers in tachycardia patients with Wolff-Parkinson-White Syndrome, as it can result in life-threatening arrhythmia in certain patients. By slowing the conduction through the AV node, preferential conduction through the accessory pathway is favored. If the patient happens to develop atrial flutter, this could lead to a 1:1 conduction with very fast ventricular rate, or worse, ventricular fibrillation in the case of atrial fibrillation.

Toxicity
Glucagon, used in the treatment of overdose, increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta blocker cardiotoxicity. Cardiac pacing is usually reserved for patients unresponsive to pharmacological therapy.
People experiencing bronchospasm due to the β2 receptor-blocking effects of nonselective beta blockers may be treated with anticholinergic drugs, such as ipratropium, which are safer than beta agonists in patients with cardiovascular disease. Other antidotes for beta blocker poisoning are salbutamol and isoprenaline.

β-receptor antagonism
Stimulation of β1 receptors by epinephrine and norepinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β1 receptors on the kidney causes renin release. Stimulation of β2 receptors induces smooth muscle relaxation, induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of β3 receptors induces lipolysis.Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions, but have minimal effect on resting subjects.
That is, they reduce the effect of excitement or physical exertion on heart rate and force of contraction, and also tremor, and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.Since β2 adrenergic receptors can cause vascular smooth muscle dilation, beta blockers may cause some vasoconstriction. However, this effect tends to be small because the activity of β2 receptors is overshadowed by the more dominant vasoconstricting α1 receptors. By far the greatest effect of beta blockers remains in the heart. Newer, third-generation beta blockers can cause vasodilation through blockade of alpha-adrenergic receptors.Accordingly, nonselective beta blockers are expected to have antihypertensive effects. The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects). It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (for those beta blockers that do cross the blood–brain barrier, e.g. propranolol).
Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. Negative chronotropic properties of beta blockers allow the lifesaving property of heart rate control. Beta blockers are readily titrated to optimal rate control in many pathologic states.
The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade—resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.
Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin–angiotensin–aldosterone system, with a resultant decrease in blood pressure due to decreased sodium and water retention.

Intrinsic sympathomimetic activity
Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound, such as norepinephrine). See partial agonist for a more general description.
Some beta blockers (e.g. oxprenolol, pindolol, penbutolol, labetalol and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low-level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.
Agents with ISA should not be used for patients with any kind of angina as it can aggravate or after myocardial infarctions. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.

α1-receptor antagonism
Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.

Examples
Nonselective agents
Nonselective beta blockers display both β1 and β2 antagonism.
Propranolol
Bucindolol (has additional α1-blocking activity)
Carteolol
Carvedilol (has additional α1-blocking activity)
Labetalol (has intrinsic sympathomimetic activity and additional α1-blocking activity)
Nadolol
Oxprenolol (has intrinsic sympathomimetic activity)
Penbutolol (has intrinsic sympathomimetic activity)
Pindolol (has intrinsic sympathomimetic activity)
Sotalol (not considered a "typical beta blocker")
Timolol

β1-selective agents
β1-selective beta blockers are also known as cardioselective beta blockers. Pharmacologically, the beta-blockade of the B1 receptors in the heart will act on cAMP. The function of cAMP as a second messenger in the cardiac cell is that it phosphorylates the LTCC and the ryanodine receptor to increase intracellular calcium levels and cause contraction. Beta-blockade of the B1 receptor will inhibit cAMP from phosphorylating, and it will decrease the ionotrophic and chronotropic effect </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Biliary atresia and can you explain it in depth? [/INST] Biliary atresia, also known as extrahepatic ductopenia and progressive obliterative cholangiopathy, is a childhood disease of the liver in which one or more bile ducts are abnormally narrow, blocked, or absent. It can be congenital or acquired.  It has an incidence of one in 10,000–15,000 live births in the United States, and a prevalence of one in 16,700 in the British Isles. Biliary atresia is most common in East Asia, with a frequency of one in 5,000.
The cause of biliary atresia in Egyptian infants has been proven to be as a result of aflatoxin induced cholangiopathy acquired prenatally in infants who have glutathione S transferase M1 deficiency. The biliary atresia phenotype caused by congenital aflatoxicosis in GST M1 deficient neonates is named Kotb disease. Syndromic biliary atresia (e.g. Biliary Atresia Splenic Malformation (BASM)) has been associated with certain genes (e.g. Polycystic Kidney Disease 1 Like 1 - PKD1L1), and some infants with isolated biliary atresia may arise as a result of an autoimmune inflammatory response, possibly due to a viral infection of the liver soon after birth. In animals plant toxins have been shown to cause biliary atresia. The only effective treatments are operations such as the Kasai procedure and liver transplantation.

Signs and symptoms
Initially, the symptoms of biliary atresia are indistinguishable from those of neonatal jaundice, a usually harmless condition commonly seen in infants. However, infants with biliary atresia develop progressive conjugated jaundice, pale white stools, and dark urine. Some infants fail to thrive as there will be a degree of fat and fat-soluble vitamin malabsorption (e.g. Vitamin K). This may cause a bleeding tendency. Eventually, and usually after 2 months, cirrhosis with portal hypertension will develop. If left untreated, biliary atresia can lead to liver failure. Unlike other forms of jaundice, however, biliary-atresia-related cholestasis mostly does not result in kernicterus, a form of brain damage resulting from liver dysfunction. This is because in biliary atresia, the liver, although diseased, is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood–brain barrier.

Causes
The cause of biliary atresia in most infants is not fully understood and it is well possible that a number of factors may play a role, but especially maternal rotavirus infection during pregnancy and subsequent transmission of the virus to the child resulting in infection of the biliary epithelium and subsequent occluding fibrosis may be important in this respect. Some cases may relate to infection with other viruses (including COVID-19) as well, for instance infection with the hepatotropic virus reovirus 3 has been proposed and congenital cytomegalovirus infection, as well. In addition autoimmune processes may contribute to pathogenesis in some cases as well. However, with regard to these alternative causation the experimental evidence remains rather weak.

Genetics
An association between biliary atresia and the ADD3 gene was first detected in Chinese populations through a genome-wide association study, and was confirmed in Thai Asians and Caucasians. A possible association with deletion of the gene GPC1, which encodes a glypican 1-a heparan sulfate proteoglycan, has been reported. This gene is located on the long arm of chromosome 2 (2q37) and is involved in the regulation of inflammation and the Hedgehog gene.Egyptian infants with biliary atresia were found to have null GSTM1 genotype while all their mothers were heterozygous for GSTM1. Thus these infants may be protected in utero by their maternal detoxification system, yet once born they cannot handle the detoxification of an aflatoxin load.

Toxins
Some cases of biliary atresia may result from exposure to aflatoxin B1, and to a lesser extent aflatoxin B2 during late pregnancy. Intact maternal detoxification protects baby during intrauterine life, yet after delivery, the baby struggles with the aflatoxin in its blood and liver. Moreover, the baby feeds aflatoxin M1 from its mom, as aflatoxin M1 is the detoxification product of aflatoxin B1. It is a milder toxin that causes cholangitis in the baby.There are isolated examples of biliary atresia in animals. For instance, lambs born to sheep grazing on land contaminated with a weed (Red Crumbweed) developed biliary atresia at certain times. The plants were later found to contain a toxin, now called biliatresone Studies are ongoing to determine whether there is a link between human cases of biliary atresia and toxins such as biliatresone. There are some indications that a metabolite of certain human gut bacteria may be similar to biliatresone.

Pathophysiology
There are three main types of extra-hepatic biliary atresia:
Type I: Atresia is restricted to the common bile duct.
Type II: Atresia of the common hepatic duct.
Type III: Atresia involves the most proximal part of the bile ducts (>95% of all cases).In approximately 10% of cases, other anomalies may be associated with biliary atresia. The most common of these syndromic forms is BASM and might include heart lesions, polysplenia, situs inversus, absent venae cavae, and a preduodenal portal vein. Progressive cirrhosis is associated with signs and symptoms of portal hypertension, such as esophagogastric varix bleeding, hypersplenism, hepatorenal syndrome, and hepatopulmonary syndrome.In an Egyptian study, abnormally high levels of aflatoxin B1 and to a lesser extent aflatoxin B2 was found in liver tissue and blood of all neonates with biliary atresia. Aflatoxins may cause extensive damage to the hepatocytes leading to hepatitis and damage to bile ducts causing inflammation, adhesions and final obstruction of bile ducts. The affected neonates have a genetic detoxification defect that does not allow them to detoxify these aflatoxins timely or effectively. The babies have homozygous deficiency of glutathione S transferase (GST) M1. The aflatoxin damaged liver cells and bile duct cells are removed by neutrophil elastase and by involvement of immune system mediators such as CCL-2 or MCP-1, tumor necrosis factor (TNF), interleukin-6 (IL-6), TGF-beta,  endothelin (ET), and  nitric oxide (NO). Among these, TGF-beta is the most important pro-fibrogenic cytokine that can be seen in progressive cirrhosis.The cascade of immune involvement to remove damaged hepatocytes and cholangiocytes ushers regeneration. Yet in infants with biliary atresia regeneration is defective, and results in cirrhosis, as these infants have disrupted p53 and disrupted GSTPi. p53 and GSTPi are responsible for DNA fidelity at regeneration. Hence, these infants get accelerated cirrhosis and march to portal hypertension.

Diagnosis
Diagnosis is made by an assessment of history, physical examination in conjunction with blood tests, a liver biopsy, and ultrasound scans imaging and is prompted by prolonged or persistent jaundice, with abnormalities in liver function tests. Ultrasound or other forms of imaging such as radio-isotope liver scans can also be used but final confirmation is usually only reached at the time of exploratory surgery.

Differential diagnoses
The differential diagnoses are extensive and include: Alagille syndrome, alpha-1-antitrypsin deficiency, Byler disease (progressive familial intrahepatic cholestasis), Caroli disease, choledochal cyst, cholestasis, congenital cytomegalovirus disease, congenital herpes simplex virus infection, congenital rubella, congenital syphilis, congenital toxoplasmosis, cystic fibrosis, galactosemia, idiopathic neonatal hepatitis, lipid storage disorders, neonatal hemochromatosis, and total parenteral nutrition-associated cholestasis.

Treatment
Most (>95%) infants with biliary atresia will undergo an operation designed to retain and salvage the native liver, restore bile flow, and reduce the level of jaundice. This is known as the Kasai procedure (after Morio Kasai, the Japanese surgeon who first developed the technique) or hepatoportoenterostomy. Although the procedure is not thought of as curative, it may relieve jaundice and stop liver fibrosis, allowing normal growth and development. Published series from Japan, North America, and the UK show that bilirubin levels will fall to normal values in about 50-55% of infants, allowing 40-50% to retain their own liver to reach the age of 5 and 10 years (and beyond). Liver transplantation is an option for those children whose liver function and symptoms fail to respond to a Kasai operation.Recent large-scale studies by Davenport et al </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Binge eating disorder and can you explain it in depth? [/INST] Binge eating disorder (BED) is an eating disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without the compensatory behaviors common to bulimia nervosa, OSFED, or the binge-purge subtype of anorexia nervosa.
BED is a recently described condition, which was required to distinguish binge eating similar to that seen in bulimia nervosa but without characteristic purging. Individuals who are diagnosed with bulimia nervosa and binge eating disorder exhibit similar patterns of compulsive overeating, neurobiological features of dysfunctional cognitive control and food addiction, and biological and environmental risk factors. Some professionals consider BED to be a milder form of bulimia with the two conditions on the same spectrum.Binge eating is one of the most prevalent eating disorders among adults, though there tends to be less media coverage and research about the disorder in comparison to anorexia nervosa and bulimia nervosa.

Signs and symptoms
Binge eating is the core symptom of BED; however, not everyone who binge eats has BED. An individual may occasionally binge eat without experiencing many of the negative physical, psychological, or social effects of BED. This may be considered disordered eating rather than a clinical disorder. Precisely defining binge eating can be problematic, however binge eating episodes in BED are generally described as having the following potential features:

Eating much faster than normal, perhaps in a short space of time
Eating until feeling uncomfortably full
Eating a large amount when not hungry
Subjective loss of control over how much or what is eaten
Binges may be planned in advance, involving the purchase of special binge foods, and the allocation of specific time for binging, sometimes at night
Eating alone or secretly due to embarrassment over the amount of food consumed
There may be a dazed mental state during the binge
Not being able to remember what was eaten after the binge
Feelings of guilt, shame or disgust following a food binge
Body image disturbanceIn contrast to bulimia nervosa, binge eating episodes are not regularly followed by activities intended to compensate for the amount of food consumed, such as self-induced vomiting, laxative or enema misuse, or strenuous exercise. BED is characterized more by overeating than dietary restriction. Those with BED often have poor body image and frequently diet, but are unsuccessful due to the severity of their binge eating.Obesity is common in persons with BED, as is depression, low self-esteem, stress and boredom. Those with BED are also at risk of Non-alcoholic fatty liver disease, menstrual irregularities such as amenorrhea, and gastrointestinal problems such as acid reflux and heartburn.

Causes
As with other eating disorders, binge eating is an "expressive disorder"—a disorder that is an expression of deeper psychological problems. People who have binge eating disorder have been found to have higher weight bias internalization, which includes low self-esteem, unhealthy eating patterns, and general body dissatisfaction. Binge eating disorder commonly develops as a result or side effect of depression, as it is common for people to turn to comfort foods when they are feeling down.There was resistance to give binge eating disorder the status of a fully fledged eating disorder because many perceived binge eating disorder to be caused by individual choices. Previous research has focused on the relationship between body image and eating disorders, and concludes that disordered eating might be linked to rigid dieting practices. In the majority of cases of anorexia, extreme and inflexible restriction of dietary intake leads at some point to the development of binge eating, weight regain, bulimia nervosa, or a mixed form of eating disorder not otherwise specified. Binge eating may begin when individuals recover from an adoption of rigid eating habits. When under a strict diet that mimics the effects of starvation, the body may be preparing for a new type of behavior pattern, one that consumes a large amount of food in a relatively short period of time.Some studies show that BED aggregates in families and could be genetic. However, very few published studies around the genetics exist.However, other research suggests that binge eating disorder can also be caused by environmental factors and the impact of traumatic events. One study showed that women with binge eating disorder experienced more adverse life events in the year prior to the onset of the development of the disorder, and that binge eating disorder was positively associated with how frequently negative events occur. Additionally, the research found that individuals who had binge eating disorder were more likely to have experienced physical abuse, perceived risk of physical abuse, stress, and body criticism. Other risk factors may include childhood obesity, critical comments about weight, low self-esteem, depression, and physical or sexual abuse in childhood. A systematic review concluded that bulimia nervosa and binge eating disorder are more impacted by family separations, a loss in their lives and negative parent-child interactions compared to those with anorexia nervosa. A few studies have suggested that there could be a genetic component to binge eating disorder, though other studies have shown more ambiguous results. Studies have shown that binge eating tends to run in families and a twin study by Bulik, Sullivan, and Kendler has shown a, "moderate heritability for binge eating" at 41 percent. More research must be done before any firm conclusions can be drawn regarding the heritability of binge eating disorder. Studies have also shown that eating disorders such as anorexia and bulimia reduce coping abilities, which makes it more likely for those suffering to turn to binge eating as a coping strategy.A correlation between dietary restraint and the occurrence of binge eating has been shown in some research. While binge eaters are often believed to be lacking in self-control, the root of such behavior might instead be linked to rigid dieting practices. The relationship between strict dieting and binge eating is characterized by a vicious circle. Binge eating is more likely to occur after dieting, and vice versa. Several forms of dieting include delay in eating (e.g., not eating during the day), restriction of overall calorie intake (e.g., setting calorie limit to 1,000 calories per day), and avoidance of certain types of food (e.g., "forbidden" food, such as sugar, carbohydrates, etc.)  Strict and extreme dieting differs from ordinary dieting. Some evidence suggests the effectiveness of moderate calorie restriction in decreasing binge eating episodes among overweight individuals with binge eating disorder, at least in the short-term."In the U.S, it is estimated that 3.5% of young women and 30% to 40% of people who seek weight loss treatments, can be clinically diagnosed with binge eating disorder."

Diagnosis
International Classification of Diseases
BED was first included in the Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1994 simply as a feature of eating disorder. In 2013 it gained formal recognition as a psychiatric condition in the DSM-5.The 2017 update to the American version of the ICD-10 includes BED under F50.81. ICD-11 may contain a dedicated entry (6B62), defining BED as frequent, recurrent episodes of binge eating (once a week or more over a period of several months) which are not regularly followed by inappropriate compensatory behaviors aimed at preventing weight gain.

Diagnostic and Statistical Manual
Previously considered a topic for further research exploration, binge eating disorder was included in the Diagnostic and Statistical Manual of Mental Disorders in 2013. Until 2013, binge eating disorder was categorized as an Eating Disorder Not Otherwise Specified, an umbrella category for eating disorders that dont fall under the categories for anorexia nervosa or bulimia nervosa. Because it was not a recognized psychiatric disorder in the DSM until 2013, it has been difficult to obtain insurance reimbursement for treatments. The disorder now has its own category under DSM-5, which outlines the signs and symptoms that must be present to classify a persons behavior as binge eating disorder. Studies have confirmed the high predictive value of these criteria for diagnosing BED.According to the World Health Organizations ICD-11 classification of BED, the severity of the disorder can be classified as mild (1-3 episodes/week), moderate (4-7 episodes/week), severe (8-13 episodes/week) and extreme (>14 episodes/week).One study claims that the method for diagnosing BED is for a clinician to conduct a structured interview using the DSM-5 criteria or taking the Eating Disorder Examination. The Structured Clinical Interview takes no more than 75 minutes to complete and has a systematic approach which follows the DSM-5 criteria. The Eating Disorder Examination is a semi-structured interview which identifies the frequency of binges and associated eating disorder features.

Treatment
Counselling and certain medication, such as lisdexamfetamine and selective serotonin reuptake inhibitor (SSRIs), may help. Some recommend a multidisciplinary approach in the treatment of the disorder.

Counselling
Cognitive behavioral therapy (CBT) treatment has been demonstrated as a more effective form of treatment for BED than behavioral weight loss programs. 50 percent of BED individuals achieve complete remission from binge eating and 68-90% will reduce the amount of binge eating episodes they have. CBT has also been shown to be an effective method to address self-image issues and psychiatric comorbidities (e.g., depression) associated with the disorder. The goal of CBT is to interrupt binge-eating behaviour, learn to create a normal eating schedule, change the perception around weight and shape and develop positive attitudes about ones body. Although this treatment is successful in eliminating binge eating episodes, it does not lead to losing any weight. Recent reviews have concluded that psychological interventions such as psychotherapy and behavioral interventions are more effective than pharmacological interventions for the treatment of binge eating disorder. A meta-analysis concluded that psychotherapy based on CBT not only significantly improved binge-eating symptomatology but also reduced a clients BMI significantly at posttreatment and longer than 6 and 12 months after treatment. There is the 12-step Overeaters Anonymous or Food Addicts in Recovery Anonymous. Behavioral weight loss treatment has been proven to be effective as a means to achieve weight loss amongst patients.

Medication
Lisdexamfetamine is a USFDA-approved drug that is used for the treatment of moderate to severe binge eating disorder in adults. As of 2021, it is the first and only medication formally approved for the treatment of BED. It is thought that lisdexamfetamine treats BED through a combination of effects on appetite and satiety, reward, and cognitive processes, including attention, impulsivity, and behavioral inhibition.Three other classes of medications are also used in the treatment of binge eating disorder: antidepressants, anticonvulsants, and anti-obesity medications. Antidepressant medications of the selective serotonin reuptake inhibitor (SSRI) have been found to effectively reduce episodes of binge eating and reduce weight. Similarly, anticonvulsant medications such as topiramate and zonisamide may be able to effectively suppress appetite. The long-term effectiveness of medication for binge eating disorder is currently unknown. For BED patients with manic episodes, risperidone is recommended. If BED patients have bipolar depression, lamotrigine is appropriate to use.Trials of antidepressants, anticonvulsants, and anti-obesity medications suggest that these medications are superior to placebo in reducing binge eating. Medications are not considered the treatment of choice because psychotherapeutic approaches, such as CBT, are more effective than medications for binge eating disorder. A meta-analysis concluded that using medications did not reduce binge-eating episodes and BMI posttreatment at 6–12 months. This indicates a potential possibility of relapse after withdrawal from the medications. Medications also do not increase the effectiveness of psychotherapy, though some patients may benefit from anticonvulsant and anti-obesity medications, such as phentermine/topiramate, for weight loss.Blocking opioid receptors leads to less food intake. Additionally, bupropion and naltrexone used together may cause weight loss. Combining these alongside psychotherapies like CBT may lead to better outcomes for BED.

Surgery
Bariatric surgery has also been proposed as another approach to treat BED and a recent meta-analysis showed that approximately two-thirds of individuals who seek this type of surgery for weight loss purposes have BED. Bariatric surgery recipients who had BED prior to receiving the surgery tend to have poorer weight-loss outcomes and are more likely to continue to exhibit eating behaviors characteristic of BED.

Lifestyle Interventions
Other treatments for BED include lifestyle interventions like weight training, peer support groups, and investigation of hormonal abnormalities.

Prognosis
Individuals with BED often have a lower overall quality of life and commonly experience social difficulties. Early behavior change is an accurate prediction of remission of symptoms later.Individuals who have BED commonly have other comorbidities such as major depressive disorder, personality disorder, bipolar disorder, substance abuse, body dysmorphic disorder, kleptomania, irritable bowel syndrome, fibromyalgia, or an anxiety disorder. Individuals may also exhibit varying degrees of panic attacks and a history of attempted suicide.While people of a normal weight may overeat occasionally, an ongoing habit of consuming large amounts of food in a short period of time may ultimately lead to weight gain and obesity. The main physical health consequences of this type of eating disorder are brought on by the weight gain resulting from calorie-laden bingeing episodes. Mental and emotional consequences of binge eating disorder include social weight stigma and emotional loss of control. Up to 70% of individuals with BED may also be obese, and therefore obesity-associated morbidities such as high blood pressure and coronary artery disease type 2 diabetes mellitus gastrointestinal issues (e.g., gallbladder disease), high cholesterol levels, musculoskeletal problems and obstructive sleep apnea may also be present.

Epidemiology
General
The prevalence of BED in the general population is approximately 1-3%.BED cases usually occur between the ages of 12.4 and 24.7, but prevalence rates increase until the age of 40.Binge eating disorder is the most common eating disorder in adults.The limited amount of research that has been done on BED shows that rates of binge eating disorder are fairly comparable among men and women. The lifetime prevalence of binge eating disorder has been observed in studies to be 2.0 percent for men and 3.5 percent for women, higher than that of the commonly recognized eating disorders anorexia nervosa and bulimia nervosa. However another systematic literature review found the prevalence average to be about 2.3% in women and about 0.3% in men. Lifetime prevalence rates for BED in women can range anywhere from 1.5 to 6 times higher than in men. One literature review found that point prevalence rates for BED vary from 0.1 percent to 24.1 percent depending on the sample. This same review also found that the 12-month prevalence rates vary between 0.1 percent to 8.8 percent.Recent studies found that eating disorders which included anorexia nervosa, bulimia nervosa and binge-eating disorder are common among sexual and gender minority populations, including gay, lesbian, bisexual and transgender people. This could be due to the minority stress and discrimination this population experiences.Due to limited and inconsistent information and research on ethnic and racial differences, prevalence rates are hard to determine for BED. Rates of binge eating disorder have been found to be similar among black women, white women, and white men, while some studies have shown that binge eating disorder is more common among black women than among white women. However, majority of the research done around BED is focused on White women. One literature review found information citing no difference between BED prevalence among Hispanic, African American, and White women while other information found that BED prevalence was highest among Hispanics followed by Black individuals and finally White people.

Worldwide Prevalences
Eating disorders have usually been considered something that was specific to Western countries. However, the prevalence of eating disorders is increasing in other non-Western countries. Though the research on binge eating disorders tends to be concentrated in North America, the disorder occurs across cultures </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Blastic plasmacytoid dendritic cell neoplasm and can you explain it in depth? [/INST] Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy. It was initially regarded as a form of lymphocyte-derived cutaneous  lymphoma and alternatively named CD4+CD56+ hematodermic tumor, blastic NK cell lymphoma, and agranular CD4+ NK cell leukemia. Later, however, the disease was determined to be a malignancy of plasmacytoid dendritic cells rather than lymphocytes and therefore termed blastic plasmacytoid dendritic cell neoplasm. In 2016, the World Health Organization designated BPDCN to be in its own separate category within the myeloid class of neoplasms. It is estimated that BPDCN  constitutes 0.44% of all hematological malignancies.Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy with features of cutaneous lymphoma (e.g. malignant plasmacytoid dendritic cell infiltrations into the skin to form single or multiple lesions) and/or leukemia (i.e. malignant plasmacytoid dendritic cells in blood and bone marrow). While commonly presenting with these clinical features, BPDCN, particularly in its more advanced stages, may also involve  malignant plasmacytoid dendritic cell infiltrations in and thereby injury to the liver, spleen, lymph nodes, central nervous system, or other tissues. The neoplasm occurs in individuals of all ages but predominates in the elderly; in children, it afflicts males and females equally but in adults is far more common (~75% of cases) in males.Blastic plasmacytoid dendritic cell neoplasm typically responds to chemotherapy regimens used to treat hematological malignancies. All too often, however, the disease rapidly recurs and does so in a more drug-resistant form. Furthermore, the disease may occur in association with the myelodysplastic syndrome or transform to acute myeloid leukemia. Consequently, BPDCN has a very low 5 year survival rate. Current translational research studies on treating BPDCN have therefore focused on non-chemotherapeutic regimens that target the molecular pathways which may promote the disease.

Presentation
Blastic plasmacytoid dendritic cell neoplasm occurs in children, including neonates, but is more common in adults, particularly those between the ages 60–80. BPDCN usually (i.e. 61% to 90% of cases) presents with skin lesions, i.e. nodules, tumors, red or purple papules, bruise-like patches, and/or ulcers that most often occur on the head, face, and upper torso. The lesions are due to diffuse infiltrations of the skin by malignant pDC. In one large study, this presentation was accompanied by swollen lymph nodes, usually in the neck, due to malignant pDC infiltrations (~50% of cases); enlarged liver (~16% of cases) and/or spleen (26% of cases), also due to malignant pDC infiltrations; increased levels of malignant pDC in blood (i.e. >2% of nucleated cells) (~40% of cases), bone marrow (~65% of cases) and cerebrospinal fluid (47% of childhood cases but less often detected in adult cases). More advanced or severe cases may present with extreme organ and/or lymph node enlargements, skin lesions in virtually any site, and clinical evidence of malignant pDC infiltrations in the breasts, eyes, kidneys, lungs, gastrointestinal tract, bone, sinuses, ears, or testes. About 10% of individuals with BPDCN present with a leukemia-like disease, i.e. they exhibit circulating malignant pDC, anemia, thrombocytopenia, and/or leukopenia due to extensive malignant pDC infiltrations in the bone marrow. A leukemic phase of the disease is a common feature of end stage and post-therapy relapsing BPDCN.

Pathophysiology
There are three types of dendritic cells, plasmacytic dendritic cells (pDC) and two types of conventional dendritic cells (cDC), myeloid cDC1 and myeloid cDC2. pDC circulate in the blood, representing <0.4% of all nucleated blood cells, and are present in various hematological tissues such as lymph nodes and spleen. Their major function is to detect and then initiate immune responses  to intracellular pathogens, particularly viruses such as the cold sore-causing Herpes simplex viruses, HIV, and hepatitis viruses but also bacteria such as the tuberculosis-causing Mycobacterium tuberculosis, fungi such as the aspergillosis-causing Aspergillus fumigatus and parasites such as malaria-causing Plasmodium falciparum. Following detection of these intracellular pathogens, pCD initiate immune responses by producing massive amounts of type I and type III interferons as well as by differentiating (i.e. maturing) into conventional dendritic cells that further promote immune responses by, e.g. functioning as antigen-presenting cells. The malignant pDC in BPDCN have the appearance of immature plasmacytoid dendritic cells. They are distinguished from other dendritic, myeloid, lymphoid and NK cell types by exhibiting at least several of the following properties: 1) plasmacytoid morphology; 2) production of large amounts of type I interferons when properly stimulated; 3) ability to differentiate into conventional dendritic cells when properly stimulated; 4) the expression of key marker proteins such as granzyme B, TCF4,  interleukin-3 receptor (i.e. CD123), CLEC4C, and Neuropilin, and 5) failure to express certain marker proteins that are commonly expressed by myeloid, lymphoid, and NK cell lineages.Blastic plasmacytoid dendritic cell neoplasm typically arises after the serial acquisition of multiple genetic abnormalities in pDC or their precursor cells. Inactivating mutations (i.e. mutations which cause the gene to make no or a less active product) in the TET2 gene are the most common genetic abnormality in the disease, occurring in 32–67% of all BPDCN cases and often accompanied by mutations in either the NPM1 or SRSF2 gene. Numerous other genetic abnormalities are associated with the disease: 1) mutations in NRAS, ASXL1, and TP53; 2) deletions of the CDKN2A-ARF-CDKN2B locus on the short arm of chromosome 9,  CDKN1B locus on the short arm of chromosome 12, RB1 locus on the long arm of chromosome 13, or NRC1 locus on the long arm of chromosome 5; 3) fusions of KMT2A on the long arm of chromosome 11 with MLLT1 on the short arm of chromosome 10, SUPT3H on the short arm of chromosome with MYC on the long arm of chromosome 8, or KMT2A on the long arm of chromosome 11 with MLLT1 on the long arm of chromosome 19; and 4) duplication or loss of entire chromosomes, particularly chromosomes 9, 13, or 15. Laboratory studies indicate that malignant pDC have a pathologically overactive NF-κB pathway that promotes their survival and production of various cytokines) that stimulate their own proliferation. Presumably, these genetic abnormalities lead to the activation of the NF-κB pathway and/or other cellular activation pathways which promote the survival, proliferation, and/or other malignant phenotypic traits in pDC and thereby cause BPDCN.

Diagnosis
BPDCN is suggested by a biopsy of skin lesions which reveals the infiltration by medium-sized blast (i.e. immature) cells into the dermis while sparing the epidermis.  These cells exhibit irregular nuclei, fine chromatin, and at least one small nucleolus. Such blast cells may also be observed in the circulation, bone marrow, or other tissues and  suggest BPDCN. However, the diagnosis of this disease requires determination that these cells are pDC blast cells rather than AML, T-cell lymphoblastic lymphoma (TCLL), or aggressive NK-cell leukemia (NKL) blast cells. Various studies have offered similar but not identical criteria to make this determination. All studies agree that pDC should have a typical plasmacytoid morphology and express a particular profile of marker proteins as detected by immunoassay and/or flow cytometry. However, the studies disagree on which marker proteins to profile. One studys profile assayed 1) CD4, CD56, CD123 (i.e. Interleukin-3 receptor, and TLC1, which are expressed on 80–100% of pDC but uncommon on AML, TCLL, or NKL blasts); 2) CD2AP and CLEC4C which are unique to pDC; and 3) myeloperoxidase, lysozyme, CD34, CD14, CD11c, and CD163 which are unique to AML, TCLL, or NKL blasts. Two other studies recommended assaying somewhat different sets of marker proteins.

Treatment
There have been no controlled studies to define the optimal treatment for BPDCN. Studies on small numbers of individuals with the disease have found that the standard chemotherapy regimens used for the initial induction treatments of AML, acute lymphoblastic leukemia, and high-grade lymphoma give complete remission rates of 77%, 93%, and 80%, respectively, in childhood PBDN and 47%, 77%, and 53%, respectively, in adult PBDN. However, these remissions were short-lived: post-treatment mean times to relapse or death were 12 months for children and 6.8 months for adults. Given these poor remission and survival rates, other treatments have been added to the initial treatment regimens. Studies have shown that the addition of intrathecally administered drugs (administered directly into the spinal canal) as prophylaxis prolongs the period of CNS-free disease and increases overall survival. Hematopoietic stem cell transplantation following initial chemotherapy-induced remission also prolongs these remissions and, it is suggested, offers potential for curing the disease. (A graft-versus-leukemia effect may have contributed to the benefits seen after transplantation.) Studies have not yet determined whether allogenic (i.e. taken from others) or autologous (i.e. taken from self) stem cells achieve better results, although one retrospective study in Japan found that autologous stem cells gave significantly better overall and progression-free survival rates. A phase I clinical research study to test the safety and efficacy of a combination chemotherapy regimen consisting of methotrexate, L-asparaginase, idarubicin, and dexamethasone followed by allogenic or autologous bone marrow transplantation in 26 participants newly diagnosed with BPDCN is planned but not yet in its recruiting phase.While few studies have reported on the treatment of BPDCN that has recurred following initial therapy, donor lymphocyte infusions coupled with alternative chemotherapy treatments have induced second complete or partial remissions in a few patients.

Tagraxofusp-erzs
Tagraxofusp-erzs (trade name Elzonris; formerly SL-401 and DT388-IL3) was approved in the United States in December 2018 for the treatment of BPDCN.  Tagraxofusp-erzs is a fusion protein consisting of interleukin 3 (i.e. IL-3) fused to diphtheria toxin. The fusion protein readily kills cultured pDC by binding to their IL-3 receptors to thereby gain entrance to the cells and then blocking these cells protein synthesis (due to diphtheria toxin-mediated inhibition of eukaryotic elongation factor 2).

Prognosis
Due to the high rates of recurrence following initial therapy and the short overall survival times of individuals with BPDCN, prognosis of the disease is poor. However, further study of treatment regimens that include intrathecal chemotherapy and hematological stem cell transplantation in initial treatment regimens (see previous section) and newer non-chemotherapeutic drug treatments (see next section) may improve this situation.

Research
UCART123
UCART123 are chimeric T cell receptor-bearing cells, i.e </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Osteomyelitis and can you explain it in depth? [/INST] Osteomyelitis (OM) is an infection of bone. Symptoms may include pain in a specific bone with overlying redness, fever, and weakness. The long bones of the arms and legs are most commonly involved in children e.g. the femur and humerus, while the feet, spine, and hips are most commonly involved in adults.The cause is usually a bacterial infection, but rarely can be a fungal infection. It may occur by spread from the blood or from surrounding tissue. Risks for developing osteomyelitis include diabetes, intravenous drug use, prior removal of the spleen, and trauma to the area. Diagnosis is typically suspected based on symptoms and basic laboratory tests as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).This is because plain radiographs are unremarkable in the first few days following acute infection. Diagnosis is further confirmed by blood tests, medical imaging, or bone biopsy.Treatment of bacterial osteomyelitis often involves both antimicrobials and surgery. In people with poor blood flow, amputation may be required. Treatment of the relatively rare fungal osteomyelitis as mycetoma infections entails the use of antifungal medications. In contrast to bacterial osteomyelitis, amputation or large bony resections is more common in neglected fungal osteomyelitis, namely mycetoma, where infections of the foot account for the majority of cases. Treatment outcomes of bacterial osteomyelitis are generally good when the condition has only been present a short time. About 2.4 per 100,000 people are affected each year. The young and old are more commonly affected. Males are more commonly affected than females. The condition was described at least as early as the 300s BC by Hippocrates. Prior to the availability of antibiotics, the risk of death was significant.

Signs and symptoms
Symptoms may include pain in a specific bone with overlying redness, fever, and weakness and inability to walk especially in children with acute bacterial osteomyelitis. Onset may be sudden or gradual. Enlarged lymph nodes may be present.
In fungal osteomyelitis, there is usually a history of walking bare-footed, especially in rural and farming areas. Contrary to the mode of infection in bacterial osteomyelitis, which is primarily blood-borne, fungal osteomyelitis starts as a skin infection, then invades deeper tissues until it reaches bone.

Cause
In children, the metaphyses, the ends of long bones, are usually affected. In adults, the vertebrae and the pelvis are most commonly affected.Acute osteomyelitis almost invariably occurs in children who are otherwise healthy, because of rich blood supply to the growing bones. When adults are affected, it may be because of compromised host resistance due to debilitation, intravenous drug abuse, infectious root-canaled teeth, or other disease or drugs (e.g., immunosuppressive therapy).Osteomyelitis is a secondary complication in 1–3% of patients with pulmonary tuberculosis. In this case, the bacteria, in general, spread to the bone through the circulatory system, first infecting the synovium (due to its higher oxygen concentration) before spreading to the adjacent bone. In tubercular osteomyelitis, the long bones and vertebrae are the ones that tend to be affected.Staphylococcus aureus is the organism most commonly isolated from all forms of osteomyelitis.Bloodstream-sourced osteomyelitis is seen most frequently in children, and nearly 90% of cases are caused by Staphylococcus aureus. In infants, S. aureus, Group B streptococci (most common) and Escherichia coli are commonly isolated; in children from one to 16 years of age, S. aureus, Streptococcus pyogenes, and Haemophilus influenzae are common. In some subpopulations, including intravenous drug users and splenectomized patients, Gram-negative bacteria, including enteric bacteria, are significant pathogens.The most common form of the disease in adults is caused by injury exposing the bone to local infection. Staphylococcus aureus is the most common organism seen in osteomyelitis, seeded from areas of contiguous infection. But anaerobes and Gram-negative organisms, including Pseudomonas aeruginosa, E. coli, and Serratia marcescens, are also common. Mixed infections are the rule rather than the exception.Systemic mycotic infections may also cause osteomyelitis. The two most common are Blastomyces dermatitidis and Coccidioides immitis.In osteomyelitis involving the vertebral bodies, about half the cases are due to S. aureus, and the other half are due to tuberculosis (spread hematogenously from the lungs). Tubercular osteomyelitis of the spine was so common before the initiation of effective antitubercular therapy, it acquired a special name, Potts disease.The Burkholderia cepacia complex has been implicated in vertebral osteomyelitis in intravenous drug users.

Pathogenesis
In general, microorganisms may infect bone through one or more of three basic methods

Via the bloodstream (haematogeneously) – the most common method
From nearby areas of infection (as in cellulitis), or
Penetrating trauma, including iatrogenic causes such as joint replacements or internal fixation of fractures, leading to a fracture-related infection, or secondary periapical periodontitis in teeth.The area usually affected when the infection is contracted through the bloodstream is the metaphysis of the bone. Once the bone is infected, leukocytes enter the infected area, and, in their attempt to engulf the infectious organisms, release enzymes that lyse the bone. Pus spreads into the bones blood vessels, impairing their flow, and areas of devitalized infected bone, known as sequestra, form the basis of a chronic infection. Often, the body will try to create new bone around the area of necrosis. The resulting new bone is often called an involucrum. On histologic examination, these areas of necrotic bone are the basis for distinguishing between acute osteomyelitis and chronic osteomyelitis. Osteomyelitis is an infective process that encompasses all of the bone (osseous) components, including the bone marrow. When it is chronic, it can lead to bone sclerosis and deformity.Chronic osteomyelitis may be due to the presence of intracellular bacteria. Once intracellular, the bacteria are able to spread to adjacent bone cells. At this point, the bacteria may be resistant to certain antibiotics. These combined factors may explain the chronicity and difficult eradication of this disease, resulting in significant costs and disability, potentially leading to amputation. The presence of intracellular bacteria in chronic osteomyelitis is likely an unrecognized contributing factor in its persistence.In infants, the infection can spread to a joint and cause arthritis. In children, large subperiosteal abscesses can form because the periosteum is loosely attached to the surface of the bone.Because of the particulars of their blood supply, the tibia, femur, humerus, vertebrae, maxilla and the mandibular bodies are especially susceptible to osteomyelitis. Abscesses of any bone, however, may be precipitated by trauma to the affected area. Many infections are caused by Staphylococcus aureus, a member of the normal flora found on the skin and mucous membranes. In patients with sickle cell disease, the most common causative agent is Salmonella, with a relative incidence more than twice that of S. aureus.

Diagnosis
The diagnosis of osteomyelitis is complex and relies on a combination of clinical suspicion and indirect laboratory markers such as a high white blood cell count and fever, although confirmation of clinical and laboratory suspicion with imaging is usually necessary.Radiographs and CT are the initial method of diagnosis, but are not sensitive and only moderately specific for the diagnosis. They can show the cortical destruction of advanced osteomyelitis, but can miss nascent or indolent diagnoses.Confirmation is most often by MRI. The presence of edema, diagnosed as increased signal on T2 sequences, is sensitive, but not specific, as edema can occur in reaction to adjacent cellulitis. Confirmation of bony marrow and cortical destruction by viewing the T1 sequences significantly increases specificity. The administration of intravenous gadolinium-based contrast enhances specificity further. In certain situations, such as severe Charcot arthropathy, diagnosis with MRI is still difficult. Similarly, it is limited in distinguishing avascular necrosis from osteomyelitis in sickle cell anemia.Nuclear medicine scans can be a helpful adjunct to MRI in patients who have metallic hardware that limits or prevents effective magnetic resonance. Generally a triple phase technetium 99 based scan will show increased uptake on all three phases. Gallium scans are 100% sensitive for osteomyelitis but not specific, and may be helpful in patients with metallic prostheses. Combined WBC imaging with marrow studies has 90% accuracy in diagnosing osteomyelitis.Diagnosis of osteomyelitis is often based on radiologic results showing a lytic center with a ring of sclerosis. Culture of material taken from a bone biopsy is needed to identify the specific pathogen; alternative sampling methods such as needle puncture or surface swabs are easier to perform, but cannot be trusted to produce reliable results.Factors that may commonly complicate osteomyelitis are fractures of the bone, amyloidosis, endocarditis, or sepsis.

Classification
The definition of OM is broad, and encompasses a wide variety of conditions. Traditionally, the length of time the infection has been present and whether there is suppuration (pus formation) or osteosclerosis (pathological increased density of bone) are used to arbitrarily classify OM. Chronic OM is often defined as OM that has been present for more than one month. In reality, there are no distinct subtypes; instead, there is a spectrum of pathologic features that reflects a balance between the type and severity of the cause of the inflammation, the immune system and local and systemic predisposing factors.
Suppurative osteomyelitis
Acute suppurative osteomyelitis
Chronic suppurative osteomyelitis
Primary (no preceding phase)
Secondary (follows an acute phase)
Non-suppurative osteomyelitis
Diffuse sclerosing
Focal sclerosing (condensing osteitis)
Proliferative periostitis (periostitis ossificans, Garrés sclerosing osteomyelitis)
OsteoradionecrosisOM can also be typed according to the area of the skeleton in which it is present. For example, osteomyelitis of the jaws is different in several respects from osteomyelitis present in a long bone. Vertebral osteomyelitis is another possible presentation.

Treatment
Osteomyelitis often requires prolonged antibiotic therapy for weeks or months. A PICC line or central venous catheter can be placed for long-term intravenous medication administration. Some studies of children with acute osteomyelitis report that antibiotic by mouth may be justified due to PICC-related complications. It may require surgical debridement in severe cases, or even amputation. Antibiotics by mouth and by intravenous appear similar.Due to insufficient evidence it is unclear what the best antibiotic treatment is for osteomyelitis in people with sickle cell disease as of 2019.Initial first-line antibiotic choice is determined by the patients history and regional differences in common infective organisms. A treatment lasting 42 days is practiced in a number of facilities. Local and sustained availability of drugs have proven to be more effective in achieving prophylactic and therapeutic outcomes. Open surgery is needed for chronic osteomyelitis, whereby the involucrum is opened and the sequestrum is removed or sometimes saucerization can be done. Hyperbaric oxygen therapy has been shown to be a useful adjunct to the treatment of refractory osteomyelitis.Before the widespread availability and use of antibiotics, blow fly larvae were sometimes deliberately introduced to the wounds to feed on the infected material, effectively scouring them clean.There is tentative evidence that bioactive glass may also be useful in long bone infections </s>